Antibiotic compounds

Abstract

Provided herein are lipidated glycopeptide compounds of formula (I): or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof. R1 is a lipid, R2 is -H or a lipid, and R3 and R4 are as defined herein. These compounds have antibacterial activity. Also provided are preparations comprising such compounds; and the use of such compounds or preparations as medicines. The compounds and preparations may also be used to treat bacterial infections.

Description

Technical Field

[0001] The present invention relates to a new class of lipidated guanidinyl derivatives of glycopeptide antibiotics. The present invention also provides preparations and compositions containing such compounds. The compounds, preparations and compositions can be used as drugs, for example, in the treatment of bacterial infections. Methods of using such compounds in the treatment of bacterial infections are also provided. Background Art

[0002] In the search for antibiotics with anti-Gram-positive activity, the bacterial cell wall, commonly referred to as the peptidoglycan layer, is an attractive target. The key to peptidoglycan biosynthesis is lipid II, the penultimate component of the bacterial cell wall. Many natural product antibiotics work 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). The most prominent of these antibiotics is the clinically used glycopeptide vancomycin, which tightly binds to the terminal d-Ala-d-Ala motif of the lipid II pentapeptide.

[0003] With the emergence of many bacterial strains, resistance to vancomycin has emerged, and these strains can use lipid II variants containing d-Ala-d-Lac terminal pentapeptides. This d-Lac of d-Ala mutation reduces the affinity of vancomycin for lipid II, and thus greatly reduces its antibacterial effect (Healy, VL, et al. (2000) Vancomycinresistance in enterococci: reprogramming of the D-ala-D-Alaligases inbacterial 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, it is still very important to develop new glycopeptide antibiotics with enhanced antibacterial activity.

[0004] It is an object of the present invention to provide compounds useful in the treatment of bacterial infections, particularly infections resistant to existing antibiotics such as vancomycin. Summary of the invention

[0005] The present invention provides compounds for treating bacterial infections. For example, these compounds can be used to treat Gram-positive bacterial infections. The compounds of the present invention are lipidated glycopeptides, wherein the lipid portion is connected to the glycan portion via a linker and a guanidinium portion.

[0006] In a first aspect, the present invention provides a compound of formula I:

[0007]

[0008] in:

[0009] R1 is a lipid;

[0010] R2 is selected from -H or a lipid;

[0011] R3 is selected from -OH, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 alkenyl, substituted or unsubstituted -C1-C4 alkylaryl and carbohydrates;

[0012] R4 is selected from -H, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 alkenyl, substituted or unsubstituted -C1-C4 alkylaryl and carbohydrate; and

[0013] L1 is the connector.

[0014] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0015] A second aspect of the present invention provides a preparation of the present invention, which comprises a compound of the present invention and an optional pharmaceutically acceptable carrier. The preparation can be a parenteral preparation or an oral preparation. The preparation can be a parenteral preparation, such as a preparation for intravenous injection.

[0016] A third aspect provides a compound or formulation of the invention for use as a medicament.

[0017] A fourth aspect provides a compound or preparation of the present invention for treating bacterial infection. The bacterial infection may be a gram-positive bacterial infection. The gram-positive bacteria may be from at least one of the following families: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococcus (e.g., Streptococcus pyogenes, Streptococcus agalactiae, Viridans streptococcus, Streptococcus pneumoniae), Enterococcus (e.g., Enterococcus faecalis), Bacillus, Clostridium, Listeria, and Corynebacterium. Bacteria (e.g., gram-positive bacteria) may be resistant to the treatment of at least one other antibiotic (e.g., methicillin, vancomycin). The bacterial infection may be an infection caused by vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), or vancomycin-resistant Staphylococcus aureus (VRSA). The bacterial infection may be selected from the group consisting of skin and structure infections, lower respiratory tract infections, bacteremia, sepsis, septicemia, infective endocarditis, peritonitis, enterocolitis mastitis, Clostridium difficile infection-associated diarrhea, and colitis.

[0018] A fifth aspect provides a method for treating a bacterial infection in a patient, comprising administering to the patient an effective amount of a compound of the present invention or a formulation of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Embodiments of the present invention will be further described below with reference to the accompanying drawings, in which:

[0020] Figure 1 Results obtained when evaluating selected compounds using the hemolytic assay are shown.

[0021] Figure 2Results obtained from UDP-MurNAc-pentapeptide accumulation analysis of selected compounds are shown. All compounds resulted in the accumulation of UDP-MurNAc-pentapeptide, indicating that these compounds interfere with the biosynthesis of the peptidoglycan cell wall in Gram-positive bacteria.

[0022] Figure 3 Results obtained when selected compounds were evaluated using the resistance development serial passage assay are shown. A) Daily fold increase in MIC over 30 days compared to the initial MIC for MRSA USA 300 grown in sublethal concentrations of daptomycin, compound 5, or compound 16. B) Daily fold increase in MIC over 30 days compared to the initial MIC for VRE E155 grown in sublethal concentrations of daptomycin, compound 5, or compound 16.

[0023] Figure 4 Results obtained when the selected compounds were evaluated using a time-kill assay are shown. A) The bactericidal activity of vancomycin, telavancin, daptomycin (left), compound 5 and compound 16 (right) against VRE E155, measured by agar plate dilution colony counts of samples at different time intervals. B) The bactericidal activity of vancomycin, telavancin, daptomycin (left) and compound 5 (right) against MRSA USA300, measured by agar plate dilution colony counts of samples at different time intervals.

[0024] Figure 5 Pharmacokinetic profiles of blood concentrations of selected compounds over 8 hours are shown.

[0025] Figure 6 Shown are the results obtained in an efficacy study of selected compounds against MRSA USA300 strain NRS384. DETAILED DESCRIPTION

[0026] Throughout the specification and claims of this specification, the words "comprise" and "contain" and their variations mean "including but not limited to", and they are not intended to (and do not) exclude other parts, additives, components, integers or steps. Throughout the specification and claims of this specification, the singular encompasses the plural, unless the context requires otherwise. In particular, where the indefinite article is used, the specification should be understood to contemplate plurality as well as the singular, unless the context requires otherwise.

[0027] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel one or any novel combination of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one or any novel combination of the steps of any method or process so disclosed.

[0028] The reader is directed to all papers and documents related to this application that are filed concurrently with or prior to this specification, which are open to public inspection with this specification, and the contents of all these papers and documents are incorporated herein by reference.

[0029] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0030] definition

[0031] The following explanations of terms and methods are provided to better describe the present disclosure and guide those of ordinary skill in the art to practice the present disclosure.

[0032] The present invention particularly relates to the treatment of disease.Term " treatment " and the therapy comprised by the present invention include following and its combination: (1) hinder, for example delay the start and / or progress of event, state, disease or patient's condition, for example in the case of maintenance treatment or secondary prevention, or in the case of at least one clinical or subclinical symptom, prevent, reduce or delay the development of event, state, disease or patient's condition or its recurrence; (2) prevent or delay the appearance of clinical symptoms of event, state, disease or patient's condition occurring in animal (for example people), the animal may suffer from or be susceptible to this state, disease or patient's condition, but have not yet experienced or shown this state, disease or patient's condition clinical or subclinical symptoms; And / or (3) alleviate and / or cure event, state, disease or patient's condition (for example, cause the disappearance of at least one of event, state, disease or patient's condition or its clinical or subclinical symptom, cure patient or make patient alleviate).The benefit to the patient to be treated can be statistically significant, or at least be perceptible to patient or doctor. It should be understood that a drug may not necessarily produce a clinical effect in every patient treated with the drug; therefore, in any individual patient or even in a particular patient population, treatment may fail or be only partially successful, and the meaning of the terms "treatment" and "prevention" and related terms should be understood accordingly. The compositions and methods described herein can be used to treat and / or prevent the above-mentioned conditions.

[0033] The term "prevention" includes and refers to a therapeutic therapy for the purpose of maintaining health or inhibiting or delaying the onset and / or progression of an event, state, disorder or condition, for example, for the purpose of reducing the chance of an event, state, disorder or condition occurring. The result of prevention can be, for example, maintaining health or delaying the onset and / or progression of an event, state, disorder or condition. It should be remembered that in any individual patient, or even in a particular patient population, treatment may fail, and this paragraph should be understood accordingly.

[0034] 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 "antimicrobial agent" is an antibiotic that is active against bacteria. The compounds of the present invention are antimicrobial agents, particularly active against Gram-positive bacteria. Gram-positive bacteria include Staphylococci (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococci (e.g., Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, Streptococcus pneumoniae), Enterococci, Bacillus, Clostridium, Listeria, and Corynebacterium.

[0035] As used herein, the term "alkyl" includes reference to a straight or branched chain alkyl moiety 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. The term includes reference to, for example, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, or tert-butyl), pentyl, hexyl, and the like. In particular, an alkyl group may be "C1-C 10 "C1-C6 alkyl", i.e., alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; or "C1-C6 alkyl", i.e., alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; "C1-C4 alkyl", i.e., alkyl having 1, 2, 3 or 4 carbon atoms; "C1-C6 alkyl", i.e., alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; or "C1-C3 alkyl", i.e., alkyl having 1, 2 or 3 carbon atoms. The term "lower alkyl" includes alkyl having 1, 2, 3 or 4 carbon atoms.

[0036] As used herein, the term "alkenyl" includes straight or branched chain alkenyl moieties having up to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms. The term includes reference to, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. In particular, alkenyl can be "C2-C 10 The term "alkenyl" refers to an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; a "C2-C6 alkenyl group" refers to an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms; a "C2-C4 alkenyl group" refers to an alkenyl group having 1, 2, 3 or 4 carbon atoms; the term "lower alkenyl" includes alkyl groups having 2, 3 or 4 carbon atoms. The alkenyl group may be monounsaturated (i.e., contains a single carbon-carbon double bond) or polyunsaturated (i.e., contains two or more carbon-carbon double bonds, such as 2, 3 or 4 carbon-carbon double bonds). For example, the alkenyl group may be a dienyl group, a trienyl group, etc.

[0037] The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred in the present invention. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically having eight or fewer carbon atoms.

[0038] As used herein, the term "cycloalkyl" includes reference to alicyclic moieties having 3, 4, 5, or 6 carbon atoms. The group may be a bridged or polycyclic ring system. The more common cycloalkyl groups are monocyclic. The term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0039] The term "heteroalkyl", by itself or in combination with another term, refers, unless otherwise stated, to a stable straight or 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, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom O, N, P, S and Si may be placed at any interior position of the heteroalkyl group or at the position at which 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. Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and –CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" by itself or as part of another substituent refers to a divalent radical derived from a heteroalkyl group, for example, but not limited to, -CH2-CH2-S-CH2-CH2- and –CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkylenamino, alkylenediamino, etc.). In addition, for alkylene and heteroalkylene linking groups, the direction in which the linking group formula is written does not imply an orientation of the linking group. For example, the formula -C(O)2R'- represents -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups as used herein include those groups that are connected to the remainder of the molecule through heteroatoms, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR' and / or -SO2R'. When "heteroalkyl" is recited, followed by a specific heteroalkyl group, such as -NR'R", etc., it should be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Instead, specific heteroalkyl groups are listed for clarity. Therefore, the term "heteroalkyl" should not be interpreted herein to exclude specific heteroalkyl groups, such as -NR'R", etc.

[0040] 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, heterocycloalkyl can contain 3, 4 or 5 ring carbon atoms and 1 or 2 ring heteroatoms selected from nitrogen and oxygen. The group can be a polycyclic system, but more commonly a monocyclic ring. The term includes groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolyl.

[0041] As used herein, the term "halogen" includes reference to F, Cl, Br or I, such as F, Cl or Br. In a particular class of embodiments, halogen is F or Cl, with F being more common.

[0042] Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a corresponding number of halogens. For example, the term "halo (C1-C4) alkyl" refers to, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0043] As used herein, the term "alkoxy" includes -O-alkyl, wherein the alkyl is linear or branched and contains 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, the alkoxy has 1, 2, 3 or 4 carbon atoms, such as 1, 2 or 3 carbon atoms. The term includes reference to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. The term "lower alkoxy" includes reference to alkoxy having 1, 2, 3 or 4 carbon atoms.

