Pleuromutilin derivative as well as preparation method and application thereof

Abstract

The invention relates to a pleuromutilin derivative as well as a preparation method and application thereof. The structure of the pleuromutilin derivative is a compound as shown in a formula (I), and a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof. The invention also provides a preparation method of the pleuromutilin derivative. The invention also provides an application of the pleuromutilin derivative in preparation of antibiotics and / or anti-mycoplasma drugs. The invention provides a novel drug which shows good antibacterial activity in vivo and in vitro, so that the problem of drug resistance of existing antibiotics is solved. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a pleuromutilin derivative and a preparation method and application thereof. Background Art

[0002] Antibiotic resistance (AMR) has become a global public health crisis. Its growth rate far outstrips the development of new antibiotics, leading to difficult-to-treat common infections, prolonged hospital stays, increased costs, and increased mortality. Methicillin-resistant Staphylococcus aureus (MRSA), listed by the World Health Organization as one of the 12 most deadly pathogens, is resistant to all known β-lactam antibiotics and is a leading cause of hospital- and community-acquired infections worldwide, contributing significantly to morbidity and mortality. Some clinical MRSA strains have also been reported to be resistant to vancomycin, linezolid, and daptomycin. Antibiotic development primarily stems from natural products derived from microorganisms. To date, approximately 28,000 antimicrobial compounds have been isolated and purified from microorganisms, and approximately 200 compounds have been directly used to treat infectious diseases. Further modification of these scaffolds has led to the development of an additional 200–300 antibiotics, exceeding the number of synthetic antibiotics, demonstrating the significant potential of semi-synthetic methods for the discovery of new antibiotics.

[0003] Pleuromutilins are a uniquely structured tricyclic diterpenoid natural product with excellent activity against Gram-positive bacteria. Currently, there are four pleuromutilin antibiotics marketed globally: the veterinary drugs tylosin fumarate and valnemulin hydrochloride, and the human drugs retapamulin and lafilmulin. Compared to sulfonamides, fluoroquinolones, β-lactams, and oxazolinones, which are developed based on the same core structure, the development of pleuromutilin antibiotics has been relatively slow. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide a pleuromutilin derivative and its preparation method and application, so as to provide a new drug that exhibits good antibacterial activity in vivo and in vitro, so as to solve the problem of drug resistance of existing antibiotics.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is as follows: a pleuromutilin derivative, the structure of which is a compound as described in formula (I) and its stereoisomers, tautomers or pharmaceutically acceptable salts thereof; In formula (I), Y is selected from 、 ,H,C 1-4Alkyl, cycloalkyl or aminoacyl, A is selected from heterocyclyl or H, B is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and there are 0 to 5 substituents on the cycloalkyl, aryl or heteroaryl; Z is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and there are 0 to 5 substituents on the cycloalkyl, aryl or heteroaryl, and the substituents are selected from H, F, Cl, Br, CN, OH, NH2, NO2, CF3, OCF3, C 1-4 Alkyl or C 1-4 Alkoxy; X is selected from N, O or S; Q is selected from NH2, C 1-4 Alkyl, C 1-4 Alkoxy, tert-butoxyacyl, p-toluenesulfonyl, benzyl or 2-(trimethylsilyl)ethoxymethyl; G is selected from N or , R is selected from CH3 or CN; cycloalkyl is a monocyclic or bicyclic hydrocarbon group with 3 to 10 ring carbon atoms, that is, C 3-10 Cycloalkyl and bicyclic hydrocarbon groups are cycloalkyl groups consisting of two saturated carbon rings with two common atoms; heterocyclic groups are C 2-11 -heterocyclyl; and is a saturated or partially saturated monocyclic or bicyclic heterocyclic group, 1, 2 or 3 of the ring atoms are heteroatoms selected from the group consisting of N, O and S, and the remaining ring atoms are carbon; a bicyclic heterocyclic group refers to a heterocyclic ring consisting of two rings with two common ring atoms, the bridge separating the two rings is a single bond, a chain of one ring atom or a chain of two ring atoms, or the two rings are connected by a common ring atom to form a spirocyclic ring; an aryl group refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system, and at least one ring is aromatic, and the whole is C 6-14 -aryl; heteroaryl refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system, at least one ring of which is aromatic, contains 1 to 4 heteroatoms, and the whole is C 5-11 -heteroaryl; heteroatom is O, S or N; C 1-4 Alkyl refers to a saturated straight-chain or branched hydrocarbon group with 1 to 4 carbon atoms; 1-4 Alkoxy refers to an alkoxy group with a total of 1 to 4 carbon atoms connected to the rest of the molecule through an oxygen atom; aminoacyl refers to the amino group substituted acyl group of an amino acid after removing the carboxylic acid hydroxyl group.

