KR20070030952A - Oxazolidinones containing oxindoles as antibacterial agents - Google Patents

Abstract

The present invention relates to oxazolidinone derivatives of the novel auxindol of formula (I) or a pharmaceutically acceptable salt thereof. Such compounds are useful as antiviral agents:

Formula I

Where

Y ¹ is -CH- or -CF-;

R ¹ is —C _1-4 alkyl or —C _3-5 cycloalkyl, optionally substituted with fluoro atoms;

R ² is -H or -CH ₃ .

Description

OXAZOLIDINONES CONTAINING OXINDOLES AS ANTIBACTERIAL AGENTS}

The present invention relates to novel oxazolidinone derivatives of auxindol, pharmaceutical compositions thereof, methods of using the same and methods of preparing such compounds. Such compounds have potent activity against Gram-positive and / or Gram-negative bacteria.

Due to the increase in antibiotic resistance, the importance of structurally novel antiviral agents with new modes of action in the treatment of bacterial infections is increasing. Effective antiviral agents are gram-positive anaerobic bacteria such as multiple-resistant Staphylococcus Cauchy (stapylococci) and streptomycin Cauchy (streptococci), anaerobic organisms such as foil steroid (bacteroides) and Clostridia (clostridia) species, and acid-organism, e.g. Mai Te represents the M. tuberculosis Leeum-to-beoku (Mycobacterium tuberculosis) and Mycobacterium Oh away many human and veterinary pathogens, including a number of potent activity against the (Mycobacterium avium).

Among the newer antiviral agents, oxazolidinone compounds are the most recent synthetic antimicrobial agents for many pathogenic microorganisms. The present invention provides novel oxindole derivatives of oxazolidinone and methods for their preparation.

International Patent Publication No. 200281470 discloses oxazolidinone compounds useful for treating bacterial infections.

International Patent Publication No. 200032599 discloses oxazolidinone derivatives useful for the treatment of microbial infections.

International Patent Publication No. 200029396 discloses 3-phenyl-5-aminomethyl-oxazolidinone derivatives useful as antibacterial agents.

International Patent Publication No. 9937630 discloses oxazolidinone derivatives, including molecular diversity mixtures.

International Patent Publication No. 9737981 discloses oxazolidinones.

German Patent 19604223 discloses new substituted oxazolidinone compounds useful as antiviral agents.

German Patent No. 19649095 discloses 5- (acyl-aminomethyl) -3-hetero-aryl-oxazolidinone compounds useful as antiviral agents.

EP 694543 discloses hetero-aryl substituted oxazolidinone derivatives useful as antiviral agents.

European Patent Publication 693491 discloses 3-hetero-aryl-2-oxazolidinone derivatives useful as antiviral agents.

European Patent Publication No. 609905 discloses indazolyl, benzimidazolyl and benzoprizzolyl oxazolidinone derivatives useful as antiviral agents.

US Pat. No. 5,164,510 discloses 5-indolinyloxazolidin-2-one useful as an antiviral agent.

US Patent Application Publication No. 2002016323 discloses oxazolidinone useful as an antiviral agent.

US Patent Application Publication No. 2002032348 discloses a process for the preparation of oxazolidinones.

US Patent Application Publication No. 2002143009 discloses bicyclic oxazolidinone derivatives useful as antimicrobial agents.

US Patent Application Publication No. 2003/216330 discloses parenteral, intravenous and oral administration of oxazolidinone for treating diabetic foot infections.

US Patent Application Publication No. 2004/176610 discloses antiviral indole oxazolidinone as an antiviral agent.

US Patent Application Publication No. 2004147760 discloses N-aryl-2-oxazolidinone-5-carboxamides having antiviral activity useful for treating microbial infections.

Summary of the Invention

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Where

Y ¹ is -CH- or -CF-;

R ¹ is —C _1-4 alkyl or —C _3-5 cycloalkyl, optionally substituted with fluoro atoms;

R ² is -H or -CH ₃ .

In another aspect, the present invention also provides a pharmaceutical composition comprising an effective amount of a compound of Formula I and a pharmaceutically acceptable carrier; A method of treating said infection in a mammal by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment for a Gram-positive or Gram-negative microbial infection; And the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of Gram-positive or Gram-negative microbial infection.

The present invention may also provide novel intermediates and novel methods useful for preparing compounds of formula (I).

Unless stated otherwise, the following terms used in this specification and claims have the meanings defined below:

The carbon atom content of the various hydrocarbon-containing moieties is indicated by a prefix indicating the minimum and maximum number of carbon atoms. That is, the prefix C _ij represents a residue from the integer "i" to the integer "j" carbon number. Thus, for example, C _1-6 alkyl refers to alkyl having 1 to 6 carbon atoms.

The term alkyl refers to straight and branched chain groups, where each radical, such as "propyl", encompasses not only straight chain radicals but also branched chain isomers, such as the specially referred to as "isopropyl".

"C _3-5 cycloalkyl" means a cyclic saturated monovalent hydrocarbon group having 1 to 5 carbon atoms, such as cyclopropyl and the like.

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

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.

The term "pharmaceutically acceptable carrier" means a carrier that generally includes a carrier that is useful for preparing a safe, non-toxic, biologically or otherwise desirable pharmaceutical composition, and that is suitable for veterinary use as well as for human pharmaceutical use. . A "pharmaceutically acceptable carrier" in this specification and in the claims includes both one and / or one or more carriers.

The term "mammal" means a human or anti-warm animal, including livestock and primate animals.

The term “optionally” or “optionally” refers to a term that includes, but does not necessarily occur, a case in which a successively disclosed thing or event may or may not occur.

Compounds that have the same molecular formula but differ in the nature or sequence of their binding or in their atomic arrangement in space are referred to as "isomers". Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers".

Those skilled in the art will understand that compounds of the present invention having chiral centers may be present or isolated in racemic form with appropriate activity. Some compounds may exist as polymorphs. It is to be understood that the present invention encompasses any racemic, compound, tautomeric or stereoisomeric form, or mixtures thereof, of the compounds of the present invention having the useful properties disclosed herein. How to prepare the type with the appropriate activity (eg, as a result of racemic type by recrystallization techniques, synthesis from starting materials with appropriate activity, chiral synthesis or chromatographic separation using chiral stationary phases) It is known how antiviral activity is measured using the standard tests disclosed in or other similar tests known in the art.

"Cure" or "treat" of a disease,

(1) prevention of the disease, ie, to prevent the clinical symptoms of the disease from progressing and to experience or show the symptoms of the disease in mammals exposed to or susceptible to the disease;

(2) inhibiting the disease, ie stopping or slowing the progression of the disease or its clinical symptoms; or

(3) alleviation of the disease, that is, improvement of the disease or its clinical symptoms.

The term "therapeutically effective amount" means an amount of a compound sufficient to treat a disease when administered to a mammal for the treatment of the disease. A "therapeutically effective amount" will depend on the compound, the disease and its severity, the age, weight, etc. of the mammal to be treated.

The term "leaving group" means a group having a meaning commonly associated with leaving group in synthetic organic chemistry, i.e., an atom or group which may be substituted with a nucleophile, and examples thereof include halogen, alkylsulfonyloxy, ester or amino such as chloro , Bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N, O-dimethylhydroxyl-amino and the like.

Compounds of the invention are generally named according to the IUPAC or CAS naming system.

Abbreviations known to those skilled in the art (eg abbreviation "Ph" for penyl, abbreviation "Me" for methyl, abbreviation "Et" for ethyl, abbreviation "h" for time, and abbreviation "for room temperature"). rt ") may be used.

The specific and preferred values disclosed below for radicals, substituents, and ranges are for illustrative purposes only, and they do not exclude other defined or other values within the ranges defined for radicals and substituents.

Specifically, alkyl refers to straight and branched chain groups, but each radical, such as "propyl", encompasses not only straight chain radicals, but also branched chain isomers, such as the specially classified "isopropyl".

In particular, alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, s-butyl and isomer types thereof.

Specifically, cycloalkyl is a cyclopropyl, cyclobutyl, cyclopentyl and isomeric type thereof.

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

Specifically, Y ¹ is -CH-.

Specifically, R ¹ is -C _{1 -3} alkyl.

Specifically R ¹ is methyl or isopropyl.

Examples of the compounds of the present invention include the following compounds:

(1) (5R) -3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide,

(2) (5R) -3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide,

(3) (5R) -3- (7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Amide,

(4) (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide,

(5) (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide,

(6) (5R) -3- [1- (2-Fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxazolidine-5 Carboxylic acid amides,

(7) (5R) -3- [1- (3-Fluoro-propyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxazolidine-5 Carboxylic acid methylamides,

(8) (5R) -3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide,

(9) (5R) -3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide,

(10) (5R) -3- (7-Fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5- Carboxylic acid amides,

(11) (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide,

(12) (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide,

(13) (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5-carboxylic acid amide,

(14) (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5-carboxylic acid methylamide,

(15) (R) -3- (7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Amide,

(16) (R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide,

(17) (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide,

(18) (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide,

(19) (R) -3- [1- (2-Fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1 H-indol-5-yl] -2-oxo-oxa Zolidine-5-carboxylic acid amide,

(20) (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide,

(21) (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide,

(22) (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, or

(23) (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide.

Compounds of the invention can be prepared according to one or more of the reaction schemes described below. All starting materials are prepared or commercially available according to the methods disclosed below by processes known to those skilled in organic chemistry. Unless otherwise stated below, the variables used in the schemes are as defined in the specification or claims.

As shown in Scheme I, substituted 5-amino-1,3-dihydroindol-2-one (1) is substituted with alkyl (2R) -epoxypropaneoate and as disclosed in US Patent Application Publication No. 2004/0044052. React with a Lewis acid such as lithium triplate. The amino alcohol (2) may then be ringed using methods known to those skilled in the art to afford aryl oxazolidinones (3). For example, (2) is treated with 1,1-carbonyldiimidazole in a solvent such as acetonitrile or tetrahydropurine at a suitable temperature, typically 20 to 60 ° C. or at a suitable temperature, typically -10 to 25 Oxazolidinone (3) can be obtained by treatment with phosgene in a solvent such as toluene or methylene chloride, or a mixture thereof in the presence of a base such as triethylamine at < RTI ID = 0.0 > Sequential treatment of oxazolidinone (3) with ammonia or optionally substituted amine (R ² NH ₂ ) in a suitable solvent such as methanol or acetonitrile yields amide 4 (R ² is H or alkyl) do.

Oxidol intermediates may be prepared according to the method of Scheme II. Gassman J. Org. Chem . 1977, 42, 1344 and US Pat. Nos. 4,188,325 and 4,252,723 are commonly used or conveniently obtained in a convenient organic solvent (e.g. DMF, THF, Alkylating agents, for example in the presence of a suitable base (for example an amine base such as triethylamine or di-iso-propylethylamine or lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate) in DMSO, dioxane or acetonitrile) Treatment with iodomethane, iodoethane or iodopropane yields N-alkylated isatin (8). Isatin (8) is converted to 1,3-dihydroindol-2-one (9) using hydrogen sulfide, or Wolf-Kishner reaction in red phosphoric and iodic or pyridine / co-solvent mixtures. Can be reduced. The most convenient procedure involves heating the isatin 8 in pure hydrazine hydrate at reflux in the absence of any additional base. The 1,3-dihydroindol-2-one (9) is regioselectively nitrated using methods known to those skilled in the art (for example concentrated nitric acid in sulfuric acid or acetic acid or concentrated at -20 to 25 ° C or Sodium nitrate in trifluoroacetic acid). Subsequently, 5-nitrooxindol (10) is dissolved or reduced by catalytic hydrogenation (eg, iron chloride and ammonium chloride in ethanol / water) to give 5-aminooxindol (1).

