Antibiotic compounds

Abstract

Provided herein are compounds of formula I JPEG2022548357000071.jpg103103 or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. R1 is a lipid, R2 is -H or a lipid, and R3 and R4 are as defined herein. These compounds have antibiotic activity. Also provided are formulations containing such compounds; and such compounds or formulations for use as pharmaceuticals. The compounds and formulations can also be used to treat bacterial infections.

Description

[Technical Field]

[0001] This invention relates to a novel class of lipid-modified guanidino derivatives of glycopeptide antibiotics. The invention also provides formulations and compositions containing such compounds. These compounds, formulations, and compositions can be used as pharmaceuticals, such as in the treatment of bacterial infections. Also provided are methods for using such compounds in the treatment of bacterial infections. [Background technology]

[0002] background In the search for antibiotics active against Gram-positive bacteria, the bacterial cell wall, often referred to as the peptidoglycan layer, offers an attractive target. Lipid II, the second-to-last building block of the bacterial cell wall, is crucial for peptidoglycan biosynthesis. Numerous natural product antibiotics operate by specifically binding to lipid II (Grein, F., et al. (2019) Docking on Lipid II-A Widespread Mechanism for Potent Bactericidal Activities of Antibiotic Peptides, J Mol Biol.; Oppedijk, SF, et al. (2016) Hit 'em where it hurts: The growing and structurally diverse family of peptides that target lipid-II, Biochim Biophys Acta 1858, 947-957). Among these, the clinically used glycopeptide vancomycin, which tightly binds to the terminal d-Ala-d-Ala motif of the lipid II pentapeptide, is particularly prominent.

[0003] The increasing number of bacterial strains capable of utilizing lipid II variants containing the d-Ala-d-Lac termination pentapeptide has led to a rise in encounters with vancomycin resistance. This d-Lac mutation in d-Ala reduces vancomycin's affinity for lipid II, thereby significantly diminishing its antibacterial effect (Healy, VL, et al. (2000) Vancomycin resistance in enterococci: reprogramming of the D-ala-D-Ala ligases in bacterial peptidoglycan biosynthesis, Chem Biol 7, R109-119; Blaskovich, MAT, et al. (2018) Developments in Glycopeptide Antibiotics, ACS Infect Dis 4, 715-735; Willyard, C. (2017) The drug-resistant bacteria that pose the greatest health threats, Nature 543, 15). Therefore, the development of novel glycopeptide antibiotics with enhanced antibacterial activity remains extremely important. [Overview of the project] [Problems that the invention aims to solve]

[0004] The object of the present invention is to provide compounds useful for treating bacterial infections, particularly infections that are resistant to existing antibiotics such as vancomycin. [Means for solving the problem]

[0005] Summary of the Invention The present invention provides compounds useful for treating bacterial infections. For example, the compounds may be useful for treating infections caused by Gram-positive bacteria. The compounds of the present invention are lipid-conjugated glycopeptides, in which the lipid portion is linked to the glycan portion via a linker and a guanidino portion.

[0006] In a first embodiment, the present invention relates to Formula I [ka] [During the ceremony, R1 is a lipid; R2 is selected from -H or lipids; R3 is -OH, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 Selected from alkenyls, substituted or unsubstituted C1-C4 alkylaryls, and carbohydrates; R4 is -H, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 Selected from alkenyls, substituted or unsubstituted C1-C4 alkylaryls and carbohydrates; and L1 is the linker. The present invention provides compounds or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

[0007] A second aspect of the present invention provides a formulation of the present invention comprising the compound of the present invention and optionally a pharmaceutically acceptable carrier. The formulation may be an enteral formulation or an oral formulation. The formulation may be an enteral formulation, such as an intravenous injection formulation.

[0008] A third aspect provides a compound or formulation of the present invention for use as a pharmaceutical.

[0009] A fourth aspect provides compounds or formulations of the present invention for use in the treatment of bacterial infections. Bacterial infections may be infections of Gram-positive bacteria. Gram-positive bacteria may consist of at least one of the families Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococcus (e.g., Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, Streptococcus pneumoniae), Enterococcus (e.g., Enterococcus faecalis), Bacillus, Clostridium, Listeria, and Corynebacterium). Bacteria (e.g., Gram-positive bacteria) may be resistant to treatment with at least one other antibiotic (e.g., methicillin, vancomycin). Bacterial infections may be caused by vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), or vancomycin-resistant Staphylococcus aureus (VRSA). Bacterial infections may be selected from skin and tissue infections, lower respiratory tract infections, bacteremia, sepsis, infectious endocarditis, peritonitis, enteritis, mastitis, Clostridium difficile-associated diarrhea, and colitis.

[0010] A fifth aspect provides a method for treating a bacterial infection in a patient, comprising administering an effective amount of the compound or formulation of the present invention to the patient. [Brief explanation of the drawing]

[0011] Embodiments of the present invention will be described below with reference to the accompanying drawings. The outlines of each drawing are as follows. [Figure 1] The results of evaluating the selected compounds using a hemolysis assay are shown. [Figure 2]The results obtained from the UDP-MurNAc-pentapeptide accumulation assay of selected compounds are shown. All compounds resulted in the accumulation of UDP-MurNAc-pentapeptide and inhibited peptidoglycan cell wall biosynthesis in Gram-positive bacteria. [Figure 3] The following are the results obtained when the selected compounds were evaluated using a resistance acquisition serial passage assay. A) The rate of increase in MIC over time compared to the initial MIC for MRSA USA 300 grown in sublethal concentrations of daptomycin, compound 5, or compound 16 over 30 days. B) The rate of increase in MIC per day compared to the initial MIC for VRE E155 grown in sublethal concentrations of daptomycin, compound 5, or compound 16 over 30 days. [Figure 4] The results obtained when the selected compounds were evaluated by a time-kill assay are shown. A) Bactericidal activity against VRE E155 of vancomycin, teravancin, daptomycin (left), compound 5, and compound 16 (right), obtained by counting the number of colonies in agar plate dilutions of the sample over time. B) Bactericidal activity against MRSA USA300 of vancomycin, teravancin, daptomycin (left), and compound 5 (right), obtained by counting the number of colonies in agar plate dilutions of the sample over time. [Figure 5] This shows the pharmacokinetic profile of the blood concentration of the selected compound over an 8-hour period. [Figure 6] The results obtained from efficacy tests of selected compounds against MRSA USA300 strain NRS384 are shown. [Modes for carrying out the invention]

[0012] Detailed description Throughout this specification and the claims, the terms “include” and “inclusive” and their variations mean “include, but not limited to” and are not intended (and do not exclude) other parts, additives, ingredients, integers or processes. Throughout this specification and the claims, singular expressions include plurals unless the context requires a different interpretation. In particular, where the indefinite article is used, this specification should be understood to include both plurals and singulars unless the context requires a different interpretation.

[0013] Any properties, integers, features, compounds, chemical structural parts, or groups described in connection with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example, insofar as they do not conflict. All properties and / or all disclosed steps of any method or process disclosed herein (including any appended claims, abstract, and drawings) can be combined in any combination, provided that at least one combination of such properties and / or steps is not mutually exclusive. The present invention is not limited to any of the aforementioned embodiments. The present invention extends to any novel one or any novel combination of any properties disclosed herein (including any appended claims, abstract, and drawings) or any novel one or any novel combination of any steps of any method or process disclosed herein.

[0014] In connection with this application, all papers and documents filed concurrently with or prior to this specification, and published together with this specification, are herein by reference fully incorporated.

[0015] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In case of any inconsistency, this specification, including its definitions, shall prevail.

[0016] definition The following explanations of terms and methods better describe the present invention and provide guidance to those skilled in the art in carrying it out.

[0017] The present invention relates, in particular, to the treatment of diseases. The terms “treatment” and “therapy” as defined herein include, and combinations thereof: (1) intervening, e.g., delaying the onset and / or progression of an event, situation, disorder or condition, e.g., stopping, reducing or delaying the progression of at least one of its clinical or subclinical symptoms, e.g., an event, situation, disorder or condition, or in the case of maintenance treatment or secondary prevention; (2) preventing or delaying the appearance of clinical symptoms of an event, situation, disorder or condition progressing in an animal (e.g., human) that is potentially affected or predisposed to the condition but has not yet experienced or shown any clinical or subclinical symptoms of the condition; and / or (3) remission and / or cure of an event, situation, disorder or condition (e.g., induction of regression of at least one of its clinical or subclinical symptoms). The patient benefit of the treatment may be statistically significant or at least recognizable to the patient or will. It is understood that medicines do not necessarily produce clinical effects in every patient to whom they are administered; therefore, in every individual patient or particular patient group, a treatment may fail or be only partially successful, and the terms “treatment” and “prevention” and related terms should be understood accordingly. The compositions and methods described herein are useful for the treatment and / or prevention of the conditions described.

[0018] The term "prevention" refers to treatment or therapy aimed at maintaining health or preventing or delaying the onset and / or progression of an event, situation, disability, or condition, for example, reducing the chances of the event, situation, disability, or condition occurring. The results of prevention may, for example, be the maintenance of health or the delay of the onset and / or progression of an event, situation, disability, or condition. It should be noted that in some individual patient or in a particular group of patients, treatment may fail, and this paragraph should be understood accordingly.

[0019] The term "antibiotic" refers to a compound that inhibits or destroys the growth of microorganisms such as bacteria (e.g., Gram-positive or Gram-negative bacteria). An "antibacterial substance" is an antibiotic that is active against bacteria. The compounds of the present invention are antibacterial substances that are particularly active against Gram-positive bacteria. Gram-positive bacteria include Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococcus (e.g., Streptococcus pyogenes, Group B Streptococcus, Streptococcus viridans, Streptococcus pneumoniae), Enterococcus, Bacillus, Clostridium, Listeria, and Corynebacterium.

[0020] The term "alkyl" as used herein includes linear or branched alkyl moieties having up to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms. This term includes, for example, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl, etc. In particular, alkyl refers to "C1-C 10 "Alkyl" can mean an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; "C1-C6 alkyl" can mean an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms; "C1-C4 alkyl" can mean an alkyl group having 1, 2, 3, or 4 carbon atoms; "C1-C6 alkyl" can mean an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms; or "C1-C3 alkyl" can mean an alkyl group having 1, 2, or 3 carbon atoms. The term "lower alkyl" includes references to alkyl groups having 1, 2, 3, or 4 carbon atoms.

[0021] The term "alkenyl" as used herein includes linear or branched alkenyl moieties having up to 20 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). This term includes references such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl. In particular, alkenyls are "C2-C 10 "Alkenyl" refers to an alkenyl having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; "C2-C6 alkenyl" refers to an alkenyl having 2, 3, 4, 5, or 6 carbon atoms; "C2-C4 alkyl" refers to an alkenyl having 1, 2, 3, or 4 carbon atoms; the term "lower alkenyl" can refer to an alkenyl group having 2, 3, or 4 carbon atoms. Alkenyls can be monounsaturated (i.e., containing one carbon-carbon double bond) or polyunsaturated (i.e., containing two or more carbon-carbon double bonds, e.g., 2, 3, or 4 carbon-carbon double bonds). For example, alkenyls can be alkadinyls, alkatrienyls, etc.

[0022] The term "alkylene" refers to a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-, either by itself or as part of another substituent. Generally, alkyl (or alkylene) groups have 1 to 24 carbon atoms, and those having 10 or fewer carbon atoms are preferred in this invention. "Lower alkyl" or "lower alkylene" generally refers to a short-chain alkyl or alkylene group having 8 or fewer carbon atoms.

[0023] The term "cycloalkyl" as used herein includes an alicyclic moiety having three, four, five, or six carbon atoms. This group can be a crosslinked or polycyclic ring system. More frequently, cycloalkyl groups are monocyclic. This term includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0024] The term "heteroalkyl", by itself or in combination with other terms, unless otherwise specified, means a stable straight-chain, branched-chain or cyclic hydrocarbon radical or combinations thereof consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, P, S and Si can be at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3 and -CN. For example, up to two heteroatoms can be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene", by itself or as part of another substituent, means a divalent radical derived from heteroalkyl, examples of which include, but are not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatoms can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkylenamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, the direction of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As noted above, the heteroalkyl groups used herein include groups that are attached to the rest of the molecule via heteroatoms such as -C(O)R', -C(O)NR', -NR'R ’’ , -OR', -SR ’ and / or -SO2R', etc. When "heteroalkyl" is recited followed by -NR'R ’’When specific heteroalkyl groups are mentioned, it is understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, they are cited to clearly indicate the specific heteroalkyl group. Therefore, the term "heteroalkyl" is used here as -NR'R''. ’’ This should not be interpreted as excluding certain heteroalkyl groups such as [specific heteroalkyl groups].

[0025] The term "heterocycloalkyl" as used herein includes a saturated heterocyclic moiety having 3, 4, 5, 6, or 7 ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. For example, a heterocycloalkyl may contain 3, 4, or 5 ring carbon atoms and 1 or 2 ring heteroatoms selected from nitrogen and oxygen. This group can be a polycyclic ring system, but more frequently it is monocyclic. This term includes groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxylanyl, pyrazolidinyl, imidazolyl, indolidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, and quinolidinyl.

[0026] The term "halo" or "halogen" as used herein includes F, Cl, Br, or I, for example, F, Cl, or Br. In certain embodiments of a particular class, the halogen is F or Cl, of which F is more common.

[0027] The term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent, unless otherwise specified. Furthermore, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with a corresponding number of halogens. For example, the term "halo(C1-C4)alkyl" means including, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0028] The term "alkoxy" as used herein includes -O-alkyl groups (where alkyl is a linear or branched chain containing one, two, three, four, five, or six carbon atoms). In some embodiments of a class, an alkoxy has one, two, three, or four carbon atoms, for example, 1, 2, or 3 carbon atoms. This term includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy, etc. The term "lower alkoxy" includes alkoxy groups having one, two, three, or four carbon atoms.

[0029] The term "haloalkoxy" used here refers to an alkoxy group in which one or more hydrogen atoms are replaced by a corresponding number of halogens.

[0030] The term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent that may be a monocyclic or a plurality of fused or covalently bonded rings (preferably 1 to 3 rings) unless otherwise specified. The term "heteroaryl" means an aryl group (or ring) containing 1 to 4 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl groups may be bonded to the rest of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrzolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, This includes 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Each substituent of the above aryl and heteroaryl ring systems is selected from the following group of permissible substituents. "Arylene" and "heteroarylene" refer to divalent radicals derived from aryl and heteroaryl, respectively.