[0006] Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms, i.e., C 3-8 -Cycloalkyl. Cycloalkyl is a monocyclic hydrocarbon group with 3 to 6 ring carbon atoms, i.e. C 3- 6 -cycloalkyl. Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Preferably, heterocyclic group refers to a C 3-9 -Heterocyclic group. Preferably, heterocyclic group refers to a C 3-5-heterocyclyl. Preferably, the heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,6-diazaspiro[3.4]octane, 1,7-diazaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[3.5]nonane, 7-oxa-2-azaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.5]nonane, morpholinyl or thiomorpholinyl. Preferably, the aryl is selected from C 6-12 -aryl. Preferably, the aryl is selected from C 6-10 -aryl. Preferably, the aryl group is selected from phenyl, naphthyl, indanyl or anthracenyl. Preferably, the heteroaryl group is selected from C 5-9 -heteroaryl. Preferably, the heteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furanyl, indolyl or quinolinyl. Preferably, C 1-4 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. 1-4 The alkoxy group is selected from methoxy, ethoxy, propoxy, or tert-butoxy. Preferably, the pharmaceutically acceptable salt is a salt formed by an acid with a nitrogen having a lone electron pair in compound (I); the acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoroacetic acid, tartaric acid, lactic acid, maleic acid, fumaric acid, malic acid, citric acid, benzenesulfonic acid, p-toluenesulfonic acid, glucuronic acid, taurine, glutamic acid, or aspartic acid.

[0007] Preferably, the compound of formula (I) is selected from compound (Ia), (Ib), (Ic), (Id) or (Ie); the structural formulas of compounds (Ia), (Ib), (Ic), (Id) and (Ie) are as follows: , , , , .

[0008] The present invention also provides a method for preparing the pleuromutilin derivative of the present invention, comprising the following steps: .

[0009] Preferably, the preparation method of the pleuromutilin derivative comprises the following steps: S1, dissolving the compound represented by formula (II), triphenylphosphine and thioacetic acid in an organic solvent, adding diisopropyl azodicarboxylate dropwise at a temperature of 0°C, stirring at room temperature, monitoring the reaction by thin layer plate, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, and subjecting the concentrated crude product to silica gel column chromatography to obtain the compound represented by formula (III); alternatively, dissolving the compound represented by formula (II) and a base in an organic solvent, adding p-toluenesulfonyl chloride or methanesulfonyl chloride dropwise at a temperature of 0°C, stirring at room temperature, monitoring the reaction by thin layer plate, adding water after the reaction is completed, extracting with an organic solvent, and combining the organic phases. , concentrated, and chromatographed to obtain a first intermediate; the first intermediate is dissolved in an organic solvent, potassium thioacetate is added dropwise at a temperature of 0°C, stirred at room temperature, and the reaction is monitored by a thin layer plate. After the reaction is completed, water is added and extracted with an organic solvent, the organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain a compound represented by formula (III); alternatively, the compound represented by formula (II), triphenylphosphine and carbon tetrabromide are dissolved in an organic solvent, stirred at room temperature, and the reaction is monitored by a thin layer plate. After the reaction is completed, water is added and extracted with an organic solvent, the organic phases are combined, concentrated, and chromatographed to obtain a second intermediate; the second intermediate is dissolved in an organic solvent, potassium thioacetate is added dropwise at a temperature of 0°C, stirred at room temperature, and the reaction is monitored by a thin layer plate. After the reaction is completed, water is added and extracted with an organic solvent, the organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain a compound represented by formula (III); S2, the compound represented by formula (III) is dissolved in an organic solvent, a base is added at a temperature of 0°C, the temperature is raised to reflux temperature and reflux reaction is carried out for 2 to 16 hours, and then the compound represented by formula (IV) is added, stirred at room temperature, and the reaction is monitored by a thin layer plate. After the reaction is completed, water is added and extracted with an organic solvent, the organic phases are combined, concentrated, and chromatographed to obtain a third intermediate; the third intermediate is dissolved in an organic solvent, an acid is added at a temperature of 0°C, stirred at room temperature, and the reaction is monitored by a thin layer plate. After the reaction is completed, the solvent is concentrated under reduced pressure to obtain a compound represented by formula S3, dissolving the compound represented by formula (V) in an organic solvent, adding chloroacetyl chloride, a heterocyclic compound and a base at a temperature of 0°C, stirring at room temperature, monitoring the reaction by thin layer plate, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, and subjecting the concentrated crude product to silica gel column chromatography to obtain the compound represented by formula (VI); alternatively, dissolving the compound represented by formula (V) in an organic solvent, adding a 2-bromo-acetamide derivative and a base at a temperature of 0°C, stirring at room temperature, monitoring the reaction by thin layer plate, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, and subjecting the concentrated crude product to silica gel column chromatography to obtain the compound represented by formula (VII);Alternatively, the compound represented by formula (V) is dissolved in an organic solvent, and an amino acid, a condensing agent, and a base are added at 0°C. The mixture is stirred at room temperature and the reaction is monitored by thin-layer plate chromatography. After the reaction is completed, water is added and the mixture is extracted with an organic solvent. The organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain the compound represented by formula (VIII). Alternatively, the compound represented by formula (V) is dissolved in an organic solvent, and an aldehyde and a reducing agent are slowly added dropwise at 0°C. The reaction is monitored by thin-layer plate chromatography. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted with an organic solvent. The organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain the compound represented by formula (IX).