Alternatively, commercially available 5-nitroaisatin may be prepared at a suitable base solvent (e.g., an amine base such as tri) in a suitable organic solvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at 0-65 ° C. N-alkylation by treatment with a suitable alkylating agent, for example iodomethane, iodoethane or iodopropane, in the presence of ethylamine or di-iso-propylethylamine or lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate) Isatin 12 is obtained. Isatin (12) may be reduced in one step to the necessary 5-aminooxindol (1) by heating in pure hydrazine hydrate at reflux or by catalytic hydrogenation.

Scheme IV illustrates another route to prepare 5-nitrooxindol (4).

Commercially available 5-nitrooxindol (13) is acylated with a suitable acid chloride or anhydride in the presence of a suitable base such as triethylamine or pyridine in a suitable solvent such as methylene chloride at 0-25 ° C. The resulting N-acylated oxindole 14 can be reduced to N-acylindole 15 in high yield by BH ₃ .THF. N-alkylindole 15 is also oxidized to the essential 5-nitrooxindol 16 by many known methods (eg DMSO / HCl, NBS).

Alternatively, commercially available 5-nitroindole can be prepared at 0-65 ° C. in the presence of a suitable base (eg sodium hydroxide or lithium hexamethyldisilase) in a suitable organic solvent (eg DMF, THF, DMSO). Treatment with a suitable alkylating agent, for example iodomethane, iodoethane or iodopropane, affords N-alkylated indole (17). Indole 17 is oxidized to the requisite auxindol as described in Scheme IV.

In another route illustrated in Scheme VI, suitably substituted 2-halo-5-nitrophenylacetic acid (18) (eg preferably 2-fluoro-5-nitrophenylacetic acid) is suitable at 35-85 ° C. Treatment with ammonia or optionally substituted amine (RNH ₂ ) in a solvent such as DMSO or acetonitrile yields aniline 19 (R is H or optionally substituted alkyl). Aniline (19) is treated with a strong acid such as HCl, H ₂ SO ₄ or THA to effectively cyclize to the essential 5-nitrooxindol (1).

Medical and Veterinary Uses

Chemical compounds, oxazolidinones, are generally known to inhibit monoamine oxidase (MAO), an enzyme useful for preventing acute blood pressure elevation by endogenous dietary amines, tyramines.

Thus, there is a need to develop oxazolidinone antibiotics with minimal MAO inhibitory activity at a lower risk of potential drug-drug interactions. The compounds of the present invention have been found to exhibit an exceptionally low MAO inhibitory activity, which is potentially because the strong inhibition of monoamine oxidase results in altered transparency ratios for some pharmaceutical agents and other compounds normally metabolized thereby. It is meant to have the ability to minimize or eliminate phosphorus drug-drug interactions.

The compounds of the present invention can be used to treat infectious Gram-positive bacterial infections caused by various bacterial organisms, requiring long term (greater than 28 days) treatment.

Examples of bacterial organisms are gram-positive bacteria such as multiple-resistant Staphylococcus Cauchy (Staphylococci), for example, Staphylococcus Cauchy Aureus (S. aureus) and Kosice Staphylococcus epidermidis (S. epidermidis); Multi-resistant Streptococcus Cauchy (Streptococci), for example, Streptomyces Cauchy On pneumoniae (S. pneumoniae), and streptomycin Kosice Kuopio jeneseu (S. pyogenes); And multiple resistant Enterococcus Cauchy (Enterococci), for example Enterococcus faecalis Cauchy par (E. faecalis); Gram-negative anaerobic bacteria in, for example, under a brush Russ (Haemophilus), for example under a brush Russ influenza (H. influenzae); Mora and Sela (Moraxella), for example, Mora Cellar Qatar Harleys (M. catarrhalis); And anaerobic organisms, such as steroid foil (bacteroides) and Clostridia (clostridia) species, and acid-organisms, such as mycobacteria (Mycobacteria), for example mycobacteria-to M. tuberculosis (M. tuberculosis) and / or Mycobacterium It includesium avium ( Mycobacterium avium ). Other examples may be mentioned the device Escherichia (Escherichia), for example, Escherichia coli, hereafter small cell microorganisms, such as Cloud Mai Dia (Chlamydia) and the rike cyano (Richettsiae).

Examples of infections that can be treated with the compounds of the present invention include central nervous system infections, external ear infections, middle ear infections such as acute otitis media, infections of the epidural sinus, eye infections, oral infections such as teeth, gums and mucosal layers, and upper respiratory tract infections. , Lower respiratory tract infections, urinary tract infections, gastrointestinal tract infections, gynecological infections, sepsis, skeletal and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antiviral prophylactic and immunosuppressed patients such as cancer Antiviral prophylaxis may be mentioned in patients undergoing chemotherapy or in patients undergoing organ transplantation. In particular, infectious diseases that can be treated using the compounds of the present invention are Gram-positive infections such as osteomyelitis, endocarditis and diabetic feet.

Antiviral activity

In vitro antiviral activity of the compounds of the present invention is described in (1) National Committee for Clinical Laboratory Standards (Jan. 2003), Methods for dilution antimicrobial tests for bacteria that grow aerobically, Approved Standard (6 ^th ed), M7-A6 , NCCLS, Wayne, PA]; (2) National Committee for Clinical Laboratory Standards (Mar. 2001), Methods for antimicrobial susceptibility testing of anaerobic bacteria, Approved Standard (5 ^th ed), Ml 1-A4, NCCLS, Wayne, PA; (3) National Committee for Clinical Laboratory Standards (Jan. 2003), MIC testing supplemental tables, MlOO-S 13 (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 MIC value is the minimum concentration of drug that prevents visible growth visually under test conditions. Table 1 below shows the results of the in vitro test.

Pharmaceutical salts

The 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, the compound may be suitably administered as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of the present invention include inorganic salts such as hydrogen chloride, bromine chloride, sulfates, nitrates, bicarbonates, carbonates and organic salts such as tosylate, methanesulfonate, acetate, citrate, malonate, tarta Latex, succinate, benzoate, ascorbate, etoglutarate and glycerophosphate.

Pharmaceutically acceptable salts can be obtained by standard procedures known in the art, for example by reacting sufficient basic compounds such as amines with suitable acids to obtain physiologically acceptable anions. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can be prepared.

Route of administration

Oxazolidin dinon antiviral prodrugs of the present invention is not limited to this, for a variety of organisms, such as Staphylococcus aureus (Staphylococcus aureus), switch the other pillow nose kusu epidermidis (Staphylococcus epidermidis), Enterococcus Cocus paesium ( Enterococcus faecium), streptococcus pneumoniae in (Streptococcus pneumoniae), Streptococcus Let blood Ness (Streptococcus pyogenes), Enterococcus faecalis nose kusu par (Enterococcus faecalis), Mora Cellar possess valuable activity against Qatar Harleys (Moraxella catarrhalis) and (Haemophilus influenzae) in a brush under Russ influenza. In therapeutic uses to treat or oppose viral infections in mammals (ie, humans and animals), the oxazolidinone prodrugs or pharmaceutical compositions thereof of the present invention may be orally, parenterally, topically, rectal, mucosal It can be administered mobile or intestinal.

Parenteral administration includes indirect injection or direct injection into the area to produce a systemic effect. Examples of such parenteral administration include subcutaneous, intravenous, intramuscular, intradermal, intradural, intraocular, intranasal, intraventricular or infusion techniques.

Topical administration includes infectious narcotic or organs that are easily accessible by topical administration, such as the skin including the ears, vagina, open wounds, epidermis and lower transdermal structures, including eyes, outer ears and middle ear infections, Or other lower intestinal tract treatment. It also includes transdermal delivery that produces a systemic effect.

Intramuscular administration includes the suppository type.

Mucosal administration includes nasal aerosol or inhalation applications.

Preferred routes of administration are oral and parenteral administration.

Composition / Formulation

The pharmaceutical compositions of the present invention can be prepared by methods known in the art, for example by conventional mixing, dissolving, granulating, dragee-making, powdering, emulsifying, encapsulating, collecting, lyophilizing or spray drying. have.

Pharmaceutical compositions for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and excipients which are easy to prepare the active compounds in pharmaceutically acceptable formulations. . Proper formulation is dependent upon the route of administration chosen.

For oral administration, the compounds can be formulated by mixing the active compounds with a pharmaceutically acceptable carrier known in the art. Such carriers are suitable for the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, emulsions, solutions, emulsions, gels, syrups, slurries, suspensions and the like for oral administration to a patient. The carrier can be one or more substances that can also serve as diluents, flavors, solubilizers, lubricants, suspending agents, binders, tablet disintegrating agents and encapsulating agents. Examples of such carriers or excipients are magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starch, gelatin, celluloid material, low melt wax, cocoa butter or powder, polymer Such as, but not limited to, polyethylene glycol and other pharmaceutically acceptable materials.

Dragee cores are provided using suitable coatings. For this reason, optionally concentrated gum solutions containing gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, racker solutions, suitable organic solvents or solvent mixtures can be used. have. It may be added to tablets or dragees to identify dyes or pigments or to characterize different combinations of dosages of active compounds.

Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient together 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. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, liquid polyethylene glycols, excipients, caps, media or long chain mono-, di- or triglycerides. Stabilizers may also be added to these formulations.

Fluid type compositions include solutions, suspensions, and emulsions. For example, solutions of the compounds of the invention dissolved in water, water-propylene glycol and water-polypropylene glycol systems may optionally be provided, including conventionally suitable conventional colorants, flavors, stabilizers and enhancers,

The compounds may also be formulated for parenteral administration, eg, by injection, pill injection or continuous infusion. Formulations for parenteral administration may be presented in unit dosage form, eg, in ampoules or in multiple dosage contents with preservatives added. The composition may be a type of suspension, solution or emulsion in an oil phase or water phase vehicle and may contain formulating materials such as suspending agents, stabilizers and / or dispersants.

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

Parenteral administration also includes, but is not limited to, aqueous solutions of the water-soluble type, such as salts of the active compounds. In addition, suspensions of the active compounds can be prepared in lipophilic vehicles. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides or substances such as liposomes. Aqueous injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain a medicament capable of producing a high concentration solution by increasing the solubility of the suitable stabilizer and / or compound.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. For suppository administration, the compounds may be formulated by mixing the medicament with a suitable non-inflammatory excipient that is solid at room temperature or liquid at rectal temperature and will therefore dissolve in the rectum to release the drug. Such materials include cocoa butter, beeswax and other glycerides.

For administration by inhalation, the compounds of the present invention may be delivered via aerosol spray, usually in solution form, in dry powder or in suspension. Aerosols may use pressurized packs or inhalers and suitable propellants. In the case of a pressurized aerosol, the dosage unit can be adjusted by providing a valve to deliver a metered amount. For example, capsules and cartridges of gelatin containing powder bases such as lactose or starch may be formulated for use in an inhaler.

For topical application, the pharmaceutical composition may 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 the present invention include, but are not limited to, mineral oils, fluid mineral oils, white mineral oils, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water. Alternatively, the pharmaceutical composition may be formulated in a suitable lotion such as a suspension, emulsion or cream containing the active ingredient 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 ester wax, catary alkyl, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic and otitis use, the pharmaceutical compositions are formulated as undifferentiated suspensions in isotonic pH adjusted sterile saline, preferably as solutions in isotonic pH adjusted sterile saline with or without preservatives such as benzylalkonium chloride. Can be. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated with an ointment, for example petrolatum.

