Siderophore-cephalosporin conjugates and uses thereof

Abstract

Formula (I): [C22] JPEG2022546780000027.jpg50108(I) wherein X is selected from the group consisting of CH, CCl, and N; Z is selected from the group consisting of CH2COOH, CH(CH3)COOH, C(CH3)2COOH, and CH2F; D is a single bond connecting A and Ar, or is selected from the group consisting of CO, NHCO, and N(C 0~6 A is selected from the group consisting of (C 1~6 ) alkanediyl and (C 3~6 cycloalkanediyl, or when D is N(C0)alkyl-CO, A forms a 4- to 7-membered aliphatic heterocycle with the nitrogen atom of the N(C0)alkyl-CO in D; Ar is a 6-membered aromatic ring having a first hydroxyl group para to D, a second hydroxyl group meta to D, and at least one electron-withdrawing element. Compounds and uses thereof.

Description

[Technical field]

[0001] The present invention relates to organic compounds, namely siderophore-cephalosporin conjugates and uses thereof. [Background technology]

[0002] Cephalosporins are a class of β-lactam antibiotics with a common core structure, namely the cephem ring system 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. The bacterial spectrum, i.e. the bactericidal activity of cephalosporins against various bacteria, varies depending on the substitution pattern. Cephalosporin compounds containing a CH=N moiety in the side chain at position 3 of the cephem ring are described, for example, in WO 96 / 35692, and oxime-type CH=NO compounds are exemplified therein in Examples 3, 4 and 6.

[0003] Siderophores are iron chelating compounds, and siderophore-drug conjugates exploit the iron uptake mechanism in bacteria. Some examples of siderophore-drug conjugates are summarized, for example, in Ji, C. et al, Future Med. Chem. (2012) 4(3), 297-313.

[0004] Siderophore-conjugated cephalosporins are described, for example, in WO 2010 / 050468, WO 2011 / 136268, WO 2012 / 134184 and WO 2012 / 147773, which cover derivatives bearing an alkyl or alkenyl with a quaternary ammonium group in the side chain at position 3 of the cephem ring. For example, WO 2010 / 050468 exemplified cefiderocol, a catechol-type siderophore cephalosporin conjugate that represents the most advanced siderophore drug conjugate, and is currently in the preregistration stage for the potential intravenous treatment of multidrug-resistant (MDR) Gram-negative bacterial infections. [ka]

[0005] Strong iron chelating properties are important because siderophore drug conjugates are able to compete with natural siderophores for excretion by microorganisms. Summary of the Invention

[0006] The present invention relates to a compound of formula (I): [ka] (In the formula, X is selected from the group consisting of CH, CCl, and N; Z is selected from the group consisting of CH2COOH, CH(CH3)COOH, C(CH3)2COOH, and CH2F; D is a single bond connecting A and Ar or CO, NHCO and N(C 0~6 ) alkyl-CO; A is, -(C 1~6 ) Alkanediyl and -(C 3~6 ) cycloalkanediyl; or When D is N(C0)alkyl-CO, A forms a 4- to 7-membered aliphatic heterocycle together with the nitrogen atom of N(C0)alkyl-CO in D; Ar is a six-membered aromatic ring having a first hydroxyl group para to D, a second hydroxyl group meta to D, and at least one electron-withdrawing element. The present invention provides a compound according to the present invention.

[0007] In the compounds according to the invention, the siderophore group (Ar) is linked to the cephalosporin core by a linkage that contains an oxime ether at the 3-position of the cephem ring. The resulting oxime-type siderophore-conjugated cephalosporins have not been described before. The inventors have surprisingly found that the oxime-type siderophore-conjugated cephalosporins, i.e. the compounds according to formula (I), have an interesting antibacterial activity combined with unexpectedly strong iron-chelating properties. The oxime linkage of the siderophore group (Ar) is responsible for the surprisingly strong iron-chelating properties. Example 4, which differs from the compound cefiderocol mainly in the linker, shows an iron-chelating activity one order of magnitude stronger than that measured for cefiderocol (see Table 1 below).

[0008] In the compound according to formula (I), Ar is believed to be primarily responsible for the iron chelating properties of the compound. Ar is a six-membered aromatic ring bearing two hydroxyl groups. Both hydroxyl groups are ortho-substituted to each other (catechol type), which is known to allow for complexation of the iron atom (i.e., iron chelation). The first hydroxyl group occupies the position opposite to that attached to the remainder of the compound (i.e., para position). The second hydroxyl group occupies the position of the carbon atom adjacent to that attached to the first hydroxyl group (i.e., meta position relative to that attached to the remainder of the compound).

[0009] In the compounds according to the invention, the siderophore group Ar further comprises at least one electron-withdrawing element.

[0010] Electron-withdrawing is a known concept in organic chemistry and refers to the polar or electrostatic force towards the reaction center, or in this case towards the electron system in the aromatic ring. The electron-withdrawing element may be, for example, an electron-withdrawing substituent on the aromatic ring. D is CO, NHCO and N(C 0~6 ) alkyl-CO, the aromatic ring Ar is substituted with a carbonyl group, which is known to have an electron-withdrawing effect, whereas according to the present invention, Ar has at least one additional electron-withdrawing element.

[0011] The further electron-withdrawing element may be a substituent located at any free position of the aromatic ring, such as, for example, a halogen, a nitrile, a carbonyl (especially a C1-C6 carbonyl, e.g., formyl, acetyl), or a halogenated alkoxyl.

[0012] In a preferred embodiment, the electron-withdrawing substituent is a substituent selected from the group consisting of F, Cl and OCF3. In particular, the electron-withdrawing substituent is a substituent at a free position on the aromatic ring, preferably at the ortho position relative to D.

[0013] Alternatively or additionally, the electron-withdrawing element may be a heteroatom in the aromatic ring Ar.

