Lactivin compounds, their preparation and use as antibacterial agents

Abstract

Lactivin compounds of formula (I) and pharmaceutically acceptable salts of the compounds of formula (I) are provided, wherein the compounds comprise antibiotics suitable for use alone or in combination with P-lactamase inhibitors and / or other antibiotics (including P-lactam and non-P-lactam antibiotics) in the treatment or prevention of bacterial infections.

Description

Lactivin compounds, their preparation and use as antibacterial agents Technical field The present invention relates to novel lactivin compounds having the unique structure of a dicyclic dipeptide, which is 2-[(4S)-4-acetamido-3-oxo-1,2-oxazolidin-2-yl]-5-oxooxolan-2-carboxylic acid, and to pharmaceutically acceptable salts thereof, their use, and methods for preparing these compounds. More particularly, novel lactivin compounds having enhanced antibacterial activity and combinations of these compounds with β-lactamase inhibitors that are active against various resistant pathogenic microorganisms are provided. Background of the technique Experts and public health officials consider the emergence and spread of antibiotic-resistant bacteria to be one of the major public health challenges of the 21st century. While the most resistant isolates continue to appear in hospital settings, clinicians and epidemiologists are finding increasing numbers of resistant bacteria in the community among people with no prior contact with healthcare. Therapeutic agents are particularly limited for infections caused by multidrug-resistant Gram-negative pathogens, including the bacteria that constitute the ESKAPE organisms, generally encompassed by the following six pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. The highly successful and well-tolerated class of β-lactam antibiotics has historically been a mainstay for treating infections caused by Gram-negative pathogens. However, a wide range of over 1,000 different β-lactamases produced by bacteria and other bacterial resistance mechanisms seriously threaten the medium-term usefulness of current β-lactam antibiotics. Extended-spectrum β-lactamases (ESBLs) and carbapenemases are particularly important drivers of resistance, as they inactivate β-lactam antibiotics and render them ineffective in treating infections. As a result, morbidity and mortality from bacterial infections in both hospital and community settings continue to rise, and bacterial resistance has become a major public health problem. New agents with resistance-breaking properties are urgently needed to fill this gap. Therefore, there is a demand for the development of new classes of antibiotics that exhibit more potent antimicrobial activity and are particularly effective against various β-lactamase-producing Gram-negative bacteria. Lactivin is the first non-β-lactam antibiotic with a dicyclic dipeptide backbone described in the literature. It was isolated by the Takeda group from soil samples collected in Japan. Lactivin possesses a unique dicyclic dipeptide structure and has been shown to have an affinity for bacterial penicillin-binding proteins (PBPs) similar to that of β-lactam antibiotics. However, it is less susceptible to β-lactamase enzymes. [Nature, 1987, Vol. 325, pp. 179-180; J. Chem. Soc. Chem. Commun., 1987, (2), pp. 62-63; Tetrahedron Lett., 1986, Vol. 27, No. 51, pp. 6229-6232; Tetrahedron, 1988, Vol. 44, No. 11, pp. 3231-3240; Tetrahedron, 1988, Vol. 44, No. 21, pp. 6589-6606; J. Antibiot., 1989, Vol. 42, No. 1, pp. 84-93; Chem. Pharm. Bull., 1990, Vol. 38, No. 1, pp. 116-122; US patent 4,851,422 (1989); EP patent 0191989 A1; WO patent 87 / 00527; EP patent 0219923 A1]. As concrete examples of lactivicin, documents US 4,851,422 and EP 0219923 B1 disclose carboxylates of 2- (3-oxo-2-isoxazolidinyl) -5-oxo-2-tetrahydrofuran of the formula that is shown in continuation, which is an example structure of lactivicins: Therefore, R5, R6, R7, and R8 are independently hydrogen, C1-6 alkyl, phenyl, or benzyl, which may be substituted with C1-6 acylamino or C1-6 alkoxy and may be linked through an oxygen or sulfur atom, or R5 and / or R6 form a chemical bond with R7 or R8 to form a double bond, or R5 or R6 with R7 or R8 form a phenyl ring. WO 86 / 06380 A1 relates to a 2-(4-substituted-amino-3-oxo-2-isoxazolidinyl)-5-oxo2-tetrahydrofuran-carboxylic acid derivative having antibacterial activity and to a method for producing the same. In particular, the antibiotic compound TAN-588 is disclosed, characterized by a 5-oxo-2-tetrahydrofurancarboxylic acid moiety linked to the nitrogen atom of a 3-oxo-isoxazolidine ring. WO 86 / 06380 A1 discloses derivatives having substituents at position 5 of the isoxazolidine ring and at positions 3 and 4 of the tetrahydrofuran ring, along with a method for producing such derivatives. Goldberg et al. (J. Med. Chem., 63 (11), 5990-6002, 2020) describe a pyrazolidinone β-lactam that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate its absorption into the periplasm and its antibiotic effect against multidrug-resistant Gram-negative bacilli. The MIC values ​​of the β-lactam are reported, along with the finding that the compound is resistant to hydrolysis by all four classes of β-lactamases. In search of a different class of antibiotics with a new core, the Takeda group produced several lactivin derivatives that had various acylamino moieties at the C-4 position [J. Chem. Soc. Chem. Commun., 1987, (2), pp. 62-63]. The compound with a 2-aminothiazol-4-yl-(Z)-2-methoxy-iminoacetyl side chain showed improved antibacterial activity compared to natural lactivin. Moreover, some of the compounds showed protective effects in experimentally infected mice [Chem. Pharm. Bull., 1990, Vol. 38, No. 1, p.116-122; Tetrahedron, 1988, Vol.44, No.21, pp.6589-6606]. The attempt to enhance cellular uptake of β-lactams by utilizing iron siderophore uptake systems in microorganisms is a concept that has been explored in the field of monobactams by Basel (document WO 2007 / 065288), NAEJA Pharmaceutical (document WO 2002 / 022613), and Squibb & Sons (documents US 5290929, EP 531976, EP 484881). Furthermore, BMS-180680 is a catechol-containing monobactam that appears to utilize the iron-regulated outer membrane receptor proteins Cir and Fiu and the TonB-dependent iron transport system to enhance uptake across the bacterial outer membrane. As a result, BMS-180680 exhibits excellent activity against many Gram-negative bacteria [Antimicrob. Agents & Chemother., 1997, Vol. 41, No. 5, pp. 1010-1016]. Additionally, Shionogi & Co. Ltd. discovered a new catechol-containing cephalosporin [Antimicrob. Agents & Chemother., 2016, Vol. 60, No. 12, pp.7396-7401] and introduced it clinically as Cefiderocol. More recently, Pfizer reinvestigated catechol-containing lactivins for receptor-mediated uptake of siderophores in gram-negative bacteria [J. Med. Chem. 2014, 57, 3845-3855]. Another group [Antimicrob. Agents & Chemother., 2016, Vol. 60, No. 7, pp. 4170-4175] showed that sideromimic modification of lactivin dramatically increases potency against clinical isolates of extremely drug-resistant Stenotrophomonas maltophilia. In general, sideromimic lactivin conjugates are clearly an underexplored class with a novel dicyclic dipeptide nucleus that warrants further investigation through the preparation of additional novel analogues in the search for new effective antibacterial agents. The present invention relates to these and other important objectives. Summary of the invention In view of the increasing development of resistance in pathogenic bacteria to known classes of antibacterial agents, including bacteria exhibiting multiple resistances, there is a constant need to find new antibacterial substances, particularly compounds that have structural motifs that differ from traditional antimicrobial molecules. Although studies on laactivin compounds have shown promising results, there remains a need for new laactivin compounds that have greater antibiotic efficacy, particularly against highly resistant gram-negative bacteria, with such compounds having structural characteristics that are significantly different from the compounds described in the patents and publications cited above. For this purpose, the present invention relates to N-acylamino compounds of formula (I) where A is defined by the formula (Ia) where X is N or CR3 and R3 represents hydrogen or halogen. Suitable halogens include chlorine and fluorine. In formula (I), R1 and R2 together with the carbon atom to which they are attached can form a (C3-C8) cycloalkyl, where (i) the cycloalkyl may contain a heteroatom selected from O, N and S; and / or (ii) The cycloalkyl group may be substituted with one, two, three, or four substituents selected independently from the group consisting of an alkyl (C1-C3) and a halogen. Suitable halogens include chlorine and fluorine. Alternatively, in formula (I), R1 and R2 can, independently of each other, represent hydrogen or (C1-C3) alkyl, wherein the (C1-C3) alkyl can be substituted with a substituent selected from hydroxy and chlorine. In formula (I), B is a fragment carrying a catechol or bicyclic hydroxypyridone fraction established in formula (Ia') that has the ability to enhance the intracellular absorption of the compounds of formula (I) by utilizing the bacterial iron absorption process in gram-negative bacteria. In formula (Ia), ring P is an unsaturated 5-membered or 6-membered ring, containing a single carbonyl group (CO) or a sulfone group (SO2) or a combination of a carbonyl group (CO) and a sulfone group (SO2), and may further contain up to two additional N atoms. In one particular embodiment, ring P is an unsaturated 5-membered ring. In formula (Ia), the Q ring can contain up to two N atoms, wherein the R4 substituent is selected from the group consisting of hydrogen, (C1-C3) alkyl, carbonyl, trifluoromethyl, cyano, and a halogen. Particular examples of Q rings are benzene and pyridine. Suitable halogens include fluorine and chlorine. The present invention also includes salts of compounds of formula (I), solvates of compounds of formula (I), and solvates of salts of compounds of formula (I). The compounds of the invention may, depending on their structure, exist in stereoisomeric forms (e.g., enantiomers, diastereomers). Therefore, the invention also encompasses the enantiomers and diastereomers of the compounds of formula (I) as defined herein and their respective mixtures. Stereoisomerically uniform constituents may be isolated in a known manner from such mixtures of enantiomers and / or diastereomers, and such constituents are also considered compounds of the present invention. With respect to compounds of formula (I), it should be understood that these compounds include Z isomers, E isomers, and mixtures thereof. As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in the arrangement and configuration of atoms, such as geometric isomers and optical isomers. If the compounds of the invention can be presented in tautomeric forms, the present invention includes all tautomeric forms of the compounds of formula (I). The preferred salts for the purposes of the present invention are "pharmaceutically acceptable salts" of the compounds of the invention, i.e., the compounds of formula (I). However, salts that are not in themselves suitable for pharmaceutical applications ("non-pharmaceutically acceptable salts") but that may be used, for example, for the isolation or purification of the compounds of the invention are also included. Examples of pharmaceutically acceptable salts of compounds of formula (I) include salts of inorganic bases such as ammonium salts, salts of alkali metals, particularly sodium or potassium salts, salts of alkaline earth metals, particularly magnesium or calcium salts; salts of organic bases derived from n-propylamine, n-butylamine, cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, dicyclohexylamine, procaine, choline, picoline, N,N-dibenzylethylenediamine, N-methylglucamine, morpholine, pyrrolidine, pyridine, piperidine, N-ethylpiperidine, and N-methylmorpholine. Basic amino acids that can form basic amino acid salts include lysine, arginine, ornithine, and histidine. As a person skilled in the art will appreciate, compounds of formula (I) containing a basic nitrogen atom are capable of forming acid addition salts. This document includes such salts with pharmaceutically acceptable acids.Examples of such acids are hydrochloric, hydrobromic, phosphoric, sulfuric, citric, oxalic, maleic, fumaric, glycolic, mandelic, tartaric, aspartic, succinic, malic, formic, acetic, trifluoroacetic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, benzenesulfonic, p-toluenesulfonic and the like. On the other hand, some compounds of formula (I), when they contain a basic group such as NH, NH2, or pyridine, piperazine, and the like, can form an internal zwitterionic salt with a COOH group. These internal salts are also considered and included in this document. Solvates, as defined herein, are those forms of the compounds of the invention which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific type of solvate in which the coordination occurs with water. A molecular complex of a compound or fraction of a compound and a solvent may be stabilized by non-covalent intramolecular forces such as, for example, electrostatic forces, Van der Waals forces, or hydrogen bonds. A molecular complex of a compound of the present invention may be formed with one or more solvent molecules in a stoichiometric or non-stoichiometric amount. In the context of the present invention, the substituents defined for formula (I) have the following definitions unless otherwise specified. The term "cycloalkyl" refers to aliphatic C3-C8 rings, preferably C3-C6, such as, in particular, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, but also includes C3-C4, C3-C5, and C3-C7 rings. The term "halogen" refers to fluorine and chlorine. The term "alkyl" refers to linear or branched (C1-C6) alkyls, preferably (C1-C4) alkyls, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, and tert-butyl, but also includes (C1-C2) alkyls, (C1-C3) alkyls, (C1-C5) alkyls, and (C1-C6) alkyls. The term alkyl includes linear or branched C3 alkyls, linear or branched C4 alkyls, linear or branched C5 alkyls, and linear or branched C6 alkyls. The expression "5-membered ring" refers to a 5-membered heterocyclic ring containing at least one and up to three N atoms and optionally one S atom. The expression "6-membered ring" refers to a 6-membered heterocyclic ring containing at least one N atom. Accordingly, in some embodiments of the invention, pharmaceutically acceptable laactivin compounds of formula (I) and their salts are provided. In some respects, these compounds may exhibit activity against pathogenic microorganisms, and are therefore useful in the treatment and / or prevention of bacterial infections in humans or animals, either alone or in combination with one or more β-lactam antibiotics, other non-β-lactam antibiotics, and β-lactamase inhibitors. In other embodiments of the invention, pharmaceutical compositions are provided comprising one or more compounds of formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent. In some respects, these compositions may exhibit activity against pathogenic microorganisms. In other embodiments of the invention, pharmaceutical compositions are provided comprising (i) one or more compounds of formula (I) or pharmaceutically acceptable salts thereof, (ii) one or more β-lactamase inhibitors, and (iii) a pharmaceutically acceptable carrier or diluent. In some respects, these compositions may exhibit activity against pathogenic microorganisms. In other embodiments of the invention, a pharmaceutical composition comprising one or more compounds of formula (I), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent is provided herein for use in the treatment or prevention of bacterial infections in a subject, wherein said subject has a bacterial infection or is at risk of developing a bacterial infection, and wherein said use comprises administering a therapeutically effective amount of a pharmaceutical composition to the subject. According to the embodiments of the invention herein, the subject may be a human being or an animal in whom the present compounds and compositions may provide a beneficial antibacterial effect. In other embodiments of the invention, a method for preparing a compound of formula (I) according to claim 1 is provided herein, comprising carrying out the reaction sequence of Scheme 1. Scheme 1 Detailed description of the invention: According to the realizations herein, pharmaceutically acceptable compounds of lactivin of formula (I) and salts of compounds of formula (I) are provided, wherein the compounds comprise antibiotics suitable for use alone or in combination with β-lactamase inhibitors and / or other antibiotics (including β-lactam and non-β-lactam antibiotics) in the treatment or prevention of bacterial infections. The term "antibiotic" refers to a compound or composition that decreases the viability of a microorganism or inhibits the growth or proliferation of a microorganism, and is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent. Compounds of the invention In particular, the present invention relates to compounds of formula (I) where A is defined by the formula (Ia) and where X is N or CR3 and R3 represents hydrogen or halogen; R1 and R2, together with the carbon atom to which they are attached, can form a (C3-C8) cycloalkyl, wherein (i) the cycloalkyl can contain a heteroatom selected from O, N and S, and / or (ii) the cycloalkyl may be substituted with one, two, three or four substituents selected independently from each other from the group consisting of alkyl (C1-C3) and halogen; or R1 and R2 can, independently of each other, represent hydrogen or alkyl (C1-C3), wherein the alkyl (C1-C3) can be substituted with a substituent selected from hydroxy and chlorine; B is a bicyclic catechol or hydroxypyridone fraction that carries a fragment defined by the formula (Ia') where P is an unsaturated 5-membered or 6-membered ring, containing a single carbonyl group (CO) or a sulfone group (SO2) or a combination of a carbonyl group (CO) and a sulfone group (SO2) and may further contain up to two additional N atoms; and where Q can contain up to two N atoms and where R4 is selected from the group consisting of hydrogen, (C1-C3) alkyl, carbonyl, trifluoromethyl, cyano and a halogen; and salts of the same, solvates of the same and solvates of the salts of the same. In formula (I), particular examples of halogens include fluorine and chlorine. In formula (Ia), a particular example of ring P is an unsaturated 5-membered ring. In formula (Ia), particular examples of ring Q are benzene and pyridine. In formula (Ia), particular fragments carrying a catechol or bicyclic hydroxypyridone fraction are those that have the ability to enhance the intracellular absorption of the compounds of formula (I) by utilizing the bacterial iron absorption process in gram-negative bacteria. In formula (I), examples of These include, but are not limited to, the following fragments: In formula (I), examples of "A" include, but are not limited to, the following: In formula (I), examples of "B" include, but are not limited to, the following: R4 is selected from hydrogen, (C1-C3) alkyl, trifluoromethyl, cyano or halogen, wherein the halogen is preferably chlorine or fluorine. Table 1 below provides examples of compounds of formula (I) covered by the invention, without being limited to the specified compounds. Table 1. continuation continuation continuation The compounds of the invention are, therefore, the compounds of formula (I), and the salts, solvates and solvates of their salts, and include the compounds in Table 1. The compounds of the invention of formula (I) and Table 1 include enantiomers or diastereomers and respective mixtures thereof. The compounds of the invention of formula (I) and Table 1 include Z isomers, E isomers, and mixtures thereof. The compounds of the invention of formula (I) and Table 1 can be presented in tautomeric forms and the present invention covers all tautomeric forms. The salts of the compounds of the present invention may be "pharmaceutically acceptable salts", examples of which have been defined above. The compounds of the present invention may be internal salts such as a zwitterionic salt formed with a COOH group and a basic group, such as NH, NH2, pyridine or piperazine present in formula (I). Compositions of the Invention The compounds of the invention exhibit a broad range of antibacterial effects. In some respects, the compounds may show activity against pathogenic microorganisms and, therefore, may be useful in the treatment and / or prevention of bacterial infections in humans or animals, either alone or in combination with one or more of: β-lactam antibiotics, other non-β-lactam antibiotics, and β-lactamase inhibitors. Therefore, the compounds of the invention are suitable for use in pharmaceutical compositions and as medicaments for the treatment, prevention, and / or prophylaxis of diseases in humans and animals. Accordingly, the present invention also relates to pharmaceutical compositions comprising (i) one or more compounds of formula (I), or pharmaceutically acceptable salts thereof, and (ii) a pharmaceutically acceptable carrier or diluent. In some respects, these compositions may exhibit activity against pathogenic organisms. As used herein, the terms "pharmaceutical composition" and "medicinal product" are synonymous. In other embodiments, the invention relates to pharmaceutical compositions comprising (i) one or more compounds of formula (I) or pharmaceutically acceptable salts thereof, (ii) one or more β-lactamase inhibitors, and (iii) a pharmaceutically acceptable carrier or diluent. In some respects, these compositions may exhibit activity against pathogenic microorganisms. Such combinations may exhibit a synergistic effect when used in the treatment or prevention of bacterial infections. The present invention further relates to pharmaceutical compositions comprising (i) one or more compounds of formula (I), or pharmaceutically acceptable salts thereof, (ii) one or more β-lactamase inhibitors, wherein the β-lactamase inhibitors may be selected from formulas (1a) to (1z'), for example, and (iii) a pharmaceutically acceptable carrier or diluent. It is understood that the compounds of formula (I) may also be used in combination with other β-lactamase inhibitors. Such combinations may exhibit a neutral effect when used in the treatment or prevention of bacterial infections. 1a (clavulanic acid) 1b (sulbactam) 1c (tazobactam) The expression "β-lactamase inhibitor" refers to a compound that is capable of inhibiting β-lactamase activity, such as compounds of formula (1a) to (1z'), for example, where inhibiting β-lactamase activity means inhibiting the activity of a class A, B, C, and / or D β-lactamase. The term "β-lactamase" denotes an enzyme capable of inactivating a β-lactam antibiotic. In the present invention it has been discovered that the efficacy of the lactivin compounds of formula (I) of the present invention against gram-negative bacteria can be enhanced by the combined use of a β-lactamase inhibitor selected from any of the formulas (1a) to (1z') mentioned above, but it should not be interpreted that the invention is limited to the use only of the β-lactamase inhibitors mentioned above. The compounds and compositions of the invention can act systemically and / or locally. For this purpose, they can be administered in a suitable manner, such as, for example, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically, or as an implant or endoprosthesis. For these routes of administration, the pharmaceutical compositions comprising the compounds of the present invention can be administered in suitable delivery forms. Parenteral administration can be performed either by bypassing an absorption step (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or by including an absorption step (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal). Suitable dosage forms for parenteral administration include, but are not limited to, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized products, or sterile powders. Suitable for other routes of administration include, for example, pharmaceutical forms for inhalation (including powder inhalers, nebulizers), nasal drops, solutions, sprays, tablets, films / wafers or capsules, for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), pastes, foams, fine powders, implants or endoprostheses. The compounds of the invention can be converted into the indicated forms of administration, i.e., the pharmaceutical compositions of the invention. This can be accomplished in a known manner per se by mixing with inert, non-toxic, pharmaceutically acceptable carriers or diluents, such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, water for injection, saline solution, buffered saline solution, dextrose, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80™), poly(ethylene) glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g., Cremophor EL), poloxamer 407 and 188, hydrophilic and hydrophobic carriers, and combinations thereof. of the same.Hydrophobic carriers include, for example, fat emulsions, lipids, pegylated phospholipids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes. The terms specifically exclude cell culture medium. The pharmaceutical compositions of the present invention may, if desired, also contain minor amounts of wetting agents (e.g., sodium dodecyl sulfate, polyoxyethylsorbitan oleate), dispersing or emulsifying agents, or pH buffering agents, and preservatives. Additionally, excipients, stabilizers, thickeners, lubricants, and colorants may be included. The pharmaceutical compositions may be formulated conventionally. The appropriate formulation depends on the chosen route of administration. In pharmaceutical compositions comprising compounds of formula (I), the weight ratio between the active ingredient and the carrier will normally be in the range of 1:20 to 20:1. When co-administered with a β-lactamase inhibitor, the present compounds and the β-lactamase inhibitor may, in combination, provide a synergistic effect. The term "synergistic effect" refers to the effect produced when two or more agents are co-administered that is greater than the additive effect produced when the agents are administered individually. Alternatively, the compound of formula (I) or a salt thereof may be administered as a separate agent during a course of treatment with the β-lactamase inhibitor. "Therapeutically effective amount" refers to the amount of a compound that, when administered to a subject to treat a disease or condition, is sufficient to affect the treatment of that disease or condition, or to improve a symptom of the disease or condition. The therapeutically effective amount may vary depending on, for example, the compound, the disease, condition and / or