In addition to the formulations described above, the compounds may also be formulated as hypotonic formulations. Such long acting formulations may be of implant type. The compounds of the invention may be formulated for administration routes using suitable polymers, hydrophobic materials or as poorly water soluble derivatives such as but not limited to poorly water soluble salts.

In addition, the compounds can be delivered using a sustained release system. Various sustained release materials are established and known by those skilled in the art. Sustained release capsules depend on their chemistry and can release the compound for up to 24 hours or days.

Dosage

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredient is contained in an amount sufficient to achieve the intended purpose, ie, the purpose of treating or preventing an infectious disease. More specifically, a therapeutically effective amount means an amount effective to prevent, alleviate or alleviate the symptoms or sustain life of the disease of the subject to be treated.

The amount of the active compound, i.e., the pharmaceutical composition and the compound of the present invention in unit dosage form thereof, may vary and be varied depending on the method of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is within the discretion of one of ordinary skill in the art. Generally the amount of active compound may be from 0.5 to 90% by weight relative to the weight of the composition.

Generally, the therapeutically effective amount of the dosage of the active ingredient is about 0.1 to about 400 mg / kg body weight per day, more preferably about 1.0 to about 50 mg / kg body weight per day. Such 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 the active compound is about 200 to 800 mg, preferably 600 mg per day.

The desired dosage can typically be administered in a single dose per day or in separate doses, in suitable times, for example at least 2, 3, 4 or more subdoses. The bottom dose may itself be further separated, for example, into many vaguely separated doses, for example from multiple inhalations or several dropwise additions from the blower.

In addition, the initial dose administered may be increased beyond the desired level so that the desired plasma concentration is achieved quickly. On the other hand, the initial dose may be less than the appropriate dose, and the daily dose may be gradually increased during the course of treatment, depending on the particular situation. If desired, the daily dosage may be separated for multiple administration, eg 2 to 4 times per day, for administration.

In the case of topical administration or selective absorption, the effective local concentration of the drug may not be related to the plasma concentration, and other procedures known in the art can be used to determine the desired dosage.

Oral efficacy

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

bm = broad polyline

BOC = t-butoxycarbonyl

bd = wide doublet

bs = broad single line

CDI = 1,1 O-carbodiimidazole

d = doublet

dd = doublet of doublet

dq = doublet of quartet

dt = doublet of triplets

DMF = dimethylformamide

DMAP = dimethylaminopyridine

DMSO = dimethyl sulfoxide

eq. = Equivalent

g = grams

h = hours

HPLC = high pressure liquid chromatography

HATU = N-[(dimethylamino) -1H-1,2,3-triazolo- [4,5-b] pyridin-1-yl-methylene] -N-methylmethanealuminum hexafluorophosphate N-oxide

LG = leaving machine

m = polyline

M = mole

M% = mol%

max = max

meq = milliequivalents

mg = milligrams

ml = milliliters

mm = millimeters

mmol = millimoles

q = quartet

S = single line

t or tr = triplet

TBS = tributylsilyl

TFA = trifluoroacetic acid

THF = tetrahydropurine

TLC = thin layer chromatography

p-TLC = preparative thin layer chromatography

μL = microliters

N = normal

MeOH = Methanol

DCM = dichloromethane

HCl = hydrochloric acid

ACN = acetonitrile

MS = mass spectrometry

rt = room temperature

EtOAc = ethyl acetate

EtO = ethoxy

Ac = acetate

NMP = l-methyl-2-pyrrolidinone

μL = microliters

J = binding constant

NMR = nuclear magnetic resonance

MHz = Megahertz

Hz = hertz

m / z = mass-to-charge ratio

min = minutes

Boc = t-butoxycarbonyl

CBZ = benzyloxycarbonyl

DCC = 1,3-dicyclohexylcarbodiimide

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

Example 1 Preparation of (5R) -3- (1-Methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Step 1 : Preparation of 1-methyl-1,3-dihydro-indol-2-one

1-Methyl-1H-indole-2,3-dione (5.00 g, 31.0 mmol) was heated with pure hydrazine hydrate (30 ml) at 130 ° C. for 1.5 h. The reaction mixture was cooled down, diluted with cold water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated to afford the title compound as a yellowish brown solid. HPLC room temperature 3.69 min; MS m / z 148.1 (M + H) ⁺ for C ₉ H ₉ NO.

Step 2 : Preparation of 1-methyl-5-nitro-1,3-dihydro-indol-2-one

1-methyl-1,3-dihydro-indol-2-one (step 1, 2.10 g, 14.3 mmol) was added in part to 70% nitric acid (10 ml) at -10 ° C. After the addition was complete, the reaction was incubated to room temperature and stirred for 5 hours. The mixture was diluted with cold water and the resulting precipitate was filtered, washed with water and dried under vacuum to afford the title compound as a brown solid. HPLC room temperature 3.97 min; MS m / z 193.9 (M + H) ⁺ for C ₉ H ₈ N ₂ O ₃ .

Step 3 : Preparation of 5-Amino-1-methyl-1,3-dihydro-indol-2-one

Iron powder (2.09 g, 37.46 mmol) was added 1-methyl-5-nitro-1,3-dihydro-indol-2-one (ethanol 2, 1.8 in ethanol (100 ml) and water (50 ml) at 90 ° C. g, 9.36 mmol) and ammonium chloride (4.96 g, 93.6 mmol). The reaction mixture was stirred vigorously and heated for 30 minutes, cooled to room temperature and diluted with dichloromethane (200 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound as a dark brown solid. HPLC room temperature l.O6 min; MS m / z 163.2 (M + H) ⁺ for C ₉ H ₁₀ N ₂ O..

Step 4 : Preparation of (5R) -2-hydroxy-3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester

5-amino-1-methyl-1,3-dihydro-indol-2-one (step 3, 1.40 g, 8.63 mmol) in acetonitrile (15 ml), methyl (2R) -glycidate (0.882 g, 8.63 mmol) and lithium trifluoromethanesulfonate (1.33 g, 8.63 mmol) were heated at 70 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (70% EtOAc / hexanes) to afford the title compound as a light brown solid. HPLC room temperature 2.44 minutes; MS m / z 265.0 (M + H) ⁺ for C ₁₃ H ₁₆ N ₂ O ₄ .

Step 5 : Preparation of (5R) -3- (1-Methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester

(5R) -2-hydroxy-3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester (step 4) in acetonitrile (5 ml) , 0.300 g, 1.13 mmol) and 1,1′-carbonyldiimidazole (0.203 g, 1.248 mmol) were stirred and heated at 60 ° C. for 15 minutes. The reaction was cooled and the resulting precipitate was filtered, washed with cold acetonitrile and dried in vacuo to afford the title compound as a light brown solid. HPLC room temperature 3.53 min; MS m / z 291.3 (M + H) ⁺ for C ₁₄ H ₁₄ N ₂ O ₅ .

Step 6 : Preparation of (5R) -3- (1-Methyl-2-oxo-2,3-dihydro-1 H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Ammonia in methanol (2M, 10 ml) was dissolved in (5R) -3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5 -Carboxylic acid methyl ester (step 5, 0.24 g, 0.826 mmol) was added at 0 ° C and the suspension was stirred at 0 ° C for 4 h. The precipitate was filtered off, washed with methanol and dried under vacuum to afford the title compound as off white solid.

C₁₃H₁₃N₃O₄에 대한 MS m/z 276(M+H)⁺.HPLC room temperature 2.865 min;

MS m / z 276 (M + H) ⁺ for C ₁₃ H ₁₃ N ₃ O ₄ .

Example 2 Preparation of (5R) -3- (1-Methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide

Methylamine (2M, 4 ml) in methanol was dissolved in solid (5R) -3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine To -5-carboxylic acid methyl ester (Example 1, step 5, 0.070 g, 0.241 mmol) was added at 0 ° C and the suspension was stirred at 0 ° C for 1 h. The resulting precipitate was filtered off, washed with methanol and dried under vacuum to afford the title compound as off white solid.

C₁₄H₁₅N₃O₄에 대한 MS m/z 290(M+H)⁺.HPLC room temperature 3.050 min;

MS m / z 290 (M + H) ⁺ for C ₁₄ H ₁₅ N ₃ O ₄ .

Example 3 (5R) -3- (7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5- Preparation of Carboxylic Acid Amides

Step 1 : Preparation of 7-Fluoro-1-methyl-1H-indole-2,3-dione

7-fluoro-1H-indole-2,3-dione (prepared according to Gasman's method, as disclosed in US Pat. No. 4,188,325, 1.0 g, 6.05 mmol), iodomethane (1.13 ml, 18.2 mmol) and potassium carbonate (1.65 g, 12.1 mmol) in DMF (15 ml) were stirred at rt for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as an orange solid. HPLC room temperature 3.79 min; MS m / z 180.0 (M + H) ⁺ for C ₉ H ₆ FNO ₂ .

Step 2 : Preparation of 7-Fluoro-1-methyl-1,3-dihydro-indol-2-one

7-Fluoro-1-methyl-1H-indole-2,3-dione (step 1, 1.05 g, 5.86 mmol) was heated at 130 ° C. with pure hydrazine hydrate (10 ml) for 1 hour. The mixture was cooled down, diluted with cold water and extracted with ethyl acetate. The extract was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light yellow solid. HPLC room temperature 4.07 min; MS m / z 165.16 (M + H) ⁺ for C ₉ H ₈ FNO.

Step 3 : Preparation of 7-Fluoro-1-methyl-5-nitro-1,3-dihydro-indol-2-one

7-Fluoro-1-methyl-1,3-dihydro-indol-2-one (step 2, 0.89 g, 5.38 mmol) was added dropwise in small portions to 70% nitric acid (5 ml) at -10 ° C. After the addition was complete, the reaction was incubated to room temperature and stirred for 7 hours. The mixture was diluted with cold water and the resulting precipitate was filtered off, washed with water and dried under vacuum to afford the title compound as a light brown solid. HPLC room temperature 4.32 min.

Step 4 : Preparation of 5-amino-7-fluoro-1-methyl-1,3-dihydro-indol-2-one

Iron powder (0.883 g, 15.8 mmol) was added 7-fluoro-1-methyl-5-nitro-1,3-dihydro-indol-2-one in ethanol (50 ml) and water (25 ml) at 90 ° C. (Step 3, 0.830 g, 3.95 mmol) and ammonium chloride (2.10 g, 39.5 mmol) were added in small amounts. The reaction mixture was stirred vigorously and heated for 30 minutes, cooled to room temperature and diluted with dichloromethane (100 ml). The mixture was filtered through celite, the organic layer was separated, washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound as a dark brown solid. HPLC room temperature 1.95 min; MS m / z 181.0 (M + H) ⁺ for C ₉ H ₉ FN ₂ O. Step 5 : Preparation of (5R) -3- (7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-7-fluoro-1-methyl-1,3-dihydro-indol-2-one (step 4, 0.64 g, 3.55 mmol) in acetonitrile (15 ml), methyl (2R) -glycid Date (0.363 g, 3.55 mmol) and lithium trifluoromethanesulfonate (0.55 g, 3.55 mmol) were heated at 60 ° C. for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (30% EtOAc / hexanes) to afford the title compound as a light yellow solid. HPLC room temperature 3.24 min; MS m / z 283.2 (M + H) ⁺ for C ₁₃ H ₁₅ FN ₂ O ₄ .