[0044] The term "haloalkoxy" as used herein refers to an alkoxy group in which one or more hydrogen atoms are replaced by a corresponding number of halogens.

[0045] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which can be a monocyclic or polycyclic (preferably 1-3 rings) fused together or covalently attached. The term "heteroaryl" refers to an aryl (or ring) containing 1-4 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl can be connected to the rest of the molecule by carbon or heteroatom. The non-limiting examples of aryl and heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4 1-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroaryl" refer to divalent radicals derived from aryl and heteroaryl, respectively.

[0046] The term "lipid" used herein to refer to a substituent represents a generally hydrophobic part. The lipid may include substituted or unsubstituted alkyl, alkenyl, cycloalkyl, bridged cycloalkyl, (alkyl) cycloalkyl, (alkyl) bridged cycloalkyl, (alkyl) cycloalkenyl and / or alkylaryl. For example, the lipid may include substituted or unsubstituted alkyl, alkenyl, (alkyl) cycloalkyl, (alkyl) cycloalkenyl and / or alkylaryl. Exemplary substituents include -OH, =O, -CN, -halogen, -NH2, -NH (C1-C6 alkyl), -N (C1-C4 alkyl) 2, -phenyl, -phenyl-halogen; for example -OH, =O, -CN, -halogen, -NH2, -NH (C1-C6 alkyl), -N (C1-C4 alkyl) 2. The backbone of the substituted or unsubstituted lipid may also be interrupted by a disulfide bond (-SS-), a thioether bond (-S-), an ether bond -O- or an ester (-C (O) O-).

[0047] Unless otherwise indicated, each of the above terms (e.g., "alkyl," "cycloalkyl," "heteroalkyl," "aryl," and "heteroaryl") is meant to include both substituted and unsubstituted forms of the indicated radical. x -substituted alkyl, where "x" is an integer), the substituent may be substituted with one or more R groups as permitted by the valence rules, wherein each R group is optionally different (e.g., R x -substituted alkyl may include multiple Rx A group in which each R x The groups are optionally different). Some examples of substituents for each group are provided below.

[0048] The term "substituted" as used herein means that one or more, in particular up to 5, more particularly 1, 2 or 3 hydrogen atoms in the moiety are replaced independently of each other by the corresponding number of the substituents. Unless otherwise indicated, exemplary 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, -C1-C6 alkylcarboxylic acid (e.g. -CH3COOH or -COOH). When the substituent is -C1-C6 alkyl or -C1-C6 haloalkyl, the C1-C6 chain is optionally interrupted by an ether bond (-O-) or an ester bond (-C(O)O-). Exemplary substituents for substituted alkyl groups may include -OH, -CN, -NH2, =O, -halogen, -CO2H, -C1-C6 haloalkyl, -C1-C6 haloalkoxy and -C2-C6 haloalkyl, -C1-C6 alkylcarboxylic acid (e.g., -CH3COOH or -COOH). For example, exemplary substituents for alkyl groups may include -OH, -CN, -NH2, =O, -halogen.

[0049] Of course, it should be understood that substituents are only located at chemically possible positions, and one skilled in the art can determine (by experiment or theory) without undue effort whether a particular substitution is possible. For example, an amino or hydroxyl group with a free hydrogen may be unstable if combined with a carbon atom with an unsaturated bond (e.g., an olefinic bond). In addition, of course, it should be understood that the substituents described herein can themselves be substituted with any substituent, so long as one skilled in the art recognizes the above-mentioned limitations on suitable substitutions.

[0050] When steric considerations dictate the position of substituents on a group, the isomer with the lowest conformational energy may be preferred.

[0051] When a compound, moiety, method or product is described as "optionally" having a certain feature, the disclosure includes such compounds, moieties, methods or products having that feature, as well as such compounds, moieties, methods or products not having that feature. Thus, when a moiety is described as "optionally substituted," the disclosure includes both unsubstituted and substituted moieties.

[0052] When two or more moieties are described as being "independently" or "each independently" selected from a certain list of atoms or groups, this means that the moieties may be the same or different. Thus, the identity of each moiety is independent of the identity of one or more other moieties.

[0053] The term "pharmaceutically acceptable" as used herein includes compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human or animal tissues without excessive toxicity, irritation, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. The term includes acceptability for human and veterinary purposes.

[0054] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either 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 similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (either neat or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galacturonic acid, etc. (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows the compounds to be converted into base or acid addition salts.

[0055] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0056] Some compounds of the present invention can exist in non-solvated form and solvated form, including hydrated form. Usually, solvated form is equivalent to non-solvated form, and is included in the scope of the present invention. Some compounds of the present invention can exist in multiple crystallization or amorphous form. In general, all physical forms are equal for the purposes considered by the present invention, and are intended to be within the scope of the present invention.

[0057] Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are all included within the scope of the present invention. The compounds of the present invention do not include those compounds known in the art that are too unstable to be synthesized and / or separated.

[0058] symbol Indicates the point at which one part of a compound is attached to the rest.

[0059] As used herein, the term "prodrug" represents a compound that is converted into a parent compound or other active compound in vivo, for example, by hydrolysis in the blood. An example of such a prodrug is a pharmaceutically acceptable carboxylic acid ester. A detailed discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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 Richard B Silverman's The organic chemistry of drug design and drug action (especially pages 497-546); each of which is incorporated herein by reference. The compounds of the invention may represent prodrugs (eg comprising a latent MBL inhibitor), wherein hydrolysis of the -lactam results in the release and activation of the latent MBL inhibitor.

[0060] As used herein, the term "pharmaceutical preparation" includes a preparation comprising at least one active compound and optionally one or more additional pharmaceutically acceptable ingredients (e.g., a pharmaceutically acceptable carrier). When a pharmaceutical preparation comprises two or more active compounds, or comprises at least one active compound and one or more additional pharmaceutically acceptable ingredients, the pharmaceutical preparation is also a pharmaceutical composition. Unless the context indicates otherwise, all references to "preparation" herein refer to pharmaceutical preparations.

[0061] As used herein, the term "product" or "product of the invention" includes reference to any product containing a compound of the invention. In particular, the term product relates to compositions and formulations, such as pharmaceutical compositions, comprising a compound of the invention.

[0062] As used herein, the term "therapeutically effective amount" refers to the amount of a drug or pharmaceutical agent that is calculated (or will) provide the desired therapeutic response in a mammal (animal or human), within the scope of sound pharmacological judgment. The therapeutic response can be, for example, for curing, delaying the progression of a disease, disorder or condition, or preventing a disease, disorder or condition. The following abbreviations are used herein:

[0063] Alloc Allyloxycarbonyl

[0064] ATCC American Type Culture Collection

[0065] BBO Broadband Observation

[0066] CFU colony forming unit

[0067] CLSI Clinical and Laboratory Standards Institute

[0068] d Double

[0069] dd double peaks

[0070] dt double triple peak

[0071] DCM Dichloromethane

[0072] DIPEA Diisopropylethylamine

[0073] DMF Dimethylformamide

[0074] DMSO Dimethyl sulfoxide

[0075] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0076] EtOAc Ethyl acetate

[0077] EtOH

[0078] eq equivalent

[0079] FBS Fetal Bovine Serum

[0080] Galactose

[0081] GalNAc N-acetylgalactosamine

[0082] Glc Glucose

[0083] GlcNAc N-acetylglucosamine

[0084] h sixfold

[0085] HEPA High Efficiency Particulate Air

[0086] HPLC High Performance Liquid Chromatography

[0087] HR-MS High Resolution Mass Spectrometry

[0088] LC Liquid Chromatography

[0089] m multiple

[0090] Mannose

[0091] ManNAc N-acetylmannosamine

[0092] MeCN Acetonitrile

[0093] MeOH Methanol

[0094] MIC minimum inhibitory concentration

[0095] MRSA Methicillin-resistant Staphylococcus aureus

[0096] MSSA Methicillin-susceptible Staphylococcus aureus

[0097] MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

[0098] MurNAc N-acetylmuramic acid

[0099] m / z mass-to-charge ratio

[0100] NEt3 Triethylamine

[0101] NLD Netherlands

[0102] NMR Nuclear Magnetic Resonance

[0103] p80 Polysorbate 80

[0104] PBS Phosphate buffered saline

[0105] PE Petroleum Ether

[0106] PFGE pulsed-field gel electrophoresis

[0107] PK Pharmacokinetics

[0108] pp pentapeptide

[0109] ppm parts per million

[0110] rpm revolutions per minute

[0111] RT Room temperature

[0112] RP-HPLC Reversed Phase High Performance Liquid Chromatography

[0113] s singlet

[0114] SD Standard deviation

[0115] t triplet

[0116] THF Tetrahydrofuran

[0117] TLC Thin Layer Chromatography

[0118] TMS trimethylsilyl

[0119] TSB Tryptic Soy Broth

[0120] UDP Uridine diphosphate

[0121] UV

[0122] VISA Vancomycin Intermediate Staphylococcus aureus

[0123] VRE Vancomycin-resistant Enterococci

[0124] VRSA Vancomycin-resistant Staphylococcus aureus

[0125] VSE Vancomycin-susceptible Enterococci

[0126] Compound

[0127] In one aspect, the present invention provides a compound of formula I as described above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. The compound of formula I represents a lipidated glycopeptide, wherein the lipid portion (R1 and optionally R2) is connected to the glycan portion via a linker (-L1-) and a guanidinyl portion. The glycopeptide portion of the compound represents a substituted vancomycin with optional additional substituents R3 and R4.

[0128] R1 may be a lipid. R1 may be selected from substituted or unsubstituted -C4-C 20 Cycloalkyl (e.g. bridged cycloalkyl), substituted or unsubstituted -C1-C4alkyl-C4-C 20 Cycloalkyl (eg, bridged 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, wherein m is selected from 2 and 3, n is selected from 0 to 20, -C2-C 12Alkyl-SS-C1-C 12 R1 can be selected from 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, wherein m is selected from 2 and 3, n is selected from 0 to 20, -C2-C 12 Alkyl-SS-C1-C 12 R1 can be selected from substituted or unsubstituted -C4-C 16 Cycloalkyl (e.g. bridged cycloalkyl), substituted or unsubstituted -C1-C4alkyl-C4-C 16 Cycloalkyl (eg, bridged 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, wherein m is selected from 2 and 3, n is selected from 0 to 14, -C2-C8 alkyl-SS-C2-C8 alkyl. R1 can be selected from 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, wherein m is selected from 2 and 3, n is selected from 0 to 14, -C2-C8 alkyl-SS-C2-C8 alkyl. R1 can be selected from -C4-C 16 Cycloalkyl (e.g. bridged cycloalkyl), -C1-C4alkyl-C4-C 16 Cycloalkyl (e.g. bridged cycloalkyl), -C4-C 16 Alkyl, -C6-C 18 alkenyl and substituted (e.g., halogen-substituted) or unsubstituted -C1-C4 alkylbiphenyl. R1 may be selected from -C4-C 16 Alkyl, -C6-C 18 alkenyl and substituted (e.g. halogen substituted) or unsubstituted -C1-C4 alkylbiphenyl. R1 can be selected from -C6-C 14 Cycloalkyl (e.g. bridged cycloalkyl), -C1-C4alkyl-C6-C 14 Cycloalkyl (e.g. bridged cycloalkyl), -C6-C 14 Alkyl, -C6-C16 alkenyl and substituted or unsubstituted -C1-C4 alkylbiphenyl. R1 can be selected from -C6-C 14 Alkyl, -C6-C 16 alkenyl and substituted or unsubstituted -C1-C4 alkylbiphenyl. R1 can be selected from -C6-C 14 Cycloalkyl (e.g., bridged cycloalkyl), -CH2-C6-C 14 Cycloalkyl (e.g. bridged cycloalkyl), -C6-C 14 R1 can be selected from -C6-C 14 R1 can be selected from C6-C 14 alkyl, -geranyl, -farnesyl, and -chlorobiphenyl.

