A pleuromutilin derivative, and a preparation method and use thereof

Abstract

The present application relates to a kind of pleuromutilin derivatives of formula I or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotopic derivative and pharmaceutically acceptable salt: Wherein, X is selected from O, S, NH, CH2 And carbonyl group;R is selected from substituted or unsubstituted aryl, heteroaryl and heterocyclic group, and the substitution is substituted by one or more Q;Q is selected from deuterium, halogen, cyano, oxo, hydroxyl, thiol, amino, alkyl, alkoxy, halogenated alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic group.The pleuromutilin derivative of the present application has better antibacterial activity.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a truncated pleurotin derivative, its preparation method, and its uses. Background Technology

[0002] Pleuroromutilin is a diterpenoid natural product with antibacterial properties. It is a white crystalline substance isolated from the fermentation broth of two fungi in the genus *Pleurotus* (Basidiomycetes): *Pleurotus mutilus* and *Pleurotus Passeckerianus*. It consists of a 5-6-8-membered ring backbone with eight chiral centers and a glycolate side chain (C-14 side chain). Pleuroromutilin compounds exhibit significant antibacterial activity against most Gram-positive bacteria, as well as mycoplasma and chlamydia. Its antibacterial effect is achieved by binding to the peptidyl transferase center of the 50S ribosomal subunit of bacteria, thereby inhibiting peptide bond formation.

[0003] The structural formula of truncated pleurotin is shown below:

[0004]

[0005] The truncated pleurotin tricyclic skeleton has been used as a precursor for semi-synthetic derivatives in veterinary and human medicine. Since its discovery in 1951, with continuous in-depth research, four truncated pleurotin antibiotics have been approved for marketing. Among them, tiamulin and vanemulin are veterinary drugs, mainly for the prevention and treatment of infections in poultry; retapamulin and lefamulin are human drugs. Lefamulin is the first antibiotic approved by the FDA in nearly 20 years for the treatment of community-acquired pneumonia.

[0006] The structural formula of tiamulin is shown below:

[0007]

[0008] The structural formula of Vorni Mullin is shown below:

[0009]

[0010] The structural formula of retaprine is shown below:

[0011]

[0012] The structural formula for Lefamorin is shown below:

[0013]

[0014] Due to the widespread use and even abuse of antibiotics, numerous bacteria have developed increasingly serious multidrug resistance, and the rise in antibiotic resistance has become a major threat to human health. Existing antibiotics such as cephalosporins, aminoglycosides, macrolides, and even polymyxins are ineffective against infections caused by certain "superbugs," or their widespread use is limited by severe adverse reactions. Therefore, developing antibiotics with good bioavailability and low toxicity is crucial for current drug development, and exploring truncated pleurotin natural derivatives is of great significance for developing new therapeutic effects in this class of antibiotics. Summary of the Invention

[0015] Based on the above-mentioned deficiencies in the prior art, the purpose of this invention is to provide a truncated pleurotin derivative or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts as shown in Formula I, which have superior antibacterial activity.

[0016] Therefore, the present invention provides the following technical solution.

[0017] The first objective of this invention is to provide a truncated pleurotin derivative of Formula I or a stereoisomer thereof, tautomer, solvate, hydrate, prodrug, stable isotopic derivative, and pharmaceutically acceptable salt thereof.

[0018]

[0019] in,

[0020] X is selected from O, S, NH, CH2, and carbonyl groups;

[0021] R is selected from substituted or unsubstituted aryl, heteroaryl, and heterocyclic groups, wherein the substitution is performed by one or more Q groups;

[0022] Q is selected from deuterium, halogen, cyano, oxo, hydroxyl, mercapto, amino, alkyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic.

[0023] Preferably, X is selected from O and S.

[0024] Preferably, X is selected from S.

[0025] Preferably, the R is selected from substituted or unsubstituted aryl and heteroaryl groups; more preferably from substituted or unsubstituted C 6-10 Aryl and 5-10-membered heteroaryl, wherein the heteroaryl contains 1-4 heteroatoms selected from N, O and S; preferably self-substituted or unsubstituted phenyl and 6-10-membered heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from N and O; preferably self-substituted or unsubstituted phenyl and 10-membered heteroaryl, wherein the heteroaryl has 1 heteroatom selected from N.