[0014] In a preferred embodiment, the electron-withdrawing element is a nitrogen atom or a substituted nitrogen atom in the aromatic ring Ar. Thus, the resulting aromatic ring Ar is a pyridine-based aromatic ring. For example, the aromatic ring is pyridine, N-(C 1~6 ) alkyl-pyridinium and pyridine-N-oxide. Preferably, the pyridine-based aromatic ring is substituted with two hydroxyl groups at the 3- and 4- (or 4- and 5-) positions relative to the nitrogen atom and is linked to D (or the remainder of the molecule) at the 2- (or 6-) position relative to the nitrogen atom. Exemplarily, Ar is selected from the group consisting of 3,4-dihydroxy-2-pyridinyl, 4,5-dihydroxy-2-pyridinyl, 3,4-dihydroxy-1-(C1-C6)alkyl-2-pyridiniumyl, 4,5-dihydroxy-1-(C1-C6)alkyl-2-pyridiniumyl, 1,3-dihydroxy-4-oxo-2-pyridyl and 1,5-dihydroxy-4-oxo-2-pyridyl, preferably 4,5-dihydroxy-2-pyridinyl, 4,5-dihydroxy-1-(C1-C6)alkyl-2-pyridiniumyl, 1,5-dihydroxy-4-oxo-2-pyridyl.

[0015] In a further preferred embodiment, the compound according to the invention has the formula (II): [ka] wherein X, Z, D, and A are defined as above; E is CH, N, N + -CH3, and N + -O - is selected from the group consisting of G is H or an electron-withdrawing substituent; However, when E is CH, D is CO, NHCO, and N(C 0~6 ) alkyl-CO, with the proviso that G is an electron-withdrawing substituent. It is a compound according to the formula:

[0016] In these embodiments, it is ensured that when E is CH, i.e. when the aromatic ring Ar is a phenyl-based ring, the substituents G and D are selected to be electron-withdrawing, meaning that when E is CH, G is an electron-withdrawing substituent and D contains a carbonyl function.

[0017] In this case, preferably, G is selected from the group consisting of F, Cl and OCF3.

[0018] In one embodiment, the linker element D is CO, NHCO, and N(C 0~6 )alkyl-CO, more preferably NHCO and N(C 0~6 )alkyl-CO, in particular NHCO and N(C0)alkyl-CO. When D is N(C0)alkyl-CO, A forms a 4-7 membered aliphatic heterocycle with the nitrogen atom of the N(C0)alkyl-CO in D. In this case, A forms both substituents on the nitrogen and there are no further alkyl substituents, i.e. defined as (C0)alkyl.

[0019] The linker element A (together with D) influences the geometric arrangement (e.g., distance, orientation) of Ar relative to the cephem ring. In general, A is selected independently from D. However, in some embodiments, the definition of A is relative to D. Based on preliminary data, it is believed to be beneficial, particularly for iron chelating activity, for the O of the oxime group and the nearest atom of Ar to be separated by at least one atom (e.g., Example 1), but preferably by 6 atoms or less, e.g., 5 atoms. The distance can be described by the number of covalent bonds of the shortest linking path within the molecule (or within a part of the molecule). This is a very simplified representation that ignores conformational / three-dimensional aspects, but allows to define some preferences for the linkers according to the invention. The skilled person will understand the concept of covalent bonds involving heteroatoms, sp 2 It will be understood that covalent (CC) bonds involving C atoms in hybridization, and cyclic (CC) bonds (due to geometric constraints within the ring system) are shorter than acyclic covalent (CC) single bonds.

[0020] As used herein, the shortest linking path in A is defined by the number of bonds stretching between the O of the oxime group and D, excluding the bond to the O of the oxime group (i.e. excluding the bond OA in formula (I) or (II)) and excluding the bond to D or the single bond of D (i.e. excluding the bond AD in formula (I) or (II)). In accordance with the term "shortest", in the case of branched or cyclic linkers, the path with the fewest number of bonds should be considered.

[0021] In one embodiment, A is selected such that the shortest linking path in A is shorter than or equal to three single covalent (CC) bonds, in particular shorter than three acyclic covalent (CC) single bonds, preferably shorter than or equal to two single covalent (CC) bonds, in particular shorter than two acyclic covalent (CC) single bonds.

[0022] In a preferred embodiment, the shortest linking path in A does not extend beyond a single (CC) bond, one cyclic or acyclic (CC) single bond, and two cyclic covalent (CC) bonds.

[0023] Thus, in a preferred embodiment, A is selected from the group consisting of methanediyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, azetidine-1,3-diyl, pyrrolidine-1,3-diyl and piperidine-1,3-diyl, where in azetidine-1,3-diyl, pyrrolidine-1,3-diyl and piperidine-1,3-diyl, D is N(C0)alkyl-CO and the nitrogen atom of N(C0)alkyl-CO in D is nitrogen in a heterocycle, Preferably, it is selected from the group consisting of methanediyl, ethane-1,2-diyl, cyclobutane-1,3-diyl, and pyrrolidine-1,3-diyl, D is N(C0)alkyl-CO, and the nitrogen atom of N(C0)alkyl-CO in D is the nitrogen in the pyrrolidine ring.

[0024] In a further embodiment, the compound according to the invention has formula (II) wherein X and Z are defined as above; D is NHCO or N(C 0~6 ) alkyl-CO; A is, -(C 1~6 ) alkanediyl, preferably (C 1~4 ) alkanediyl, for example in particular (C2) alkanediylethane-1,2-diyl, -(C 3~6 ) cycloalkanediyl, preferably (C 4~5 ) cycloalkanediyl, for example in particular (C4) cycloalkanediylcyclobutane-1,3-diyl, or A forms a 4- to 7-membered aliphatic heterocycle, preferably a 5-membered aliphatic heterocycle, together with the nitrogen atom of N(C0)alkyl-CO in D, for example, the 5-membered heterocycle pyrrolidine-1,3-diyl, particularly the nitrogen in pyrrolidine, together with the nitrogen atom of N(C0)alkyl-CO in D; E is CH, G is Cl) It is a compound according to the formula:

[0025] Or, E is N, N + -CH3, and N + When -O, i.e. when the aromatic ring Ar is a pyridinyl-based ring, no such requirement is imposed on G and D. The heteroatom N is an electron-withdrawing element in Ar. Thus, G can be hydrogen and / or D can be a single bond (i.e., D is not present as an individual moiety).

