Antibacterial compounds

Abstract

The present invention relates to antibacterial compounds and their use in the treatment of infection with, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae and / or the genus Haemophilus.

Description

[Technical Field]

[0001] The present invention relates to antibacterial compounds as defined herein, pharmaceutical compositions containing the compounds, and the use of the compounds and pharmaceutical compositions containing the compounds in the treatment of bacterial infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae, particularly Gram-negative bacteria of the order Enterobacteriaceae that have acquired resistance to existing antibiotics. [Background technology]

[0002] New antibacterial compounds are needed to combat the emergence of bacterial pathogens with resistance to existing antibacterial compounds. The increasing incidence of bacterial resistance to existing antibiotics threatens to lead to multidrug resistance becoming common among many bacterial pathogens, significantly increasing the burden of common infections on society. For example, antibiotic-resistant strains of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), such as carbapenem-resistant Enterobacteriaceae (CRE), multidrug-resistant (MDR) Acinetobacter, MDR Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE), are included in the list of antibiotic-resistant microorganisms identified as posing an urgent or serious threat to human health. Other prominent antibiotic-resistant pathogens include the gram-positive anaerobic bacterium Clostridium difficile, drug-resistant Neisseria gonorrhoeae, and drug-resistant Mycobacterium tuberculosis.

[0003] Specifically, resistance of Gram-negative bacteria, particularly those of the Enterobacteriaceae order, to existing antibiotic agents, such as carbapenem (β-lactam) antibiotics, is increasing. Antibiotic-resistant Gram-negative Enterobacteriaceae strains, such as Escherichia coli NDM-1 (New Delhi metallo-β-lactamase) and carbapenemase-producing Enterobacteriaceae strains, such as Klebsiella pneumoniae, are difficult to treat, are becoming increasingly prevalent, and are becoming increasingly virulent. Furthermore, newly emerging hypervirulent, multidrug-resistant, and highly infectious strains of carbapenem-resistant Klebsiella pneumoniae, such as the ST11 carbapenem-resistant hypervirulent Klebsiella pneumoniae strain, have been identified and are associated with deadly outbreaks. Such strains are resistant to historical and currently recommended antibiotics and are currently a major public health concern worldwide.

[0004] Currently, Enterobacteriaceae infections suspected to be caused by carbapenem-resistant Enterobacteriaceae (CRE) are commonly treated with broad-spectrum agents. Such treatment typically consists of a combination of a β-lactam antibiotic and a β-lactamase inhibitor (BLI / BLI) or the use of the last-resort antibiotic colistin. BL / BLI combinations are effective in the short term but are predicted to eventually succumb to the bacteria's pre-existing resistance mechanisms. Furthermore, these broad-spectrum agents are not active against all Ambler's β-lactamase classes and are inactive against metallo-β-lactamases, which confer resistance to a broad range of β-lactam antibiotics, including carbapenems.

[0005] Therefore, there is a need for new antibacterial compounds that can provide reliable and effective treatment for infections caused by, or diseases exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae that are resistant to known antibiotics, such as carbapenems and other β-lactams, or that are associated with multidrug-resistant infectious agents. Furthermore, there is a need to provide antibiotic formulations that can avoid or reduce the side effects associated with known antibacterial compounds.

[0006] It is an object of aspects of the present invention to provide solutions to the above-mentioned problems and other problems. Summary of the Invention

[0007] According to a first aspect of the present invention, there is provided a compound (I):

[0008] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0009] According to a second aspect of the present invention, there is provided a compound (I) for use in the treatment or prevention of infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus:

[0010] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0011] According to a third aspect of the present invention, there is provided a compound (I) for use in a method for the treatment of infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus:

[0012] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0013] According to a fourth aspect of the present invention, there is provided a compound (I) for the manufacture of a medicament for use in the treatment of infections with gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus, or diseases caused or exacerbated thereby:

[0014] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0015] According to a further aspect of the present invention, there is provided a method for treating an infection with, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus in a subject in need thereof, comprising administering an effective amount of Compound (I):

[0016] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof to said subject.

[0017] Compound (I) has bactericidal activity against Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and can be used in the treatment or prevention of infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, or diseases caused or exacerbated thereby.

[0018] According to a further aspect of the present invention, there is provided a compound (I) for use in the treatment of infections caused by, or diseases aggravated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus:

[0019] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0020] According to a further aspect of the present invention, compound (I):

[0021] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof to inhibit the growth of Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus in vitro.

[0022] According to a further aspect of the present invention, there is provided Compound (I), formulated together with a pharmaceutically acceptable excipient or carrier:

[0023] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0024] According to a further aspect of the present invention, compound (I):

[0025] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and a pharmaceutically acceptable excipient or carrier.

[0026] According to a further aspect of the present invention there is provided a pharmaceutical composition for use in the treatment of infection with, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus, comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, and a pharmaceutically acceptable excipient or carrier, wherein Compound (I) is

[0027] [ka] The present invention provides a pharmaceutical composition comprising:

[0028] According to a further aspect of the present invention there is provided a pharmaceutical composition for use in the treatment of infection with, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus, comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, and a pharmaceutically acceptable excipient or carrier, wherein Compound (I) is

[0029] [ka] and the pharmaceutical composition is administered by intravenous infusion at a dose of 50 to 6000 mg per day of Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0030] definition As used herein, the term "disease" or "bacterial disease" is used to define an abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, disease, abnormality, lesion, disorder, condition, or syndrome in which physiological function is impaired, regardless of the nature of the etiology (or indeed whether an etiological basis for the disease has been established). Thus, the term encompasses conditions resulting from trauma, injury, surgery, radiological ablation, poisoning, or nutritional deficiency. The term refers to any disease involving (e.g., caused by, exacerbated by, associated with, or characterized by) bacteria residing and / or replicating within the body and / or cells of a subject. Thus, the term includes diseases caused or exacerbated by bacterial toxins (sometimes referred to herein as "bacterial poisoning").

[0031] As used herein, the term "infection" or "bacterial infection" is used to define a condition in which a subject is infected with bacteria. The infection may be symptomatic or asymptomatic. If symptomatic, the subject can be identified as infected based on established diagnostic criteria. If asymptomatic, the subject can be identified as infected based on various tests, including, for example, biochemical tests, serological tests, microbial culture methods, and / or microscopic observation. Thus, the present invention typically finds use in treating subjects in which a bacterial infection has been diagnosed or detected.

[0032] As used herein, the term "treatment" or "treating" refers to an intervention (e.g., administration of a drug to a subject) that cures, alleviates, or reduces the symptoms of a disease, or eliminates (or reduces the effects of) its cause (e.g., a causative bacterium). In this context, the term is used synonymously with the term "therapy." Thus, treatment of infection according to the present invention can be characterized by the bactericidal action (direct or indirect) of the compounds of the present invention. Thus, the compounds of the present invention find use in methods of killing or preventing the growth of bacterial cells.

[0033] Furthermore, the term "treatment" or "treating" refers to an intervention (e.g., administration of a drug to a subject) that prevents or delays the onset or progression of, or reduces the incidence of (or eradicates) a disease in a treated population. In this context, the term treatment is used interchangeably with the term "prophylaxis."

[0034] The term "subject" (which should be interpreted as including "individual," "animal," "patient," or "mammal," as the context allows) defines any subject for which treatment is indicated, particularly a mammalian subject.Mammalian subjects include, but are not limited to, humans, domestic animals, livestock, zoo animals, sport animals, pet animals, such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, and cows; primates, such as apes, monkeys, orangutans, and chimpanzees; canines, such as dogs and wolves; felines, such as cats, lions, and tigers; equines, such as horses, donkeys, and zebras; food animals, such as cows, pigs, and sheep; ungulates, such as deer and giraffes; rodents, such as mice, rats, hamsters, and guinea pigs; etc.Preferably, the subject is human.

[0035] The terms "Gram-negative bacteria" and "Gram-positive bacteria" are terms of art that define two different classes of bacteria based on certain cell wall staining characteristics.

[0036] As used herein, an "effective amount" of a compound or agent is an amount that achieves a desired pharmacological effect or therapeutic improvement without undue adverse side effects. As used herein, a "therapeutically effective amount" refers to a sufficient amount of an agent or compound being administered that alleviates to some extent one or more symptoms of an infection or disease. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of an infection or disease, or any other desired change in a biological system. A therapeutic result need not be a complete cure. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. It is understood that an "effective amount" or "therapeutically effective amount" can vary from subject to subject depending on the individual's age, weight, general condition, mode of administration, the condition being treated, the severity of the condition being treated, and other factors.

[0037] As used herein, a "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects before the onset of disease or at an early stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0038] The term "effective" includes beneficial effects such as additivity, synergy, reduced side effects, reduced toxicity, improved performance, reduced bacterial load during infection, or activity.

[0039] The term "pharmaceutically acceptable salt" as applied to Compound (I) of the present invention defines any organic or inorganic acid addition salt of the free base that is suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response, and that is commensurate with a reasonable benefit / risk ratio. Suitable pharmaceutically acceptable salts are well known in the art. Examples include salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid), organic carboxylic acids (e.g., acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and mandelic acid), and organic sulfonic acids (e.g., methanesulfonic acid and p-toluenesulfonic acid).

[0040] The term "solvate" as applied to Compound (I) of the present invention refers to a physical association of Compound (I) with one or more solvent molecules, whether organic or inorganic. This physical association can include hydrogen bonding. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. A solvate may contain either a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate containing a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, and the like. Solvation methods are generally known in the art.

[0041] The term "hydrate" as applied to Compound (I) of the present invention refers to Compound (I) when associated with water in molecular form, i.e., where the H-OH bond is unsplit and can be represented, for example, by the formula R·H2O, where R is a compound of the present invention. A given compound may form more than one hydrate, including, for example, a monohydrate (R·H2O) or polyhydrate (R·nH2O, where n is an integer >1), such as a dihydrate (R·2H2O), trihydrate (R·3H2O), etc., or a hemihydrate, for example, R·n / 2H2O, R·n / 3H2O, R·n / 4H2O, etc., where n is an integer.