[0129] R1 may be substituted or unsubstituted -C4-C 20 Alkyl, such as substituted or unsubstituted -C4-C 16 R1 may be substituted or unsubstituted -C4-C 20 Alkyl, such as unsubstituted -C4-C 16 R1 may be substituted or unsubstituted -C4-C 20 Alkenyl, such as substituted or unsubstituted -C6-C 18 R1 may be substituted or unsubstituted -C4-C 20 Alkenyl, such as unsubstituted -C6-C 18 R1 may be a substituted or unsubstituted C1-C4-alkylaryl. R1 may be an unsubstituted C1-C4-alkylaryl, wherein the aryl substituent may be a biaryl. R1 may be a substituted C1-C4-alkylaryl, wherein the aryl substituent may be a halogenated biaryl, such as chlorobiphenyl. R1 may be a substituted CH2-alkylarene, wherein the aryl substituent may be a halogenated biaryl, such as chlorobiphenyl. R1 may be -C1-C4-alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3, wherein m is selected from 2 and 3, and n is selected from 0 to 20. m may be 2. m may be 3. n may be selected from 2 to 16, for example, n may be selected from 4 to 12. m may be 2, and n may be selected from 2 to 16. m may be 3, and n may be selected from 2 to 16. R1 may be -C2-C 12 Alkyl-SS-C1-C 12 Alkyl, such as -C2-C 10 Alkyl-SS-C2-C 10Alkyl; for example -C2-C8 alkyl-SS-C2-C8 alkyl. R1 can be substituted or unsubstituted -C4-C 20 Cycloalkyl, such as substituted or unsubstituted -C4-C 16 Cycloalkyl or substituted or unsubstituted -C6-C 14 R1 may be unsubstituted -C4-C 20 Cycloalkyl, such as unsubstituted -C4-C 16 Alkyl or unsubstituted -C6-C 14 R1 can be an unsubstituted bridged-C6-C 14 R1 may be an unsubstituted bridged C 10 R1 may be a substituted or unsubstituted -C1-C4 alkyl-C4-C 20 Cycloalkyl, such as substituted or unsubstituted -C1-C4alkyl-C4-C 16 Cycloalkyl or substituted or unsubstituted -C1-C4 alkyl-C6-C 14 R1 can be unsubstituted -C1-C4 alkyl-C4-C 20 Cycloalkyl, such as unsubstituted -C1-C4alkyl-C4-C 16 Cycloalkyl or unsubstituted -C1-C4alkyl-C6-C 14 R1 can be unsubstituted -C1-C4 alkyl-C6-C 14 R1 may be an unsubstituted -C1-C4 alkyl-C 10 Cycloalkyl, wherein the cycloalkyl is bridged, such as -C1-C4 alkyl-adamantyl. R1 may be unsubstituted -CH2-C 10 Cycloalkyl, wherein the cycloalkyl is bridged, for example -CH2-adamantyl.

[0130] When R1 is a substituted moiety, it may be substituted with at least one -OH, =O, -CN, -halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C4 alkyl)2; for example, it may be substituted with at least one -OH, =O, -CN, -halogen. When R1 is a substituted or unsubstituted alkyl, the carbon backbone of the alkyl may be interrupted by at least one disulfide bond (-SS-), thioether bond (-S-), ether bond -O-, or ester bond (-C(O)O-).

[0131] R2 may be selected from -H or a lipid. R2 may be -H. R2 may be a lipid. R2 may be selected from -H, substituted or unsubstituted -C4-C 20 Alkyl, substituted or unsubstituted -C4-C 20alkenyl, substituted or unsubstituted -C1-C4 alkylaryl, -C1-C4 alkyl-[O(CH2) p ] q -O(CH2) p-1 CH3 (wherein p is selected from 2 and 3, q ​​is selected from 0 to 20), -C2-C 12 Alkyl-SS-C1-C 12 R2 can 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 (wherein p is selected from 2 and 3, q ​​is selected from 0 to 14), -C2-C8 alkyl-SS-C2-C8 alkyl. R2 can be selected from -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 (wherein p is selected from 2 and 3, q ​​is selected from 0 to 20). R2 can be selected from -H, -C4-C 12 Alkyl and -C4-C 12 R2 can be selected from -H, -C4-C 16 Alkyl, -C6-C 18 R2 can be selected from -H, -C6-C 14 Alkyl, -C6-C 16 alkenyl and substituted or unsubstituted -C1-C4 alkylbiphenyl. R2 can be selected from C6-C 14 alkyl, -geranyl, -farnesyl, and -chlorobiphenyl.

[0132] When R2 is a lipid, R2 may be selected from substituted or unsubstituted -C4-C 20 Cycloalkyl (e.g. bridged cycloalkyl), substituted or unsubstituted -C1-C4alkyl-C4-C 20 Cycloalkyl (eg, bridged 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-1CH3 (wherein p is selected from 2 and 3, q ​​is selected from 0 to 20), -C2-C 12 Alkyl-SS-C1-C 12 R2 can be selected from substituted or unsubstituted -C4-C 20 Alkyl, substituted or unsubstituted -C4-C 20 Alkenyl, substituted or unsubstituted -C1-C4 alkyl-[O(CH2)p]qO(CH2) p-1 CH3 (wherein p is selected from 2 and 3, q ​​is selected from 0 to 20), -C2-C 12 Alkyl-SS-C1-C 12 R2 can be selected from substituted or unsubstituted -C4-C 16 Cycloalkyl (e.g., bridged cycloalkyl), substituted or unsubstituted -C1-C4alkyl-C4-C 16 Cycloalkyl (e.g., bridged 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 (wherein p is selected from 2 and 3, q ​​is selected from 0 to 14), -C2-C8 alkyl-SS-C2-C8 alkyl. R2 can be selected from 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-1 CH3 (wherein p is selected from 2 and 3, q ​​is selected from 0 to 14), -C2-C8 alkyl-SS-C2-C8 alkyl. R2 can be selected from -C4-C 16 Cycloalkyl (e.g., bridged cycloalkyl), -C1-C4alkyl-C4-C 16 Cycloalkyl (e.g., bridged cycloalkyl), -C4-C 16 Alkyl, -C6-C 18 alkenyl and substituted (e.g., halogen-substituted) or unsubstituted -C1-C4 alkylbiphenyl. R2 may be selected from -C4-C 16 Alkyl, -C6-C 18 alkenyl and substituted (e.g. halogen substituted) or unsubstituted -C1-C4 alkylbiphenyl. R2 may be selected from -C6-C 14 Cycloalkyl (e.g. bridged cycloalkyl), -C1-C4alkyl-C6-C 14 Cycloalkyl (e.g. bridged cycloalkyl), -C6-C 14 Alkyl, -C6-C16 R2 can be selected from -C6-C 14 Alkyl, -C6-C 16 R2 can be selected from -C6-C 14 Cycloalkyl (e.g., bridged cycloalkyl, such as adamantane), -CH2-C6-C 14 Cycloalkyl (eg, bridged cycloalkyl, such as adamantane), -C6-C 14 alkyl, -geranyl, -farnesyl, and -chlorobiphenyl.

[0133] R2 can be selected from -H, -C6-C 14 R2 can be selected from -H, C6-C 14 alkyl, -geranyl, -farnesyl, and -chlorobiphenyl.

[0134] R2 may be -H. R2 may be substituted or unsubstituted -C4-C 20 Alkyl, such as substituted or unsubstituted -C4-C 16 R2 may be substituted or unsubstituted -C2-C 14 Alkyl, such as substituted or unsubstituted -C4-C 12 Alkyl, such as C4-C 10 R2 may be substituted or unsubstituted -C4-C 20 Alkyl, such as unsubstituted -C4-C 16 R2 may be substituted or unsubstituted -C4-C 20 Alkenyl, such as substituted or unsubstituted -C6-C 18 R2 may be unsubstituted -C4-C 20 Alkenyl, such as unsubstituted -C6-C 18 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, wherein p is selected from 2 and 3, and q is selected from 0 to 20. p may be 2. p may be 3. q may be selected from 2 to 16, for example, q may be selected from 4 to 12. p may be 2, and q may be selected from 2 to 16. p may be 3, and q may be selected from 2 to 16. R2 may be -C2-C 12 Alkyl-SS-C1-C 12 Alkyl, such as -C2-C 10 Alkyl-SS-C2-C 10Alkyl; for example -C2-C8alkyl-SS-C2-C8alkyl.

[0135] When R2 is a substituted moiety, it may be substituted with at least one -OH, =O, -CN, -halogen, -NH2, -NH(C1-C6 alkyl), -N(C1-C4 alkyl)2; for example, it may be substituted with at least one -OH, =O, -CN, -halogen. When R2 is a substituted or unsubstituted alkyl, the carbon backbone of the alkyl may be interrupted by at least one disulfide bond (-SS-), thioether bond (-S-), ether bond -O-, or ester bond (-C(O)O-).

[0136] R1 and R2 can each be independently selected from 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 (wherein m is selected from 2 and 3, and n is selected from 0 to 20) and -C2-C 12 Alkyl-SS-C1-C 12 R1 and R2 can each be independently selected from -C2-C 12 Alkyl, -C2-C 12 alkenyl, -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3 (wherein m is selected from 2 and 3, and n is selected from 0 to 20) and -C2-C 12 Alkyl-SS-C1-C 12 R1 and R2 can each be independently selected from -C2-C 10 Alkyl, -C2-C 10 alkenyl, -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3 (wherein m is selected from 2 and 3, and n is selected from 2 to 16) and -C2-C 10 Alkyl-SS-C2-C 10 R1 and R2 can each be independently selected from -C2-C 10 Alkyl, -C2-C 10 Alkenyl and -C1-C4 alkyl-[O(CH2) m ] n -O(CH2) m-1 CH3 (wherein m is selected from 2 and 3, and n is selected from 2 to 16). R1 ​​and R2 may each be independently selected from substituted or unsubstituted -C2-C 12Alkyl and substituted or unsubstituted -C2-C 12 R1 and R2 can each be independently selected from -C2-C 12 Alkyl and -C2-C 12 R1 and R2 can each be independently selected from substituted or unsubstituted -C2-C 10 Alkyl and substituted or unsubstituted -C2-C 10 R1 and R2 can each be independently selected from -C2-C 10 Alkyl and -C2-C 10 R1 and R2 can each be independently selected from substituted or unsubstituted -C4-C 10 Alkyl and substituted or unsubstituted -C4-C 10 R1 and R2 can each be independently selected from -C4-C 10 Alkyl and -C4-C 10 R1 and R2 may each be independently selected from substituted or unsubstituted -C4-C8 alkyl and substituted or unsubstituted -C4-C8 alkenyl. R1 and R2 may each be independently selected from -C4-C8 alkyl and -C4-C8 alkenyl.

[0137] R1 and R2 can each be substituted or unsubstituted -C2-C 12 R1 and R2 can each be -C2-C 12 R1 and R2 can each be a substituted or unsubstituted -C2-C 10 R1 and R2 can each be -C2-C 10 R1 and R2 can each be a substituted or unsubstituted -C4-C 10 R1 and R2 can each be -C4-C 10 R1 and R2 can each be a substituted or unsubstituted -C4-C8 alkyl group. R1 and R2 can each be a substituted or unsubstituted -C4-C8 alkyl group. R1 and R2 can each be a substituted or unsubstituted -C2-C 12 R1 and R2 can each be -C2-C 12 R1 and R2 can each be a substituted or unsubstituted -C2-C 10 R1 and R2 can each be -C2-C 10 R1 and R2 can each be a substituted or unsubstituted -C4-C 10 R1 and R2 can each be -C4-C 10 R1 and R2 can each be a substituted or unsubstituted -C4-C8 alkenyl. R1 and R2 can each be a -C4-C8 alkenyl. R1 and R2 can each be a -C1-C4 alkyl-[O(CH2) m ] n-O(CH2) m-1 CH3, wherein 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 and R2 can each be -C2-C 12 Alkyl-SS-C1-C 12 Alkyl, such as -C2-C 10 Alkyl-SS-C2-C 10 Alkyl; for example -C2-C8alkyl-SS-C2-C8alkyl.

[0138] R1 and R2 may be the same, for example, R1 and R2 may each be the same substituted or unsubstituted -C2-C 12 Alkyl. R1 and R2 may be different, for example R2 may be -H and R1 may be another substituent as specified elsewhere herein.