symptoms of the disease, the severity of the disease or condition, and the age, weight, and / or health of the patient being treated. Typically, the therapeutically effective amount of a compound of the invention for adult humans is approximately 50 mg to approximately 3000 mg of a compound of formula (I). In another embodiment, the therapeutically effective amount is approximately 100 mg to approximately 2000 mg. In yet another embodiment, the therapeutically effective amount is approximately 500 mg to approximately 1200 mg. Typically, the doses (noted amounts) are administered 1 to 4 times daily. In one embodiment, the doses are administered 3 times daily. In some cases, it may be necessary to use doses outside these limits. The terms "dose", "unit dose", "unit pharmaceutical form" or "effective dose" refer to physically discrete units that contain a predetermined amount of active ingredient calculated to produce a desired therapeutic effect. The present invention further relates to medicaments comprising at least one compound of the invention, generally together with one or more inert, non-toxic, pharmaceutically acceptable carriers or diluents, and to their use for the aforementioned purposes. The compositions may take the form of injectable preparations, suspensions, emulsions, coated tablets, granules, gelatin capsules, liquid-containing capsules, powders, sustained-release formulations, suppositories, aerosols, sprays, ointments, creams, or any other suitable dosage form. Treatment methods The present invention also relates to the compounds of the invention for use in the treatment, prevention and / or prophylaxis of diseases caused by bacteria, especially gram-negative bacteria. The present invention also relates to the compounds of the invention for the treatment, prevention and / or prophylaxis of diseases, especially bacterial infections. Accordingly, the present invention relates to a pharmaceutical composition for use in the treatment or prevention of bacterial infections in a subject, wherein said subject has a bacterial infection or is at risk of developing a bacterial infection and wherein said use comprises administering a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I), as defined herein, and a pharmaceutically acceptable carrier or diluent to the subject. In another further embodiment, the invention relates to a pharmaceutical composition for use in the treatment or prevention of bacterial infections in a subject, wherein such use comprises administering a therapeutically effective amount of a pharmaceutical composition comprising (i) one or more compounds of formula (I), as defined herein, (ii) a pharmaceutically acceptable carrier or diluent, and (iii) one or more β-lactamase inhibitors, to a subject having a bacterial infection, or a subject at risk of developing a bacterial infection. In this latter embodiment, the β-lactamase inhibitors may, for example, be selected from formula (1a) to (1z'). The compounds of the invention exhibit an excellent antibacterial spectrum against Gram-negative bacteria. The compounds of the present invention are particularly useful in the treatment of humans and in veterinary medicine for the prophylaxis, prevention, and / or treatment of local and systemic infections. Therefore, in each embodiment and aspect of the invention, the subject is a human being, a non-human primate, bird, horse, cow, goat, sheep, a companion animal such as a dog, cat, rodent, or other mammal. Examples of bacteria against which the compounds of the invention will have antibacterial activity include, but are not limited to, Enterobacterales, Escherichia coli, Enterobacter spp., Klebsiella spp., Serratia spp., Pseudomonas spp., Stenotrophomonas spp., Citrobacter spp., Acinetobacter spp., Campylobacter spp., Helicobacter spp., Vibrio spp., Bordetella spp., Salmonella spp., Shigella spp., Francisella spp., Burkholderia spp., Clostridia spp., Alcaligenes spp., Moraxella spp., Proteus spp., Neisseria spp., Haemophilus spp., Achromobacter spp., and Erwinia spp. Methods of Preparation The present invention also relates to methods for the preparation of compounds of formula (I). Scheme 1 below illustrates the general method of preparation and is not intended to be limited to any specific compound described herein. Pg' and Pg" in formula (II), (III) and (IV) represent carboxyl protecting groups frequently used in β-lactam chemistry to protect carboxyl groups. The carboxyl protecting groups Pg' and Pg" can be the residue of an ester-forming aliphatic or araliphatic alcohol. Examples of carboxyl protecting groups include isopropyl, tert-butyl, methoxymethyl, ethoxymethyl, isobutoxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, p-methoxybenzyl, benzyl, o-nitrobenzyl, p-nitrobenzyl, 2,4-dinitrobenzyl, benzhydryl, phthalidyl, and allyl. In any of the intermediate products for preparing formula (I), when an amino group is present in the molecule, it should be understood that it must be protected with a suitable amino protecting group commonly used in β-lactam chemistry. Examples of amino protecting groups include trityl, p-nitrobenzyloxycarbonyl (PNZ), and tert-butoxycarbonyl (Boc) and the like. Similarly, it should be understood that the hydroxy groups of the catechol or hydroxypyridone fraction present in formulas (III) and (IV) have to be protected with suitable hydroxy protecting groups. Examples of suitable hydroxy protecting groups include, but are not limited to, benzyl ether, diphenylmethyl ether, and diphenylmethylene ketal. Protecting groups can be removed by any convenient method described in the literature or that the skilled chemist knows to be appropriate for the removal of the protecting group in question, such methods being chosen to effect the removal of the protecting group with the least disturbance of groups elsewhere in the molecule. The removal of carboxyl, amino, and hydroxyl protecting groups from the catechol or hydroxypyridone moiety of intermediate (IV) can be accomplished by a conventional procedure such as treatment with an acid or a reducing agent. Examples of acids include trifluoroacetic acid, formic acid, acetic acid, and hydrochloric acid. The Lewis acid to be used is illustrated by boron trifluoride etherate, zinc chloride, tin tetrachloride, aluminum chloride, titanium tetrachloride, or boron trichloride. When the removal is carried out by catalytic hydrogenolysis, any procedure using palladium or platinum catalysts may be adopted. The removal of carboxyl protecting groups, hydroxy protecting groups from the catechol and hydroxypyridone fraction, and amino protecting groups can preferably be performed simultaneously or by a stepwise approach. Also included in the present invention are methods for preparing specific fragments, such as compounds (IIIa') and (IIIa'') of formula (III) in Scheme 1, as described in Schemes 2 and 3 below, respectively, which illustrate only the general method of preparation and are not intended to be limiting to any specific compound described herein. The compounds of the present invention can be prepared by removing the protecting groups from the compounds of formula (IV) under acidic conditions and catalytic hydrogenolysis. Acidic conditions may involve treating compounds of formula (IV) with boron trichloride, formic acid, acetic acid, trifluoroacetic acid, or hydrochloric acid at temperatures ranging from -78 °C to 100 °C for a time ranging from 10 min to 16 hours. Boron trichloride is preferably used at temperatures ranging from -78 °C to -20 °C for 1–3 hours. Compounds of formula (II) can be synthesized according to the following bibliographic references, which have been incorporated in the present document by reference in their entirety: Chem. Pharm. Bull., 1990, Vol.38, No. 11, pp. 116-122; J. Chem. Soc., Chem. Commun., 1987, (2), pp. 62-63; J. Med. Chem., 2014, Vol. 57, pp. 3845-3855 or by adapting the referenced procedures in a manner known to a person skilled in the art. Substituted esters of 2-oxoglutaric acid of formula (III) can be synthesized according to the following bibliographic reference: J. Med. Chem., 2014, Vol. 57, pp. 3845–3855, or by adapting the referenced procedures in a manner known to a person skilled in the art. The preparation of specific fragments such as (IIIa') and (IIIa'') is shown according to Scheme 2 and Scheme 3, respectively. The coupling reaction of an intermediate of formula (II) with an intermediate of formula (III) generally takes place in inert solvents in the presence of a coupling reagent and, where applicable, with the addition of a base at a temperature ranging from -20 °C to 80 °C for 1–24 hours, preferably at a temperature of 20–30 °C overnight. Inert solvents include, for example, dichloromethane (DCM), toluene, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolididin-2-one (NMP), and acetonitrile, as well as mixtures of the aforementioned solvents. A preferred solvent is tetrahydrofuran. Suitable coupling reagents include, for example, carbodiimides such as N,N'-diethyl-, N,N-dipropyl-, N,N-diisopropyl-, N,N-dicyclohexylcarbodiimide, N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 1-hydroxybenzotriazole (HOBt) or (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or N-hydroxysuccinimide, as well as mixtures of the coupling reagents mentioned above, with or without the addition of a base. Suitable bases include, for example, carbonates and bicarbonates, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, or 4-dimethylaminopyridine. The reaction generally takes place in a single solvent or in solvent mixtures at a temperature ranging from 0 °C to 100 °C for 1–24 hours. Suitable protic solvents include, for example, methanol, ethanol, isopropanol, tert-butanol, and water. Suitable solvents for forming mixtures include, for example, dichloromethane, trichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, and N,N-dimethylformamide. Examples As previously stated, the present invention also includes methods for the preparation of compounds of formula (I). The following examples and comparative examples, which are not within the scope of the claims, provide specific methodologies for the preparation of some of the specific compounds in Table 1. In the following description, the following symbols are used to represent particular meanings: Ac: acetyl a: broad (spectral) Boc: tert-butyloxycarbonyl Bn: benzyl d: doublet (spectral) DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DCC: N, N'-dicyclohexylcarbodiimide DI: deionized DIC: N,N-diisopropylcarbodiimide DIPEA: N, N-diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide h: hour or hours HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate m: multiplet (spectral) min: minute or minutes MW: microwave NHS: N-hydroxyuccinimide Ph: phenyl s: singlet (spectral) t: triplet (spectral) t-Bu: tert-butyl TBSCl: tert-butyldimethylsilyl chloride TEA: triethylamine THF: tetrahydrofuran TMEDA: tetramethylethylenediamine TMS: trimethylsilyl group TMSCN: trimethylsilyl cyanide Comparative Example 1 Acid (4S)-2-[ (4S)-4-{[ (2z)-2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (1-carboxycyclopropyl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid (Comparative Compound 1) Comparative Compound 1 Step 1: tert-butyl 1-(aminooxy)cyclopropane-1-carboxylate (2) A solution of 1-hydroxycyclopropane-1-tert-butyl carboxylate (4.86 g, 30.72 mmol) in anhydrous THF (120 mL) was cooled to 0–5 °C and O-diphenylphosphinylhydroxylamine (9.32 g, 39.97 mmol) was added, followed by sodium tert-butoxide (3.84 g, 39.96 mmol). The reaction mixture was stirred for 2 h at 0–10 °C, and then hexanes (30 mL) and brine (75 mL) were added. The resulting suspension was stirred at 15–25 °C for 30 min. The precipitated solids were removed by filtration and washed with 10% ethyl acetate in hexanes. The organic phase of the filtrate was separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated with hexanes and filtered.The filtrate was concentrated under reduced pressure to provide 2-(aminooxy)cyclopropane-1-carboxylate tert-butyl 1-(5.02 g, 94%) as a yellow oil. 1H NMR (400 MHz, CDCl3) 5.78 (sa, 2H), 1.49 (s, 9H), 1.34-1.28 (m, 2H), 1.22-1.16 (m, 2H). Step 2: (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetic acid (3) A solution of 2-(aminooxy)cyclopropane-1-tert-butyl 1-carboxylate (5.92 g, 34.18 mmol) in MeOH (100 mL) was mixed with {2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}(oxo)acetic acid (8.46 g, 31.07 mmol), and the resulting mixture was stirred for 4 h at room temperature. The reaction mixture was then concentrated to half volume and inactivated by the addition of water (100 mL) and 0.5 M HCl solution (100 mL). The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in EtOH (50 ml) and water was added slowly until no more precipitate formed.The resulting suspension was stirred at 0-10 °C for 15 min, the precipitated solid was collected by filtration and air dried to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetic acid 3 (12, 20 g, 92%) as a whitish solid. 1H NMR (400 MHz, DMSO-d6) 13.91 (sa, 1H) , 11.78 (s, 1H) , 7.42 (s, 1H) , 1.45 (s, 9H) , 1.41-1.31 (m, 11H) , 1.27-1.19 (m, 2H) . MS (ESI) m / z: [M+1]+ 428, 1 Step 3: tert-butyl 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethylidene)amino]oxy}cyclopropane-1-carboxylate (4) A mixture of (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-cyclopropyl]oxy}imino)acetic acid 3 (10.93 g, 25.57 mmol) and NHS (3.53 g, 30.67 mmol) in anhydrous DCM (120 mL) was slowly mixed with DIC (4.59 mL, 29.64 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then at room temperature for 3 h. The resulting suspension was filtered and the solids were washed with DCM. The filtrate was concentrated under reduced pressure and the residue was treated with a mixture of methanol (50 mL) and heptane (40 mL). The mixture was stirred at room temperature for 30 min, then at ~10 °C for an additional 30 mins and subsequently filtered to produce 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}cyclopropane-1-carboxylate 4 (13, 50 g, 100%) as a white solid. RMN de 1H (400 MHz, CDCl3) 8.36 (s, 1H) , 7.60 (s, 1H) , 2.99-2.83 (m, 4H) , 1.54 (s, 9H) , 1.51-1.45 (m, 4H) , 1.43 (s, 9H) . MS (ESI) m / z: [M+1]+ 525.0 Etapa 4: 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxi}ciclopropano-1-carboxilato de tert-butilo (5) To a solution of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}cyclopropane-1-carboxylate 4 (13.50 g, 25.57 mmol) and L-cycloserine (3.13 g, 30.66 mmol) in anhydrous DMF (140 ml) DIPEA (5.34 ml, 30.72 mmol) was added at room temperature. The reaction mixture was stirred at 45 °C for 18 h and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a methanol gradient from 0 to 2.5% in DCM, followed by grinding using DCM and hexanes to produce 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}cyclopropane-1-carboxylate 5 (5, 56 g, 43%) as a white solid. NMR of 1H (400 MHz, DMSO-d6) 11, 81 (s, 1H) , 11, 59 (s, 1H) , 9, 00 (d, J = 8, 0 Hz, 1H) , 7, 45 (s, 1H) 7 , 1, 4, 4, , 4, 58 (t, J = 8, 5 Hz, 1H) , 4, 08-3, 96 (m, 1H) , 1, 45 (s, 9H) , 1, 37 (s, 9H) , 1, 34-1, 18 (m ., 4H) MS (ESI) m / z: [M+Na]+ 534, 1 Stage 5: (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[1- (terc-butoxycarbonyl) cyclopropyl]oxythyl}amino-1-1-ace 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro- 2H, 6H-[1, 3]dioxolo[4, 5-F]isoindol-6-yl) -5-oxooxolane-2-carboxylate of terc- To a solution of tert-butyl acid 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}cyclopropane-1-carboxylate (1.04 g, 2.03 mmol) and (2S)-5-tert-butoxy-2-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-4,5-dioxopentanoic acid 6 (1.10 g, 2.02 mmol, prepared as described in J. Med. Chem., 2014, Vol. 57, pp. 3845–3855) in anhydrous THF (60 mL) was mixed with DMAP (50 mg, 0.41 mmol), followed by DCC (585 mg, 2.84 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was treated with 30% DCM in hexanes and the precipitated solids were removed by filtration.The filtrate was concentrated to vacuo and the residue was purified by silica gel column chromatography using a 10 to 35 % ethyl acetate gradient in hexanes to provide (4S) -2-[ (4S) -4-{[ (2z) -2-{2-amino toxic]-[terc 3-thiazol-4-yl}-2- ({[1- (tert-butoxicarbonyl) cyclopropyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5H[, 7-di 3]dioxolo[4, 5-f]isoindol-6-yl) -5-oxooxolane-2-tert-butyl carboxylate 7 (720 mg, 34 %) as a brown foam. NMR of 1H (400 MHz, CDCl3) 8, 68–8, 56 (s, 1H) , 8, 56–8, 26 (m, 1H) , 7, 58–7, 49 (m, 4H) , 7, 46–7, 7,J35) (m 1 Hz, 2H) , 5, 38 (m, 1H) , 5, 21-4, 81 (m, 2H) , 4, 40-4, 19 (m, 1H) , 3, 70-3, 28 (m, 1H) , , 2, 1, 70-2) ( 66-1, 46 (m, 21H) , 1, 46-1, 30 (m, 10H) . MS (ESI) m / z: [M+Na]+ 1059, 4 Stage 6: (4S)-2-[ (4S)-4-{[ (2z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxycyclopropyl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H--isoindol-2-yl) -5-oxooxolano-2-carboxílico (Compare Table 1) To a solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) cyclopropyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, Tert-butyl 7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate 7 (562 mg, 0.54 mmol) in anhydrous DCM (20 mL) was added dropwise to BCl3 solution. (1.0M in DCM, 4.34ml, 4. 34 mmol) at -50 °C. The reaction mixture was stirred at a temperature between -50 °C and -35 °C for 2.5 h. Then, a mixture of NaHCO3 (873 mg) and Na2HPO4 (273.5 mg) dissolved in water (47 mL) at -50 °C was added to the reaction mixture. The cold bath was replaced with an ice-water bath, and the resulting heterogeneous mixture was stirred from 0 to 5 °C until the aqueous phase thawed (~40 min) and the phases were carefully separated.The aqueous layer was filtered using a 1.0 µm syringe filter and immediately subjected to C18 reversed-phase column chromatography using a Biotage system and a gradient of 0 to 30% formic acid in 0.1% acetonitrile and 0.1% formic acid in water. The fractions containing the product were combined and lyophilized to provide Comparative Compound 1 (182 mg, 51%) as a whitish solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 25 (s, 2H) , 7, 15-7, 10 (m, 1H) , 5, 45-5, 18 (m, 1H) , 5, 18-5, 02 (m, 1H) , 4, 77-4, 66 (m, 1H) , 4, 31-4, 19 (m, 1H) , 3, 60-3, 24 (m, 1H) , 2, 92-2, 65 (m, 1H) , 1, 55-1, 45 (m, 2H) , 1, 45-1, 33 (m, 2H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 661, 1 Comparative Example 2 Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxycyclobutyl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolano-2-carboxílico (Compuesto Comparativo 4) Comparative Compuesto 4 Step 1: 1-{[ (Z) - (1-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxi}cyclobutane-1-carboxylate de terc-butyl (9) To a stirred solution of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}cyclobutane-1-carboxylate 8 (11.0 g, 20.42 mmol) prepared as described in WO 2012 / 073138) and L-cycloserine (2.5 g, 24.51 mmol) in anhydrous DMF (110 ml) DIPEA (4.23 ml, 24.51 mmol) was added at room temperature. The reaction mixture was heated to 45 °C overnight and then concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography using a 0-3% MeOH gradient in DCM and yielded 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}cyclobutane-1-carboxylate 9 (4.5 g, 42%) as a whitish solid. RMN de 1H (400 MHz, DMSO-d6) 11, 83 (s, 1H) , 11, 59 (s, 1H) , 9, 10 (d, J = 7, 9 Hz, 1H) , 7, 43 (s, 1H) , 4, 92 (sa, 1H) , 4, 60 (t, J = 8. 4 Hz, 1H) 40 (s, 9H) . Etapa 2: (4S)-2-[ (4S)-4-{[ (2Z) -2-{2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il}-2- ({[1- (terc-butoxicarbonil) ciclobutil]oxy}imino) acetil]amino}-3-oxo-1, 2-oxazolidin-2-il]-4- (10) To a stirred solution of tert-butyl 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}cyclopropane-1-carboxylate 9 (1.0 g, 1.84 mmol) and (2S)-5-tert-butoxy-2-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-4,5-dioxopentanoic acid 6 (1.06 g, 2.02 mmol, prepared as described in J. Med. Chem., 2014, Vol. 57, pp. 3845–3855) in anhydrous DCM (30 mL) DCC (0.53 g, 2.58 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight and then filtered to remove the precipitated solids.The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography using a 0 to 35% ethyl acetate gradient in hexanes to provide (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[1-(tert-butoxycarbonyl)cyclobutyl]oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate 10(1, 0 g, 57%) as a grey solid. 1H NMR (400 MHz, CDCl3) 8, 33-8, 25 (s, 1H) , 7, 57-7, 49 (m, 4H) , 7, 45-7, 36 (m, 6H) , 7, 30 (s, 1H) , 7, 26 (s, 2H) , 5, 44-5, 31 (m, 1H), 5, 19-4, 95 (m, 1H), 4, 94-4, 81 (m, 1H), 4, 23 (m, 1H), 3, 49-3, 24 (m, 1H), 2, 94-2, 74 (m, 1H), 2, 65-2, 43 (m, 4H), 2, 14-1, 90 (m, 2H), 1, 58-1, 50 (m, 18H), 1, 48 (s, 9H). MS (ESI) m / z: [M+1]+ 1073, 4 Stage 3: (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxycyclobutyl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolano-2-carboxílico (Compare Table 4) A stirred solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) cyclobutyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, Tert-butyl 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate 10 (300 mg, 0.28 mmol) in anhydrous DCM (10 mL) was cooled to -50 °C in an atmosphere of nitrogen. After 10 minutes, a solution of BCl3 in DCM (1.0 M, 2.28 mL, 2.28 mmol) was added dropwise over 10 minutes while maintaining the external temperature at -50 °C. The reaction mixture was stirred from -50 °C to -40 °C for 2.5 minutes, and then 25.2 mL of a buffer solution (prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 mL of deionized water) was added at -50 °C.The cold bath was replaced with an ice-water bath, and the resulting heterogeneous mixture was stirred at 0–5 °C until the aqueous phase thawed (~30 min), at which point the phases were carefully separated. The aqueous layer was filtered using a 1.0 µm syringe filter and immediately subjected to C18 reversed-phase column chromatography using a Biotage system and a gradient of 0–30% formic acid in 0.1% acetonitrile and 0.1% formic acid in water. The fractions containing the product were combined and lyophilized to yield Comparative Compound 4 (105 mg, 55%) as a pale yellow solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 43 (s, 2H) , 7, 29 (s, 1H) , 5, 62-5, 52 (m, 1H) , 5, 33 (m, 1H) , 4, 92 (m, 1H) , 4, 53-4, 40 (m, 1H) , 3, 51 (m, 1H) , 2, 92 (m, 1H) , 2, 79-2, 63 (m, 2H) , 2, 58-2, 41 (m, 2H) , 2, 21-1, 96 (m, 2H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 675 Comparative Example 3 Acid (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (3-carboxyxetan-3-yl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-il) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 5) y ácido (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (2-carboxy-1-chloro-3-hydroxypropan-2-yl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 6) Compuesto Comparativo 5 Compuesto Comparativo 6 Etapa 1: 3-[(trimethylsilyl) oxi]oxethane-3-carbonitrilo (12) Oxetan-3-one 11 (8.10 mL, 138.18 mmol) was added to LiClO4 (14.70 g, 138.18 mmol), followed by TMSCN (22.0 mL, 175.85 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM and filtered. The filtrate was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude 3-[(trimethylsilyl)oxy]oxethane-3-carbonitrile 12 (22.05 g, 93%) was obtained as a brown oil and used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 4.95-4.84 (s, 2H), 4.78-4.64 (m, 2H), 0.43-0.20 (s, 9H). Step 2: 3-hydroxyoxethane-3-carbonitrile (13) A stirred solution of 3-[(trimethylsilyl)oxy]oxetano-3-carbonitrile (22.05 g, 128.74 mmol) in THF (130 mL) was slowly added to a 2 M HCl solution (130 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, then saturated with solid NaCl and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground using DCM and hexanes to yield 3-hydroxyoxetano-3-carbonitrile (11.12 g, 87%) as a whitish product. 1H NMR (400 MHz, DMSO-d6) 7.48 (s, 1H), 4.96-4.71 (m, 2H), 4.68-4.38 (m, 2H). Step 3: 3-(benzyloxy)oxetane-3-carbonitrile (14) A solution of 3-hydroxyoxethane-3-carbonitrile (6.69 g, 67.51 mmol) in THF (200 mL) was mixed with NaOH (powder, 8.10 g, 202.5 mmol). The resulting mixture was stirred at room temperature for 10 min, then cooled to 5–10 °C (cold water bath) and benzyl bromide (12.05 mL, 101.31 mmol) was added, followed by n-Bu4NI (2.50 g, 6.77 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for 19 h. The reaction was then quenched with water, and the mixture was extracted with diethyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0–8% ethyl acetate in hexanes. The resulting product was ground with hexanes to give pure 3-(benzyloxy)oxethane-3-carbonitrile (2.61 g, 20%) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) 7, 51-7, 32 (s, 5H), 4, 85 (d, J = 8, 1 Hz, 2H), 4, 74-4, 61 (m, 4H). Step 4: 3-(benzyloxy)oxethane-3-carboxylic acid (15) A solution of 3-(benzyloxy)oxethane-3-carbonitrile (5.51 g, 29.12 mmol) in MeOH (60 mL) was reacted with an aqueous solution of NaOH (2 M, 29.2 mL). The reaction mixture was heated at reflux temperature for 6 h, then cooled to room temperature and concentrated under reduced pressure to remove the MeOH. The aqueous solution was cooled to 0 °C and acidified to pH ~2 using 1 M aqueous HCl. The precipitated white solid was collected by filtration and then dissolved with 10% MeOH in DCM. The resulting solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 3-(benzyloxy)oxethane-3-carboxylic acid (5.30 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 13.42 (sa, 1H), 7.46-7.19 (m, 5H), 4.76 (d, J = 7.2 Hz, 2H), 4.59 (d, J = 7.1 Hz, 2H), 4.47 (s, 2H) . MS (ESI) m / z: [M-1]- 207, 0 Step 5: 3-(benzyloxy)oxethane-3-carboxylate tert-butyl (16) To a stirred solution of 3-(benzyloxy)oxethane-3-carboxylic acid (5.30 g, 25.46 mmol) in anhydrous THF (80 mL) tert-butyl N,N'-diisopropylcarbamimidate (15 mL, 57.6 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was treated with 25% DCM in hexanes and filtered. The filtrate was concentrated under vacuum and the crude mixture was purified by silica gel column chromatography using a 0 to 8% gradient of ethyl acetate in hexanes to provide tert-butyl 3-(benzyloxy)oxethane-3-carboxylate 16 (5, 65 g, 84%) as a white solid. 1H NMR (500 MHz, CDCl3) 7.45-7.30 (s, 5H), 4.92-4.87 (m, 2H), 4.76-4.71 (m, 2H), 4.51 (s, 2H), 1.58 (s, 9H). Step 6: tert-butyl 3-hydroxyoxethane-3-carboxylate (17) To a solution of tert-butyl 3-(benzyloxy)oxetano-3-carboxylate 16 (5.65 g, 21.38 mmol) in a mixture of ethyl acetate and MeOH (1:1, 120 mL) Pd(OH)2 (20 wt.%, 1.30 g) was added. The reaction mixture was purged with hydrogen three times, then stirred at room temperature under hydrogen pressure (50 psi) for 5 h and filtered through a Celite layer. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 10–30% ethyl acetate in hexanes to give tert-butyl 3-hydroxyoxetano-3-carboxylate 17 (3.31 g, 89%) as a white solid. RMN-1H (500 MHz, CDCl3) 4, 88 (d, J = 6, 9 Hz, 2H), 4, 75 (d, J = 7, 3 Hz, 2H), 3, 75 (s, 1H), 1, 60 (s, 9H). Etapa 7:3-(aminooxy)oxetano-3-carboxilato de terc-butilo (18) Sodium tert-butoxide (2.19 g, 22.79 mmol) was added to a solution of 3-hydroxyoxethane-3-carboxylate (3.31 g, 19.0 mmol) and O-diphenylphosphinylhydroxylamine (5.32 g, 22.81 mmol) in anhydrous THF (90 mL) at 0–5 °C. The reaction mixture was stirred at 0–5 °C for 2 h, then brine (50 mL) and hexanes (30 mL) were added, and the resulting mixture was stirred at 15–25 °C for 30 min. The precipitated solids were removed by filtration and washed with 30% ethyl acetate in hexanes. The two layers of the biphasic filtrate were separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated with hexanes, the resulting mixture was filtered, and the filtrate was concentrated under vacuum to provide tert-butyl 3-(aminooxy)oxethane-3-carboxylate (3.41 g, 95%) as a yellow solid. RMN de 1H (500 MHz, CDCl3) 4, 88 (dd, J = 7, 2, 0, 8 Hz, 2H), 4, 76-4, 64 (m, 2H), 1, 62-1, 55 (m, 9H). Etapa 8: acido (2Z)-{2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il} ({[3- (terc-butoxicarbonil) oxetan-3-ill]oxy}imino) acético (19) A solution of tert-butyl 3-(aminooxy)oxetano-3-carboxylate (3.41 g, 18.02 mmol) in MeOH (50 mL) was mixed with {2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}(oxo)acetic acid (4.46 g, 16.38 mmol) and the reaction mixture was stirred at room temperature for 4 h. Water (100 mL) and an aqueous solution of HCl (0.1 M, 100 mL) were then added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was treated with 5% diethyl ether in hexanes and the resulting suspension was shaken for 1 h and then filtered to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[3-(tert-butoxycarbonyl)oxetan-3-yl]oxy}imino)acetic acid 19 (6, 96 g, 96%) as a white solid. 1, 41 (s, 9H). MS (ESI) m / z: [M+1]+ 443, 8 Etapa 9: 3-{[ (Z)-(1-{2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il}-2-[ (2, 5-dioxopyrrolidin-1-il) oxi]-2-oxoetiliden) amino]oxy}oxetan-3-carboxilato de terc-butilo (20) To a solution of (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[3-(tert-butoxycarbonyl)oxetan-3-yl]oxy}imino)acetic acid (6.96 g, 15.69 mmol) and NHS (2.17 g, 18.85 mmol) in anhydrous DCM (80 mL) DIC (2.82 mL, 18.21 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then at room temperature for 3 h. The resulting suspension was filtered and the solid was rinsed with DCM. The filtrate was concentrated under reduced pressure and the residue was treated with a mixture of methanol (20 mL) and n-heptane (20 mL). The resulting mixture was stirred at room temperature for 30 min, then at ~10 °C for 30 min and subsequently filtered to produce 3-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}oxetano-3-carboxylate tert-butyl 20 (7.69 g, 91%) as a white solid. RMN de 1H (400 MHz, CDCl3) 8, 51 (sa, 1H) , 7, 61 (s, 1H) , 5, 09-5, 03 (m, 2H) , 4, 94-4, 88 (m, 2H) , 3, 05-2, 77 (m, 4H) , 1, 65-1, 53 (m, 9H), 1, 53-1, 47 (m, 9H). MS (ESI) m / z: [M+1]+ 541, 1 Etapa 10: 3-{[ (Z)-(1-{2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il}-2-oxo-2-{[ (4S)-3-oxo-1, 2-oxazolidin-4-il]amino}etiliden) amino]oxy}oxetan-3-carboxilato de terc-butilo (21) To a mixture of 3-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidin-1-yl) oxy]-2-oxoethylidene) amino]oxy}oxetan-3-carboxylate tert-butyl 20 (7.69 g, 14.23 mmol) and L-cycloserine (1.74 g, 17.05 mmol) in anhydrous DMF (80 ml) DIPEA (2.97 ml, 17.05 mmol) was added at room temperature. The reaction mixture was stirred at 45 °C for 18 h, then cooled to room temperature and concentrated to dryness under reduced pressure. The crude mixture was subjected to purification by silica gel column chromatography using a methanol gradient of 0 to 2.5% in DCM.The fractions containing the product were combined, concentrated under vacuum, and the residue was further purified by trituration using diethyl ether and hexanes to provide 3-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}oxetan-3-carboxylate 21 (2, 37 g, 32%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 11.85 (s, 1H) , 11.63 (s, 1H) , 9.26 (d, J = 7.8 Hz, 1H) , 7.49 (s, 1H) , 4.95 (sa, 1H) , 4.81 (d, J = 7, 3 Hz, 2H), 4, 62 (dd, J = 12, 3, 7, 4 Hz, 3H), 4, 10 (t, J = 9, 1 Hz, 1H), 1, 45 (s, 9H), 1, 43 (s, 9H). MS (ESI) m / z: [M+1]+ 528, 0 Stage 11: (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[3- (terc-butoxycarbonyl) oxetan-3-oxo-yl amino-1,]acetyl]imino 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxol[4, 5-f]isoindole-6-yl) -5-oxooxolane-2-carboxylate ( 22-tert-) To a stirred mixture of tert-butyl 3-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}oexetan-3-carboxylate 21 (444 mg, 0.84 mmol) and (2S)-5-tert-butoxy-2-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-4,5-dioxopentanoic acid 6 (457 mg, 0.84 mmol, prepared as described in J. Med. Chem., 2014, Vol. 57, pp. 3845-3855) in anhydrous THF (17 ml) DMAP (21 mg, 0.17 mmol) was added, followed by DCC (243 mg, 1.18 mmol) at 0 °C. The reaction mixture was allowed to heat slowly to room temperature and was stirred for 18 h. Afterwards, the mixture was concentrated under reduced pressure and the residue was treated with 30% DCM in hexanes.The solids were removed by filtration, the filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography using a 10–40% ethyl acetate gradient in hexanes to provide tert-butyl (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[3-(tert-butoxycarbonyl)oxetan-3-yl]oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate 22 (550 mg, 62%) as a brown foam. 1H NMR (400 MHz, CDCl3) 8.46 (sa, 1H), 8.13-7.91 (m, 1H), 7.63-7.52 (m, 4H), 7.47-7.38 (m, 7H), 7.33 (d, J = 1.6 Hz, 2H) , 5, 38 (m, 1H) , 5, 25-4, 86 (m, 6H) , 4, 39-4, 20 (m, 1H) , 3, 75-3, 24 (m, 1H) , 2, 93-2, 72 (m, 1H) , 1, 62-1, 49 (m, 27H). MS (ESI) m / z: [M+Na]+ 1075, 4 Step 12: Acid (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (3-carboxyxetan-3-yl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-il) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 5) y ácido (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-il) -2-{[ (2-carboxy-1-chloro-3-hydroxypropan-2-yl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 6) Comparative Compound 5 Comparative Compound 6 To a solution of (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[3- (tert-butoxycarbonyl) oxetan-3-yl]oxy}imino) acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate 22 (150 mg, 0.14 mmol) in anhydrous DCM (7 ml) a solution of BCl3 was added drop by drop (1.0 M in DCM, 1.14 mL, 1.14 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 2.5 h, then a solution of NaHCO3 (233 mg) and Na2HPO4 (73 mg) dissolved in water (12.6 mL) at -78 °C was added. The cold bath was replaced with an ice-water bath, and the resulting heterogeneous mixture was stirred from 0 to 5 °C until the aqueous phase thawed (~30 min) and the phases were carefully separated.The aqueous layer was filtered using a 1.0 µm syringe filter and immediately subjected to C18 reversed-phase column chromatography using a Biotage system and a gradient of 0 to 30% formic acid in 0.1% acetonitrile and 0.1% formic acid in water. The fractions containing pure products were lyophilized to give Comparative Compound 5 (8.5 mg, 9%) and Comparative Compound 6 (38 mg, 19%) as off-white solids. For Compound 5: 1H NMR (400 MHz, a mixture of D2O and CD3CN) 10, 05 (s, 2H) , 10, 01-9, 95 (m, 1H) , 8, 23-8, 05 (m, 1H) , 8, 02-7, 88 (m, 1H) , 7, 80 (d, J = 7, 8 Hz, 2H) , 7, 65-7, 49 (m, 3H) , 7, 14-7, 05 (m, 1H) , 6, 38-6, 10 (m, 1H) , 5, 76-5, 52 (m, 1H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 677, 1 For Compound 6: 1H NMR (400 MHz, a mixture of D2O and CD3CN) 10, 05 (s, 2H) , 9, 98 (s, 1H) , 8, 28-8, 03 (m, 1H) , 8, 03-7, 83 (m, 1H) , 7, 60-7, 46 (m, 1H) , 7, 14-7, 07 (m, 1H) , 6, 89-6, 72 (m, 5H) , 6, 38-6, 07 (m, 1H) , 5, 75-5, 49 (m, 1H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 713, 0 Comparative Example 4 Acid 3- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)azetidine-3-carboxylic (Comparative Compound 7) Comparative Compound 7 Step 1: 3-hydroxyazetidine-1,3-tert-butyl dicarboxylate (24) To a solution of 1-(tert-butoxycarbonyl)-3-hydroxyazetidine-3-carboxylic acid 23 (4.33 g, 19.93 mmol, prepared as described in WO2013 / 96771 A1) in anhydrous THF (100 ml) N,N'-diisopropylcarbamimidate tert-butyl (7.4 ml, ~39.86 mmol) was added and the reaction mixture was stirred at room temperature for 14 h. The precipitated solids were removed by filtration and washed with THF. The filtrate was concentrated under reduced pressure and the residue was treated with a mixture of DCM and hexanes (1:1, 100 ml). The resulting mixture was stirred at ~5 °C for 10 minutes, the solid was separated by filtration and washed with a mixture of DCM and hexanes (1:1, 20 ml).The filtrate was collected, concentrated under vacuum, and the residue was purified by silica gel column chromatography using a 10 to 20% ethyl acetate gradient in hexanes to provide tert-butyl 3-hydroxyazetidine-1,3-dicarboxylate 24 as a whitish solid (4.35 g, 80% yield). 1H NMR (400 MHz, CDCl3): 4.21 (d, J = 13.7 Hz, 2H), 3.97 (d, J = 13.7 Hz, 2H), 1.53 (s, 9H), 1.44 (s, 9H). Step 2: 3-(aminooxy)azetidine-1,3-dicarboxylate di-tert-butyl (25) To a solution of 3-hydroxyazetidine-1,3-dicarboxylate di-tert-butyl 24 (4.33 g, 15.84 mmol) in anhydrous THF (100 mL) was added O-diphenylphosphinylhydroxylamine (4.43 g, 19.0 mmol). The resulting heterogeneous mixture was cooled to 0 °C and sodium tert-butoxide (1.83 g, 19.0 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h, then a 5% aqueous NaCl solution (200 mL) was added and the mixture was stirred at 10–15 °C for 30 min. Ethyl acetate (200 mL) was then added and the mixture was stirred for 15 min. The organic phase was separated and the aqueous layer was further extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide di-tert-butyl 3-(aminooxy)azetidine-1,3-dicarboxylate 25 as a thick yellow oil (4.08 g, 89% yield). RMN 1H (400 MHz, CDCl3): 4, 15 (d, J = 9, 5 Hz, 2H), 3, 94 (d, J = 9, 54 Hz, 2H), 1, 52 (s, 9H), 1, 45 (s, 9H). Etapa 3: Acido (2Z) - ({[1, 3-bis (terc-butoxicarbonil) azetidin-3-il]oxy}imino) {2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il}acético (26) A solution of 3-(aminooxy)azetidine-1,3-dicarboxylate di-tert-butyl 25 (3.97 g, 13.77 mmol) in anhydrous MeOH (40 ml) was mixed with 2-(2-(tert-butoxycarbonylamino)thiazol-4-yl)-2-oxoacetic acid (3.41 g, 12.51 mmol) and the reaction mixture was stirred at room temperature for 3 h. Most of the methanol was removed under reduced pressure and the residue was dissolved in 200 ml of ethyl acetate. The organic phase was washed with a dilute solution of HCl (100 ml of water and 13 ml of 1 M HCl), then brine (100 ml), dried over sodium sulfate, filtered and concentrated under vacuum to give (2Z) - ({[1, 3-bis (tert-butoxycarbonyl) azetidin-3-yl]oxy}imino) {2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}acetic acid 26 as a whitish foamy solid (7.19 g, crude). 1H NMR (400 MHz, DMSO-d6): 7.45 (s, 1H), 4.21 (d, J = 9.6 Hz, 2H), 3.90 (d, J = 9.6 Hz, 2H), 1.45 (s, 9H), 1.41 (s, 9H), 1. 38 (s, 9H) . Stage 4: 3-{[ (Z) - (1-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidin-1-yl) oxi]-2-oxoethylidene) amino]oxi}azetidin-1, 3-di-terc-butyl dicarboxylate (27) A solution of (2Z)-({[1,3-bis(tert-butoxycarbonyl)azetidin-3-yl]oxy}imino){2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}acetic acid (7.19 g crude, ~13.25 mmol) and NHS (1.83 g, 15.90 mmol) in anhydrous DCM (140 mL) was cooled to 0 °C. N,N'-Diisopropylcarbodiimide (2.00 g, 15.90 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 15 minutes and then at room temperature for 3 h. The precipitated solids were separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 ml of methanol, the mixture was concentrated to a volume of ~5 ml, and n-heptane (20 ml) was added. The mixture was stirred for 30 minutes at room temperature, then cooled to ~10 °C and stirred for a further 15 minutes.The precipitate was collected by filtration, washed with heptane and vacuum dried to provide 3-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidin-1-yl) oxy]-2-oxoethylidene) amino]oxy}azetidine-1, 3-dicarboxylate di-tert-butyl 27 as a whitish solid (8.41 g, 99% yield). 1H NMR (400 MHz, CDCl3) : 8.24 (sa, 1H), 7.57 (s, 1H), 4.36 (d, J = 9.8 Hz, 2H), 4.20 (d, J = 9.8 Hz, 2H), 2.91 (s, 4H), 1.53 (s, 9H) , 1, 45 (s, 9H) , 1, 44 (s, 9H) . Step 5: Di-tert-butyl 3-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}azetidine-1,3-dicarboxylate (28) A mixture of 3-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-[(2,5-dioxopyrrolidine-1-yl)oxy]-2-oxoethylidene)amino]oxy}azetidine-1,3-di-tert-butyl dicarboxylate 27 (8.4 g, 13.1 mmol) and L-cycloserine (1.60 g, 15.7 mmol) in anhydrous DMF (100 mL) was mixed with DIPEA (2.7 mL, 15.7 mmol) at room temperature. The heterogeneous reaction mixture was stirred at 45 °C in a nitrogen atmosphere for 18 h, then cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using 30% acetonitrile in DCM and then 2% MeOH in a 30% acetonitrile-DCM mixture as eluent to provide 3-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}azetidine-1,3-dicarboxylate di-tert-butyl 28 as a white solid (3.1 g, 37% yield). RMN 1H (400 MHz, DMSO-d6): 9, 23 (d, J = 8, 0 Hz, 1H) , 7, 46 (s, 1H) , 5, 45 (d, J = 7, 4 Hz, 1H) , 4, 92 (sa, 1H) , 4, 63-4, 60 (m, 1H), 4, 21-4, 17 (m, 2H), 4, 01-3, 85 (m, 2H), 1, 45 (s, 9H), 1, 42 (s, 9H), 1, 38 (s, 9H). MS (ESI) m / z: [M+1]+ 627, 0 Etapa 6: 3- ({ (Z)-[1-{2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il}-2- ({ (4S) -2-[ (4S) -2- (terc-butoxicarbonil) -4- (5, 7-dioxo-2, 2-difenil-5, 7-dihidro-2H, (29) Use of acid (2S) -5-terc-butoxi-2- (5, 7-dioxo-2, 2-difenil-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-il) -4, 5-dioxopentanoico 6 (1, 09 g, 2, 0 mmol, Preparado se describe in J. Med., 2014, Vol. 57, pages. 3845-3855) and 3-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}azetidine-1, 3-dicarboxylate of di-tert-butyl 28 (1.25 g, 2.0 mmol) in anhydrous THF (30 ml) was cooled to 0 °C. DMAP (50 mg, 0.40 mmol) was added followed by DCC (0.58 g, 2.80 mmol), the reaction mixture was stirred at 5-10 °C for 1 h and then stirred at room temperature overnight. The mixture was concentrated under reduced pressure at 25 °C and the residue was collected in 40% DCM in hexanes (25 ml). The precipitated solids were separated by filtration, washed with 30% DCM in hexanes (25 ml) and then with hexanes.The filtrate was concentrated under vacuum and the crude product was purified by silica gel column chromatography using a 10–35% ethyl acetate gradient in hexanes to provide 3-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy) azetidine-1,3-dicarboxylate di-tert-butyl 29 as a whitish foamy solid (1.44 g, 62% yield). 1H NMR (400 MHz, CDCl3): 8.03 (d, J = 6.0 Hz, 1H), 7.58-7.53 (m, 4H), 7.47-7.40 (m, 6H), 7.35-7.31 (m, 2H), 5.42-5.34 (m, 1H) , 5, 05-4, 85 (m, 1H) , 4, 42-4, 19 (m, 5H) , 3, 55-3, 25 (m, 1H) , 2, 93-2, 81 (m, 1H) , 2, 00-1, 91 (m, 1H) , 1, 77-1, 68 (m, 1H), 1.59 (m, 9H), 1.56 (m, 9H), 1.53 (m, 9H), 1.48 (m, 9H). Stage 7: Ácido 3- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoetilidene]amino}oxi) azetidina-3-carboxílico (Compuesto Comparativo 7) To a solution of 3- ({ (Z) -[1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (tert-butoxycarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)azetidine-1,3-dicarboxylate di-tert-butyl 29 (240 mg, 0.21 mmol) in anhydrous DCM (15 ml) a solution of trichloride was added drop by drop. Boron (1.0 M solution in DCM, 1.7 mL, 1.7 mmol) was added to the reaction mixture at -50 °C. The reaction mixture was stirred from -50 to -35 °C for 2.5 h, then cooled to -50 °C and inactivated by the addition of 18.3 mL of a buffer solution (prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 mL of water). The cold bath was replaced with an ice-water bath, and the resulting heterogeneous mixture was stirred from 0 to 5 °C until the aqueous phase thawed (~30 min) and the phases were carefully separated.The aqueous layer was filtered using a 1.0 µm syringe filter and immediately subjected to C18 reversed-phase column chromatography using a Biotage system and a gradient of 0 to 30% formic acid in 0.1% acetonitrile and 0.1% formic acid in water. The fractions containing pure product were lyophilized to give Comparative Compound 7 (40.5 mg, 29%) as a pale yellow, foamy solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN): 7, 53 (s, 2H) , 7, 40 (s, 1H) , 5, 73-5, 58 (m, 1H) , 5, 51-5, 37 (m, 1H) , 5, 02 (m, 1H) , 4, 84-4, 73 (m, 3H) , 4, 55-4, 45 (m, 2H) , 3, 68-3, 53 (m, 1H) , 3, 07-2, 94 (m, 1H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 676, 1 Comparative Example 5 Ácido 4- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoetilidene]amino}oxi) oxano-4-carboxílico (Compuesto Comparativo 8) Comparative Compuesto 8 Etapa 1: 4-[(trimethylsilyl)oxi]oxane-4-carbonitrilo (31) Oxan-4-one 30 (10.0 mL, 108.29 mmol) was added to LiClO4 (11.57 g, 108.75 mmol), followed by TMSCN (17.20 mL, 137.48 mmol), and the resulting mixture was stirred at room temperature for 3.5 h. The reaction mixture was then diluted with DCM and filtered. The filtrate was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude 4-[(trimethylsilyl)oxy]oxane-4-carbonitrile 31 (20.69 g, 96%) was obtained as a colorless oil and used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 3.95-3.85 (s, 2H) , 3.66-3.61 (m, 2H) , 2.13-2.02 (m, 2H) , 1.90-1.81 (m, 2H) , 0.48-0.08 (m, 9H). MS (ESI) m / z: [M+1]+ 200, 1 Stage 2: 4-hydroxyoxane-4-carboxylic acid (32) A stirred mixture of 4-[(trimethylsilyl)oxy]oxane-4-carbonitrile 31 (20.69 g, 103.80 mmol) and glacial AcOH (45 mL) was cooled to 0 °C. Concentrated HCl (37%, 45 mL) was added dropwise at 0 °C, the cooling bath was removed, and the resulting mixture was heated to 90 °C for 4 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (80 mL), and the aqueous phase was extracted with ethyl acetate (4 x 120 mL). The aqueous layer was then saturated with solid NaCl and further extracted with ethyl acetate (4 x 120 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under vacuum. Traces of solvents were removed by co-evaporation with toluene to provide 4-hydroxyoxane-4-carboxylic acid 32 (15.05 g, 99%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) 5.26 (sa, 1H), 3.68-3.56 (m, 4H), 1.96-1.79 (m, 2H), 1.55-1.42 (m, 2H). MS (ESI) m / z: [M-1]- 145, 0 Step 3: tert-butyl 4-hydroxyoxane-4-carboxylate (33) To a solution of 4-hydroxyoxane-4-carboxylic acid (8.08 g, 55.29 mmol) in anhydrous THF (150 mL) tert-butyl N,N'-diisopropylcarbamimidate (32 mL, 122.9 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, then the cooling bath was removed and stirring continued at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, the residue was treated with 30% DCM in hexanes, and the urea byproduct was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography using a 0 to 20% ethyl acetate gradient in hexanes to provide tert-butyl 4-hydroxyoxane-4-carboxylate 33 (9, 42 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) 3, 88-3, 74 (s, 4H), 3, 16 (s, 1H), 2, 16-2, 03 (m, 2H), 1, 53-1, 43 (m, 11H). MS (ESI) m / z: [M+Na]+ 225, 1 Step 4: tert-butyl 4-(aminooxy)oxane-4-carboxylate (34) A mixture of tert-butyl 4-hydroxyoxane-4-carboxylate (5.00 g, 24.72 mmol) and O-diphenylphosphinylhydroxylamine (8.65 g, 37.09 mmol) in anhydrous THF (120 mL) was reacted with sodium tert-butoxide (3.56 g, 37.08 mmol) at 0 °C. The reaction mixture was stirred at 0–10 °C for 6 h. Brine (65 mL) was then added, followed by hexanes (40 mL), and the resulting mixture was stirred at 15–25 °C for 30 min. The two layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0 to 40% ethyl acetate in hexanes to provide tert-butyl 4-(aminooxy)oxane-4-carboxylate 34 (4, 14 g, 77%) as an off-white solid. RMN de 1H (400 MHz, CDCl3) 5, 57 (sa, 2H), 3, 79-3, 62 (m, 4H), 2, 10-1, 97 (m, 2H), 1, 94-1, 83 (m, 2H), 1, 49 (s, 9H). Etapa 5: acido (2Z)-{2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il} ({[4- (terc-butoxicarbonil) oxan-4-il]oxy}imino) acético (35) A solution of tert-butyl 4-(aminooxy)oxane-4-carboxylate 34 (4.12 g, 18.96 mmol) in MeOH (50 mL) was reacted with 2-(2-(tert-butoxycarbonylamino)thiazol-4-yl)-2-oxoacetic acid (4.70 g, 17.26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h, then water (75 mL) and aqueous HCl solution (0.1 M, 80 mL) were added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground using 5% diethyl ether in hexanes to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[4-(tert-butoxycarbonyl)oxan-4-yl]oxy}imino)acetic acid 35 (7, 94 g, 98%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 11.76 (s, 1H) , 7.37 (s, 1H) , 3.69-3.48 (m, 4H) , 2.03-1.89 (m, 2H) , 1.83 (m, 2H) , 1.45 (s, 9H), 1, 39 (s, 9H). MS (ESI) m / z: [M+1]+ 472, 1 Stage 6: 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidin-1-yl) oxy]-2-oxoethylidene) amino]oxy-}buboxylate-4 tert-carbon To a mixture of (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[4-(tert-butoxycarbonyl)oxan-4-yl]oxy}imino)acetic acid 35 (7.94 g, 16.84 mmol) and NHS (2.33 g, 20.24 mmol) in anhydrous DCM (90 mL) DIC (3.03 mL, 19.57 mmol) was slowly added at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, the cooling bath was removed, and stirring was continued at room temperature for 3 h. The precipitated solids were removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure, and the residue was collected in a mixture of methanol (20 mL) and n-heptane (20 mL). The resulting suspension was shaken at room temperature for 30 min, then at ~10 °C for an additional 30 mins and filtered to produce 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}oxane-4-carboxylate tert-butyl 36 (8, 83 g, 92%) as a white solid. RMN de 1H (400 MHz, CDCl3) 8.07 (sa, 1H) , 7.50 (s, 1H) , 3.92-3.67 (m, 4H) , 3.06-2.77 (m, 4H) , 2.29-2.06 (m, 4H) , 1.53 (s, 9H) , 1.43 (s, 9H) . MS (ESI) m / z: [M+1]+ 569.0 Etapa 7: 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxi}oxano-4-carboxilato de tert-butilo (37) A mixture of 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}oxane-4-carboxylate tert-butyl 36 (8.83 g, 15.53 mmol) and L-cycloserine (1.91 g, 18.67 mmol) in anhydrous DMF (75 ml) was mixed with DIPEA (3.25 ml, 18.66 mmol) at room temperature. The reaction mixture was heated to 45 °C for 18 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0 to 30% acetonitrile gradient in DCM, followed by a 0 to 2% methanol gradient in a 30% acetonitrile mixture in DCM to produce tert-butyl 4-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}oxane-4-carboxylate 37 (3, 16 g, 37%) as a white foamy solid. NMR of 1H (400 MHz, DMSO-d6) 11, 69 (s, 1H) , 11, 48 (s, 1H) , 9, 05 (d, J = 7, 8 Hz, 1H) , 7, 29 (s, 1H, 8) ( 4, 4, J = 8, 4 Hz, 1H) , 3, 97 (t, J = 9, 0 Hz, 1H) , 3, 66-3, 38 (m, 4H) , 1, 91-1, 66 (m, 4H) , 1, 35 (s, 1,9H) 2 MS (ESI) m / z: [M+1]+ 556, 0 Stage 8: 4- ({ (Z) -[1-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (terc-butoxycarbonyl) -4- (H, 5, -7-hydro-dioxo-2 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -5-oxoxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxy) oxano-4-carboxylate (38) To a solution of 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}oxane-4-carboxylate of tert-butyl 37 (556 mg, 1.00 mmol) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) -4,5-dioxopentanoic acid 6 (571 mg, 1.05 mmol) in anhydrous THF (20 ml) DMAP (25 mg, 0.20 mmol), followed by DCC (289 mg, 1.40 mmol) at 0 °C. The reaction mixture was gradually heated to room temperature and stirred for 18 h. The mixture was then concentrated under reduced pressure, the residue was treated with 30% DCM in hexanes and filtered.The filtrate was concentrated in vacuo and the crude product was purified by silica gel column chromatography using a gradient of 10 to 40 % of ethyl acetate in hexanes to afford 4- ({ (Z) -[1-{2-2-[ (terc-butoxycarbonyl) amino (4-thyl}-1, -2-[ (4S) -2- (tert-butoxicarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -5-oxoyl-1,3-3-5 2-oxazolidin-4-yl}amino) -2-oxoethyliden]amino}oxy)oxane-4-tert-butyl carboxylate 38 (756 mg, 70 %) as a whitish foamy solid. NMR of 1H (400 MHz, CDCl3) 8, 23–7, 96 (s, 2H) , 7, 58–7, 49 (m, 4H) , 7, 45–7, 36 (m, 6H) , 7, 35–7, 7 ,31) (m , 5, 42-5, 31 (m, 1H) , 5, 22-4, 83 (m, 2H) , 4, 38-4, 16 (m, 1H) , 3, 92-3, 65 (m, 4H) , 3, 149 (1, 2, 2H) 69 (m, 1H) , 2, 31-2, 07 (m, 4H) , 1, 63-1, 48 (m, 18H) , 1, 48-1, 34 (m, 9H) . MS (ESI) m / z: [M+Na]+ 1103, 4 Stage 9: 4-({ (Z)-[1-(2-amino-1, 3-thiazol-4-yl)-2-({ (4S)-2-[ (4S)-2-carboxy-4-(5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) oxano-4-carboxílico (Compuesto Comparativo 8) To a solution of 4-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1, Tert-butyl 3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)oxane-4-carboxylate 38 (100 mg, 0.092 mmol) in anhydrous DCM (5 mL) was added. drop by drop a solution of boron trichloride (solution 1.0 M in DCM, 0.74 mL, 0.74 mmol) at -50 °C. The reaction mixture was stirred at -50 °C to -35 °C for 2.5 h, then cooled to -50 °C and a solution of NaHCO3 (152 mg) and Na2HPO4 (48 mg) in water (8.2 mL) at -50 °C was added. The cold bath was replaced with an ice-water bath, and the resulting heterogeneous mixture was stirred from 0 to 5 °C until the aqueous phase thawed (~20 min) and the phases were carefully separated.The aqueous layer was filtered using a 1.0 µm syringe filter and immediately subjected to C18 reversed-phase column chromatography using a Biotage system and a gradient of 0 to 30% formic acid in 0.1% acetonitrile and 0.1% formic acid in water. The fractions containing pure product were lyophilized to give Comparative Compound 8 (46 mg, 71%) as a whitish solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 25 (s, 2H) , 7, 20-7, 09 (m, 1H) , 5, 46-5, 24 (m, 1H) , 5, 21-5, 08 (m, 1H) , 4, 75 (m, 1H) , 4, 35-4, 26 (m, 1H) , 3, 83-3, 73 (m, 2H) , 3, 64-3, 26 (m, 3H) , 2, 88-2, 70 (m, 1H) , 2, 18-1, 99 (m, 4H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 705, 1 Comparative Example 6 Acid 4- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-1-methylpiperidine-4-carboxylic (Comparative Compound 9) Comparative Compound 9 Step 1: 1-methyl-4-[(trimethylsilyl)oxy]piperidine-4-carbonitrile (40) Trimethylsilyl cyanide (12.4 ml, 99.0 mmol) was added to a stirred solution of 1-methylpiperidin-4-one (39) (11.0 ml, 90.0 mmol) in anhydrous THF (60 ml) at room temperature. The reaction mixture was heated to 65 °C for 5 hours in a nitrogen atmosphere, then allowed to cool to room temperature and stirred overnight. Volatiles were removed under reduced pressure, and the residue was further dried under high vacuum to provide 1-methyl-4-((trimethylsilyl)oxy)piperidine-4-carbonitrile 40 as a brown oil (20.64 g, quantitative yield), which was used directly in the next step. 1H NMR (400 MHz; CDCl3): 2.76-2.54 (m, 2H), 2.41-2.28 (m, 2H), 2.31 (s, 3H), 2.10-1.99 (m, 2H), 1.93-1.79 (m, 2H), 0, 22 (s, 9H) . Step 2: 4-hydroxy-1-methylpiperidine-4-carboxylic acid hydrochloride (41) A mixture of 1-methyl-4-((trimethylsilyl)oxy)piperidine-4-carbonitrile 40 (20.64 g, ~90 mmol) and glacial acetic acid (50 mL) was cooled to 0 °C, and concentrated hydrochloric acid solution (50 mL) was added dropwise over a period of 15 minutes. The resulting reaction mixture was stirred at 0 °C for 15 minutes and then at room temperature for 15 minutes. Subsequently, the reaction mixture was heated and stirred at 110 °C for 4 h. The reaction mixture was allowed to cool to room temperature, the volatiles were removed under reduced pressure, and the residue was further dried under high vacuum. The crude product was crushed with ethyl acetate (3 x 75 ml), filtered and dried under high vacuum to provide 4-hydroxy-1-methylpiperidine-4-carboxylic acid hydrochloride (41) as a light brown solid (24, 1 g, crude) which was used in the next stage without further purification. 