[0026] Preferably, Q is selected from deuterium, halogen, cyano, oxo, hydroxyl, mercapto, amino, alkyl, alkoxy, haloalkyl, and aryl; more preferably from cyano, oxo, aryl, and C. 1-6 Alkyl and C 1-6 Alkyl group; preferably cyano, oxo, and phenyl.

[0027] Preferably, R is selected from any of the following:

[0028]

[0029] A second objective of this invention is to provide a truncated pleurotin derivative or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, wherein the truncated pleurotin derivative is selected from any of the following:

[0030]

[0031] Preferably, the pharmaceutically acceptable salt is a salt formed by the truncated pleurotin derivative with hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, glutamic acid, aspartic acid, succinic acid, citric acid, or malic acid.

[0032] A third object of the present invention is to provide a pharmaceutical composition comprising, as described above, a truncated pleurotin derivative or its stereoisomer, tautomer, solvate, hydrate, prodrug, stable isotopic derivative, and pharmaceutically acceptable salt.

[0033] A fourth object of the present invention is to provide the use of the truncated pleurotin derivatives or their stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotopic derivatives and pharmaceutically acceptable salts, or pharmaceutical compositions as described above, in the preparation of antibacterial agents; preferably, the bacteria are methicillin-resistant Staphylococcus aureus MRSA ATCC 43300 and Staphylococcus aureus ATCC 29213.

[0034] The present invention has the following technical effects:

[0035] The truncated pleurotin derivative of Formula I provided by this invention has superior antibacterial activity and is simple to prepare. Attached Figure Description

[0036] Figure 1 This is the proton NMR spectrum of compound 1 in this invention;

[0037] Figure 2 This is the carbon spectrum of compound 1 in this invention;

[0038] Figure 3This is the proton NMR spectrum of compound 2 in this invention;

[0039] Figure 4 This is the carbon spectrum of compound 2 in this invention. Detailed Implementation

[0040] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0041] On one hand, the present invention provides a truncated pleurotin derivative of Formula I or a stereoisomer thereof, tautomer, solvate, hydrate, prodrug, stable isotopic derivative, and pharmaceutically acceptable salt thereof:

[0042]

[0043] in,

[0044] X is selected from O, S, NH, CH2, and carbonyl groups;

[0045] R is selected from substituted or unsubstituted aryl, heteroaryl, and heterocyclic groups, wherein the substitution is performed by one or more Q groups;

[0046] Q is selected from deuterium, halogen, cyano, oxo, hydroxyl, mercapto, amino, alkyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic.

[0047] In some implementations, X is selected from O and S.

[0048] In some implementations, X is selected from S.

[0049] In some embodiments, R is selected from substituted or unsubstituted aryl and heteroaryl groups.

[0050] In some embodiments, the R is selected from substituted or unsubstituted C. 6-10 Aryl and 5-10 heteroaryl groups, wherein the heteroaryl group contains 1-4 heteroatoms selected from N, O and S.

[0051] In some embodiments, R is selected from substituted or unsubstituted phenyl groups and 6-10 heteroaryl groups, wherein the heteroaryl group contains 1-2 heteroatoms selected from N and O.

[0052] In some embodiments, R is selected from substituted or unsubstituted phenyl groups and 10-membered heteroaryl groups, wherein the heteroaryl group has one heteroatom selected from N.

[0053] In some embodiments, Q is selected from deuterium, halogen, cyano, oxo, hydroxyl, mercapto, amino, alkyl, alkoxy, haloalkyl, and aryl.

[0054] In some embodiments, Q is selected from cyano, oxo, aryl, and C. 1-6 Alkyl and C 1-6 Alkyl group.

[0055] In some embodiments, Q is selected from cyano, oxo, and phenyl.

[0056] In some implementations, R is selected from any of the following:

[0057]

[0058] The present invention also provides a truncated pleurotin derivative or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, wherein the truncated pleurotin derivative is selected from any one of the following:

[0059]

[0060] In some embodiments, the pharmaceutically acceptable salt is a salt formed by the truncated pleurotin derivative with hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, glutamic acid, aspartic acid, succinic acid, citric acid, or malic acid.