[0139] R1 can be selected from

[0140]

[0141] R2 can be selected from H,

[0142] R1 can be selected from And R2 can be H. R1 can be And R2 can be R1 can be And R2 can be R1 can be And R2 can be

[0143] R3 can be selected from -OH, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 alkenyl, substituted or unsubstituted -C1-C4 alkylaryl and carbohydrates. 20 The alkyl group can be, for example, -NHCH2CH2CH2N(CH3)2 or The carbohydrate can be, 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 -Cellobiose and -(NHCH2CH2) x -maltose, wherein x is 0 or 1. R3 may be selected from -OH, -C1-C 20 Alkyl, -C2-C 20 R3 can be selected from -OH, substituted or unsubstituted -C1-C4 alkylaryl, and carbohydrate. 10 Alkyl, substituted or unsubstituted -C2-C 10 R3 can be selected from -OH, -C1-C4 alkenyl, substituted or unsubstituted -C1-C4 alkylaryl and carbohydrate. 10 Alkyl, -C2-C 10 R3 can be selected from -OH, -NHCH2CH2CH2N(CH3)2, -(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. x may be 0. x may be 1.

[0144] R3 may be -OH. R3 may be substituted or unsubstituted -C1-C 20 Alkyl; for example, substituted or unsubstituted C1-C 10 Alkyl, for example substituted or unsubstituted C1-C6 alkyl. R3 can be -C1-C 20 Alkyl; for example C1-C 10 R3 may be a substituted or unsubstituted -C2-C 20 Alkenyl; for example, substituted or unsubstituted C2-C 10 R3 may be -C2-C6 alkenyl, for example substituted or unsubstituted C2-C6 alkenyl. 20 Alkenyl; for example C2-C 10R3 may be a substituted or unsubstituted -C1-C4 alkaryl, such as a substituted or unsubstituted -C1-C4 alkaryl. R3 may be a carbohydrate (e.g., a polysaccharide selected from Glc, Gal, Man, GlcNAc, MurNAc, ManNAc, GalNAc, cellobiose, and maltose), optionally comprising a linker, such as -NHCH2CH2-. R3 may be -NHCH2CH2CH2N(CH3)2. R3 may be R3 can be -(NHCH2CH2) x -Glc. R3 can be -(NHCH2CH2) x -Gal. R3 can be -(NHCH2CH2) x -Man. R3 can be -(NHCH2CH2) x -GlcNAc. R3 can be -(NHCH2CH2) x -MurNAc. R3 can be -(NHCH2CH2) x -ManNAc. R3 can be -(NHCH2CH2) x -GalNAc. R3 can be -(NHCH2CH2) x -cellobiose. R3 may be -(NHCH2CH2) x -maltose. x could be 0. x could be 1.

[0145] R4 can be selected from -H, substituted or unsubstituted -C1-C 20 Alkyl, substituted or unsubstituted -C2-C 20 alkenyl, substituted or unsubstituted -C1-C4 alkylaryl and carbohydrates. 20 The alkyl group may be substituted with one or more nitrogen, phosphorus or oxygen; for example, a substituted -C1-C 20 The alkyl group may be -CH2NHCH2P(O)(OH)2, -CH2N(CH2PO3H2)2, -CH2NHCH2CH2CH2N(CH3)2, -CH2NHCH2CH2COOH, -CH2N(CH3)CH2(CH(OH))4CH2OH, -CH2NHCH(COOH)CH2COOH, -CH2NH(CH2CH2OH)2. The carbohydrate group may 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 -Cellobiose and -(NHCH2CH2) y -maltose, wherein y is 0 or 1. R4 can be selected from -H, -C1-C 20 Alkyl, -C2-C 20 R4 can be selected from -H, substituted or unsubstituted -C1-C4 alkylaryl, and carbohydrate. 10 Alkyl, substituted or unsubstituted -C2-C 10 R4 is selected from -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 -Cellobiose and -(NHCH2CH2) y -maltose, wherein y is 0 or 1. y can be 0. y can be 1.

[0146] R4 may be -H. R4 may be substituted or unsubstituted -C1-C 20 Alkyl; for example, substituted or unsubstituted C1-C 10 Alkyl, for example substituted or unsubstituted C1-C6 alkyl. R4 can be -C1-C 20 Alkyl; for example C1-C 10 R4 can be substituted or unsubstituted -C2-C 20 Alkenyl; for example, substituted or unsubstituted C2-C 10 R4 may be -C2-C6 alkenyl, for example substituted or unsubstituted C2-C6 alkenyl.20 Alkenyl; for example C2-C 10 R4 may be a substituted or unsubstituted -C1-C4 alkaryl, for example a substituted or unsubstituted -C1-C4 alkaryl. R4 may be a carbohydrate (e.g., a polysaccharide comprising a moiety selected from Glc, Gal, Man, GlcNAc, MurNAc, ManNAc, GalNAc, cellobiose and maltose), optionally comprising a linker, for example -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 may be -CH2NH(CH2CH2OH)2. R4 may be -(NHCH2CH2) y -Glc. R4 can be -(NHCH2CH2) y -Gal. R4 can be -(NHCH2CH2) y -Man. R4 can be -(NHCH2CH2) y -GlcNAc. R4 can be -(NHCH2CH2) y -MurNAc. R4 can be -(NHCH2CH2) y -ManNac. R4 can be -(NHCH2CH2) y -GalNAc. R4 can be -(NHCH2CH2) y -cellobiose. R4 can be -(NHCH2CH2) y -maltose. y can be 0. y can be 1.

[0147] L1 can be selected from –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-C4alkyl)arylene- and -C(S)NHC1-C4alkyl-[O(CH2) r ] s -O(CH2) r -, wherein r is selected from 2 and 3, and s is selected from 0 to 20. L1 may be selected from -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-C4alkyl)arylene- and -C(S)NHC1-C4alkyl-[O(CH2) r ] s -O(CH2) r -, wherein r is selected from 2 and 3, and s is selected from 0 to 20. L1 may be selected from -C2-C10 Alkylene-, –C2-C 10 Alkenylene-, -(C1-C4 alkyl)arylene-, -C2-C4 alkyl-[O(CH2) r ] s -O(CH2) r -, -C2-C8 alkyl-SS-C1-C8 alkyl-, -C(O)C1-C 10 Alkylene-, -C(O)C2-C 10 Alkenylene-, -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-C4alkyl)arylene- and -C(S)NHC1-C4alkyl-[O(CH2) r ] s -O(CH2) r -, wherein r is selected from 2 and 3 (eg, 2), and s is selected from 0 to 20 (eg, 2 to 16).

[0148] L1 can be selected from –C2-C 20 Alkylene-, –C2-C 20 Alkenylene- and -(C1-C4 alkyl)arylene-. L1 can be selected from -C2-C 12 Alkylene-, –C2-C 12 Alkenylene- and -(C1-C4 alkyl)arylene-. L1 can be selected from -C2-C 10 Alkylene-, –C2-C 12 Alkenylene- and -(C1-C4 alkyl)arylene-. L1 can be selected from -C2-C 20 Alkylene- and -(C1-C4 alkyl)arylene-. L1 can be selected from -C2-C 12 Alkylene- and -(C1-C4 alkyl)arylene-. L1 can be selected from -C2-C 10 Alkylene- (eg, -C2-C8alkylene-) and -(C1-C4alkyl)arylene-.

[0149] L1 can be -(C1-C4 alkyl)arylene-; for example -CH2Ph-. L1 can be -C2-C 20 Alkylene-; for example –C2-C 12 Alkylene, such as –C2-C 10 Alkylene- (e.g. -C2-C8 alkylene-). L1 can be -C2-C 20 Alkenylene-; for example -C2-C 12 Alkenylene-, for example -C2-C 10 Alkenylene-. L1 can be -C2-C4 alkyl-[O(CH2) r ] s -O(CH2) r -. L1 can be -C2-C 12 Alkyl-SS-C2-C 12 Alkyl, such as -C2-C 10 Alkyl-SS-C2-C 10 Alkyl; for example -C2-C8 alkyl-SS-C2-C8 alkyl-. L1 can be -C(O)C2-C 20 Alkenylene-; for example -C(O)C1-C 12 Alkylene-, for example -C(O)C1-C 10 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 -. L1 can be -C(O)NHC1-C 20 Alkylene-; for example -C(O)NHC1-C 12 Alkylene-, for example -C(O)NHC1-C 10 Alkylene-. L1 can be -C(O)NHC2-C 20 Alkenylene-; for example -C(O)NHC2-C 12 Alkenylene-, for example -C(O)NHC2-C 10 Alkenylene-. L1 can be -C(O)NH(C1-C4 alkyl)arylene. L1 can be -C(O)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -. L1 can be -C(S)NHC1-C 20 Alkylene-; for example -C(S)NHC1-C 12 Alkylene-, for example -C(S)NHC1-C 10 Alkylene-. L1 can be -C(S)NHC2-C20 Alkenylene-; for example -C(S)NHC2-C 12 Alkenylene-, for example -C(S)NHC2-C 10 Alkenylene-. L1 can be -C(S)NH(C1-C4 alkyl)arylene. L1 can be -C(S)NHC1-C4 alkyl-[O(CH2) r ] s -O(CH2) r -.

[0150] r may be 2. r may be 3. s may be selected from 2 to 16, for example s may be selected from 4 to 12. r may be 2 and s may be selected from 2 to 16. r may be 3 and s may be selected from 2 to 16.

[0151] The compound may be selected from:

[0152]

[0153] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0154] Exemplary compounds can be prepared according to the synthetic methods illustrated in the Examples and according to Reaction Schemes A and B. Furthermore, as will be appreciated by the skilled artisan, these methods and the methods illustrated in Reaction Schemes A and B (see below) can be readily adapted to provide other compounds of the present invention and disclosure.

[0155] Preparation and administration

[0156] According to another aspect of the present invention, there is provided a pharmaceutical formulation or composition comprising a compound of the present invention, optionally in admixture with at least one pharmaceutically acceptable adjuvant, diluent or carrier.

[0157] The preparation or composition may be a parenteral preparation or an oral preparation. The preparation may be a parenteral preparation, such as a preparation for intravenous injection. The preparation may be an oral preparation.

[0158] The compounds, formulations or compositions of the present invention may be administered orally, topically, intravenously, subcutaneously, orally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or by inhalation. The compounds may be administered in the form of pharmaceutical preparations comprising the compounds in the form of free compounds or in pharmaceutically acceptable dosage forms such as pharmaceutically acceptable nontoxic organic or inorganic acid or base addition salts. Depending on the disease to be treated and the patient and the route of administration, the compositions may be administered in different doses.

[0159] Therefore, the pharmaceutical compounds of the present invention can generally be administered parenterally ("parenteral" as used herein refers to administration methods including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion) or orally to the host to obtain an antibacterial effect. For example, the pharmaceutical compounds of the present invention can be administered by intravenous injection or infusion. In the case of larger animals such as humans, the compound can be administered alone or as a composition in combination with a pharmaceutically acceptable diluent, excipient or carrier.

[0160] The actual dosage level of the active ingredient in the pharmaceutical preparation and pharmaceutical composition of the present invention can be varied so as to obtain the amount of the active compound that effectively achieves the desired therapeutic response for a specific patient, composition and mode of administration. The selected dosage level will depend on the activity of the specific compound, the route of administration, the severity of the condition being treated, and the condition and past medical history of the treated patient. However, it is within the skill of those skilled in the art to start the dosage of the compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. Suitable dosages are generally within the range of 0.01-100 mg / kg / day, for example, within the range of 0.1-50 mg / kg / day.

[0161] The pharmaceutical preparation of the present invention or composition for parenteral (e.g., intravenous) injection may include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstructing into sterile injection solutions or dispersions before use. The example of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients includes water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters, such as ethyl oleate. For example, it is possible to maintain suitable fluidity by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions and by using a surfactant. The preparation or composition for parenteral injection may represent preferred formulations or compositions of the present invention.