Step 6 : (5R) -3- (7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Preparation of Methyl Ester

(5R) -3- (7-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid in acetonitrile (4 ml) Methyl ester (step 5, 0.15 g, 0.531 mmol) and 1,1-carbonyldiimidazole (0.095 g, 0.584 mmol) were stirred at 60 ° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light yellow solid. HPLC room temperature 4.0 min; MS m / z 309.1 (M + H) ⁺ for C ₁₄ H ₁₃ FN ₂ O ₅ .

Step 7 : (5R) -3- (7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Preparation of Amide

Ammonia (2M, 5 ml) in methanol was added to (5R) -3- (7-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2 at 0 ° C. -Oxo-oxazolidine-5-carboxylic acid methyl ester (step 6, 0.100 g, 0.324 mmol) was added. The reaction was incubated to room temperature and stirred for 2 hours. The solvent was evaporated and the residue was purified by PTLC (10% MeOH / DCM) to afford the title compound as a white solid.

C₁₃H₁₂FN₃O₄에 대한 MS m/z 294(M+H)⁺. HPLC room temperature 3.264 min;

MS m / z 294 (M + H) ⁺ for C ₁₃ H ₁₂ FN ₃ O ₄ .

Example 4 Preparation of (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Step 1 : Preparation of 1-ethyl-1H-indole-2,3-dione

1H-indole-2,3-dione (5.00 g, 0.034 mol), iodoethane (5.44 ml, 0.068 mol) and potassium carbonate (9.28 g, 0.068 mol) in DMF (50 ml) for 72 hours at room temperature Stirred. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as an orange solid. HPLC room temperature 3.96 min; MS m / z 176.1 (M + H) ⁺ for C ₁₀ H ₉ NO ₂ .

Step 2 : Preparation of 1-ethyl-1,3-dihydro-indol-2-one

1-ethyl-1H-indole-2,3-dione (step 1, 5.60 g, 31.9 mmol) was heated at 130 ° C. with pure hydrazine hydrate (20 ml) for 1 hour. The reaction mixture was cooled down, diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a yellowish orange solid. HPLC room temperature 4.12 minutes; MS m / z 162.1 (M + H) ⁺ for C ₁₀ H ₁₁ NO.

Step 3 : Preparation of l-ethyl-5-nitro-1,3-dihydro-indol-2-one

1-ethyl-1,3-dihydro-indol-2-one (step 2, 4.00 g, 24.8 mmol) was added to stirred sodium nitrate (2.10 g, 24.8 mmol) in trifluoroacetic acid (100 ml). . The reaction mixture was stirred at rt for 30 min and poured onto ice. The resulting precipitate was filtered off, washed with water and dried under vacuum to afford the title compound as a brown solid. HPLC room temperature 4.29 min; MS m / z 207.2 (M + H) ⁺ for C ₁₀ H ₁₀ N ₂ O ₃ .

Step 4 : Preparation of 5-amino-1-ethyl-1,3-dihydro-indol-2-one

Iron powder (3.89 g, 69.8 mmol) was added 1-ethyl-5-nitro-1,3-dihydro-indol-2-one in ethanol (150 ml) and water (75 ml) at 90 ° C. (step 3, 3.60 g, 17.5 mmol) and a small dropwise addition to a mixture of ammonium chloride (9.24 g, 175 mmol). The reaction mixture was stirred vigorously and heated for 30 minutes, cooled to room temperature and diluted with dichloromethane (300 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound as a dark brown solid. HPLC room temperature 1.86 min; MS m / z 177.1 (M + H) ⁺ for C ₁₀ H ₁₂ N ₂ O..

Step 5 : Preparation of (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-1-ethyl-1,3-dihydro-indol-2-one (step 4, 1.10 g, 6.24 mmol) in acetonitrile (10 ml), methyl (2R) -glycidate (0.637 g, 6.24 mmol) and lithium trifluoromethanesulfonate (0.961 g, 6.24 mmol) were heated at 70 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (70% EtOAc / hexanes) to afford the title compound as a light brown solid. HPLC room temperature 2.66 min; MS m / z 279.4 (M + H) ⁺ for C ₁₄ H ₁₈ N ₂ O ₄ .

Step 6 : Preparation of (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester

(5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester (step 5) in acetonitrile (5 ml) , 0.200 g, 0.718 mmol) and 1,1-carbonyldiimidazole (0.127 g, 0.789 mmol) were stirred at 60 ° C. for 30 minutes and heated. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light brown solid. HPLC room temperature 3.81 min; MS m / z 305.2 (M + H) ⁺ for C ₁₅ H ₁₆ N ₂ O ₅ .

Step 7 : Preparation of (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Ammonia in methanol (2M, 6 ml) was added (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazoli at 0 ° C. To dean-5-carboxylic acid methyl ester (step 6, 0.12 g, 0.394 mmol) was added and the suspension was stirred at 0 ° C. for 2 h. The solvent was evaporated and the residue was purified by PTLC (10% MeOH / DCM) to afford the title compound as off white solid.

C₄H₁₅N₃O₄에 대한 MS m/z 290(M+H)^+. HPLC room temperature 3.120 minutes;

MS m / z 290 (M + H) ⁺ for C ₄ H ₁₅ N ₃ O ₄ ^.

Example 5 Preparation of (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide

Methylamine (2M, 3 ml) in methanol was added to solid (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo- at 0 ° C. To oxazolidine-5-carboxylic acid methyl ester (Example 4, step 4, 0.060 g, 0.197 mmol) was added and the mixture was stirred at 0 ° C. for 1 hour. The precipitate was filtered off, washed with methanol and dried under vacuum to afford the title compound as off white solid.

C₁₅H₁₇N₃O₄에 대한 MS m/z 304(M+H)⁺.HPLC room temperature 3.314 min;

MS m / z 304 (M + H) ⁺ for C ₁₅ H ₁₇ N ₃ O ₄ .

Example 6 : (5R) -3- [1- (2-Fluoro-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxazolidine-5 Preparation of Carboxylic Acid Amides

Step 1 : Preparation of 1- (2-Fluoro-ethyl) -1H-indole-2,3-dione

1H-indole-2,3-dione (2.5.0 g, 0.017 mol) in DMF (25 ml), 1-iodo-2-fluoroethane (5.96 ml, 0.034 mol) and potassium carbonate (4.64 g, 0.034 mol) was stirred at rt for 72 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as an orange solid. HPLC room temperature 3.77 min; MS m / z 194.1 (M + H) ⁺ for C ₁₀ H ₈ FNO ₂ .

Step 2 : Preparation of 1- (2-Fluoro-ethyl) -1,3-dihydro-indol-2-one

1- (2-Fluoro-ethyl) -1H-indole-2,3-dione (step 1,3.00 g, 15.5 mmol) was heated with pure hydrazine hydrate (10 ml) at 130 ° C. for 30 minutes. The reaction mixture was cooled down, diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a yellow solid. HPLC room temperature 3.94 min; MS m / z 180.1 (M + H) ⁺ for C ₁₀ H ₁₀ FNO.

Step 3 : Preparation of 1- (2-Fluoro-ethyl) -5-nitro-1,3-dihydro-indol-2-one

1- (2-Fluoro-ethyl) -1,3-dihydro-indol-2-one (step 2, 1.9Og, 10.6 mmol) was added sodium nitrate (0.90 g, 10.6 in trifluoroacetic acid (48 ml). mmol) was added to the solution and stirred at room temperature for 30 minutes. The reaction mixture was diluted with cold water and the resulting precipitate was filtered, washed with water, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a brown solid. HPLC room temperature 4.15 min.

Step 4 : Preparation of 5-amino-1- (2-fluoro-ethyl) -1,3-dihydro-indol-2-one

Iron powder (1.83 g, 33.0 mmol) was added 1- (2-fluoro-ethyl) -5-nitro-1,3-dihydro-indole-2 in ethanol (80 ml) and water (40 ml) at 90 ° C. A small amount was added to -one (step 3, 1.85 g, 8.25 mmol) and ammonium chloride (4.36 g, 82.5 mmol). The reaction mixture was stirred vigorously and heated for 30 minutes, cooled to room temperature and diluted with dichloromethane (300 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a dark brown solid. HPLC room temperature 1.36 min; MS m / z 195.1 (M + H) ⁺ for C ₁₀ H ₁₁ FN ₂ O.

Step 5 : (5R) -3- [1- (2-Fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-ylamino] -2-hydroxy-propionic acid methyl ester Manufacture

5-amino-1- (2-fluoro-ethyl) -1,3-dihydro-indol-2-one (step 4, 0.70 g, 3.60 mmol) in acetonitrile (6 ml), methyl (2R)- Glycidate (0.368 g, 3.60 mmol) and lithium trifluoromethanesulfonate (0.55 g, 3.60 mmol) were heated at 70 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (70% EtOAc / hexanes) to afford the title compound as a light brown solid. HPLC room temperature 2.55 min; MS m / z 297.2 (M + H) ⁺ for C ₁₄ H ₁₇ FN ₂ O ₄ .

Step 6 : (5R) -3- [1- (2-Fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxazolidine-5 Preparation of Carboxylic Acid Methyl Ester

(5R) -3- [1- (2-fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-ylamino] -2-hydroxy- in acetonitrile (5 ml) Propionic acid methyl ester (0.35 g, 1.18 mmol) and 1,1-carbonyldiimidazole (0.21 g, 0.13 mmol) were stirred and heated at 60 ° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light brown solid. HPLC room temperature 3.72 min; MS m / z 323.2 (M + H) ⁺ for C ₁₅ H ₁₅ FN ₂ O ₅ .

Step 7 : (5R) -3- [1- (2-Fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxazolidine-5 Preparation of Carboxylic Acid Amides

Ammonia in methanol (2M, 5 ml) was solid (5R) -3- [1- (2-fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-yl at 0 ° C. ] -2-oxo-oxazolidine-5-carboxylic acid methyl ester (step 6, 0.10 g, 0.31 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 30 minutes. The solvent was evaporated and the residue was purified by PTLC (10% MeOH / DCM) to afford the title compound as off white solid.

C₁₄H₁4FN₃O₄에 대한 MS m/z 308(M+H)⁺.HPLC room temperature 2.994 min;

MS m / z 308 (M + H) ⁺ for C ₁₄ H ₁ 4FN ₃ O ₄ .

Example 7 (5R) -3- [1- (3-Fluoro-propyl) -2-oxo-2,3-dihydro-1 H-indol-5-yl] -2-oxo-oxazolidine- Preparation of 5-carboxylic acid methylamine

Methylamine (2M, 4 ml) in methanol was added to solid (5R) -3- [1- (2-fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indole-5- at 0 ° C. To] -2-oxo-oxazolidine-5-carboxylic acid methyl ester (Example 6, step 6, 0.070 g, 0.217 mmol) and the reaction mixture was stirred at 0 ° C. for 1 h. The resulting precipitate was filtered off, washed with methanol and dried under vacuum to afford the title compound as off white solid.

C₁₅H₁₆FN₃O₄에 대한 MS m/z 322(M+H)⁺.HPLC room temperature 2.994 min;

MS m / z 322 (M + H) ⁺ for C ₁₅ H ₁₆ FN ₃ O ₄ .

Example 8 Preparation of (5R) -3- (1-Isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Step 1 : Preparation of 1-isopropyl-1H-indole-2,3-dione

1H-indole-2,3-dione (5.0 g, 0.034 mol), iodopropane (6.83 ml, 0.068 mol) and potassium carbonate (9.28 g, 0.068 mol) in DMF (30 ml) were 72 hours at room temperature. Was stirred. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as an orange solid. HPLC room temperature 4.38 min; MS m / z 190.1 (M + H) ⁺ for C ₁₁ H ₁₁ NO ₂ .