[0010] Preferably, the organic solvent is selected from at least one of pyridine, chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, chlorobenzene, toluene, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide; the base is selected from at least one of sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, potassium carbonate, sodium bicarbonate and sodium carbonate; the acid is selected from one or both of trifluoroacetic acid and hydrochloric acid. The condensing agent is selected from at least one of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and N,N'-dicyclohexylcarbodiimide (DCC); and the reducing agent is selected from at least one of lithium aluminum hydride (LiAlH4), sodium cyanoborohydride (NaBH3CN), and sodium triacetoxyborohydride (NaBH(OAc)3). Pharmacological studies have shown that pleuromutilin inhibits bacterial protein synthesis by binding to the V region of the peptidyl transferase center (PTC) of the 23S RNA of the bacterial 50S ribosomal subunit. The side chain at C14 in the pleuromutilin molecule is able to penetrate deep into the hydrophobic group of the ribosomal subunit, enhancing its antibacterial activity. Furthermore, pleuromutilin does not interact with mammalian cell ribosomes and does not interfere with protein synthesis in eukaryotic cells. The ingenious mechanism of action, unique chemical structure and the easy modification of its C14 side chain make in-depth research on pleuromutilin of great significance.

[0011] The present invention also provides a use of a pleuromutilin derivative in the preparation of antibiotics and / or anti-mycoplasma drugs. The present invention also provides a use of a pleuromutilin derivative in the preparation of anti-Gram-positive bacteria and / or anti-Mycoplasma pneumonia drugs.

[0012] Beneficial effects of the present invention: The present invention provides a novel pleuromutilin derivative having a 2-amino-3-(1H-indol-3-yl)propane-1-thiol side chain, good water solubility, and low cytotoxicity. In vitro and in vivo antibacterial activity studies have shown that the derivative's antibacterial activity is superior to that of the marketed antibacterial products, tylosin fumarate and valnemulin hydrochloride. Furthermore, the derivative's simple and mild synthesis process and low production cost make it suitable for development into an antibiotic for use against drug-resistant bacteria in animals or humans, effectively addressing the drug resistance problem of existing antibiotics. The pleuromutilin derivative of the present invention can be used as a potential new antibacterial agent for treating local or systemic infections in animals and humans, and has potential for widespread application in the field of medicinal chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 is the mass spectrum of compound 1; Figure 2 is the mass spectrum of compound 7; Figure 3 is the mass spectrum of compound 38; Figure 4 is the mass spectrum of compound 52; Figure 5 is the mass spectrum of compound 87. DETAILED DESCRIPTION

[0014] The following will describe the embodiments of the present invention with reference to preferred embodiments. Those skilled in the art will readily appreciate the other advantages and benefits of the present invention from the disclosure herein. The present invention may also be implemented or applied through various other specific embodiments, and the details in this specification may be modified or altered based on different viewpoints and applications without departing from the spirit of the present invention. It should be understood that the preferred embodiments are intended only to illustrate the present invention and are not intended to limit the scope of protection of the present invention.