[0061] The present invention also provides a pharmaceutical composition characterized in that it comprises the aforementioned truncated pleurotin derivative or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts.

[0062] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0063] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned truncated pleurotin derivative based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned truncated pleurotin derivative. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned truncated pleurotin derivative. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned truncated pleurotin derivative. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned truncated pleurotin derivative.

[0064] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.

[0065] All compounds disclosed herein, as well as mixtures and compositions containing compounds disclosed herein, can be formulated into a single dose, containing the active compound disclosed herein, as well as carriers, excipients, etc. The dosage form can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalers, suspensions, dry suspensions, patches, or lotions, etc. These dosage forms may contain commonly used pharmaceutical ingredients, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, isotonic adjusters, or anti-adhesives, etc.

[0066] The present invention also provides the use of the truncated pleurotin derivative or its stereoisomers, tautomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, or the use of the pharmaceutical composition thereof in the preparation of antibacterial agents.

[0067] In some embodiments, the bacteria are methicillin-resistant Staphylococcus aureus (MRSA ATCC 43300) and Staphylococcus aureus (S. aureus ATCC 29213).

[0068] Terminology Explanation:

[0069] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0070] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents selected from deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0071] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8), and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0072] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0073]

[0074] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0075]

[0076] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0077]

[0078] The cycloalkyl group includes cycloalkyl groups (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred

[0079] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0080] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, they are preferably one or more of the following groups, independently selected from deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0081] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) ring atoms, wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0082] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may be optionally oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0083]

[0084] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0085]

[0086] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0087]

[0088] The heterocyclic group further includes heterocyclic groups (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic groups) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0089] wait.

[0090] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0091] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0092]

[0093] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, oxo, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0094] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl includes heteroaryl groups fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples of heteroaryl groups include:

[0095]

[0096] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0097] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0098] The term "hydroxyl group" refers to -OH.

[0099] The term "amino" refers to -NH2.

[0100] The term "cyano" refers to -CN.

[0101] The term "thiol" refers to -SH.

[0102] The term "oxo" refers to =O.

[0103] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and hindered isomers, etc.

[0104] The term "tautomer" refers to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization, lactam-lactamimide isomerization, pyrazolyl isomerization, and so on.

[0105] The compounds disclosed herein include their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of this disclosure, in which hydrogen is replaced by "deuterium" or "tritium," or fluorine is replaced by 18F-fluorine labeling (18F isotope), or carbon atoms are replaced by 11C-, 13C-, or 14C-enriched carbon (11C-, 13C-, or 14C-carbon labeling; 11C-, 13C-, or 14C-isotope), are within the scope of this disclosure. Such compounds can be used as analytical tools or probes, for example, in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare deuterated compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds typically retain activity comparable to their undeuterated counterparts, and deuteration at certain sites can result in better metabolic stability, thus providing certain therapeutic advantages.

[0106] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0107] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0108] "Pharmaceutical-grade salts" refer to salts of the compounds disclosed herein that are safe and effective in mammalian use and possess the intended biological activity. Salts can be prepared independently during the final isolation and purification of the compounds, or by reacting suitable groups with suitable bases or acids. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases as well as organic bases. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

[0109] As used herein, the term "solvent" refers to the physical bond between a compound of this disclosure and one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonds. In some cases, such as when one or more, preferably one to three, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0110] "Prodrugs" refer to compounds that can be converted in the body to produce active drug compounds under physiological conditions, such as through hydrolysis in the blood.

[0111] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0112] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0113] The terms involved in this invention have been defined above. Those skilled in the art can also understand the above terms in conjunction with the prior art. The following is a further description based on the content of this invention and the definition of the terms.

[0114] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods not specifically described in the following examples are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages.

[0115] Furthermore, NMR spectra were obtained using a Varian 400MHz NMR spectrometer or equivalent equipment, typically with CDCl3 and DMSO-d6 as solvents, and chemical shifts were reported in ppm. The various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet). Coupling constants are expressed in Hz.

[0116] The abbreviations used in the experimental section are shown in Table 1.