[0026] Preferably, in this case, the compound according to the invention has the formula (II): wherein X and Z are defined as above; D is a single bond, A is, -(C 1~6 ) alkanediyl, preferably (C 1~4 ) alkanediyl, for example methanediyl, -(C 3~6 ) cycloalkanediyl, or E is N + -O - and G is H) It is a compound according to the formula:

[0027] In another embodiment, -AD-Ar in formula (I) is [ka] and is selected from the group consisting of Preferably, [ka] and is selected from the group consisting of More preferably, [ka] and It is preferably selected from the group consisting of:

[0028] The compounds of the invention contain a thiazole ring (X is CH or X is CCl) or a 1,3,4-thiadiazole (X is N).

[0029] In a preferred embodiment, X is CH or N.

[0030] The oxime substituted at the 7-position is O-substituted with a substituted alkyl Z selected from the group consisting of CH2COOH, CH(CH3)COOH, C(CH3)2COOH and CH2F.

[0031] In a preferred embodiment, Z is C(CH3)2COOH or CH2F.

[0032] In another aspect, the present invention provides a composition comprising a compound according to the present invention in combination with at least one pharmaceutical excipient.

[0033] In one embodiment, the composition optionally further comprises at least one pharma- ceutical active agent.

[0034] In another aspect, the present invention provides a compound or composition according to the invention for use as a medicament.

[0035] The compounds or compositions according to the invention can be used in a method for the treatment or prevention of a disease, in which the compounds according to the invention or a composition comprising the compounds are applied to a subject in need thereof.

[0036] The compounds according to the invention have been found to have fungicidal activity and are therefore suitable for the treatment and prevention of infectious diseases.

[0037] Thus, in one embodiment the invention provides a compound or composition according to the invention for use in the treatment and prevention of an infectious disease mediated by a microorganism or bacteria, preferably a gram-negative bacteria.

[0038] In a preferred embodiment, the infectious disease is - upper and / or lower respiratory tract infections, where respiratory tract infections include cystic fibrosis and bronchiectasis, -urinary tract infection, - intra-abdominal infection, - Systemic infections, - artificial joint infection, - Gastrointestinal infections, as well as - Skin and / or soft tissue infections is selected from the group consisting of:

[0039] In another embodiment, the infectious disease is selected from the group consisting of Escherichia coli, Salmonella typhimurium, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter baumannii, and / or Salmonella typhimurium. baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, Burkholderia vietnamensis, Streptococcus spp., and Streptococcus pneumoniae, and preferably selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, Burkholderia vietnamensis, Streptococcus spp., and Streptococcus pneumoniae. The infection is mediated by a bacterium selected from the group consisting of Bacillus subtilis, Bacillus baumannii, Pseudomonas aeruginosa, and Burkholderia cepacia.

[0040] In a further aspect, the present invention provides a method of treating an infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to formula (I), wherein X, Z, A, D and Ar are defined as above.

[0041] In one embodiment, the compound is administered in the form of a pharmaceutical composition. Treatment includes treatment and prophylaxis. For antibacterial treatment and cystic fibrosis treatment, the appropriate dosage (effective amount) will of course vary depending on, for example, the chemical nature and pharmacokinetic data of the compound of the present invention used, the individual host, the mode of administration, and the nature and severity of the disease(s) to be treated. However, in general, for satisfactory results in large mammals, such as humans, the indicated daily dosage is in the range of about 0.5 mg to 3 g of the compound of the present invention, conveniently administered in divided doses up to four times a day. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] (C X~Y The definition of the (C) group includes any group having X to Y carbon atoms. For example, 1~5 Examples of (C1-C6) alkyl include methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, trimethylmethyl, 2-methylprop-1-yl, pentyl, pent-2-yl, pent-3-yl, 2-methylbutyl, 3-methylbutyl, and 3-methylbut-2-yl. Similarly, (C1-C6) alkyl or (C 1~6 ) Alkanediyl also includes straight-chain and branched alkane groups.

[0043] Any group defined as part of the compounds according to the invention may be unsubstituted or substituted, for example one or more times.

[0044] (C 1~6 ) alkyl, (C 1~6 ) alkanediyl, cycloalkyl, (C 3~6) cycloalkanediyl, 4- to 7-membered aliphatic heterocycle, and 6-membered aromatic ring each include unsubstituted or substituted (C 1~6 ) alkyl, (C 1~6 ) alkanediyl, cycloalkyl, (C 3~6 ) cycloalkanediyl, 4- to 7-membered aliphatic heterocycles, and 6-membered aromatic rings. These groups may be substituted, for example, by conventional groups in organic chemistry. Examples of the substituents include (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkoxy, hydroxy, oxo, carboxyl, (C1-C6) alkylcarbonyl, amido, ureido, guanidino, thioureido, amino, and halogen.

[0045] Both groups A and D (when D is not a single bond) are linking groups with two free valences for forming bonds with other parts of the compound. Unless otherwise indicated, the linking groups A or D are oriented in formula (I) or (II) as written from left to right. For example, if D is NHCO in formula (I), the nitrogen atom of the amide is linked to A and the carbon atom is linked to Ar.

[0046] The compounds according to the invention have two oxime ether functionalities, also called oxyimine functionalities. Different stereochemical orientations are possible for these functionalities based on the E / Z configuration at the double bond to the nitrogen atom (C=N bond). It is to be understood that the orientation diagrams in the formulae do not exclude alternative configurations. Thus, in compounds according to formulae (I) or (II), where stereochemistry is not explicitly indicated (i.e., as in the case of the chiral carbon atom of the cephem ring), it is to be understood that all configurational isomers are covered. In particular, for both oxime functionalities, both configurations are included in formulae (I) or (II), independently of each other, and thus the four respective diastereomeric forms are also covered. However, it is preferred that each oxime functionality, independently of each other, is in the configuration as visualized by the diagram of formulae (I) or (II), and more preferably, both are in the configuration as visualized by the diagram of formulae (I) or (II).