[0162] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. By adding various antibacterial and antifungal agents, such as parabens, chlorobutanol or phenol sorbic acid, it is possible to ensure that the action of microorganisms is inhibited. It may also be desirable to include isotonic agents, such as sugar or sodium chloride. The extended absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0163] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or one or more of the following: a) fillers or extenders (such as starches, lactose, sucrose, glucose, mannitol and silicic acid); b) binders (such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia); c) humectants (such as glycerol); d) disintegrants (such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate); e) solution retarding agents (such as paraffin); f) absorption accelerators (such as quaternary ammonium compounds); g) wetting agents (such as cetyl alcohol and glyceryl monostearate); h) absorbents (such as kaolin and bentonite), and i) lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using, for example, such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0164] Oral preparations may contain a dissolution aid. Examples of dissolution aids 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 sulfides, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol ... glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkanolamides and alkylamine oxides; bile acids and their salts (e.g., chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and their salts, and glycine or taurine conjugates thereof); ionic surfactants, such as sodium dodecyl 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, such as betaines and aminocarboxylates.

[0165] Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical preparation field. They may optionally contain opacifying agents and may also be compositions such that they release the active ingredient only or preferably in a certain part of the intestinal tract and / or in a delayed manner. Examples of embedding compositions include polymeric substances and waxes.

[0166] The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0167] The active compound may be in finely divided form, for example may be micronized.

[0168] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly 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 the inert diluent, the oral composition can also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0169] Compositions for rectal or vaginal administration may be in the form of suppositories which may be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0170] The dosage form of the compound of the present invention for topical application includes powders, sprays, creams, foams, gels, ointments and inhalants. The active compound is mixed with a pharmaceutically acceptable carrier and any required preservative, buffer or propellant under aseptic conditions. Ophthalmic preparations, eye ointments, powders and solutions are also considered to be within the scope of the present invention.

[0171] Liquid (e.g., aqueous) preparations and compositions, whether for parenteral or oral use, can include additional compounds to help prevent precipitation of the active compound. The compounds of the present invention are glycopeptide derivatives. By adding monosaccharides to the solution, precipitation of these compounds in aqueous solutions can be avoided or minimized. For example, aqueous preparations or compositions can include glucose. In particular, parenteral (e.g., intravenous) preparations or compositions can include compounds of the present invention, water for injection, and glucose.

[0172] The formulations or compositions according to the inventive subject matter may contain other active agents, in particular active agents useful in treating bacterial infections, to the extent that they do not interfere with the activity of the compounds.

[0173] The formulations according to the present subject matter may also contain inactive ingredients. Suitable inactive ingredients are well known in the art and are described in standard textbooks, such as 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 Ed., Mack Publishing Co., Easton, Pa. (1990), both of which are incorporated herein by reference in their entirety.

[0174] These preparations can be used in combination with additional pharmaceutical dosage forms to enhance their effectiveness in treating any of the diseases described herein. In this regard, the preparations of the present invention can be used as part of a regimen that also includes any other drugs and / or pharmaceutical dosage forms known in the art to be effective in treating any of these diseases.

[0175] use

[0176] The compounds of the present invention represent novel guanidine-containing derivatives of the glycopeptide vancomycin.

[0177] Vancomycin is an antibiotic active against Gram-positive bacteria because it interferes with the synthesis of the peptidoglycan layer of Gram-positive bacteria according to the following mechanism. Critical to peptidoglycan biosynthesis is lipid II, the penultimate bacterial cell wall building block. Vancomycin binds tightly to the terminal d-Ala-d-Ala motif of the lipid II pentapeptide.

[0178] Resistance to vancomycin is increasing because many bacterial strains have emerged that can use lipid II variants containing the d-Ala-d-Lac terminal pentapeptide. This d-Lac mutated to d-Ala reduces the affinity of vancomycin for lipid II and thus greatly reduces its antibacterial effect (Healy, VL, et al. (2000) Vancomycin resistance in enterococci: reprogramming of the D-ala-D-Al a 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 which are incorporated herein by reference in their entirety). We have noted that this resistance pattern is partially overcome in some related lipoglycopeptides, where the attachment of a hydrophobic group to the vancomycin unit enhances activity. This is represented 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 which are incorporated herein by reference in their entirety). Although telavancin is more effective than vancomycin, it is not without its drawbacks. Compared to vancomycin, telavancin has a significantly reduced solubility in aqueous media and also poses serious health risks.The FDA recently applied a black box warning to telavancin due to suspected effects on heart rate (QT interval prolongation) and increased mortality compared with vancomycin in patients with renal insufficiency (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, which is incorporated herein by reference in its entirety). Therefore, telavancin is considered a last resort drug and is used only when other treatments have failed.

[0179] The compounds provided herein represent antibiotics, particularly antibiotics for treating conditions associated with Gram-positive bacterial infections. Compared with known antibiotics such as vancomycin, telavancin, teicoplanin, oritavancin and / or dalbavancin, the compounds of the present invention can provide similar or better antibiotic activity, for example, as measured by MIC. The compounds of the present invention can also provide good safety.

[0180] When compound is used for treating bacterial infection, bacterial infection may be caused by gram-negative or gram-positive bacteria. For example, bacterial infection can be caused by bacteria from one or more (e.g., at least one) following families: clostridium, pseudomonas, escherichia, klebsiella, enterococcus, enterobacter, serratia, stenotrophomonas, aeromonas, morganella, yersinia, salmonella, proteus, pasteurella, haemophilus, citrobacter, burkholderia, brucella, moraxella, mycobacterium, streptococcus or staphylococcus. Specific example includes clostridium, pseudomonas, escherichia, klebsiella, enterococcus, enterobacter, streptococcus and staphylococcus. The bacterial infection can be caused, for example, by one or more bacteria selected from the group consisting of Moraxella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter rodentium, Escherichia coli, Haemophilus pneumoniae, Klebsiella pneumoniae, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium, Clostridium difficile, Yersinia enterocolitica, Mycobacterium tuberculosis, Staphylococcus aureus, Group B Streptococcus, Streptococcus pneumoniae, and Streptococcus pyogenes.

[0181] The compounds of the present invention are particularly suitable for treating bacterial infections caused by gram-positive bacteria. For example, bacterial infections can be caused by bacteria from one or more (e.g., at least one) of the following families: Staphylococci (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococci (e.g., Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, Streptococcus pneumoniae), Enterococci (e.g., Enterococcus faecalis), Bacillus, Clostridium, Listeria, and Corynebacterium. Bacterial infections can be caused by bacteria from one or more (e.g., at least one) of the following families: Staphylococci (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), Streptococci (e.g., Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, Streptococcus pneumoniae), Enterococci. The bacterium can be resistant to the treatment of methicillin and / or vancomycin, for example, the bacterium can include methicillin and / or vancomycin resistant Staphylococcus (e.g., Staphylococcus aureus), Streptococcus or Enterococcus (e.g., Enterococcus faecium, Enterococcus faecalis) strains. Bacterial infection can include infection caused by vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Staphylococcus aureus (VRSA). Bacterial infection can include infection with Staphylococcus aureus or Enterococcus faecium. Bacterial infection can include infection caused by one or more of Staphylococcus aureus ATCC29213, Staphylococcus aureus USA300, Enterococcus faecium E155, Enterococcus faecium E7314, Enterococcus faecium E980, Enterococcus faecium E1246 or Enterococcus faecium E7406.

[0182] Exemplary bacterial (e.g., Gram-positive) infections that can be treated with the compounds of the invention include skin and structural infections, lower respiratory tract infections, bacteremia, sepsis, infective endocarditis, peritonitis (e.g., associated with continuous ambulatory peritoneal dialysis), enterocolitis (e.g., Staphylococcus), mastitis, diarrhea and colitis associated with Clostridium difficile infection. Infections that can be treated can be selected from skin and structural infections and bacteremia. Exemplary skin and structural infections include cellulitis / erysipelas, large skin abscesses, and wound infections. Such skin and structural infections may be due to Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginae (including Streptococcus angiospermicus, Streptococcus intermedius, Streptococcus constellatus), or Streptococcus faecalis. Exemplary lower respiratory tract infections include pneumonia, community-acquired pneumonia (CAP), hospital-acquired pneumonia, and pleural empyema.

[0183] Synthesis of compounds

[0184] The compounds of the present invention can be prepared according to reaction schemes A and B. Scheme A illustrates a general scheme that can be used, while Scheme B outlines a method that can be used for exemplary compounds. As the skilled artisan will appreciate, Scheme B can be readily adapted to provide additional compounds wherein substituents R1 and R2 are defined as for the present invention and disclosed compounds.

[0185] Reaction Scheme A

[0186]

[0187] R1, R2, R3, R4 and L1 are as defined for the present invention and disclosed compounds.

[0188] Reaction Scheme B

[0189]

[0190]

[0191] test

[0192] The biological activity of the compounds of the invention may be assessed using any suitable assay known to those skilled in the art. Exemplary assays for evaluating the compounds of the invention are provided in the following paragraphs.

[0193] Minimum inhibitory concentration

[0194] The antibacterial activity of the compounds was tested against a panel of bacteria including Gram-positive bacteria (Staphylococcus aureus ATCC29213, Staphylococcus aureus USA300, Staphylococcus aureus LIM-2, NR-45881, Staphylococcus aureus HIP13419, NR-46413, Enterococcus faecium E155, Enterococcus faecium E7314, Enterococcus faecium E980, Enterococcus faecalis E1246, Enterococcus faecalis E7406 and Streptococcus pneumoniae 153). The compounds were further tested for their antibacterial activity 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 some Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae). The minimum inhibitory concentration (MIC) in μg / mL was performed according to the CLSI guidelines. Bacterial strains from glycerol stocks were cultured 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). For enterococci, VISA and VRSA strains, the cultures were grown at 37°C until the optical density of the suspension reached a level equivalent to the 0.5 McFarland standard. Dilute the bacterial suspension to 10% with TSB containing 0.002% p80 6 Bacterial cell density was calculated by measuring the bacterial cell density of CFU / mL. For other (vancomycin-susceptible) S. aureus strains, direct colony suspension was used. For these strains, colonies were immediately diluted to 10 after transfer to TSB containing 0.002% p80. 6 CFU / mL rather than incubation prior to dilution. In the case of S. pneumoniae, direct colony suspension was used by immediately suspending multiple colonies from a fresh blood agar plate in TSB + 0.002% p80 to an OD of 600 0.5, then diluted to 10 with TSB + 0.002% p80 + 5% dissolved horse blood 6 CFU mL -1 Antibiotic dilutions for this strain were also prepared in TSB + 0.002% p80 + 5% dissolved horse blood. Agar and microtiter plates containing S. pneumoniae were incubated at 37°C with 5% CO2 for 24 h with constant shaking (600 rpm). In the case of the VRSA strain, the medium was supplemented with 6 μg mL -1 Vancomycin. The culture was grown at 37°C until exponential phase (OD 600 =0.5). The bacterial suspension was diluted with TSB containing 0.002% p80 (for VRSA, vancomycin was not added to the culture medium here) to reach 10 6 CFU mL-1 In a polypropylene 96-well microtiter plate, test compounds were added in triplicate and serially diluted 2-fold by transfer and mixing from one well to the next to achieve a final volume of 50 μL per well. 6 CFU mL -1 ) were added to the wells. The plates were sealed with a breathable membrane and incubated at 37°C with constant shaking (600 rpm) for 24 hours. In a polypropylene microtiter plate, 100 μL of the test compound was added in triplicate to the first row, and 50 μL of culture medium was added to the other wells. The compounds were serially diluted by transferring and mixing 50 μL from one well to the next. Subsequently, 50 μL of bacterial suspension (10 6 CFU / mL) was added to the wells. The plates were sealed with a breathable membrane and incubated at 37°C with continuous shaking (600 rpm) for 24 hours. The positive growth control consisted of wells containing bacterial suspension and no antibiotics. The negative growth control consisted of medium without bacterial suspension or antibiotics only. The MIC was determined by the median of at least three replicates. The MIC in the presence of serum followed the same protocol, but TSB + 0.002% p80 + 50% serum was used as the growth medium.