[0117] Table 1

[0118] DCM dichloromethane <![CDATA[PPh3]]> Triphenylphosphine EtoAc Ethyl acetate DIEA N,N-Diisopropylethylamine

[0119] Example 1

[0120] The reaction formula for preparing compound 1 is as follows:

[0121]

[0122] Specifically, the steps include the following:

[0123] (1) Preparation of intermediate compound A

[0124] Add 40% sodium hydroxide (40.4 mg, 1.1 mmol) aqueous solution to 8 mL of methyl tert-butyl ether solution containing truncated pleurotin (379 mg, 1 mmol). After stirring the mixture, slowly add p-toluenesulfonyl chloride (210 mg, 1.1 mmol) overnight at room temperature. Extract the solvent with 3× NaCl and 3× H₂O, dry the bound organic layer with magnesium sulfate and evaporate, and purify by flash chromatography to give compound A (274 mg, 72%) as a white solid.

[0125] (2) Preparation of intermediate compound D

[0126] Cyclohexane-1,3-dione (compound B, 224 mg, 2 mmol) and 1,1-dimethoxy-n,n-dimethylmethaneamine (238 mg, 2 mmol) were added to 1,4-dioxycyclohexane and stirred at room temperature for 2 h. The solvent was evaporated to give crude product C. Crude product C, 2-cyanothioacetamide (100 mg, 1 mmol), and sodium methoxy (540 mg, 1 mmol) were placed in 10 mL of MeOH. The reaction was carried out at 65 °C and stirred for 3 h. The pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid, and the mixture was filtered and washed with MeOH to give 0.165 g of the orange substance, compound D.

[0127] (3) Preparation of compound 1

[0128] Compound D (102 mg, 0.5 mmol) was dissolved in 5 mL of MeOH, and 22 mg of NaOH was dissolved in 100 μL of H₂O. The two solutions were then mixed and stirred at room temperature for 10 minutes to obtain a mixed solution. 10 mL of compound A (226 mg, 0.5 mmol) dissolved in PPh₃ was added to the above mixed solution and stirred overnight. The reaction solution was extracted with DCM (3x), and the bound organic layer was dried on anhydrous sodium sulfate, filtered, and evaporated. Purification by flash chromatography yielded compound 1 (200 mg, 75%) as a white solid. The 1H NMR spectrum of compound 1 is shown below. Figure 1 Carbon spectrum Figure 2 .

[0129] 1H NMR (600MHz, DMSO-d6) δ8.49(s,1H),6.12(dd,J=17.8,11.2Hz,1H),5.54(d,J=8.4Hz,1H),5.05(d,J=17.8Hz,1H),4.99(d,J=11.2Hz,1H),4.53(d,J= 6.2Hz,1H),4.18(d,J=2.5Hz,2H),3.42(d,J=6.0Hz,1H),3.02(d,J=3.4Hz ,2H),2.65(t,J=6.6Hz,2H),2.39(s,1H),2.21–2.16(m,1H),2.09(d,J=3.6 Hz,1H),2.07(s,1H),2.06(s,1H),2.04(s,1H),2.02(d,J=7.3Hz,1H),1.6 7–1.58(m,2H),1.48(d,J=6.0Hz,1H),1.39–1.34(m,1H),1.33(s,3H),1.27 (d,J=6.6Hz,1H),1.26–1.23(m,1H),1.21(d,J=15.8Hz,1H),1.03(s,3H), 0.99(dd,J=13.9,4.4Hz,1H), 0.80(d,J=7.0Hz,3H), 0.63(d,J=7.1Hz,3H). 13 CNMR(151MHz,DMSO)δ217.17,196.40,168.71,166.86,164.31,141.17,140.17,124.58,115.70,115.33,105.71,72.98,70.79,57. 58,45.40,44.47,43.89,42.00,37.90,36.79,36.75,34.46,33.26,32.84,30.51,28.86,27.05,24.89,21.11,16.71,14.82,11.93.

[0130] Example 2

[0131] The reaction formula for preparing compound 2 is as follows:

[0132]

[0133] Specifically, the steps include the following:

[0134] Pleurotin (189 mg, 0.5 mmol), 4-biphenylsulfonyl chloride (190 mg, 0.75 mmol), PPh3 (590 mg, 2.25 mmol) were mixed with 5 mL of EtoAc solution and stirred at room temperature for 1 h. Then, DIEA (129.24 mg, 1 mmol) was added, and the mixture was stirred at 50 °C for 1 h. The mixture was purified by flash chromatography to obtain compound 2 (106 mg, 56%) as a white solid. The 1H NMR spectrum of compound 2 is shown below. Figure 3 Carbon spectrum Figure 4 .