[0042] As used herein, the term "prodrug" as applied to Compound (I) refers to a pharmacologically acceptable derivative, such as an ester, amide, or phosphate, in which the in vivo biotransformation product of the resulting derivative is an active drug as defined by the compound of Formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed., McGraw-HiM, Int. Ed. 1992, "Biotransformation of Drugs," pp. 13-15), which generally describes prodrugs, is incorporated herein. Prodrugs of Compound (I) of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs of the compounds of the present invention include compounds in which the amino group of Compound (I) is bonded to any group that cleaves to form a free amino group when the prodrug is administered to a subject. The term includes all positional isomers thereof.

[0043] In its broadest aspect, the present invention contemplates all optical isomers of Compound (I) or pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs thereof.

[0044] In cases where the stereochemical form of Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is important to pharmaceutical utility, the present invention contemplates the use of the isolated eutomer.

[0045] As used herein, the term "resistant bacterial strain" refers to a bacterial strain that has demonstrated resistance or insensitivity to one or more known antibacterial agents, particularly those widely considered standard of care in the treatment of infections caused by bacterial strains. A "non-susceptible strain" is a bacterial strain in which the MIC (minimum inhibitory concentration) of a given compound or compound class against that strain has shifted to a value higher than the MIC against the corresponding susceptible strain. For example, a non-susceptible strain may refer to a strain that is insensitive to β-lactam antibiotics, a strain that is insensitive to one or more fluoroquinolones, and / or a strain that is insensitive to one or more other antibiotics (i.e., antibiotics other than β-lactams and fluoroquinolones). In some cases, the term "resistant" may refer to a strain in which the MIC of a given compound or compound class against that strain has shifted to a value significantly higher than the MIC against the corresponding susceptible strain. A bacterial strain may be said to be resistant to a given antibiotic if it is inhibited in vitro by a certain concentration of this drug, which is associated with a high probability of treatment failure.

[0046] As used herein, the term "multidrug-resistant" or "multidrug-resistant" refers to organisms, such as highly resistant Gram-negative bacteria (e.g., carbapenemase-producing Klebsiella pneumoniae), that exhibit in vitro and / or in vivo resistance to two or more antibacterial agents. Such organisms may be resistant to all currently available antibacterial agents or may remain susceptible only to older, potentially more toxic, antibacterial agents.

[0047] As used herein, the term "hypervirulent" refers to an organism that is exceptionally virulent, generally as a result of the acquisition of a hypervirulence plasmid. Such organisms are capable of causing severe disease. For completeness, "hypervirulent" refers to an organism that is capable of causing extremely severe or deleterious effects and disease.

[0048] As used herein, the term "antibacterial treatment" refers to the treatment of an infection or disease in a subject with an antibacterial agent other than Compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof. Typically, in the context of the present invention, this is with a known antibiotic or treatment method, including a carbapenem or other β-lactam antibiotic, other than Compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof. [Brief explanation of the drawings]

[0049] [Figure 1-1] FIG. 1a shows the results of in vitro pharmacological binding assays for Compound (I), Comparative Compound (II), and Comparative Compound (III) for all 44 ligands tested. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] FIG. 1d shows only the results of the in vitro pharmacological binding assay for Compound (I), Comparative Compound (II) and Comparative Compound (III) that show greater than 50% inhibition. [Figure 2] FIG. 2 shows the results of evaluating compound (I) and comparative compound (III) in a proof-of-concept study in a mouse model for the treatment of respiratory infections caused by Gram-negative bacteria of the order Enterobacteriaceae. [Figure 3] FIG. 3 shows the results of evaluating Compound (I) and comparative Compound (III) in a proof-of-concept study in a mouse model for the treatment of bacteremia or bloodstream infections due to Gram-negative bacteria of the order Enterobacteriaceae. [Figure 4-1]FIG. 4a shows the results of evaluating compound (I) and comparative compound (III) in a proof-of-concept study in a mouse model for the treatment of urinary tract infections due to Gram-negative bacteria of the order Enterobacteriaceae. [Figure 4-2] Same as above. [Figure 4-3] Same as above. [Figure 5] FIG. 5 shows the results of compound (I) being further evaluated in a proof-of-concept study in a mouse model for the treatment of respiratory infections caused by Gram-negative bacteria of the order Enterobacteriaceae. [Figure 6-1] FIG. 6a shows the results of compound (I) being further evaluated in a proof-of-concept study in a mouse model for the treatment of urinary tract infections caused by Gram-negative bacteria of the order Enterobacteriaceae. [Figure 6-2] Same as above. [Figure 6-3] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0050] Detailed Description of the Invention The present invention provides a solution to a previously unmet clinical need for the treatment of infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae, particularly carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum β-lactamase (ESBL) Enterobacteriaceae bacteria. The present invention can also be used to treat infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the genus Haemophilus.

[0051] It has surprisingly and advantageously been found that compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof enables the treatment of infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, such as Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, which are resistant to known β-lactam antibiotics and are a major cause of death.

[0052] Compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof may be particularly advantageous in treating multisite infections, i.e., infections caused by Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus, occurring at different infection sites (intracellular sites in tissues and / or organs) in a subject (as demonstrated by the data provided in the Examples section of this application). When antibacterial treatment of a disease or infection in a subject in need of treatment has failed, or when the subject is allergic or otherwise contraindicated to a drug used or contemplated for use in antibacterial treatment, Compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof may be further advantageously utilized in treating infections caused by Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus, or diseases caused or exacerbated thereby.

[0053] Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug appears to have rapid bactericidal activity and is believed to be highly active against all currently tested clinical resistance mechanisms, including all Ambler beta-lactamase classes (including metallo-beta-lactams). Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug appears to be resistant to inactivation by the full range of carbapenem-metabolizing enzymes and has demonstrated activity against all currently tested CRE, regardless of carbapenemase or other resistance characteristics. In contrast to known BL / BLI combination treatments, Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug has shown a low propensity for resistance development when tested in vitro.

[0054] Furthermore, Compound (I) or its pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs does not exhibit cross-resistance with currently tested classes of antibiotics, and no contraindications have been observed. Compound (I) or its pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs have also demonstrated safety both in vitro and in vivo in pharmacological studies.

[0055] Therefore, compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof can be used to treat bacterial infections or diseases caused by or exacerbated by bacteria resistant to known antibiotics, such as Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, particularly, carbapenem-resistant Enterobacteriale (CRE) and extended-spectrum β-lactamase (ESBL) Enterobacteriale bacteria. Compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof has bactericidal activity against bacteria resistant to known antibiotics, such as Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, particularly, carbapenem-resistant Enterobacteriale (CRE) and extended-spectrum β-lactamase (ESBL) Enterobacteriale bacteria.

[0056] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can target one or more Gram-negative bacteria of the order Enterobacteriaceae. Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can target one or more Gram-negative bacteria of the family and genera of the order Enterobacteriaceae of Gram-negative bacteria. The order Enterobacteriaceae includes the families Enterobacteriaceae, Budviciaceae, Erwiniaceae, Hafniaceae, Morganellaceae, Pectobacteriaceae, and Yersiniaceae, and all genera thereof. Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can target one or more of the following genera of Gram-negative bacteria in the order Enterobacteriale: Arsenophonus, Atlantibacter, Biostraticola, Brenneria, Buchnera, Budvicia, Buttiauxella, Cedecea, Chania, Citrobacter, Cosenzaea, Cronobacter, Zickeya (Dickeya), Edwardsiella, Enterobacillus, Enterobacter, Erwinia, Escherichia, Ewingella, Franconibacter, Gibbsiella, Hafnia, Izhakiella, Kosakonia, Klebsiella, Kluyvera, Leclercia, Lelliottia, Leminorella,Levinea, Lonsdalea, Mangrovibacter, Moellerella, Morganella, Obesumbacterium, Pantoea, Pectobacterium, Phaseolubacter, Photorhabdus, Plesiomonas, Pluralibacter, Pragia, Proteus, Providencia, Pseudocitrobacter, Rahnella ella, Raoultella, Rosenbergiella, Rouxiella, Saccharobacter, Salmonella, Samsonia, Serratia, Shigella, Shimwellia, Siccibacter, Sodalis, Tatumella, Thorsellia, Trabulsiella, Wigglesworthia, Xenorhabdus, Yersinia, and Yokenella.

[0057] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can target one or more Gram-negative bacteria of the genus Haemophilus, which belong to the family Pasteurellaceae, order Pasteurellales.

[0058] Preferably, compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, targets one or more Gram-negative bacteria of the order Enterobacteriaceae. Preferably, compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is used to treat infection with, or a disease caused or exacerbated by, a Gram-negative bacteria of the order Enterobacteriaceae.

[0059] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, will typically have the same or similar activity against all Gram-negative bacteria of the order Enterobacteriaceae. This is the result of sufficiently high sequence homology among Gram-negative bacteria of the order Enterobacteriaceae. Therefore, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, will interact similarly with all Gram-negative bacteria of the order Enterobacteriaceae. This is particularly true for selected Enterobacteriaceae bacterial genera, as detailed below. Preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, targets one or more Gram-negative bacteria from the bacterial genera Cedecea, Citrobacter, Erwinia, Escherichia, Enterobacter, Klebsiella, Kluyvera, Plesiomonas, Proteus, Providencia, Raoultella, Salmonella, Serratia, Shigella, and Yersinia of the order Enterobacteriaceae. More preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, targets one or more Gram-negative bacteria from the Enterobacteriaceae bacterial genera Erwinia, Escherichia, Enterobacter, Klebsiella, Proteus, Salmonella, Serratia, Shigella, and Yersinia.The genus Escherichia includes Escherichia coli, such as extraintestinal pathogenic Escherichia coli (ExPEC) strains and carbapenem-resistant Escherichia coli strains, e.g., Escherichia coli of sequence type ST131 and Escherichia coli ATCC BAA-2469 (NDM-1 strain: American Type Culture Collection). The genus Enterobacter includes Enterobacter spp. The genus Klebsiella includes Klebsiella pneumoniae, e.g., carbapenem-resistant Klebsiella pneumoniae strains, e.g., Klebsiella pneumoniae of sequence type ST25 and Klebsiella pneumoniae ATCC 43816 (American Type Culture Collection). Preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, targets one or more Gram-negative bacteria from the Enterobacteriaceae bacterial genera Escherichia, Enterobacter, and Klebsiella, more preferably Escherichia and Klebsiella. Preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, targets Enterobacter spp., Escherichia coli, and Klebsiella pneumoniae, more preferably Escherichia coli and Klebsiella pneumoniae.