1H NMR (400 MHz; D2O): 3.39-3.36 (m, 2H), 3.21-3.14 (m, 2H), 2.79 (s, 3H), 2.22-2.14 (m, 2H), 1.97-1.85 (m, 2H). MS (ESI) m / z: [M+1]+ 160, 2 Step 3: tert-butyl 4-hydroxy-1-methylpiperidine-4-carboxylate (42) Triethylamine (12.5 mL, 90 mmol) was added to a stirred suspension of 4-hydroxy-1-methylpiperidine-4-carboxylic acid hydrochloride (12.01 g, crude) in anhydrous THF (200 mL). The resulting mixture was stirred at room temperature for 15 minutes, and then tert-butyl N,N'-diisopropylcarbamimidate (prepared as described in EP2471792A1, 27 mL, ~135 mmol) was added. The reaction mixture was stirred at room temperature for 14 h, an additional tert-butyl N,N'-diisopropylcarbamimidate (20 mL) was added, and stirring was continued for a further 24 h. The precipitated solid was removed by filtration, washed with THF, and the combined filtrates were concentrated under reduced pressure. The residue was collected in a mixture of DCM and hexanes (1:1, 200 ml) and the resulting suspension was cooled using an ice-water bath for 10 minutes. The solid was separated by filtration and washed with a mixture of DCM and hexanes (1:1, 50 ml).The filtrates were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a 0 to 6% methanol gradient in DCM followed by a 6% (7 N) methanolic ammonia solution in DCM as eluents to provide tert-butyl 4-hydroxy-1-methylpiperidine-4-carboxylate 42 (5.41 g, 56% yield) as a light brown solid. 1H NMR (400 MHz; CDCl3): 3.18-3.06 (m, 1H), 2.71-2.69 (m, 2H), 2.37-2.33 (m, 5H), 2.10 (td, J = 12.9.4.4 Hz, 2H), 1. 58 (dd, J = 13, 6, 2, 6 Hz, 2H), 1, 47 (s, 9H). MS (ESI) m / z: [M+1]+ 216, 2 Step 4: tert-butyl 4-(aminooxy)-1-methylpiperidine-4-carboxylate (43) To a solution of tert-butyl 4-hydroxy-1-methylpiperidine-4-carboxylate 42 (4.89 g, 22.7 mmol) in anhydrous THF (300 mL) sodium tert-butoxide (3.27 g, 34.0 mmol) was added, and the resulting mixture was stirred at room temperature until a clear solution was obtained. O-Diphenylphosphinylhydroxylamine (6.35 g, 27.2 mmol) was added, and the heterogeneous mixture was stirred at room temperature for 4 h. Additional portions of sodium tert-butoxide (1.63 g, 17.0 mmol) and O-diphenylphosphinylhydroxylamine (3.17 g, 13.6 mmol) were then added, and stirring at room temperature was continued overnight. The addition of sodium tert-butoxide (1.63 g, 17.0 mmol) and O-diphenylphosphinylhydroxylamine (3.17 g, 13.6 mmol) was repeated once more, and the mixture was stirred at room temperature for 14 h to complete the reaction. Most of the THF was removed under reduced pressure, and the residue was collected in a DCM (300 mL).A saturated aqueous solution of ammonium chloride (20 mL) was added, the organic phase was separated and concentrated under reduced pressure. The residue was passed through a silica gel layer and eluted with a 6% (7 N) methanolic ammonia solution in DCM to provide tert-butyl 4-(aminooxy)-1-methylpiperidine-4-carboxylate 43 (2.32 g, crude) as a brown liquid. 1H NMR (400 MHz; CDCl3): 5.28 (sa, 2H), 2.60-2.55 (m, 2H), 2.27 (s, 3H), 2.25-2.16 (m, 2H), 2.02-1.96 (m, 4H), 1.46 (s, 9H) . MS (ESI) m / z: [M+1]+ 231, 2 Step 5: (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl} ({[4-(tert-butoxycarbonyl)-1-methylpiperidin-4-yl]oxy}imino)acetic acid (44) A solution of tert-butyl 4-(aminooxy)-1-methylpiperidine-4-carboxylate (2.33 g, 10.14 mmol) in anhydrous MeOH (40 mL) was reacted with {2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}(oxo)acetic acid (1.38 g, 5.07 mmol) followed by glacial acetic acid (0.3 mL, 5.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The crude product was purified by C18 reversed-phase column chromatography using 0.1% formic acid in water and 0.1% formic acid acetonitrile as eluents. The fractions containing the product were combined and lyophilized to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[4-(tert-butoxycarbonyl)-1-methylpiperidin-4-yl]oxy}imino)acetic acid 44 (1.27 g, 52%) as a white solid. RMN de 1H (400 MHz; DMSO-d6): 11, 66 (s, 1H) , 7, 18 (s, 1H) , 3, 14-2, 91 (m, 2H) , 2, 67 (s, 3H) , 2, 13-1, 99 (m, 4H) , 1, 44 (s, 9H), 1, 41 (s, 9H). MS (ESI) m / z: [M+1]+ 485, 6 y [M-1]- 483, 4 Etapa 6: 4-{[ (Z)-(1-{2-[ (terc-butoxicarbonil) amino]-1, 3-tiazol-4-il}-2-oxo-2-{[ (4S)-3-oxo-1, 2-oxazolidin-4-il]amino}etiliden) amino]oxy}-1-metilpiperidina-4-carboxilato de terc-butilo (45) To a suspension of (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[4-(tert-butoxycarbonyl)-1-methylpiperidin-4-yl]oxy}imino)acetic acid 44 (0.73 g, 1.51 mmol) in anhydrous DMF (10 ml) N,N-diisopropylethylamine (0.39 ml, 2.26 mmol) was added and the resulting mixture was stirred at room temperature for 10 minutes. Then HATU (0.57 g, 1.51 mmol) was added and stirring was continued at room temperature for 14 h. Anhydrous DMF (15 mL) and N,N-diisopropylethylamine (1.05 mL, 6.02 mmol) were then added, and the mixture was stirred at room temperature for 10 minutes before the addition of L-cycloserine (0.23 g, 2.26 mmol). The reaction mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure. The crude mixture was purified by C18 reversed-phase column chromatography using 0.1% formic acid in water and 0.1% formic acid acetonitrile as eluents.The fractions containing the product were combined and lyophilized to provide 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}-1-methylpiperidine-4-carboxylate tert-butyl 45 (702 mg, 76%) as a white solid. 1H NMR (400 MHz; DMSO-d6): 11.77-11.66 (m, 2H), 9.28 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 4.97 (c, J = 8.5 Hz, 1H), 4.61 (t, J = 8.5 Hz, 1H), 4.08 (t, J = 9.0 Hz, 1H), 3.25-2.99 (m, 4H), 2.76 (s, 3H), 2.17-2.07 (m, 4H), 1.45 (s, 9H), 1.40 (s, 9H). MS (ESI) m / z: [M+1]+ 569, 2 Step 7: 4-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-1-methylpiperidine-4-carboxylate tert-butyl (46) To a stirred mixture of 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}-1-methylpiperidine-4-carboxylate tert-butyl 45 (455 mg, 0.80 mmol) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) -4,5-dioxopentanoic acid 6 (435 mg, 0.80 mmol) in anhydrous THF (20 ml) DMAP was added (50 mg, 0.40 mmol), followed by DCC (231 mg, 1.12 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and then at room temperature overnight. The mixture was concentrated under reduced pressure at 25 °C and the residue was dissolved in DCM (15 mL). Hexanes (15 mL) were then added, the precipitated solids were removed by filtration, and the mixture was sequentially washed with 50% DCM in hexanes (25 mL) and hexanes. The filtrates were combined and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography using a gradient of MeOH from 0 to 5 % in DCM as eluent to provide 4- ({ (Z)-[1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-4 (2-yl}-2) (tert-butoxicarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -5-oxoxolan-2-yl]-3-amino-oxo-yl} 2-oxodine-1, -2-oxoethylidene]amino}oxy) -1-methylpiperidine-4-tert-butyl carboxylate 46 (435 mg, 50 %) as a beige solid. NMR of 1H (400 MHz; CDCl3): 7, 53 (dd, J = 5, 5, 2, 7 Hz, 4H) , 7, 40 (t, J = 3, 1 Hz, 6H) , 7, 33-7, 29 (m, 5, 3, J = , 4, 0 Hz, 1H) , 5, 25-5, 03 (m, 1H) , 4, 86-4, 73 (m, 1H) , 4, 41-4, 24 (m, 1H) , 3, 32-3, 29 (m-2, 2,H) 8 , 2, 52-2, 42 (m, 4H) , 1, 54 (m, 18H) , 1, 44 (s, 9H) . Stage 8: 4-({ (Z)-[1-(2-amino-1, 3-thiazol-4-yl)-2-({ (4S)-2-[ (4S)-2-carboxy-4-(5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) -1-methylpiperidine-4-carboxylic acid (Compare Table 9) 46 Comparative Compound 9 To a solution of 4- ({ (Z) -[1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (tert-butoxycarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, tert-butyl 6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-1-methylpiperidine-4-carboxylate 46 (422 mg, 0.386 mmol) in Anhydrous DCM (15 ml) was added dropwise to a solution of boron trichloride (1.0 M solution in DCM, 3.1 mL, 3.09 mmol) at -50 °C. The reaction mixture was stirred from -45 to -35 °C for 3 h, then cooled to -50 °C and a buffer solution (34 mL, prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 mL of water) was added. The cold bath was replaced with an ice-water bath and the heterogeneous mixture was stirred until the aqueous phase thawed.The phases were carefully separated and the aqueous layer was immediately subjected to C18 reversed-phase chromatography using 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents to provide 4-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-1-methylpiperidine-4-carboxylic acid Compound 9 (32 mg, 12%) a pale yellow solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN): 7, 25 (s, 2H) , 6, 99 (s, 1H) , 5, 41 (t, J = 10, 0 Hz, 1H) , 5, 20-5, 08 (m, 1H) , 4, 74 (t, J = 8, 6 Hz, 1H) , 3, 49-3, 26 (m, 3H) , 3, 17-3, 01 (m, 2H) , 2, 85-2, 70 (m, 4H) , 2, 45-2, 27 (m, 2H) , 2, 27-2, 07 (m, 2H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 718, 1 Comparative Example 7 Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxy-4, 4-difluorociclohexyl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 10) , Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxy-4-chloro-4-fluorocyclohexil) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-il]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-il) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 11) y ácido (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-il) -2-{[ (1-carboxy-4, 4-diclorociclohexil) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-il]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolano-2-carboxylico (Compuesto Comparativo 12) Compuesto Comparativo 10 Compuesto Comparativo 11 Comparative Compound 12 Step 1.4, tert-butyl 4-difluoro-1-hydroxycyclohexane-1-carboxylate (48) A solution of 4,4-difluoro-1-hydroxycyclohexane-1-carboxylic acid (5.19 g, 28.8 mmol) in anhydrous THF (80 mL) was slowly mixed with tert-butyl N,N'-diisopropylcarbamimidate (23 mL, ~90 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 5 h before concentration under reduced pressure. The residue was treated with 30% DCM in hexanes, and the precipitated solid was removed by filtration. The filtrate was concentrated and the crude product was purified by silica gel column chromatography using a gradient of 0% to 8% ethyl acetate in hexanes to provide tert-butyl 4,4-difluoro-1-hydroxycyclohexane-1-carboxylate 48 (5.63 g, 83%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 3.13 (s, 1H), 2.24-1.97 (m, 6H), 1.75-1.67 (m, 2H), 1.49 (s, 9H). Step 2: tert-butyl 1-(aminooxy)-4,4-difluorocyclohexane-1-carboxylate (49) To a stirred mixture of 4,4-difluoro-1-hydroxycyclohexane-1-carboxylate tert-butyl 48 (3.03 g, 12.8 mmol) and O-diphenylphosphinylhydroxylamine (3.59 g, 15.4 mmol) in anhydrous THF (120 ml) sodium tert-butoxide (1.48 g, 15.4 mmol) was added at 0-5 °C. The reaction mixture was stirred at 0-10 °C for 1 h and then more O-diphenylphosphinylhydroxylamine (2.39 g, 10.3 mmol) was added followed by sodium tert-butoxide (990 mg, 10.3 mmol) at 0-10 °C. Stirring was continued at 0–10 °C for 1 h. Additional portions of O-diphenylphosphinylhydroxylamine (1.50 g, 6.43 mmol) and sodium tert-butoxide (620 mg, 6.45 mmol) were added at 0–10 °C, and the reaction mixture was stirred for 1 h. Brine (40 mL) and hexanes (30 mL) were then added, and the resulting mixture was stirred at 15–25 °C for 30 min. The two layers were separated, and the aqueous layer was extracted with ethyl acetate.The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0–15% gradient of ethyl acetate in hexanes to provide tert-butyl 1-(aminooxy)-4,4-difluorocyclohexane-1-carboxylate 49 (2.99 g, 93%) as a white solid. 1H NMR (400 MHz, CDCl3) 5.34 (s, 2H), 2.17-2.13 (m, 2H), 2.00-1.91 (m, 6H), 1.49 (s, 9H). Step 3: (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl} ({[1-(tert-butoxycarbonyl)-4,4-difluorocyclohexyl]oxy}imino)acetic acid (50) To a solution of tert-butyl 1-(aminooxy)-4,4-difluorocyclohexane-1-carboxylate (2.99 g, 11.9 mmol) in MeOH (32 mL) was added {2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}(oxo)acetic acid (2.95 g, 10.83 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h, then water (60 mL) and an aqueous solution of hydrochloric acid (0.5 M, 40 mL) were added. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground using 5% diethyl ether in hexanes to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-4,4-difluorocyclohexyl]oxy}imino)acetic acid 50 (5.37 g, 98%) as a white solid. NMR of 1H (400 MHz, DMSO-d6) 11, 77 (s, 1H) , 7, 40 (s, 1H) , 2, 19-2, 05 (m, 2H) , 1, 98-1, 87 (m, 6H, 5) , 1, s (s, 9H) . MS (ESI) m / z: [M+1]+ 506, 4 Stage 4: 1-{[ (Z) - (1-{2-[ (tert-butoxicarbonyl) amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidin-1-yl) oxy]-2-oxoethylidene) amino]oxylano debutyl phluoro}1 tercycloccarbox 4-yl (51) To a mixture of (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-4,4-difluorocyclohexyl]oxy}imino)acetic acid 50 (5.17 g, 10.23 mmol) and N-hydroxysuccinimidine (1.41 g, 12.25 mmol) in anhydrous DCM (60 mL) DIC (1.84 mL, 11.88 mmol) was slowly added at 0 °C. The reaction mixture was stirred for 15 min at 0 °C and then at room temperature for 3 hours. The precipitated solids were removed by filtration and rinsed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0 to 20% ethyl acetate in hexanes to provide 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}-4, 4-difluorocyclohexane-1-carboxylate tert-butyl 51 (5, 96 g, 97%) as a white foam.NMR of 1H (400 MHz, CDCl3) 8, 13 (s, 1H) , 7, 51 (s, 1H) , 2, 91 (s, 4H) , 2, 38-2, 36 (m, 2H) , 2, 17-5 (m, 1, 69) 9H) , 1, 42 (s, 9H) . MS (ESI) m / z: [M+1]+ 603, 4 Stage 5: 1-{[ (Z) - (1-{2-[ (tert-butoxicarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene-4,] amino 4-difluorocyclohexane-1-tert-butyl carboxylate (52) To a mixture of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-[ (2, 5-dioxopyrrolidine-1-yl) oxy]-2-oxoethylidene) amino]oxy}-4, tert-butyl 4-difluorocyclohexane-1-carboxylate 51 (5.96 g, 9.89 mmol) and L-cycloserine (1.21 g, 11.85 mmol) in anhydrous DMF (50 ml) DIPEA (2.07 ml, 11.88 mmol) was added at room temperature. The reaction mixture was heated to 45 °C for 18 h and then concentrated under reduced pressure. The residue was dissolved in a mixture of diethyl ether and ethyl acetate (6:4) and the organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated.The crude mixture was purified by silica gel column chromatography using a 0 to 30% acetonitrile gradient in DCM to provide 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy-4, 4-difluorocyclohexane-1-carboxylate tert-butyl 52 (1.87 g, 32%) as a white foam. 1H NMR (400 MHz, DMSO-d6) 11.79 (s, 1H), 11.59 (s, 1H), 9.20 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 4.96-4.88 (m, 1H), 4.58 (t, J = 8.4 Hz, 1H), 4.04 (t, J = 9.0 Hz, 1H), 2.16-1.82 (m, 8H), 1.45 (s, 9H), 1.38 (s, 9H). MS (ESI) m / z: [M+1]+ 590, 2 Step 6: (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[1-(tert-butoxycarbonyl)-4,4-difluorocyclohexyl]oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate of tert-butyl (53) A mixture of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy-4,4-difluorocyclohexane-1-carboxylate tert-butyl 52 (199 mg, 0.34 mmol) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) -4,5-dioxopentanoic acid 6 (188 mg, 0.35 mmol) in anhydrous THF (6 ml) was given DMAP (9 mg, 0.074 mmol) ), followed by DCC (98 mg, 0.47 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature and was stirred for 18 h. Afterwards, the mixture was concentrated under reduced pressure and the residue was collected in 25% DCM in hexanes.The insoluble matter was removed by filtration, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography using a 0–30% gradient of ethyl acetate in hexanes to provide (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[1-(tert-butoxycarbonyl)-4,4-difluorocyclohexyl]oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate tert-butyl (53 (215 mg, 57%) as a brown foam. RMN de 1H (400 MHz, CDCl3) 8, 15-8, 09 (s, 2H) , 7, 55-7, 51 (m, 4H) , 7, 42-7, 39 (m, 6H) , 7, 34 (d, J = 3, 8 Hz, 1H) , 7, 30 (d, J = 1, 2 Hz, 2H) , 5, 36 (td, J = 10, 1, 3, 0 Hz, 1H) , 5, 23-4, 87 (m, 2H) , 4, 37-4, 18 (m, 1H) , 3, 66-3, 26 (m, 1H) , 2, 88-2, 71 (m, 1H) , 2, 51-2, 31 (m, 2H) , 2, 18-1, 87 (m, 6H) , 1, 60-1, 58 (m, 9H) , 1, 51-1, 49 (m, 9H) , 1, 48-1, 41 (m, 9H) . Stage 7: (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxy-4, 4-difluorociclohexyl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico Acid (Compare Table 10) , (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxy-4-chloro-4-fluorocyclohexil) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-il]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-il) -5-oxooxolan-2-carboxílico (Compare Composition 11) and (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-il) -2-{[ (1-carboxy-4, 4-diclorociclohexil) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-il]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolano-2-carboxílico (Compuesto Comparativo 12) 53 Compuesto Comparativo 10 Compuesto Comparativo 11 Comparative Compound 12 To a solution of (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) -4, 4-difluorocyclohexyl]oxy}imino) acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate 53 (215 mg, 0.19 mmol) in anhydrous DCM (10 ml) a solution of boron trichloride (1 M in DCM (1.54 mL, 1.54 mmol) at -50 °C. The reaction mixture was stirred from -50 °C to -35 °C for 2.5 h and then inactivated by the addition of NaHCO3 (314 mg) and Na2HPO4 (98 mg) solution in H2O (17 mL) at -50 °C. The mixture was then stirred at 0–5 °C (ice-water bath) for 20 min and then at room temperature until the aqueous phase thawed. The resulting suspension was filtered through a 1.0 µm syringe filter and the phases carefully separated.The aqueous solution was immediately subjected to C-18 reversed-phase column chromatography using a Biotage system and 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents.The fractions containing pure products were collected and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-carboxy-4,4-difluorocyclohexyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid Comparative Compound 10 (32 mg, 22%) , (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[ Comparative Compound 11 (41 mg, 28%) and (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (1-carboxy-4, 4-dichlorocyclohexyl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolane-2-carboxylic Comparative Compound 12 (17 mg, 11%) as whitish solids. For Comparative Compound 10: 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 25 (s, 2H) , 7, 11-7, 08 (m, 1H) , 5, 45-5, 24 (m, 1H) , 5, 18-5, 09 (m, 1H) , 4, 76-4, 68 (m, 1H) , 4, 31-4, 24 (m, 1H) , 3, 58-3, 26 (m, 1H) , 2, 88-2, 70 (m, 1H) , 2, 29-1, 76 (m, 8H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 739, 1 For Comparative Compound 11: 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 25 (s, 2H) , 7, 12-7, 09 (m, 1H) , 5, 44-5, 24 (m, 1H) , 5, 18-5, 08 (m, 1H) , 4, 76-4, 68 (m, 1H) , 4, 30-4, 24 (m, 1H) , 3, 57-3, 27 (m, 1H) , 2, 88-2, 70 (m, 1H) , 2, 32-2, 05 (m, 8H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 755, 0 For Comparative Compound 12: 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 25 (s, 2H) , 7, 10-7, 08 (m, 1H) , 5, 45-5, 24 (m, 1H) , 5, 18-5, 08 (m, 1H) , 4, 76-4, 69 (m, 1H) , 4, 32-4, 24 (m, 1H) , 3, 59-3, 28 (m, 1H) , 2, 88-2, 70 (m, 1H) , 2, 46-2, 10 (m, 8H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 771, 0 Comparative Example 8 Acid 3- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4 S) -2-carboxy-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylic (Comparative Compound 13) Comparative Compound 13 Step 1: 3-[(trimethylsilyl)oxy]-8-oxabicyclo[3.2.1]octane-3-carbonitrile (55) Zinc iodide (174 mg, 0.55 mmol) was placed in a dry round-bottom flask and dried under high vacuum with gentle heating for 30 minutes. A solution of oxabicyclo[3.2.1]octan-3-one 54 (3.44 g, 27.25 mmol) was added to anhydrous DCM (60 mL), and the resulting mixture was cooled to 0 °C. Trimethylsilyl cyanide (4.09 mL, 32.7 mmol) was slowly added at 0 °C, and the reaction mixture was then allowed to warm to room temperature and stirred for 5 h. The mixture was concentrated under reduced pressure, and the residue was collected in 10% DCM in hexanes (75 mL). The solids were removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting brown oil was further dried under high vacuum to provide 3-((trimethylsilyl)oxy)-8-oxabicyclo[3.2.1]octane-3-carbonitrile.55 (6.41 g, quantitative yield). 1H NMR (400 MHz; CDCl3): 4.47-4.43 (m, 2H), 2.38 (d, J = 4.3 Hz, 1H), 2.34 (d, J = 4.3 Hz, 1H), 2.20 (s, 1H), 2.18 (s, 1H), 2, 05-2, 02 (m, 2H), 1, 94-1, 90 (m, 2H), 0, 29 (s, 9H). Step 2: 3-hydroxy-8-oxabicyclo[3.2.1]octane-3-carboxylic acid (56) A mixture of 3-((trimethylsilyl)oxy)-8-oxabicyclo[3.2.1]octane-3-carbonitrile 55 (6.4 g gross, ~27 mmol) and glacial acetic acid (30 mL) was cooled to 0 °C and concentrated hydrochloric acid solution (30 mL) was added dropwise over a period of 10 minutes. The reaction mixture was stirred at 0 °C for 15 minutes, then at room temperature for 15 minutes, and subsequently stirred and heated to 110 °C for 4 h. The reaction mixture was allowed to cool to room temperature, the volatiles were removed under reduced pressure, and the residue was further dried under high vacuum. The residue was dissolved in water (100 mL), and the aqueous phase was saturated using solid NaCl and extracted with ethyl acetate (2 x 150 mL). The extracts were combined and washed with water and brine, dried over sodium sulfate, filtered, vacuum concentrated and dried under high vacuum to produce 3-hydroxy-8ºxabicyclo[3.2.1]octane-3-carboxylic 56 (2.43 g, 52% yield) as a brown solid. 1H NMR (400 MHz; DMSO-d6): 12.50-12.34 (m, 1H), 4.29-4.25 (m, 2H), 2.18-2.13 (m, 2H), 2.07 (d, J = 4.3 Hz, 1H), 2.03 (d, J = 3.4 Hz, 1H), 1.72-1.66 (m, 2H), 1.58 (s, 1H), 1.54 (s, 1H). MS (ESI) m / z: [M-1]- 171, 0 Step 3: tert-butyl 3-hydroxy-8-oxabicyclo[3.2.1]octane-3-carboxylate (57) A solution of 3-hydroxy-8-oxabicyclo[3.2.1]octane-3-carboxylic acid (2.44 g, 14.18 mmol) in anhydrous THF (50 mL) was mixed with tert-butyl N,N'-diisopropylcarbamimidate (11.4 mL, 56.72 mmol, prepared as described in EP2471792A1), and the reaction mixture was stirred at room temperature for 16 h. The precipitated solids were removed by filtration and washed with THF. The filtrates were combined and concentrated under reduced pressure. The residue was ground using a mixture of DCM and hexanes (1:2, 90 mL) at 0–4 °C, the precipitate was separated by filtration, and washed with a mixture of DCM and hexanes (1:2, 50 mL). The filtrate was collected and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using a 10 to 40% ethyl acetate gradient in hexanes to give 3-hydroxy-8-oxabicyclo[3.2.1]tert-butyl 3-octanecarboxylate 57 (2.31 g, 71% yield) as a light yellow solid. 1H NMR (400 MHz; CDCl3) : 4.48-4.45 (m, 2H), 3.40 (s, 1H), 2.37 (d, J = 4.3 Hz, 1H), 2.35-2.33 (m, 3H), 1.96-1.90 (m, 2H), 1.59 (t, J = 1.1 Hz, 1H), 1.55 (t, J = 1.1 Hz, 1H), 1.49 (s, 9H). MS (ESI) m / z: [M-1]- 226, 8 Step 4: tert-butyl 3-(aminooxy)-8-oxabicyclo[3.2.1]octane-3-carboxylate (58) To a solution of tert-butyl 3-hydroxy-8-oxabicyclo[3.2.1]octane-3-carboxylate 57 (1.74 g, 7.62 mmol) in anhydrous THF (75 mL) sodium hydride (60% in mineral oil, 0.46 g, 11.43 mmol) was added in portions at 0 °C. The mixture was stirred for 15 min, then O-diphenylphosphinylhydroxylamine (2.67 g, 11.43 mmol) was added and stirring continued at 0 °C for 30 min. The reaction mixture was allowed to warm to room temperature and was stirred for 17 h. Next, additional sodium hydride (60% in mineral oil, 0.23 g, 5.72 mmol) and O-diphenylphosphinylhydroxylamine (1.33 g, 5.72 mmol) were added, and the resulting mixture was stirred at room temperature for 24 h. Most of the THF was then removed under reduced pressure, water (75 mL) was added, and the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic phase was dried over sodium sulfate, filtered, concentrated under vacuum, and further dried under high vacuum.The residue was subjected to silica gel column chromatography using a 10 to 30% ethyl acetate gradient in hexanes and provided tert-butyl 3-(aminooxy)-8-oxabicyclo[3.2.1]octane-3-carboxylate 58 (1.06 g, 57% yield) as a white solid. 1H NMR (400 MHz; CDCl3): 5.29 (sa, 2H), 4.42-4.39 (m, 2H), 2.23 (d, J = 4.3 Hz, 1H), 2.20 (d, J = 4.4 Hz, 1H), 2.04-1.97 (m, 4H), 1, 96-1, 88 (m, 2H), 1, 49 (s, 9H) Step 5: (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl} ({[3-(terC-butoxycarbonyl)-8-oxabicyclo[3.2.1]octan-3-yl]oxy}imino)acetic acid (59) A solution of tert-butyl 3-(aminooxy)-8-oxabicyclo[3.2.1]octane-3-carboxylate 58 (0.42 g, 1.73 mmol) in anhydrous MeOH (10 ml) was mixed with {2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}(oxo)acetic acid (0.47 g, 1.73 mmol) and the reaction mixture was stirred at room temperature for 17 h. Next, the reaction mixture was concentrated under reduced pressure and the crude product was further dried under high vacuum to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[3-(tert-butoxycarbonyl)-8-oxabicyclo[3.2.1]octan-3-yl]oxy}imino)acetic acid 59 (0.86 g, 100%) as a white solid. 1H NMR (400 MHz; CDCl3): 7.37 (s, 1H), 4.41-4.40 (m, 2H), 2.33-2.23 (m, 4H), 2.05-2.00 (m, 2H), 1.86-1.81 (m, 2H), 1, 55 (s, 9H) , 1, 44 (s, 9H) . MS (ESI) m / z: [M+1]+ 498, 1 Step 6: 3-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy-8-oxabicyclo[3, 2.1]octane-3-carboxylate tert-butyl (60) To a solution of (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[3-(tert-butoxycarbonyl)-8-oxabicyclo[3.2.1]octan-3-yl]oxy}imino)acetic acid 59 (0.60 g, 1.20 mmol) in anhydrous DMF (8 ml) N,N-diisopropylethylamine (0.31 ml, 1.80 mmol) was added and the resulting mixture was stirred at room temperature for 10 minutes. Then HATU (0.46 g, 1.20 mmol) was added and stirring continued at room temperature for 14 h. Subsequently, the reaction mixture was diluted with anhydrous DMF (8 mL) and DIPEA (0.84 mL, 4.80 mmol) was added, followed by L-cycloserine (184 mg, 1.80 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was dissolved in DCM (50 mL), and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography using a 0-3% MeOH gradient in DCM to provide 3-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-8-oxabicyclo[3.2.1]octane-3-carboxylate tert-butyl 60 (0.69 g, 98%) as a whitish solid. 