[0195] Hemolysis

[0196] Defibrinated sheep whole blood (4 mL) was centrifuged at 400 g for 15 minutes at 4°C. The upper layer was discarded, the lower layer was washed with phosphate buffered saline (PBS) and centrifuged at 400 g for 15 minutes at 4°C. The washing cycle was repeated three times. Polypropylene microtiter plates were prepared by adding 150 μL of compounds in PBS containing 0.002% p80 (256 μg / mL, containing ≤1% DMSO) in triplicate to the first row. PBS (75 μL) containing 0.002% p80 was added to all other wells. Compounds were serially diluted by transferring and mixing 75 μL from one well to the next. Concentrated blood cells were diluted 25 times with PBS containing 0.002% p80, and 75 μL of this solution was added to all wells. The final concentration range of the test compound in the plate was 2-128 μg / mL. The plate was incubated at 37°C with continuous shaking (500 rpm) for 18 hours. After incubation, the plate was centrifuged at 800g for 5 minutes and 25 μL of supernatant was transferred to a UV-star flat-bottom polystyrene plate. 100 μL of MQ-H2O was added to all wells of the UV-star plate and the absorbance was measured at 415 nm. The positive control wells (100% hemolysis) consisted of 0.1% Triton X-100 containing blood cells. The negative control wells (no hemolysis) consisted of 1% DMSO containing blood cells. In a separate experiment, the optimal wavelength for the hemolysis test was determined by performing a full scan. In another separate experiment, the linear detection range was determined, based on which a 25-fold blood cell dilution was selected in the main experiment.

[0197] UDP-MurNAc-pentapeptide accumulation

[0198] Overnight cultures of bacterial suspensions (Staphylococcus aureus ATCC29213, Enterococcus faecium E155, Enterococcus faecium E7314, and Enterococcus faecium E980) were diluted 100-fold in TSB supplemented with 0.002% p80 and cultured at 37°C until the optical density of the suspension reached a level equivalent to that of the 0.5McFarland standard. Chloramphenicol was added at a final concentration of 130 μg / mL, and the culture was cultured for another 15 minutes at 37°C. Next, the culture was divided into 5 mL cultures, and test antibiotics (vancomycin, 5, 6, 7, 14, 16) were added at a final concentration of 5 μM. Vancomycin (5 μM) was used as a positive control, and untreated samples were used as negative controls. The culture was cultured at 37°C for 1 hour, and then the bacteria were centrifuged and precipitated. The supernatant was removed and the precipitate was resuspended in 1 mL MQ-H2O. The samples were boiled at 100°C for 15 minutes and then centrifuged at 12000 rpm for 30 minutes. The supernatant of the sample was lyophilized and redissolved in 250 μL buffer A (50 mM ammonium bicarbonate, 5 mM NEt3, pH 8.3). The samples were analyzed by analytical RP-HPLC using a 0-25% buffer B (MeOH) gradient for 25 minutes.

[0199] Lipid II antagonism assay

[0200] An appropriate amount (5-fold molar excess compared to the test antibiotic) of lipid II in chloroform was added to a 96-well plate and the chloroform was evaporated. The test antibiotics (vancomycin, telavancin, 5, 6, 7, 14, 16) were dissolved in DMSO at a high stock concentration of 12.8 mg / mL and then diluted to a concentration of 16xMIC using TSB supplemented with 0.002% p80 (containing no more than 1% DMSO). Of these dilutions, 50 μL was mixed with a 5-fold molar excess of pure lipid II in the plate, in triplicate, and added to the plate in triplicate in the absence of lipid II. Staphylococcus aureus ATCC29123 colonies were suspended in TSB containing 0.002% p80 by direct colony suspension to an optical density equivalent to a 0.5 McFarlan standard. The bacterial suspension was diluted to 106 CFU / mL in TSB containing 0.002% p80, and then 50 μL was added to the test compound in the microtiter plate to achieve a final concentration of 8xMIC for the test compound. The samples were cultured at 37°C with continuous shaking (600 rpm) for 24 hours and checked for visible bacterial growth. The positive growth control consisted of a well containing a bacterial suspension and no antibiotics or lipid II. The negative growth control consisted of medium without bacterial suspension, antibiotics or lipid II only.

[0201] Serial passage assay for drug resistance development

[0202] Bacterial strains from glycerol stocks were cultured on blood agar plates and incubated overnight at 37°C. Single colonies were grown to exponential phase (OD600=0.5) in TSB+0.002% p80 and diluted 1:100 in fresh medium. In polypropylene 96-well microtiter plates, antibiotics were added in triplicate and serially diluted 2-fold by transferring and mixing from one well to the next well to reach a final volume of 50 μL per well. An equal volume of bacterial suspension was added to the wells and the plates were incubated overnight at 37°C. Bacterial cultures corresponding to 0.25xMIC were diluted 100-fold in fresh medium and added (50 μL per well) to a freshly prepared antibiotic dilution series (50 μL per well) and then incubated overnight at 37°C. This procedure was repeated for 30 days, with MIC recorded every day. Cultures containing daptomycin were supplemented with 50 mg L -1 CaCl2 and 10 mg L -1 MgSO4. The experiment was performed in triplicate and for each replicate, the MIC was determined from the median of a minimum of three replicates.

[0203] Time Killing Test

[0204] Bacterial strains from glycerol stocks were cultured 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 in fresh medium and grown to early exponential phase (OD 600 =0.2-0.4), and then diluted in culture medium to OD 600 =0.0025. The culture was divided into separate culture tubes containing 2 mL. Antibiotics (concentrations as shown in the experimental results) were added to the culture and incubated at 37°C for a total of 24 hours. At the specified time points (t=0, t=1, t=2, t=4, t=8 and t=24 hours), 100L of each culture was transferred to eppendorfs and centrifuged for 5 minutes (10,000rpm). The supernatant was removed and the cell pellet was resuspended in an equal volume of 0.9% NaCl aqueous solution (filter sterilized). The sample was diluted continuously in a filter-sterilized 0.9% NaCl aqueous solution by a factor of 10. In these serial dilutions, 100-fold, 1000-fold, 10,000-fold and 100,000-fold dilutions were spread on blood agar plates (20L) in duplicate, then allowed to evaporate and incubated at 37°C for 24 hours. Count the colonies and calculate the CFU (mL) remaining in the original culture by taking into account the dilution factor. -1 The experiments were performed in duplicate.

[0205] HepG2 cytotoxicity assay

[0206] Mammalian cell toxicity assay was performed by Cyprotex. Cytotoxicity was assessed using the MTT method. In brief, HepG2 human hepatoma cells (100 μL per well) were plated on black-walled, transparent-bottomed polystyrene 96-well tissue culture treated plates 24 hours before cell administration. Test compounds (dissolved in 0.5% DMSO in growth medium containing 10% FBS) were administered to 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, cells were loaded with MTT dye (yellow; 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolyl bromide) and then incubated for another 1 hour (the total incubation time for the final antibiotic was 24 hours). Subsequently, the plate was dried and 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 hydrogenases in living cells. The production of formazan indicates loss of mitochondrial function and cell loss. Carbonyl cyanide 3-chlorophenylhydrazone was used as a non-reactive control, and chlorpromazine was used as a control known to be cytotoxic. Then, solvent control wells (0.5% DMSO in growth medium containing 10% FBS) were used to determine the significance limits of wells with low or high responder scores higher than expected. If a clear dose-response relationship is observed, or at least two consecutive concentration points are above the significance level, the minimum effective concentration is determined from the lowest concentration at which the mean exceeds the significance level. If a clear dose-response relationship is observed, the AC50 value can also be determined. The experiment was performed in triplicate.

[0207] In vivo studies

[0208] Mouse studies used pathogen-free CD1 mice (ICR), a well-characterized outbred mouse strain (provided by Charles River, Margate UK). All mice were male, weighed 11-15 grams upon arrival, and were adapted for at least 7 days before the start of the study. The mice were housed individually in sterile ventilated cages, provided with HEPA-filtered sterile air and poplar sheet bedding (changed at least once a week). Food and water were available ad libitum. The room temperature was 22°C ± 1°C, the relative humidity was 60%, and the maximum background noise was 56 dB. The mice were exposed to a 12-hour light / dark cycle.

[0209] Tolerance

[0210] In naive mice (n=2) that were not immunosuppressed or infected, 100 mg kg -1 The tolerability of Compound 5 was assessed by subcutaneous injection (in 10% DMSO water for injection).

[0211] PK

[0212] In naive mice (n=3) that were not immunosuppressed or infected, 3 mg kg -1 The test article 5 was injected subcutaneously at a dose of 5. Whole blood was collected from the tail vein at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours and 8 hours. The last sample was a final cardiac puncture.

[0213] effect

[0214] 150 mg kg was injected subcutaneously 4 and 1 day before infection -1 and 100 mg kg -1 Cyclophosphamide induced neutropenia in mice. Under temporary anesthesia, both thighs of mice were infected intramuscularly with MRSA USA300 strain NRS384 (1.47 x 10 6 CFU mL -1 , each thigh 7.33×10 4 CFU). Starting 1 hour after infection, vehicle (10% DMSO in water for injection) was used every 6 hours and 25 mg kg -1 Vancomycin (in water for injection), 3 mg kg every 6 hours -1 or 10 mg kg -1 Mice were treated with compound 5 (in 10% DMSO in water for injection). The pre-treated group was euthanized 1 hour after infection, and the other treatment groups were euthanized 23 hours after infection. The weighed thighs were homogenized and incubated on MSA agar at 37°C for 18-24 hours, followed by colony counts. Each group consisted of n = 6 mice with both thighs infected (n = 12 thighs per treatment group), and each thigh was treated as a separate sample. Data analysis was performed using StatsDirect software v.3.2.8 using nonparametric statistical models (Kruskal-Wallis using Conover-Inman for all pairwise comparisons between groups).

[0215] Example

[0216] Thin layer chromatography (TLC) was performed on SiliaPlate TLC plates (SiliCycle, glass backing, silica gel, 250 μm). Visualization was performed using UV light, ninhydrin stain, permanganate stain, or ceric ammonium molybdate stain. P60 silica gel (SiliCycle) carries out silica gel column chromatography.Use Reprosil Gold 120C1810 μ m post (length: 250mm, ID: 25mm, batch number: 8768, part number: r10.9g.s2525, serial number: 18020211570.Dr Maisch GmbH) and BESTA pump, FLASH 10DAD UV detector and SCPA PrepCon 5 software by preparative reverse phase high performance liquid chromatography (RP-HPLC) purification final compound.Phemomenex Jupiter su C18 300A post (250x4, 60mm, 5mm) is used to analyze HPLC to assess compound purity on Shimadzu LC-2030Plus instrument.All spectra showing purity are recorded at 214nm. Except in the uridine diphosphate N-acetylmuramic acid pentapeptide (UDP-MurNAc-pp) accumulation analysis, in all cases, the buffer used for preparation and analysis of HPLC was 50mM ammonium acetate as buffer A and 95% MeCN + 5% H2O as buffer B. In this analysis, Phemomenex Jupiter su C18 300A column (250x4, 60mm, 5mm) was used to analyze on a Shimadzu LC-2030Plus instrument. The buffer was 50mM ammonium bicarbonate, 5mM NEt3, pH 8.3 as buffer A, MeOH as buffer B, and the displayed data were recorded at 254nm. The samples were lyophilized on a VirTis BenchTop Pro with Omnitronics. Nuclear magnetic resonance (NMR) spectra were obtained from a Bruker DPX-300 superconducting magnet with a field strength of 7.0 Tesla, equipped with a 5 mm BBO, Broadband Observe probe, high-resolution Z-Gradient, and 5 mm 19 F / 1H dual high-resolution probe. High-resolution mass spectrometry (HR-MS) analysis was performed on a Thermo Scientific Dionex UltiMate 3000 HPLC system with a Phenomenex Kinetex C18 column (2.1x150 mm, 2.6 μm) at 35°C and equipped with a diode array detector. The following solvent system was used with a flow rate of 0.3 mL / min: solvent A, 0.1% formic acid in water; solvent B, 0.1% formic acid in acetonitrile. The gradient elution was as follows: 95:5 (A / B) for 1 min, 95:5 to 5:95 (A / B) for 9 min, 5:95 to 2:98 (A / B) for 1 min, 2:98 (A / B) for 1 min, then back to 95:5 (A / B) in 2 min, 95:5 (A / B) for 1 min. The system was connected to a Bruker micrOTOF-Q II mass spectrometer (electrospray ionization) internally calibrated with sodium formate. Tecan Spark was used for absorbance measurements.