[0060] The one or more Gram-negative bacteria targeted by Compound (I) or its pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs are typically multidrug-resistant, including carbapenem-resistant or β-lactam-resistant, and exhibit resistance to these known antibiotics and related antibacterial treatments. Such bacteria include, for example, carbapenem-resistant Escherichia coli ATCC BAA-2469, ExPEC Escherichia coli ST131, Klebsiella pneumoniae ST258, and Klebsiella pneumoniae ATCC 42816.

[0061] The National Collection of Type Cultures (NCTC) reference strain for ExPEC Escherichia coli ST131 is NCTC13441. Further details regarding ExPEC Escherichia coli ST131 are provided in: Pitout et al., 'Escherichia coli ST131: a multidrug-resistant clone primed for global domination', F1000Research 2017, 6(F1000 Faculty Rev):195; Ciesielczuk et al., 'Trends in ExPEC serogroups in the UK and their significance', Eur J Clin Microbial Infect Dis (2016) 35:1661-1666; Day et al., 'Extended-spectrum β-lactamase-producing Escherichia coli in human-derived and food chain-derived samples from England, Wales, and Scotland: an epidemiological surveillance and typing study', Lancet Infect Dis 2019, vol. 19; and Day et al., 'Population structure of Escherichia coli causing bacteraemia in the UK and Ireland between 2001 and 2010', J Antimicrob Chemother 2016, 71, 2139-2142.

[0062] The National Collection of Type Cultures (NCTC) reference strain for Klebsiella pneumonia ST258 is NCTC 13438. Further details on Klebsiella pneumonia ST258 are provided in: Chen et al., 'Carbapenemase-producing Klebsiella pneumonia: molecular and genetic decoding', Trends Microbiol., December 2014, 22(12), 686-696.

[0063] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be used to treat infections caused by Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus in the form of biofilms.

[0064] Diseases or infections caused or exacerbated by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus may include intoxication by one or more bacterial toxins, including, for example, endotoxins, exotoxins, and / or toxic enzymes. Thus, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, finds application in the treatment of Enterobacteriale and / or Haemophilus intoxication. In such cases, treatment of intoxication by bacterial endotoxins, exotoxins, and / or toxic enzymes, for example, endotoxins, exotoxins, and / or toxic enzymes produced by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, is preferred.

[0065] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, as described in various embodiments herein, can be used to treat the human body, i.e., the subject to be treated is a human.

[0066] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can also be used to treat the animal body, i.e., the subject to be treated is an animal. In particular, it is intended to treat commercial animals such as livestock. Alternatively, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be used to treat pet animals such as cats and dogs. It will be understood that the treatment of the animal body is carried out in a similar manner for all subjects, i.e., both humans and animals.

[0067] Preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is used to treat the human body, i.e., the subject to be treated is a human.

[0068] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be used to treat infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus. Specifically, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be used to treat bacteremia or bloodstream infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, urinary tract infections (UTIs) (typically complicated UTIs) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, pyelonephritis (kidney infection) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and intraperitoneal infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus. In particular, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be used to treat bacteremia or bloodstream infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, urinary tract infections (UTI) (typically complicated UTI) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, pyelonephritis (kidney infection) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and intraperitoneal infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus when antibacterial treatment of the infection has failed.It is further noted that Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or protected form thereof, can be used to treat bacteremia or bloodstream infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, urinary tract infections (UTI) (typically complicated UTI) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, pyelonephritis (kidney infection) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and intraperitoneal infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, when the subject in need of treatment is allergic to or otherwise contraindicated to the agent used in the antibacterial treatment.

[0069] Bacteremia or bloodstream infections due to gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus can lead to conditions such as sepsis (also known as septicaemia).

[0070] Respiratory infections caused by Gram-negative bacteria of the order Enterobacteriaceae and / or the genus Haemophilus include infections of the airways or lungs, including pneumonia. In the context of the present invention, pneumonia typically refers to healthcare pneumonia, including hospital-acquired pneumonia and ventilator-associated pneumonia, or pneumonia that has resulted in the subject being hospitalized.

[0071] Urinary tract infections (UTIs) caused by gram-negative bacteria of the order Enterobacteriaceae and / or the genus Haemophilus include uncomplicated and complicated UTIs affecting the bladder (cystitis), urethra (urethritis) or kidneys (renal infection).

[0072] Intra-abdominal infections (IAI) caused by gram-negative bacteria of the order Enterobacteriaceae and / or the genus Haemophilus can cause conditions such as peritonitis, diverticulitis, cholecystitis, cholangitis, and pancreatitis.

[0073] Preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or protected form thereof, can be used to treat bacteremia or bloodstream infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and urinary tract infections (UTIs) (typically complicated UTIs) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and more preferably can be used to treat respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and urinary tract infections (UTIs) (typically complicated UTIs) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus.

[0074] Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug may be effective in treating multisite infections, i.e., infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, occurring at different infection sites (intracellular sites in tissues and / or organs) in a subject (as demonstrated by the data provided in the Examples section of this application). This may be the case, for example, in both the bloodstream to treat bacteremia or bloodstream infections caused by or exacerbated by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and in the respiratory organs to treat respiratory infections caused by or exacerbated by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus. It will be understood that infections at multiple sites are typically caused by or exacerbated by the same species of Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus. Infections by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus may occur simultaneously or subsequently in different tissues and / or organs of a subject. Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be used for multi-site treatment of infections by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, or diseases caused or exacerbated thereby.

[0075] As indicated above, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be utilized, particularly after unsuccessful empirical antibacterial treatment with known antibiotics that are considered the standard of care for treating an alleged infection. Thus, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, may be promoted after antibiotic-resistant Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus have been determined to be the cause of a subject's infection or disease.

[0076] After determining the presence of antibiotic-resistant Enterobacteriale gram-negative bacteria and / or Gram-negative bacteria of the genus Haemophilus, such as carbapenem-resistant Enterobacteriale (CRE) or extended-spectrum β-lactamase (ESBL) Enterobacteriale bacteria that are resistant to known β-lactam antibiotics, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be utilized to treat infections in a subject caused by, or caused by, or exacerbated by, these resistant Enterobacteriale and / or Haemophilus strains.

[0077] Methods for determining the presence of antibiotic-resistant Enterobacteriaceae Gram-negative bacteria and / or Haemophilus genus Gram-negative bacteria, such as carbapenem-resistant Enterobacteriaceae (CRE) or extended-spectrum β-lactamase (ESBL) Enterobacteriaceae bacteria, will be well known to those skilled in the art. Suitable methods include those disclosed in Al-Zahrani, 'Routine detection of carbapenem-resistant gram-negative bacilli in clinical laboratories', Saudi Medical Journal, 2018 Sept., pp. 861-872.

[0078] Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug can be used in any clinical practice or treatment. For example, compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug can be used in a hospital setting, for example, for hospitalized patients with severe illness. Alternatively or additionally, compound (I) can be used in outpatient treatment, such as outpatient parenteral antimicrobial therapy (OPAT), or by patients in a home setting. As described above, treatment with compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug can be performed after unsuccessful antimicrobial treatment. However, compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug can also be used as a first antimicrobial treatment, for example, in environments with high infection rates, such as epidemics in local or regional areas.

[0079] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be used to treat hospital-acquired infections (HAIs) caused by Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus, e.g., introduced by a central line or catheter.

[0080] Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug can be formulated as a pharmaceutical composition together with a pharmaceutically acceptable carrier or excipient.Suitable pharmaceutically acceptable carriers and excipients depend on the mode of administration of the pharmaceutical composition and will be described in more detail below.Typically, Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug is administered in a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier or excipient.

[0081] The pharmaceutical compositions claimed herein may further comprise pharmaceutically acceptable ingredients selected from, but not limited to, stabilizers, antioxidants, colorants, diluents, and combinations thereof. The ingredients of the pharmaceutical compositions are selected so as to minimize side effects and not impair the performance of Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, to an extent that treatment is ineffective.

[0082] The pharmaceutical compositions according to the present invention can be administered to a subject in need thereof by any suitable route, including, but not limited to, enteral administration, e.g., oral, rectal, gastric or duodenal administration; parenteral administration (such as intravenous by injection or infusion); vaginal, buccal or sublingual administration; topical administration or inhalation.

[0083] Parenteral administration includes subcutaneous, intravenous, intradermal, intramuscular, and intraperitoneal administration, as well as injection techniques such as sterile injectable aqueous emulsions and oily suspensions. Such suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild, fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, omega-3 polyunsaturated fatty acids can also be used in the preparation of injectables.

[0084] Preferably, intravenous administration to a human subject can be given in the form of either a bolus (injected all at once) (IV bolus) or intravenous infusion (IV infusion), e.g., slowly injected into the plasma through a vein of the subject at a constant or zero-order rate. Preferably, intravenous administration is administered in the form of intravenous infusion (IV infusion).

[0085] Such intravenous infusions, preferably to human subjects, can be provided as isotonic solutions. Such solutions generally have an osmolality of 250-375 mOsm / L. Preferred examples of isotonic solutions include normal saline (preferably about 0.9% sodium chloride), phosphate-buffered saline, lactated Ringer's solution, about 5% dextrose in water (D5W), and Ringer's solution. For intravenous infusion, isotonic solutions preferably have a pH of 5-8, e.g., 6-8 or 7.1-7.5.