1H NMR (400 MHz; DMSO-d6): 11.84 (sa, 1H), 11.55 (sa, 1H), 9.09 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 4.98-4.90 (m, 1H), 4. 59 (t, J = 8.5 Hz, 1H) , 4.34-4.27 (m, 2H) , 4.13 (dd, J = 9.9.8.4 Hz, 1H) , 2.16-2.06 (m, 2H) , 1.94-1.89 (m, 4H) , 1, 71-1, 66 (m, 2H), 1, 47 (s, 9H), 1, 36 (s, 9H). MS (ESI) m / z: [M+1]+ 582, 2 Stage 7: 3- ({ (Z) -[1-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (terc-butoxycarbonyl) -4- (H, -7, -7-hydro-dioxo-2 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -5-oxoxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino-aminoxy) -8-oxabicylato de3[1]carbutyl-3, (61) To a mixture of tert-butyl 3-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-8-oxabicyclo[3.2.1]octane-3-carboxylate 60 (0.38 g, 0.65 mmol) and (2S) -5-tert-butoxy-2- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -4, 5-dioxopentanoic acid 6 (0.353 g, 0.65 mmol) in anhydrous THF (15 ml) , DMAP (16 mg, 0.13 mmol) was added at 0 °C followed by DCC (188 mg, 0.91 mmol). The reaction mixture was stirred at 0 °C for 1 h, then at room temperature overnight and concentrated under reduced pressure at 25 °C. The residue was ground using 30% DCM in hexanes (20 ml) and the precipitated solids were removed by filtration and rinsed with 30% DCM in hexanes (15 ml) and hexanes (15 ml).The filtrates were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using a 10–50% gradient of ethyl acetate in hexanes to provide 3-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1 tert-butyl octane-3-carboxylate 61 (355 mg, 49%) as a tan-colored solid. 1H NMR (400 MHz; CDCl3): 7.57-7.54 (m, 4H), 7.45-7.42 (m, 6H), 7.36 (m, 1H), 7.33 (m, 2H), 5.42-5.36 (m, 1H), 5. 22-4, 89 (m, 2H) , 4, 49-4, 45 (m, 2H) , 4, 29-4, 22 (m, 1H) , 3, 54-3, 47 (m, 1H) , 3, 43-3, 31 (m, 1H) , 2, 91-2, 84 (m, 1H), 2, 44-2, 28 (m, 4H), 2, 03-1, 88 (m, 4H), 1, 75-1, 69 (m, 1H), 1, 59-1, 42 (m, 27H). Stage 8: 3-({ (Z)-[1-(2-amino-1, 3-thiazol-4-yl)-2-({ (4S)-2-[ (4 S)-2-carboxy-4-(5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) -8-oxabiciclo[3.2.1]octano-3-carboxílico (Compuesto Comparativo 13) To a solution of 3- ({ (Z) -[1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (tert-butoxycarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, tert-butyl 3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylate 61 (345 mg, 0.31 mmol) in Anhydrous DCM (16 ml) was added dropwise with a solution of Boron trichloride (1.0 M solution in DCM, 2.5 mL, 2.50 mmol) was added to -50 °C. The reaction mixture was stirred from -45 to -35 °C for 3 h, then cooled to -50 °C and 31 mL of a buffer solution (prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 mL of water) was added. The cold bath was replaced with an ice-water bath and the resulting mixture was stirred until the aqueous layer thawed and the phases separated.The organic phase was carefully removed and the collected aqueous phase was immediately subjected to C18 reversed-phase column chromatography using a Biotage system and 0.1% formic acid in acetonitrile and 0.1% formic acid in water as mobile phases to provide 3-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylic acid Comparative Compound 13 (100 mg, 44%) as a pale yellow, foamy solid. 1H NMR (400 MHz; a mixture of D2O and CD3NC): 7.25 (s, 2H), 7.08 (s, 1H), 5.41-5.33 (m, 1H), 5.16-5.06 (m, 1H), 4.76-4.66 (m, 1H) , 4, 32-4, 24 (m, 2H) , 3, 35-3, 27 (m, 1H) , 2, 79-2, 68 (m, 1H) , 2, 32-2, 18 (m, 2H) , 2, 11-2, 01 (m, 2H) , 1, 86-1, 71 (m, 4H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+H]+ 731, 0 Ejemplo Comparativo 9 Ácido (4S) -2-[ (4S) -4-{[ (2Z) -2-(5-amino-1, 2, 4-thiadiazol-3-il) -2-{[ (1-carboxycyclopropyl)oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4-(5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-il)-5-oxooxolan-2-carboxylico (Compuesto Comparativo 18) Compuesto Comparativo 18 Etapa 1: Ácido (2Z) -{5-[ (terc-butoxycarbonil) amino]-1, 2, 4-tiadiazol-3-il} ({[1- (terc- butoxycarbonil) ciclopropil]oxi}imino) acético (63) A solution of tert-butyl 1-(aminooxy)cyclopropane-1-carboxylate 2 (364 mg, 2.10 mmol, prepared as described in Comparative Example 1, step 1) in anhydrous MeOH (10 ml) was mixed with {5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}(oxo)acetic acid 62 (546 mg, 2.00 mmol, prepared as described in WO 2017 / 155765). The reaction mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The residue was collected in diethyl ether (50 mL) and the organic phase was washed with a 0.1 M hydrochloric acid solution (33 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was further dried under high vacuum to yield (2Z)-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetic acid 63 (696 mg, 81%) as a pale yellow solid. 1H NMR (400 MHz; DMSO-d6) : 12, 62 (s, 1H) , 12, 51 (s, 1H) , 1, 49 (s, 9H) , 1, 36 (m, 11H) , 1, 28 (m, 2H) . Stage 2: 1-{[ (Z) - (1-{5-[ (terc-butoxycarbonyl) amino]-1, 2, 4-thiazol-3-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxi}cyclopropane-1-carboxylate de terc-butyl (64) To a solution of (2Z)-{5-[(tert-butoxycarbonyl)amino],-1,2,4-thiazol-3-yl}({[1-(tert-butoxycarbonyl)-cyclopropyl]oxy}imino)acetic acid 63 (514 mg, 1.20 mmol) in anhydrous DMF (8 ml) N,N-diisopropylethylamine (0.31 ml, 1.80 mmol) was added and the resulting mixture was stirred at room temperature for 10 minutes. Then HATU (456 mg, 1.20 mmol) was added and stirring was continued at room temperature for 14 h. Next, anhydrous DMF (10 mL) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol) were added, followed by L-cycloserine (184 mg, 1.80 mmol), and the reaction mixture was stirred at room temperature for 1 h. The volatiles were then removed under reduced pressure, and the residue was collected in DCM (30 mL). The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated.The raw product was purified by silica gel column chromatography using a gradient of 0 to 3% methanol in DCM to provide 1-{[ (Z) - (1-{5-[ (terc-butoxycarbonyl) amino]1, 2, 4-thiadiazol-3-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxi}cyclopropane-1-carboxylate of terc-butyl 64 (204 mg, 33%) as a white solid. NMR de 1H (400 MHz; DMSO-d6) : 12, 59 (s, 1H) , 11, 57 (s, 1H) , 9, 07 (d, J = 7, 6 Hz, 1H) , 4, 91-4, 78 (m, 1H) , 4, 59 (t, J = 8, 3 Hz, 1H) , 3, 91 (t, J = 8, 8 Hz, 1H) , 1, 49 (s, 9H) , 1, 38 (s, 9H) , 1, 34 (m, 2H) , 1, 24 (m, 2H) Stage 3: (4S)-2-[ (4S)-4-{[ (2Z)-2-{5-[ (terc-butoxycarbonyl) amino]-1, 2, 4-thiadiazol-3-yl}-2- ({[1- (terc-butoxycarbonyl) cyclopropyl]oxi}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl)-5-oxooxolano-2-carboxylate de terc-butyl (65) A stirred mixture of 1-{[ (Z) - (1-{5-[ (tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-oxo-2-{[ (4S) -3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}cyclopropane-1-carboxylate tert-butyl 64 (196 mg, 0.38 mmol) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) -4,5-dioxopentanoic acid 6 (207 mg, 0.38 mmol) in anhydrous THF (20 ml) was cooled to 0 °C. DMAP (14 mg, 0.11 mmol) was added, followed by DCC (110 mg, 0.53 mmol) and the reaction mixture was stirred at 0 °C for 1 h, then at room temperature overnight and concentrated under reduced pressure at 25 °C. The residue was treated with 40% DCM in hexanes (25 ml), the precipitated solids were removed by filtration and rinsed with 40% DCM in hexanes (25 ml) and hexanes (15 ml).The filtrates were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using a 10–40% gradient of ethyl acetate in hexanes to provide tert-butyl (4S)-2-[(4S)-4-{[(2Z)-2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate 65 (197 mg, 50%) as a white solid. 1H NMR (400 MHz; CDCl3): 8.56 (s, 1H), 8.18 (dd, J = 8.1.5.0 Hz, 1H), 7.54-7.51 (m, 4H), 7.41 (c, J = 3.3 Hz, 6H), 7.30 (s, 2H) , 5, 38 (td, J = 10, 0, 8, 3 Hz, 1H) , 5, 16-4, 96 (m, 2H) , 4, 30-4, 22 (m, 1H) , 3, 49-3, 29 (m, 1H) , 2, 88-2, 82 (m, 1H), 1, 57-1.53 ​​(m, 22H), 1.43 (d, J = 2.7 Hz, 9H). Stage 4: (4S)-2-[ (4S)-4-{[ (2Z)-2- (5-amino-1, 2, 4-thiadiazol-3-yl)-2-{[ (1-carboxycyclopropyl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 18) A solution of (4S)-2-[ (S)-4-{[ (Z)-2-{5-[ (tert-butoxycarbonyl)amino]-1, 2, 4-thiadiazol-3-yl}-2- ({[1- (tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetyl]amino}-3-oxoisoxazolidin-2-yl]-4- (5, Tert-butyl 7-dioxo-2,2-diphenyl-5,7-dihydro-6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate 65 (190 mg, 0.183 mmol) in anhydrous DCM (10 mL) was cooled to -50 °C and added dropwise to drop boron trichloride (1.0 M in DCM, 1. 46 ml, 1.46 mmol). The reaction mixture was stirred from -45 °C to -35 °C for 3 h, then cooled to -50 °C and 16.5 ml of a buffer solution (prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 ml of water) was added. The cold bath was replaced with an ice-water bath and the resulting mixture was stirred until the aqueous layer thawed.The organic phase was carefully separated and the aqueous phase was immediately subjected to reversed-phase chromatography (C18) using a Biotage system and 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents to provide (4S)-2-[(4S)-4-{[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-{[(1-carboxycyclopropyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-carboxylic acid (Compound 18 (50 mg, 41%) as a pale yellow, foamy solid. NMR 1H (400 MHz; a mixture of D2O and CD3NC): 7, 25 (s, 2H) , 5, 44-5, 34 (m, 1H) , 5, 15-5, 04 (m, 1H) , 4, 73 (c, J = 8, 4 Hz, 1H) , 4, 32-4, 14 (m, 1H) , 3, 45-3, 31 (m, 1H) , 2, 91-2, 73 (m, 1H) , 1, 55-1, 45 (m, 2H) , 1, 45-1, 42 (m, 2H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+H]+ 662, 1 Comparative Example 10 Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (2-carboxipropan-2-yl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (2, 3-dihidroxi-5, 7-dioxo-5, 7-dihidro-6H-pirrolo[3, 4-b]piridin-6-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 36) Comparative Compuesto 36 Stage 1: 2, 2-diphenyl-2H-[1, 3]dioxolo[4, 5-b]pyridine-5, 6-dicarboxylate de diethyl (66) A stirred mixture of diethyl 5-hydroxy-6-oxo-1,6-dihydropyridine-2,3-dicarboxylate 66 (6.83 g, 26.76 mmol, prepared as described in US5252538(A), 1993) and potassium carbonate (4.07 g, 29.45 mmol) in anhydrous DMA (60 mL) was heated to 100 °C and a solution of 1,1'-(dichloromethylene)dibenzene (5.65 mL, 29.43 mmol) in DMA (20 mL) was added dropwise. The reaction mixture was then heated to 170 °C and stirred at 170 °C for 20 h. Afterward, the reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with a 2:1 mixture of diethyl ether and ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0–16% ethyl acetate in hexanes.The product obtained was further purified by recrystallization in diethyl ether and hexanes to provide 2,2-diphenyl-2H-[1,3]dioxolo[4,5-b]pyridine-5,6-dicarboxylate diethyl 67 (1.66 g, 15%) was a white solid. 1H NMR (400 MHz, CDCl3) 7.57-7.53 (s, 4H), 7.45 (s, 1H), 7.41-7.38 (m, 6H), 4.40 (c, J = 7.2 Hz, 2H), 4.34 (c, J = 7.1 Hz, 2H) , 1.38 (t, J = 7.2 Hz, 3H) , 1.34 (t, J = 7.1 Hz, 3H) . Step 2: 2,2-Diphenyl-2H-[1,3]dioxolo[4,5-b]pyridine-5,6-dicarboxylic acid (68) A stirred suspension of diethyl 2,2-diphenyl-2H-[1,3]dioxolo[4,5-b]pyridine-5,6-dicarboxylate 67 (1.75 g, 4.17 mmol) in a mixture of MeOH, THF, and water (1:1:1, 30 mL) was mixed with a solution of sodium hydroxide (835 mg, 20.88 mmol, in 10 mL of water) at room temperature. The reaction mixture was heated to 80 °C for 5 h, then cooled to room temperature and concentrated under reduced pressure to remove the THF and MeOH. The aqueous phase was washed twice with diethyl ether, cooled to 0 °C and acidified to pH = 1. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2,2-diphenyl-2H-[1,3]dioxolo[4,5-b]pyridin-5,6-dicarboxylic acid 68 (1.46 g, 96%) as a white solid which was used directly in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6) 7.78 (s, 1H), 7.56-7.52 (m, 4H), 7.49-7.45 (m, 6H). Step 3: 2,2-diphenyl-2H-[1,3]dioxolo[4,5-b]furo[3,4-e]pyridine-5,7-dione (69) Acetic anhydride (16 mL) was added to 2,2-diphenyl-2H-[1,3]dioxolo[4,5-b]pyridin-5,6-dicarboxylic acid 68 (1.46 g, 4.02 mmol) at room temperature. The resulting mixture was heated at 100 °C for 3 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Trace volatiles were removed by co-evaporation with toluene (3x), and the residue was further dried under high vacuum to provide 2,2-diphenyl-2H-[1,3]dioxolo[4,5-b]furo[3,4-e]pyridine-5,7-dione 69 (1.27 g, 92%) as a whitish foam, which was used directly in the next step. 1H NMR (400 MHz, DMSO-d6) 8,08(s,1H),7,58-7,55(m,4H),7,52-7,49(m,6H). Stage 4: (2S)-5-tert-butoxy-2- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-b]pyrrolo[3, 4-e]pyridin-6-yl)-4, 5-dioxopentanoic acid (71) . A solution of 2,2-diphenyl-2H-[1,3]dioxolo[4,5-b]furo[3,4-mi]pyridine-5,7-dione 69 (crude, 1.27 g, 3.68 mmol) in anhydrous pyridine (25 mL) at room temperature was added to (2S)-2-amino-5-tert-butoxy-4,5-dioxopentanoic acid 70 (2.03 g, 7.68 mmol, prepared as described in J. Med. Chem. 2014, 57, 3845-3855). The reaction mixture was stirred and heated to 90 °C for 2.5 h, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (10 ml) and water (120 ml) was added. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.The raw product was purified by silica gel column chromatography using an acetonitrile gradient of 0 to 16% in DCM to provide acid (2S) -5-terc-butoxy-2- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-b]pyrrolo[3, 4-e]pyridin-6-yl) -4, 5-dioxopentanoico 71 (390 mg, 19%) as a brown foam. 1H NMR (400 MHz, DMSO-d6) 7, 93 (s, 1H) , 7, 57-7, 53 (m, 4H) , 7, 51-7, 47 (m, 6H) , 5, 19-5, 16 (m, 1H) , 3, 71-3, 62 (m, 1H) , 3, 37-3, 34 (m, 1H) , 1, 44 (s, 9H) . MS (ESI) m / z: [M+1]+ 545, 2 Etapa 5: (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[1- (terc-butoxy-2-methyl-1-oxopropan-2-yl) oxi}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-b]pyrrolo[3, 4-e]pyridin-6-yl) -5-oxooxolano-2-carboxylate de terc-butyl (73) To a mixture of (2S) -5-tert-butoxy-2- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-b]pyrrolo[3, 4-e]pyridin-6-yl) -4, 5-dioxopentanoic acid 71 (390 mg, 0.72 mmol) and tert-butyl 2-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-2-methylpropanoate 72 (368 mg, 0.72 mmol, prepared as described in J. Med. Chem., 2014, 57, 3845-3855) in anhydrous THF (20 ml) was mixed with DMAP (18 mg, 0.15 mmol), followed by DCC (207 mg, 1.0 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature and was stirred for 18 h. The mixture was then concentrated under reduced pressure and the residue was ground with 30% DCM in hexanes.The precipitated solids were removed by filtration, the filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography using a 10–35% ethyl acetate gradient in hexane to provide (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[1-(tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl) tert-butyl -5-oxooxolane-2-carboxylate 73 (375 mg, 50%) as a brown foam. 1H NMR (400 MHz, CDCl3) 8, 44-8, 39 (s, 1H) , 7, 57-7, 54 (m, 4H) , 7, 44-7, 40 (m, 8H) , 5, 45-5, 39 (m, 1H) , 5, 18-4, 85 (m, 2H), 4, 38-4, 21 (m, 1H), 3, 68-3, 33 (m, 1H), 2, 89-2, 77 (m, 1H), 1, 66-1, 65 (m, 6H), 1, 57-1, 55 (m, 9H), 1, 54-1, 52 (m, 9H) , 1, 45-1, 44 (m, 9H) . Stage 6: (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (2-carboxipropan-2-yl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (2, 3-dihidroxi-5, 7-dioxo-5, 7-dihidro-6H-pirrolo[3, 4-b]piridin-6-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 36) 73 Comparative Compuesto 36 To a solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-{[ (1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl)-5-oxooxolane-2-carboxylate 73 (100 mg, 0. 096 mmol) in anhydrous DCM (5 ml) trichloride was added dropwise Boron (1.0 M in DCM, 0.77 mL, 0.77 mmol) was added at -50 °C. The reaction mixture was stirred from -50 °C to -35 °C for 2.5 min, and then a solution of NaHCO3 (157 mg) and Na2HPO4 (49 mg) in H2O (8.5 mL) at -50 °C was added. The cold bath was replaced with an ice-water bath, and the mixture was stirred for 20 min. The heterogeneous mixture was then stirred at room temperature until the aqueous phase thawed completely. The resulting mixture was filtered through a 1 mm syringe filter, and the organic layer was carefully removed.The aqueous phase was immediately subjected to C-18 reversed-phase chromatography using a Biotage system and 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents. The fractions containing the product were combined and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(2,3-dihydroxy-5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxooxolane-2-carboxylic acid Comparative Compound 36 (23 mg, 36%) as a yellow solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 09-7, 08 (m, 1H) , 7, 08-7, 06 (m, 1H) , 5, 42-5, 22 (m, 1H) , 5, 17-5, 08 (m, 1H) , 4, 76-4, 68 (m, 1H) , 4, 34-4, 23 (m, 1H) , 3, 53-3, 29 (m, 1H) , 2, 88-2, 64 (m, 1H) , 1, 53-1, 45 (m, 6H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 664, 1 Comparative Example 11 Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxycyclopropyl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (2, 3-dihidroxi-5, 7-dioxo-5, 7-dihidro-6H-pirrolo[3, 4-b]piridin-6-yl) -5-oxooxolano-2-carboxílico (Compuesto Comparativo 3) Comparative Compuesto 3 Stage 1: (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[1- (terc-butoxycarbonyl) cyclopropyl]oxi}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-b]pirrolo[3, 4-e]piridin-6-yl)-5-oxooxolano-2-carboxylate de terc-butyl (74) A mixture of (2S)-5-tert-butoxy-2-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl)-4,5-dioxopentanoic acid 71 (105 mg, 0.2 mmol, prepared as described in Comparative Example 10, Step 4) and 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}cyclopropane-1-carboxylate 5 (100 mg, 0, 2 mmol, prepared as described in Comparative Example 1, Step 4) in anhydrous THF (2 ml) was mixed with DMAP (5 mg, 0.04 mmol), followed by DCC (56 mg, 0.27 mmol) at 0 °C. The reaction mixture was gradually heated to room temperature and stirring continued for 18 h. The reaction mixture was then concentrated under reduced pressure and the residue was ground with 25% DCM in hexanes. The insoluble material was separated by filtration and the filtrate was concentrated.The crude product was purified by silica gel column chromatography using a 10 to 40 % ethyl acetate gradient in hexanes to provide (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (terc-butoxycarbonyl-l}l)-34-ti ({[1- (tert-butoxycarbonyl) cyclopropyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H, 5H-ro[3ob][4][3b] 4-e]pyridin-6-yl) -5-oxooxolane-2-tert-butyl carboxylate 74 (50 mg, 25 %) as a white foam. NMR of 1H (599 MHz; CDCl3) 8, 59 (t, J = 7, 5 Hz, 1H) , 8, 20-8, 05 (sa, 1H) , 7, 58-7, 52 (d, 5H) , 7, 70,43 (3, 4, 4, J = 19, 8, 10, 0 Hz, 1H) , 5, 15-5, 12 (m, 1H) , 4, 90 (dt, J = 26, 1, 8, 4 Hz, 1H) , 4, 30-4, J 21 (m-3, 1, H) 9, 8 Hz, 1H) , 2, 86 (dd, J = 13, 3, 11, 3 Hz, 1H), 1, 59-1, 57 (m, 9H) , 1, 55-1, 51 (m, 13H) , .1, 94) (s Step 2: Acid (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (1-carboxycyclopropyl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (2, 3-dihydroxy-5, 7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxooxolane-2-carboxylic (Comparative Compound 3) 74 Comparative Compound 3 A solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-{[ (1-tert-butoxycarbonyl) cyclopropyl)oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, tert-Butyl 7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl)-5-oxooxolane-2-carboxylate 74 (50 mg, 0.05 mmol) in anhydrous DCM (4 mL) was cooled to -50 °C and a solution of Boron trichloride (1.0 M in DCM, 0.39 mL, 0.39 mmol) was added. The reaction mixture was stirred from -30 °C to -25 °C for 2.5 h, then cooled to -50 °C before adding a solution of NaHCO3 (75 mg) and Na2HPO4 (24 mg) in H2O (4 mL). The resulting heterogeneous mixture was stirred for 20 min at 0–5 °C (ice-water bath) and then at room temperature until the aqueous phase thawed. The layers were allowed to separate, and the organic layer was carefully removed.The aqueous solution was then purified by C-18 reversed-phase column chromatography using a Biotage system and a mixture of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as mobile phases. The fractions containing pure product were collected and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-carboxycyclopropyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(2,3-dihydroxy-5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxooxolane-2-carboxylic acid Compound 3 (8 mg, 25%) as a yellow solid. 1H NMR (599 MHz; a mixture of D2O and CD3CN) 7, 06 (s, 1H) , 7, 04 (s, 1H) , 5, 40-5, 16 (m, 1H) , 5, 14-5, 03 (m, 1H) , 4, 69 (dt, J = 17, 4, 8, 7 Hz, 1H) , 4, 29-4, 18 (m, 1H) , 3, 52-3, 26 (m, 1H) , 2, 87-2, 63 (m, 1H) , 1, 42 (s, 2H) , 1, 34 (s, 2H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+H]+ 662, 0 Comparative Example 12 Ácido 4- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (2, 3-dihidroxi-5, 7-dioxo-5, 7-dihidro-6H-pirrolo[3, 4-b]piridin-6-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoetilidene]amino}oxi) oxano-4-carboxylic acid (Compuesto Comparativo 26) Comparative Compuesto 26 Etapa 1: 4- ({ (Z) -[1-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (terc-butoxycarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxol[4, 5-b]pyrrolo[3, 4-e]pyridin-6-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) oxane-4-carboxylate de terc-butyl (75) A mixture of 4-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}oxane-4-carboxylate 71 (316 mg, 0.58 mmol, prepared as described in Comparative Example 5, Step 7) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl) -4,5-dioxopentanoic acid 37 (293 mg, 0, 53 mmol, prepared as described in Comparative Example 10, Step 4) in anhydrous THF (9 ml) was mixed with DMAP (14 mg, 0.11 mmol), followed by DCC (153 mg, 0.74 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 h. The mixture was then concentrated and the residue was treated with 30% DCM in hexanes and the precipitated solids were removed by filtration.The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography using a 10–40% ethyl acetate gradient in hexanes to provide 4-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy) tert-butyl oxane-4-carboxylate 75 (238 mg, 42%) as a light brown foam. 1H NMR (400 MHz, CDCl3) 8, 26-8, 01 (s, 2H), 7, 59-7, 56 (m, 4H), 7, 46-7, 42 (m, 7H), 7, 37-7, 34 (m, 1H), 5, 46-4, 88 (m, 3H), 4, 39-4, 21 (m, 1H), 3, 89-3, 33 (m, 5H), 2, 91-2, 77 (m, 1H), 2, 26-2, 12 (m, 4H), 1, 60-1, 57 (m, 9H), 1, 56-1, 51 (m, 9H) , 1, 49-1, 42 (m, 9H) . Step 2: 4-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(2,3-dihydroxy-5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)) acid -5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)oxane-4-carboxylic (Comparative Compound 26) 75 Comparative Compound 26 To a solution of 4-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1, tert-butyl 3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)oxane-4-carboxylate 75 (238 mg, 0.22 mmol) in DCM anhydrous (17 ml), a solution of Boron trichloride (1.0 M solution in DCM, 1.76 mL, 1.76 mmol) was added at -50 °C. The reaction mixture was stirred from -50 °C to -25 °C for 2.5 minutes, and then a solution of NaHCO3 (362 mg) and Na2HPO4 (114.5 mg) in water (19.6 mL) at -50 °C was added. The resulting heterogeneous mixture was stirred at 0–5 °C (ice-water bath) for 20 minutes and then at room temperature until the aqueous phase thawed. The mixture was filtered through a syringe filter, and the organic layer was carefully separated.The aqueous layer was then purified by C-18 reversed-phase chromatography using a Biotage system and a mixture of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as mobile phases. The fractions containing the product were collected and lyophilized to provide 4-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(2,3-dihydroxy-5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy) oxane-4-carboxylic acid Comparative Compound 26 (47 mg, 30%) as a yellow solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 07-7, 06 (m, 2H) , 5, 39-5, 07 (m, 2H) , 4, 74-4, 67 (m, 1H) , 4, 30-4, 23 (m, 1H) , 3, 78-3, 72 (m, 2H) , 3, 60-3, 28 (m, 3H) , 2, 86-2, 64 (m, 1H) , 2, 12-1, 96 (m, 4H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 706, 0 Comparative Example 13 3- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (2, 3-dihydroxy-5, 7-dioxo-5, 7-dihydro-6H-pyrrolo[3, 4-b]pyridin-6-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) -8-oxabiciclo[3.2.1]octano-3-carboxylic acid (Compare Table 27) Comparative Compuesto 27 Etapa 1: 3- ({ (Z) -[1-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (terc-butoxycarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxol[4, 5-b]pyrrolo[3, 4-e]pyridin-6-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) -8-oxabicyclo-[3.2.1]octane-3-carboxylate de terc-butyl (76) A mixture of 3-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}-8-oxabicyclo[3.2.1]oxane-3-carboxylate tert-butyl 60 (337 mg, 0.62 mmol, prepared as described in Comparative Example 8, Step 6) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl) -4,5-dioxopentanoic acid 71 (343 mg, 0.59 mmol, prepared as described in Comparative Example 1, Step 4) in THF (9 ml) was mixed with DMAP (15 mg, 0.12 mmol), followed by DCC (171 mg, 0.83 mmol) at 0 °C. The reaction mixture was allowed to warm gradually to room temperature and stirred for 18 h. Afterward, the mixture was concentrated and the residue was ground with 30% DCM in hexanes and filtered.The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography using a 10–40% ethyl acetate gradient in hexanes to provide 3-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy) tert-butyl -8-oxabicyclo[3.2.1]octane-3-carboxylate 76 (274 mg, 42%) as a light brown foam. 1H NMR (400 MHz, CDCl3) 8, 19-8, 01 (s, 2H) , 7, 60-7, 54 (m, 4H) , 7, 47-7, 42 (m, 7H) , 7, 36 (d, J = 4, 2 Hz, 1H) , 5, 47-4, 89 (m, 3H) , 4, 50-4, 22 (m, 3H) , 3, 71-3, 34 (m, 1H) , 2, 92-2, 79 (m, 1H) , 2, 44-2, 19 (m, 4H) , 2, 05-1, 87 (m, 4H) , 1, 61-1, 53 (m, 18H) , 1, 46-1, 44 (m, 9H) . Step 2: 3-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(2,3-dihydroxy-5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylic acid (Comparative Compound 27) To a solution of 3- ({ (Z) -[1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (tert-butoxycarbonyl) -4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, tert-butyl 3]dioxolo[4,5-b]pyrrolo[3,4-e]pyridin-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]oxane-3-carboxylate 76 (265 mg, 0.24 mmol) in anhydrous DCM (17 A solution of boron trichloride (1.0 M solution in DCM, 1.91 mL, 1.91 mmol) was added dropwise to a sample of 1.91 mL at -50 °C. The reaction mixture was stirred from -50 °C to -25 °C for 2.5 minutes, and then a solution of NaHCO3 (393 mg) and Na2HPO4 (124 mg) in H2O (21.3 mL) was added at -50 °C. The cold bath was replaced with an ice-water bath, and the resulting heterogeneous mixture