[0015] Example 1 A method for preparing a pleuromutilin derivative as shown in Compound 1 comprises the following steps: Step 1. Compound 1-1 (CAS: 82689-19-8) (2.0 g, 6.9 mmol) was added to a 50 mL eggplant-shaped flask equipped with a magnetic stirrer and anhydrous tetrahydrofuran (20 mL). Triphenylphosphine (3.6 g, 13.8 mmol) and diisopropyl azodicarboxylate (2.8 g, 13.8 mmol) were added while stirring at 0°C. After reacting at 0°C for 2 hours, thioacetic acid (1.0 g, 13.8 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 16 hours. After the thin-layer chromatography (TLC) plate showed complete disappearance of the starting material spot, the solution was concentrated under reduced pressure. Ethyl acetate (20 mL) and water (50 mL) were then added sequentially. The organic phase was extracted and washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The crude product was added with ethanol (15 mL) and then a large amount of water to form a large suspension. The solid was filtered under reduced pressure, and the filter cake was washed with diethyl ether, methyl tert-butyl ether, and water in sequence and dried under reduced pressure to obtain a white solid 1-2 (3.94 g, yield 82%). Step 2: Compound 1-2 (3.9 g, 11.2 mmol) was added to a 50 mL eggplant-shaped flask equipped with a magnetic stirrer and methanol (20 mL). Potassium tert-butoxide (18.8 g, 16.8 mmol) was added with stirring at room temperature. The reaction mixture was refluxed for 16 hours, followed by the addition of compound 1-3 (6.0 g, 11.2 mmol). The reaction mixture was stirred at room temperature overnight. After the starting material spot disappeared as monitored by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure. Water (10 mL) and ethyl acetate (10 mL) were then added for extraction. The mixture was then extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined and washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The organic phase was then concentrated under reduced pressure. The crude product was dissolved in acetonitrile (12 mL). Water (10 mL) was slowly added dropwise with stirring at 0°C. The resulting suspension was filtered, and the filter cake was washed with petroleum ether (10 mL) and water (20 mL). The mixture was then dried under reduced pressure to obtain the first white solid (4.92 g, 66% yield). The first white solid (4.9 g, 7.36 mmol) was dissolved in 1,4-dioxane (20 mL). 4 mol / L hydrochloric acid / 1,4-dioxane (7.5 mL) was slowly added dropwise with stirring at 0°C. The reaction solution was stirred at room temperature for 16 hours. After the raw material spot completely disappeared as monitored by thin-layer chromatography, the reaction solution was concentrated under reduced pressure to obtain compound 1 (4.36 g, yield 100%), namely 14-O-({[(S)-2-amino-3-(1H-indol-3-yl)propyl]thio}-acetyl) tert-butyl ester. The mass spectrum of compound 1 is shown as follows: Figure 1 As shown, MS (ESI) m / z: 567.32565[M+H] + .

[0016] The reaction equation of compound 1 is: Example 2 A method for preparing a pleuromutilin derivative as shown in Compound 2 comprises the following steps: Step 1. Compound 1 (10.0 g, 17.7 mmol) from Example 1 was added to an eggplant-shaped flask equipped with a magnetic stirrer and dry dichloromethane (150 mL). Triethylamine (2.7 g, 26.6 mmol) and chloroacetyl chloride (2.4 g, 21.2 mmol) were then added sequentially at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was washed with water (75 mL x 3), and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (v / v = 3 / 1 to 1 / 1) to obtain 1-4 (7.2 g, 63% yield) as an off-white solid.