[0031] The term "lipid" used herein to refer to substituents generally refers to the hydrophobic portion. Lipids may contain substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cross-linked cycloalkyl, (alkyl)cycloalkyl, (alkyl)cross-linked cycloalkyl, (alkyl)cycloalkenyl, and / or alkylaryl groups. For example, lipids may contain substituted or unsubstituted alkyl, alkenyl, (alkyl)cycloalkyl, (alkyl)cycloalkenyl, and / or alkylaryl groups. Examples of substituents include -OH, =O, -CN, -halo, -NH2, -NH(C1-C6 alkyl), -N(C1-C4 alkyl)2, -phenyl, -phenyl-halo; for example, -OH, =O, -CN, -halo, -NH2, -NH(C1-C6 alkyl), and -N(C1-C4 alkyl)2. The main chain of substituted or unsubstituted lipids may be interrupted by disulfide bonds (-SS-), thioether bonds (-S-), ether bonds (-O-), or esters (-C(O)O-).

[0032] Each of the above terms (e.g., "alkyl," "cycloalkyl," "heteroalkyl," "aryl," and "heteroaryl") is intended to include both substituted and unsubstituted forms of the radical unless otherwise specified. x When it is a substituted alkyl group (where "x" is an integer), the substituent may be substituted with one or more R groups that can be determined by chemical valence testing, and the R groups may vary as desired (e.g., R x Substituting alkyls have multiple R x Includes the base, where R x The base can vary as desired. Specific examples of substituents for each type of radical are provided below.

[0033] The term “substitution” as used herein, referring to a portion, means that one or more hydrogen atoms in that portion, in particular up to five, more specifically one, two, or three, are substituted independently of each other in corresponding numbers by the listed substituents. Unless otherwise specified, examples of substituents include -OH, -CN, -NH2, -NH(C1-C6 alkyl), -N(C1-C4 alkyl)2, =O, -halo, -C1-C6 alkyl, -C2-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkoxy and -C2-C6 haloalkenyl, and -C1-C6 alkylcarboxylic acids (e.g., -CH3COOH or -COOH). When the substituent is -C1-C6 alkyl or -C1-C6 haloalkyl, the C1-C6 chain may be interrupted optionally by an ether bond (-O-) or an ester bond (-C(O)O-). Examples of substituents on substituted alkyls may include -OH, -CN, -NH2, =O, -halo, -CO2H, -C1-C6 haloalkyl, -C1-C6 haloalkoxy and -C2-C6 haloalkenyl, and -C1-C6 alkylcarboxylic acids (e.g., -CH3COOH or -COOH). For example, examples of substituents on alkyls may include -OH, -CN, -NH2, =O, and -halo.

[0034] Naturally, it is understood that substituents exist only in chemically possible positions, and those skilled in the art can determine, without undue effort (experimentally or theoretically), whether a particular substitution is possible. For example, an amino or hydroxyl group with free hydrogen may be unstable if bonded to a carbon atom with an unsaturated (e.g., olefin) bond. Furthermore, it is understood that the substituents described herein can themselves be substituted with any substituent, and are subject to the above limitations on appropriate substitutions, as recognized by those skilled in the art.

[0035] When the arrangement of substituents on a group is determined by stereochemistry, the isomer with the lowest conformational energy may be preferred.

[0036] When a compound, part, process, or product is described as having a certain property "optionally," the present invention includes such compounds, parts, processes, or products having that property and also such compounds, parts, processes, or products not having that property. Therefore, when a part is described as being "optionally substituted," the present invention includes unsubstituted and substituted parts.

[0037] When it is stated that two or more parts are selected "independently" or "each independently" from the list of atoms or groups, it means that the parts may be identical or different. The existence of each part is therefore independent of the existence of one or more other parts.

[0038] As used herein, the term "pharmaceutically acceptable" includes compounds, substances, compositions, and / or dosage forms that, within the bounds of reasonable medical judgment, are suitable for use in contact with human or animal tissue without excessive toxicity, irritation, allergic responses, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio. This term includes acceptance for both human and veterinary purposes.

[0039] The term “pharmaceutically acceptable salt” means a salt of the active compound prepared with a relatively non-toxic acid or base, depending on the specific substituents found in the compounds described herein. When the compounds of the present invention contain a relatively acidic functional group, a base addition salt may be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or analogs. When the compounds of the present invention contain a relatively basic functional group, an acid addition salt may be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired acid neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginates and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups, and the compounds can be converted to either a base or an acid addition salt.

[0040] The neutral form of the compound is preferably regenerated by conventional methods of contacting the salt with a base or acid and then isolating the parent compound. The parent compound differs from various salt forms in certain physical properties, such as solubility in polar solvents.

[0041] Some compounds of the present invention can exist in solvated forms, including unsolvated and hydrated forms. Generally, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention. Some compounds of the present invention can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the intended uses of the present invention and are intended to be within the scope of the present invention.

[0042] Some compounds of the present invention have an asymmetric carbon atom (optical center) or a double bond; racemates, diastereomers, tautomers, geometric isomers, and individual isomers are included within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable for synthesis and / or isolation.

[0043] symbol [ka] This indicates the bonding site of one part of the compound to the rest of the compound.

[0044] The term "prodrug" as used herein refers to a compound that is converted in vivo, for example, by hydrolysis in the blood, to a parent compound or another active compound. Examples of such prodrugs are pharmaceutically acceptable esters of carboxylic acids. This is described in detail in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, ed., Design of Prodrugs, Elsevier, 1985; and Judkins, et al. Synthetic Communications, 26(23), 4351-4367 (1996); and The organic chemistry of drug design and drug action by Richard B Silverman, particularly pp. 497-546, which are incorporated herein by reference. The compounds of the present invention may represent prodrugs (e.g., potential MBL inhibitors), where hydrolysis of the β-lactam leads to the release and activation of the potential MBL inhibitor.

[0045] As used herein, the term "pharmaceutical preparation" includes preparations comprising at least one active compound and optionally one or more further acceptable components, such as a pharmaceutically acceptable carrier. When a pharmaceutical preparation comprises two or more active compounds or at least one active compound and one or more further acceptable components, it is also a pharmaceutical composition. Unless otherwise indicated by the context, all mention of "preparation" herein refers to pharmaceutical preparations.

[0046] As used herein, the terms “product” or “product of the present invention” include references to any product containing the compound of the present invention. In particular, the term “product” refers to compositions and formulations containing the compound of the present invention, such as pharmaceutical compositions.

[0047] The term "therapeutic dose" as used herein refers to the amount of drug or agent calculated, within the bounds of reasonable pharmacological judgment, to provide (or be provided by) a desired therapeutic response in a mammal (animal or human). A therapeutic response is, for example, one that helps cure, slow the progression of, or prevent a disease, disorder, or condition. The following abbreviations will be used here: Alloc: Allyloxycarbonyl ATCC American Type Culture Collection BBO Broadband Observe CFU Colony-forming units CLSI Clinical & Laboratory Standards Institute d doublet dd doublet doublet dt Triplet doublet DCM Dichloromethane DIPEA Diisopropylethylamine DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl ethyl acetate EtOH Ethanol eq equivalent FBS (Fetal Bovine Serum) Gal galactose GalNAc N-acetylgalactosamine Glc (glucose) GlcNAc N-acetylglucosamine h sextet HEPA High-Efficiency Particulate Air HPLC (High-Performance Liquid Chromatography) HR-MS High-Resolution Mass Spectrometry LC (Reset Chromatography) m (multiple terms) Man Mannos ManNAc (N-acetylmannoseamine) MeCN acetonitrile MeOH methanol MIC minimum inhibitory concentration MRSA (Methicillin-resistant Staphylococcus aureus) MSSA Methicillin-Susceptible Staphylococcus aureus MTT 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide MurNAc N-acetylmuramic acid m / z mass-to-charge ratio NEt3 Triethylamine NLD (Netherlands) NMR nuclear magnetic resonance p80 Polysorbate 80 PBS (phosphate-buffered saline) PE (Petroleum Ether) PFGE (Pulsed-Field Gel Electrophoresis) PK (Pharmacokinetics) pp pentapeptide ppm parts per million rpm (revolutions per minute) RT room temperature RP-HPLC (Reverse-Phase High-Performance Liquid Chromatography) s singlet SD standard deviation t triplet THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) TMS (trimethylsilyl) TSB Triptych Soy Broth UDP Uridine Diphosphate UV ultraviolet light VISA vancomycin-resistant Staphylococcus aureus VRE vancomycin-resistant enterococci VRSA (Vancomycin-resistant Staphylococcus aureus) VSE vancomycin-sensitive enterococci

[0048] compound In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. The compound of formula I is a lipid-added glycopeptide, where the lipid moiety / moiety (R1 and optionally R2) is attached to the glycan moiety by a linker (-L1-) and a guanidino moiety. The glycopeptide moiety of the compound is substituted vancomycin, with optional further substitutions R3 and R4.

[0049] R1 can be a lipid. R1 is either substituted or unsubstituted -C4-C 20 Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C1-C4 alkyl-C4-C 20 Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C4-C 20 Alkyl, substituted or unsubstituted C4-C 20 Alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 0 to 20), -C2-C 12 Alkyl-SS-C1-C 12 It can be selected from alkyl groups. R1 is substituted or unsubstituted -C4-C 20 Alkyl, substituted or unsubstituted C4-C 20 Alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 0 to 20), -C2-C 12 Alkyl-SS-C1-C 12 It can be selected from alkyl groups. R1 is substituted or unsubstituted -C4-C 16Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C1-C4 alkyl-C4-C 16 Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C4-C 16 Alkyl, substituted or unsubstituted C4-C 16 Alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 0 to 14), -C2-C8 alkyl-SS-C2-C8 alkyl. R1 is substituted or unsubstituted -C4-C 16 Alkyl, substituted or unsubstituted C4-C 16 Alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 0 to 14), -C2-C8 alkyl-SS-C2-C8 alkyl. R1 is -C4-C 16 Cycloalkyl (e.g., cross-linked cycloalkyl), -C1-C4 alkyl-C4-C 16 Cycloalkyl (e.g., cross-linked cycloalkyl), -C4-C 16 Alkyl, -C6-C 18 Alkenyls and substituted (e.g., halo-substituted) or unsubstituted -C1-C4 alkylbisphenyls can be selected. R1 is -C4-C 16 Alkyl, -C6-C 18 Alkenyls and substituted (e.g., halo-substituted) or unsubstituted -C1-C4 alkylbisphenyls can be selected. R1 is -C6-C 14 Cycloalkyl (e.g., cross-linked cycloalkyl), -C1-C4 alkyl-C6-C 14 Cycloalkyl (e.g., cross-linked cycloalkyl), -C6-C 14 Alkyl, -C6-C 16 It can be selected from alkenyls and substituted or unsubstituted C1-C4 alkylbisphenyls. R1 is C6-C14 Alkyl, -C6-C 16 It can be selected from alkenyls and substituted or unsubstituted C1-C4 alkylbisphenyls. R1 is C6-C 14 Cycloalkyl (e.g., cross-linked cycloalkyl), -CH2-C6-C 14 Cycloalkyl (e.g., cross-linked cycloalkyl), -C6-C 14 It can be selected from alkyl, -geranyl, -farnesyl, and -chlorobisphenyl. R1 is -C6-C 14 R1 can be selected from alkyl, -C1-C4 adamantyl, -adamantyl, -geranyl, -farnesyl, and -chlorobisphenyl. 14 The following can be selected: alkyl, geranyl, farnesyl, and chlorobisphenyl.

[0050] R1 is either substituted or unsubstituted -C4-C 20 Alkyl, e.g., substituted or unsubstituted -C4-C 16 It can be an alkyl group. R1 is an unsubstituted-C4-C 20 Alkyl, for example, unsubstituted-C4-C 16 It can be alkyl. R1 is substituted or unsubstituted -C4-C 20 Alkenyl, e.g., substituted or unsubstituted -C6-C 18 It can be an alkenyl. R1 is an unsubstituted-C4-C 20 Alkenyls, e.g., unsubstituted-C6-C 18 It may be an alkenyl. R1 may be a substituted or unsubstituted C1-C4 alkylaryl. R1 may be an unsubstituted C1-C4 alkylaryl, where the aryl substituent is a biaryl. R1 may be a substituted C1-C4 alkylaryl, where the aryl substituent is a halosubstituted biaryl, e.g., chlorobisphenyl. R1 may be a substituted CH2-alkylaryl, where the aryl substituent is a halosubstituted biaryl, e.g., chlorobisphenyl. R1 may be a -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1It can be CH3 (where m is selected from 2 and 3, and n is selected from 0 to 20). m can be 2. m can be 3. n can be selected from 2 to 16, for example, n can be selected from 4 to 12. m can be 2 and n can be selected from 2 to 16. m can be 3 and n can be selected from 2 to 16. R1 is -C2-C 12 alkyl - S - S - C1 - C 12 alkyl, for example -C2-C 10 alkyl - S - S - C2 - C 10 alkyl; for example, it can be -C2-C8 alkyl - S - S - C2-C8 alkyl. R1 is substituted or unsubstituted -C4-C 20 cycloalkyl, for example substituted or unsubstituted -C4-C 16 cycloalkyl or substituted or unsubstituted -C6-C 14 It can be cycloalkyl (for example, bridged cycloalkyl). R1 is unsubstituted -C4-C 20 cycloalkyl, for example unsubstituted -C4-C 16 alkyl or unsubstituted -C6-C 14 It can be cycloalkyl. R1 is unsubstituted bridged -C6-C 14 It can be cycloalkyl. R1 is unsubstituted bridged C 10 It can be cycloalkyl, for example adamantyl. R1 is substituted or unsubstituted -C1-C4 alkyl - C4-C 20 cycloalkyl, for example substituted or unsubstituted -C1-C4 alkyl - C4-C 16 cycloalkyl or substituted or unsubstituted -C1-C4 alkyl - C6-C 14 It can be cycloalkyl. R1 is unsubstituted -C1-C4 alkyl - C4-C 20 cycloalkyl, for example unsubstituted -C1-C4 alkyl - C4-C 16 cycloalkyl or unsubstituted -C1-C4 alkyl - C6-C 14 It can be cycloalkyl. R1 is unsubstituted -C1-C4 alkyl - C6-C 14 It can be cycloalkyl, where the cycloalkyl is bridged. R1 is unsubstituted -C1-C4 alkyl - C 10It may be cycloalkyl, where the cycloalkyl is bridged, for example -C1-C4 alkyl - adamantyl. R1 is unsubstituted -CH2-C 10 It may be cycloalkyl, where the cycloalkyl is bridged, for example -CH2 - adamantyl.

[0051] When R1 is a substituted moiety, it may be substituted with at least one -OH, =O, -CN, -halo, -NH2, -NH(C1-C6 alkyl), -N(C1-C4 alkyl)2; for example, it may be substituted with at least one -OH, =O, -CN, -halo. When R1 is substituted or unsubstituted alkyl, the carbon main chain of the alkyl may be interrupted by at least one disulfide bond (-S-S-), thioether bond (-S-), ether bond -O- or ester bond (-C(O)O-).