[0086] For subcutaneous, intravenous, intramuscular, inhalation, or intraperitoneal administration, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, may be provided as an injectable dose in a pharmaceutically acceptable diluent (which may be a sterile liquid or mixture of liquids), together with a pharmaceutically acceptable excipient or carrier.

[0087] For intramuscular, intraperitoneal, subcutaneous, inhalation, and intravenous use, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity.

[0088] Preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, or a pharmaceutical composition formulated therefrom, is administered parenterally or by inhalation, more preferably intravenously, more preferably intravenously in the form of intravenous infusion (IV infusion). Most preferably, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is administered intravenously to a human subject, especially in the form of intravenous infusion (IV infusion).

[0089] Pharmaceutically acceptable excipients and carriers include all of the above and the like.The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks.See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott, Williams and Wilkins), 2000;Lieberman et al., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980), and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).

[0090] In addition to hydroxypropyl β-cyclodextrin and phosphate buffer, suitable pharmaceutically acceptable carriers or excipients for use in the pharmaceutical compositions of the present invention include isotonic solutions, such as saline (preferably about 0.9% sodium chloride), phosphate-buffered saline, lactated Ringer's solution, about 5% dextrose in water (D5W), and Ringer's solution. The isotonic solutions preferably have a pH of 5 to 8, e.g., 6 to 8 or 7.1 to 7.5. The pH of the phosphate buffer may be 5 to 7, preferably 6.

[0091] For intravenous infusion into a human subject, the pharmaceutically acceptable carrier or excipient may be selected from saline (preferably about 0.9% sodium chloride), phosphate buffered saline, lactated Ringer's solution, about 5% dextrose in water (D5W), Ringer's solution, and acid buffer. The pH of the phosphate buffer may be 5 to 7, preferably 6. Preferably, for intravenous infusion into a human subject, the pharmaceutically acceptable carrier or excipient is phosphate buffer, preferably at pH 6.

[0092] For Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, the dosage of Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, will, of course, vary depending on the mode of administration, the desired treatment, and the infection or disease being treated.

[0093] The size of a dose of Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for therapeutic purposes will naturally vary according to well-known principles of medicine and depending on the nature and severity of the condition, the age and sex of the subject, and the mode of administration.

[0094] Dosage levels, dosing frequency, and duration of treatment of Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, are expected to vary depending on the formulation, mode of administration, and the patient's clinical indication, age, and comorbid medical conditions.

[0095] When the method of administration is intravenous infusion into a human subject, Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug can typically be administered in a dose of 50 to 6000 mg per day in a pharmaceutical composition according to the present invention. Preferably, Compound (I) or its pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug is administered at a dose of 50 to 4000 mg per day, or 50 to 3000 mg per day, for example, 50 to 2000 mg per day, or 100 to 2000 mg per day, for example, 200 to 2000 mg per day, or 200 to 1750 mg per day, or 200 to 1500 mg per day, or 250 to 1000 mg per day. When Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is administered more than once daily, such as twice or three times daily, as discussed below, the dose is divided according to the number of times per day it is administered.

[0096] When the administration method is intravenous infusion to a human subject, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, may be administered at the above-mentioned doses once (QD), twice (BID), or three times (TID). Twice-daily (BID) administration by intravenous infusion to a human subject includes twice-daily administration spaced 1 to 12 hours apart, e.g., 1 to 8 hours, or 2 to 7 hours, or 2 to 6 hours, or 3 to 5 hours apart, e.g., 1 to 4 hours apart. Three-times-daily (TID) administration by intravenous infusion to a human subject includes three-times-daily administration spaced 2 to 7 hours apart, or 2 to 6 hours, or 3 to 5 hours apart, e.g., 1 to 4 hours apart. The number of hours is calculated from the time the first administration is initiated. This is the period from the start of the first administration to the start of the second administration. It will be further understood that when administered twice or three times daily, the same dose or different doses can be administered each time. Each dose of intravenous infusion may be administered over a period of 30 minutes to 6 hours, such as 30 minutes to 4 hours, or 30 minutes to 3 hours, or 30 minutes to 2 hours, or 30 minutes to 1 hour, or about 1 hour.

[0097] Preferably, compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is administered by intravenous infusion to a human subject at the above-mentioned daily dose once daily (QD), twice daily (BID), at intervals of 1 to 12 hours, for example, at intervals of 1 to 8 hours, or at intervals of 2 to 6 hours, or at intervals of 2 to 5 hours, or at intervals of 3 to 5 hours, or at intervals of 1 to 4 hours, or three times daily (TID), at intervals of 2 to 7 hours, for example, at intervals of 2 to 6 hours, or at intervals of 3 to 5 hours, for example, at intervals of 1 to 4 hours. More preferably, compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is administered by intravenous infusion to a human subject at the above-mentioned daily dose twice daily, at intervals of 1 to 12 hours, for example, at intervals of 1 to 8 hours, or at intervals of 2 to 6 hours, or at intervals of 2 to 5 hours, or at intervals of 3 to 5 hours, or at intervals of 1 to 4 hours.

[0098] When the method of administration is intravenous infusion to a human subject, Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or protected form thereof, at the above-mentioned doses and administrations per day, is preferably used to treat respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and / or urinary tract infections (UTI) (typically complicated UTI) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus.

[0099] When the method of administration is intravenous infusion into a human subject, at the above doses and administrations per day, the course of treatment may last from 1 to 10 days, for example, from 1 to 7 days, or from 1 to 5 days. By "course of treatment" is meant the time during which the treatment is administered on consecutive days.

[0100] Therefore, the pharmaceutical composition according to the present invention comprising compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is preferably administered at a dose of 50 to 6000 mg per day, or 50 to 4000 mg per day, or 50 to 3000 mg per day, for example, 50 to 2000 mg per day, or 100 to 2000 mg per day, for example, 200 to 2000 mg per day, or 200 to 1750 mg per day, or 200 to 1500 mg per day, or 250 to 1000 mg per day, It may be administered to a human subject by intravenous infusion once a day (QID), twice a day (BID), or three times a day (TID), more preferably once a day (QID), twice a day (BID), at intervals of 1 to 12 hours, for example, at intervals of 1 to 8 hours, or at intervals of 2 to 6 hours, or at intervals of 2 to 5 hours, or at intervals of 3 to 5 hours, or at intervals of 1 to 4 hours, or three times a day (TID), at intervals of 2 to 7 hours, for example, at intervals of 2 to 6 hours, or at intervals of 3 to 5 hours, for example, at intervals of 1 to 4 hours, more preferably twice a day, at intervals of 1 to 12 hours, for example, at intervals of 1 to 8 hours, or at intervals of 2 to 6 hours, or at intervals of 2 to 5 hours, or at intervals of 3 to 5 hours, or at intervals of 1 to 4 hours.

[0101] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, may be in any form, which may be synthesized, purified, or isolated from natural sources using techniques described in the art.

[0102] Compound (I) can be obtained, stored, and / or administered in the form of a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts are prepared from formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acid, β-hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0103] Suitable pharmaceutically acceptable base addition salts include metal ion salts and organic ion salts. Metal ion salts include, but are not limited to, appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metal ions. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc ions. Organic salts can be made from tertiary amines and quaternary ammonium salts, such as trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of the above salts can be prepared by conventional means from the corresponding compounds by those skilled in the art. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs," ME Aulton, Churchill Livingstone, 1988.

[0104] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can also be used for the in vitro inhibition of the growth of Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, particularly carbapenem-resistant Enterobacteriale (CRE) and extended-spectrum β-lactamase (ESBL) Enterobacteriale bacteria. Accordingly, the present invention further encompasses an in vitro method for inhibiting the growth of Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, particularly carbapenem-resistant Enterobacteriale (CRE) and extended-spectrum β-lactamase (ESBL) Enterobacteriale bacteria, using Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0105] Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, can be synthesized by any suitable method.

[0106] Suitable methods for synthesizing Compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, include, but are not limited to, methods corresponding to synthetic route 1 of WO2019 / 086890.

[0107] Compound (I) can be synthesized according to the following method. This method represents a preferred method for synthesizing compound (I), and the method includes a preferred linking step detailed below. However, in the context of the present invention, it will be understood that these preferred steps are separable, and one or more of the steps can be replaced with any other suitable step identified by a person skilled in the art. When step X has options A and B, for example, step 6A or step 6B, either step XA or XB can be used as step X, i.e., either step 6A or 6B can be used as step 6.

[0108] Step 1

[0109]

change

[0110] Step 2

[0111]

Chemical Structure

[0112] Step 3

[0113] [ka]

[0114] A 5.0 L four-neck round-bottom flask equipped with a mechanical stirrer was charged with a mixture of EtOH (2.0 L, 3V), 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-bromoethan-1-one (3) and 1-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-chloroethan-1-one (3A) (685 g, 2.30 mol, 92% purity by LCMS), followed by the addition of pyrimidin-2-amine (4) (546 g, 5.74 mol) at 20 °C. The reaction mixture was further stirred and refluxed for 3 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature (approximately 20° C.), and the resulting precipitated solid was filtered, washed with EtOH (2×250 mL), and dried under vacuum to give 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) as an off-white solid (418 g). MS (ESI+) m / z 295.06 [M+H] for CHNOS. + . 1H NMR (400 MHz, DMSO-d6 + d-TFA): δ 9.27 (d, J = 6.40 Hz, 1H), 8.97-9.02 (m, 1H), 8.65 (s, 1H), 8.44 (bs, 1H), 7.63-7.69 (m, 2H), 7.10 (d, J = 8.40 Hz, 1H), 4.33-4.36 (m, 2H), 3.89-3.93 (m, 2H), 2.32 (s, 3H). The regioisomeric structure was confirmed by nOe.