[0217] The bacterial strains used were Staphylococcus aureus ATCC 29213 (MSSA, Rosenbach strain), Staphylococcus aureus USA300 (MRSA, hospitalized patient, Texas, USA, PFGE type: USA300.SCCmec Iva type), Enterococcus faecium E155 (VRE, hospitalized patient, Chicago, USA, VanA gene, MIC vancomycin 1024, 1995), Enterococcus faecium E980 (VSE, human community isolate (commensal), VanA without VanB gene, 1998), Enterococcus faecium E7314 (VRE, hospitalized patient, NLD, VanB gene), Enterococcus faecalis E1246 (VRE, VanA gene, clinical isolate) and Enterococcus faecalis E7406 (VRE, VanB gene, clinical isolate).

[0218] Example 1: Synthesis of Compound 1: O-allyl carbonyl isothiocyanate

[0219]

[0220] Compound 1 was synthesized according to a published literature procedure (Martin, NI, Woodward, JJ & Marletta, MANG-Hydroxyguanidines from Primary Amines. Org. Lett. 8, 4035–4038 (2006)). Briefly, 18-crown-6 (924 mg, 3.5 mmol, 0.05 eq.) and allyl chloroformate (7.4 mL, 70 mmol, 1 eq.) were added to a solution of potassium thiocyanate (9 g, 92 mmol, 1.3 eq.) in CCl4 (200 mL), and 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 for further use. The crude product of 1 was used in the next reaction.

[0221] Example 2: Synthesis of Compound 2: 4-(1,3-dioxolane-2-yl)aniline

[0222]

[0223] Compound 2 was synthesized according to the improved literature procedure (Hughes, A. et al. Diamide compounds having muscarinic receptor antagonist and β2andrenergic receptor agonist activity (2010)). Under a nitrogen atmosphere, a solution of 2-(4-nitrophenyl)-1,3-dioxolane (9.8 grams, 50mmol, 1 equivalent) and NaHCO3 (4.3 grams, 50mmol, 1 equivalent) in EtOH (350mL) was added with monohydrated platinum (iv) oxide (1.2 grams, 5mmol, 0.1 equivalent). The reaction mixture was sprayed with hydrogen for 15 minutes, and then stirred at room temperature for 18 hours under a hydrogen atmosphere. Next, the solution was filtered through diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to obtain 2, which was immediately used in the next step as a crude product.

[0224] Example 3: Synthesis of Compound 3

[0225]

[0226] To a crude solution of 2 (50 mmol, 1 eq.) and DIPEA (8.7 mL, 50 mmol, 1 eq.) in DCM (50 mL) was added 1 at room temperature until TLC (in DCM containing 5% EtOAc) confirmed complete conversion of 2 to 3. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (DCM, gradient increasing to 5% EtOAc). Yield over two steps; 77%. 1H-NMR (300MHz, 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=17.2,1.4Hz,1H),5.33(dd,J=10.4,1.2Hz,1H),4.70(dt,J=5 .8,1.3Hz,2H),4.18–3.98(m,4H).13C-NMR(75MHz,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 / z309.0913(observed),309.0909(calculated for [M+H+]).

[0227] Example 4: Synthesis of trans, trans-farnesyl bromide: (E)-1-bromo-3,7-dimethylocta-2,6-diene

[0228]

[0229] (E)-1-Bromo-3,7-dimethylocta-2,6-diene was synthesized according to a modified literature procedure (Zahn, T.J. 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, J.M., Naider, F. & Gibbs, R.A. Synthesis and Biological Evaluation of the Geometric Farnesylated Analogues of the a-Factor Mating Peptide of Saccharomyces cerevisiae. J. Org. Chem. 65, 8552–8563 (2000)). Briefly, triphenylphosphine (4 mL, 18 mmol, 1 eq.) and tetrabromomethane (7.4 g, 22.5 mmol, 1.25 eq.) were added to a DCM solution of trans, trans-farnesol (4.5 mL, 18 mmol, 1 eq.) under an argon atmosphere. The reactants were stirred at room temperature for 4 hours. After removal of the solvent under reduced pressure, hexane (15 mL) was added to the residue to precipitate the by-products. The mixture was centrifuged (4500 rpm, 5 minutes) and the supernatant was concentrated under reduced pressure. Three additional cycles of precipitation-centrifugation-evaporation were performed, after which crude trans, trans-farnesyl bromide was obtained and used directly in the next step.

[0230] 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-trimethyldodecyl-2,6,10-trien-1-amine

[0231]

[0232] (E)-3,7-Dimethylocta-2,6-dien-1-amine and (2E,6E)-3,7,11-trimethyldodecyl-2,6,10-trien-1-amine were synthesized according to modified literature methods (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, MA Convenient Preparation of Farnesylamine. Synth. Commun. 23, 535–541 (1993)). In brief, pure trans-geranyl bromide or crude trans-, trans-farnesyl bromide (1 equivalent) was added to lithium bis(trimethylsilyl)amide (10 mL, 1 M in THF) under an argon atmosphere. The reaction was stirred at room temperature for 18 hours and then quenched with saturated ammonium chloride solution. The mixture was extracted twice with methyl tert-butyl ether, and the organic phases were combined and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure to give 2xTMS amine. The product was dissolved in 40 mL of methanol and 5 mL of DCM and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to give crude trans-geranylamine or trans-, trans-farnesylamine, which was immediately used in the next step.

[0233] Example 6: Synthesis of chlorobenzidine: 4'-chloro-[1,1'-biphenyl]-4-yl)methylamine

[0234]

[0235] 4'-Chloro-[1,1'-biphenyl]-4-yl]methylamine was prepared according to a published literature procedure (Lee, H. et al. (Biphenyl-4-yl)methylammonium Chlorides: Potent Anticonvulsants That Modulate Na+ Currents. J. Med. Chem. 56, 5931–5939 (2013)). To a solution of 4-bromobenzylamine (4.32 g, 23 mmol, 1 eq) in MeCN (250 mL) was added 4-chlorophenylboronic acid (4 g, 26 mmol, 1.1 eq), Pd(PPh3)4 (1.36 g, 1.16 mmol, 0.05 mmol) and 2M K2CO3 aqueous solution (58 mL) under argon. After the solution was sparged with argon for 30 min, the reaction was stirred at 90°C under reflux for 16 h. The solvent was removed under reduced pressure. The obtained residue was dissolved in EtOAc (100mL) and washed with water (2×100mL) and brine (2×100mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was redissolved in EtOAc, and concentrated hydrochloric acid aqueous solution (2mL) was added to cause precipitation. H2O was added to EtOAc and the layers were separated. The pH of the aqueous layer was adjusted with 4N NaOH and extracted with DCM (2x). The DCM layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. To the obtained residue redissolved in DCM, 4N HCl dissolved in dioxane was added to cause precipitation. The precipitate was filtered and washed with hexane to obtain 4'-chloro-[1,1'-biphenyl]-4-yl)methylamine as the final product, which was used in the next reaction step as a crude product.

[0236] Example 7: Synthesis of 4a

[0237]

[0238] To a solution of 3 (1.80 g, 5.8 mmol, 1 eq) in DCM was added hexylamine (1.5 mL, 11.7 mmol, 2 eq) and NEt3 (1.6 mL, 11.7 mmol, 2 eq). Subsequently, EDC HCl (2.2 g, 11.7 mmol, 2 eq) was added and the reaction mixture was stirred at room temperature. 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% EtOAc). Yield: 100%. 1H-NMR (300MHz, CDCl3) δ / ppm: 10.70 (s, 1H), 7.53 (d, J = 8.0Hz, 2H), 7.22 (d, J = 6.8Hz, 2H), 6.13–5.91 (m, 1H), 5.7 8(s,1H),5.34(d,J=17.3Hz,1H),5.21(d,J=10.4Hz,1H),4.62(d,J=5.6Hz,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). 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 (observed), 376.2236 (calculated for [M+H+]).

[0239] Example 8: Synthesis of 5a-16a

[0240] According to the scheme of 4a above, compounds 5a-16a were synthesized and purified using the corresponding aliphatic amines, except 16a, which produced a product mixture of 16a and 16b after reaction. 16a and 16b were combined and crudely used in the next step. The results of these compounds are summarized in Table 1.

[0241] Table 1: Compounds 5a-16a

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254] Example 9: Synthesis of 17a and 18a

[0255] According to the above scheme of 4a, compounds 17a and 18a were synthesized and purified using the corresponding aliphatic amines. The results for these compounds are summarized in Table 2.

[0256] Table 2: Compounds 17a and 18a

[0257]

[0258]

[0259] Example 10: Synthesis of 4b

[0260]

[0261] To a solution of 4a (2.19 g, 5.8 mmol, 1 eq) in THF was added 1 M aqueous HCl (11.7 mmol, 2 eq) and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NaHCO and the product was extracted twice with DCM. The organic layers were combined, dried over NaSO and filtered. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (2 / 1 PE / EtOAc). Yield: 100%. 1 H-NMR (300MHz, CDCl3) δ / ppm: 9.86 (s, 1H), 7.82 (d, J = 7.9Hz, 2H), 7.28 (d, J = 7.9Hz, 2H), 6.07–5.86 (m, 1H), 5.33 (dd, J = 17.2, 1.4Hz, 1H),5.23(dd,J=10.4,1.3Hz,1H),4.61(d,J=5.7Hz,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). 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 (observed), 332.1974 (calculated for [M+H+]).

[0262] Example 11: Synthesis of 5b-16b

[0263] Compounds 5b-16b were synthesized and purified according to the above scheme of 4b using their corresponding precursors (5a-16a). The results of these compounds are summarized in Table 3.

[0264] Table 3: Compounds 5b-16b

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] Example 12: Synthesis of 17b and 18b

[0278] Compounds 17b and 18b were synthesized and purified according to the above scheme of 4b using their corresponding precursors (17a and 18a). The results for these compounds are summarized in Table 4.

[0279] Table 4: Compounds 17b and 18b

[0280]

[0281]

[0282] Example 13: Synthesis of 4c

[0283]

[0284] Vancomycin hydrochloride (400 mg, 269 μmol, 1 eq) and DIPEA (0.23 mL, 1.35 mmol, 5 eq) were added to a DMF / MeOH (4 mL) solution of 4b (178 mg, 538 μmol, 2 eq). After stirring the reaction for 2 h at 70 °C under reflux conditions, NaBH3CN (169 mg, 2.69 mmol, 10 eq) was added and the reaction temperature was lowered to 50 °C. After 5 h, another 10 eq NaBH3CN (169 mg, 2.69 mmol) was added, and after 18 h, 10 eq NaBH3CN (169 mg, 2.69 mmol) and 1 eq 4b (89 mg, 269 μmol) were added. After another 18 hours, the reaction mixture was quenched by the addition of water. The solvent was evaporated under reduced pressure, the residue was redissolved in DMF, and precipitated twice in cold ether. The precipitate was dried and the crude product was used in the next step.

[0285] Example 14: Synthesis of 5c-16c

[0286] According to the above scheme of 4c, compounds 5c-16c were synthesized using their corresponding aldehyde precursors (5b-16b). Compounds 5c-16c were used as crude products in the next reaction step.

[0287] Example 15: Synthesis of 17c and 18c

[0288] According to the above scheme of 4c, compounds 17c and 18c were synthesized using their corresponding aldehyde precursors (17b and 18b). Compounds 17c and 18c were used as crude products in the next reaction step.

[0289] Example 16: Synthesis of 4

[0290]

[0291] To a solution of crude product 4c (269 μmol, 1 eq.) in anhydrous DMF (5 mL) was added Pd(PPh3)4 (78 mg, 67 μmol, 0.25 eq.) and phenylsilane (0.83 mL, 6.7 mmol, 25 eq.) under argon atmosphere. The reaction mixture was stirred at room temperature for 1 h under argon atmosphere. After complete deprotection, the reaction was quenched 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 all solid residues were removed by centrifugation. The supernatant was applied to preparative RP-HPLC and the product was purified using a 20-55% buffer B gradient within 50 minutes. The purity of the fractions was evaluated on analytical RP-HPLC using a 0-100% buffer B gradient within 30 minutes. The pure fractions were combined and freeze-dried to give a white powder. The purity of the combined final compound was assessed on analytical RP-HPLC using a 0-100% buffer B gradient over 60 minutes. Two step yield; 54.4%. HR-MS: m / z 840.3100 (observed), 840.3097 ([M+2H + ] / 2). Retention time RP-HPLC analysis: 20.37 minutes.