[0047] Pyridine-N-oxides, pyridinones or pyridiniums may exist in the tautomeric forms: [ka]

[0048] The present invention includes all tautomeric forms, regardless of which tautomer is selected for drawing each formula or nomenclature.

[0049] The compounds of the present invention include compounds in any form, such as free form / internal salt / zwitterionic form, salt form, solvate form, or salt and solvate form. Salts preferably include pharma- ceutically acceptable salts, but any salt is included, e.g., for preparation / isolation / purification purposes.

[0050] Methods for preparing the compounds of the invention are known or can be prepared, for example, by conventional methods or similarly according to the methods specified in the following synthetic scheme 1: [ka]

[0051] In the compounds of formula (I), formula (A) and formula (D), X, Z, A, D and Ar are as defined above.

[0052] In the preparation of the compounds of the invention, the intermediates or starting materials (A), (B) and (D), optionally in protected form or in the form of a salt or both, are known or may be prepared, for example analogously, to a method as conventional.

[0053] The intermediates or starting materials of formulae (B) and (C) contain an aldehyde, which may be present with a proximal carboxylic acid as a hemiacylal: [ka]

[0054] The compounds of the invention may be used for (or applied in methods for) treatment or prophylaxis (i.e., prevention), in which the compounds of the invention are applied, i.e., administered, to a subject.

[0055] The compounds of the invention may be administered by any conventional route, for example enterally, such as nasal, buccal, oral administration; parenterally, such as intravenous, intramuscular, subcutaneous administration; or topically, such as by inhalation, transdermal, intranasal, intratracheal, intraaural, intraocular administration, for example in the form of coated or uncoated tablets, capsules, injectable solutions or suspensions, for example in the form of ampoules, vials, creams, gels, pastes, inhalation liquids, inhalation powders, sprays, foams, tinctures, or drops.

[0056] Preferably, the compounds according to the present invention are not administered in pure form, but are formulated into compositions.

[0057] Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound according to the invention, in combination with at least one pharmaceutical excipient (e.g., carrier or diluent), wherein the compound according to the invention may be in free form or in the form of a pharma- ceutically acceptable salt and / or solvate.

[0058] According to the route of administration, the composition is formulated according to the prior art of pharmaceuticals.Those skilled in the art can select at least one pharmaceutical excipient from known excipients, including, for example, filler, binder, disintegrant, flow conditioner, lubricant, sugar and sweetener, flavoring agent, preservative, stabilizer, wetting agent and / or emulsifier, solubilizer, salt for adjusting osmotic pressure and / or buffer.

[0059] The compounds of the present invention can be used (or applied in a method for) treatment or prevention, either alone or in combination with one or more other pharmacologic active agents. Such other pharmacologic active agents include, for example, beta-lactamase inhibitors, enhancers and other antibiotics, and when the compounds of the present invention are used in the treatment of cystic fibrosis, the other pharmacologic active agents further include agents that are conventionally used in the treatment of cystic fibrosis.

[0060] The other pharma- ceutical active agents may be provided in a composition containing a compound according to the invention, or the other pharma- ceutical active agents may be administered separately.

[0061] The uses and methods of the present invention primarily concern treatment and prevention in human subjects, but can also be used for treatment and prevention in other mammalian subjects, i.e. animals and pets, such as poultry, pigs, calves, dogs, cats, i.e. for veterinary purposes, and for diluting fluids for artificial insemination and egg soaking techniques.

[0062] The compounds of the present invention can be used (or applied in a method for) treating or preventing infectious diseases. Infectious diseases can be diagnosed by those skilled in the art, who associate the symptoms of a subject with infection by a microorganism or bacteria, or infectious diseases can be diagnosed by detecting a microorganism or bacteria in the subject or in a sample taken from the subject.

[0063] The compounds according to the invention exhibit pharmacological activity and are therefore useful as pharmaceuticals. For example, the compounds of the present invention are effective against gram-negative bacteria such as Escherichia coli, Salmonella typhimurium, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter baumannii, and the like. baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, Burkholderia vietnamensis, as well as Gram-positive bacteria such as Streptococcus spp. and Streptococcus pneumoniae.

[0064] Infectious diseases mediated by gram-negative bacteria include, for example, Escherichia coli, Salmonella typhimurium, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter baumannii, and others. baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, and Burkholderia vietnamensis.

[0065] Therefore, the compounds according to the present invention are suitable for the treatment and prevention of diseases mediated by microorganisms, such as bacteria.Based on the antibacterial activity against gram-positive and gram-negative bacteria, the compounds according to the present invention are suitable for the treatment and prevention of infectious diseases.The diseases that can be treated with the compounds according to the present invention include, for example, upper and lower respiratory tract infections, including cystic fibrosis and bronchiectasis, as well as urinary tract infections, intraperitoneal infections, systemic infections, prosthetic joint infections, gastrointestinal infections, and soft tissue infections.

[0066] In vitro activity against bacteria was determined by standard broth microdilution according to the Clinical and Laboratory Standards Institute CLSI document (Performance Standards for Antimicrobial Susceptibility Testing) M100Ed29E (2019) and (Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically) M07Ed11 (2018). Data were obtained using cation-adjusted Mueller-Hinton Broth Medium (CAMHB) and additionally iron-depleted CAMHB medium (ID-CAMHB) for compounds with iron chelating activity. Results for Examples 1-8 and comparative compounds are summarized in Table 1.