[0115] Step 4

[0116] [ka] A 10 L four-neck round-bottom flask equipped with a mechanical stirrer was charged with N,N-dimethylacetamide (2.0 L), 1-(6-(imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (5) (250 g, 849 mmol), 2,2-dimethylpropanoic acid (34.7 g, 340 mmol), potassium carbonate (587 g, 4.25 mol), and 4-bromo-3-methylpyridine (6) (264 g, 1.44 mol) at 20 °C under a N atmosphere. The resulting reaction mixture was purged with N2 (gas) for 30 minutes, followed by the addition of Pd(OAc)2 (19.1 g, 84.9 mmol) and PCy3·HBF4 (31.2 g, 84.9 mmol) under a N2 atmosphere. The reaction mixture was again purged with N2 (gas) for an additional 15 minutes. The resulting reaction mixture was further stirred at 125 °C for 7 hours. The reaction was monitored by LCMS. Crude LCMS confirmed the formation of a regioisomeric mixture of the desired product in a regioisomeric ratio of 98:2. The reaction mixture was filtered through a Celite bed (height 1.3 cm, diameter 25 cm). The Celite bed was washed with 10% MeOH in DCM (15 L). The filtrate was evaporated under reduced pressure to give the crude residue as a brown liquid. The brown liquid was stirred in heptane (3 × 6.0 L) for 10 hours to remove excess DMA. The heptane / DMA mixture was decanted (a trace of the desired product was observed in the decanted fractions) to give a waxy solid. The waxy solid was stirred in MTBE (3.0 L) for an additional 15 minutes. The resulting precipitate was filtered and washed with MTBE (2.0 L) to give the desired product as a brown solid. The brown solid was passed through a small silica plug and eluted with 10% MeOH in DCM (approximately 35 L). The resulting solvent fractions were concentrated to 1 / 10 of their original volume. The concentrated fractions were diluted with MTBE (200 mL) and stirred for 30 minutes.The resulting precipitate was filtered, washed with MTBE (1.0 L), and dried under vacuum to give a regioisomeric mixture of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) as a light brown solid. Yield: 66% (97% by LCMS, regioisomeric ratio 98:2). MS (ESI+) m / z for CHNOS: 386.18 [M+1]. + .1H NMR (400 MHz, DMSO-d6 + d-TFA): δ 9.14 (s, 1H), 9.01-9.04 (m, 2H), 8.86 (d, J = 6.7 Hz, 1H), 8.23 ​​(d, J = 5.8 Hz, 1H), 8.01 (bs, 1H), 7.55-7.58 (m, 1H), 7.41(d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 4.09-4.33 (m, 2H), 3.71-3.92 (m, 2H), 2.17 (s, 3H), 2.11 (bs, 3H).

[0117] Step 5A

[0118] [ka] To a solution of a regioisomeric mixture (97:3) of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (24.0 g, 62.3 mmol) in methanol (150 mL) was added 6.0 N aqueous HCl (62 mL) at room temperature. The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated to one-quarter of its original volume. The concentrated reaction mixture was basified to pH 8-9 with saturated aqueous NaHCO3 and extracted with 10% MeOH in DCM (3 x 250 mL). The organic layer was washed with brine (300 mL), dried over (Na2SO4), filtered, and concentrated under reduced pressure to 1 / 10 of its original volume. The concentrated mixture was diluted with heptane (100 mL) and stirred for 30 min. The resulting precipitate was filtered, washed with heptane (100 mL), and dried under reduced pressure to give a mixture of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) (20.0 g) as a yellow solid. Yield: 71% (a mixture of two regioisomers in a 2:1 regioisomeric ratio, 89% by LCMS). LCMS showed two peaks with 56% and 33% of the desired mass, respectively. (ESI+) m / z 344.20 [M+H] for CHNOS. + .

[0119] Or Step 5B

[0120] [ka] A suspension of a regioisomeric mixture (98:2) of 1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7) and 1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one (7A) (10.0 g, 25.9 mmol) in 2.0 M aqueous NaOH solution (52 mL, 104 mmol) was heated at 100° C. for 24 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with water (approximately 500 mL) and dried to give a mixture of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) as a light brown solid. Yield: 8.1 g, 90% (mixture of two regioisomers in a regioisomeric ratio of 98:2, 98.7% by LCMS). MS (ESI+) m / z 344.20 [M+H] for CHNOS. + ; 1 H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.54-8.62 (m, 2H), 8.25 (d, J = 6.8 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 6.96-7.03 (m, 2H), 6.46-6.55 (m, 2H), 5.87 (s, 1H), 4.11 (t, J = 4.0 Hz, 2H), 3.25 (bs, 2H), 1.94 (s, 3H).

[0121] Step 6A (HMPA-mediated amino acid coupling)

[0122] [ka] To a suspension of 2-amino-2-methylpropanoic acid (9) (12 g, 116 mmol) in HMPA (84 mL, 7 V) was added slowly a solution of thionyl chloride (9.29 g, 128 mmol) in ACN (8.4 mL) at 3 °C (external temperature was 0 °C). 10 min after complete addition of the solution of thionyl chloride in ACN, the suspension became clear. The resulting reaction mixture was stirred at 0° C. for 20 minutes, followed by the addition of a regioisomeric mixture of 6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8) and 6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (8A) (8 g, 23.3 mmol) in portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with EtOAc (300 mL). The resulting precipitate was filtered and washed with EtOAc (250 mL). The solid was dissolved in water (50 mL), neutralized to pH 8 with saturated sodium bicarbonate solution, extracted with 10% MeOH in DCM (4 x 100 mL), and concentrated under reduced pressure to 1 / 10 the volume of the original reaction mixture. The crude mixture was diluted with MTBE (50 mL) and stirred for 15 min. The resulting precipitate was filtered, washed with MTBE (25 mL), and dried under vacuum to give a regioisomeric mixture of 2-amino-2-methyl-1-(6-(3-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10) and 2-amino-2-methyl-1-(6-(2-(3-methylpyridin-4-yl)imidazo[1,2-a]pyrimidin-3-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)propan-1-one (10A) as a brown solid. Yield: 66% (97% by LCMS, regioisomeric ratio 98:2). CHNOS MS (ESI+) m / z 429.16 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.54 - 8.62 (m, 2H), 8.29 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 6.98 - 7.05 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 4.45 - 4.67 (m, 2H), 4.30 (bs, 2H), 2.12 (bs, 2H), 1.97 (s, 3H), 1.34 (s, 6H).

[0123] Alternatively, Step 6B (DMPU-mediated amino acid coupling)

[0124]

Chem.

[0125] Step 7

[0126]

Chem.

[0127] Preferably, step 5B is selected.

[0128] Those skilled in the art will appreciate that pharmaceutically acceptable salts, hydrates, solvates, complexes, or prodrugs of Compound (I) can be readily synthesized, typically using any of the syntheses disclosed herein, with the known additional steps required to form Compound (I) and then form a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[0129] The present invention will now be described with reference to specific examples. These are merely exemplary and for illustrative purposes only; they are not intended to limit in any way the scope of the claimed exclusivity or the described invention. These examples constitute the best mode presently contemplated for practicing the invention. [Example]

[0130] Comparative compound (II):

[0131] [ka] was synthesized by a method corresponding to synthetic route 1 described in WO2019 / 086890. Comparative compound (II) can also be synthesized by modifying the method outlined above for compound (I). Such modifications include the selection of an appropriate pyridyl starting material and the use of glycine as the amino acid.

[0132] Comparative compound (III):

[0133] [ka] was synthesized by a method corresponding to synthetic route 1 described in WO2019 / 086890. Comparative compound (III) can also be synthesized by modifying the method outlined above for compound (I). Such modifications include the selection of an appropriate pyridyl starting material and the use of glycine as the amino acid.

[0134] The minimum inhibitory concentration (MIC) and minimum inhibitory concentration 90 value (MIC) were determined for compound (I) and comparative compounds (II) and (III). 90 ) was analyzed as follows.

[0135] Antimicrobial susceptibility Minimum inhibitory concentrations (MICs) against Escherichia coli (NCTC 13441) and Klebsiella pneumoniae (NCTC 13438) (planktonic bacteria) were determined by a broth microdilution procedure following the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Eleventh Edition, CLSI document M07, 11 January 2018). The broth dilution method involved two-fold serial dilutions of compounds in 96-well microtiter plates, resulting in a final concentration range of 0.39–200 μM, with a maximum final concentration of 2% DMSO. The bacterial strains tested were Escherichia coli (NCTC 13441) and Klebsiella pneumoniae (NCTC 13438). Strains were grown on cation-adjusted Mueller-Hinton broth or Luria-Bertani agar at 37°C in ambient atmosphere. The MIC (μM) was determined as the lowest concentration of compound that inhibited growth after a 20- to 24-hour incubation period. The results are shown in Table 1.

[0136] [Table 1]

[0137] Using the methodology outlined above, the minimum inhibitory concentrations (MICs) versus Proteus mirabilis (DSM4479) were determined for compound (I) and comparative compounds (II) and (III). The results are shown in Table 2. Compound (I) exhibits superior potency relative to comparative compounds (II) and (III).

[0138] [Table 2]

[0139] Minimum inhibitory concentrations (MICs) against 100 isolates of Escherichia coli and Klebsiella pneumoniae 90 The minimum inhibitory concentration (MIC) at which 90% of the isolated bacteria (strains) were inhibited was measured. 90 MICs were determined by broth microdilution according to the EUCAST susceptibility testing standard (www.eucast.org). Bacterial inocula were prepared at approximately 1 x 10^6 CFU / mL by diluting a 0.5 McFarland suspension 100-fold. Antimicrobial panels containing 50 μl of antimicrobial solution at twice the final concentration were diluted 2-fold with 50 μl of inoculum to obtain a final inoculum of approximately 5 x 10^5 CFU / mL and the desired test concentrations of antimicrobial agents (0.03–64 μg / mL). Plates were incubated according to the guidelines of the Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Eleventh Edition, CLSI document M07, 11 January 2018). ... 90 The MIC (μg / ml) is the MIC value at which 90% or more of the isolates (strains) in the test population are inhibited. The results are shown in Table 3.

[0140] [Table 3]

[0141] Using the methodology outlined above for 100 isolates of Escherichia coli and Klebsiella pneumoniae, the minimum inhibitory concentrations (MICs) versus Proteus spp. and Providencia spp. were determined for Compound (I) and Comparative Compound (III). The results are shown in Table 4. Compound (I) shows superior potency relative to Comparative Compound (III).