Step 2: Preparation of 1-isopropyl-1,3-dihydro-indol-2-one

1-Isopropyl-1H-indole-2,3-dione (step 1,3.00 g, 15.9 mmol) was heated at 30 ° C. with pure hydrazine hydrate for 1.5 h. The reaction was cooled down, diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light brown solid. HPLC room temperature 4.54 min; MS m / z 176.1 (M + H) ⁺ for C ₁₁ H ₁₃ NO.

Step 3 : Preparation of 1-isopropyl-5-nitro-1,3-dihydro-indol-2-one

1-isopropyl-1,3-dihydro-indol-2-one (step 2, 2.50 g, 14.3 mmol) was added to a stirred solution of sodium nitrate (1.2Og, 14.26 mmol) in trifluoroacetic acid (50 ml). And stirred at room temperature for 5 hours. The reaction was diluted with cold water and the resulting precipitate was filtered off, washed with water and dried under vacuum to afford the title compound as a brown solid. HPLC room temperature 4.71 min; MS m / z 219.0 (MH) ⁺ for C ₁₁ H ₁₂ N ₂ O ₃ .

Step 4 : Preparation of 5-amino-1-isopropyl-1,3-dihydro-indol-2-one

Iron powder (2.63 g, 47.2 mmol) was added 1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (step 3, in ethanol (80 ml) and water (40 ml) at 90 ° C. 2.60 g, 11.8 mmol) and ammonium chloride (6.27 g, 118 mmol) were added in small amounts. The reaction mixture was stirred vigorously, heated for 45 minutes, then cooled to room temperature and diluted with dichloromethane (250 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a dark brown gummy solid. HPLC room temperature 2.51 min; MS m / z 191.1 (M + H) ⁺ for C ₁₁ H ₁₄ N ₂ O..

Step 5 : Preparation of (5R) -2-hydroxy-3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester

5-Amino-1-isopropyl-1,3-dihydro-indol-2-one (step 4, 1.00 g, 5.25 mmol) in methyl acetonitrile (10 ml), methyl (2R) -glycidate (0.536 g) , 5.25 mmol) and lithium trifluoromethanesulfonate (0.81 g, 5.25 mmol) were heated at 70 ° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (70% EtOAc / hexanes) to afford the title compound as a light brown solid. HPLC room temperature 2.95 min; MS m / z 293.0 (M + H) ⁺ for C ₁₅ H ₂₀ N ₂ O ₄ .

Step 6 : Preparation of (5R) -3- (1-Isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester

(5R) -2-hydroxy-3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester (step) in acetonitrile (10 ml) 5, 0.57 g, 1.95 mmol) and 1,1-carbonyldiimidazole (0.348 g, 2.14 mmol) were stirred and stirred at 60 ° C. for 45 minutes. The mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light pink effervescent solid. HPLC room temperature 4.18 min; MS m / z 319.2 (M + H) ⁺ for C ₁₆ H ₁₈ N ₂ O ₅ .

Step 7 : Preparation of (5R) -3- (1-Isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Ammonia (2M, 15 ml) in methanol was added to (5R) -3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxa at 0 ° C. To Zolidine-5-carboxylic acid methyl ester (step 6, 0.40 g, 1.25 mmol) was added and the reaction stirred at 0 ° C. for 1 hour. The mixture was evaporated and the residue was purified by PTLC (10% MeOH / DCM) to afford the title compound as off white solid.

C₁₅H₁₇N₃O₄에 대한 MS m/z 304(M+H)⁺.HPLC room temperature 3.499 min;

MS m / z 304 (M + H) ⁺ for C ₁₅ H ₁₇ N ₃ O ₄ .

Example 9 of (5R) -3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide Produce

Methylamine (2M, 4 ml) in methanol was dissolved in solid (5R) -3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo at 0 ° C. -Oxazolidine-5-carboxylic acid methyl ester (Example 8, step 6, 0.11 g, 0.345 mmol) was added and stirred at 0 ° C for 10 minutes. The reaction was evaporated and the residue was purified by PTLC (10% MeOH / DCM) to afford the title compound as off white solid.

C₁₆H₁₉N₃O₄에 대한 MS m/z 318(M+H)⁺.HPLC room temperature 3.656 min;

MS m / z 318 (M + H) ⁺ for C ₁₆ H ₁₉ N ₃ O ₄ .

Example 10 : (5R) -3- (7-Fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5 Preparation of Carboxylic Acid Amides

Step 1 : Preparation of 7-Fluoro-1-isopropyl-1H-indole-2,3-dione

7-fluoro-1H-indole-2,3-dione (1.50 g, 9.08 mmol), iodopropane (1.82 ml, 18.2 mmol) and potassium carbonate (2.48 g, 18.2 mmol) in DMF (20 ml) Was stirred at rt for 72 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (10% EtOAc / hexanes) to afford the title compound as an orange solid. HPLC room temperature 4.99 min.

Step 2 : Preparation of 7-Fluoro-1-isopropyl-1,3-dihydro-indol-2-one

7-Fluoro-1-isopropyl-1H-indole-2,3-dione (step 1, 1.3 g, 6.27 mnmol) was heated at 130 ° C. with pure hydrazine hydrate (10 ml) for 1 hour. The mixture was cooled down, diluted with cold water and extracted with ethyl acetate. The extract was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light brown viscous liquid, which slowly solidified upon standing. HPLC room temperature 5.10 min.

Step 3 : Preparation of 7-Fluoro-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one

70% nitric acid (0.297 ml, 4.65 mmol) was 7-fluoro-1-methyl-1,3-dihydro-indol-2-one (step 2, 0.90 g) in nitric acid (14.5 ml) concentrated at -10 ° C. , 4.65 mmol) dropwise. The reaction was stirred at −10 ° C. for 30 minutes and then poured into cold water. The resulting precipitate was filtered off, washed with water and dried under vacuum to afford the title compound as a light brown solid. HPLC room temperature 5.31 min.

Step 4 : Preparation of 5-amino-7-fluoro-1-isopropyl-1,3-dihydro-indol-2-one

Iron powder (0.854 g, 15.3 mmol) was added 7-fluoro-1-isopropyl-5-nitro-1,3-dihydro-indole-2- in ethanol (50 ml) and water (25 ml) at 90 ° C. A small amount was added dropwise to a mixture of one (step 3, 0.91 g, 3.82 mmol) and ammonium chloride (2.04 g, 38.2 mmol). The reaction mixture was stirred vigorously and heated for 30 minutes, cooled to room temperature and diluted with dichloromethane (150 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound as a dark brown gummy solid. HPLC room temperature 2.97 min; MS m / z 209.1 (M + H) ⁺ for C ₁₁ H ₁₃ FN ₂ O.

Step 5 : Preparation of 3- (7-Fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-7-fluoro-1-isopropyl-1,3-dihydro-indol-2-one (step 4, 0.79 g, 3.79 mmol) in acetonitrile (10 ml), methyl (2R) -glyci Date (0.387 g, 3.79 mmol) and lithium trifluoromethanesulfonate (0.587 g, 0.387 mmol) were heated at 90 ° C. for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (60% EtOAc / hexanes) to afford the title compound as a brown solid. HPLC room temperature 4.05 min; MS m / z 311.0 (M + H) ⁺ for C ₁₅ H ₁₉ FN ₂ O ₄ .

Step 6 : (5R) -3- (7-Fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5- Preparation of Carboxylic Acid Methyl Ester

(5R) -3- (7-fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy- in acetonitrile (5 ml) Propionic acid methyl ester (step 5, 0.16 g, 0.515 mmol) and 1,1-carbonyldiimidazole (0.092 g, 0.567 mmol) were stirred and heated at 60 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by PTLC (5% MeOH / DCM) to afford the title compound as off white solid. HPLC room temperature 4.75 min; MS m / z 337.1 (M + H) ⁺ for C ₁₆ H ₁₇ FN ₂ O ₅ .

Step 7 : (5R) -3- (7-Fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5- Preparation of Carboxylic Acid Amides

Ammonia in methanol (2M, 3 ml) was solid (5R) -3- (7-fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) at 0 ° C. To 2-oxo-oxazolidine-5-carboxylic acid methyl ester (step 6, 0.040 g, 0.119 mmol) was added and stirred at 0 ° C. for 1 hour. The reaction was evaporated and the residue was purified by PTLC (10% MeOH / DCM) to afford the title compound as off white solid.

C₁₅H₁₆N₃O₄에 대한 MS m/z 322(M+H)⁺.HPLC room temperature 3.999 min;

MS m / z 322 (M + H) ⁺ for C ₁₅ H ₁₆ N ₃ O ₄ .

Example 11 Preparation of (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Step 1 : Preparation of (2-fluoro-5-nitrophenyl) acetic acid

(2-fluorophenyl) acetic acid (5 g, 0.0324 mol) was dissolved in concentrated nitric acid (20 ml) and the resulting solution was cooled to -10 ° C with vigorous stirring. Nitric acid (2.08 ml, 69.3%, 0.0324 mol) and sulfuric acid (2 ml) solutions were added dropwise at a rate that kept the temperature at -5 ° C. The thick slurry was stirred for 15 minutes and then poured onto ice. The resulting white precipitate was filtered and dried under vacuum to afford the title compound.

Step 2 : Preparation of 1-cyclopropyl-5-nitro-1,3-dihydro-indol-2-one

(2-fluoro-5-nitrophenyl) acetic acid (step 1, 1.00 g, 0.00502 mol) and cyclopropylamine (6 eq., 2.08 ml, 0.0301 mol) were mixed in DMSO (5 ml) and overnight at 45 ° C. Stirred. Excess cyclopropylamine was removed under vacuum and 2N hydrochloric acid (20 ml) was added in part. The mixture was stirred at rt for 20 min and the resulting light yellow precipitate was filtered off, washed with water and dried in vacuo.

Step 3 : Preparation of 5-Amino-1-cyclopropyl-1,3-dihydro-indol-2-one

Iron powder (1.26 g, 22.9 mmol) was added 1-cyclopropyl-5-nitro-1,3-dihydro-indol-2-one (step 2, in ethanol (50 ml) and water (25 ml) at 90 ° C. 1.25 g, 5.72 mmol) and ammonium chloride (3.01 g, 57.2 mmol) were added dropwise. The reaction was stirred vigorously and heated for 30 minutes, then cooled to room temperature and diluted with dichloromethane (150 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a dark brown solid. HPLC room temperature 2.21 min; MS m / z 189.1 (M + H) ⁺ for C ₁₁ H ₁₂ N ₂ O..

Step 4 : Preparation of (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-1-cyclopropyl-1,3-dihydro-indol-2-one (step 3, 0.98 g, 5.20 mmol) in acetonitrile (10 ml), methyl (2R) -glycidate (0.531 g) , 5.20 mmol) and lithium trifluoromethanesulfonate (0.80 g, 5.20 mmol) were heated at 70 ° C. for 3 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (70% EtOAc / hexanes) to afford the title compound as off white solid. HPLC room temperature 2.73 min; MS m / z 291.3 (M + H) ⁺ for C ₁₅ H ₁₈ N ₂ O ₄ ^.

Step 5 : Preparation of (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester

(5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxypropionic acid methyl ester (step) in acetonitrile (5 ml) 4, 0.16 g, 0.551 mmol) and 1,1-carbonyldiimidazole (0.099 g, 0.606 mmol) were heated at 60 ° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as off white solid. HPLC room temperature 3.91 min; MS m / z 317.1 (M + H) ⁺ for C ₁₆ H ₁₆ N ₂ O ₅ .