[0052] R2 may be selected from -H or a lipid. R2 may be -H. R2 may be a lipid. R2 is -H, substituted or unsubstituted -C4-C 20 alkyl, substituted or unsubstituted -C4-C 20 alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl - [O(CH2) p q -O(CH2) p-1 CH3 (where p is selected from 2 and 3, and q is selected from 0 to 20), -C2-C 12 alkyl - S - S - C1-C 12 alkyl, and may be selected from -H, substituted or unsubstituted -C4-C 16 alkyl, substituted or unsubstituted -C4-C 16 alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl - [O(CH2) p q -O(CH2) p-1 CH3 (where p is selected from 2 and 3, and q is selected from 0 to 14), and may be selected from -C2-C8 alkyl - S - S - C2-C8 alkyl. R2 is -H, -C4-C 12 alkyl, -C4-C 12 ​​Alkenyl, substituted or unsubstituted -C1-C4 alkylaryl and -C1-C4 alkyl-[O(CH2) p ] q -O(CH2) p-1 CH3 can be selected from (where p is selected from 2 and 3, and q is selected from 0 to 20). R2 is -H, -C4-C 12 Alkyl and -C4-C 12 It can be selected from alkenyls. R2 is -H, -C4-C 16 Alkyl, -C6-C 18 R2 can be selected from alkenyls and substituted (e.g., halo-substituted) or unsubstituted -C1-C4 alkylbisphenyls. 14 Alkyl, -C6-C 16 R2 can be selected from alkenyls and substituted or unsubstituted C1-C4 alkylbisphenyls. 14 The following can be selected: alkyl, geranyl, farnesyl, and chlorobisphenyl.

[0053] When R2 is a lipid, R2 is either substituted or unsubstituted -C4-C 20 Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C1-C4 alkyl-C4-C 20 Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C4-C 20 Alkyl, substituted or unsubstituted C4-C 20 Alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl-[O(CH2) p ] q -O(CH2) p-1 CH3 (where p is selected from 2 and 3, and q is selected from 0 to 20), -C2-C 12 Alkyl-SS-C1-C 12 It can be selected from alkyl groups. R2 is substituted or unsubstituted -C4-C 20 Alkyl, substituted or unsubstituted C4-C 20 Alkenyl, substituted or unsubstituted C1-C4 alkyl-[O(CH2)] p ] q -O(CH2) p-1CH3 (where p is selected from 2 and 3, and q is selected from 0 to 20), -C2-C 12 Alkyl-SS-C1-C 12 It can be selected from alkyl groups. R2 is substituted or unsubstituted -C4-C 16 Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C1-C4 alkyl-C4-C 16 Cycloalkyl (e.g., cross-linked cycloalkyl), substituted or unsubstituted -C4-C 16 Alkyl, substituted or unsubstituted C4-C 16 Alkenyl, substituted or unsubstituted-C1-C4 alkylaryl-C1-C4 alkyl-[O(CH2)] p ] q -O(CH2) p-1 CH3 (where p is selected from 2 and 3, and q is selected from 0 to 14), -C2-C8 alkyl-SS-C2-C8 alkyl. R2 is substituted or unsubstituted -C4-C 16 Alkyl, substituted or unsubstituted C4-C 16 Alkenyl, substituted or unsubstituted C1-C4 alkyl-[O(CH2)] p ] q -O(CH2) p-1 CH3 (where p is selected from 2 and 3, and q is selected from 0 to 14), -C2-C8 alkyl-SS-C2-C8 alkyl. R2 is -C4-C 16 Cycloalkyl (e.g., cross-linked cycloalkyl), -C1-C4 alkyl-C4-C 16 Cycloalkyl (e.g., cross-linked cycloalkyl), -C4-C 16 Alkyl, -C6-C 18 R2 can be selected from alkenyls and substituted (e.g., halo-substituted) or unsubstituted -C1-C4 alkylbisphenyls. 16 Alkyl, -C6-C 18 R2 can be selected from alkenyls and substituted (e.g., halo-substituted) or unsubstituted C1-C4 alkylbisphenyls. 14 Cycloalkyl (e.g., cross-linked cycloalkyl), -C1-C4 alkyl-C6-C 14Cycloalkyl (e.g., cross-linked cycloalkyl), -C6-C 14 Alkyl, -C6-C 16 R2 can be selected from alkenyls and substituted or unsubstituted C1-C4 alkylbisphenyls. 14 Alkyl, -C6-C 16 R2 can be selected from alkenyls and substituted or unsubstituted C1-C4 alkylbisphenyls. 14 Cycloalkyl (e.g., cross-linked cycloalkyl such as adamantyl), -CH2-C6-C 14 Cycloalkyl (e.g., cross-linked cycloalkyl such as adamantyl), -C6-C 14 The following can be selected: alkyl, geranyl, farnesyl, and chlorobisphenyl.

[0054] R2 is -H, -C6-C 14 R1 can be selected from alkyl, -C1-C4 adamantyl, -adamantyl, -geranyl, -farnesyl, and -chlorobisphenyl. 14 The following can be selected: alkyl, geranyl, farnesyl, and chlorobisphenyl.

[0055] R2 can be -H. R2 is either substituted or unsubstituted -C4-C 20 Alkyl, e.g., substituted or unsubstituted -C4-C 16 It can be an alkyl group. R2 is substituted or unsubstituted -C2-C 14 Alkyl, e.g., substituted or unsubstituted -C4-C 12 Alkyl, for example, -C4-C 10 It can be an alkyl group. R2 is an unsubstituted-C4-C 20 Alkyl, for example, unsubstituted-C4-C 16 It can be alkyl. R2 is substituted or unsubstituted -C4-C 20 Alkenyl, e.g., substituted or unsubstituted -C6-C 18 It can be an alkenyl. R2 is an unsubstituted-C4-C 20 Alkenyls, e.g., unsubstituted-C6-C 18It may be an alkenyl. R2 may be a substituted or unsubstituted C1-C4 alkylaryl. R2 may be a C1-C4 alkyl-[O(CH2) p ] q -O(CH2) p-1 CH3 can be (where p is selected from 2 and 3, and q is selected from 0 to 20). p can be 2. p can be 3. q can be selected from 2 to 16, for example q can be selected from 4 to 12. p can be 2, and q can be selected from 2 to 16. p can be 3, and q can be selected from 2 to 16. R2 is -C2-C 12 Alkyl-SS-C1-C 12 Alkyl, for example, -C2-C 10 Alkyl-SS-C2-C 10 Alkyl; for example, it could be -C2-C8 alkyl-SS-C2-C8 alkyl.

[0056] When R2 is a substituted portion, it can be substituted with at least one -OH, =O, -CN, -halo, -NH2, -NH(C1-C6 alkyl), or -N(C1-C4 alkyl)2; for example, it can be substituted with at least one -OH, =O, -CN, or -halo. When R2 is a substituted or unsubstituted alkyl, the alkyl carbon backbone may be interrupted by at least one disulfide bond (-SS-), thioether bond (-S-), ether bond (-O-), or ester bond (-C(O)O-).

[0057] Each of R1 and R2 is independently substituted or unsubstituted -C2-C 12 Alkyl, substituted or unsubstituted -C2-C 12 Alkenyl, -C1-C4 alkyl-[O(CH2)] m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 0 to 20) and -C2-C 12 Alkyl-SS-C1-C 12 It can be alkyl. Each of R1 and R2 is -C2-C 12 Alkyl, -C2-C 12Alkenyl, -C1-C4 alkyl-[O(CH2)] m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 0 to 20) and -C2-C 12 Alkyl-SS-C1-C 12 It can be selected independently of alkyl. Each of R1 and R2 is -C2-C 10 Alkyl, -C2-C 10 Alkenyl, -C1-C4 alkyl-[O(CH2)] m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 2 to 16) and -C2-C 10 Alkyl-SS-C2-C 10 It can be selected independently of alkyl. Each of R1 and R2 is -C2-C 10 Alkyl, -C2-C 10 Alkenyl and -C1-C4 alkyl-[O(CH2)] m ] n -O(CH2) m-1 CH3 (where m is selected from 2 and 3, and n is selected from 2 to 16) can be selected independently. Each of R1 and R2 is either substituted or non-substituted -C2-C 12 Alkyl and substituted or unsubstituted C2-C 12 It can be selected independently of the alkenil. Each of R1 and R2 is -C2-C 12 Alkyl and -C2-C 12 It can be selected independently of the alkenyl. Each of R1 and R2 is either substituted or unsubstituted -C2-C 10 Alkyl and substituted or unsubstituted C2-C 10 It can be selected independently of the alkenil. Each of R1 and R2 is -C2-C 10 Alkyl and -C2-C 10 It can be selected independently of the alkenyl. Each of R1 and R2 is either substituted or unsubstituted -C4-C 10 Alkyl and substituted or unsubstituted C4-C 10 It can be selected independently of the alkenil. Each of R1 and R2 is -C4-C10 Alkyl and -C4-C 10 It can be selected independently of alkenyls. Each of R1 and R2 can be selected independently of substituted or unsubstituted -C4-C8 alkyl and substituted or unsubstituted -C4-C8 alkenyl. Each of R1 and R2 can be selected independently of -C4-C8 alkyl and -C4-C8 alkenyl.

[0058] Each of R1 and R2 is either substituted or non-substituted -C2-C 12 It can be alkyl. Each of R1 and R2 is -C2-C 12 It can be alkyl. Each of R1 and R2 is substituted or unsubstituted -C2-C 10 It can be alkyl. Each of R1 and R2 is -C2-C 10 It may be alkyl. Each of R1 and R2 is substituted or unsubstituted -C4-C 10 It can be alkyl. Each of R1 and R2 is -C4-C 10 It may be an alkyl group. Each of R1 and R2 may be a substituted or unsubstituted C4-C8 alkyl group. Each of R1 and R2 may be a C4-C8 alkyl group. Each of R1 and R2 may be a substituted or unsubstituted C2-C 12 It can be an alkenyl. Each of R1 and R2 is -C2-C 12 It can be an alkenyl. Each of R1 and R2 is substituted or unsubstituted -C2-C 10 It can be an alkenyl. Each of R1 and R2 is -C2-C 10 It can be an alkenyl. Each of R1 and R2 is either substituted or unsubstituted -C4-C 10 It can be an alkenyl. Each of R1 and R2 is -C4-C 10 It may be an alkenyl. Each of R1 and R2 may be a substituted or unsubstituted -C4-C8 alkenyl. Each of R1 and R2 may be a -C4-C8 alkenyl. Each of R1 and R2 may be a -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1CH3 can be (where m is selected from 2 and 3, and n is selected from 0 to 20). m can be 2. m can be 3. n can be selected from 2 to 16, for example n can be selected from 4 to 12. m can be 2 and n can be selected from 2 to 16. m can be 3 and n can be selected from 2 to 16. Each of R1 and R2 is -C2-C 12 Alkyl-SS-C1-C 12 Alkyl, for example, -C2-C 10 Alkyl-SS-C2-C 10 Alkyl; for example, it could be -C2-C8 alkyl-SS-C2-C8 alkyl.

[0059] R1 and R2 may be the same; for example, R1 and R2 are 、 Each is either identically substituted or non-substituted -C2-C 12 It may be an alkyl group. R1 and R2 may be different, for example, R2 may be -H and R1 may be other substituents as specified elsewhere herein.

[0060] R1 is [ka] It can be selected from the following.

[0061] R2 is [ka] It can be selected from the following.

[0062] R1 is [ka] R2 can be selected from and R1 is [ka] And R2 is [ka] It is possible. R1 is [ka] And R2 is [ka] It is possible. R1 is [ka] And R2 is [ka] It is possible.

[0063] R3 is -OH, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 Alkenyls, substituted or unsubstituted C1-C4 alkylaryls, and carbohydrates can be selected. 20 Alkyls are, for example, -NHCH2CH2CH2N(CH3)2 or [ka] It is possible. Carbohydrates, for example, -(NHCH2CH2) x -Glc, -(NHCH2CH2) x -Gal, -(NHCH2CH2) x -Man, -(NHCH2CH2) x -GlcNAc, -(NHCH2CH2) x -MurNAc, -(NHCH2CH2) x -ManNAc, -(NHCH2CH2) x -GalNAc, -(NHCH2CH2) x -Cerobiose and -(NHCH2CH2) x -It can be maltose (where x is 0 or 1). R3 is -OH, -C1-C 20 Alkyl, -C2-C 20 R3 can be selected from alkenyls, -C1-C4 alkylaryls, and carbohydrates. R3 is -OH, substituted or unsubstituted -C1-C10 Alkyl, substituted or unsubstituted -C2-C 10 Alkenyls, substituted or unsubstituted C1-C4 alkylaryls, and carbohydrates can be selected. R3 is -OH, -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C1-C4 alkylaryl and carbohydrate can be selected. R3 is -OH, -NHCH2CH2CH2N(CH3)2 [ka] ,-(NHCH2CH2) x -Glc, -(NHCH2CH2) x -Gal, -(NHCH2CH2) x -Man, -(NHCH2CH2) x -GlcNAc, -(NHCH2CH2) x -MurNAc, -(NHCH2CH2) x -ManNAc, -(NHCH2CH2) x -GalNAc, -(NHCH2CH2) x -Cerobiose and -(NHCH2CH2) x -Can be selected from maltose (where x is 0 or 1). x can be 0. x can be 1.

[0064] R3 can be -OH. R3 can be substituted or unsubstituted -C1-C 20 Alkyl; e.g., substituted or unsubstituted C1-C 10 Alkyl, for example, substituted or unsubstituted C1-C6 alkyl. R3 is -C1-C 20 Alkyl; for example, C1-C 10 It can be an alkyl group, for example, a C1-C6 alkyl group. R3 is substituted or unsubstituted-C2-C 20 Alkenyl; e.g., substituted or unsubstituted C2-C 10 R3 may be an alkenyl, for example, a substituted or unsubstituted C2-C6 alkenyl. 20 Alkenyls; e.g., C2-C 10R3 may be an alkenyl, e.g., a C2-C6 alkenyl. R3 may be a substituted or unsubstituted C1-C4 alkylaryl, e.g., a C1-C4 alkylaryl. R3 may optionally contain a linker such as -NHCH2CH2-, and may contain a carbohydrate (e.g., a glycan selected from Glc, Gal, Man, GlcNAc, MurNAc, ManNAc, GalNAc, cellobiose, and maltose). R3 may be -NHCH2CH2CH2N(CH3)2. R3 is, [ka] It is possible. R3 is -(NHCH2CH2) x -Glc is possible. R3 is -(NHCH2CH2) x -It could be Gal. R3 is -(NHCH2CH2) x -It could be Man. R3 is -(NHCH2CH2) x -GlcNAc is possible. R3 is -(NHCH2CH2) x -MurNAc is possible. R3 is -(NHCH2CH2) x -ManNAc is possible. R3 is -(NHCH2CH2) x -It could be GalNAc. R3 is -(NHCH2CH2) x -It could be cellobiose. R3 is -(NHCH2CH2) x - It can be maltose. x can be 0. x can be 1.