was stirred for 20 minutes at 5–10 °C and then at room temperature until the aqueous phase thawed completely. The mixture was filtered through a syringe filter, and the organic layer was carefully separated.The aqueous solution was immediately subjected to C-18 reversed-phase column chromatography using a Biotage system and 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents. The fractions containing pure product were combined and lyophilized to provide 3-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(2,3-dihydroxy-5,7-dioxo-5,7-dihydro-6h-pyrrolo[3,4-b]pyridin-6-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylic acid Comparative Compound 27 (95 mg, 54%) as a yellow solid. NMR of 1H (400 MHz, a mixture of D2O and CD3CN) 7,13–7, 11 (m, 1H) , 7, 07–7, 06 (m, 1H) , 5, 38–5, 24 (m, 1H) , 5,4, 0H7–5) 74-4, 68 (m, 1H) , 4, 42-4, 39 (m, 2H) , 4, 34-4, 24 (m, 1H) , 3, 48-3, 28 (m, 1H) , 2, 2, 87-2, 1,6) 3 (m, m, 2H) , 2, 09-2, 04 (m, 2H) , 1, 83-1, 70 (m, 4H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 732, 0 Example 14 Acid (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (2-carboxypropane-2-yl) oxy]imino}acetyl]amino}-3-oxo-yl,-zoly], 4-2-oxa-yl] 6-dihydroxy-1-oxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxoxolan-2-carboxylic (Compound 35, Table 1 Compound 35 Stage 1: 6-methyl-2, 2-diphenyl-2H-1, 3-benzodioxol-5-methyl carboxylate (78) A mixture of methyl 4,5-dihydroxy-2-methylbenzoate 77 (7.45 g, 40.90 mmol) and 1,1'-(dichloromethylene)dibenzene (7.86 mL, 40.94 mmol) was heated to 170 °C and stirred at 170 °C for 30 min. The reaction mixture was then cooled and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of 0–6% ethyl acetate in hexanes, followed by trituration with hexanes to produce methyl 6-methyl-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate 78 (12.37 g, 87%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.54-7.50 (s, 4H), 7.45 (s, 1H), 7.36-7.32 (m, 6H), 6.72 (s, 1H), 3.81 (s, 3H), 2.50 (s, 3H) . MS (ESI) m / z: [M+1]+ 347, 1 Step 2: 6-(bromomethyl)-2,2-diphenyl-2H-1,3-methylbenzodioxol-5-carboxylate (79) 78 79 To a mixture of methyl 6-methyl-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate (12.37 g, 35.71 mmol) and NBS (7.0 g, 39.33 mmol) in carbon tetrachloride (120 mL) AIBN (587 mg, 3.57 mmol) was added at room temperature. The reaction mixture was heated to 70 °C and stirred overnight at 70 °C, then cooled and concentrated under reduced pressure. The residue was ground with hexanes and the insoluble material was separated by filtration. The filtrate was concentrated and the crude product was purified by silica gel column chromatography using a 0 to 4% ethyl acetate gradient in hexanes to provide methyl 6-(bromomethyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate 79 (9.83 g, 65%) as a colorless sticky oil. 1H NMR (400 MHz, CDCl3) 7.56-7.53 (s, 4H), 7.51 (s, 1H), 7.40-7.36 (m, 6H), 6.96 (s, 1H), 4.93 (s, 2H), 3.89 (s, 3H) . Stage 3: 1-methyl(2S)-2- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindole-6-yl) butanodioate of 4-tert-butyl (81) To a mixture of methyl 6-(bromomethyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate 79 (5.28 g, 12.42 mmol) and 4-tert-butyl-1-methyl L-aspartate hydrochloride 80 (3.28 g, 13.68 mmol) in anhydrous acetonitrile (60 mL) DIPEA (4.76 mL, 27.33 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 1 h. Afterward, the reaction mixture was heated under reflux, stirred at reflux temperature for 20 h, then cooled and concentrated. The residue was extracted with ethyl acetate, the solids were removed by filtration, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0 to 4% ethyl acetate in hexanes to provide 4-tert-butyl 1-methyl (2S)-2-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)butanedioate 81 (5.08 g, 79%) as a white foam. RMN de 1H (400 MHz, CDCl3) 7, 59-7, 54 (s, 4H) , 7, 42-7, 35 (m, 6H) , 7, 30 (s, 1H) , 6, 91 (d, J = 0, 3 Hz, 1H) , 5, 30 (dd, J = 8, 5, 5, 7 Hz, 1H), 4, 45-4, 28 (m, 2H), 3, 71 (s, 3H), 3, 01-2, 84 (m, 2H), 1, 39 (s, 9H). MS (ESI) m / z: [M+1]+ 516, 2 Etapa 4: Acido(3S)-4-metoxi-4-oxo-3- (5-oxo-2, 2-difenil-5, 7-dihidro-2H, 6H-[1, 3]dioxolo[4, 5-F]isoindol-6-il) butanoico (82) A solution of 4-tert-butyl 1-methyl (2S)-2-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)butanedioate (245 mg, 0.475 mmol) in anhydrous DCM (12 mL) was added dropwise to a solution of boron trichloride (1.0 M in DCM, 0.86 mL, 0.86 mmol) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C and then gradually heated to -45 °C. Subsequently, the reaction mixture was diluted with ethyl acetate and water was added at -50 °C. The resulting mixture was stirred until the aqueous phase thawed, then the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure.The residue was ground with a mixture of ethyl acetate and hexanes and the precipitated solid was collected by filtration and further dried under high vacuum to provide (3S)-4-methoxy-4-oxo-3-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)butanoic acid 82 (154 mg, 71%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 12.52 (sa, 1H) , 7.54-7.50 (m, 4H) , 7.47-7.40 (m, 6H) , 7.26 (s, 1H) , 7.25 (s, 1H) , 5.08 (t, J = 7.0 Hz, 1H), 4.33 (s, 2H), 3.60 (s, 3H), 2.99-2.83 (m, 2H). MS (ESI) m / z: [M+1]+ 460, 1 Step 5: (2S)-5-cyano-4-oxo-2- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -5- (14-thiolan-1-ylidene) methyl pentanoate (83) A solution of (3S)-4-methoxy-4-oxo-3-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)butanoic acid 82 (189 mg, 0.41 mmol) in anhydrous DMF (4 mL) was treated with HATU (172 mg, 0.45 mmol) at room temperature. The resulting mixture was cooled to 0 °C and DIPEA (0.22 mL, 1.26 mmol) was added, followed by 1-(cyanomethyl)thiolan-1-ium bromide (112 mg, 0.54 mmol). The reaction mixture was stirred at 0 °C for 30 min, then allowed to warm slowly to room temperature and stirred overnight. Subsequently, the reaction was stopped by adding a saturated ammonium chloride solution at 0 °C, and the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography using an acetone gradient of 0 to 40% in ethyl acetate to provide (2S)-5-cyano-4-oxo-2- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxol[4, 5-f]isoindol-6-yl) -5- (14-thiolan-1-ylidene) pentanoate 83 (247 mg, quantity) as a white foam. 1H NMR (400 MHz, CDCl3) 7, 59-7, 53 (s, 4H) , 7, 42-7, 36 (m, 6H) , 7, 27 (s, 1H) , 6, 95-6, 91 (m, 1H) , 5, 55-5, 50 (m, 1H) , 4, 51-4, 36 (m, 2H) , 3, 77-3, 71 (m, 3 H) , 3, 55-3, 12 (m, 6H) , 2, 53-2, 40 (m, 2H) , 2, 12-2, 00 (m, 2H) . Step 6: Pentanoic acid (4S) -5-methoxy-2, 5-dioxo-4- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxol[4, 5-f]isoindol-6-yl) pentanoic acid (84) To a solution of (2S)-5-cyano-4-oxo-2-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-(14-thiolan-1-ylidene) methyl pentanoate 83 (244 mg, 0.41 mmol) in a mixture of THF and water (1:1, 9 mL) OXONE (264 mg, 0.86 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Then an additional portion of OXONE (132 mg, 0.43 mmol) and water (2 mL) was added and stirring continued at room temperature for 1 h. The reaction mixture was concentrated to remove the THF and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide (4S)-5-methoxy-2,5-dioxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)pentanoic acid 84 (220 mg) as a white foam, which was used in the next stage. RMN de 1H (400 MHz, CDCl3) 7, 56-7, 53 (s, 4H) , 7, 39-7, 36 (m, 6H) , 7, 28 (s, 1H) , 6, 88 (s, 1H) , 5, 38-5, 34 (m, 1H) , 4, 43-4, 27 (m, 2H), 3, 74 (dd, J = 17, 8, 6, 3 Hz, 1H), 3, 70 (s, 3H), 3, 46 (dd, J = 17, 8, 7, 7 Hz, 1H). Etapa 7: (4S)-2-oxo-4- (5-oxo-2, 2-difenil-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-il) butanodioato de 1-terc-butilo y 5-metilo (85) To a solution of (4S)-5-methoxy-2,5-dioxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)pentanoic acid 84 (220 mg, 0.41 mmol) in anhydrous THF (5 mL) N,N'-di(propan-2-yl) tert-butyl carbamimidate (0.4 mL, 1.54 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 3 h. The mixture was concentrated under reduced pressure and the residue was ground with 25% DCM in hexanes. The insoluble material was removed by filtration, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography using a 10 to 30% ethyl acetate gradient in hexanes to provide (4S)-2-oxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) 5-methyl 1-tert-butyl butanedioate 85 (181 mg, 81% in 2 stages) as a white solid. RMN de 1H (400 MHz, CDCl3) 7, 57-7, 54 (s, 4H) , 7, 40-7, 36 (m, 6H) , 7, 28 (s, 1H) , 6, 90 (s, 1H) , 5, 24 (dd, J = 7, 5, 5, 6 Hz, 1H) , 4, 45 (d, J = 16, 5 Hz, 1H) , 4, 27 (dd, J = 16, 5 Hz, 1H) , 3, 71 (s, 3H) , 3, 63 (dd, J = 18, 5, 5, 6 Hz, 1H) , 3, 49 (dd, J = 18, 5, 7, 5 Hz, 1H), 1, 53 (s, 9H). MS (ESI) m / z: [M+1]+ 544, 2 Etapa 8: Acido(2S)-5-terc-butoxi-4, 5-dioxo-2- (5-oxo-2, 2-difenil-5, 7-dihidro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-il)pentanoico (86) A solution of (4S)-2-oxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) 5-methyl 1-tert-butyl pentanedioate (181 mg, 0.33 mmol) in a mixture of THF and water (1:1, 4 mL) was cooled to 0 °C and LiOH·H2O (14 mg, 0.33 mmol) was added. The reaction mixture was stirred at 0 °C for 40 min and then at room temperature for 10 min. The reaction mixture was then cooled to 0 °C and 1 M HCl (0.33 mL) was added. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography using 30% ethyl acetate in hexanos, followed by a MeOH gradient of 0 to 5% in DCM to produce acid (2S) -5-terc-butoxy-4, 5-dioxo-2- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxol[4, 5-f]isoindol-6-yl) pentanoic 86 (115 mg, 65%) as a white foam. 1H NMR (400 MHz, DMSO-d6) 7, 58-7, 54 (m, 4H) , 7, 42-7, 36 (m, 6H) , 7, 32-7, 27 (m, 1H) , 6, 93-6, 87 (m, 1H) , 5, 63-5, 51 (m, 1H) , 4, 39-4, 23 (m, 2H) , 3, 01-2, 85 (m, 1H) , 2, 63-2, 35 (m, 1H) , 1, 57-1, 52 (m, 9H) . MS (ESI) m / z: [M+1]+ 530, 2 Etapa 9: (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-{[ (1-terc-butoxy-2-methyl-1-oxopropan-2-yl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-5-oxo-4- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) oxolano-2-carboxylate de tert-butyl (87) To a mixture of (2S)-5-tert-butoxy-4, 5-dioxo-2- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) pentanoic acid 86 (112 mg, 0.21 mmol) and 2-{[ (Z) - Tert-butyl (1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-2-methylpropanoate 72 (109 mg, 0.21 mmol) in anhydrous THF (4 mL) was added DMAP (6 mg, 0.049 mmol), followed by DCC (62 mg, 0.30 mmol) at 0 °C. The reaction mixture was gradually heated to room temperature and stirred for 18 h. The mixture was then concentrated and the residue was treated with 25% DCM in hexanes and filtered.The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography using a 10–40% ethyl acetate gradient in hexanes to provide tert-butyl (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-5-oxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)oxolane-2-carboxylate 87 (132 mg, 61%) as a white foam. 1H NMR (400 MHz, CDCl3) 8, 21-8, 18 (s, 1H), 7, 57-7, 52 (m, 4H), 7, 41-7, 34 (m, 7H), 7, 30-7, 29 (m, 1H), 6, 92-6, 90 (m, 1H), 5, 47-5, 39 (m, 1H), 5, 20-4, 85 (m, 2H), 4, 34-4, 21 (m, 3H), 3, 51-3, 31 (m, 1H), 2, 93-2, 49 (m, 1H), 1, 61-1, 58 (m, 6H) , 1, 55-1, 52 (m, 18H), 1, 43 (s, 9H) . Stage 10: Acid (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (2-carboxypropane-2-yl) oxy]imino}acetyl]yl amino}-li, 4-2-oxa-1] 6-dihydroxy-1-oxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolane-2-carboxyl (Compound 35) 87 Compound 35 A stirred solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-{[ (1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-5-oxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)oxolane-2-carboxylate 87 (132 mg, 0.13 mmol) in anhydrous DCM (7 ml) was cooled to -50 °C and a solution of Boron trichloride (1.0 M in DCM, 1.03 mL, 1.03 mmol) was added. The reaction mixture was stirred from -50 °C to -35 °C for 2.5 h and then cooled to -50 °C before adding a solution of NaHCO3 (212 mg) and Na2HPO4 (67 mg) in water (11.4 mL). The cold bath was replaced with an ice-water bath, and the heterogeneous mixture was stirred at 5–10 °C for 10 min and then at room temperature until the aqueous layer thawed. The mixture was filtered through a syringe filter, and the organic layer was carefully removed.The aqueous solution was then immediately subjected to C18 reversed-phase chromatography using a Biotage system and a mixture of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as mobile phases. The pure fractions were collected and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1-oxo 1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid Compound 35 (27 mg, 32%) as a white solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 15-7, 13 (m, 1H) , 7, 10-7, 06 (m, 1H) , 7, 00-6, 98 (m, 1H) , 5, 46-5, 08 (m, 2H) , 4, 77-4, 68 (m, 1H) , 4, 42-4, 23 (m, 3H) , 3, 46-3, 32 (m, 1H) , 2. 91-2, 62 (m, 1H) , 1, 53-1, 47 (m, 6H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 649, 1 Example 15 Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxycyclopropyl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1-oxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolano-2-carboxílico (Compuesto 28, Tabla 1) Composition 28 Stage 1: (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-{[ (1-terc-butoxycarbonyl) cyclopropyl]oxi}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-5-oxo-4- (5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) oxolano-2-carboxylate de terc-butyl (88) A mixture of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}cyclopropane-1-carboxylate 5 (358 mg, 0.70 mmol, prepared as described in Comparative Example 1, Step 4) and (2S) -5-tert-butoxy-4,5-dioxo-2- (5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)pentanoic acid 86 (370 mg, 0.70 mmol, prepared as described in Example Step 8 (14) in anhydrous THF (20 mL) was cooled to 0 °C. DMAP (17 mg, 0.14 mmol) was added, followed by DCC (202 mg, 0.98 mmol), and the reaction mixture was stirred at 0 °C for 1 hour and then at room temperature overnight. The solvent was evaporated at 25 °C, and the residue was ground with 25% DCM in hexanes (25 mL). The precipitated solids were separated by filtration, washed with 25% DCM in hexanes (15 mL), and hexanes.The combined filtrates were concentrated under reduced pressure and the crude product was purified by silica gel column chromatography using a 10–50% ethyl acetate gradient in hexanes as the eluent to provide tert-butyl (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-5-oxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)oxolane-2-carboxylate 88 (460 mg, 64% yield) as a whitish solid. 1H NMR (400 MHz; (CDCl3) 8.59 (d, J = 6.1 Hz, 1H) , 8.17 (sa, 1H) , 7.60-7.55 (m, 4H) , 7.42-7.39 (m, 6H) , 7.32 (s, 1H) , 6. 93 (s, 1H) , 5, 49-5, 43 (m, 1H) , 5, 23-5, 17 (m, 1H) , 4, 94 (t, J = 8, 3 Hz, 1H) , 4, 37-4, 25 (m, 3H) , 3, 45-3, 35 (m, 1H) , 2, 60 (dd, J = 14, 0, 10, 4 Hz, 1H), 1, 58-1, 51 (m, 22H), 1, 45 (s, 9H). Stage 2: (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxycyclopropyl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1-oxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolano-2-carboxílico (Compuesto 28) 88 Compuesto 28 A solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) cyclopropyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-5-oxo-4- tert-Butyl (5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)oxolane-2-carboxylate 88 (450 mg, 0.44 mmol) in anhydrous DCM (22 mL) was cooled to −50 °C. A solution of boron trichloride (1.0 M in DCM, (3.52 mL, 3.52 mmol)) was added dropwise at -50 °C, and the reaction mixture was stirred from -45 to -30 °C for 2.5 h. Subsequently, the reaction mixture was cooled to -50 °C, and 40 mL of a buffer solution (prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 mL of water) was added. The cold bath was then replaced with an ice-water bath to allow the frozen heterogeneous mixture to thaw and separate into two layers.The organic phase was carefully removed and the aqueous phase was collected and immediately purified by C18 reversed-phase chromatography using a Biotage system and a mixture of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as mobile phases. The fractions containing the product were combined and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-carboxycyclopropyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1-oxo-1,3-dihydro-2-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid Compound 28 (70 mg, 24%) in the form of a whitish foam. NMR of 1H (400 MHz; a mixture of D2O and CD3CN) 7, 12 (s, 1H) , 7, 09 (s, 1H) , 6, 97 ( s, 1H) , 5, 40 ( t , J = 10, 1 Hz, 5, 1 H 1) ( 1 , 1 H 1 ) , , 4, 73-4, 64 (m, 1H) , 4, 35-4, 21 (m, 3H) , 3, 37-3, 30 (m, 1H) , 2, 64 (dd, J = 14, 2, 11, 1 Hz) (m, 1, 2, 4) , 1, 42-1, 37 (m, 2H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 647, 0 Example 16 Acid 4- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (5, 6-dihydroxy-1-oxo -1, 3-dihydro)l-2H-iso -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxy)oxane-4-carboxylic (Compound 29, Table 1) Compound 29 Step 1: 4-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-5-oxo-4-(5-oxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl)oxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)oxano-4-carboxylate de tert-butyl (89) To an agitated mixture of (2S)-5-tert-butoxy-4,5-dioxo-2-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)pentanoic acid 86 (400 mg, 0.76 mmol, prepared as described in Example 14, Step 8) and 4-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}oxane-4-carboxylate 37 (420 mg, 0.76 mmol) in anhydrous THF (10 DMAP (19 mg, 0.16 mmol) was added to a solution of 19 mg, followed by DCC (219 mg, 1.06 mmol) at 0 °C. The reaction mixture was gradually heated to room temperature and stirred for 18 h. The mixture was then concentrated, and the residue was treated with 50% DCM in hexanes. The precipitated solids were separated by filtration.The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a 20–45% ethyl acetate gradient in hexanes to provide 4-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-5-oxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)oxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy) tert-butyl oxane-4-carboxylate 89 (545 mg, 68%) as a white foam. 1H NMR (400 MHz, CDCl3) 8, 14-8, 03 (s, 2H) , 7, 57-7, 52 (m, 4H) , 7, 41-7, 36 (m, 6H) , 7, 34-7, 32 (m, 1H) , 7, 30-7, 28 (m, 1H), 6, 92-6, 89 (m, 1H), 5, 49-5, 37 (m, 1H), 5, 23-4, 84 (m, 2H), 4, 36-4, 18 (m, 3H), 3, 85-3, 66 (m, 4H), 3, 49-3, 29 (m, 1H) , 2, 92-2, 48 (m, 1H) , 2, 24-2, 09 (m, 4H) , 1, 56-1, 52 (m, 18H) , 1, 44-1, 40 (m, 9H) . Step 2: Acid 4- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (5, 6-dihidroxi-1-oxo -1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) oxano-4-carboxylic acid (Compuesto 29) 89 Compuesto 29 To a solution of 4-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-5-oxo-4-(5-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1, Tert-butyl 3]dioxolo[4,5-f]isoindol-6-yl)oxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)oxane-4-carboxylate 89 (541 mg, 0.51 mmol) in anhydrous DCM (30 mL) was added dropwise to drop a solution of boron trichloride (solution 1, 0 M in DCM, 4.06 mL, 4.06 mmol) at -50 °C. The reaction mixture was stirred at -50 °C–25 °C for 2.5 h, then cooled to -50 °C before adding a solution of NaHCO3 (835 mg) and Na2HPO4 (264 mg) in water (45.2 mL). The resulting heterogeneous mixture was stirred at 5–10 °C (ice-water bath) for 10 minutes and then at room temperature until the aqueous phase thawed and two layers separated. The mixture was filtered through a 1 mm syringe filter and the organic layer was carefully removed.The aqueous solution was then purified by C18 reversed-phase chromatography using a Biotage system and a mixture of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents. The pure fractions were collected and lyophilized to produce 4-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(5,6-dihydroxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy) oxane-4-carboxylic acid Compound 29 (161 mg, 46%) as a white solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 13-7, 06 (m, 2H), 6, 97-6, 96 (m, 1H), 5, 44-5, 06 (m, 2H), 4, 76 4, 67 (m, 1H), 4, 40-4, 22 (m, 3H), 3, 78-3, 72 (m, 2H), 3, 60-3, 52 (m, 2H), 3, 44-3, 29 (m, 1H), 2, 90-2, 61 (m, 1H), 2, 14-1, 96 (m, 4H). No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 691, 0 Example 17 Acid 3- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4S) -2-carboxy-4- (5, 6-dihydroxy-1-oxo-1, 3-dihydrol-2H-isoindoyl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxy) -8-oxabicyclo[3.2.1]octane-3-carboxylic (Compound 30, Table 1) Compound 30 Stage 1: 3- ({ (Z) -[1-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (terc-butoxycarbonyl) -5-oxo-diphenyl-2,-5-2xo 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) oxolan-2-yl]-3-oxo-1, 2-oxazolidine-4-yl}amino) -2-oxoethylidene]amino}oxy) -[o3-octano2cycbi.1o] tert-butyl (90) A mixture of (2S)-5-tert-butoxy-4,5-dioxo-2-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)pentanoic acid 86 (461 mg, 0.87 mmol, prepared as described in Example 14, Step 8) and 3-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-8-oxabicyclo[3.2.1]oxane-3-carboxylate tert-butyl 60 (507 mg, 0.87 mmol, prepared as described in Comparative Example 8, Step 6) in anhydrous THF (4 ml) was mixed with DMAP (21 mg, 0.17 mmol), followed by DCC (252 mg, 1.2 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 h. The mixture was then concentrated and the residue was treated with 25% DCM in hexanes. The solids were separated by filtration and the filtrate was concentrated under reduced pressure.The crude product was purified by silica gel column chromatography using a 10–40% ethyl acetate gradient in hexanes to provide 3-({(Z)-[1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({(4S)-2-[(4S)-2-(tert-butoxycarbonyl)-5-oxo-4-(5-oxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)oxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylate 90 (460 mg, 48%) as a white foam. NMR of 1H (400 MHz; CDCl3) 8, 27-8, 25 (m, 1H) , 8, 06 (d, J = 6, 3 Hz, 1H) , 7, 64-7, 51 ( s , 4H) , 7, H73 (- 5, 6, 6, 1H), 7, 32 (s, 1H) , 6, 93 (s, 1H) , 5, 51-5, 43 (m, 1H) , 5, 27-5, 15 (m, J = 6, 3 Hz, 1H) , 4, 3 J = 9,8 (t, 1H) 52-4, 42 (m, 2H) , 4, 36-4, 22 (m, 3H) , 3, 44-3, 34 (m, 1H) , 2, 58 (dd, J = 14, 0, 10, 4 Hz, 1H, 5) (m, 2, 2, 1H) 4, 2, 2, 03-1, 88 (m, 4H) , 1, 69 (s, 2H) , 1, 58-1, 55 (m, 18H) , 1, 44 (s, 9H) . Stage 2: Acid 3- ({ (Z) -[1- (2-amino-1, 3-thiazol-4-yl) -2- ({ (4S) -2-[ (4 S) -2-carboxy-4- (5, 6-dihydroxy-1-oxo -1, -22-dihydro-l -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxy) -8-oxabicycle[3.2.1]octane-3carboxylic (Compound 30) To a solution of 3- ({ (Z) -[1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({ (4S) -2-[ (4S) -2- (tert-butoxycarbonyl) -5-oxo-4- (5-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, tert-butyl 3]dioxolo[4,5-f]isoindol-6-yl)oxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylate 90 (338 mg, 0.31 mmol) in anhydrous DCM (25 ml) a solution of Boron trichloride (1.0 M solution in DCM, 2.48 mL, 2.48 mmol) was added to the reaction flask at -50 °C. The reaction mixture was stirred from -30 °C to -25 °C for 2.5 h, then cooled to -50 °C and buffered (prepared by dissolving NaHCO3 (514 mg) and Na2HPO4 (163 mg) in 28 mL of water) was added. The reaction flask was transferred to an ice-water bath and the heterogeneous mixture was stirred at 0–5 °C for 20 min, and then at room temperature until the aqueous phase thawed completely and two layers separated.The organic layer was carefully removed and the aqueous solution was immediately subjected to purification by C18 reversed-phase chromatography using a Biotage system and a mixture of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents. The pure fractions were combined and lyophilized to provide 3-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(5,6-dihydroxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)-8-oxabicyclo[3.2.1]octane-3-carboxylic Compound 30 (95 mg, 43%) as a green-stained solid. NMR of 1H (599 MHz; a mixture of D2O and CD3CN) 7, 12 (s, 1H) , 7, 02 (s, 1H) , 6, 97 (s, 1H) , 5, 44-5, 41 (m, 1H,8) - 5, 4, 10 75-4, 68 (m, 1H) , 4, 43--4, 34 (m, 5H) , 4, 34-4, 23 (m, 3H) , 3, 45-3, 28 (m, 1H) , 2, 89-2, 1, 59 (m, 1H) 2, 6, 89-2, 1H 2H) , 2, 07-1, 98 (m, 2H) , 1, 79-1, 72 (m, 4H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 717, 0 Example 18 Acid (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (2-carboxypropane-2-yl) oxy]imino}acetyl]amino}-3-oxo-yl,-zoly], 4-2-oxa-yl] 6-dihydroxy-1, 1, 3-trioxo-1, 3-dihydro-2H-16, 2-benzothiazol-2-yl) -5-oxooxolan-2-carboxylic (Compound 37, Table 1 Compound 37 Stage 1: 1- (prop-2-en-1-yl) N-{[ (9H-fluoren-9-yl)methoxy]carbonyl}-L-aspartate of 4-tert-butyl (92) To a solution of allyl bromide (16 mL, 184.9 mmol) and DIPEA (12.7 mL, 72.9 mmol) in anhydrous acetonitrile (75 mL) was added (2S)-4-tert-butoxy-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-oxobutanoic acid (15.0 g, 36.5 mmol). The reaction mixture was heated to 40 °C and stirred at 40 °C for 4 h, then cooled and concentrated under vacuum. The residue was collected in EtOAc and the organic phase was sequentially washed with 0.5 M aqueous hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a 5% to 20% gradient of ethyl acetate in hexanes to provide 1-(prop-2-en-1-yl) N-{[(9H-fluoren-9-yl) methoxy]carbonyl}-L-aspartate 4-tert-butyl 92 (15, 19 g, 92%) as a white solid. RMN de 1H (400 MHz, CDCl3) 7, 80-7, 78 (s, 2H) , 7, 64-7, 61 (m, 2H) , 7, 45-7, 40 (m, 2H) , 7, 33 (td, J = 7, 5, 1, 2 Hz, 2H) , 5, 94-5, 92 (m, 1H) , 5, 85-5, 82 (m, 1H) , 5, 38-5, 34 (m, 1H) , 5, 29-5, 26 (m, 1H) , 4, 71-4, 64 (m, 3H) , 4, 46-4, 43 (m, 1H) , 4, 39-4, 34 (m, 1H) , 4, 29-4, 26 (m, 1H) , 2, 98-2, 97 (m, 1H) , 2.83-2.82 (m, 1H) , 1, 48-1, 46 (m, 9H) . Etapa 2: 1- (prop-2-en-1-il) L-aspartato de 4-terc-butilo (93) Diethylamine (80 mL) was added to a solution of 4-tert-butyl 1-(prop-2-en-1-yl) N-{[(9H-fluoren-9-yl) methoxy]carbonyl}-L-aspartate 92 (15.19 g, 33.64 mmol) in anhydrous DCM (80 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 5% to 100% ethyl acetate in hexanes to give 4-tert-butyl 1-(prop-2-en-1-yl) L-aspartate 93 (7.84 g, quantitative) as a light yellow oil. 1H NMR (400 MHz, CDCl3) 5.95-5.86 (s, 1H), 5.35-5.29 (m, 1H), 5.26-5.23 (m, 1H), 4.67-4.58 (m, 2H), 3.77 (dd, J = 6. 8, 4, 8 Hz, 1H), 2, 69 (cd, J = 14, 3, 5, 8 Hz, 2H), 1, 71-1, 67 (m, 3H). Step 3: methyl 6-bromo-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate (95) A mixture of methyl 2-bromo-4,5-dihydroxybenzoate 94 (9.53 g, 38.58 mmol) and 1,1'-(dichloromethylene)dibenzene (7.41 mL, 38.59 mmol) was heated to 170 °C and stirred for 50 min. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0% to 10% ethyl acetate in hexanes to give methyl 6-bromo-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate 95 (15.01 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) 7, 57-7, 53 (s, 4H), 7, 43-7, 39 (m, 7H), 7, 18 (s, 1H), 3, 90 (s, 3H). Step 4: 6-(benzylsulfanyl)-2,2-diphenyl-2H-1,3-methylbenzodioxol-5-carboxylate (96) A suspension of NaH (60% in mineral oil, 1.67 g, 41.75 mmol) in anhydrous THF (120 mL) was given dropwise benzenemethamphetamine (4.30 mL, 36.63 mmol) at 0 °C, and the resulting solution was stirred at 0 °C for 10 min. Then, methyl 6-bromo-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate (14.30 g, 34.77 mmol) was added, and the reaction mixture was heated to 45 °C and stirred at 45 °C for 13 h. The reaction mixture was cooled to room temperature, diluted with a mixture of ethyl acetate and hexanes (7:3), and then water was added. The organic phase was separated and the aqueous layer was further extracted with a mixture of ethyl acetate and hexanes (7:3). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography using a gradient of 0% to 8% ethyl acetate in hexanes to provide methyl 6-(benzylsulfanyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate 96 (7.88 g, 50%) as a white foam. 1H NMR (400 MHz, CDCl3) 7.57-7.53 (s, 5H), 7.42-7.39 (m, 8H), 7.35-7.25 (m, 3H), 6.92 (s, 1H), 4.12 (d, J = 2.4 Hz, 2H) , 3, 87 (s, 3H) . Step 5: 6-(chlorosulfonyl)-2,2-diphenyl-2H-1,3-methylbenzodioxol-5-carboxylate (97) To a stirred suspension of methyl 6-(benzylsulfanyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate (7.88 g, 17.34 mmol) in a mixture of acetonitrile (170 mL), acetic acid (6.3 mL) and water (4.25 mL) were added. 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (6.84 g, 34.72 mmol) was added in small portions at 0 °C. The reaction mixture was stirred from 0 to 5 °C for 2 h and then concentrated under vacuum. The residue was collected in a DCM (110 mL), the resulting solution was cooled to 0 °C, and a saturated aqueous solution of sodium bicarbonate (110 mL) was slowly added while maintaining the temperature below 10 °C. The resulting mixture was stirred between 0 and 5 °C for 15 min, then the aqueous phase was separated, and the organic layer was washed with pre-cooled brine (<10 °C). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography using a gradient of 0% to 10% ethyl acetate in hexanes to give methyl 6-(chlorosulfonyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate 97 (7, 40 g, 99%) as a white foam. 1H NMR (400 MHz, CDCl3) 7,64 (s, 1H) , 7,56-7,53 (m, 4H) , 7,46-7,43 (m, 6H) , 7,20 (s, 1H) , 3,97 (s, 3H) . Step 6: N-[6-(methoxycarbonyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-sulfonyl]-L-aspartate 4-tert-butyl 1-(prop-2-en-1-yl) (98) A solution of methyl 6-(chlorosulfonyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-carboxylate 97 (7.40 g, 17.17 mmol) in anhydrous DCM (150 ml) was cooled to 0 °C. Triethylamine (2.90 ml, 20.81 mmol), a solution of 4-tert-butyl 1-(prop-2-en-1-yl) L-aspartate 93 (4.33 g, 18.89 mmol) in DCM (25 ml) and DMAP (210 mg, 1.72 mmol) were then sequentially added at 0 °C, and the reaction mixture was stirred at 0 °C for 10 min. The reaction mixture was then stirred at room temperature for 4 h, and subsequently concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the organic phase was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum.The residue was purified by silica gel column chromatography using a gradient of 0% to 20% ethyl acetate in hexanes to provide N-[6-(methoxycarbonyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-sulfonyl]-L-aspartate of 4-tert-butyl and 1-(prop-2-en-1-yl) 98 (8, 43 g, 79%) as a white foam. 1H NMR (400 MHz, CDCl3) 7.60 (s, 1H) , 7.58-7.53 (m, 4H) , 7.44-7.41 (m, 7H) , 7.27 (d, J = 8.6 Hz, 1H) , 5.64-5.54 (m, 1H) , 5, 10-5, 00 (m, 2H) , 4, 39-4, 31 (m, 3H) , 3, 96 (s, 3H) , 2, 96 (dd, J = 16, 9, 4, 7 Hz, 1H) , 2, 82 (dd, J = 16, 9, 5, 0 Hz, 1H), 1, 44 (s, 9H) . Step 7: 4-tert-butyl 1-(prop-2-en-1-yl) (2S)-2-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)butanedioate (99) A solution of N-[6-(methoxycarbonyl)-2,2-diphenyl-2H-1,3-benzodioxol-5-sulfonyl]-L-aspartate of 4-tert-butyl 1-(prop-2-en-1-yl) 98 (9.25 g, 14.83 mmol) in anhydrous toluene (400 mL) was mixed with DMAP (544 mg, 4.45 mmol) and triethylamine (5.80 mL, 41.61 mmol) at room temperature. The resulting mixture was stirred under reflux for 120 h, then cooled and concentrated under vacuum. The residue was collected in ethyl acetate, and the organic phase was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0% to 15% ethyl acetate in hexanes to provide (2S)-2-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl) 4-tert-butyl 1-(prop-2-en-1-yl) 99 (6.26 g, 71%) foam. RMN de 1H (400 MHz, CDCl3) 7, 53-7, 51 (s, 4H) , 7, 43-7, 41 (m, 7H) , 7, 30 (d, J = 0, 4 Hz, 1H) , 5, 88-5, 78 (m, 1H) , 5, 30-5, 24 (m, 2H) , 5, 20-5, 16 (m, 1H) , 4, 69-4, 59 (m, 2H) , 3, 35 (dd, J = 16, 8, 7, 6 Hz, 1H) , 2, 98 (dd, J = 16, 8, 7, 1 Hz, 1H) , 1, 45 (s, 9H) . Etapa 8: Acido(3S)-4-oxo-4-[(prop-2-en-1-il)oxy]-3- (1, 1, 3-trioxo-6, 6-difenil-1, 3-dihidro-2H, 6H-16-[1, 3]dioxolo[4, 5-f][1, 2]benzotiazol-2-il) butanoico (100) A solution of (2S)-2-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl) 4-tert-butyl 1-(prop-2-en-1-yl) butanedioate (1.08 g, 1.83 mmol) in anhydrous DCM (42 mL) was added dropwise to a solution of boron trichloride (1.0 M in DCM, 3.29 mL, 3.29 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h and then from -78 °C to -45 °C for 30 min. The reaction mixture was then diluted with ethyl acetate and water was added at -50 °C. The heterogeneous mixture was stirred at room temperature until the layers separated, and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was initially purified by C18 reversed-phase chromatography using mixtures of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents, and the product-containing fractions were combined and concentrated under reduced pressure.The product obtained was further purified by silica gel column chromatography using a methanol gradient from 0% to 4% in DCM to provide (3S)-4-oxo-4-[(prop-2-en-1-yl)oxy]-3-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)butanoic acid 100 (395 mg, 40%) as a white foam. 1H NMR (400 MHz, CDCl3) 7.57-7.52(s,4H) 5, 23-5, 20 (m, 1H), 4, 72-4, 63 (m, 2H), 3, 53 (dd, J = 17, 1, 7, 8 Hz, 1H), 3, 11 (dd, J = 17, 1, 6, 7 Hz, 1H). Step 9: (2S)-5-cyano-4-oxo-5- (14-thiolan-1-ylidene)-2- (1, 1, 3-trioxo-6, 6-diphenyl-1, 3-dihydro-2H, 6H-16-[1, 3]dioxolo[4, 5-F][1, 2]benzothiazol-2-yl) pentanoate prop-2-en-1-yl (101) 100 101 A solution of (3S)-4-oxo-4-[(prop-2-en-1-yl)oxy]-3-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)butanoic acid 100 (783 mg, 1.46 mmol) in anhydrous DCM (14 mL) was treated with HATU (612 mg, 1.61 mmol) at room temperature. The resulting mixture was cooled to 0 °C and DIPEA (0.76 mL, 4.36 mmol) was added, followed by 1-(cyanomethyl)thiolan-1-ium bromide (396 mg, 1.90 mmol). The reaction mixture was stirred at 0 °C for 5 min and then at room temperature for 1 h. The mixture was cooled to 0 °C and a saturated aqueous solution of ammonium chloride was added. Subsequently, the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography using a gradient from 50% ethyl acetate to 100% in hexanos to proportion (2S) -5-cyano-4-oxo-5- (14-thiolan-1-ylidene) -2- (1, 1, 3-trioxo-6, 6-diphenyl-1, 3-dihydro-2H, 6H-16-[1, 3]dioxolo[4, 5-f][1, 2]benzothiazol-2-yl) pentanoato de prop-2-en-1-ilo 101 (970 mg, raw) as a white foam. 1H NMR (400 MHz, CDCl3) 7, 57-7, 52 (s, 4H) , 7, 47-7, 42 (m, 7H) , 7, 30 (s, 1H) , 5, 91-5, 81 (m, 1H) , 5, 36 (dd, J = 8, 1, 5, 9 Hz, 1H) , 5, 32-5, 27 (m, 1H) , 5, 21-5, 18 (m, 1H) , 4, 71-4, 61 (m, 2H) , 3, 55-3, 30 (m, 6H) , 2, 65-2, 56 (m, 2H) , 2, 10-2.00 (m, 2H) . Step 10: Acid (4S) -2, 5-dioxo-5-[ (prop-2-en-1-yl) oxi]-4- (1, 1, 3-trioxo-6, 6-diphenyl-1, 3-dihydro-2H, 6H-16-[1, 3]dioxol[4, 5-f][1, 2]benzothiazol-2-yl)pentanoic acid (102) 101 102 To a solution of (2S)-5-cyano-4-oxo-5-(14-thiolan-1-ylidene)-2-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)prop-2-en-1-yl pentanoate 101 (970 mg, ~1.46 mmol) in THF (11 ml) water (11 ml) was added, followed by OXONA (898 mg, 2.92 mmol). The reaction mixture was stirred at room temperature for 1 h, additional OXONA (898 mg, 2.92 mmol) was added in two portions over 1 h and stirring was continued at room temperature for 2 h. Most of the THF was removed under reduced pressure and the aqueous solution was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give crude (4S)-2,5-dioxo-5-[(prop-2-en-1-yl)oxy]-4-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)pentanoic acid 102 (900 mg, crude) as a white foam which was used directly in the next stage. RMN de 1H (400 MHz, CDCl3) 7, 56-7, 53 (s, 4H) , 7, 47-7, 43 (m, 7H) , 7, 33 (s, 1H) , 5, 87-5, 79 (m, 1H) , 5, 43-5, 39 (m, 1H), 5, 32-5, 22 (m, 2H), 4, 72-4, 62 (m, 2H), 4, 14-4, 08 (m, 1H), 3, 59-3, 52 (m, 1H). Etapa 11: (4S)-2-oxo-4- (1, 1, 3-trioxo-6, 6-difenil-1, 3-dihidro-2H, 6H-16-[1, 3]dioxolo[4, 5-f][1, 2]benzotiazol-2-il) pentanodioato de 1-terc-butilo y 5- (prop-2-en-1-ilo) (103) 102 103 To a solution of (4S)-2,5-dioxo-5-[(prop-2-en-1-yl)oxy]-4-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)pentanoic acid 102 (900 mg, crude) in anhydrous THF (10 mL) N,N'-diisopropylcarbamimidate tert-butyl (0.38 mL, 1.52 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 5 min, the cooling bath was removed, and stirring was continued at room temperature for 1 h. Additional tert-butyl N,N'-diisopropylcarbamimidate (0.42 mL, 1.68 mmol) was added in small portions over 2 h, and stirring was continued at room temperature for 1 h. Most of the THF was removed under reduced pressure, and the mixture was treated with 30% DCM in hexanes. The precipitated solids were separated by filtration, and the filtrate was concentrated under vacuum.The residue was purified by silica gel column chromatography using an ethyl acetate gradient from 0% to 20% in hexanes to provide (4S)-2-oxo-4-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl) 1-tert-butyl pentanedioate 5-(prop-2-en-1-yl) 103 (341 mg, 38% in 3 stages) as a white foam. 1H NMR (400 MHz, CDCl3) 7,53-7,50 (s, 4H), 7,44-7,40 (m, 7H), 7,29 (s, 1H), 5,86-5,77 (m, 1H), 5,41-5,37 (m, 1H), 5, 29-5, 17 (m, 2H), 4, 68-4, 59 (m, 2H), 3, 93 (dd, J = 18, 4, 7, 6 Hz, 1H), 3, 46 (dd, J = 18, 4, 6, 8 Hz, 1H), 1, 54 (s, 9H) . Step 12: (2S)-5-tert-butoxy-4, 5-dioxo-2- (1, 1, 3-trioxo-6, 6-diphenyl-1, 3-dihydro-2H, 6H-16-[1, 3]dioxolo[4, 5-f][1, 2]benzothiazol-2-yl) pentanoic acid (104) 103 104 To a solution of (4S)-2-oxo-4-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)pentanedioate of 1-tert-butyl 5-(prop-2-en-1-yl) 103 (239 mg, 0.39 mmol) in anhydrous THF (7 ml) morpholine (0.10 ml, 1.14 mmol) was added at -5 °C. The mixture was purged with nitrogen for 10 min, PD (PPh) 3) 4 (23 mg, 0.02 mmol) was added and the reaction mixture was stirred from -5 °C to 0 °C in a nitrogen atmosphere for 2 h. The reaction mixture was diluted with diethyl ether and the organic phase was washed with 1 M HCl and brine, then dried over sodium sulfate, filtered and concentrated to provide (2S)-5-tert-butoxy-4,5-dioxo-2-(1,1,3-trioxo-6,6-diphenyl-1,3-dihydro-2H,6H-16-[1,3]dioxolo[4,5-f][1,2]benzothiazol-2-yl)pentanoic acid 104 (231 mg, crude) as a yellow foam which was used directly in the next stage. NMR of 1H (400 MHz, DMSO-d6) 8, 11 (s, 1H) , 7, 74 (s, 1H) , 7, 54-7, 45 ( m, 10H) , 5, 12 ( t , J = 7, 3 H 3, 1 , 6 ) , 3, 44-3, 38 (m, 1H) , 1, 45 (s, 9H) . Stage 13: (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-{[ (1-terc-butoxy-2-methyl-1-oxopropan-2-yl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-5-oxo-4- (1, 1, 3-trioxo-6, 6-diphenyl-1, 3-dihydro-2H, 6H-16-ti-[1, 3]dioxol-f]-2,[1, 3]dioxol-2-ben tert-butyl oxolane-2-carboxylate (105) To a mixture of (2S) -5-tert-butoxy-4, 5-dioxo-2- (1, 1, 3-trioxo-6, 6-diphenyl-1, 3-dihydro-2H, 6H-16-[1, 3]dioxolo[4, 5-f][1, 2]benzothiazol-2-yl) pentanoic acid 104 (231 mg, crude) and tert-Butyl 2-{[(z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-2-methylpropanoate 72 (189 mg, 0.37 mmol) in Anhydrous THF (7 ml) was added to DMAP (9 mg, 0.074 mmol), followed by DCC (99 mg, 0.48 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 h. The mixture was then concentrated under reduced pressure and the residue was treated with 25% DCM in hexanes. The precipitated solids were removed by filtration and the filtrate was concentrated under vacuum.El residue se purificó tramite cromografia en columna de gel de silica uso un gradiente de acetato de ethylo del 10 % al 30 % en hexanos para proporcionar (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (terc-butoxicarbonyl) amino]-1, 3-thiazol-4-il}-2-{[ (1-terc-butoxi-2-metil-1-oxopropan-2-il) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-il]-5-oxo-4- (1, 1, 3-trioxo-6, 6-difenil-1, 3-dihidro-2H, 6H-16-[1, 3]dioxolo[4, 5-f][1, 2]benzothiazol-2-yl) oxolano-2-carboxylate of tert-butyl 105 (209 mg, 53%) as a light amarillo colored foam. 1H MRI (400 MHz, CDCl3) 8, 23-8, 04 (s, 2H) , 7, 56-7, 51 (m, 4H) , 7, 47-7, 43 (m, 7H) , 7, 35 (m, 2H) , 5, 34-4, 82 (m, 3H) , 4, 38-4, 21 (m, 1H) , 3, 78-3, 42 (m, 1H) , 3, 00-2, 88 (m, 1H) , 1, 63-1, 60 (m, 6H) , 1, 58-1, 54 (m, 9H) , 1, 55 (s, 9H) , 1, 47-1, 44 (m, 9H) . Stage 14: Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (2-carboxipropan-2-yl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 1, 3-trioxo-1, 3-dihidro-2H-16, 2-benzothiazol-2-yl) -5-oxooxolan-2-carboxílico (Compuesto 37) 105 Compuesto 37 To a solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-{[ (1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-5-oxo-4-(1, 1, 3-trioxo-6, 6-diphenyl-1, 3-dihydro-2H, 6H-16-[1, 3]dioxolo[4, 5-f][1, 2]benzothiazol-2-yl) oxolane-2-carboxylate 105 (209 mg, 0.19 mmol) in anhydrous DCM (7 ml), a Boron trichloride solution (1.0 M in DCM, 1.56 mL, 1.56 mmol) was added at -50 °C. The reaction mixture was stirred from -50 °C to -25 °C for 2.5 minutes, and then a solution of NaHCO3 (320 mg) and Na2HPO4 (100 mg) in water (17.3 mL) at -50 °C was added. The mixture was then stirred from 0 °C to -5 °C (ice-water bath) for 10 minutes and then at room temperature until the aqueous phase thawed. The mixture was filtered through a 1 mm syringe filter, and the organic layer was carefully separated.The aqueous solution was then purified by C18 reversed-phase column chromatography using a Biotage system and mixtures of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents. The fractions containing the product were combined and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,1,3-trioxo-1,3-dihydro-2H-16,2-benzothiazol-2-yl)-5-oxooxolane-2-carboxylic acid Compound 37 (45 mg, 33%) as a whitish solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 43 (s, 1H) , 7, 36-7, 34 (m, 1H) , 7, 08-7, 06 (m, 1H) , 5, 27-5, 07 (m, 2H) , 4, 74-4, 67 (m, 1H) , 4, 32-4, 22 (m, 1H) , 3, 67-3, 35 (m, 1H) , 2, 98-2, 78 (m, 1H) , 1, 48 (s, 6H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 699, 0 Comparative Example 19 Acid (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-5-chloro-1, 3-thiazol-4-yl) -2-{[ (1-carboxycyclopropyl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic (Comparative Compound 24) Comparative Compound 24 Step 1: {2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}(oxo)acetic acid (107) 106 107 NCS (2.7 g, 20.2 mmol) was added to a solution of {2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}(oxo)acetic acid 106 (5.0 g, 18.4 mmol) in anhydrous 1,4-dioxane (35 mL) at room temperature. The reaction mixture was heated and stirred at 40 °C for 6 hours, then cooled and concentrated under reduced pressure. The crude mixture was ground using a mixture of diethyl ether (40 mL) and hexanes (20 mL). The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was further dried under high vacuum and then ground with hexanes. The precipitated whitish powder was collected by filtration to provide {2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}(oxo)acetic acid 107 (5, 7 g, quantitative yield). 1H NMR (400 MHz; DMSO-d6) 12, 21 (s, 1H), 1, 46 (s, 9H). Step 2: (2Z)-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetic acid (108) 107 108 To a solution of {2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}(oxo)acetic acid 107 (5.6 g, 18.4 mmol) in methanol (150 mL) was added 1-(aminooxy)cyclopropane-1-carboxylate 2 (3.5 g, 20.2 mmol). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. Traces of methanol were co-evaporated with hexane (3 x 50 mL) and the residue was further dried under high vacuum. The crude product was treated with 5% diethyl ether in hexanes and the resulting suspension was stirred overnight. The precipitated solid was collected by filtration to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetic acid 108 (8.3 g, 98%) as a whitish powder. 1H NMR (400 MHz; CDCl3) 2.81 (s, 1H), 1.64-1.61 (m, 2H), 1.60-1.51 (m, 11H), 1.48 (s, 9H). Stage 3: 1-{[ (Z) - (1-{2-[ (terc-butoxycarbonyl) amino]-5-chloro-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxi}cyclobutane-1-carboxylate de terc-butyl (109) 108 109 To a solution of (2Z)-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)cyclopropyl]oxy}imino)acetic acid 108 (8.3 g, 18.0 mmol) in anhydrous DMF (100 mL) DIPEA (4.7 mL, 26.9 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 5 min, then HATU was added and stirring continued at room temperature for 2 h. The reaction mixture was then diluted with anhydrous DMF (100 mL) and DIPEA (4.7 mL, 26.9 mmol) was added, followed by L-cycloserine (2.2 g, 21.6 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated to dryness under reduced pressure.The residue was purified by silica gel chromatography using a 0 to 4 % methanol gradient in DCM to provide 1-{[ (Z) - (1-{2-[ (terc-butoxycarbonyl) amino]-5-chloro-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxi}cyclopropane-1-carboxylate of tert-butyl 109 (7, 5 g, 76%) as an amorphous white solid. 1H NMR (400 MHz; DMSO-d6) 12, 04 (s, 1H) , 11, 58 (s, 1H) , 9, 02 (m, 1H) , 3, 95 (t, J = 8, 8 Hz, 1H) , 1, 45 (s, 9H) , 1, 39 (s, 9H) , 1, 34-1, 26 (m, 4H) . Stage 4: (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (terc-butoxycarbonyl) amino]-5-chloro-1, 3-thiazol-4-yl}-2- ({[1- (terc-butoxycarbonyl) cyclopropyl]oxi}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl)-5-oxooxolano-2-carboxylate de terc-butyl (110) 109 6 110 A mixture of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-5-chloro-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}cyclopropane-1-carboxylate of tert-butyl 109 (402 mg, 0.74 mmol) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) -4,5-dioxopentanoic acid 6 (400 mg, 0.74 mmol) in anhydrous THF (10 ml) was given DMAP (18 mg, 0.15 mmol) at 0 °C. The resulting mixture was stirred for 5 min, then DCC (212 mg, 1.0 mmol) was added at 0 °C. The reaction mixture was allowed to warm gradually to room temperature and stirred overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was ground with 30% DCM in hexanes (20 mL). The precipitated solids were removed by filtration and the filtrate was concentrated under vacuum.The crude mixture was purified by silica gel column chromatography using a gradient of 0 to 30% ethyl acetate in hexanes, and the resulting product was treated with 25% ethyl acetate in hexanes (20 ml). The separated solids were removed by filtration and the filtrate was concentrated to provide (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (tert-butoxycarbonyl)amino]-5-chloro-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl)cyclopropyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) -5-oxooxolane-2-carboxylate tert-butyl 110 (450 mg, 57%) as a whitish foam. NMR of 1H (400 MHz; CDCl3) 8, 39–8, 30 (m, 1H) , 7, 97–7, 93 (m, 1H) , 7, 57–7, 54 (m, 4H) , 7, 43 (t, 2 J = 3, 7, 6) 2H) , 5, 41 (c, J = 10, 0 Hz, 1H) , 5, 11-4, 93 (m, 2H) , 4, 28-4, 23 (m, 1H) , 3, 49-3, 29 (m, 1, J 8, 8 , 2 4 Hz, 1H) , 1, 63-1, 58 (m, 9H) , 1, 58-1, 50 (m, 13H) , 1, 49-1, 44 (m, 9H) . Stage 5: Acid (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-5-chloro-1, 3-thiazol-4-yl) -2-{[ (1-carboxycyclopropyl) oxy]-imino}acetyl]amino-ylxa}-li-3-4-o (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolane-2-carboxylic (Comparative Compound 24) 110 Comparative Compound 24 To a solution of (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (tert-butoxycarbonyl) amino]-5-chloro-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) cyclopropyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- Tert-butyl (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate 110 (200 mg, 0.19 mmol) in anhydrous DCM (16 mL) was added dropwise to a solution of boron trichloride (1.0 M in DCM, 1.49 mL, 1.49 mmol) at -50 °C. The reaction mixture was stirred from -35 °C to -30 °C for 2.5 h, then cooled to -50 °C and a solution of NaHCO3 (300 mg) and Na2HPO4 (100 mg) in water (16 mL) was added. The cold bath was replaced with an ice-water bath, the heterogeneous mixture was stirred at 5 °C–10 °C for 20 min, and then at room temperature until the aqueous layer thawed and the layers separated.The organic layer was carefully removed and the aqueous solution was purified by C18 reversed-phase column chromatography using a Biotage system and mixtures of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents. The pure fractions were collected and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-{[(1-carboxycyclopropyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid Comparative Compound 24 (70 mg, 54%) as a whitish solid. 1H NMR (400 MHz; CD3CN with D2O as co-solvent) 7, 23 (s, 2H) , 5, 45-5, 30 (m, 1H) , 5, 19-5, 01 (m, 1H) , 4, 72-4, 65 (m, 1H) , 4, 24-4, 17 (m, 1H) , 3, 59-3, 27 (m, 1H) , 2, 86-2, 61 (m, 1H) , 1, 47 (s, 2H) , 1, 43 (s, 2H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 695, 0 Comparative Example 20 Acid (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (1-carboxy-4, 4-dimethylcyclohexyl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-carboxylic acid (Comparative Compound 38) Comparative Compound 38 Step 1: 4,4-dimethyl-1-[(trimethylsilyl)oxy]cyclohexane-1-carbonitrile (112) 111 112 Zinc iodide (160 mg, 0.5 mmol) was placed in a dry round-bottom flask and dried under high vacuum with gentle heating for 30 minutes. A solution of 4,4-dimethylcyclohexan-1-one (3.16 g, 25.0 mmol) was added to anhydrous DCM (60 mL), and the reaction mixture was cooled to 0 °C. Trimethylsilyl cyanide (3.75 mL, 30.0 mmol) was slowly added at 0 °C, then the ice bath was removed, and stirring was continued at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was ground using 10% DCM in hexanes (100 mL). The precipitated solids were removed by filtration and the filtrate was collected and concentrated under vacuum to provide 4,4-dimethyl-1-[(trimethylsilyl)oxy]cyclohexane-1-carbonitrile 112 (5.18 g, 92%) as a light yellow oil. RMN de 1H (400 MHz; CDCl3) 2, 00-1, 94 (m, 2H) , 1, 83-1, 76 (m, 2H) , 1, 47 (t, J = 6, 2 Hz, 4H) , 0, 98 (s, 3H) , 0, 95 (s, 3H) , 0, 26 (s, 9H). Etapa 2: acido 1-hidroxi-4, 4-dimetilciclohexano-1-carboxílico (113) 112 113 A solution of 4,4-dimethyl-1-[(trimethylsilyl)oxy]cyclohexane-1-carbonitrile (5.1 g, 22.6 mmol) in glacial acetic acid (25 mL) was cooled to 0 °C. Concentrated HCl (25 mL) was added dropwise over a period of 10 minutes, and the reaction mixture was stirred at 0 °C for 15 minutes and then at room temperature for 15 minutes. Subsequently, the reaction mixture was heated and stirred at 100 °C for 4 h. The resulting mixture was allowed to cool to room temperature, and the volatiles were removed under reduced pressure. The residue was further dried under high vacuum and then collected in water (100 mL). The aqueous phase was saturated using solid sodium chloride and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 1-hydroxy-4,4-dimethylcyclohexane-1-carboxylic acid 113 (3.79 g, 97%) as a yellow solid. RMN de 1H (400 MHz; DMSO-d6) 12, 25 (s, 1H) , 4, 79 (s, 1H) , 1, 80-1, 72 (m, 2H) , 1, 48-1, 40 (m, 4H) , 1, 13-1, 08 (m, 2H) , 0, 87 (s, 3H) , 0, 85 (s, 3H) . Etapa 3: 1-hidroxi-4, 4-dimetilciclohexano-1-carboxilato de terc-butilo (114) 113 114 A solution of 1-hydroxy-4,4-dimethylcyclohexane-1-carboxylic acid (3.71 g, 21.54 mmol) in anhydrous THF (100 mL) was mixed with tert-butyl N,N'-diisopropylcarbamimidate (17.3 mL, 86.16 mmol, prepared as described in EP2471792A1), and the reaction mixture was stirred at room temperature for 14 h. The separated solid was separated by filtration and washed with THF. The combined filtrates were collected and concentrated under vacuum. The residue was collected in a mixture of DCM and hexanes (1:3, 100 mL), and the resulting suspension was cooled in an ice-water bath for 10 min. The precipitates were removed by filtration, rinsed with DCM and hexanes (1:3, 30 ml) and the filtrates were combined and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography using a 0 to 5% ethyl acetate gradient in hexanes to provide tert-butyl 1-hydroxy-4,4-dimethylcyclohexane-1-carboxylate 114 as a yellow solid (4, 12 g, 84%). 1H NMR (400 MHz; CDCl3) 2.96 (s, 1H), 1.92 (td, J = 13.1.4.2 Hz, 2H), 1.63-1.56 (m, 2H), 1.54-1.49 (m, 11H), 1.31-1, 26 (m, 2H) , 0.96 (s, 3H) , 0.96 (s, 3H) . Step 4: 1-(aminooxy)-4,4-dimethylcyclohexane-1-carboxylate tert-butyl (115) 114 115 A solution of tert-butyl 1-hydroxy-4,4-dimethylcyclohexane-1-carboxylate (1.57 g, 6.88 mmol) in nhydro THF (50 mL) was cooled to 0 °C under a nitrogen atmosphere. Sodium hydride (60% in mineral oil, 0.41 g, 10.32 mmol) was added in small portions, and the resulting mixture was stirred for 15 minutes at 0 °C. O-Diphenylphosphinylhydroxylamine (2.40 g, 10.32 mmol) was then added at 0 °C, and stirring continued for 30 minutes. The reaction mixture was allowed to warm gradually to room temperature and stirred for 4 hours. Additional O-diphenylphosphinylhydroxylamine (0.5 g, 2.14 mmol) was added, and stirring continued for 14 hours. Most of the THF was removed under reduced pressure and the residue was collected in a saturated sodium chloride solution (75 ml). The aqueous phase was extracted with ethyl acetate (2 x 150 ml) and the combined organic extracts were dried over sodium sulfate, filtered, concentrated, and dried under high vacuum.The crude product was purified by silica gel column chromatography using a 5% to 15% ethyl acetate gradient in hexanes to provide tert-butyl 115-(aminooxy)-4,4-dimethylcyclohexane-1-carboxylate 115 as a whitish solid (1.11 g, 66% yield). 1H NMR (400 MHz; CDCl3): 5.26 (s, 2H), 1.92-1.80 (m, 4H), 1.51 (s, 9H), 1.46-1.39 (m, 2H), 1.26-1.20 (m, 2H), 0.95 (s, 3H) , 0.94 (s, 3H) . Step 5: (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-4,4-dimethylcyclohexyl]oxy}imino)acetic acid (116) 115 116 A solution of 1-(aminooxy)-4,4-dimethylcyclohexane-1-carboxylate tert-butyl 115 (1.06 g, 4.35 mmol) in anhydrous MeOH (25 ml) was mixed with 2-(2-(tert-butoxycarbonylamino)thiazol-4-yl)-2-oxoacetic acid (1.06 g, 3.92 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was further dried under high vacuum to provide (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-4,4-dimethylcyclohexyl]oxy}imino)acetic acid 116 as a white solid (2.07 g, crude). 