[0135] 1 H NMR(600MHz,Chloroform-d)δ7.48(d,J=7.1Hz,2H),7.43(d,J=8.4Hz,2H),7.37(s,2H),7.36(d,J=6.5Hz,2H),7.28(d,J=8.5Hz,1H),6.34(dd, J=17.4,11.0Hz,1H),5.67(d,J=8.5Hz,1H),5.23(d,J=11.0Hz,1H),5.07(d,J=15.9Hz,1H),3.53(s,2H),3.25(d,J=6.5Hz,1H),2.24(t,J=7.0H z,1H),2.17(s,1H),2.12(t,J=9.4Hz,1H),1.99(s,1H),1.92(dd,J=16.1,8.5Hz,1H),1.68(d,J=14.5Hz,1H),1.57(d,J=6.9Hz,2H),1.46(dd,J =11.5,2.6Hz,1H),1.37(s,1H),1.34(s,3H),1.26(s,2H),1.21(s,1H), 1.02(s,3H),1.01(s,1H),0.79(d,J=7.0Hz,3H),0.62(d,J=7.0Hz,3H). 13 C NMR (151MHz, CDCl3) δ217.05,167.79,140.27,139.93,138.91,133.86,130.70,128.92,127.67,127.50,126.93,116.72,74. 62,69.61,58.19,45.45,44.77,43.86,41.78,37.21,36.77,36.00,34.46,30.43,26.84,26.33,24.84,16.75,15.45,11.50.

[0136] Example 3

[0137] In vitro antibacterial activity of compounds 1 and 2

[0138] Using tiamulin as a control, the minimum inhibitory concentrations (MICs) of compounds 1 and 2 against two pathogens, methicillin-resistant Staphylococcus aureus (MRSA ATCC 43300) and Staphylococcus aureus (S. aureus ATCC 29213), were determined. The MIC value was recorded as the lowest drug concentration completely visible on a 96-well plate at 37°C to inhibit bacterial growth. Compounds 1 and 2 were diluted to working concentrations (1.028 mg / mL) with ultrapure water containing no more than 5% dimethyl sulfoxide (DMSO). The experiment employed a microdilution method using half-diluted Mueller-Hinton broth (MHB), with each drug tested in duplicate.

[0139] The measurement results are shown in Table 2.

[0140] Table 2

[0141]

[0142] Note: MRSA ATCC 43300 is methicillin-resistant Staphylococcus aureus; S. aureus ATCC 29213 is Staphylococcus aureus.

[0143] As shown in Table 2, compared with tiamulin, compounds 1 and 2 have better inhibitory activity against both methicillin-resistant Staphylococcus aureus (MRSA ATCC 43300) and Staphylococcus aureus (S. aureus ATCC 29213). Moreover, compound 1 has significantly better inhibitory activity against Staphylococcus aureus (S. aureus ATCC 29213) than tiamulin.

[0144] The preparation method of the present invention is simple, green and energy-saving, and has a high yield.

[0145] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A truncated pleurotin derivative or a stable isotopic derivative thereof and a pharmaceutically acceptable salt, characterized in that, The truncated pleurotin derivative is: 。 2. The truncated pleurotin derivative or its stable isotopic derivative and pharmaceutically acceptable salt according to claim 1, characterized in that, The pharmaceutically acceptable salt is the salt formed by the truncated pleurotin derivative with hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, glutamic acid, aspartic acid, succinic acid, citric acid, or malic acid.

3. A pharmaceutical composition, characterized in that, It comprises a truncated pleurotin derivative or a stable isotopic derivative thereof as described in any one of claims 1-2, and a pharmaceutically acceptable salt thereof.

4. The use of the truncated pleurotin derivative or its stable isotopic derivative and pharmaceutically acceptable salt as described in any one of claims 1-2, or the use of the pharmaceutical composition as described in claim 3 in the preparation of an antibacterial agent, wherein the bacteria are methicillin-resistant Staphylococcus aureus MRSA ATCC 43300 and Staphylococcus aureus ATCC 29213.

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