[0065] R4 is -H, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 Alkenyls, substituted or unsubstituted C1-C4 alkylaryls, and carbohydrates can be selected. 20 Alkyl can be substituted with one or more nitrogen, phosphorus, or oxygen atoms; for example, substituted C1-C 20Alkyl compounds can be -CH2NHCH2P(O)(OH)2, -CH2N(CH2PO3H2)2, -CH2NHCH2CH2CH2N(CH3)2, -CH2NHCH2CH2COOH, -CH2N(CH3)CH2(CH(OH))4CH2OH, -CH2NHCH(COOH)CH2COOH, or -CH2NH(CH2CH2OH)2. Carbohydrates can be, for example, -(NHCH2CH2) y -Glc, -(NHCH2CH2) y -Gal, -(NHCH2CH2) y -Man, -(NHCH2CH2) y -GlcNAc, -(NHCH2CH2) y -MurNAc, -(NHCH2CH2) y -ManNac, -(NHCH2CH2) y -GalNAc, -(NHCH2CH2) y -Cerobiose and -(NHCH2CH2) y -It can be maltose (where y is 0 or 1). R4 is -H, -C1-C 20 Alkyl, -C2-C 20 Alkenyls, C1-C4 alkylaryls, and carbohydrates can be selected. R4 is C1-C4, substituted or unsubstituted C1-C4. 10 Alkyl, substituted or unsubstituted -C2-C 10 R4 can be selected from alkenyls, substituted or unsubstituted -C1-C4 alkylaryls and carbohydrates. R4 can be -H, -CH2NHCH2P(O)(OH)2, -CH2N(CH2PO3H2)2, -CH2NHCH2CH2CH2N(CH3)2, -CH2NHCH2CH2COOH, -CH2N(CH3)CH2(CH(OH))4CH2OH, -CH2NHCH(COOH)CH2COOH, -CH2NH(CH2CH2OH)2, -(NHCH2CH2) y -Glc, -(NHCH2CH2) y -Gal, -(NHCH2CH2) y -Man, -(NHCH2CH2) y -GlcNAc, -(NHCH2CH2) y -MurNAc, -(NHCH2CH2) y-ManNac, -(NHCH2CH2) y -GalNAc, -(NHCH2CH2) y -Cerobiose and -(NHCH2CH2) y - Selected from maltose (where y is 0 or 1). y can be 0. y can be 1.

[0066] R4 can be -H. R4 is either substituted or unsubstituted -C1-C 20 Alkyl; e.g., substituted or unsubstituted C1-C 10 Alkyl, for example, substituted or unsubstituted C1-C6 alkyl. R4 is -C1-C 20 Alkyl; for example, C1-C 10 It can be an alkyl group, for example, a C1-C6 alkyl group. R4 is substituted or unsubstituted C2-C 20 Alkenyl; e.g., substituted or unsubstituted C2-C 10 It may be an alkenyl, for example, a substituted or unsubstituted C2-C6 alkenyl. R4 is -C2-C 20 Alkenyls; e.g., C2-C 10 R4 may be an alkenyl, for example, a C2-C6 alkenyl. R4 may be a substituted or unsubstituted C1-C4 alkylaryl, for example, a C1-C4 alkylaryl. R4 may be a carbohydrate (for example, a glycan selected from Glc, Gal, Man, GlcNAc, MurNAc, ManNAc, GalNAc, cellobiose and maltose) optionally containing a linker such as -NHCH2CH2-. R4 may be -CH2NHCH2P(O)(OH)2. R4 may be -CH2N(CH2PO3H2)2. R4 may be -CH2NHCH2CH2CH2N(CH3)2. R4 may be -CH2NHCH2CH2COOH. R4 may be -CH2N(CH3)CH2(CH(OH))4CH2OH. R4 may be -CH2NHCH(COOH)CH2COOH. R4 could be -CH2NH(CH2CH2OH)2. R4 could be -(NHCH2CH2) y -Glc is possible. R4 is -(NHCH2CH2) y-It could be Gal. R4 is -(NHCH2CH2) y -It could be Man. R4 is -(NHCH2CH2) y -GlcNAc is possible. R4 is -(NHCH2CH2) y -MurNAc is possible. R4 is -(NHCH2CH2) y -It could be ManNac. R4 is -(NHCH2CH2) y -It could be GalNAc. R4 is -(NHCH2CH2) y -It could be cellobiose. R4 is -(NHCH2CH2) y - It can be maltose. y can be 0. y can be 1.

[0067] L1 is -C1-C 20 Alkylene-,-C2-C 20 Alkenylene-,-(C1-C4 alkyl)arylene-,-C2-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C2-C 12 Alkyl-SS-C1-C 12 Alkyl-,-C(O)C1-C 20 Alkylene-,-C(O)C2-C 20 Alkenylene-,-C(O)(C1-C4 alkyl)arylene-,-C(O)C1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C(O)NHC1-C 20 Alkylene-,-C(O)NHC2-C 20 Alkenylene-,-C(O)NH(C1-C4 alkyl)arylene-,-C(O)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C(S)NHC1-C 20 Alkylene-,-C(S)NHC2-C 20 Alkenylene-, -C(S)NH(C1-C4 alkyl)arylene- and -C(S)NHC1-C4 alkyl-[O(CH2) r ] s-O(CH2) r -(where r is selected from 2 and 3, and s is selected from 0 to 20) can be selected from. L1 is -C2-C 12 Alkylene-,-C2-C 12 Alkenylene-,-(C1-C4 alkyl)arylene-,-C2-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C2-C 10 Alkyl-SS-C1-C 10 Alkyl-,-C(O)C1-C 12 Alkylene-,-C(O)C2-C 12 Alkenylene-,-C(O)(C1-C4 alkyl)arylene-,-C(O)C1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C(O)NHC1-C 12 Alkylene-,-C(O)NHC2-C 12 Alkenylene-,--C(O)NH(C1-C4 alkyl)arylene-,-C(O)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C(S)NHC1-C 12 Alkylene-,-C(S)NHC2-C 12 Alkenylene-, -C(S)NH(C1-C4 alkyl)arylene- and -C(S)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -(where r is selected from 2 and 3, and s is selected from 0 to 20) can be selected from. L1 is -C2-C 10 Alkylene-,-C2-C 10 Alkenylene-,-(C1-C4 alkyl)arylene-,-C2-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C2-C8alkyl-SS-C1-C8alkyl-, -C(O)C1-C 10 Alkylene-,-C(O)C2-C 10Alkenylene-,-C(O)(C1-C4 alkyl)arylene-,-C(O)C1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C(O)NHC1-C 10 Alkylene-,-C(O)NHC2-C 10 Alkenylene-,--C(O)NH(C1-C4 alkyl)arylene-,-C(O)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C(S)NHC2-C 10 Alkylene-,-C(S)NHC2-C 10 Alkenylene-, -C(S)NH(C1-C4 alkyl)arylene- and -C(S)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -(where r is selected from 2 and 3, e.g., 2), and s can be selected from 0 to 20 (e.g., 2 to 16).

[0068] L1 is -C2-C 20 Alkylene-,-C2-C 20 Alkenylene- and -(C1-C4 alkyl)arylene- can be selected. L1 is -C2-C 12 Alkylene-,-C2-C 12 Alkenylene- and -(C1-C4 alkyl)arylene- can be selected. L1 is -C2-C 10 Alkylene-,-C2-C 12 Alkenylene- and -(C1-C4 alkyl)arylene- can be selected. L1 is -C2-C 20 Alkylene- and -(C1-C4 alkyl)arylene- can be selected. L1 is -C2-C 12 Alkylene- and -(C1-C4 alkyl)arylene- can be selected. L1 is -C2-C 10 Alkylenes (e.g., C2-C8 alkylenes) and arylenes (C1-C4 alkyl) can be selected.

[0069] L1 may be -(C1-C4 alkyl)arylene-; for example, -CH2Ph-. L1 may be -C2-C 20 Alkylene-; e.g., C2-C 12 Alkylene-, for example, -C2-C 10 It can be an alkylene (e.g., -C2-C8 alkylene). L1 is -C2-C 20 Alkenylene-; e.g., C2-C 12 Alkenylene-, e.g., -C2-C 10 It may be an alkenylene. L1 is -C2-C4 alkyl-[O(CH2) r ] s -O(CH2) r -This is possible. L1 is -C2-C 12 Alkyl-SS-C2-C 12 Alkyl-, for example, -C2-C 10 Alkyl-SS-C2-C 10 Alkyl-; for example, it could be -C2-C8alkyl-SS-C2-C8alkyl-. L1 is -C(O)C2-C 20 Alkenylene-; for example, -C(O)C1-C 12 Alkylene-, for example, -C(O)C1-C 10 It can be alkylene-. L1 can be -C(O)(C1-C4 alkyl)arylene-. L1 can be -C(O)C1-C4 alkyl-[O(CH2) r ] s -O(CH2) r - is possible. L1 is -C(O)NHC1-C 20 Alkylene-; e.g., -C(O)NHC1-C 12 Alkylene-, for example, -C(O)NHC1-C 10 It can be an alkylene. L1 is -C(O)NHC2-C 20 Alkenylene-; e.g., -C(O)NHC2-C 12 Alkenylene-, e.g., -C(O)NHC2-C 10 It can be an alkenylene. L1 can be a -C(O)NH(C1-C4 alkyl)arylene. L1 can be a -C(O)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r-This is possible. L1 is -C(S)NHC1-C 20 Alkylene-; e.g., -C(S)NHC1-C 12 Alkylene-, for example, -C(S)NHC1-C 10 It can be alkylene-. L1 is -C(S)NHC2-C 20 Alkenylene-; e.g., -C(S)NHC2-C 12 Alkenylene-, e.g., -C(S)NHC2-C 10 It can be an alkenylene. L1 can be a -C(S)NH(C1-C4 alkyl)arylene. L1 can be a -C(S)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r - It is possible.

[0070] r can be 2. r can be 3. s can be selected from 2 to 16, for example, s can be selected from 4 to 12. r can be 2, and s can be selected from 2 to 16. r can be 3, and s can be selected from 2 to 16.

[0071] The compound may be selected from the following or their pharmaceutically acceptable salts, solvates, or / or prodrugs: [ka] [ka] [ka]

[0072] Examples of compounds can be prepared according to the synthesis methods described in the Examples and according to reaction schemes A and B. Furthermore, as will be recognized by those skilled in the art, these methods and the methods described in reaction schemes A and B (see below) can be readily adapted to provide other compounds and disclosures of the present invention.

[0073] Formulation and administration According to a further aspect of the present invention, there is provided a pharmaceutical formulation or composition comprising a compound of the present invention, optionally mixed with at least one pharmaceutically acceptable adjuvant, diluent or carrier.

[0074] The formulation or composition can be a parenteral formulation or an oral formulation. The formulation can be a parenteral formulation, for example, a formulation for intravenous injection. The formulation can be an oral formulation.

[0075] The compound, formulation or composition of the present invention can be administered orally, topically, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, by oral or nasal spray or by inhalation. The compound can be administered in the form of a pharmaceutical formulation, in a pharmaceutically acceptable dosage form, as the free compound or, for example, as a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt. Depending on the disorder to be treated, the patient and the route of administration, the composition can be administered in various doses.

[0076] Therefore, generally, the pharmaceutical compound of the present invention can be administered to a host parenterally (as used herein, "parenteral" refers to a method of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injections and infusions) or orally to obtain an antibacterial effect. For example, the pharmaceutical compound of the present invention can be administered by intravenous injection or infusion. In the case of large animals such as humans, the compound can be administered alone or as a composition combined with a pharmaceutically acceptable diluent, additive or carrier.

[0077] The actual dosage levels of the active ingredients in the pharmaceutical formulations and compositions of the present invention can vary in order to obtain an amount of the active compound that is effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and history of the patient being treated. However, it is within the skill of the art to initiate administration of the compound at a lower level than that required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Suitable dosages are generally in the range of 0.01 to 100 mg / kg / day, for example in the range of 0.1 to 50 mg / kg / day.

[0078] The pharmaceutical formulations or compositions of the present invention for parenteral (e.g., intravenous) injection can be pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and organic esters for injection such as ethyl oleate. Suitable fluidity can be maintained, for example, by coating substances such as lecithin, by maintenance of the required particle size in the case of dispersions and by the use of surfactants. The parenteral injectable formulations or compositions are preferred formulations or compositions of the present invention.

[0079] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol or phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars or sodium chloride. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption (such as, aluminum monostearate and gelatin).

[0080] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is generally mixed with at least one inert, pharmaceutically acceptable additive or carrier, e.g., sodium citrate or dipotassium phosphate and / or one or more: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acid and sodium carbonate; e) solution retarders, e.g., paraffin; f) absorption accelerators, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. Similar types of solid compositions can also be used as fillers for soft and hard-filled gelatin capsules, for example, with additives such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0081] Oral formulations may contain solubilizers. Examples of solubilizers include nonionic surfactants, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g., sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, and pentaerythritol fatty acid esters. The following are included: propylene glycol mono-fatty acid esters, polyoxyethylene propylene glycol mono-fatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkyl olamides and alkylamine oxides; bile acids and their salts (e.g., chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and their salts and their glycine or taurine conjugates); ionic surfactants, e.g., sodium lauryl sulfate, fatty acid soaps, alkyl sulfonates, alkyl phosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soaps and alkyl quaternary ammonium salts; and amphoteric surfactants, e.g., betaine and aminocarboxylate salts.

[0082] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules may be coated and shelled, such as enteric coatings and other coatings well known in the pharmaceutical field. They may optionally contain opacifiers and may be compositions that release the active ingredient only in certain parts of the intestinal tract, predominantly, and / or in a delayed manner. Examples of embedding compositions include polymeric substances and waxes.

[0083] The active compound may, if appropriate, be in the form of microencapsulation along with one or more of the above-mentioned additives.

[0084] The active compound may be in a micronized form, for example, it may be made into fine particles.

[0085] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methhydroxyl, bentonite, agar and tragacanth, and mixtures thereof.

[0086] The rectal or vaginal administration composition may be in the form of a suppository, which can be prepared by mixing the compound of the present invention with a suitable non-irritating additive or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, that is solid at room temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active compound.

[0087] The topical administration forms of the compounds of the present invention include powders, sprays, creams, foams, gels, ointments, and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative, buffer, or propellant. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be within the scope of the present invention.