[0067] The iron chelating properties were determined by the Chrome Azurol assay according to Schwyn B., et al., Universal Chemical Assay for the Detection and Determination of Siderophores, 1987. Analytical Biochemistry 160: 47-56. The assay uses the affinity of Chrome Azurol S / iron(III) / hexadecyltrimethylamimonium bromide for iron(III). When a strong chelating agent removes iron from the dye, its color changes from blue to orange, and the absorbance measured at 630 nm indicates the chelating properties of the siderophore. The results of Examples 1-8 and the comparative compounds are summarized in Table 1.

[0068] Thus, in one embodiment, the compounds according to the invention have an IC of 40 μM or less, preferably less than 20 μM. 50 The iron chelating activity is determined by chrome azurol assay. [Table 1]

[0069] Abbreviations in Table 1: CI95 LL-UL 95% probability confidence interval, lower limit to upper limit EC Escherichia coli KP Klebsiella pneumoniae AB Acinetobacter baumannii PA Pseudomonas aeruginosa BC Burkholderia cepacia CF Cystic Fibrosis nd undecided EXAMPLES

[0070] The following abbreviations are used herein, including in the examples and reaction schemes: 1 H-NMR Proton Nuclear Magnetic Resonance Spectroscopy ℃ Celsius BOC tert-Butyloxycarbonyl BSA N,O-Bis(trimethylsilyl)-acetamide DMSO Dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride eq equivalent h time HOBT 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography MS mass spectrometry N Normal NMR nuclear magnetic resonance spectroscopy m / e mass / charge ratio THF Tetrahydrofuran

[0071] Example 1: (6R,7R)-7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid [ka] Step 1: Amide formation To an ice-cooled solution of compound B (WO 95 / 29182) (1.47 g, 6.44 mmol) and BSA (3.15 mL, 2 eq.) in acetonitrile (10 mL) was added a suspension of compound A1 (US Pat. No. 4,500,526) (3.8 g, 1 eq.) in acetonitrile (20 mL). The resulting reaction mixture was stirred under ice-cooling for 1 h and at room temperature for 1 h, then slowly added to ice water. The resulting precipitate was filtered and dried under reduced pressure to give compound C1 as a yellow solid, which was used directly for the next step. 1 H-NMR (400 MHz, DMSO-d6, δ, ppm): 9.46 (d, 1H, CONH, J = 8.2 Hz), 7.43-7.18 (m, 15H, trityl-H), 6.71 (s, 1H, thiazole-H), 6.30, 6.22 (2xs, 1H, O-CH-O), 5.90 (dd, 1H, H-6, J = 5.2 Hz, 8.2 Hz), 5.16 (d, 1H, H-7, J = 5.2 Hz), 3.76 (d, 1H, H-2a, J = 18.6 Hz), 3.58 (d, 1H, H-2b, J = 18.6 Hz), 1.41 (s, 6H, 2xCH3), 1.37 (s, 9H, COO t Bu). MS m / e: 782 [M+H] +

[0072] Step 2: Oxime formation To a suspension of compound C1 (Example 1, Step 1) and compound D1 (EP 0430286) (1.11 g, 1 eq.) in acetonitrile (15 mL), 1N hydrochloric acid (19.3 mL, 3 eq.) was added under ice cooling. The resulting mixture was warmed to room temperature, stirred for 3 hours, and then slowly added to ice water. The resulting precipitate was filtered off and dried under reduced pressure to obtain the protected form of compound I1 as a solid, which was used directly for the next step. 1 H-NMR (400 MHz, DMSO-d6, δ, ppm): 9.41 (d, 1H, CONH, J = 8.1 Hz), 8.36 (s, 1H, azomethine), 7.80 (s, 1H, dihydropyridine H-6), 7.38-7.17 (m, 15H, trityl-H), 6.74 (s, 1H, dihydropyridine H-3), 6.68 (s, 1H, thiazo le-H), 5.79(dd, 1H, H-6, J=5.0Hz, 8.1Hz), 5.23(d, 1H, H-7, J=5.0Hz), 5.15(s, 2H, O-CH2), 3.8 5(d, 1H, H-2a, J=18.0Hz), 3.58(d, 1H, H-2b, J=18.0Hz), 1.38(bs, 6H.2xCH3), 1.35(s, 9H, COO t Bu). MS m / e: 936 [M+H] +

[0073] Step 3: Deprotection Compound I1 in protected form (Example 1, step 2) was dissolved in trifluoroacetic acid (20 mL) under ice cooling. The resulting mixture was stirred under ice cooling for 4 hours, and then slowly added to cold diethyl ether. The resulting precipitate was filtered off and dried under reduced pressure to obtain compound I1 in the form of trifluoroacetate salt as a solid. 1H-NMR (400 MHz, MeOH-d4, δ, ppm): 8.46 (s, 1H, azomethine), 7.84 (s, 1H, dihydropyridine H-6), 6.94 (s, 1H, thiazole-H), 6.84 (s, 1H, dihydropyridine H-3), 5.87 (d, 1H, H-6, J = 5.1 Hz), 5.20 (s, 2H, O-CH2), 5.16 (d, 1H, H-7, J = 5.1 Hz), 3.89 (d, 1H, H-2a, J = 18.2 Hz), 3.50 (d, 1H, H-2b, J = 18.2 Hz), 1.52 (s, 3H, CH3), 1.51 (s, 3H, CH3). MS m / e: 638 [M+H] +

[0074] Step 4a (Optional): Salt Exchange and Chromatography Compound I1 (1.6 g, 1.85 mmol) in the form of the trifluoroacetate salt (Example 1, step 3) was suspended in water and 1N NaOH was slowly added until a pH of 6-6.5 was reached. To the resulting solution, 1N HCl was added until a pH of 2 was reached and the resulting precipitate was filtered off and subjected to reverse phase chromatography to obtain compound I1 in the form of the hydrochloride salt as an off-white solid (530 mg) after lyophilization. 1 H-NMR (400 MHz, MeOH-d4, δ, ppm): 8.45 (s, 1H, azomethine), 7.77 (s, 1H, dihydropyridine H-6), 6.81 (s, 1H, thiazole-H), 6.77 (s, 1H, dihydropyridine H-3), 5.87 (d, 1H, H-6, J = 5.0), 5.18 (s, 2H, O-CH2), 5.14 (d, 1H, H-7, J = 5.0 Hz), 3.86 (d, 1H, H-2a, J = 18.0 Hz), 3.48 (d, 1H, H-2b, J = 18.0 Hz), 1.52 (s, 3H, CH3), 1.50 (s, 3H, CH3). MS m / e: 638 [M+H] +