[0017] Step 2: Compound 1-4 (500 mg, 0.78 mmol) was added to an eggplant-shaped flask equipped with a magnetic stirrer and acetonitrile (10 mL). Potassium carbonate (161 mg, 1.2 mmol) and piperidine hydrochloride (113 mg, 0.94 mmol) were then added sequentially at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane / methanol (v / v = 18 / 1) as the eluent to obtain an off-white solid (226 mg, 42% yield), namely, compound 2, 14-O-({[(S)-2-(2-(piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetraline. MS (ESI) of compound 2: m / z: 692.40972 [M+H] + .

[0018] The reaction equation of compound 2 is: Examples 3 to 37 A method for preparing a pleuromutilin derivative as shown in compounds 3 to 37, wherein the azocyclic compound piperidine hydrochloride used for nucleophilic substitution in step 2 and the amount thereof are replaced in sequence with azetidine (54 mg, 0.94 mmol), pyrrole (57 mg, 0.94 mmol), (S)-pyrrolidin-3-ol (82 mg, 0.94 mmol), anhydrous piperazine (67 mg, 0.78 mmol), 1-methylpiperazine (85 mg, 0.94 mmol), 1-ethylpiperazine (107 mg, 0.94 mmol), 1-isopropylpiperazine (120 mg, 0.94 mmol), 2,6-dimethylpiperazine (107 mg, 0.94 mmol), (S)-2-methylpiperazine (94 mg, 0.94 mmol), 1-acetylpiperazine (120 mg, 0.94 mmol), cyclopropyl(piperazin-1-yl)methylpiperazine (1 Ketone (145 mg, 0.94 mmol), 1-(oxetane-3-yl)piperazine (133 mg, 0.94 mmol), 1-cyclopropylpiperazine (118 mg, 0.94 mmol), 1-(cyclopropylmethyl)piperazine (132 mg, 0.94 mmol), 1-(pyridin-4-yl)piperazine (153 mg, 0.94 mmol), 1-(6-nitropyridin-3-yl)piperazine (196 mg, 0.94 mmol). , 0.94mmol), 4-fluoropiperidine (97mg, 0.94mmol), 4-phenylpiperidine (151mg, 0.94mmol), 1,4'-bipiperidine (158mg, 0.94mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (253mg, 0.94mmol), 1-methyl-4-(piperidin-4-yl)piperazine (172mg, 0.94mmol), N, N-dimethylpiperidin-4-amine (120 mg, 0.94 mmol), piperidin-4-ol (95 mg, 0.94 mmol), 4-aminopiperidine (94 mg, 0.94 mmol), 3,5-dimethylpiperidine (113 mg, 0.94 mmol), 4,4-dimethylpiperidine (113 mg, 0.94 mmol), 2,6-dimethylpiperidine (113 mg, 0.94 mmol), morpholine (82 mg, 0.94 mmol), 2,7-diazaspiro[3.5 ] nonane-2-carboxylic acid tert-butyl ester (212 mg, 0.94 mmol), 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (212 mg, 0.94 mmol), 7-oxa-2-azaspiro[3.5]nonane (119 mg, 0.94 mmol), 2-oxa-8-azaspiro[4.5]decane (133 mg, 0.94 mmol), 2-aminocyclopentan-1-ol (95 mg, 0.94 mmol), 2-aminocyclohexan-1-ol (108 mg, 0.94 mmol).Except for the addition of tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (229 mg, 0.94 mmol), the remaining preparation steps and conditions were the same as those in Example 2.