[0292] Example 17: Synthesis of 5-16

[0293] Using their corresponding precursors (5c-16c), compounds 5-16 were synthesized according to Scheme 4 above. The preparative RP-HPLC purification buffer gradient was adjusted for each compound based on the hydrophobicity of the R groups present. In addition, the percentage of buffer B present in the initial solvent system of the preparative RP-HPLC was also adjusted (from 20% to 50%) based on the hydrophobicity of the R groups. The results for these compounds are shown in Table 5.

[0294] Table 5: Compounds 5a-16a

[0295]

[0296] Example 18: Synthesis of 17 and 18

[0297] Compounds 17 and 18 were synthesized according to Scheme 4 above using their corresponding precursors (17c and 18c). The preparative RP-HPLC purification buffer gradient was adjusted for each compound based on the hydrophobicity of the R groups present. In addition, the percentage of buffer B present in the initial solvent system of the preparative RP-HPLC was also adjusted (from 20% to 50%) based on the hydrophobicity of the R groups. The results for these compounds are shown in Table 6.

[0298] Table 6: Compounds 17a and 18a

[0299]

[0300] Example 19: Minimum Inhibitory Concentration Test

[0301] In the MIC test, the activity of the compounds was evaluated against a group of Gram-positive bacteria. In this test, the minimum inhibitory concentration, i.e., the lowest tested concentration that prevents visible bacterial growth, is determined and compared with clinically used antibiotics. Compared with clinically used glycopeptides, almost all compounds have equal or better activity against most tested MRSA, MSSA, VRE, VSE, VISA, VRSA and S. pneumoniae strains. In some cases (depending on the compound and bacteria tested), the activity was increased by more than 1000 times compared to vancomycin (the data obtained are summarized in Table 7, MIC values ​​are in μg / mL). Tables 8-12 provide more MIC data.

[0302] Table 7: Clinically available glycopeptide antibiotics and MIC results of 4-18 against Gram-positive bacteria group.

[0303]

[0304]

[0305] Table 8: Clinically available glycopeptide antibiotics and 4-18 against vancomycin intermediates Staphylococcus aureus LIM-2, NR- MICs of 45881, vancomycin-resistant (VanA) Staphylococcus aureus HIP13419, NR-46413, and Streptococcus pneumoniae 153 result.

[0306]

[0307] Table 9: Clinically available glycopeptide antibiotics and further MIC results of 4-18 against Gram-positive bacteria group .

[0308]

[0309] Table 10: Clinically available glycopeptide antibiotics and 5, 6, 7, 12, 14 and 16 31 vancomycin-resistant Enterococcus faecium strains MIC results of bacterial strain groups.

[0310]

[0311]

[0312]

[0313] Table 11: Clinically available glycopeptide antibiotics and 5, 6, 7, 12, 14 and 16 MIC results against Gram-negative bacteria.

[0314]

[0315] Table 12: Clinically available glycopeptide antibiotics and 5, 12 and 16 rightVISA and VRSA strain groups MIC results.

[0316]

[0317]

[0318] In another MIC assay, In the presence of sheep serum , further evaluation of the compounds on MRSA USA300 strain active Cultures grown in the presence of serum used TSB + 0.002% P80 + 50% sheep serum as growth medium, as opposed to the normal MIC performed in TSB + 0.002% P80 alone.

[0319] Table 13: Clinically available glycopeptide antibiotics and 4-18 against MRSA USA300 in the presence of sheep serum MIC results.

[0320]

[0321]

[0322] Example 20: Testing of compounds in hemolytic assays

[0323] In the hemolysis test, sheep blood was treated with the test compound for 18 hours to determine whether the compound could lyse these blood cells. In general, the percentage of hemolysis seemed to increase as the lipid length increased. However, many compounds did not have hemolytic properties even at 1000 times the MIC (for some strains), which means that these compounds are non-hemolytic at relevant concentrations (the data obtained are summarized in Figure 1 ).

[0324] Example 21: Testing of compounds in the UDP-MurNAc-pentapeptide accumulation assay

[0325] UDP-MurNAc-pentapeptide accumulation analysis was performed to elucidate part of the mechanism of action of the compounds. UDP-MurNAc-pentapeptide is the final soluble precursor of peptidoglycan cell wall biosynthesis. In this assay, living cells accumulate this final soluble precursor when treated with compounds that interfere with the membrane-bound stage 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 tested in the assay, and all showed accumulation of UDP-MurNAc-pentapeptide (the data obtained are summarized in Figure 2This suggests that part of the molecule's mechanism of action involves interference with cell wall biosynthesis in Gram-positive bacteria. Figure 2 faecium E155, E7314 and E980 were tested and accumulation of UDP-MurNAc-pentapeptide was visible for all tested compounds in all tested strains (data not shown).

[0326] Example 22: Testing of Compounds in the Lipid II Antagonist Assay

[0327] 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 test, lipid II is incubated with the test antibiotic in the presence of bacterial culture. When lipid II binds to glycopeptides, the binding of these antibiotics to their targets in the growing bacterial culture is antagonized. This ultimately leads to reduced antibiotic activity, and bacterial growth that is usually invisible (at 8xMIC) becomes visible. Therefore, this test can be used to determine whether part of the mechanism of action of our compound involves binding to lipid II. All five tested compounds (5, 6, 7, 14, 16) showed bacterial growth after incubation with lipid II, indicating that binding of the compounds to lipid II is part of their mode of action, as is also the case for other clinically used glycopeptide antibiotics (the data obtained are summarized in Table 11).

[0328] Table 11. Lipid II antagonism assay - indicates no significant increase, + indicates significant increase.

[0329]

[0330] Example 23: Testing of compounds in a serial passage assay for drug resistance development The serial passage assay for drug resistance development was performed as described in the "Assay" section herein. The results obtained in this assay are shown in Table 2. Figure 3As shown. It is clear from the results that when MRSA is serially passaged in the presence of sublethal concentrations of antibiotics for more than 30 days, compounds 5 and 16 do not induce resistance, while clinically used daptomycin induces significant levels of resistance, increasing the MIC by 16-fold. In VanA type VRE strains, this difference is even more obvious: low-level resistance induction is observed for compounds 5 and 16, in contrast to high resistance induction with a 128-fold MIC increase for daptomycin.

[0331] Example 24: Testing of compounds in time kill assays

[0332] The time-killing experiment was performed as described in the "Assay" section of this article. The results obtained in this experiment are shown in Figure 4 middle.

[0333] Example 25: Mammalian cell toxicity test

[0334] Mammalian cell toxicity assay was performed as described in the "Experimental" section herein. The results obtained in this assay are shown in Table 12.

[0335] Table 12: MEC and AC50 of selected glycopeptides measured by MTT assay after 24 h in HepG2 cells grown in the presence of 10% FBS (n=3 replicates per concentration).

[0336]

[0337] Example 26: In vivo studies

[0338] As described in the "Experiments" section herein, several in vivo studies were performed. In particular, the tolerability, PK, and efficacy of the compounds were evaluated.

[0339] Tolerance

[0340] Compound 5 was administered to two mice at a dose of 100 mg / kg (SC) and was well tolerated. No adverse reactions and normal gross morphology were observed.

[0341] PK

[0342] Compound 5 was added at 3 mg kg -1 The drug was administered subcutaneously to mice and samples were taken continuously. Data are mean ± SD (n = 3). The pharmacokinetic data obtained are shown in Figure 5 As shown in Table 13.

[0343] Table 13: Compound 5 (3 mg kg -1 , subcutaneous) of individual and mean / median mouse pharmacokinetic parameters.

[0344]

[0345] effect

[0346] Colony-forming units in each thigh of neutropenic mice infected with MRSA followed by the first subcutaneous injection of the indicated concentration of antibiotics 1 h later and subsequent injections of the same doses at the indicated time intervals were performed and the bacterial load in homogenized thighs was determined after 23 h post-treatment (24 h post-infection). -1 Significant differences were found between vehicle and vancomycin at 3 mg kg -1 and 10 mg kg -1 Significant differences were found between vehicle and compound 5 (all p<0.0001) at 25 mg kg -1 Vancomycin and 10 mg kg -1 Significant differences were also found between compound 5 at 25 mg kg -1 Vancomycin and 3 mg kg -1 No significant difference was found between the two different doses of compound 5. A significant difference was found between the two different doses of compound 5 (p = 0.0001). Compared with pretreatment, vancomycin (25 mg kg -1 ) and compound 5 (3 mg kg -1 and 10 mg kg -1 ) also showed a significant decrease in thigh load (p=0.0042, p=0.0001 and p<0.0001, respectively). Data are mean±SEM (n=12, six mice per group, two thighs per mouse). Figure 6 The data obtained in this efficacy study are described.

[0347] Table 14: Colony forming units (CFU) g -1 Thigh load. BLD = below detection limit.

[0348]

[0349] Colony

[0350] Table 15: Kruskal-Wallis statistical comparison of thigh loads. Corrected for multiple comparisons, StatsDirect-Conover-Inman. NS = not significant.

[0351]

Claims

1. The compound of the formula in: R1 is selected from substituted or unsubstituted -C4-C 20 Cycloalkyl, substituted or unsubstituted -C1-C4 alkyl -C4-C 20 Cycloalkyl, substituted or unsubstituted -C4-C 20 Alkyl, substituted or unsubstituted -C4-C 20 alkenyl and substituted or unsubstituted -C1-C4 alkylaryl; R2 is selected from substituted or unsubstituted -C4-C 20 Alkyl and substituted or unsubstituted -C4-C 20 alkenyl; in, When substituted, any of the above groups is substituted by one or more substituents selected from the group consisting of -OH, -CN, -NH2, -NH(C1-C6 alkyl), -N(C1-C4 alkyl), =O, -halo, -C1-C6 alkyl, -C2-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkoxy, and -C2-C6 haloalkenyl, and -C1-C6 alkylcarboxylic acid; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1 is selected from -C6-C 14 Alkyl, -C6-C 16 alkenyl and substituted or unsubstituted -C1-C4 alkylbiphenyl.

3. The compound according to claim 1, wherein R1 is selected from -C6-C 14 alkyl, -C1-C4adamantyl, -adamantyl, -geranyl, -farnesyl and -chlorobiphenyl.

4. The compound according to claim 1, wherein R1 is selected from 5. The compound according to claim 1, wherein R2 is selected from -H, -C4-C 12 Alkyl, -C4-C 12 Alkenyl.

6. The compound of claim 1, wherein R2 is -H.

7. The compound according to claim 1, wherein R1 and R2 are each independently selected from -C2-C 10 Alkyl and -C2-C 10 Alkenyl.

8. The compound according to claim 1, wherein the substituted or unsubstituted -C4-C 20 The cycloalkyl group in the cycloalkyl group is a bridged cycloalkyl group.

9. The compound according to claim 1, wherein the substituted or unsubstituted -C1-C4 alkyl-C4-C 20 The cycloalkyl group in the cycloalkyl group is a bridged cycloalkyl group.

10. The compound according to claim 1, wherein R1 is selected from -C6-C 12 alkyl, -geranyl, -farnesyl and -chlorobiphenyl.

11. The compound according to claim 1, which is selected from: or a pharmaceutically acceptable salt thereof.

12. A formulation comprising the compound of any one of claims 1 to 11 and optionally a pharmaceutically acceptable carrier.

13. The preparation according to claim 12, wherein the preparation is a parenteral preparation or an oral preparation.

14. The formulation according to claim 12 or 13, wherein the formulation is a parenteral formulation.

15. The preparation according to claim 14, wherein the preparation is a preparation for intravenous injection.

16. Use of a compound according to any one of claims 1 to 11 or a formulation according to any one of claims 12 to 15 for the preparation of a medicament for treating a bacterial infection, wherein the bacterial infection is an infection caused by a gram-positive bacterium.

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