[0075] Compounds of formula (III), in which R, X and Z are as defined in Table 2 (Examples 2-8), are prepared, for example, analogously to conventional methods or according to the methods described in Example 1, steps 2-3, and optionally step 4 above, but using appropriate starting materials. [ka] [Table 2] JPEG0007645874000014.jpg245169JPEG0007645874000015.jpg78169

[0076] Suitable starting materials C2 and C3 (WO 98 / 43981) are eg similarly prepared according to conventional methods or analogously, eg as described in Example 1, step 1. [ka]

[0077] Appropriate starting materials D2, D3 and D4 are prepared, for example, by conventional methods or analogously to the methods described below.

[0078] [ka] To a solution of 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid (EP 0416410) (1 g, 2.33 mmol) in dichloromethane, HOBT (316 mg, 1 eq.), EDC (446 mg, 1 eq.) and O-(2-aminoethyl)hydroxylamine hydrochloride (348 mg, 1 eq.) were added and stirred at room temperature for 1 h. Triethylamine (976 μL, 3 eq.) was then added and the resulting reaction mixture was stirred at room temperature for an additional 2 h. The resulting reaction mixture was concentrated to dryness and the residue was purified by chromatography (ethyl acetate / methanol=10 / 1) to give compound D2 as a white solid (1.92 g). 1 H-NMR (400MHz, MeOH-d4, δ, ppm): 7.41 (m, 2H, arom.), 7.30 (m, 2H, arom.), 7.22 (d, 1H, arom., J=8.5Hz), 7.12 (d, 1H, arom., J=8.5Hz), 6.96 (m, 2H, arom.) , 6.82(m, 2H, arom.), 5.11(s, 2H, OCH2), 4.94(s, 2H, OCH2), 3.83(s, 3H, OCH3 ), 3.80(t, NOCH2, J=5.3Hz), 3.79(s, 3H, OCH3), 3.58(t, 2H, NCH2, J=5.3Hz). MS m / e: 487 [M+H] + , 531 [M+HCOO - ]

[0079] [ka] Process a To a solution of N-hydroxy-phthalimide (730 mg, 4.48 mmol) in DMSO was added potassium carbonate (1.55 g, 2.5 eq.) and cis-tert-butyl N-(3-iodocyclobutyl)carbamate (1.99 g, 1.5 eq.). The resulting reaction mixture was stirred at 80° C. for 3 h and then slowly added to ice water. The resulting precipitate was filtered, dried under reduced pressure, and purified by chromatography (dichloromethane / methanol=100 / 1) to give trans-tert-butyl N-[3-(1,3-dioxoisoindolin-2-yl)oxycyclobutyl]carbamate as a white solid (290 mg). MS m / e: 350 [M+NH4 + ]

[0080] Process b To a solution of trans-tert-butyl N-[3-(1,3-dioxoisoindolin-2-yl)oxycyclobutyl]carbamate (2.26 g, 6.80 mmol) in dichloromethane was added hydrogen chloride (2 M in diethyl ether, 12 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness to give trans-2-(3-aminocyclobutoxy)isoindoline-1,3-dione as a light brown solid (1.84 g, wet). MS m / e: 233 [M+H] +

[0081] Process c To a solution of 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid (EP 0416410) (3.40 g, 7.92 mmol) in dichloromethane was added HOBT (1.07 g, 1 equiv.), EDC (1.52 g, 1 equiv.) and trans-2-(3-aminocyclobutoxy)isoindoline-1,3-dione as a light brown solid (1.84 g, wet, 6.80 mmol) and stirred at room temperature for 1 h. Triethylamine (3.29 mL, 3 equiv.) was then added and the resulting reaction mixture was stirred at room temperature overnight. The resulting reaction mixture was concentrated to dryness, and the residue was purified by chromatography (dichloromethane / methanol / ammonia=100 / 5 / 0.5) to give trans-2-chloro-N-[3-(1,3-dioxoisoindolin-2-yl)oxycyclobutyl]-3,4-bis[(4-methoxyphenyl)methoxy]benzamide as a pale yellow solid (2.49 g).

[0082] Process d To a solution of trans-2-chloro-N-[3-(1,3-dioxoisoindolin-2-yl)oxycyclobutyl]-3,4-bis[(4-methoxyphenyl)methoxy]benzamide (1.99 g, 3.09 mmol) in acetonitrile, hydrazine hydrate (64-65% hydrazine, 0.30 mL, 2 equiv.) was added and stirred at room temperature for 4 h. The resulting reaction mixture was filtered. The filtrate was diluted with aqueous ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, dried over Na2SO4, and concentrated to give compound D3 as a white solid (0.98 g). MS m / e: 513 [M+H] +

[0083] [ka] Process a To a solution of (3R)-hydroxypyrrolidine (919 mg, 10.56 mmol) in dichloromethane, 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid (EP 0416410) (4.53 g, 1 eq.), EDC (2.02 g, 1 eq.) and HOBT (1.43 g, 1 eq.) were added and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was concentrated to dryness and purified by chromatography (dichloromethane / methanol / ammonia=100 / 5 / 0.5) to give [2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]phenyl]-[(3R)-3-hydroxypyrrolidin-1-yl]methanone (3.93 g). MS m / e: 498 [M+H] +

[0084] Process b To a solution of [2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]phenyl]-[(3R)-3-hydroxypyrrolidin-1-yl]methanone (3.77 g, 7.57 mmol) in THF was added triethylamine (1.59 mL, 1.5 equiv.) and methanesulfonyl chloride (0.71 mL, 1.2 equiv.) under ice cooling and stirred at room temperature for 2 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water, and the organic phase was washed with saturated aqueous NaCl. The organic phase was again separated, dried over Na2SO4, and evaporated to dryness to give crude [(3R)-1-[2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoyl]pyrrolidin-3-yl]methanesulfonate (4.36 g, wet). MS m / e: 573 [M+H] +