[0142] [Table 4]

[0143] Compound (I) and comparative compounds (II) and (III) were subjected to the following analyses regarding lipophilicity and volume of distribution (Vss).

[0144] lipophilic The LogP values ​​of Compound (I) and Comparative Compound (III) were measured by performing an acid-based titration using a Sirius T3 instrument manufactured by Sirius Analytical to measure the pKa shift when the sample solution came into contact with an immiscible solvent (octanol). The LogP of Comparative Compound (II) was calculated using Marvin (physical and chemical calculation software). The results are shown in Table 5. The lipophilicity data for Compound (I) and Comparative Compounds (II) and (III) were collected in separate experiments performed on different days and are compared in Table 5.

[0145] [Table 5]

[0146] distribution volume The volume of distribution (Vss) of Compound (I) and comparative compounds (II) and (III) was determined from analysis of plasma concentration-time profiles obtained from rodent species (mice) after an IV bolus dose of 5 mg / kg, respectively. The volume of distribution was obtained by analyzing the rodent plasma profiles of Compound (I) and comparative compounds (II) and (III) using a two-compartment IV bolus model in PK Solver (Excel). The output Vss values ​​are shown in Table 6. The amount of distribution data for Compound (I) and comparative compound (II) was collected in separate experiments performed on different days and is compared in Table 6.

[0147] [Table 6]

[0148] Discussion of the results Without being bound by theory, the inventors believe that the above results regarding lipophilicity and volume of distribution demonstrate that compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof can be advantageously used to treat infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus, particularly for the treatment of multi-site infections caused by gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus. The inventors believe that the above results demonstrate that compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof has the ability to effectively distribute to all sites of infection around a subject's body at sufficient concentrations to allow effective treatment at all sites. As well as ensuring that sufficient amounts of compound are available to exert a pharmacological effect, a balance must be maintained between ensuring that distribution of the compound from the plasma is fast enough to allow the drug to act quickly against the infection, and avoiding a very rapid release that would prevent the drug from reaching all possible sites of infection in sufficient concentrations.

[0149] Such a balance is believed to be demonstrated by the above results, which are discussed in more detail below.

[0150] The LogP value of a compound provides an indication of polarity and therefore the ability of the compound to reach the target tissue of a subject, i.e., the ease with which the drug can cross membrane barriers and distribute to possible intracellular infection sites around the subject's body.

[0151] Table 5 shows that compound (I) of the present invention has a higher LogP value, and therefore a lower polarity, compared to both comparative compounds (II) and (III), indicating improved tissue distribution of compound (I) compared to the more polar comparative compounds (II) and (III). The inventors believe that this improved tissue distribution of compound (I) allows sufficient drug to reach each of the infection sites to enable treatment, allowing the compound to distribute to all possible infection sites around the subject's body. As seen for comparative compounds (II) and (III) based on the LogP values ​​in Table 5, ineffective drug distribution would result in insufficient drug concentration throughout the infection sites, preventing treatment of the infection. As discussed above, there is a balance to be achieved regarding the efficiency with which the drug distributes around the subject's body. The LogP values ​​of compound (I) indicate that, relative to comparative compounds (II) and (III), compound (I) distributes to multiple infection sites and provides adequate drug concentrations at all of these infection sites.

[0152] The volume of distribution (Vss) provides a measure of the extent to which a compound distributes into the body tissues of a subject rather than into the plasma, ie, the tendency of a compound to leave the plasma and distribute into the body tissues of a subject.

[0153] Table 6 shows that Compound (I) has surprising and unexpectedly superior tissue penetration properties compared to Comparative Compounds (II) and (III), both of which are structurally very similar to Compound (I).

[0154] The inventors have concluded that compound (I) exhibits good permeability. The lipophilicity and permeability of compound (I) allow the compound to reach and penetrate target tissues of interest. The surprising and unexpectedly superior tissue distribution and permeation properties of compound (I) versus comparative compounds (II) and (III) are attributed to the advantageous lipophilicity and permeability of compound (I).

[0155] In vitro safety pharmacology studies In vitro pharmacological binding assays were performed for Compound (I), Comparative Compound (II), and Comparative Compound (III) to evaluate the percentage of inhibition of 44 ligands (including receptors, transporters, ion channels, enzymes, and kinases) at a concentration of 10 μM. Compound binding was calculated as the percentage of inhibition of the binding of radiolabeled ligands specific to each target. Results showing greater than 50% inhibition were considered to represent a discernible effect of Compound (I), Comparative Compound (II), or Comparative Compound (III). Results for all 44 ligands tested are shown in Figures 1a, 1b, and 1c, while Figure 1d shows only results showing greater than 50% inhibition. In vitro pharmacological binding assays for Compound (I) and Comparative Compounds (II) and (III) were performed separately on different days and are compared in Figures 1a, 1b, 1c, and 1d.

[0156] 1a, 1b, 1c, and 1d show that compound (I) has a different CEREP profile than both comparative compounds (II) and (III). Compound (I) exhibited greater than 50% inhibition with only a single ligand, i.e., fewer (and different) ligands than comparative compounds (II) and / or (III).

[0157] Proof-of-Concept Studies Compound (I) and comparative compound (III) were evaluated in proof-of-concept studies in mouse models for the treatment of respiratory infections caused by Gram-negative bacteria of the order Enterobacteriaceae, bacteremia or bloodstream infections caused by Gram-negative bacteria of the order Enterobacteriaceae, and urinary tract infections caused by Gram-negative bacteria of the order Enterobacteriaceae. The results are shown in Figures 2, 3, and 4a-c. Each dot, triangle, or square indicator represents one mouse. LOD refers to the limit of bacterial detection. Stasis indicates the level of bacteria (colony-forming units (CFU)) in the subject before treatment. Each proof-of-concept study was performed separately. Vehicle refers to a pharmaceutically acceptable carrier or excipient.

[0158] For a proof-of-concept study on the treatment of respiratory infections caused by or exacerbated by Gram-negative bacteria of the order Enterobacteriaceae, CD-1 mice were infected with Klebsiella pneumoniae ATCC 43816. Two hours post-infection ("Pretreatment" in Figure 2), vehicle (20% hydroxypropyl β-cyclodextrin) without Compound (I) or Comparative Compound (III), or vehicle (20% hydroxypropyl β-cyclodextrin) containing Compound (I) or Comparative Compound (III) was administered by IV bolus at 20 mg / kg TID (8-hour intervals) for 1 day.

[0159] Figure 2 shows that at the end of the study (26 hours after initial infection; "Compound (I)" and "Comparative Compound (III)" in Figure 2), Compound (I) unexpectedly had a significant reduction in colony-forming units (CFU) compared to Comparative Compound (III), i.e., bacterial burden was significantly reduced by treatment with Compound (I) versus Comparative Compound (III) compared to pretreatment and vehicle. In fact, the CFU values ​​for Comparative Compound (III) in Figure 2 remained relatively close to resting levels, i.e., no bacterial killing occurred. Figure 2 also shows that at the end of the study (26 hours after initial infection), Compound (I) reduced bacterial burden in the lungs by 6.24 logs compared to vehicle, while Comparative Compound (III) only showed a 4.16 log reduction compared to vehicle. Thus, compound (I) is 2 logs more effective than comparative compound (III) in treating respiratory infections caused by Klebsiella pneumonia, particularly multidrug-resistant Klebsiella pneumonia.

[0160] For a proof-of-concept study of bacteremia or bloodstream infection caused by Gram-negative Enterobacteriaceae bacteria, CD-1 mice were infected with human urine isolate Escherichia coli (E. coli) BAA-2469 (NDM-1 positive). One hour after infection ("Pretreatment" in Figure 3), vehicle (20% hydroxypropyl β-cyclodextrin) containing no Compound (I) or Comparative Compound (III), or vehicle (20% hydroxypropyl β-cyclodextrin) containing Compound (I) or Comparative Compound (III) was administered as a single IV bolus dose at 20 mg / kg.

[0161] Figure 3 shows that at the end of the study (9 hours after initial infection; "Compound (I)" and "Comparative Compound (III)" in Figure 3), Compound (I) unexpectedly had a significant reduction in colony-forming units (CFU) compared to Comparative Compound (III), i.e., bacterial load was significantly reduced by treatment with Compound (I) versus Comparative Compound (III) compared to pretreatment and vehicle. Indeed, the CFU values ​​for Comparative Compound (III) in Figure 3 remained above static levels, i.e., instances where bacterial killing did not occur. Figure 3 also shows that at the end of the study (9 hours after initial infection), Compound (I) reduced blood bacterial load below the limit of detection (LOD), a 7.43-log reduction compared to vehicle. In contrast, Comparative Compound (III) only showed a 4.86-log reduction compared to vehicle. Thus, compound (I) is 2.5 logs more effective than the comparative compound (III) in treating bacteremia or bloodstream infections due to Escherichia coli, particularly multidrug-resistant Escherichia coli.

[0162] For a proof-of-concept study of the treatment of urinary tract infections caused by Enterobacteriaceae bacteria, female C3H / HeN mice were infected with Escherichia coli (E. coli) UTI89. 24 hours post-infection ("Pretreatment" in Figure 4a-c), vehicle (20% hydroxypropyl β-cyclodextrin) without Compound (I) or Comparative Compound (III) or vehicle (20% hydroxypropyl β-cyclodextrin) containing Compound (I) or Comparative Compound (III) was administered by IV bolus at 20 mg / kg TID (8-hour intervals) for 3 days.