Step 6 : Preparation of (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Ammonia (2M, 10 ml) in methanol was added to (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxa at 0 ° C. To zolidine-5-carboxylic acid methyl ester (step 5, 0.160 g, 0.505 mmol) was added and stirred at 0 ° C for 2 h. The reaction was evaporated and the residue was redissolved with methanol to give the title compound as off white solid.

C₁₅H₁₅N₃O₄에 대한 MS m/z 302(M+H)⁺.HPLC room temperature 3.233 min;

MS m / z 302 (M + H) ⁺ for C ₁₅ H ₁₅ N ₃ O ₄ .

Example 12 : (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide Produce

Methylamine (2M, 4 ml) in methanol was added to (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo- at 0 ° C. To oxazolidine-5-carboxylic acid methyl ester (Example 11, step 4, 0.04 g, 0.126 mmol) was added and stirred at 0 ° C. for 1 hour. The resulting precipitate was filtered off, washed with methanol and dried under vacuum to afford the title compound as a white solid.

C₁₆H₁₇N₃O₄에 대한 MS m/z 316(M+H)⁺.HPLC room temperature 3.365 minutes;

MS m / z 316 (M + H) ⁺ for C ₁₆ H ₁₇ N ₃ O ₄ .

Example 13 Preparation of (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5-carboxylic acid amide

Step 1 : Preparation of 5-nitro- 1 -propyl-1,3-dihydro-indol-2-one

(2-Fluoro-5-nitrophenyl) acetic acid (step 1, Example 11, 5.00 g, 0.0251 mol) and n-propylamine (5 eq., 10.4 ml, 0.126 mol) were mixed in DMSO (25 ml) And stirred at 45 ° C. overnight. Excess n-propylamine was removed under vacuum and 2N hydrochloric acid (80 ml) was added in part. The mixture was stirred at rt for 20 min and the resulting light yellow precipitate was filtered, washed with water and dried in vacuo to afford the title compound. HPLC room temperature 4.68 min; MS m / z 220.9 (M + H) ⁺ for C ₁₁ H ₁₂ N ₂ O ₃ .

Step 2 : Preparation of 5-amino-1-propyl-1,3-dihydro-indol-2-one

Iron powder (3.30 g, 59 mmol) was added 5-nitro-1-propyl-1,3-dihydro-indol-2-one (3.25 g, 14.8) in ethanol (100 ml) and water (50 ml) at 90 ° C. mmol) and ammonium chloride (7.8 g, 148 mmol) in small amounts. The reaction was stirred vigorously and heated for about 60 minutes, cooled to room temperature and diluted with dichloromethane (500 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound. HPLC room temperature 2.62 minutes; MS m / z 191.1 (M + H) ⁺ for C ₁₁ H ₁₄ N ₂ O..

Step 3 : Preparation of (R) -2-hydroxy-3- (2-oxo-1-propyl-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester

5-amino-1-propyl-1,3-dihydro-indol-2-one (1.12 g, 5.88 mmol), methyl (2R) -glycidate (0.601 g, 5.88 mmol) in acetonitrile (7 ml) And lithium trifluoromethanesulfonate (0.904 g, 5.88 mmol) were heated at 90 ° C. for 4 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (55% EtOAc / hexanes) to afford the title compound as a light brown solid. HPLC room temperature 2.94 min; MS m / z 293.4 (M + H) ⁺ for C ₁₅ H ₂₀ N ₂ O ₄ .

Step 4 : Preparation of (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5-carboxylic acid methyl ester

(R) -2-hydroxy-3- (2-oxo-1-propyl-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester (1.06 g) in acetonitrile (7 ml) , 3.63 mmol) and 1,1-carbonyldiimidazole (0.648 g, 3.99 mmol) were stirred and stirred at 60 ° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as off white solid. HPLC room temperature 4.18 min; MS m / z 318.9 (M + H) ⁺ for C ₁₆ H ₁₈ N ₂ O ₅ .

Step 5 : Preparation of (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5-carboxylic acid amide

Ammonia (2M, 5 ml) in methanol was added to (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazoli at 0 ° C. To hexane-5-carboxylic acid methyl ester (0.180 g, 0.565 mmol) was added and stirred at 0 ° C for 2 h. The reaction was evaporated and the residue was redissolved with methanol to give the title compound (0.125 g, 73%) as off-white solid.

C₁₅H₁₇N₃O₄에 대한 MS m/z 304.2(M+H)⁺.HPLC room temperature 3.233 min;

MS m / z 304.2 (M + H) ⁺ for C ₁₅ H ₁₇ N ₃ O ₄ .

Example 14 Preparation of (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl) -oxazolidine-5-carboxylic acid methylamide

Methylamine (2M, 5 ml) in methanol was added to 2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5 at 0 ° C. Add to carboxylic acid methyl ester (Example 36, 0.150 g, 0.471 mmol) and stir at 0 ° C. for 30 minutes. The resulting precipitate was filtered off, washed with methanol and dried under vacuum to afford the title compound as a white solid.

C₁₆H₁₉N₃O₄에 대한 MS m/z 318.2(M+H)⁺.HPLC room temperature 3.59 min;

MS m / z 318.2 (M + H) ⁺ for C ₁₆ H ₁₉ N ₃ O ₄ .

Example 15 : (R) -3- (7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5- Preparation of Carboxylic Acid Amides

Step 1 : Preparation of (2,3-difluoro-5-nitrophenyl) acetic acid

(2,3-Difluoro-penyl) -acetic acid (5 g, 0.0290 mol) was dissolved in concentrated nitric acid (20 ml) and the resulting solution was cooled to -10 ° C with vigorous stirring. Nitric acid (1.88 ml, 69.3%, 0.0290 mol) and sulfuric acid (2 ml) solutions were added dropwise at a rate where the temperature was maintained at -5 ° C. The thick slurry was stirred for 15 minutes and then poured onto ice. The resulting white precipitate was filtered and dried under vacuum (6.3 g, 99%) to give a product consisting of a 50/50 mixture of 5 and 6-NO ₂ regioisomers suitable for direct use in the next step.

Step 2 : Preparation of 7-Fluoro-5-nitro-1-propyl-1,3-dihydro-indol-2-one

Crude (2,3-difluoro-5-nitrophenyl) acetic acid (2.00 g, 9.2 mmol) and n-propylamine (6 eq., 4.54 ml, 0.0553 mol) are dissolved in DMSO (10 ml) and 50 ° C. Stirred for 2 h. A small amount of 2N hydrochloric acid (40 ml) was added and the mixture was stirred at rt for 2 h. The resulting light yellow precipitate was filtered off, washed with water and dried under vacuum. The residue was purified by flash column chromatography (20% ethyl acetate / hexanes) to give the product as a yellow solid (0.93 g, 42% isolated yield, 85% where the starting material was assumed to be the 50% target 5-NO ₂ isomer). ) Was obtained. HPLC room temperature 5.40 min; MS m / z 239.1 (M + H) ⁺ for C ₁₁ H _{1 1} FN ₂ O ₃ .

Step 3 : Preparation of 5-amino-7-fluoro-1-propyl-1,3-dihydro-indol-2-one

Iron powder (0.855 g, 15.3 mmol) was added 7-fluoro-5-nitro-1-propyl-1,3-dihydro-indol-2-one in ethanol (60 ml) and water (30 ml) at 90 ° C. (Step 1, 0.910 g, 3.82 mmol) and ammonium chloride (2.02 g, 38.2 mmol) in small amounts. The reaction mixture was stirred vigorously and heated for 60 minutes, cooled to room temperature and diluted with dichloromethane (300 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound as a dark brown solid. HPLC room temperature 3.03 min; MS m / z 209.0 (M + H) ⁺ for C ₁₁ H ₁₃ FN ₂ O.

Step 4 : Preparation of (R) -3- (7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-7-fluoro-1-propyl-1,3-dihydro-indol-2-one (0.300 g, 1.44 mmol) in acetonitrile (5 ml), methyl (2R) -glycidate (0.147 g, 1.44 mmol) and lithium trifluoromethanesulfonate (0.220 g, 1.44 mmol) were heated at 90 ° C. for 8 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by PTLC (5% methanol / dichloromethane) to afford the title compound as a yellow solid. HPLC room temperature 4.03 min; MS m / z 311.2 (M + H) ⁺ for C ₁₅ H ₁₉ FN ₂ O ₄ .

Step 5 : (R) -3- (7-Fluoro-2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Preparation of Methyl Ester

(R) -3- (7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxypropionic acid in acetonitrile (4 ml) Methyl ester (0.250 g, 0.805 mmol) and 1,1-carbonyldiimidazole (0.130 g, 0.805 mmol) were stirred and heated at 60 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as an off-white solid (0.135 g, 50%); HPLC room temperature 4.78 min; MS m / z 337.1 (M + H) ⁺ for C ₁₆ H ₁₇ FN ₂ O ₅ .

Step 6 : (R) -3- (7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Preparation of Amide

Ammonia (2M, 4 ml) in methanol was added to (R) -3- (7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl) -2 at 0 ° C. -Oxo-oxazolidine-5-carboxylic acid methyl ester (step 4, 0.130 g, 0.387 mmol) was added and stirred at 0 ° C. for 2 hours and then at room temperature for 2.5 hours. The reaction was evaporated and the residue was redissolved with methanol to afford the title compound as a white solid.

C₁₅H₁₆FN₃O₄에 대한 MS m/z 322.0(M+H)⁺.HPLC room temperature 3.96 min;

MS m / z 322.0 (M + H) ⁺ for C ₁₅ H ₁₆ FN ₃ O ₄ .

Example 16 : of (R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide Produce

Step 1 : Preparation of (2-t-butylamino-5-nitro-penyl) -acetic acid

(2-fluoro-5-nitrophenyl) acetic acid (step 1, Example 11,3.00 g, 15.07 mmol) and t-butylamine (4.8 ml, 45.2 mmol) were mixed in dimethyl sulfoxide (20 ml) and Stir overnight at 45 ° C. The mixture was diluted with water and the resulting yellow precipitate was filtered off, washed with water and dried in vacuo to afford the title compound. HPLC room temperature 5.04 min.

Step 2 : Preparation of 1-t-butyl-5-nitro-1,3-dihydro-indol-2-one

(2-t-butylamino-5-nitro-penyl) -acetic acid (2.00 g, 7.93 mmol) and 2N hydrochloric acid (40 ml) were heated at 50 ° C. for 12 h. The resulting precipitate was filtered and dried under vacuum to afford the title compound as a light yellow solid. HPLC room temperature 4.90 min.

Step 3 : Preparation of 5-Amino-1-t-butyl-1,3-dihydro-indol-2-one

Iron powder (0.752 g, 13.7 mmol) was added 1-t-butyl-5-nitro-1,3-dihydro-indol-2-one (0.80 g) in ethanol (20 ml) and water (10 ml) at 90 ° C. , 3.42 mmol) and ammonium chloride (1.81 g, 34.2 mmol) were added dropwise. The reaction was stirred vigorously for 30 minutes, cooled to room temperature and diluted with dichloromethane (100 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a brown solid. HPLC room temperature 2.24 min; MS m / z 205.1 (M + H) ⁺ for C ₁₂ H ₁₆ N ₂ O..

Step 4 : Preparation of (R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-1-t-butyl-1,3-dihydro-indol-2-one (0.48 g, 2,35 mmol) in acetonitrile (10 ml), methyl (2R) -glycidate (0.23 g , 2,35 mmol) and lithium trifluoromethanesulfonate (0.366 g, 2,35 mmol) were heated at 70 ° C. for 12 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (70% EtOAc / hexanes) to afford the title compound as an off-white solid (0.25 g, 40%); HPLC room temperature 3.37 min; MS m / z 307.2 (M + H) ⁺ for C ₁₆ H ₂₂ N ₂ O ₄ .