[0085] Process c To a solution of crude [(3R)-1-[2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoyl]pyrrolidin-3-yl]methanesulfonate (3.83 g, 6.65 mmol) in DMSO, potassium carbonate (2.30 g, 2.5 equiv.) and N-hydroxy-phthalimide (2.00 g, 1 equiv.) were added and stirred at 80° C. for 3 h. The reaction mixture was partitioned between ethyl acetate and water and the resulting organic phase was washed with saturated aqueous NaCl. The organic phase was again separated, dried over Na2SO4, and concentrated to dryness to give crude 2-[(3S)-1-[2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoyl]pyrrolidin-3-yl]oxyisoindoline-1,3-dione (2.73 g, wet). MS m / e: 643 [M+H] +

[0086] Process d To a solution of crude 2-[(3S)-1-[2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoyl]pyrrolidin-3-yl]oxyisoindoline-1,3-dione (2.96 g, 4.60 mmol) in acetonitrile (20 mL) was added hydrazine hydrate (64-65% hydrazine, 0.45 mL, 2 equiv.) and stirred at room temperature for 1 h. The resulting reaction mixture was diluted with aqueous ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, dried over Na2SO4, and concentrated to give crude [(3S)-3-aminooxypyrrolidin-1-yl]-[2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]phenyl]methanone (1.83 g, wet). MS m / e: 513 [M+H] +

[0087] Process e To a solution of crude [(3S)-3-aminooxypyrrolidin-1-yl]-[2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]phenyl]methanone (1.01 g, 1.97 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) and stirred at room temperature for 1 h. The resulting reaction mixture was concentrated, hydrogen chloride (2 M in diethyl ether, 1 eq.) was added, and evaporated to dryness again to give crude (3S)-3-aminooxypyrrolidin-1-yl]-(2-chloro-3,4-dihydroxy-phenyl)methanone hydrochloride (1.36 g). MS m / e:273[MH] + The present invention may include the following aspects. [1] Formula (I): [ka] (In the formula, X is selected from the group consisting of CH, CCl, and N; Z is CH 2 COOH, CH(CH 3 )COOH, C(CH 3 ) 2 COOH and CH 2 F, D is a single bond connecting A and Ar or CO, NHCO and N(C 0~6 ) alkyl-CO; A is, -(C 1~6 ) Alkanediyl and -(C 3~6 ) cycloalkanediyl; or D is N(C 0 )alkyl-CO, A is N(C 0 ) forms a 4- to 7-membered aliphatic heterocycle with the nitrogen atom of alkyl-CO, Ar is a six-membered aromatic ring having a first hydroxyl group para to D, a second hydroxyl group meta to D, and at least one electron-withdrawing element. Compound by. [2] 2. The compound of claim 1, wherein the electron-withdrawing element can be a heteroatom in the aromatic ring or an electron-withdrawing substituent in the aromatic ring. [3] The compound has formula (II):

change

[10] -AD-Ar but,

change

change

change

[11] 11. The compound according to any one of claims 1 to 10, wherein X is CH or N.

[12] Z is C(CH 3 ) 2 COOH or CH 2 12. The compound according to any one of claims 1 to 11, wherein F.

[13] (6R,7R)-7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[[3-[(2-chloro-3,4-dihydroxy-benzoyl)amino]-trans-cyclobutoxy]iminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-{[(3S)-1-(2-chloro-3,4-dihydroxy-benzoyl)pyrrolidin-3-yl]oxyiminomethyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 13. The compound according to any one of claims 1 to 12, selected from the group consisting of:

[14] 14. A composition comprising a compound according to any one of claims 1 to 13 in combination with at least one pharmaceutical excipient, and optionally further comprising at least one pharma- ceutical active agent.

[15] A compound according to any one of claims 1 to 13 or a composition according to claim 11 for use as a medicament.

[16] 15. A compound according to any one of claims 1 to 13 or a composition according to claim 14 for use in the treatment and prevention of infectious diseases mediated by microorganisms or bacteria, preferably gram-negative bacteria.

[17] 17. The compound for use according to claim 16 or the composition for use according to claim 16, wherein the infectious disease is selected from the group consisting of lower and / or upper respiratory tract infections, urinary tract infections, intra-abdominal infections, systemic infections, prosthetic joint infections, gastrointestinal infections, and skin and / or soft tissue infections, wherein upper and lower respiratory tract infections include cystic fibrosis and bronchiectasis.

[18] The infectious disease is caused by Escherichia coli, Salmonella typhimurium, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter baumannii, or any of the following: baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, Burkholderia vietnamensis, Streptococcus spp.18. A compound for use according to claim 16 or 17 or a composition for use according to claim 16 or 17, the infection being mediated by a bacterium selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia cepacia, selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia cepacia.

[19] A method for treating an infectious disease in a subject in need thereof, comprising administering an effective amount of a compound of formula (I):

change

[20] 20. The method of claim 19, wherein the infectious disease is mediated by a microorganism or bacteria, preferably a gram-negative bacterium.

[21] 20. The method of claim 19, wherein the infectious disease is selected from the group consisting of lower and / or upper respiratory tract infections, urinary tract infections, intra-abdominal infections, systemic infections, prosthetic joint infections, gastrointestinal infections, and skin and / or soft tissue infections, wherein upper and lower respiratory tract infections include cystic fibrosis and bronchiectasis.

[22] The infectious disease is caused by Escherichia coli, Salmonella typhimurium, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter baumannii, or any of the following: baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, Burkholderia vietnamensis, Streptococcus spp., and Streptococcus pneumoniae, and preferably selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Acinetobacter lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, Burkholderia vietnamensis, Streptococcus spp., and Streptococcus pneumoniae. 20. The method of claim 19, wherein the infection is mediated by a bacterium selected from the group consisting of: Clostridium baumannii, Pseudomonas aeruginosa, and Burkholderia cepacia.