[0088] Liquid (e.g., aqueous) formulations and compositions, whether intended for non-enteral or oral use, may contain further compounds that help prevent the precipitation of the active compound. The compounds of the present invention are glycopeptide derivatives. Precipitation of such compounds in aqueous solutions can be avoided or minimized by incorporating monosaccharides into the solution. For example, aqueous formulations or compositions may contain glucose. In particular, non-enteral (e.g., intravenous injection) formulations or compositions may contain the compounds of the present invention, water for injection, and glucose.

[0089] The formulations or compositions of this subject matter may contain other activators, in particular intended for use in the treatment of bacterial infections, provided that they do not interfere with the activity of the compound.

[0090] The formulations described in this subject may also contain inactive ingredients. Suitable inactive ingredients are well known in this field, as seen in Goodman and Gillman's: The Pharmacological Bases of Therapeutics, 13 th Ed., Brunton et al., Eds. McGraw-Hill Education (2017) and Remington's Pharmaceutical Sciences, 17 th This is described in standard textbooks such as Ed., Mack Publishing Co., Easton, Pa. (1990), and both are included herein by citation.

[0091] The formulation may be used in combination with further pharmaceutical dosage forms to enhance its efficacy in treating any of the disorders described herein. In this regard, the formulation may be administered as part of a regimen further comprising any other pharmaceutical and / or pharmaceutical dosage forms known in the art to be effective in treating any of these disorders.

[0092] use The compound of the present invention is a novel guanidino-containing derivative of the glycopeptide vancomycin.

[0093] Vancomycin is an antibiotic active against Gram-positive bacteria because it interferes with the synthesis of the peptidoglycan layer in Gram-positive bacteria through the following mechanism: Lipid II, the second-to-last building block of the bacterial cell wall, is crucial for peptidoglycan biosynthesis. Vancomycin tightly binds to the terminal d-Ala-d-Ala motif of the lipid II pentapeptide.

[0094] The increasing number of bacterial strains capable of utilizing lipid II variants containing the d-Ala-d-Lac termination pentapeptide has led to a rise in encounters with vancomycin resistance. This d-Ala mutation in d-Lac reduces vancomycin's affinity for lipid II, thereby significantly reducing its antibacterial effect (Healy, VL, et al. (2000) Vancomycin resistance in enterococci: reprogramming of the D-ala-D-Ala ligases in bacterial peptidoglycan biosynthesis, Chem Biol 7, R109-119; Blaskovich, MAT, et al. (2018) Developments in Glycopeptide Antibiotics, ACS Infect Dis 4, 715-735; Willyard, C. (2017) The drug-resistant bacteria that pose the greatest health threats, Nature 543, 15; all of these are incorporated herein by reference). We found that this mode of resistance is partially overcome by certain related glycolipid peptides in which the binding of hydrophobic groups to the vancosamine unit enhances its activity. This is exemplified by the clinically used drug telavancin (Blaskovich, MAT, et al. (2018) Developments in Glycopeptide Antibiotics, ACS Infect Dis 4, 715-735; Willyard, C. (2017) The drug-resistant bacteria that pose the greatest health threats, Nature 543, 15; Corey, GR, et al. (2009) Telavancin, Nat Rev Drug Discov 8, 929-930; all of these are incorporated herein by reference as a whole). Although telavancin is more potent than vancomycin, it does not escape this drawback.Compared to vancomycin, telavancin has significantly lower solubility in aqueous media and carries a severe health risk. The FDA recently applied a black box warning to telavancin due to suspected effects on heart rate (QT interval prolongation) and increased mortality compared to vancomycin in patients with renal impairment (included here as a whole by citation: Barriere, SL (2014) The ATTAIN trials: efficacy and safety of telavancin compared with vancomycin for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia, Future Microbiol 9, 281-289). Teravancin is therefore considered a last resort drug and should only be used in cases where other treatments are ineffective.

[0095] The compounds provided herein are antibiotics, particularly those useful for treating conditions associated with infections caused by Gram-positive bacteria. The compounds of the present invention may provide similar or better antibiotic activity compared to known antibiotics such as vancomycin, teravancin, teicoplanin, oritabancin, and / or dalbavancin, as measured, for example, by MIC. The compounds of the present invention may also provide a favorable safety profile.

[0096] When a compound is used to treat a bacterial infection, the infection may be caused by Gram-negative or Gram-positive bacteria. For example, a bacterial infection may be caused by bacteria from one or more (e.g., at least one) of the following families: Clostridium, Pseudomonas, Escherichia, Klebsiella, Enterococcus, Enterobacter, Serratia, Stenotrophomonas, Aeromonas, Morganella lla), Yersinia, Salmonella, Proteus, Pasteurella, Haemophilus, Citrobacter, Burkholderia, Brucella, Moraxella, Mycobacterium, Streptococcus, or Staphylococcus. Specific examples include Clostridium, Pseudomonas, Escherichia, Klebsiella, Enterococcus, Enterobacter, Streptococcus, and Staphylococcus.Bacterial infections include, for example, Moraxella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter species, Escherichia coli, Haemophilus pneumonia, Klebsiella pneumonia, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium, Clostridium difficile, Yersinia enterocolitica, Mycobacterium tuberculosis, Staphylococcus aureus, and Group B Streptococcus. It can be caused by one or more bacteria selected from Streptococcus pneumoniae and Streptococcus pyogenes.

[0097] The compounds of the present invention are useful in the treatment of bacterial infections, particularly those caused by Gram-positive bacteria. For example, the bacterial infection can be caused by bacteria from one or more (e.g., at least one) of the following families: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococcus (e.g., Streptococcus pyogenes, Group B hemolytic Streptococcus, Streptococcus viridans, Streptococcus pneumoniae), Enterococcus (e.g., Enterococcus faecalis), Bacillus, Clostridium, Listeria and Corynebacterium. The bacterial infection can be caused by bacteria from one or more (e.g., at least one) of the following families: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococcus (e.g., Streptococcus pyogenes, Group B hemolytic Streptococcus, Streptococcus viridans, Streptococcus pneumoniae), Enterococcus. The bacteria can be resistant to treatment with methicillin and / or vancomycin, and for example, the bacteria can include strains of methicillin and / or vancomycin-resistant Staphylococcus (e.g., Staphylococcus aureus), Streptococcus or Enterococcus (e.g., Enterococcus faecium, Enterococcus faecalis). The bacterial infection can include infections by vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Staphylococcus aureus (VRSA). The bacterial infection can include infections by Staphylococcus aureus or Enterococcus faecium. The bacterial infection can include infections by one or more of Staphylococcus aureus ATCC 29213, Staphylococcus aureus USA 300, Enterococcus faecium E155, Enterococcus faecium E7314, Enterococcus faecium E980, Enterococcus faecalis E1246 or Enterococcus faecalis E7406.

[0098] Examples of bacterial (e.g., Gram-positive) infections that can be treated with the compounds of the present invention include skin and structural infections, lower respiratory tract infections, bacteremia, sepsis, infectious endocarditis, peritonitis (e.g., associated with sustained self-managed peritoneal dialysis), enteritis (e.g., staphylococcal), mastitis, Clostridium difficile infection-associated diarrhea, and colitis. Infections that can be treated may be selected from skin and structural infections and bacteremia. Examples of skin and structural infections include cellulitis / erysipelas, large cutaneous abscesses, and wound infections. Such skin and structural infections may be caused by infection with Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes, Group B Streptococcus, Streptococcus dysgalactiae, Streptococcus anginosus (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), or Enterococcus faecalis. Examples of lower respiratory tract infections include pneumonia, community-acquired pneumonia (CAP), hospital-acquired pneumonia, and empyema.

[0099] Compound Synthesis The compounds of the present invention can be prepared according to reaction schemes A and B. Scheme A describes a general scheme that can be used, while scheme B outlines a method that can be used with the exemplary compounds. As will be recognized by those skilled in the art, scheme B can be readily adapted to provide further compounds in which substituents R1 and R2 are as defined in the present invention and in this disclosure. [ka] R1, R2, R3, R4, and L1 are the compounds of the present invention and as defined herein. [ka]

[0100] Assay The compounds of the present invention can be evaluated for their biological activity using any suitable assay known to those skilled in the art. Examples of assays useful for evaluating the compounds of the present invention are provided in the following paragraphs.

[0101] minimum inhibitory concentration The antibacterial activity of the compound was tested against a group of Gram-positive bacteria, including Staphylococcus aureus ATCC29213, Staphylococcus aureus USA300, Staphylococcus aureus LIM-2, NR-45881, Staphylococcus aureus HIP13419, NR-46413, Faecium faecium E155, Faecium faecium E7314, Faecium faecium E980, Enterococcus faecalis E1246, Enterococcus faecalis E7406, and Streptococcus pneumoniae 153. The antibacterial activity of the compounds was further tested against Staphylococcus aureus NY-155, NR-46236, Staphylococcus aureus HIP12864, NR-46074, Staphylococcus aureus 880 (BR-VRSA), NR-49120, Enterococcus faecalis E1246, Enterococcus faecalis E7604, and certain Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae). The minimum inhibitory concentration (MIC) (μg / mL) was determined according to CLSI guidelines. Bacterial strains were cultured from glycerol stocks on blood agar plates and incubated at 37°C for 18 hours. Single colonies were transferred to tryptic soy broth (TSB) containing 0.002% polysorbate 80 (p80). Enterococcus, VISA, and VRSA strains were incubated at 37°C until the optical density of the suspension reached a level equivalent to 0.5 McFarland standards. The bacterial suspension was then divided into 10 6 The bacteria were grown in 0.002% p80-containing TSB until a bacterial cell concentration of CFU / mL was reached. For other (vancomycin-susceptible) Staphylococcus aureus strains, the direct colony suspension method was used. For these strains, the colonies were transferred to 0.002% p80-containing TSB and then 10 6 Diluted immediately to CFU / mL and not incubated before this dilution. For Streptococcus pneumoniae, directly transferred the colony suspension to a fresh blood agar plate with multiple colonies at 0.5 OD. 600Immediately suspend in TSB+0.002%p80, then in TSB+0.002%p80+5% horse blood for 10 minutes. 6 CFU mL -1 It was used after dilution to the specified amount. Antibiotic dilutions for this strain were also performed with TSB + 0.002% p80 + 5% equine hemolytic solution. Both agar and microplates containing Streptococcus pneumoniae were incubated at 37°C with 5% CO2 for 24 hours with constant stirring (600 rpm). For VRSA strains, 6 μg mL was used. -1 Vancomycin was added to this culture medium. The culture was then subjected to a logarithmic phase (OD). 600 The bacteria were grown at 37°C until the concentration reached 0.5%). The bacterial suspension was diluted with 0.002% p80-containing TSB (for VRSA, vancomycin was not added to this medium from this point onward, and 10 6 CFU mL -1 The bacterial cell concentration was brought to the desired level. In a polypropylene 96-well microtiter plate, the test compound was added as a biological triplicate, and sequentially diluted 2-fold by transferring it from one well to the next and mixing, until a final volume of 50 μL per well was achieved. Equivalent volumes of bacterial suspension (10 6 CFU mL -1 The ) was added to the wells. The plate was sealed with a permeable membrane and incubated at 37°C for 24 hours with constant stirring (600 rpm). In a polypropylene microtiter plate, 100 μL of the test compound was added to the first row as a biological triplicate, and 50 μL of medium was added to the other wells. The compound was serially diluted by moving 50 μL from one well to the next and mixing. Subsequently, 50 μL of the bacterial suspension (10 6 CFU / mL was added to the wells. The plates were sealed with a permeable membrane and incubated at 37°C for 24 hours with constant agitation (600 rpm). Positive growth controls consisted of wells containing bacterial suspension but no antibiotics. Negative growth controls consisted of only bacterial suspension or antibiotic-free medium. MICs were determined from the median of the smallest triplicates. MICs in the presence of serum followed the same protocol, but TSB + 0.002% p80 + 50% serum was used as the growth medium.

[0102] hemolysis Four mL of defibrinated sheep blood was centrifuged at 400 g at 4°C for 15 minutes. The upper layer was discarded, and the lower layer was washed with phosphate-buffered saline (PBS) and centrifuged at 400 g at 4°C for 15 minutes. The washing cycle was repeated three times. Polypropylene microtiter plates were prepared by adding 150 μL of PBS containing 0.002% p80 of the compound (256 μg / mL, containing ≤1% DMSO) to the first row as a biological triplicate. 75 μL of PBS containing 0.002% p80 was added to all other wells. The compound was serially diluted by transferring 75 μL from one well to the next and mixing. Concentrated blood cells were diluted 25-fold with PBS containing 0.002% p80, and 75 μL of this solution was added to all wells. The final concentrations of the test compound in the plates ranged from 2 to 128 μg / mL. The plates were incubated at 37°C for 18 hours with continuous shaking (500 rpm). After incubation, the plates were centrifuged at 800 g for 5 minutes, and 25 μL of the supernatant was added to a UV-star flat-bottom polystyrene plate. 100 μL of MQ-H2O was added to all wells of the UV-star plate, and absorption was measured at 415 nm. The positive control well (100% hemolysis) consisted of 0.1% Triton X-100 containing blood cells. The negative control well (no hemolysis) consisted of 1% DMSO containing blood cells. In a separate experiment, the optimal wavelength for the hemolysis assay was determined by performing a full scan. In yet another experiment, the linear detection range was determined based on the 25-fold blood cell dilution selected in the main experiment.

[0103] UDP-MurNAc-pentapeptide accumulation Overnight cultures of bacterial suspensions (Staphylococcus aureus ATCC29213, Faecium faecium E155, Faecium faecium E7314, and Faecium faecium E980) were diluted 100-fold with 0.002% p80 supplemented TSB and incubated at 37°C until the optical density of the suspension reached a level equivalent to 0.5 McFarland standard. Chloramphenicol was added to a final concentration of 130 μg / mL, and the cultures were incubated for a further 15 minutes at 37°C. Next, the cultures were divided into 5 mL cultures, and test antibiotics (vancomycin, 5, 6, 7, 14, 16) were added to a final concentration of 5 μM. Vancomycin (5 μM) was used as a positive control, and the untreated samples were used as a negative control. The cultures were incubated at 37°C for 1 hour, and then centrifuged to pelletize the bacteria. The supernatant was removed, and the pellets were resuspended in 1 mL MQ-H2O. The sample was boiled at 100°C for 15 minutes, followed by centrifugation at 12000 rpm for 30 minutes. The supernatant was lyophilized and resuspended in 250 μL of buffer A (50 mM ammonium bicarbonate, 5 mM NEt3, pH 8.3). The sample was analyzed by analytical RP-HPLC using a 0–25% buffer B (MeOH) gradient over 25 minutes.