Step 5 : of (R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester Produce

(R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxypropionic acid methyl ester in acetonitrile (5 ml) 0.25 g, 0.812 mmol) and 1,1-carbonyldiimidazole (0.13 g, 0.812 mmol) were stirred and heated at 60 ° C. for 12 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a white solid. HPLC room temperature 4.09 min; MS m / z 333.1 (M + H) ⁺ for C ₁₇ H ₂₀ N ₂ O ₅ .

Step 6 : Preparation of (R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Ammonia (2M, 4 ml) in methanol was added to (R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo- at 0 ° C. To oxazolidine-5-carboxylic acid methyl ester (0.080 g, 0.241 mmol) was added and stirred at 0 ° C. for 2 hours. The reaction was evaporated and the residue was redissolved with methanol to give the title compound (0.030 g, 38%) as off-white solid.

C₁₆H₁₉N₃O₄에 대한 MS m/z 318.1(M+H)⁺. HPLC room temperature 3.20 min;

MS m / z 318.1 (M + H) ⁺ for C ₁₆ H ₁₉ N ₃ O ₄ .

Example 17 : (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide Produce

Step 1 : Preparation of 1-s-butyl-5-nitro-1,3-dihydro-indol-2-one

(2-fluoro-5-nitrophenyl) acetic acid (step 1, Example 11, 2.00 g, 10.0 mmol) and s-butylamine (6 eq., 6.08 ml, 60.2 mmol) were added to dimethyl sulfoxide (10 ml). ) And stirred at 45 ° C. overnight. Excess s-butylamine was removed under vacuum and 2N hydrochloric acid (40 ml) was added in part. The mixture was stirred at 45 ° C. for 1.5 h and then extracted with dichloromethane. The extract was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash column chromatography to give the title compound as a yellow solid. HPLC room temperature 5.05 min; MS m / z 235.3 (M + H) ⁺ for C ₁₂ H ₁₄ N ₂ O ₃ .

Step 2 : Preparation of 5-amino-1-s-butyl-1,3-dihydro-indol-2-one

Iron powder (1.55 g, 28.0 mmol) was added 1-s-butyl-5-nitro-1,3-dihydro-indol-2-one (1.64 g) in ethanol (70 ml) and water (35 ml) at 90 ° C. , 7.00 mmol) and a small dropwise addition to ammonium chloride (3.70 g, 70 mmol). The reaction was stirred vigorously and heated for 45 minutes, cooled to room temperature and diluted with dichloromethane (200 ml). The mixture was filtered through celite, the organic layer was separated, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound (1.41 g, 99%) as a dark brown solid. HPLC room temperature 2.80 min; MS m / z 205.1 (M + H) ⁺ for C ₁₂ H ₁₆ N ₂ O..

Step 3 : Preparation of (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-1-s-butyl-1,3-dihydro-indol-2-one (step 3, 0.90 g, 4.40 mmol) in acetonitrile (7 ml), methyl (2R) -glycidate (0.45 g, 4.40 mmol) and lithium trifluoromethanesulfonate (0.676 g, 4.40 mmol) were heated at 90 ° C. for 3 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (50% EtOAc / hexanes) to give the title compound (0.710 g, 53%) as off-white solid. HPLC room temperature 3.22 min; MS m / z 307.0 (M + H) ⁺ for C ₁₆ H ₂₂ N ₂ O ₄ .

Step 4 : of (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester Produce

(R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxypropionic acid methyl ester in acetonitrile (5 ml) 0.71 g, 2,32 mmol) and 1,1-carbonyldiimidazole (0.414 g, 2.55 mmol) were stirred and heated at 60 ° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound (0.77 g, 99%) as off-white solid. HPLC room temperature 4.46 min; MS m / z 333.3 (M + H) ⁺ for C ₁₇ H ₂₀ N ₂ O ₅ .

Step 5 : Preparation of (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Ammonia (2M, 5 ml) in methanol was added to (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo- at 0 ° C. To oxazolidine-5-carboxylic acid methyl ester (step 5, 0.200 g, 0.601 mmol) was added and stirred at 0 ° C. for 2 hours. The reaction was evaporated and the residue was purified by PTLC (10% methanol / dichloromethane) to give the title compound (0.105 g, 55%) as a pinkish white solid.

C₁₆H₁₉N₃O₄에 대한 MS m/z 318.2(M+H)⁺.HPLC room temperature 3.72 min;

MS m / z 318.2 (M + H) ⁺ for C ₁₆ H ₁₉ N ₃ O ₄ .

Example 18 (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamine Manufacture

Methylamine (2M, 3 ml) in methanol was added to (2R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo at 0 ° C. -Oxazolidine-5-carboxylic acid methyl ester (Example 18, 0.125 g, 0.376 mmol) was added and stirred at 0 ° C for 15 minutes. The reaction was evaporated and the residue was purified by PTLC (10% methanol / dichloromethane) to afford the title compound as a white solid.

C₁₇H₂₁N₃O₄에 대한 MS m/z 332.2(M+H)⁺.HPLC room temperature 3.91 min;

MS m / z 332.2 (M + H) ⁺ for C ₁₇ H ₂₁ N ₃ O ₄ .

Example 19 : (R) -3- [1- (2-Fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1 H-indol-5-yl] -2-oxo- Preparation of Oxazolidine-5-carboxylic Acid Amide

Step 1 : Preparation of Toluene-4-sulfonic acid-2-fluoro-1-methyl-ethyl ester

p-Toluenesulfonic anhydride (16.3 g, 49.9 mmol) was added 1-fluoro-2-propanol (3.00 g, 38.4 mmol) in dichloromethane (30 ml) at 0 ° C., triethylamine (16.1 ml, 115 mmol) and 4- (dimethylamino) pyridine (1.41 g, 11.5 mmol) were added dropwise and warmed to room temperature and stirred for 2 hours. The mixture was diluted with dichloromethane, washed with citric acid and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as an oil.

Step 2 : Preparation of 1- (2-Fluoro-1-methyl-ethyl) -1H-indole-2,3-dione

Isatin (2.70 g, 18.4 mmol), toluene-4-sulfonic acid 2-fluoro-1-methyl-ethyl ester (step 1, 6.40 g, 27.6 mmol) and potassium carbonate in dimethylformaamide (20 ml) (7.61 g, 55.1 mmol) was stirred at 50 ° C. for 24 h. The reaction was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash column chromatography (30% ethyl acetate / hexanes) to give the title compound (2.40 g, 63%) as an orange solid. HPLC room temperature 4.38 min; MS m / z 207.9 (M + H) ⁺ for C ₁₁ H ₁₀ FNO ₂ .

Step 3 : Preparation of 1- (2-Fluoro-1-methyl-ethyl) -1,3-dihydro-indol-2-one

1- (2-Fluoro-1-methyl-ethyl) -1H-indole-2,3-dione (step 2, 2,30 g, 11.1 mmol) was added pure hydrazine hydrate (20 ml) at 130 ° C. for 30 minutes. Heating). The reaction mixture was cooled down, diluted with cold water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated to afford the title compound as a yellowish brown solid. HPLC room temperature 4.50 min.

Step 4 : Preparation of 1- (2-Fluoro-1-methyl-ethyl) -5-nitro-1,3-dihydro-indol-2-one

1- (2-fluoro-1-methyl-ethyl) -1,3-dihydro-indol-2-one (step 3, 1.68 g, 8.69 mmol) was dissolved in sodium nitrate (15 ml) in trifluoroacetic acid (15 ml). 0.737 g, 8.69 mmol). After the addition was complete, the reaction was stirred at rt for 8 h. The mixture was diluted with cold water and the resulting precipitate was filtered off, washed with water and dried under vacuum. Final purification by flash column chromatography (30% ethyl acetate / hexanes) afforded the title compound as a light yellow solid. HPLC room temperature 4.75 min; MS m / z 239.1 (M + H) ⁺ for C ₁₁ H ₁₁ FN ₂ O ₃ .

Step 5 : Preparation of 5-amino-1- (2-fluoro-1-methyl-ethyl) -1,3-dihydro-indol-2-one

Iron powder (0.714 g, 12.8 mmol) was added 1-methyl-5-nitro-1,3-dihydro-indol-2-one in ethanol (50 ml) and water (25 ml) at 90 ° C. (step 4, 0.760). g, 3.19 mmol) and ammonium chloride (1.68 g, 31.9 mmol) in small amounts. The reaction mixture was stirred vigorously and heated for 45 minutes, cooled to room temperature and diluted with dichloromethane (250 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound as a dark brown solid. HPLC room temperature 2.50 min; MS m / z 209.0 (M + H) ⁺ for C ₁₁ H ₁₃ FN ₂ O.

Step 6 : (R) -3- [1- (2-Fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-ylamino] -2-hydroxy Preparation of Methyl Propionate

5-amino-1- (2-fluoro-1-methyl-ethyl) -1,3-dihydro-indol-2-one (0.300 g, 1.44 mmol) in acetonitrile (3 ml), methyl (2R) Glycidate (0.147 g, 1.44 mmol) and lithium trifluoromethane-sulfonate (0.220 g, 1.44 mmol) were heated at 90 ° C. for 4 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by PTLC (5% methanol / dichloromethane) to afford the title compound as off white solid. HPLC room temperature 3.04 min; MS m / z 311.2 (M + H) ⁺ for C ₁₅ H ₁₉ FN ₂ O ₄ .

Step 7 : (R) -3- [1- (2-Fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxa Preparation of zolidine-5-carboxylic acid methyl ester

(R) -3- [1- (2-fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1 H-indol-5-ylamino]-in acetonitrile (3 ml) 2-hydroxy-propionic acid methyl ester (step 6, 0.260 g, 0.837 mmol) and 1,1-carbonyldiimidazole (0.149 g, 0.920 mmol) were stirred and heated at 60 ° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by PTLC (5% methanol / dichloromethane) to afford the title compound as off white solid. HPLC room temperature 4.17 min; MS m / z 337.1 (M + H) ⁺ for C ₁₆ H ₁₇ FN ₂ O ₅ .

Step 8 : (R) -3- [1- (2-Fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxa Preparation of Zolidine-5-carboxylic Acid Amide

Ammonia (2M, 3 ml) in methanol was added to (R) -3- [1- (2-fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1H-indole- at 0 ° C. 5-yl] -2-oxo-oxazolidine-5-carboxylic acid methyl ester (step 5, 0.090 g, 0.268 mmol) and stirred at 0 ° C. for 45 minutes. The reaction was evaporated and the residue was purified by PTLC (5% methanol / dichloromethane) to afford the title compound as off white solid.

C₁₅H₁₆FN₃O₄에 대한 MS m/z 322.0(M+H)⁺.HPLC room temperature 3.37 min;

MS m / z 322.0 (M + H) ⁺ for C ₁₅ H ₁₆ FN ₃ O ₄ .

Example 20 Preparation of (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Step 1 : Preparation of 1-isobutyl-5-nitro-1,3-dihydro-indol-2-one

(2-fluoro-5-nitrophenyl) acetic acid (step 1, Example 11, 2.50 g, 12.6 mmol) and isobutylamine (5 eq., 6.23 ml, 62.8 mmol) were added to dimethyl sulfoxide (12 ml). Mixed in and stirred at 45 ° C. overnight. Excess isobutylamine was removed under vacuum and 2N hydrochloric acid (50 ml) was added in part. The mixture was stirred at rt for 2 h and the resulting precipitate was filtered, washed with water and dried to afford the title compound as a yellow solid. HPLC room temperature 5.31 min; MS m / z 235.3 (M + H) ⁺ for C ₁₂ H ₁₄ N ₂ O ₃ .