[0019] The obtained compound 3 is 14-O-({[(S)-2-(2-(azetidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 320 mg and a yield of 62%. MS (ESI) m / z: 664.4 [M+H] + Compound 4 is 14-O-({[(S)-2-(2-(pyrrolidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 370 mg and a yield of 70%. MS (ESI) m / z: 678.3[M+H] + Compound 5 is 14-O-({[(S)-2-(2-(3-hydroxypyrrolidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 249 mg and a yield of 46%. MS (ESI) m / z: 695.4[M+H] + Compound 6 is 14-O-({[(S)-2-(2-(piperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 259 mg and a yield of 48%. MS (ESI) m / z: 693.4[M+H] + Compound 7 is 14-O-({[(S)-2-(2-(4-methylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 364 mg and a yield of 66%. The mass spectrum is as follows: Figure 2 As shown, MS (ESI) m / z: 707.4[M+H] + Compound 8 is 14-O-({[(S)-2-(2-(4-ethylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 342 mg and a yield of 61%. MS (ESI) m / z: 721.4 [M+H] + Compound 9 is 14-O-({[(S)-2-(2-(4-isopropylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 361 mg and a yield of 63%. MS (ESI) m / z: 735.4[M+H] +Compound 10 is 14-O-({[(S)-2-(2-(3,5-dimethylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 314 mg and a yield of 56%. MS (ESI) m / z: 721.4[M+H] + Compound 11 is 14-O-({[(S)-2-(2-((S)-3-methylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 231 mg and a yield of 42%. MS (ESI) m / z: 707.4 [M+H] + Compound 12 is 14-O-({[(S)-2-(2-(4-acetylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 384 mg and a yield of 67%. MS (ESI) m / z: 735.4 [M+H] + Compound 13 is 14-O-({[(S)-2-(2-(4-cyclopropanecarbonyl)piperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 380 mg and a yield of 64%. MS (ESI) m / z: 761.4 [M+H] + Compound 14 is 14-O-({[(S)-2-(2-(4-(oxetane-3-yl)piperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 286 mg and a yield of 49%. MS (ESI) m / z: 749.4 [M+H] + Compound 15 is 14-O-({[(S)-2-(2-(4-cyclopropylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 297 mg and a yield of 52%. MS (ESI) m / z: 733.4 [M+H] + Compound 16 is 14-O-({[(S)-2-(2-(4-cyclopropylmethylpiperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 338 mg and a yield of 58%. MS (ESI) m / z: 747.4 [M+H] + Compound 17 is 14-O-({[(S)-2-(2-(4-(pyridin-4-yl)piperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 276 mg and a yield of 46%. MS (ESI) m / z: 770.4 [M+H]+ Compound 18 is 14-O-({[(S)-2-(2-(4-(6-nitropyridin-3-yl)piperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 241 mg and a yield of 20%. MS (ESI) m / z: 815.4 [M+H] + Compound 19 is 14-O-({[(S)-2-(2-(4-fluoropiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 360 mg and a yield of 65%. MS (ESI) m / z: 710.4 [M+H] + Compound 20 is 14-O-({[(S)-2-(2-(4-phenylpiperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 359 mg and a yield of 60%. MS (ESI) m / z: 768.4 [M+H] + Compound 21 is 14-O-({[(S)-2-(2-([1,4'-bipiperidinyl]-1'-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 326 mg and a yield of 54%. MS (ESI) m / z: 775.5[M+H] + Compound 22 is 14-O-({[(S)-2-(2-(4-(piperazin-1-yl)piperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 326 mg and a yield of 54%. MS (ESI) m / z: 776.4[M+H] + Compound 23 is 14-O-({[(S)-2-(2-(4-methylpiperazin-1-yl)piperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 234 mg and a yield of 38%. MS (ESI) m / z: 790.5[M+H] + Compound 24 is 14-O-({[(S)-2-(2-(4-(dimethylamino)piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 378 mg and a yield of 66%. MS (ESI) m / z: 735.4[M+H] +Compound 25 is 14-O-({[(S)-2-(2-(4-hydroxypiperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 248 mg and a yield of 45%. MS (ESI) m / z: 708.3[M+H] + Compound 26 is 14-O-({[(S)-2-(2-(4-aminopiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 281 mg and a yield of 51%. MS (ESI) m / z: 707.4[M+H] + Compound 27 is 14-O-({[(S)-2-(2-(3,5-dimethylpiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 320 mg and a yield of 57%. MS (ESI) m / z: 720.4[M+H] + Compound 28 is 14-O-({[(S)-2-(2-(4,4-dimethylpiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 354 mg and a yield of 63%. MS (ESI) m / z: 720.3[M+H] + Compound 29 is 14-O-({[(S)-2-(2-(2,6-dimethylpiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 309 mg and a yield of 51%. MS (ESI) m / z: 720.4[M+H] + Compound 30 is 14-O-({[(S)-2-(2-(morpholin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 352 mg and a yield of 65%. MS (ESI) m / z: 694.4 [M+H] + Compound 31 is 14-O-({[(S)-2-(2-(2,7-diazaspiro[3.5]non-7-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 206 mg and a yield of 36%. MS (ESI) m / z: 733.2 [M+H] + Compound 32 is 14-O-({[(S)-2-(2-(2,7-diazaspiro[3.5]non-2-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 206 mg and a yield of 36%. MS (ESI) m / z: 733.4 [M+H] +Compound 33 is 14-O-({[(S)-2-(2-(7-oxa-2-azaspiro[3.5]non-2-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 303 mg and a yield of 36%. MS (ESI) m / z: 734.3[M+H] + Compound 34 is 14-O-({[(S)-2-(2-(2-oxa-8-azaspiro[4.5]decan-8-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 402 mg and a yield of 69%. MS (ESI) m / z: 748.4[M+H] + Compound 35 is 14-O-({[(S)-2-((2-(2-hydroxycyclopentyl)amino)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 116 mg and a yield of 21%. MS (ESI) m / z: 708.4 [M+H] + Compound 36 is 14-O-({[(S)-2-((2-(2-hydroxycyclohexyl)amino)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 135 mg and a yield of 24%. MS (ESI) m / z: 722.4 [M+H] + Compound 37 is 14-O-({[(S)-2-(2-(2-(piperazin-1-yl)ethyl)amino)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 103 mg and a yield of 18%. MS (ESI) m / z: 736.4 [M+H] + ; The structural formulas of compounds 3 to 37 are: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0020] Example 38 A method for preparing a pleuromutilin derivative as shown in Compound 38 comprises the following steps: Step 1. Compound 1 (500 mg, 0.88 mmol) prepared in Example 1 was added to a 25 mL eggplant-shaped flask equipped with a magnetic stirrer and anhydrous acetonitrile (5 mL). Potassium carbonate (183 mg, 1.33 mmol) and 2-bromoacetamide (138 mg, 1.0 mmol) were added with stirring at room temperature. After mixing, the reaction solution was reacted at room temperature for 3 hours. After completion of the reaction, water (15 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (10 mL × 3). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane / methanol (V / V = 20 / 1) as the eluent to afford an off-white solid (357 mg, 65% yield), compound 38, 14-O-({[(S)-2-((2-amino-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine. The mass spectrum of compound 38 is shown in FIG. Figure 3 As shown, MS (ESI) m / z: 624.34712 [M+H] + .