[0163] Because urinary tract infections can affect the bladder and kidneys, we assessed bacterial burden in the urine, bladder, and kidneys (Figures 4a-c, respectively). Figures 4a and 4b show that at the end of the study (96 hours after initial infection: "Compound (I)" and "Comparative Compound (III)" in Figures 4a and 4b), Compound (I) unexpectedly had significantly fewer colony-forming units (CFU) than Comparative Compound (III), indicating that bacterial burden was significantly reduced by treatment with Compound (I) versus Comparative Compound (III) compared to pretreatment and vehicle. Figure 4c shows that at the end of the study (96 hours after initial infection: "Compound (I)" and "Comparative Compound (III)" in Figure 4c), Compound (I) also had significantly fewer colony-forming units (CFU) than Comparative Compound (III), indicating that bacterial burden was significantly reduced by treatment with Compound (I) versus Comparative Compound (III) compared to pretreatment and vehicle. Figure 4a shows that at the end of the study (96 hours after initial infection), Compound (I) reduced the bacterial load in the urine below the limit of detection (LOD), a 6.59-log reduction compared to vehicle. In contrast, Comparative Compound (III) showed only a 3.36-log reduction compared to vehicle. Thus, Compound (I) is 3 logs more effective than Comparative Compound (III) in reducing CFU in the urine, thereby facilitating the treatment of Escherichia coli urinary tract infections (UTIs). Figure 4b shows that at the end of the study (96 hours after initial infection), Compound (I) reduced the bacterial load in the bladder by 5.67 logs compared to vehicle. In comparison, Comparative Compound (III) showed only a 3.71-log reduction compared to vehicle. Thus, Compound (I) is 3 logs more effective than Comparative Compound (III) in reducing CFU in the bladder, thereby facilitating the treatment of Escherichia coli urinary tract infections (UTIs). Figure 4c shows that at the end of the study (96 hours after initial infection), compound (I) reduced bacterial burden in the kidney by 4.73 logs compared to vehicle.

[0164] Compound (I) was further evaluated in proof-of-concept studies in mouse models for the treatment of respiratory infections caused by Gram-negative bacteria of the order Enterobacteriaceae and urinary tract infections caused by Gram-negative bacteria of the order Enterobacteriaceae. The results are shown in Figures 5 and 6a-c. Each dot, triangle, or square indicator represents one mouse. LOD refers to the limit of bacterial detection. Stasis indicates the level of bacteria (colony-forming units (CFU)) in the subject before treatment. Each proof-of-concept study was performed separately. Vehicle refers to a pharmaceutically acceptable excipient or carrier.

[0165] For further proof-of-concept studies on the treatment of respiratory infections caused or exacerbated by Gram-negative bacteria of the order Enterobacteriaceae, male CD-1 mice were infected with Klebsiella pneumoniae ATCC 43816.

[0166] Two hours after infection ("Pretreatment" in Figure 5), mice were treated with either a vehicle control (phosphate buffer) without Compound (I) or a vehicle (phosphate buffer) containing Compound (I) administered at a dose of 20 mg / kg via a 1-hour (QD) intravenous infusion. Mice receiving the vehicle control without Compound (I) and some mice receiving the vehicle containing Compound (I) were administered an additional 1-hour continuous intravenous infusion (BID, 3-hour intervals) 3 hours after the start of the first dose.

[0167] Figure 5 shows that at the end of the study (26 hours after initial infection: "Compound (I) QD" and "Compound (I) BID" in Figure 5), Compound (I) reduced colony-forming units (CFU), i.e., treatment with Compound (I) reduced bacterial load compared to pretreatment and vehicle ("Vehicle BID" in Figure 5). This was particularly evident when Compound (I) was administered twice (BID, 3 hours apart) (P values ​​< 0.0001 compared to both pretreatment and vehicle). For a single dose of Compound (I) (QD), the P values ​​were 0.0042 compared to pretreatment and < 0.0001 compared to vehicle. 5 shows that at the end of the study (26 hours after initial infection), Compound (I) reduced the bacterial burden in the lungs by 4.35 and 5.20 logs compared to vehicle (one QD and two BID doses, 3 hours apart, respectively), and by 0.95 and 1.80 logs (one QD and two BID doses, 3 hours apart, respectively) compared to pre-treatment (resting levels). Thus, Compound (I) is effective in treating respiratory infections caused by Klebsiella pneumoniae, particularly multidrug-resistant Klebsiella pneumoniae.

[0168] For further proof-of-concept studies on the treatment of urinary tract infections caused by Enterobacteriaceae bacteria, female C3H / HeN mice were infected with Escherichia coli (E. coli) UTI89.

[0169] Twenty-four hours after infection ("Pretreatment" in Figure 6a-c), mice were treated with either a vehicle control (20% hydroxypropyl β-cyclodextrin) without Compound (I) or a vehicle (20% hydroxypropyl β-cyclodextrin) containing Compound (I) at a dose of 20 mg / kg administered by 1-hour (QD) intravenous infusion. For some mice receiving the vehicle containing Compound (I), an additional 1-hour continuous intravenous infusion (BID, 5-hour intervals) was administered 5 hours after the start of the first dose. Dosing was continued once or twice daily for 3 days. For QD administration, administration occurred between 24-25 hours, 48-49 hours, and 72-73 hours postinfection. For BID administration, administration occurred between 24-25 hours, 29-30 hours, 48-49 hours, 53-54 hours, 72-73 hours, and 77-78 hours postinfection.

[0170] Because urinary tract infections can affect the bladder and kidneys, we assessed the bacterial burden in the urine, bladder, and kidneys (Figures 6a-c, respectively). Figures 6a, 6b, and 6c show that at the end of the study (96 hours after initial infection: "Compound (I) QD" and "Compound (I) BID" in Figures 6a, 6b, and 6c), Compound (I) significantly reduced colony-forming units (CFUs), i.e., treatment with Compound (I) significantly reduced bacterial burden compared to pretreatment and vehicle. This was particularly evident when Compound (I) was administered twice daily (BID, 5 hours apart). Figure 6a shows that at the end of the study (96 hours after initial infection), both QD and BID daily administration of Compound (I) reduced bacterial load in urine below the limit of detection (LOD), with 4.86 and 5.87 log reductions (for once-daily (QD) and twice-daily (BID, 5-hour intervals), respectively) compared to vehicle. The P value for Compound (I) was <0.0001 compared to vehicle, regardless of whether it was administered QD or twice-daily (BID, 5-hour intervals). Thus, Compound (I) is effective in reducing CFU in urine, thus facilitating the treatment of Escherichia coli urinary tract infections (UTIs). Figure 6b shows that at the end of the study (96 hours after initial infection), both QD and BID daily administration of Compound (I) reduced the bacterial burden in the bladder below the limit of detection (LOD), with a 5.01 and 5.84 log reduction (for once-daily (QD) and twice-daily (BID, 5 hours apart), respectively) compared to vehicle. The P value for once-daily administration (QD) was 0.001 and for twice-daily administration (BID, 5 hours apart) was 0.0002 compared to vehicle. Thus, Compound (I) is effective in reducing CFU in the bladder, thereby facilitating the treatment of Escherichia coli urinary tract infections (UTIs).Figure 6c shows that at the end of the study (96 hours after initial infection), Compound (I) reduced the bacterial burden in the kidney below the limit of detection (LOD) when administered BID, with a 3.17-log and 4.3-log reduction (for once-daily (QD) and twice-daily (BID, 5-hour intervals), respectively) compared to vehicle. Compared to vehicle, the P value for once-daily (QD) administration was 0.0007, and for twice-daily (BID, 5-hour intervals) administration was <0.0001. Thus, Compound (I) is effective in reducing CFU in the kidney, thereby facilitating the treatment of Escherichia coli urinary tract infections (UTIs). The present invention can provide the following aspects. [1] Compound (I): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof. [2] A compound according to [1], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in the treatment or prevention of infection with, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus. [3] Compound (I) according to [1], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in a method for treating infections caused by Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus, or diseases caused or exacerbated thereby. [4] Compound (I) according to [1], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for the manufacture of a medicament for use in the treatment of infection with, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus. [5] Compound (I) according to [1], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, for use in treating infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus. [6] A method for treating an infection caused by, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus in a subject in need thereof, comprising administering to the subject an effective amount of compound (I) according to [1], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof. [7] The infection with, or the disease caused or exacerbated by, gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus is selected from the group consisting of: bacteremia or bloodstream infection with gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus; respiratory infection with gram-negative bacteria of the order Enterobacteriale and / or gram-negative bacteria of the genus Haemophilus; and / or intraperitoneal infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and preferably, the infections caused by or diseases caused or exacerbated by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus are one or more of: urinary tract infections (UTIs) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus; pyelonephritis caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus; and intraperitoneal infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and preferably, the infections caused by or diseases caused or exacerbated by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus are one or more of: bacteremia or bloodstream infection caused by Gram-negative bacteria and / or Gram-negative bacteria of the genus Haemophilus, respiratory infection caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and urinary tract infection (UTI) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, more preferably one or more of the aforementioned caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus. The compound (I) according to any one of [2] to [5], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, or the method according to [6], wherein the infection, or the disease caused or exacerbated thereby, is one or more of the following: respiratory infection caused by a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus, and urinary tract infection (UTI) caused by a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus. [8] The compound (I) according to any one of [2] to [5] or [7], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, or the method according to [6] or [7], wherein the infection caused by, or the disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus is a multisite infection. [9] Compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof according to any of [2] to [5], [7], or [8], or the method according to any of [6] to [8], wherein compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is administered parenterally, preferably intravenously, more preferably by intravenous infusion (IV infusion).

[10] The compound (I) according to any one of [2] to [5] and [7] to [9], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, or the method according to any one of [6] to [9], wherein the Gram-negative bacterium of the order Enterobacteriale and / or the Gram-negative bacterium of the genus Haemophilus is a carbapenem-resistant Enterobacteriale bacterium or an extended-spectrum β-lactamase Enterobacteriale bacterium.

[11] The compound (I) according to any one of [2] to [5] and [7] to

[10] , or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or the method according to any one of [6] to

[10] , wherein the Gram-negative bacterium is of the order Enterobacteriaceae.