Step 2 : Preparation of 5-amino-1-isobutyl-1,3-dihydro-indol-2-one

Iron powder (2,37 g, 42,3 mmol) was subjected to 1-isobutyl-5-nitro-1,3-dihydro-indol-2-one in ethanol (100 ml) and water (50 ml) at 90 ° C. (2.48 g, 10.5 mmol) and small amounts dropwise to ammonium chloride (5.23 g, 100 mmol). The reaction was stirred vigorously for 30 minutes, cooled to room temperature and diluted with dichloromethane (250 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a dark brown solid. MS m / z 227.2 (M + H) ⁺ for C ₁₂ H ₁₆ N ₂ O..

Step 3 : Preparation of (R) -2-hydroxy-3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester

5-amino-1-isobutyl-1,3-dihydro-indol-2-one (0.60 g, 2.94 mmol) in methyl acetonitrile (6 ml), methyl (2R) -glycidate (0.300 g, 2.94 mmol) ) And lithium trifluoromethanesulfonate (0.449 g, 2.94 mmol) were heated at 90 ° C. for 5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (70% EtOAc / hexanes) to afford the title compound as off white solid. HPLC room temperature 3.38 min; MS m / z 307.0 (M + H) ⁺ for C ₁₆ H ₂₂ N ₂ O ₄ .

Step 4 : Preparation of (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester

(R) -2-hydroxy-3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -propionic acid methyl ester (0.54) in acetonitrile (5 ml) g, 1.76 mmol) and 1,1-carbonyldiimidazole (0.314 g, 1.94 mmol) were stirred and heated at 60 ° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a light brown solid. HPLC room temperature 4.62 min; MS m / z 355.3 (M + H) ⁺ for C ₁₇ H ₂₀ N ₂ O ₅ .

Step 5 : Preparation of (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Ammonia (2M, 5 ml) in methanol was added to 3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5 at O < 0 > C. -Added to carboxylic acid methyl ester (0.250 g, 0.752 mmol) and stirred at O < 0 > C for 60 minutes, then warmed to room temperature and stirred for an additional 30 minutes. The reaction was evaporated and the residue redissolved with methanol to afford the title compound as a white solid.

C₁₆H₁₉N₃O₄에 대한 MS m/z 318.2(M+H)⁺.HPLC room temperature 3.86 min;

MS m / z 318.2 (M + H) ⁺ for C ₁₆ H ₁₉ N ₃ O ₄ .

Example 21 of (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide Produce

Methylamine (2M, 4 ml) in methanol was added to (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo- at 0 ° C. It was added to oxazolidine-5-carboxylic acid methyl ester (Example 21, 0.150 g, 0.451 mmol) and stirred for 1 hour. The resulting precipitate was filtered off, washed with methanol and dried to afford the title compound as a white solid.

C₁₇H₂₁N₃O₄에 대한 MS m/z 332.2(M+H)⁺.HPLC room temperature 3.98 min;

MS m / z 332.2 (M + H) ⁺ for C ₁₇ H ₂₁ N ₃ O ₄ .

Example 22 Preparation of (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

Step 1 : Preparation of 1-cyclobutyl-5-nitro-1,3-dihydro-indol-2-one

(2-Fluoro-5-nitrophenyl) acetic acid (step 1, Example 11, 2.00 g, 10.0 mmol) and cyclobutylamine (6 eq., 5.14 ml, 60.2 mmol) were added to dimethyl sulfoxide (10 ml). Mixed in and stirred at 45 ° C. overnight. Excess cyclobutylamine was removed under vacuum and 2N hydrochloric acid (40 ml) was added in part. The mixture was stirred at 45 ° C. for 1.5 h and the resulting precipitate was filtered, washed with water and dried to give the title compound as a yellowish solid. HPLC room temperature 4.94 min; MS m / z 233.1 (M + H) ⁺ for C ₁₂ H ₁₂ N ₂ O ₃ .

Step 2 : Preparation of 5-amino-1-cyclobutyl-1,3-dihydro-indol-2-one

Iron powder (1.91 g, 34.4 mmol) was added 1-cyclobutyl-5-nitro-1,3-dihydro-indol-2-one (2.00 g, in ethanol (70 ml) and water (35 ml) at 90 ° C. 8.61 mmol) and ammonium chloride (4.55 g, 86.1 mmol) were added dropwise. The reaction was stirred vigorously and heated for 45 minutes, cooled to room temperature and diluted with dichloromethane (350 ml). The mixture was filtered through celite, the organic layer was separated and washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated to afford the title compound as a dark brown solid. HPLC room temperature 2.81 minutes; MS m / z 203.1 (M + H) ⁺ for C ₁₂ H ₁₄ N ₂ O..

Step 3 : Preparation of (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxy-propionic acid methyl ester

5-amino-1-cyclobutyl-1,3-dihydro-indol-2-one (1.18 g, 5.83 mmol), methyl (2R) -glycidate (0.596 g, 5.83 mmol in acetonitrile (8 ml) ) And lithium trifluoromethanesulfonate (0.896 g, 5.83 mmol) were heated at 90 ° C. for 10 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography (50% EtOAc / hexanes) to afford the title compound as off white solid. HPLC room temperature 3.19 min; MS m / z 304.9 (M + H) ⁺ for C ₁₆ H ₂₀ N ₂ O ₄ .

Step 4 : Preparation of (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methyl ester

(R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino) -2-hydroxypropionic acid methyl ester (1.00 in acetonitrile (5 ml) g, 3.29 mmol) and 1,1-carbonyldiimidazole (0.587 g, 3.61 mmol) were stirred and heated at 60 ° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (Na20SO4) and evaporated to afford the title compound as off white solid. HPLC room temperature 4.40 min; MS m / z 331.1 (M + H) ⁺ for C ₁₇ H ₁₈ N ₂ O ₅ .

Step 5 : Preparation of (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide

C₁₆H₁₇N₃O₄에 대한 MS m/z 316.1(M+H)⁺.Ammonia (2M, 5 ml) in methanol was added to (7R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxa at 0 ° C. To zolidine-5-carboxylic acid methyl ester (step 5, 0.200 g, 0.605 mmol) was added and stirred at 0 ° C. for 30 minutes, then warmed to room temperature and stirred for an additional 45 minutes. The reaction was evaporated to purify the residue by PTLC (10% methanol / dichloromethane) to afford the title compound as off white solid. HPLC room temperature 3.71 min;

MS m / z 316.1 (M + H) ⁺ for C ₁₆ H ₁₇ N ₃ O ₄ .

Example 23 (R) -3- (1-cyclobutyl-2--oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid ethylamide Manufacture

C₁₇H₁₉N₃O₄에 대한 MS m/z 330.1(M+H)⁺.Methylamine (2M, 3 ml) in methanol was added to (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo- at 0 ° C. To oxazolidine-5-carboxylic acid methyl ester (Example 22, 200 g, 0.605 mmol) was added and stirred at 0 ° C. for 45 minutes. The resulting precipitate was filtered off, washed with methanol and dried to afford the title compound as a white solid. HPLC room temperature 3.90 min;

MS m / z 330.1 (M + H) ⁺ for C ₁₇ H ₁₉ N ₃ O ₄ .

Claims (16)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula I

Where Y ¹ is -CH- or -CF-; R ¹ is —C _1-4 alkyl or —C _3-5 cycloalkyl, optionally substituted with fluoro atoms; R ² is -H or -CH ₃ . The method of claim 1, Y ¹ is -CH-. The method of claim 1, R ¹ is methyl, ethyl, propyl or isopropyl. The method of claim 1, (5R) -3- (1-Isopropyl-2-oxo-2,3-dihydro-1 H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide. The method of claim 1, A compound selected from the group consisting of: (1) (5R) -3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, (2) (5R) -3- (1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide, (3) (5R) -3- (7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Amide, (4) (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, (5) (5R) -3- (1-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide, (6) (5R) -3- [1- (2-Fluoro-ethyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxazolidine-5 Carboxylic acid amides, (7) (5R) -3- [1- (3-Fluoro-propyl) -2-oxo-2,3-dihydro-1H-indol-5-yl] -2-oxo-oxazolidine-5 Carboxylic acid methylamides, (8) (5R) -3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, (9) (5R) -3- (1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide, (10) (5R) -3- (7-Fluoro-1-isopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5- Carboxylic acid amides, (11) (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, (12) (5R) -3- (1-cyclopropyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide, (13) (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5-carboxylic acid amide, (14) (R) -2-oxo-3- (2-oxo-1-propyl-2,3-dihydro-1 H-indol-5-yl) -oxazolidine-5-carboxylic acid methylamide, (15) (R) -3- (7-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid Amide, (16) (R) -3- (1-t-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, (17) (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, (18) (R) -3- (1-s-butyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide, (19) (R) -3- [1- (2-Fluoro-1-methyl-ethyl) -2-oxo-2,3-dihydro-1 H-indol-5-yl] -2-oxo-oxa Zolidine-5-carboxylic acid amide, (20) (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, (21) (R) -3- (1-isobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide, (22) (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid amide, and (23) (R) -3- (1-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -2-oxo-oxazolidine-5-carboxylic acid methylamide. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method of treating a bacterial infection comprising administering a pharmaceutically effective amount of the compound of claim 1 to a mammal to be treated. The method of claim 7, wherein A method of orally administering the compound of claim 1. The method of claim 7, wherein A method of administering the compound of claim 1 parenterally, topically, rectally or intranasally. The method of claim 7, wherein A method of administering the compound of claim 1 in an amount of about 0.1 to about 100 mg / kg body weight / day. The method of claim 7, wherein A method of administering the compound of claim 1 in an amount of about 1 to about 50 mg / kg body weight / day. The method of claim 7, wherein Bacterial infection is an ear infection, eye infection, respiratory infection, skin and skin structure infection, bacterial endocarditis, osteomyelitis, endocarditis or diabetes. The method of claim 7, wherein The bacterial infection is caused by gram-positive bacteria, gram-negative bacteria, anaerobic organisms or acidic organisms. The method of claim 7, wherein Bacterial infection is Staphylococcus Cauchy (staphylococci), streptomycin Cauchy (streptococci), Enterococcus Cauchy (Enterococci), under a brush Russ (Haemophilus), Mora Cellar (Moraxella), watermelon teroyi de (bacteroides), Clostridia (Clostridia), M. the method is caused by a bacteria, including bacteria (Mycobacteria) or chlamydia (Chlamydia). The method of claim 14, Kosice is Staphylococcus bacteria Staphylococcus aureus Kosice (S. aureus) and Kosice Staphylococcus epidermidis (S. epidermidis); Ah Streptococcus pneumoniae in Kosice Kosice Streptococcus (S. pneumoniae), and streptomycin Kosice Kuopio jeneseu (S. pyogenes); The Cauchy Enterococcus Enterococcus faecalis Cauchy par (E. faecalis); Under a brush on a brush under the Russ influenza (H. influenzae) Russ; Mora Cellar Qataris Mora Cellar Harleys (M. catarrhalis); Mycobacteria , Mycobacteria tuberculosis ( M. tuberculosis ); Or M. The method Te Solarium Oh Away (Mycobacterium avium). The method of claim 7, wherein Bacterial Infections Are Multidrug- Resistant Staphylococci The method caused by Aureus .