[0104] Lipid II antagonist assay Lipid II in chloroform was added to a 96-well plate in an appropriate amount (5-fold molar excess compared to the test antibiotics), and the chloroform was evaporated. The test antibiotics (vancomycin, teravancin, 5, 6, 7, 14, 16) were dissolved in DMSO at a high storage concentration of 12.8 mg / mL, and then diluted to a concentration of 16 × MIC in 0.002% p80-containing TSB (maximum DMSO content not exceeding 1%). 50 μL of these dilutions were mixed in triplicate with 5-fold molar excess pure lipid II in the plate, and triplicate was also added to the plate in the absence of lipid II. Staphylococcus aureus ATCC29123 colonies were suspended in 0.002% p80-containing TSB by direct colony suspension until the optical density reached a level equivalent to 0.5 McFarland standard. The bacterial suspension was diluted with 0.002% p80-containing TSB and 10 6CFU / mL was obtained, and 50 μL was added to the test compound in the microplate to obtain the final concentration of the test compound at 8×MIC. The samples were incubated at 37°C for 24 hours with constant stirring (600 rpm), and bacterial growth was visually observed. The positive growth control consisted of wells containing bacterial suspension but without antibiotics or lipid II. The negative growth control consisted only of culture medium without bacterial suspension, antibiotics, or lipid II.

[0105] Resistance Acquisition Serial Passaging Assay Bacterial strains were cultured from glycerol stocks on blood agar plates and incubated overnight at 37°C. Single colonies were analyzed using TSB+0.002% p80 in a logarithmic phase (OD). 600 The cultures were grown to a MIC of 0.5 and diluted 1:100 with fresh medium. In a 96-well polypropylene microtiter plate, the antibiotic was added as a biological triplicate, and sequentially diluted 2-fold by moving from one well to the next and mixing, until a final volume of 50 μL per well was achieved. Equal volumes of bacterial suspension were added to the wells, and the plates were incubated overnight at 37°C. Bacterial cultures corresponding to 0.25 × MIC were diluted 100-fold with fresh medium and added to a newly prepared antibiotic dilution series (50 μL / well), followed by overnight incubation at 37°C. This process was repeated for 30 days, and the MIC was recorded daily. 50 mg L of daptomycin was added to the daptomycin-containing culture. -1 CaCl2 and 10 mg L -1 MgSO4 was added. The experiment was performed using biological replicates, and for each replicate, the MIC was determined from the median of the smallest triplicate.

[0106] Time-kill assay Bacterial strains were cultured from glycerol stocks on blood agar plates and incubated overnight at 37°C. Subsequently, single colonies were cultured overnight at 37°C in TSB + 0.002% p80. The cultures were diluted 100-fold with fresh medium and subjected to the early logarithmic phase (OD). 600 Grow until it reaches (0.2-0.4), then in culture medium. 600The culture was diluted to 0.0025. The culture was divided into separate culture tubes containing 2 mL. Antibiotics were added to the culture (at the concentrations shown in the experimental results) and incubated at 37°C for a total of 24 hours. At the indicated time points (t=0, t=1, t=2, t=4, t=8 and t=24 hours), 100 μL of each culture was transferred to an Eppendorf container and centrifuged for 5 minutes (10,000 rpm). The supernatant was removed and the cell pellet was resuspended in an equal volume of 0.9% NaCl aqueous solution (filter-sterilized). The samples were sequentially diluted 10-fold with filter-sterilized 0.9% NaCl aqueous solution. These series of dilutions, 100-fold, 1,000-fold, 10,000-fold and 100,000-fold, were seeded onto blood agar plates (20 μL) in duplicate, followed by evaporation and incubation at 37°C for 24 hours. The colonies were counted, and considering the dilution factor, the amount of CFU remaining in the original medium was calculated as mL. -1 This was used to calculate [the value]. The experiment was conducted using biological duplicates.

[0107] HepG2 cytotoxicity assay Mammalian cytotoxicity assays were performed using Cyprotex. Cytotoxicity was evaluated using the MTT assay. Briefly, HepG2 human hepatocellular carcinoma cells (100 μL / well) were seeded in 96-well polystyrene tissue cultures with black walls and clear bottoms that had been treated for 24 hours prior to cell administration. The test compound (dissolved in 0.5% DMSO in 10% FBS-containing growth medium) was added to the cells at a range of concentrations (0.04 μM, 0.1 μM, 0.4 μM, 1 μM, 4 μM, 10 μM, 40 μM, 100 μM). After 23 hours, the cells were loaded with the MTT dye (yellow; 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) and subsequently incubated for another hour (total incubation time with antibiotics was 24 hours). Next, the plates are dried, dissolved in DMSO, and then scanned at 570 nm using a microplate absorbance reader. Cell viability is determined by the conversion of soluble MTT to insoluble formazan (purple) by mitochondrial hydrogenase in viable cells. Formazan indicates loss of mitochondrial function and cell loss. Carbonyl cyanide 3-chlorophenylhydrazone is used as no response control, and chlorpromazine is used as a control known to be cytotoxic. Then, the significance limit is determined for wells with fractions exceeding the prediction for low or high responders using a solvent control well (0.5% DMSO in growth medium containing 10% FBS). The minimum effective concentration is determined from the lowest concentration where the mean is above the significance level, as long as a clear dose-response correlation is observed or at least two consecutive concentration points are above the significance level. 50 The value was determined. The experiment was conducted using triplicates.

[0108] In vivo testing The mouse study was conducted using pathogen-free CD1 mice (ICR), a well-characterized, non-inbred mouse strain (provided by Charles River, Margate, UK). All mice were male, weighed 11–15 grams upon arrival, and were acclimatized for at least 7 days prior to the start of the study. Mice were housed individually in sterile, ventilated cages with HEPA-filtered sterile air and aspen chip bedding (changed at least once a week). Food and water were provided ad libitum. Room temperature was 22°C ± 1°C, with 60% relative humidity and a maximum background noise of 56 dB. Mice were exposed to a 12-hour light / dark cycle.

[0109] Tolerance The tolerability of compound 5 was assessed in immunosuppressed or non-infected naive mice (n=2) at a dose of 100 mg / kg. -1 Evaluation was performed by subcutaneous injection (10% DMSO in sterile water for injection).

[0110] PK Test sample 5 was administered at a dose of 3 mg / kg to immunosuppressed or uninfected naive mice (n=3). -1 The drug was administered subcutaneously. Whole blood was collected from microvenules at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours. The final sample was collected by final cardiac puncture.

[0111] Effectiveness Mice were given 150 mg kg four days and one day before infection, respectively. -1 and 100 mg kg -1 Neutropenia was induced by subcutaneous injection of cyclophosphamide. Mice were given MRSA USA300 strain NRS384 (1.47 × 10¹⁴) in both thighs under temporary anesthesia. 6 CFU mL -1 , 7.33×10 4 CFU (Cellular Fibre Units / femoral tissue) was induced intramuscularly in mice. Starting 1 hour after infection, mice were given 25 mg / kg of the medium (10% DMSO in water for injection) every 6 hours. -1 Vancomycin (injectable water) 3 mg / kg every 12 hours -1 or 10 mg kg -1The mice were treated with compound 5 (in 10% DMSO in water for injection) every 6 hours. The pre-treatment group was sacrificed 1 hour after infection, and the other treatment groups were sacrificed 23 hours after infection. The weighted thighs were homogenized and cultured on MSA agar at 37°C for 18-24 hours, followed by colony counting. Each group consisted of n=6 mice, with both thighs infected (n=12 thighs / treatment group), and each thigh treated as a separate sample. Data analysis was performed using StatsDirect software v. 3.2.8 with a nonparametric statistical model (Kruskal-Wallis using Conover-Inman for all-pair comparisons between groups). [Examples]

[0112] Thin-layer chromatography (TLC) was performed on SiliaPlate TLC plates (SiliCycle, glass back, silica, 250 μm). Visualization was performed using UV light, ninhydrin staining, permanganate staining, or cerium ammonium molybdate staining. Silica gel column chromatography was performed on SiliaFlash® P60 silica gel (SiliCycle). The final compound was subjected to preparative reverse-phase high-performance liquid chromatography (RP-HPLC) using a Reprosil Gold 120 C18 10 μm column (length: 250 mm, ID: 25 mm; Lot No: 8768; part No: r10.9g.s2525; Serial No: 18020211570; Dr Maisch GmbH), a BESTA pump, a FLASH 10 DAD UV detector, and SCPA PrepCon 5 software. Analytical HPLC was performed to evaluate the purity of the compounds using a Phemomenex Jupiter su C18 300A column (250 × 4, 60 mm, 5 micron) on a Shimadzu LC-2030 Plus instrument. The full spectrum, representing purity, was recorded at 214 nm. The buffers used in preparative and analytical HPLC were 50 mM ammonium acetate as buffer A and 95% MeCN + 5% H2O as buffer B in all cases, except for the uridine diphosphate N-acetylmuramic acid pentapeptide (UDP-MurNAc-pp) accumulation assay. In that assay, the analysis was performed using a Phemomenex Jupiter su C18 300A column (250 × 4, 60 mm, 5 micron) on a Shimadzu LC-2030 Plus instrument. The buffers were 50 mM ammonium bicarbonate, 5 mM NEt3, pH 8.3 as buffer A and MeOH as buffer B, and the data shown was recorded at 254 nm. Samples were lyophilized on an Omnitronics VirTis BenchTop Pro. Nuclear magnetic resonance (NMR) spectra were recorded at high resolution and 5 mm using a 5 mm BBO, Broadband Observe probe head, and Z-gradient. 19 F / 1The samples were obtained from a Bruker DPX-300 superconducting electromagnet with a field intensity of 7.0 Tesla, equipped with a dual H high-resolution probe. High-resolution mass spectrometry (HR-MS) analysis was performed at 35°C using a Thermo Scientific Dionex UltiMate 3000 HPLC system with a Phenomenex Kinetex C18 column (2.1 × 150 mm, 2.6 μm) and a diode array detector. The following solvent systems were used at a flow rate of 0.3 mL / min: Solvent A, 0.1% formic acid aqueous solution; Solvent B, 0.1% formic acid in acetonitrile solution. The gradient elution was as follows: 95:5 (A / B) for 1 minute, 95:5 to 5:95 (A / B) for 9 minutes, 5:95 to 2:98 (A / B) for 1 minute, 2:98 (A / B) for 1 minute, then back to 95:5 (A / B) for 2 minutes, and finally 95:5 (A / B) for 1 minute. This system was connected to a Bruker micrOTOF-Q II spectrometer (electrospray ionization) internally calibrated with sodium formate. A Tecan Spark was used for absorbance measurement.

[0113] The bacterial strains used were Staphylococcus aureus ATCC 29213 (MSSA, Rosenbach strain), Staphylococcus aureus USA300 (MRSA, hospitalized patient, Texas, USA. PFGE type: USA300. SCCmec type Iva), Faecium faecium E155 (VRE, hospitalized patient, Chicago, USA, VanAgene, MIC vancomycin 1024, 1995), Faecium faecium E980 (VSE, commonly isolated in humans (commercially available), VanA of VanBgene, 1998), Faecium faecium E7314 (VRE, hospitalized patient, NLD, VanBgene), Enterococcus faecalis E1246 (VRE, VanAgene, clinically isolated), and Enterococcus faecalis E7406 (VRE, VanBgene, clinically isolated).

[0114] Example 1: Synthesis of Compound 1: O-allyl carbon isothiocyanate [ka] Compound 1 was synthesized according to a published literature method (Martin, NI, Woodward, JJ & Marletta, MA NG-Hydroxyguanidines from Primary Amines. Org. Lett. 8, 4035-4038 (2006)). Briefly, potassium thiocyanate (9 g, 92 mmol, 1.3 equivalents) was dissolved in CCl4 (200 mL) and 18-crown-6 (924 mg, 3.5 mmol, 0.05 equivalents) and allyl chloroformate (7.4 mL, 70 mmol, 1 equivalent) were added. The reaction mixture was refluxed at 90°C for 18 hours. After incubation, the reaction mixture was diluted with PE (200 mL) and stirred on ice for 1 hour. Subsequently, the mixture was filtered through Celite and washed with DCM. The filtrate was concentrated under reduced pressure, redissolved in DCM to an estimated concentration of 0.5 M, and stored at 4°C until use. Product 1 was used in its crude form in the next reaction.

[0115] Example 2: Synthesis of Compound 2: 4-(1,3-dioxolan-2-yl)aniline [ka] Compound 2 was synthesized by modifying a method described in the literature (Hughes, A. et al. Diamide compounds having muscarinic receptor antagonist and β2 andrenergic receptor agonist activity (2010)). To a solution of 2-(4-nitrophenyl)-1,3-dioxolane (9.8 g, 50 mmol, 1 equivalent) and NaHCO3 (4.3 g, 50 mmol, 1 equivalent) in EtOH (350 mL), platinum(iv) oxide monohydrate (1.2 g, 5 mmol, 0.1 equivalent) was added under a nitrogen atmosphere. The reaction mixture was covered with hydrogen for 15 minutes, and then stirred at RT under a hydrogen atmosphere for 18 hours. Next, the solution was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain compound 2, which was immediately used crudely in the next step.

[0116] Example 3: Synthesis of Compound 3 [ka] To a solution of crude 2 (50 mmol, 1 equivalent) and DIPEA (8.7 mL, 50 mmol, 1 equivalent) in DCM (50 mL), 1 was added by RT until TLC (in DCM containing 5% siRNA) showed complete conversion from 2 to 3. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (DCM and siRNA with increasing gradient up to 5%). Yield of the two-step process: 77%. 1 H-NMR (300 MHz, CDCl3) δ / ppm: 11.47 (s, 1H), 8.42 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.5, 2H), 6.00 - 5.85 (m, 1H), 5.83 (s, 1H), 5.39 (dd, J=17.2, 1.4 Hz, 1H), 5.33 (dd, J=10.4, 1.2 Hz, 1H), 4.70 (dt, J=5.8, 1.3 Hz, 2H), 4.18 - 3.98 (m, 4H). 13 ¹³C-NMR (75 MHz, CDCl₃) δ / ppm: 177.75, 152.65, 138.30, 136.59, 130.84, 127.15, 124.10, 119.86, 103.25, 67.37, 65.40. HR-MS: m / z 309.0913 (measured value), 309.0909 (calculated for [M+H+]).