[12] The Gram-negative bacteria of the order Enterobacteriale are selected from the group consisting of Arsenophonus, Atlantibacter, Biostraticola, Brenneria, Buchnera, Budvicia, Buttiauxella, Cedecea, Chania, Citrobacter, Cosenzaea, Cronobacter, and the like. cter, Dickeya, Edwardsiella, Enterobacillus, Enterobacter, Erwinia, Escherichia, Ewingella, Franconibacter, Gibbsiella, Hafnia, Izhakiella, Kosakonia, Klebsiella bsiella, Kluyvera, Leclercia, Lelliottia, Leminorella, Levinea, Lonsdalea, Mangrovibacter, Moellerella, Morganella, Obesumbacterium, Pantoea, Pectobacterium, Fa Phaseolubacter, Photorhabdus, Plesiomonas, Pluralibacter, Pragia, Proteus, Providencia, Pseudocitrobacter, Rahnella, Raoultella, Rosenbergiella, Rouxiella,Saccharobacter, Salmonella, Samsonia, Serratia, Shigella, Shimwellia, Siccibacter, Sodalis, Tatumella, Thorsellia, Trabulsiella, Wigglesworthia, Xenorhabdus, Elsevier Preferably, the Gram-negative bacterium of the order Enterobacteriale is selected from Cedecea, Citrobacter, Erwinia, Escherichia, Enterobacter, Klebsiella, Kluyvera, Plesiomonas, Proteus, Providencia, Raoh, The Gram-negative bacteria of the order Enterobacteriale are selected from Raoultella, Salmonella, Serratia, Shigella, and Yersinia, and preferably, the Gram-negative bacteria of the order Enterobacteriale are selected from Erwinia, Escherichia, Enterobacter, Klebsiella, Proteus, Salmonella, Serratia, Shigella, ), and Yersinia, preferably, the Gram-negative bacterium of the order Enterobacteriale is selected from Enterobacter, Escherichia, and Klebsiella, more preferably, the Gram-negative bacterium of the order Enterobacteriale is selected from Escherichia and Klebsiella,or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or the method according to any one of [6] to

[11] .

[13] The compound (I) according to any one of [2] to [5] and [7] to

[12] , or the method according to any one of [6] to

[12] , wherein the Gram-negative bacterium of the order Enterobacteriaceae is selected from Enterobacter spp., Escherichia coli, and Klebsiella pneumoniae, more preferably Escherichia coli and Klebsiella pneumoniae.

[14] A method for inhibiting the growth of Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus in vitro, using compound (I) according to [1] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof.

[15] Compound (I), formulated together with a pharmaceutically acceptable excipient or carrier:

change

[16] A pharmaceutical composition comprising compound (I) according to [1], or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and a pharmaceutically acceptable excipient or carrier.

[17] Compound (I) according to

[15] , or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or the pharmaceutical composition according to

[16] , wherein the pharmaceutically acceptable excipient or carrier is a pharmaceutically acceptable excipient or carrier suitable for intravenous infusion into a human subject.

[18] The pharmaceutical composition according to

[16] or

[17] , wherein the compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is present in an amount of 50 to 6000 mg, preferably 50 to 4000 mg, for example, 50 to 3000 mg, for example, 50 to 2000 mg, for example, 100 to 2000 mg, for example, 200 to 2000 mg, for example, 200 to 1750 mg, for example, 200 to 1500 mg, or for example, 250 to 1000 mg.

[19] A pharmaceutical composition for use in treating infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus, comprising compound (I) according to [1] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and a pharmaceutically acceptable excipient or carrier, the pharmaceutical composition being preferably administered to a human subject by intravenous infusion.

[20] A pharmaceutical composition for use in treating infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus, comprising compound (I) according to [1] or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, and a pharmaceutically acceptable excipient or carrier, wherein compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof is administered to a human subject by intravenous infusion at a dose of 50 to 6,000 mg per day.

[21] The pharmaceutical composition according to

[19] , wherein the compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex, or prodrug thereof, is administered to a human subject at a dose of 50 to 6000 mg per day.

[22] The compound (I), or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, is administered to a human subject at a dose of 50 to 4000 mg per day, for example, 50 to 3000 mg per day, for example, 50 to 2000 mg per day, for example, 100 to 2000 mg per day, for example, 200 to 2000 mg per day, for example, 200 to 1750 mg per day, for example, 200 to 1500 mg per day, for example, 250 to 1000 mg per day.

[19] ,

[20] or

[21] . The pharmaceutical composition according to.

[23] The pharmaceutical composition according to any one of

[20] to

[22] , which is administered to a human subject by intravenous infusion once daily, twice daily, or three times daily, preferably twice daily.

[24] When administered twice a day, the administration is at intervals of 1 to 12 hours, for example, at intervals of 1 to 8 hours, or 2 to 6 hours, or 2 to 5 hours, or 3 to 5 hours, or 1 to 4 hours.

[23] The pharmaceutical composition according to claim 23.

[25] 2. The pharmaceutical composition according to any one of

[20] to

[24] , which is administered to a human subject by intravenous infusion and is for use in treating respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and urinary tract infections (UTIs) (typically complicated UTIs) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus.

[26] 2. The pharmaceutical composition according to any one of

[20] to

[25] , which is administered to a human subject by intravenous infusion, wherein the treatment of infection with, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus involves a treatment course of 1 to 10 days, for example, 1 to 7 days or 1 to 5 days.

Claims

1. Compound (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

2. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus.

3. 10. The compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use in a method for treating infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus.

4. 2. The compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus.

5. 10. The compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of infections caused by, or diseases caused or exacerbated by, gram-negative bacteria of the order Enterobacteriaceae and / or gram-negative bacteria of the genus Haemophilus.

6. 6. The compound (I) according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein the infection caused by, or disease caused or exacerbated by, a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus is one or more of the following: bacteremia or bloodstream infection caused by a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus; a respiratory infection caused by a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus; a urinary tract infection (UTI) caused by a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus; pyelonephritis caused by a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus; and an intraperitoneal infection caused by a gram-negative bacterium of the order Enterobacteriale and / or a gram-negative bacterium of the genus Haemophilus.

7. 6. The compound (I) according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein the infection with, or disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus is a multisite infection.

8. 6. The compound (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 2 to 5, wherein the compound (I), or a pharmaceutically acceptable salt thereof, is administered parenterally.

9. 6. The compound (I) according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein the Gram-negative bacterium of the order Enterobacteriale and / or the Gram-negative bacterium of the genus Haemophilus is a carbapenem-resistant Enterobacteriale bacterium or an extended-spectrum β-lactamase Enterobacteriale bacterium.

10. 6. The compound (I) according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein the Gram-negative bacterium is of the order Enterobacteriaceae.

11. The Gram-negative bacteria of the order Enterobacteriale are selected from the group consisting of Arsenophonus, Atlantibacter, Biostraticola, Brenneria, Buchnera, Budvicia, Buttiauxella, Cedecea, Chania, Citrobacter, Cosenzaea, Cronobacter, and the like. cter, Dickeya, Edwardsiella, Enterobacillus, Enterobacter, Erwinia, Escherichia, Ewingella, Franconibacter, Gibbsiella, Hafnia, Izhakiella, Kosakonia, Klebsiella bsiella), Kluyvera, Leclercia, Lelliottia, Leminorella, Levinea, Lonsdalea, Mangrovibacter, Moellerella, Morganella, Obesumbacterium, Pantoea, Pectobacterium, Fa Phaseolubacter, Photorhabdus, Plesiomonas, Pluralibacter, Pragia, Proteus, Providencia, Pseudocitrobacter, Rahnella, Raoultella, Rosenbergiella, Rouxiella,The compound (I) according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, is selected from Saccharobacter, Salmonella, Samsonia, Serratia, Shigella, Shimwellia, Siccibacter, Sodalis, Tatumella, Thorsellia, Trabulsiella, Wigglesworthia, Xenorhabdus, Yersinia and Yokenella.

12. 6. The compound (I) according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein the Gram-negative bacterium of the order Enterobacteriaceae is selected from Enterobacter spp., Escherichia coli, and Klebsiella pneumoniae.

13. 10. A method for inhibiting the growth of Gram-negative bacteria of the order Enterobacteriaceae and / or the genus Haemophilus in vitro using compound (I) of claim 1, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound (I) of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

15. 15. The pharmaceutical composition of claim 14, wherein the compound (I), or a pharmaceutically acceptable salt thereof, is present in an amount of 50 to 6000 mg.

16. 10. A pharmaceutical composition for use in the treatment of infections caused by, or diseases exacerbated by, Gram-negative bacteria of the order Enterobacteriaceae and / or Gram-negative bacteria of the genus Haemophilus, comprising compound (I) of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

17. 1. A pharmaceutical composition for use in treating infections caused by, or diseases caused or exacerbated by, Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, comprising compound (I) of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier, wherein compound (I), or a pharmaceutically acceptable salt thereof, is administered to a human subject by intravenous infusion at a dose of 50 to 6000 mg per day.

18. 17. The pharmaceutical composition of claim 16, wherein the compound (I), or a pharmaceutically acceptable salt thereof, is administered to a human subject at a dose of 50 to 6000 mg per day.

19. 19. The pharmaceutical composition according to claim 16, 17 or 18, wherein the compound (I), or a pharmaceutically acceptable salt thereof, is administered to a human subject at a dose of 50 to 4000 mg per day.

20. 19. The pharmaceutical composition of claim 17 or 18, administered to a human subject by intravenous infusion once daily, twice daily, or three times daily.

21. 21. The pharmaceutical composition of claim 20, when administered twice daily, at intervals of 1 to 12 hours.

22. 19. The pharmaceutical composition of claim 17 or 18, administered to a human subject by intravenous infusion, for use in treating respiratory infections caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus, and urinary tract infections (UTIs) caused by Gram-negative bacteria of the order Enterobacteriale and / or Gram-negative bacteria of the genus Haemophilus.

23. 19. The pharmaceutical composition according to claim 17 or 18, which is administered to a human subject by intravenous infusion, wherein said treatment of infection with, or a disease caused or exacerbated by, a Gram-negative bacterium of the order Enterobacteriaceae and / or a Gram-negative bacterium of the genus Haemophilus involves a course of treatment of 1 to 10 days.

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