[0021] The reaction formula of compound 38 is: Example 39 to Example 51 A method for preparing pleuromutilin derivatives as shown in compounds 39 to 51, except that the 2-bromoacetamide used in step 1 and the amount thereof are replaced by 2-bromo-N-methylacetamide (152 mg, 1.0 mmol), 2-bromo-N-ethylacetamide (166 mg, 1.0 mmol), 2-bromo-N-isopropylacetamide (180 mg, 1.0 mmol), 2-bromo-N-cyclopropylacetamide (178 mg, 1.0 mmol), 2-bromo-N-cyclobutylacetamide (192 mg, 1.0 mmol), 2-bromo-N-cyclopentylacetamide (206 mg, 1.0 mmol), 2-bromo-N-cyclohexylacetamide (234 mg, 1.0 mmol), 2-bromo-N-(pyridin-4-yl)acetamide (215 mg, 1.0 mmol), 2-bromo-N-(1H-imidazol-2-yl)acetamide (204 mg, 1.0 mmol), 2-bromo-N-(thiazol-2-yl)acetamide (221 mg, 1.0 mmol), 2-bromo-N-(oxazol-2-yl)acetamide (205 mg, 1.0 mmol), 2-bromo-N-(pyrimidin-2-yl)acetamide (216 mg, 1.0 mmol) and 2-bromo-N-(pyrimidin-4-yl)acetamide (216 mg, 1.0 mmol), the remaining preparation steps and conditions were the same as those in Example 38.