[0117] Example 4: Synthesis of trans,trans-farnesyl bromide: (E)-1-bromo-3,7-dimethylocta-2,6-diene [ka] (E)-1-bromo-3,7-dimethylocta-2,6-diene was synthesized by modifying the literature method (Zahn, TJ et al. Evaluation of Isoprenoid Conformation in Solution and in the Active Site of Protein-Farnesyl Transferase Using Carbon-13 Labeling in Conjunction with Solution- and Solid-State NMR. J. Am. Chem. Soc. 122, 7153-7164 (2000); Xie, H., Shao, Y., Becker, JM, Naider, F. & Gibbs, RA Synthesis and Biological Evaluation of the Geometric Farnesylated Analogues of the α-Factor Mating Peptide of Saccharomyces cerevisiae. J. Org. Chem. 65, 8552-8563 (2000)). In short, triphenylphosphine (4 mL, 18 mmol, 1 equivalent) and tetrabromomethane (7.4 g, 22.5 mmol, 1.25 equivalents) were added to a DCM solution of trans,trans-farnesol (4.5 mL, 18 mmol, 1 equivalent) under an argon atmosphere. The reaction mixture was stirred at RT for 4 hours. After removing the solvent under reduced pressure, hexane (15 mL) was added to the residue to precipitate the product. The mixture was centrifuged (4500 rpm, 5 min), and the supernatant was concentrated under reduced pressure. Three further precipitation-centrifugation-evaporation cycles were performed to obtain crude trans,trans-farnesyl bromide, which was then used directly in the next step.

[0118] Example 5: Synthesis of trans-geranylamine and trans,trans-farnesylamine: (E)-3,7-dimethylocta-2,6-dien-1-amine and (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-amine [ka] (E)-3,7-dimethylocta-2,6-diene-1-amine and (2E,6E)-3,7,11-trimethyldodeca-2,6,10-triene-1-amine were synthesized by modifying the literature method (Koopmans, T. et al. Semisynthetic Lipopeptides Derived from Nisin Display Antibacterial Activity and Lipid II Binding on Par with That of the Parent Compound. J. Am. Chem. Soc. 137, 9382-9389 (2015); Coppola, GM & Prashad, M. A Convenient Preparation of Farnesylamine. Synth. Commun. 23, 535-541 (1993)). In short, 10 mL of lithium bis(trimethylsilyl)amide (1 M in THF) was mixed with either pure trans-geranyl bromide or crude trans,trans-farnesyl bromide (1 equivalent) under an argon atmosphere. The reaction mixture was stirred at RT for 18 hours, followed by termination with saturated ammonium chloride solution. The mixture was extracted twice with methyl t-butyl ether, the organic phases were combined, and the mixture was dried over Na2SO4. After filtration, the solvent was removed under reduced pressure to obtain 2×TMSamine. This product was dissolved in 40 mL of MeOH and 5 mL of DCM and stirred at RT for 18 hours. The solvent was removed under reduced pressure to obtain crude trans-geranylamine or trans,trans-farnesylamine, which was used directly in the next step.

[0119] Example 6: Synthesis of chlorobisphenylamine: 4'-chloro-[1,1'-biphenyl]-4-yl)methaneamine [ka] 4'-chloro-[1,1'-biphenyl]-4-yl)methaneamine was prepared according to a method described in published literature (Lee, H. et al. (Biphenyl-4-yl)methylammonium Chlorides: Potent Anticonvulsants That Modulate Na+ Currents. J. Med. Chem. 56, 5931-5939 (2013)). 4-bromobenzylamine (4.32 g, 23 mmol, 1 equivalent) was dissolved in MeCN (250 mL) and 4-chlorophenylboronic acid (4 g, 26 mmol, 1.1 equivalents), Pd(PPh3)4 (1.36 g, 1.16 mmol, 0.05 mmol), and 2 M aqueous K2CO3 (58 mL) were added under argon. After argon was sprayed over the solution for 30 minutes, the reaction mixture was stirred under reflux at 90°C for 16 hours. The solvent was removed under reduced pressure. The obtained residue was dissolved in HCl (100 mL) and washed with water (2 × 100 mL) and brine (2 × 100 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was redissolved in HCl, and concentrated aqueous solution (2 mL) was added to precipitate it. H₂O was added to HCl, and the layers were separated. The pH of the aqueous layer was adjusted with 4N NaOH, and it was extracted with DCM (2 ×). The DCM layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained residue, redissolved in DCM, was precipitated by adding 4N HCl in dioxane. The precipitate was filtered and washed with hexane to obtain 4'-chloro-[1,1'-biphenyl]-4-yl)methaneamine as the final product, which was used crudely in the next reaction step.

[0120] Example 7: Synthesis of 4a [ka] To a solution of DCM (1.80 g, 5.8 mmol, 1 equivalent), hexylamine (1.5 mL, 11.7 mmol, 2 equivalents) and NEt3 (1.6 mL, 11.7 mmol, 2 equivalents) were added. Subsequently, EDC HCl (2.2 g, 11.7 mmol, 2 equivalents) was added, and the reaction mixture was stirred under RT. After 2 hours, the reaction was complete, and the solution was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM + 5% Â). Yield: 100%. 1 H-NMR (300 MHz, CDCl3) δ / ppm: 10.70 (s, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.22 (d, J=6.8 Hz, 2H), 6.13 - 5.91 (m, 1H), 5.78 (s, 1H), 5.34 (d, J=17.3 Hz, 1H), 5.21 (d, J=10.4 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H), 4.21 - 3.99 (m, 4H), 3.43 - 3.29 (m, 2H), 1.57-1.38 (m, 2H), 1.36-1.16 (m, 6H), 0.94 - 0.78 (m, 3H). 13 ¹³C-NMR (75 MHz, CDCl₃) δ / ppm: 164.21, 158.64, 137.02, 136.61, 133.67, 128.33, 117.42, 103.14, 66.02, 65.48, 41.37, 31.45, 29.40, 26.51, 22.54, 14.02. HR-MS: m / z 376.2242 (measured value), 376.2236 (calculated for [M+H+])

[0121] Example 8: Synthesis of 5a to 16a Compounds 5a to 16a were synthesized and purified according to the protocol described in 4a, using the corresponding lipid amines, with the exception of 16a, which yielded a product mixture of 16a and 16b after the reaction. 16a and 16b were combined and used crudely in the next step. The results for these compounds are summarized in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0122] Example 9: Synthesis of 17a and 18a Compounds 17a and 18a were synthesized and purified using the corresponding lipid amines according to the protocol described in 4a. The results for these compounds are summarized in Table 2. [Table 2]

[0123] Example 10: Synthesis of 4b [ka] To a THF solution of 4a (2.19 g, 5.8 mmol, 1 equivalent), 1 M aqueous HCl (11.7 mmol, 2 equivalents) was added, and the reaction mixture was stirred under RT for 1 hour. The reaction was stopped with saturated NaHCO3, and the product was extracted twice by DCM. The organic layers were combined, dried over Na2SO4, and filtered. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (2 / 1 PE / siRNA). Yield: 100%. 1 H-NMR (300 MHz, CDCl3) δ / ppm: 9.86 (s, 1H), 7.82 (d, J=7.9 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 6.07 - 5.86 (m, 1H), 5.33 (dd, J=17.2, 1.4 Hz, 1H), 5.23 (dd, J=10.4, 1.3 Hz, 1H), 4.61 (d, J=5.7 Hz, 2H), 3.47 - 3.30 (m, 2H), 1.67 - 1.52 (m, 2H), 1.43 - 1.22 (m, 6H), 0.94 - 0.82 (m, 3H). 13 ¹³C-NMR (75 MHz, CDCl₃) δ / ppm: 190.84, 132.51, 131.41, 123.21, 118.14, 66.27, 41.51, 31.35, 29.08, 26.50, 22.45, 13.94. HR-MS: m / z 332.1980 (measured value), 332.1974 (calculated for [M+H+]).

[0124] Example 11: Synthesis of 5b-16b Compounds 5b–16b were synthesized and purified using their corresponding precursors (5a–16a) according to the protocol described in 4b. The results for these compounds are summarized in Table 3. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0125] Example 12: Synthesis of 17b and 18b Compounds 17b and 18a were synthesized and purified using their corresponding precursors (17a and 18a) according to the protocol described in 4b. The results for these compounds are summarized in Table 4. [Table 4]

[0126] Example 13: Synthesis of 4c [ka] To a 4 mL solution of 4b (178 mg, 538 μmol, 2 equivalents) in DMF / MeOH, vancomycin hydrochloride (400 mg, 269 μmol, 1 equivalent) and DIPEA (0.23 mL, 1.35 mmol, 5 equivalents) were added. The reaction mixture was stirred under reflux at 70°C for 2 hours, then NaBH3CN (169 mg, 2.69 mmol, 10 equivalents) was added and the reaction temperature was lowered to 50°C. After 5 hours, another 10 equivalents of NaBH3CN (169 mg, 2.69 mmol) were added, and after 18 hours, 10 equivalents of NaBH3CN (169 mg, 2.69 mmol) and 1 equivalent of 4b (89 mg, 269 μmol) were added. After another 18 hours, the reaction mixture was stopped by adding water. The solvent was evaporated under reduced pressure, the residue was redissolved in DMF, and precipitated twice with cold diethyl ether. The precipitate was dried and used as a crude product in the next step.

[0127] Example 14: Synthesis of 5c~16c Compounds 5c to 16c were synthesized using their corresponding aldehyde precursors (5b to 16b) according to the protocol for 4c described above. All compounds 5c to 16c were used crudely in the subsequent reaction step.

[0128] Example 15: Synthesis of 17c and 18c Compounds 17c and 18c were synthesized using their corresponding aldehyde precursors (17b and 18b) according to the protocol described in 4c. Compounds 17c and 18c were all used crudely in the subsequent reaction step.

[0129] Example 16: Synthesis of 4 [ka] To a solution of crude 4c (269 μmol, 1 equivalent) in dried DMF (5 mL), Pd(PPh3)4 (78 mg, 67 μmol, 0.25 equivalents) and phenylsilane (0.83 mL, 6.7 mmol, 25 equivalents) were added under an argon atmosphere. The reaction mixture was stirred under an argon atmosphere at RT for 1 hour. After deprotection was complete, the reaction was stopped with water and the solvent was evaporated under reduced pressure. The residue was redissolved in a mixture of buffer A (50 mM ammonium acetate) and 20% buffer B (95% MeCN, 5% water), and the mixture was centrifuged to remove all solid residue. The supernatant was subjected to preparative RP-HPLC, and the product was purified using a 20–55% buffer B gradient over 50 minutes. The purity of the fraction was evaluated by analytical RP-HPLC using a 0–100% buffer B gradient over 30 minutes. The pure fraction was collected and lyophilized to obtain a white powder. The purity of the final stored compound was evaluated by analytical RP-HPLC using a 0-100% buffer B gradient over 60 minutes. Yield over two steps: 54.4%. HR-MS: m / z 840.3100 (measured), 840.3097 ([M+2H + (Calculated for ] / 2). Retention time RP-HPLC analysis: 20.37 minutes.

[0130] Example 17: Synthesis of 5-16 Compounds 5–16 were synthesized using their corresponding precursors (5c–16c) according to the protocol described in section 4. The preparative RP-HPLC purification buffer gradient was adjusted for each compound based on the hydrophobicity of the R group present. Furthermore, the percentage of buffer B present in the initial solvent system during preparative RP-HPLC (from 20% to 50%) was similarly adjusted based on the hydrophobicity of the R group. The results for these compounds are shown in Table 5. [Table 5]

[0131] Example 18: Synthesis of 17 and 18 Compounds 17 and 18 were synthesized using their corresponding precursors (17c and 18c) according to the protocol described in 4. The preparative RP-HPLC purification buffer gradient was adjusted for each compound based on the hydrophobicity of the R group present. Furthermore, the percentage of buffer B present in the initial solvent system in preparative RP-HPLC (from 20% to 50%) was similarly adjusted based on the hydrophobicity of the R group. The results for these compounds are shown in Table 6. [Table 6]

[0132] Example 19: Minimum Inhibitory Concentration Assay The activity of the compounds was evaluated against a population of Gram-positive bacteria using MIC assays. In this assay, the minimum inhibitory concentration (MDI), which represents the lowest test concentration at which visible bacterial growth is inhibited, was determined and compared to clinically used antibiotics. Compared to clinically used glycopeptides, almost all compounds exhibited equivalent or superior activity against most of the MRSA, MSSA, VRE, VSE, VISA, VRSA, and Streptococcus pneumoniae strains tested. In some cases (depending on the compound and bacteria tested), there was a 1000-fold increase in activity compared to vancomycin (the obtained data are summarized in Table 7, with MIC values ​​shown in μg / mL). Further MIC data are provided in Tables 8-12. [Table 7] [Table 8] [Table 9] [Table 10-1] [Table 10-2] [Table 11] [Table 12]

[0133] The activity of the compound, In the presence of sheep serum, against 300 strains of MRSA USA, Further evaluation was performed using other MIC assays. Unlike the standard MIC assay, which uses TSB + 0.002% P80 + 50% sheep serum as the growth medium, cultures grown in the presence of serum were used. [Table 13]

[0134] Example 20: Compound testing in hemolysis assay In hemolysis assays, sheep blood was treated with the test compound for 18 hours to determine whether the compound lysed these blood cells. Overall, it appeared that the percentage of hemolysis increased similarly with increasing lipid length. However, even at a 1000x MIC (for some strains), many compounds did not exhibit hemolytic activity, meaning these compounds are non-hemolytic at the relevant concentrations (the obtained data are summarized in Figure 1).

[0135] Example 21: Testing of compounds in UDP-MurNAc-pentapeptide accumulation assay A UDP-MurNAc-pentapeptide accumulation assay was performed to elucidate part of the mechanism of action of the compounds. UDP-MurNAc-pentapeptide is the final soluble precursor in peptidoglycan cell wall biosynthesis. In this assay, viable cells accumulate this final soluble precursor when treated with compounds that interfere with the membrane-binding step of peptidoglycan biosynthesis (Sass, V. et al. Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci. Infect. Immun. 78, 2793-2800 (2010)). Five compounds (5, 6, 7, 14, 16) were assayed in this test, and all showed accumulation of UDP-MurNAc-pentapeptide (data obtained are summarized in Figure 2), similar to glycopeptides used clinically (data not shown). This indicates that part of the molecular mechanism of action involves interference with cell wall biosynthesis in Gram-positive bacteria. The assay was performed using Staphylococcus aureus ATCC29213 (shown in Figure 2), Faecium faecium E155, Faecium faecium E7314, and Faecium faecium E980. Accumulation of UDP-MurNAc-pentapeptide was visible in all of these strains for all test compounds (data not shown).