1H NMR (400 MHz; DMSO-d6) 11.75 (s, 1H), 7.33 (s, 1H), 1.83-1.80 (m, 4H), 1.45 (s, 9H), 1.40-1.35 (m, 11H), 1.17-1, 13 (m, 2H) , 0.88 (s, 3H) , 0.86 (s, 3H) . Step 6: 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy-4, 4-dimethylcyclohexane-1-carboxylate of tert-butyl (117) 116 117 To a solution of (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-4,4-dimethylcyclohexyl]oxy}imino)acetic acid 116 (1.00 g, 2.00 mmol) in anhydrous DMF (10 mL) DIPEA (0.52 mL, 3.00 mmol) was added and the resulting mixture was stirred at room temperature for 10 min. Then HATU (0.76 g, 2.00 mmol) was added and stirring continued at room temperature for 14 h. After that, an additional 15 mL of anhydrous DMF was added followed by DIPEA (1.4 mL, 8.00 mmol) and the mixture was stirred at room temperature for 10 min. L-cycloserine (0.30 g, 3.00 mmol) was added to this solution, the reaction mixture was stirred for 2 h and then concentrated under reduced pressure. Traces of DMF were removed by co-evaporation with toluene (3 x 10 mL) and the residue was dissolved in DCM (100 mL). The organic layer was washed with water (50 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography using a 0-3% MeOH gradient in DCM to provide 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-4,4-dimethylcyclohexane-1-carboxylate tert-butyl 117 as a white solid (1.02 g, 98%). 1H NMR (400 MHz; DMSO-d6) 11.78 (s, 1H), 11.57 (s, 1H), 9.04 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 4.92-4.86 (m, 1H), 4.57 (t, J = 8.5 Hz, 1H) , 4.07 (t, J = 9.0 Hz, 1H) , 1.90-1.71 (m, 4H) , 1.45 (s, 9H) , 1.39-1.33 (m, 11H) , 1.18-1.06 (m, 2H), 0.87 (s, 6H) . Stage 7: (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) -4, 4-dimethylxycyclohexyl acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl-8caroxyl butylato-5-dexo-2-o-f] A mixture of tert-butyl 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-4,4-dimethylcyclohexane-1-carboxylate 117 (0.38 g, 0.70 mmol) and (2S)-5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-FAcid]isoindol-6-yl)-4,5-dioxopentanoic acid 6 (0.407 g, 0.70 mmol) in anhydrous THF (20 mL) was cooled to 0 °C in a nitrogen atmosphere. DMAP (17 mg, 0.14 mmol) was added, followed by DCC (0.202 g, 0.98 mmol), and the reaction mixture was stirred at 0 °C for 1 h. The mixture was then allowed to warm gradually to room temperature and stirred overnight. The mixture was then concentrated at 25 °C, and the residue was ground with 30% DCM in hexanes (40 mL). The precipitated solids were removed by filtration, rinsed with 30% DCM in hexanes (15 mL), and hexanes (15 mL). The filtrates were combined and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography using a 0 to 30% ethyl acetate gradient in hexanes to provide (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[1-(tert-butoxycarbonyl)-4,4-dimethylcyclohexyl]oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate 118 as a whitish solid (0, 363 g, 47%). 1H NMR (400 MHz; CDCl3) 8, 11-8, 00 (m, 2H), 7, 58-7, 53 (m, 4H), 7, 45-7, 41 (m, 6H), 7, 35-7, 32 (m, 3H), 5, 42-5, 32 (m, 1H) , 5, 17-4, 93 (m, 2H) , 4, 27-4, 21 (m, 1H) , 3, 44-3, 31 (m, 1H) , 2, 90-2, 84 (m, 1H) , 2, 20-1, 90 (m, 4H) , 1, 61-1, 57 (s, 9H) , 1, 57-1, 53 (s, 9H) , 1, 49-1, 43 (s, 9H) , 1, 33-1, 24 (m, 4H) , 0, 99-0, 96 (s, 3H) , 0, 96-0, 92 (s, 3H) . Stage 8: (Ácido (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxy-4, 4-dimetilciclohexil) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 38) 118 Comparative Compuesto 38 To a solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl)-4, 4-dimethylcyclohexyl]oxy}imino)acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate 118 (346 mg, 0.312 mmol) in DCM anhydrous (16 ml), a solution of boron trichloride (1 M in DCM, 2.5 mL, 2.5 mmol) at -50 °C. The reaction mixture was stirred from -45 to -30 °C for 2.5 h, then cooled to -50 °C and inactivated using 30 mL of a buffer solution (prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 mL of water). The cold bath was replaced with an ice-water bath and the mixture was stirred until the aqueous layer thawed and two layers separated.The DCM layer was carefully removed and the aqueous phase was collected, filtered and immediately purified by C18 reversed-phase column chromatography using a Biotage system and mixtures of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents to provide ((4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-carboxy-4,4-dimethylcyclohexyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid Comparative Compound 38 as a pale yellow foamy solid with a yield of 35% (80 mg). 1H NMR (400 MHz; a mixture of D2O and CD3CN) 7, 23 (s, 2H), 7, 05 (s, 1H), 5, 38-5, 29 (m, 1H), 5, 14-5, 04 (m, 1H), 4, 74-4, 66 (m, 1H), 4, 31-4, 27 (m, 1H), 3, 35-3, 26 (m, 1H), 2, 80-2, 68 (m, 1H), 1, 98-1, 88 (m, 4H), 1, 35-1, 24 (m, 2H), 1, 24-1, 15 (m, 2H) , 0, 88 (s, 3H) , 0, 84 (s, 3H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 731, 2 Comparative Example 21 Acid (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (1-carboxy-3, 3-dimethylcyclobutyl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-carboxylic acid (Comparative Compound 14) Comparative Compound 14 Stage 1: 1-bromo-3, 3-dimethylcyclobutane-1-carboxylic acid (120) 119 120 A mixture of 3,3-dimethylcyclobutane-1-carboxylic acid (5.0 g, 39.0 mmol) and bromine (3 mL, 58.5 mmol) was placed in a round-bottom pressure flask, and PBr3 (0.6 mL, 6.5 mmol) was carefully added at room temperature. An ice-water bath was used during the addition to control the temperature of the reaction mixture. The reaction flask was sealed, and the reaction mixture was heated and stirred at 100 °C overnight. The reaction mixture was then cooled to room temperature, and the flask was carefully opened to release some of the accumulated internal pressure. The mixture was diluted with ethyl acetate (100 mL) and washed with 5% NaHSO3 solution (2 x 30 mL), water (2 x 30 mL), and brine (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give 1-bromo-3,3-dimethylcyclobutane-1-carboxylic acid 120 as a whitish solid (8.0 g, quantitative yield). 1H NMR (599 MHz; CDCl3) 2.89-2.86 (m, 2H), 2.56-2.53 (m, 2H), 1.38 (s, 3H), 1.08 (s, 3H). Step 2: tert-butyl 1-bromo-3,3-dimethylcyclobutane-1-carboxylate (121) 120 121 To a stirred mixture of 1-bromo-3,3-dimethylcyclobutane-1-carboxylic acid 120 (8.0 g, 36.6 mmol), t-BuOH (4.0 g, 54.1 mmol), and DMAP (472 mg, 3.9 mmol), triethylamine (11.9 mL, 85.0 mmol) was added, followed by di-tert-butyl dicarbonate (11.0 g, 50.2 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The reaction mixture was then partitioned between hexanes (150 mL) and water (50 mL), and the layers were separated. The aqueous phase was further extracted with EtOAc (4 x 30 mL). The combined organic extracts were washed with 1 N HCl (2 x 30 ml) and water (2 x 30 ml) and then concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography using a gradient of 0 to 5% ethyl acetate in hexanes to provide tert-butyl 1-bromo-3,3-dimethylcyclobutane-1-carboxylate 121 as a colorless liquid (6.45 g, 63%). RMN de 1H (400 MHz; CDCl3) 2, 83-2, 80 (m, 2H) , 2, 53-2, 49 (m, 2H) , 1, 52 (s, 9H) , 1, 31 (s, 3H) , 1, 04 (s, 3H) . Etapa 3: 1- ({ (z)-[1- (2-amino-1, 3-tiazol-4-il) -2-etoxi-2-oxoetiliden]amino}oxy)-3, 3-dimetilciclobutano-1-carboxilato de terc-butilo (122) 121 122 Potassium carbonate (210 mg, 1.5 mmol) was added to a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetate (200 mg, 0.91 mmol) in anhydrous DMSO (5 mL) at room temperature. The resulting mixture was stirred at 50 °C for 5 min, and tert-butyl 1-bromo-3,3-dimethylcyclobutane-1-carboxylate (200 mg, 0.76 mmol) was added. The reaction mixture was stirred at 50 °C for 2 days, then cooled, diluted with water (30 mL), and extracted with diethyl ether (8 × 20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0 to 20% ethyl acetate gradient in hexanes to provide 1-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-ethoxy-2-oxoethylidene]amino}oxy)-3,3-dimethylcyclobutane-1-carboxylate tert-butyl 122 as a whitish solid (150 mg, 50%). RMN de 1H (400 MHz; CDCl3) 6, 61 (s, 1H), 6, 57-6, 57 (m, 2H), 4, 41 (c, J = 7, 1 Hz, 2H), 2, 41-2, 37 (m, 2H), 2, 09-2, 06 (m, 2H), 1, 45 (s, 9H), 1, 37 (t, J = 7, 1 Hz, 3H), 1, 20 (s, 3H), 1, 15 (s, 3H). Etapa 4: 1- ({(Z)-(1-(2-amino]-1, 3-tiazol-4-il)-2-etoxi-2-oxoetiliden)amino]oxy)-3, 3-dimetilciclobutano-1-carboxilato de terc-butilo (123) 122 123 A solution of 1-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-ethoxy-2-oxoethylidene]amino}oxy)-3,3-dimethylcyclobutane-1-carboxylate tert-butyl 122 (1.0 g, 2.5 mmol) in anhydrous THF (10 mL) was cooled to 0 °C. TMEDA (0.02 mL, 0.13 mmol) was added, followed by a solution of tert-butyl dicarbonate (0.577 g, 2.6 mmol) in THF (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure and traces of solvent were removed by co-evaporation with MeOH (4 x 30 ml). The residue was purified by silica gel column chromatography using a 0 to 20% ethyl acetate gradient in hexanes to provide 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-ethoxy-2-oxoethylidene)amino]oxy}-3,3-dimethylcyclobutane-1-carboxylate DE tert-butyl 123 as a white foam (1.20 g, 96%). RMN de 1H (400 MHz; CDCl3) 7, 21 (s, 1H), 4, 42 (c, J = 7, 1 Hz, 2H), 2, 41 (d, J = 14, 0 Hz, 2H), 2, 11 (d, J = 14, 0 Hz, 2H), 1, 52 (s, 9H), 1, 45 (s, 9H), 1, 37 (t, J = 7, 1 Hz, 3H), 1, 21 (s, 3H), 1, 16 (s, 3H). Etapa 5: Acido(2Z)-{2-[(terc-butoxicarbonil)amino]-1, 3-tiazol-4-il} ({[1-(terc-butoxicarbonil)-3.3-dimetilciclobutil]oxy}imino) acético (124) 123 124 To a solution of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-ethoxy-2-oxoethylidene)amino]oxy}-3, 3-dimethylcyclobutane-1-carboxylate tert-butyl 123 (3.2 g, 6.4 mmol) in MeOH (25 mL) LiOH monohydrate (0.81 g, 19.3 mmol) in H2O (10 mL) was added at room temperature. The reaction mixture was heated and stirred at 55 °C overnight. The reaction mixture was then concentrated under reduced pressure to remove the methanol, and the pH of the aqueous solution was acidified to ~4 using 1 N HCl (~20 mL). The aqueous solution was then extracted with ethyl acetate (6 x 20 ml) and the combined organic extracts were washed with brine (2 x 20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-3,3-dimethylcyclobutyl]oxy}imino)acetic acid 124 as a whitish foam (3.0 g, 99%).The product obtained was used in the next stage without further purification. 1H NMR (400 MHz; CDCl3) 7, 43 (s, 1H) , 2, 42-2, 32 (s, 4H) , 1, 55 (s, 9H) , 1, 51 (s, 9H) , 1, 36-1, 35 (m, 2H) , 1, 31-1, 30 (m, 2H) , 1, 26 (s, 3H) , 1, 22 (s, 3H) . Step 6: tert-butyl 1-{[(Z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy-3,3-dimethylcyclobutane-1-carboxylate (125) 124 125 To a solution of the compound (2Z)-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}({[1-(tert-butoxycarbonyl)-3,3-dimethylcyclobutyl]oxy}imino)acetic acid 124 (3.0 g, 6.4 mmol) in anhydrous DMF (35 ml) were added DIPEA (1.67 ml, 9.6 mmol) and HATU (2.43 g, 6.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h and then DIPEA (1.67 ml, 9.6 mmol) and DMF (35 ml) were added followed by L-cycloserine (0.783 g, 7.7 mmol). The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate (150 ml). The organic phase was washed with water (6 x 30 ml) and the aqueous layers were combined and re-extracted with diethyl ether (5 x 30 ml). The organic extracts were combined, washed with brine (2 x 30 ml), dried over anhydrous sodium sulfate, and concentrated under vacuum.The residue was purified by silica gel column chromatography using a 0 to 5% methanol gradient in DCM to provide 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}-3, 3-dimethylcyclobutane-1-carboxylate tert-butyl 125 as a whitish solid (1.97 g, 56%). 1H NMR (400 MHz; DMSO-d6) 11.85 (s, 1H), 11.60 (s, 1H), 9.15 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 5.04-4.87 (a, J = 1.1 Hz, 1H), 4, 69-4, 56 (m, 1H), 4, 14-4, 05 (m, 1H), 2, 36-2, 24 (m, 2H), 2, 09-1, 98 (m, 2H), 1, 47 (s, 9H), 1, 41 (s, 9H) , 1, 17 (s, 3H) , 1, 13 (s, 3H) . Stage 7: (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (tert-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) -3, 3-dimethylimino}cyclobutyl acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-5-f]isoindol-6-yl-yl-ylcarboxyl butylato-5-o-2-o-f] 125 6 126 A mixture of 1-{[ (Z) - (1-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-oxo-2-{[ (4S) -3-oxo-1, 2-oxazolidin-4-yl]amino}ethylidene) amino]oxy}-3, 3-dimethylcyclobutane-1-carboxylate tert-butyl 125 (408 mg, 0.74 mmol) and (2S) -5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5f]isoindol-6-yl) -4,5-dioxopentanoic acid 6 (400 mg, 0.74 mmol) in anhydrous THF (10 ml) was cooled to At 0 °C, DMAP (18 mg, 0.15 mmol) was added, followed by DCC (212 mg, 1.0 mmol). The resulting mixture was allowed to warm gradually to room temperature and stirred overnight. The reaction mixture was then concentrated under reduced pressure, and the residue was ground with 30% DCM in hexanes (20 mL). The precipitated solids were removed by filtration, and the filtrate was concentrated under vacuum.The crude mixture was purified by silica gel column chromatography using a gradient of 0 to 30% ethyl acetate in hexanes and the resulting product was ground with 25% ethyl acetate in hexanes (20 ml). The precipitate was separated by filtration and the filtrate was concentrated to give (4S) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl) -3, 3-dimethylcyclobutyl]oxy}imino) acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl) -5-oxooxolane-2-carboxylate tert-butyl 126 as a whitish foam (520 mg, 65%). NMR of 1H (400 MHz; CDCl3) 8, 34-8, 27 (m, 1H) , 8, 12-8, 00 (m, 1H) , 7, 57-7, 54 (m, 4H) , 7, 47-7, 76, 42 (m, 3 , 4) (m (m, 2H) , 5, 44-5, 35 (m, 1H) , 5, 22-4, 99 (m, 1H) , 4, 99-4, 86 (m, 1H) , 4, 29-4, 17 (m, 1H Hz) 48, - m3, 3, . 1H) , 2, 90-2, 84 (m, 1H) , 2, 48-2, 26 (m, 4H) , 1, 60-1, 57 (m, 9H) , 1, 56-1, 54 (s, 9H) , 1, 1, 41-H 27-1, 24 (m, 3H) , 1, 24-1, 23 (m, 3H) . Stage 8: Acid P (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (1-carboxy-3, 3-dimethylcyclobutyl) oxy]imino}-acetyl-1-oxon-]amino 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxylic (Comparative Compound 14) 126 Comparative Compound 14 To a solution of (4S)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2- ({[1- (tert-butoxycarbonyl)-3, 3-dimethylcyclobutyl]oxy}imino)acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolan-2-carboxylate 126 (200 mg, 0.19 mmol) in anhydrous DCM (16 ml) a solution of boron trichloride (1.0 M in DCM, 1.48 mL, 1.48 mmol) at -50 °C. The reaction mixture was stirred from -35 °C to -30 °C for 2.5 h, then cooled to -50 °C and a solution of NaHCO3 (300 mg) and Na2HPO4 (100 mg) in H2O (16 mL) was added. The cold bath was replaced with an ice-water bath, the mixture was stirred for 30 min and then at room temperature until the aqueous layer thawed (~30 min). The layers were allowed to separate and the organic phase was carefully removed.The aqueous solution was then purified by C18 reversed-phase column chromatography using a Biotage system and mixtures of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents. The fractions containing the product were collected and lyophilized to provide (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-carboxy-3,3-dimethylcyclobutyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid Comparative Compound 14 (55 mg, 42%) as a whitish solid. 1H NMR (400 MHz; a mixture of CD3CN with D2O) 7, 23 (s, 2H), 7, 10 (s, 1H), 5, 42-5, 21 (m, 1H), 5, 16-5, 08 (m, 1H), 4, 77-4, 66 (m, 1H), 4, 32-4, 22 (m, 1H) , 3, 55-3, 24 (m, 1H) , 2, 87-2, 67 (m, 1H) , 2, 39 (d, J = 7, 2 Hz, 2H) , 2, 06 (d, J = 7, 2 Hz, 2H) , 1, 11 (s, 3H), 1, 09 (s, 3H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 703, 1 Comparative Example 22 Acid (4S)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (2-carboxypropan-2-yl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihydroxy-1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-carboxylic acid (Comparative Compound 40) Comparative Compound 40 Etapa 1: (4R) -2-[ (4S) -4-{[ (2Z) -2-{2-[ (terc-butoxycarbonyl) amino]-1, 3-thiazol-4-yl}-2-{[ (1-terc-butoxy-2-methyl-1-oxopropan-2-yl) oxi]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -5-oxooxolano-2-carboxylate de terc-butyl (127) The acid (2R) -5-terc-butoxy-2- (5, 7-dioxo-2, 2-diphenyl-5, 7-dihydro-2H, 6H-[1, 3]dioxolo[4, 5-f]isoindol-6-yl) -4, 5-dioxopentanoico 128 It is prepared in a similar way to the one described in J. Med. Chem., 2014, 57, 3845-3855, starting from N-[(benciloxi) carbonyl]-4-oxo-D-glutamate de 5-terc-butyl y 1-methylo y 2, 2-diphenyl-2H-furo[3, 4-f][1, 3]benzodioxol-5, 7-diona. To a mixture of (2R)-5-tert-butoxy-2- (5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-4,5-dioxopentanoic acid 128 (200 mg, 0.37 mmol) and 2-{[ (z)-(1-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-oxo-2-{[(4S)-3-oxo-1,2-oxazolidin-4-yl]amino}ethylidene)amino]oxy}-2-methylpropanoate tert-butyl 72 (189 mg, 0.37 mmol) in anhydrous THF (4 ml) DMAP (9 mg, 0.074 mmol) and DCC (107 mg, 0.52 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was ground with 40% DCM in hexanes (20 mL) and the separated solid was separated by filtration and washed with hexanes.The combined filtrates were concentrated and the crude product was purified by silica gel column chromatography using a 10–35% ethyl acetate gradient in hexanes to yield tert-butyl (4S)-2-[(4S)-4-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-({[1-(tert-butoxy-2-methyl-1ºxopropan-2-yl)oxy}imino)acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate 127 (174 mg, 45%) as a light brown foam. 1H NMR (400 MHz, CDCl3) 8, 09 (sa, 1H), 7, 52-7, 48 (m, 4H), 7, 40-7, 37 (m, 6H), 7, 27 (s, 2H), 7, 23 (s, 1H), 5, 41-5, 28 (m, 1H) , 5, 15-4, 82 (m, 2H) , 4, 24-4, 15 (m, 1H) , 3, 50-3, 38 (m, 2H) , 2, 88-2, 76 (m, 1H) , 1, 95-1, 85 (m, 1H) , 1, 72-1, 61 (m, 1H), 1.58 (s, 6H), 1.54 (d, 9H), 1.50 (s, 9H), 1.41 (s, 9H) Stage 2: (4R)-2-[ (4S)-4-{[ (2Z)-2- (2-amino-1, 3-thiazol-4-yl)-2-{[ (2-carboxipropan-2-yl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1, 3-dioxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico (Compuesto Comparativo 38) 127 Comparative Compuesto 40 A solution of (4R)-2-[ (4S)-4-{[ (2Z)-2-{2-[ (tert-butoxycarbonyl)amino]-1, 3-thiazol-4-yl}-2-{[ (1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1, tert-Butyl 2-oxazolidin-2-yl]-4-(5,7-dioxo-2,2-diphenyl-5,7-dihydro-2H,6H-[1,3]dioxolo[4,5-f]isoindol-6-yl)-5-oxooxolane-2-carboxylate 127 (170 mg, 0.163 mmol) in DCM Anhydrous solution (10 ml) was cooled to -50 °C and a solution of Boron trichloride (1.0 M in DCM, 1.3 mL, 1.3 mmol). The reaction mixture was stirred from -50 to 35 °C for 2.5 h, then cooled to -50 °C before adding 14.3 mL of a buffer solution (prepared by dissolving 776 mg of NaHCO3 and 243 mg of Na2HPO4 in 42 mL of water). The cold bath was replaced with an ice-water bath and the heterogeneous mixture was stirred until the aqueous phase thawed and two layers separated.The organic layer was carefully removed and the aqueous phase was immediately purified by C18 reversed-phase column chromatography using a Biotage system and a mixture of 0.1% formic acid in acetonitrile and 0.1% formic acid in water as eluents to provide (4R)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolane-2-carboxylic acid Comparative Compound 40 (40 mg, 37%) as a pale yellow solid. 1H NMR (400 MHz, a mixture of D2O and CD3CN) 7, 35 (s, 2H) , 7, 18 (s, 1H) , 5, 54-5, 48 (m, 1H) , 5, 28-5, 20 (m, 1H) , 4, 91-4, 76 (m, 1H) , 4, 4.- 4, 30 (m, 1H) , 3, 52-3, 32 (m, 1H) , 2, 89-2, 76 (m, 1H) , 1, 58 (s, 6H) . No exchangeable protons were observed in D2O. MS (ESI) m / z: [M+1]+ 663, 1 BIOLOGICAL ACTIVITY Method for in vitro antibacterial evaluation Bacterial isolates Gram-negative and Gram-positive bacterial strains were obtained from the American Type Culture Collection (ATCC) or from clinical samples for in vitro determination of the minimum inhibitory concentration (MIC). All strains were genotypically characterized, and their respective antibiotic resistance markers were identified. Table 2 below shows the strains used and their respective resistance markers. Table 2. Bacterial strains used for in vitro MIC tests continuation Determination of the CMI The isolates were subcultured on appropriate media and stored in skim milk at -80 °C. After two subcultures of frozen stock, in vitro antimicrobial susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Briefly, freshly prepared cultures were suspended in culture media to obtain a final stock inoculum size of 5 × 10⁷ colony-forming units per milliliter of broth (CFU / ml). Test compounds were prepared at a stock solution concentration of 128 µg / ml, then diluted to a final working concentration of 32 µg / ml. The first wells of a 96-well plate were added to 100 µl of the stock solutions and then diluted using a double dilution method to give a range of 32-0.025 µg / ml.Then, 100 µl of the bacterial suspensions were added to 96-well plates to obtain a final working inoculum size of 5 x 10⁵ CFU / ml. The final compound concentration range was 16–0.0125 µg / ml. All compounds were tested in Mueller-Hinton broth with iron-depleted cations, and the minimum inhibitory concentration (MIC) was read as the first well in which growth was significantly reduced (a button <1 mm or slight turbidity) compared to the growth control. MICs for comparator agents were determined using custom-designed, in-house prepared 96-well broth microdilution panels. Determination of synergistic activity The same method used to test the activity of the claimed compounds was used to determine their synergistic activity when combined with a β-lactamase inhibitor, except that a fixed concentration or fixed ratio of a β-lactamase inhibitor was added to the 96-well plates before the addition of the bacterial cultures. Synergistic activity was defined as the reduction in the MIC of a given compound when tested using the β-lactamase inhibitor versus testing the compound in the absence of a β-lactamase inhibitor. Test results As shown in Tables 3-6, the indicated compounds exhibited activity against Gram-negative bacteria, including resistant strains. MICs for the indicated compounds against wild-type strains of Acinetobacter baumannii, Citrobacter, Escherichia coli, and Pseudomonas aeruginosa ranged from 0.03 to >16 µg / ml. The compounds were also active against resistant strains of Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella oxytoca, and Pseudomonas aeruginosa. The MIC for these strains ranged from <0.015 to >16.0 µg / ml (Tables 3-6). The MIC of selected compounds was enhanced by the use of Avibactam. There was a 3- to 4-fold reduction in MIC due to beta-lactamase inhibition by Avibactam (Tables 7 and 8). Table 3. Antibacterial activity of the comparative compounds Continuation Table 4. Antibacterial activity of the comparative compounds Continuation Table 5. Antibacterial activity of the representative comparative compounds Continuation Table 6. Antibacterial activity of the representative comparative compounds Continuation Table 7. MIC against elevated Am C CMY-DHA-producing ceas in the presence of Avibactam at 4 / ml Continuation 1 CAZ ceftazidime; 2 AVI Avibactam Table 8. MIC against elevated Am C CMY-DHA-producing ceas in the presence of Avibactam at 4 / ml Continuation 1 CAZ ceftazidime; 2 AVI Avibactam

Claims

1. A compound of formula (I) where A is defined by formula (Ia) and where X is N or CR3 and R3 represents hydrogen or halogen; R1 and R2, together with the carbon atom to which they are attached, may form a (C3-C8) cycloalkyl, wherein (i) the cycloalkyl may contain a heteroatom selected from O, N and S, and / or (ii) the cycloalkyl may be substituted with one, two, three or four substituents selected independently from each other from the group consisting of (C1-C3) alkyl and halogen; or R1 and R2 may, independently of each other, represent hydrogen or (C1-C3) alkyl, wherein the (C1-C3) alkyl may be substituted with a substituent selected from hydroxy and chlorine; B is a bicyclic catechol or hydroxypyridone fraction bearing a fragment defined by the formula (Ia') wherein P is a 5-membered or 6-membered unsaturated ring,comprising a single carbonyl group (CO) or a sulfone group (SO2) or a combination of a carbonyl group (CO) and a sulfone group (SO2) and may further contain up to two additional N atoms; and wherein Q may contain up to two N atoms and wherein R4 is selected from the group consisting of hydrogen, (C1-C3) alkyl, carbonyl, trifluoromethyl, cyano, and a halogen; and salts thereof, solvates thereof, and solvates of the salts thereof.

2. The compound according to claim 1, wherein the halogen of R3 is fluorine or chlorine; or the halogen of the cycloalkyl (ii) is fluorine or chlorine; or the halogen of R4 is fluorine or chlorine; or P is a 5-membered unsaturated ring; or Q is benzene or pyridine.

3. The compound according to claim 1, wherein of formula (I) is selected from the group consisting of:

4. The compound according to claim 1 or 3,wherein A of formula (I) is selected from the group consisting of:

5. The compound according to any one of claims 1, 3 or 4, wherein B of formula (I) is selected from the group consisting of: wherein R4 is selected from the group consisting of hydrogen, (C1-C3) alkyl, trifluoromethyl, cyano and halogen.

6. The compound according to claim 1, wherein the compound of formula (I) is: (4S)-2-[(4S)-4-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-carboxycyclopropyl)oxy]imino}acetyl]amino}-3-oxo-1,2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-carboxylic acid 4-({(Z)-[1-(2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(5,6-dihydroxy-1-oxo-1, 3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy)oxane-4-carboxylic acid 3- ({ (Z) -[1- (2-amino-1,3-thiazol-4-yl)-2-({(4S)-2-[(4S)-2-carboxy-4-(5,6-dihydroxy-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino)-2-oxoethylidene]amino}oxy) -8-oxabiciclo[3.2.1]octano-3-carboxílico Ácido 2-[ (4S)-4-{[ (2Z)-2-(2-amino-1, 3-thiazol-4-yl)-2-{[ (1-carboxycyclopropyl) oxy]imino}acetyl]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4-(5,6-dihydroxy-1,1-dihydroxy) 3-trioxo-1, 3-dihydro-2H-16, 2-benzothiazol-2-yl) -5-oxooxolan-2-carboxylic acid 4-({ (Z) -[1-(2-amino-1, 3-thiazol-4-yl) -2-({ (4S) -2-[2-carboxy-4-(5, 6-dihydroxy-1, 1, 3-trioxo-1, 3-dihydro-2H-16, 2-benzothiazol-2-yl) -5-oxooxolan-2-yl]-3-oxo-1, 2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxy)oxano-4-carboxylic acid 3-({ (Z) -[1-(2-amino-1, 3-thiazol-4-yl) -2-({ (4S) -2-[2-carboxy-4-(5, 6-dihydroxy-1, 1,3-trioxo-1,3-dihydro-2H-16,2-benzothiazol-2-yl)-5-oxooxolan-2-yl]-3-oxo-1,2-oxazolidin-4-yl}amino) -2-oxoethylidene]amino}oxi) -8-oxabicyclo[3.2.1]octano-3-carboxílico Ácido (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{[ (2-carboxipropan-2-yl) oxi]imino}acetil]amino}-3-oxo-1, 2-oxazolidin-2-yl]-4- (5, 6-dihidroxi-1-oxo-1, 3-dihidro-2H-isoindol-2-yl) -5-oxooxolan-2-carboxílico Ácido (4S) -2-[ (4S) -4-{[ (2Z) -2- (2-amino-1, 3-thiazol-4-yl) -2-{,