[23] 23. The method according to any one of claims 19 to 22, wherein an effective amount of a compound according to formula (I) is administered in the form of a pharmaceutical composition.

Claims

1. Formula (II): 【Chemistry 17】 (In the formula, X is selected from the group consisting of CH, CCl, and N; Z is selected from the group consisting of CH2COOH, CH(CH3)COOH, C(CH3)2COOH and CH2F; D is a single bond or is selected from the group consisting of CO, NHCO and N(C 0-6 )alkyl-CO; A is, -(C 1-6 )alkanediyl, and -(C 3-6 )cycloalkanediyl; or When D is N(C 0 )alkyl-CO, A forms a 4- to 7-membered aliphatic heterocycle together with the nitrogen atom of N(C 0 )alkyl-CO in D; E is CH, N, N ＋ -CH ３ , and N ＋ -O － is selected from the group consisting of G is H or an electron-withdrawing substituent selected from the group consisting of F, Cl and OCF 3 ; However, when E is CH, D is CO, NHCO, and N(C ０～６ ) alkyl-CO, with the proviso that G is an electron-withdrawing substituent. Compound by.

2. the shortest connection path in A is defined by the number of bonds extending between the O of the oxime group and D, excluding the bond to the O of said oxime group and excluding the bond to D or the single bond of D; 2. The compound of claim 1, wherein A is selected such that the shortest linkage path in A is shorter than or equal to three covalent (C-C) single bonds.

3. The shortest connection path in A is defined by the number of bonds extending between O of the oxime group and D, excluding the bond to O of the oxime group, and excluding the bond to D or the single bond of D; 2. The compound of claim 1, wherein A is selected such that the shortest linking path in A is shorter than three acyclic covalent (C-C) single bonds.

4. The shortest connection path in A is defined by the number of bonds extending between O of the oxime group and D, excluding the bond to O of the oxime group, and excluding the bond to D or the single bond of D; 2. The compound of claim 1, wherein A is selected such that the shortest linkage path in A is shorter than or equal to two covalent (C-C) single bonds.

5. 3. The compound according to claim 2, wherein the shortest linking path in A does not exceed any of a single (C-C) bond, one cyclic or acyclic (C-C) single bond, and two cyclic covalent (C-C) bonds.

6. A is selected from the group consisting of methanediyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,3-diyl, azetidine-1,3-diyl, pyrrolidine-1,3-diyl and piperidine-1,3-diyl, in which D is N(C ０ ) alkyl-CO, and N(C ０ 6. The compound according to claim 1, wherein the nitrogen atom of alkyl-CO is a nitrogen in a heterocycle.

7. D is NHCO or N(C ０～６ ) alkyl-CO; A - (C １～６ ) alkanediyl, - (C ３～６ ) cycloalkanediyl, or A is N(C ０ ) forms a 4- to 7-membered aliphatic heterocycle with the nitrogen atom of alkyl-CO; E is CH; G is Cl; 7. A compound according to any one of claims 1 to 6.

8. D is a single bond, A - (C １～６ ) alkanediyl, or - (C ３～６ ) cycloalkanediyl, E is N ＋ -O － and G is H, 7. A compound according to any one of claims 1 to 6.

9. 【Chemistry】 but, 【Chemistry 18】 Selected from the group consisting of:

7. A compound according to any one of claims 1 to 6.

10. 【Chemistry】 but, 【Chemistry 20】 Selected from the group consisting of: The compound of claim 1.

11. 11. The compound according to any one of claims 1 to 10, wherein X is CH or N.

12. Z is C(CH ３ ) ２ COOH or CH ２ 12. The compound according to any one of claims 1 to 11, wherein F is

13. (6R,7R)-7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)acetyl]amino]-3-[(1,5-dihydroxy-4-oxo-2-pyridyl)methoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimino)-acetyl]amino]-3-[2-[(2-chloro-3,4-dihydroxy-benzoyl)amino]ethoxyiminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-[[3-[(2-chloro-3,4-dihydroxy-benzoyl)amino]-trans-cyclobutoxy]iminomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 7-[[(2Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methyl-ethoxy)imino-acetyl]amino]-3-{[(3S)-1-(2-chloro-3,4-dihydroxy-benzoyl)pyrrolidin-3-yl]oxyiminomethyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 13. The compound according to any one of claims 1 to 12, selected from the group consisting of:

14. 14. A composition comprising a compound according to any one of claims 1 to 13 in combination with at least one pharmaceutical excipient, and optionally further comprising at least one pharma- ceutical active agent.

15. 15. The composition according to claim 14 for use as a medicament.

16. 16. A composition according to claim 14 or 15 for use in the treatment or prevention of an infectious disease mediated by a microorganism or bacteria.

17. The composition described in claim 16, wherein the infectious disease is mediated by gram-negative bacteria.

18. 17. The composition of claim 16, wherein the infectious disease is selected from the group consisting of lower and / or upper respiratory tract infections, urinary tract infections, intra-abdominal infections, systemic infections, prosthetic joint infections, gastrointestinal infections, and skin and / or soft tissue infections, wherein upper and lower respiratory tract infections include cystic fibrosis and bronchiectasis.

19. The infectious disease is selected from the group consisting of Escherichia coli, Salmonella typhimurium, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Moraxella catarrhalis, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Serratia marcescens, Acinetobacter baumannii, Acinetobacter ruofi, and the like.

19. The composition of claim 16 or 18, wherein the infection is mediated by a bacterium selected from the group consisting of: Borrelia lwoffi, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia, Burkholderia cenocepatia, Burkholderia vietnamensis, Streptococcus spp., and Streptococcus pneumoniae.

20. The composition of any one of claims 16 to 18, wherein the infectious disease is mediated by a bacterium selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia cepacia.

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