[0136] Example 22: Compound testing in lipid II antagonist assay Lipid II is a known target of vancomycin and other glycopeptides (Ling, LL et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455 (2015); Breukink, E. & de Kruijff, B. Lipid II as a target for antibiotics. Nat. Rev. Drug Discov. 5, 321-323 (2006)). In the antagonism assay, Lipid II is co-incubated with the test antibiotic in the presence of a bacterial culture. When Lipid II binds to glycopeptides, the binding of these antibiotics to their targets in the growing bacterial culture is antagonized. The final result is a decrease in antibiotic activity and the visualization of bacterial growth that is not normally observed (at 8×MIC). Therefore, this assay is used to determine whether part of the mechanism of action of this compound involves binding to Lipid II. Bacterial growth was observed after co-incubation with lipid II for all five test compounds (5, 6, 7, 14, 16), indicating that binding of the compounds to lipid II is part of the mechanism of action, similar to other clinically used glycopeptide antibiotics (the obtained data are summarized in Table 11). [Table 14]

[0137] Example 23: Testing of compounds in a resistance acquisition serial passaging assay. The resistance acquisition serial passage assay was performed as described in the "Assay" section. The results obtained from this assay are shown in Figure 3. Clearly, when MRSA was serially passaged for 30 days in the presence of sublethal antibiotic concentrations, compounds 5 and 16 did not induce resistance, while daptomycin, which is used clinically, induced a significant level of resistance 16 times the MIC. This difference was even more pronounced in VanA-type VRE strains: low levels of resistance induction were observed with compounds 5 and 16, whereas daptomycin induced a high level of resistance 128 times the MIC.

[0138] Example 24: Compound testing in a time-kill assay The time-kill assay was performed as described in the "Assassination" section. The results obtained from this assay are shown in Figure 4.

[0139] Example 25: Mammalian Cytotoxicity Assay The mammalian cytotoxicity assay was performed as described in the "Assay" section. The results of this assay are shown in Table 12. [Table 15]

[0140] Example 26: In vivo study Several in vivo studies were conducted as described here in the "Assays" section. In particular, the tolerability, pharmacokinetics (PK), and efficacy of the compounds were evaluated.

[0141] Tolerance Two mice were well-tolerated after being administered compound 5 at a dose of 100 mg / kg (SC). No adverse effects were observed, and normal macroscopic morphology was observed.

[0142] PK Compound 5 was administered to mice at a dose of 3 mg / kg. -1 The drug was administered subcutaneously, followed by continuous sampling. Data are mean ± SD (n=3). The obtained PK data are shown in Figure 5 and Table 13. [Table 16]

[0143] Effectiveness Colony-forming units in neutropenic mice were obtained by infecting each thigh with MRSA, administering the antibiotic subcutaneously at the indicated concentration 1 hour later, followed by administration at the same dose at the indicated intervals. The mice were sacrificed 23 hours after treatment (24 hours after infection), and bacterial load was determined in the homogenized thighs. (Various media and 25 mg / kg) -1 Vancomycin (Q12H) and media and 3 mg kg -1 and 10 mg kg -1 A significant difference was observed in compound 5(q6h) of both compounds (overall p<0.0001). 25 mg kg -1 Vancomycin and 10 mg kg -1 A similar significant difference was observed with compound 5 (p<0.0001), while with 25 mg kg -1 Vancomycin and 3 mg kg -1 No significant difference was observed in compound 5. Significant differences were observed in two different compound 5 doses (p=0.0001). Vancomycin (25 mg kg -1 ) and compound 5 (3 mg kg -1 and 10 mg kg -1 The treatment also showed a significant reduction in thigh load compared to before treatment (p=0.0042, p=0.0001, and p<0.0001, respectively). Data are mean ± SEM (n=12, 6 mice / group, 2 thighs / mouse). The data obtained from this efficacy study are shown in Figure 6. [Table 17]

[0144] colony [Table 18]

Claims

1. formula: 【Chemistry 1】 [During the ceremony, R ６ , ６ , ６ , ２ , １ is a substituted or unsubstituted -C ４ -C ２０ cycloalkyl, substituted or unsubstituted C １ -C ４ alkyl-C ４ -C ２０ cycloalkyl, substituted or unsubstituted -C ４ -C ２０ alkyl, substituted or unsubstituted -C ４ -C ２０ alkenyl, and substituted or unsubstituted -C １ -C ４ alkylaryl, wherein when substituted, any of the above groups is -CN, -N(C １ -C ４ alkyl) ２ , =O, -halo, -C １ -C ６ alkyl, -C ２ -C ６ alkenyl, -C １ -C ６ haloalkyl, -C １ -C ６ haloalkoxy, and -C ２ -C ６ substituted with one or more substituents selected from haloalkenyl; R ２ -H, substituted or unsubstituted -C ４ -C ２０ Alkyl, and substituted or unsubstituted C ４ -C ２０ Selected from alkenyls, where, if substituted, any of the above groups is -CN, -N(C １ -C ４ Alkyl) ２ , = O, - Halo, - C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C １ -C ６ Haloalkyl, -C １ -C ６ Haloalkoxy and -C ２ -C ６ Substituted with one or more substituents selected from haloalkenyls; R ３ is selected from -OH, substituted or unsubstituted -C １ -C ２０ alkyl, substituted or unsubstituted -C ２ -C ２０ alkenyl, substituted or unsubstituted -C １ -C ４ alkylaryl, and -(NHCH ２ CH ２ ) ｘ -Glc, -(NHCH ２ CH ２ ) ｘ -Gal, -(NHCH ２ CH ２ ) ｘ -Man, -(NHCH ２ CH ２ )[[ID=3�]] ｘ -GlcNAc, -(NHCH ２ CH ２ ) ｘ -MurNAc, -(NHCH ２ CH ２ ) ｘ -ManNAc, -(NHCH ２ CH ２ ) ｘ -GalNAc, -(NHCH ２ CH ２ ) ｘ -cellobiose and -(NHCH ２ CH ２ ) ｘ -maltose, and x is 0 or 1, where when substituted, any of the above groups is -OH, -CN, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ４ alkyl) ２ , =O, -halo, -C １ -C ６ alkyl, -C ２ -C ６ alkenyl, -C １ -C ６ haloalkyl, -C １ -C ６ haloalkoxy, -C ２ -C ６ Haloalkenyls and -C １ -C ６ Substituted with one or more substituents selected from alkylcarboxylic acids, or R3 is -OH, -NHCH2CH2CH2N(CH3)2 【Chemistry 2】 , selected from -(NHCH2CH2)x -Glc, -(NHCH2CH2)x -Gal, -(NHCH2CH2)x -Man, -(NHCH2CH2)x -GlcNAc, -(NHCH2CH2)x -MurNAc, -(NHCH2CH2)x -ManNAc, -(NHCH2CH2)x -GalNAc, -(NHCH2CH2)x -cellobiose and -(NHCH2CH2)x -maltose (where x is 0 or 1); R ４ is -H, substituted or unsubstituted -C １ -C ２０ alkyl, substituted or unsubstituted -C ２ -C ２０ alkenyl, substituted or unsubstituted -C １ -C ４ alkylaryl, and -(NHCH ２ CH ２ ) ｘ -Glc, -(NHCH ２ CH ２ ) ｘ -Gal, -(NHCH ２ CH ２ ) ｘ -Man, -(NHCH ２ CH ２ ) ｘ -GlcNAc, -(NHCH ２ CH ２ ) ｘ -MurNAc, -(NHCH ２ CH ２ ) ｘ -ManNAc, -(NHCH ２ CH ２ ) ｘ -GalNAc, -(NHCH ２ CH ２ ) ｘ -cellobiose and -(NHCH ２ CH ２ ) ｘ -maltose, selected from carbohydrates selected from, x is 0 or 1, where, when substituted, any of the above groups is -OH, -CN, -NH ２ , -NH(C １ -C ６ alkyl), -N(C<l １ -C ４ alkyl) ２ , =O, -halo, -C １ -C ６ alkyl, -C ２ -C ６ alkenyl, -C １ -C ６ haloalkyl, -C １ -C ６ haloalkoxy, -C ２ -C ６ Haloalkenyls and -C １ -C ６ [Substituted with one or more substituents selected from an alkylcarboxylic acid], or R 4 is -H, -CH2NHCH2P(O)(OH)2, -CH2N(CH2PO3H2)2, -CH2NHCH2CH2CH2N(CH3)2, -CH2NHCH2CH2COOH, -CH2N(CH3)CH2(CH(OH))4CH2OH, -CH2NHCH(COOH)CH2COOH, -CH2NH(CH2CH2OH)2, -(NHCH2CH2)y-Glc, -(NHCH2CH2)y-Gal, -(NHCH2CH2)y - Man, - (NHCH 2 CH 2) y - GlcNAc, - (NHCH 2 CH 2) y - MurNAc, - (NHCH 2 CH 2) y - ManNAc, - (NHCH 2 CH 2) y - GalNAc, - (NHCH 2 CH 2) y - Cellobiose and - (NHCH 2 CH 2) y - Maltose (where y is 0 or 1) are selected. A compound represented by or a pharmaceutically acceptable salt or solvate thereof.

2. R １ ga-C ４ -C ２０ Alkyl, -C ４ -C ２０ Alkenyl and substituted or unsubstituted C １ -C ４ A compound according to claim 1, selected from alkylaryl compounds.

3. R １ ga-C ６ -C １４ Alkyl, -C ６ -C １６ Alkenyl and substituted or unsubstituted C １ -C ４ A compound according to claim 1 or 2, selected from alkylbisphenyls.

4. R １ However, -C ６ -C １４ Alkyl, -C １ -C ４ A compound according to claim 1, selected from adamantyl, -adamantyl, -geranyl, -farnesyl, and -chlorobisphenyl.

5. R １ However, -C ６ -C １２ The compound according to claim 4, selected from alkyl, -geranyl, -farnesyl, and -chlorobisphenyl.

6. R １ but 【Transformation 3】 A compound according to claim 1, selected from the following.

7. R ２ -H, -C ４ -C １２ Alkyl and -C ４ -C １２ A compound according to any one of claims 1 to 6, selected from alkenyls.

8. R ２ The compound according to any one of claims 1 to 7, wherein is -H.

9. R １ and R ２ Each of these independently can be substituted or not substituted - C ４ -C １０ Alkyl, and substituted or unsubstituted C ４ -C １０ A compound according to claim 1, selected from alkenyls.

10. R ３ -OH, substituted or unsubstituted -C １ -C １０ Alkyl, substituted, or unsubstituted C ２ -C １０ Alkenyl, substituted or unsubstituted - C １ -C ４ Alkylaryl, and -(NHCH ２ CH ２ ) ｘ -Glc, -(NHCH ２ CH ２ ) ｘ -Gal, -(NHCH ２ CH ２ ) ｘ -Man, -(NHCH ２ CH ２ ) ｘ -GlcNAc, -(NHCH ２ CH ２ ) ｘ -MurNAc, -(NHCH ２ CH ２ ) ｘ -ManNAc, -(NHCH ２ CH ２ ) ｘ -GalNAc, -(NHCH ２ CH ２ ) ｘ - Cellobiose and - (NHCH ２ CH ２ ) ｘ - A compound according to any one of claims 1 to 9, selected from carbohydrates selected from maltose, wherein x is 0 or 1.

11. R ３ ga-OH,-NHCH ２ CH ２ CH ２ N(CH ３ ) ２ , 【Chemistry 4】 ,-(NHCH ２ CH ２ ) ｘ -Glc, -(NHCH ２ CH ２ ) ｘ -Gal, -(NHCH ２ CH ２ ) ｘ -Man, -(NHCH ２ CH ２ ) ｘ -GlcNAc, -(NHCH ２ CH ２ ) ｘ -MurNAc, -(NHCH ２ CH ２ ) ｘ -ManNAc, -(NHCH ２ CH ２ ) ｘ -GalNAc, -(NHCH ２ CH ２ ) ｘ - Cellobiose and - (NHCH ２ CH ２ ) ｘ - A compound according to any one of claims 1 to 9, selected from maltose (where x is 0 or 1).

12. R ３ The compound according to any one of claims 1 to 11, wherein the hyphen is -OH.

13. R ４ -H, substituted or unsubstituted -C １ -C １０ Alkyl, substituted, or unsubstituted C ２ -C １０ Alkenyl, substituted or unsubstituted - C １ -C ４ Alkylaryl, and -(NHCH ２ CH ２ ) ｘ -Glc, -(NHCH ２ CH ２ ) ｘ -Gal, -(NHCH ２ CH ２ ) ｘ -Man, -(NHCH ２ CH ２ ) ｘ -GlcNAc, -(NHCH ２ CH ２ ) ｘ -MurNAc, -(NHCH ２ CH ２ ) ｘ -ManNAc, -(NHCH ２ CH ２ ) ｘ -GalNAc, -(NHCH ２ CH ２ ) ｘ - Cellobiose and - (NHCH ２ CH ２ ) ｘ - A compound according to any one of claims 1 to 12, selected from carbohydrates selected from maltose, wherein x is 0 or 1.

14. R ４ が-H、-CH ２ NHCH ２ P(O)(OH) ２ 、-CH ２ N(CH ２ PO ３ H ２ ) ２ 、-CH ２ NHCH ２ CH ２ CH ２ N(CH ３ ) ２ 、-CH ２ NHCH ２ CH ２ COOH、-CH ２ N(CH ３ )CH ２ (CH(OH)) ４ CH ２ OH、-CH ２ NHCH(COOH)CH ２ COOH、-CH ２ NH(CH ２ CH ２ (OH) ２ 、-(NHCH ２ CH ２ ) ｙ -Glc、-(NHCH ２ CH ２ ) ｙ -Gal、-(NHCH ２ CH ２ ) ｙ -Man、-(NHCH ２ CH ２ ) ｙ -GlcNAc、-(NHCH ２ CH ２ ) ｙ -MurNAc、-(NHCH ２ CH ２ ) ｙ -ManNAc、-(NHCH ２ CH ２ ) ｙ -GalNAc、-(NHCH ２ CH ２ ) ｙ -セロビオースおよび-(NHCH ２ CH ２ ) ｙ - A compound according to any one of claims 1 to 12, selected from maltose (where y is 0 or 1).

15. R ４ The compound according to any one of claims 1 to 14, wherein is -H.

16. A compound according to any one of claims 1 to 15, selected from those represented by the following formulas, or a pharmaceutically acceptable salt or solvate thereof. 【Transformation 5】 【Transformation 6】 【Transformation 7】

17. A pharmaceutical formulation for the treatment of bacterial infections, comprising the compound described in any one of claims 1 to 16.

18. The pharmaceutical formulation according to claim 17, wherein the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.

19. The pharmaceutical preparation according to claim 17 or 18, wherein the pharmaceutical preparation is a non-enteral preparation or an oral preparation.

20. A pharmaceutical preparation according to any one of claims 17 to 19, wherein the pharmaceutical preparation is a non-enteral preparation.

21. The pharmaceutical preparation according to claim 20, wherein the pharmaceutical preparation is a pharmaceutical preparation for intravenous injection.

22. A pharmaceutical preparation according to any one of claims 17 to 21, wherein the bacterial infection is an infection of Gram-positive bacteria.

23. Use of the compound according to any one of claims 1 to 16 in the manufacture of a pharmaceutical preparation for the treatment of bacterial infections.

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