[0022] The obtained compound 39 was 14-O-({[(S)-2-(2-((methylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 381 mg and a yield of 68%. MS (ESI) m / z: 638.3 [M+H] + Compound 40 is 14-O-({[(S)-2-(2-(ethylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 326 mg and a yield of 57%. MS (ESI) m / z: 652.2[M+H] + Compound 41 is 14-O-({[(S)-2-(2-(isopropylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 363 mg and a yield of 62%. MS (ESI) m / z: 666.4 [M+H] + Compound 42 is 14-O-({[(S)-2-((2-(cyclopropylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 338 mg and a yield of 58%. MS (ESI) m / z: 664.3[M+H] +Compound 43 is 14-O-({[(S)-2-((2-(cyclobutylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 292 mg and a yield of 49%. MS (ESI) m / z: 678.3[M+H] + Compound 44 is 14-O-({[(S)-2-((2-(cyclopentylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 334 mg and a yield of 55%. MS (ESI) m / z: 692.4 [M+H] + Compound 45 is 14-O-({[(S)-2-((2-(cyclohexylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 423 mg and a yield of 60%. MS (ESI) m / z: 706.3 [M+H] + Compound 46 is 14-O-({[(S)-2-(2-(pyridin-4-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 238 mg and a yield of 34%. MS (ESI) m / z: 701.2[M+H] + Compound 47 is 14-O-({[(S)-2-((2-(1H-imidazol-2-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 324 mg and a yield of 47%. MS (ESI) m / z: 690.3[M+H] + Compound 48 is 14-O-({[(S)-2-((2-(thiazol-2-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 311 mg and a yield of 44%. MS (ESI) m / z: 707.2[M+H] + Compound 49 is 14-O-({[(S)-2-((2-(oxazol-2-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 242 mg and a yield of 35%. MS (ESI) m / z: 691.3 [M+H] + Compound 50 is 14-O-({[(S)-2-((2-(pyrimidin-2-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 225 mg and a yield of 32%. MS (ESI) m / z: 702.4 [M+H]+ Compound 51 is 14-O-({[(S)-2-((2-(pyrimidin-4-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 267 mg and a yield of 38%. MS (ESI) m / z: 702.4 [M+H] + ; The structural formulas of compounds 39 to 51 are: 、 、 、 、 、 、 、 、 、 、 、 、 .

[0023] Example 52 A method for preparing a pleuromutilin derivative as shown in Compound 52 comprises the following steps: Step 1. Compound 1 (500 mg, 0.88 mmol) prepared in Example 1 and N-tert-butyloxycarbonyl-L-glycine (175 mg, 1.0 mmol) were added to a 25 mL eggplant-shaped flask equipped with a magnetic stirrer and anhydrous N,N-dimethylformamide (10 mL). HATU (456 mg, 1.2 mmol) and triethylamine (133 mg, 1.32 mmol) were added while stirring on ice. After stirring on ice for 30 minutes, the reaction solution was brought to room temperature and reacted for 6 hours. After completion of the reaction, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane / methanol (v / v = 30 / 1) as the eluent to obtain an off-white solid (337 mg, 53% yield). The above off-white solid (337 mg) was dissolved in dry dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added dropwise at room temperature. After the addition was complete, the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure and water (10 mL) was added. After full dissolution, saturated sodium bicarbonate was added dropwise to adjust the pH to 7-8, followed by extraction with ethyl acetate (5 mL × 3). The organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The crude product was purified by column chromatography and eluted with dichloromethane / methanol (V / V = 15 / 1) to obtain an off-white solid (180 mg, yield 62%), namely compound 52, 14-O-(2-{[(S)-2-(2-aminoacetamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) tert-butyl ester. The mass spectrum of compound 52 is shown in FIG. Figure 4 As shown, MS (ESI) m / z: 624.34712[M+H] + .

[0024] The reaction formula of compound 52 is: Examples 53 to 68 A method for preparing pleuromutilin derivatives as shown in compounds 53 to 68, wherein the N-tert-butyloxycarbonyl-L-glycine used in step 1 is replaced by N-tert-butyloxycarbonyl-L-alanine (189 mg, 1.0 mmol), N-tert-butyloxycarbonyl-L-valine (217 mg, 1.0 mmol), N-tert-butyloxycarbonyl-L-serine (205 mg, 1.0 mmol), N-tert-butyloxycarbonyl-L-leucine (231 mg, 1.0 mmol), N-tert-butyloxycarbonyl-L-isoleucine (231 mg, 1.0 mmol), N-tert-butyloxycarbonyl-L-threonine (219 mg, 1.0 mmol), respectively. mg, 1.0 mmol), N-tert-butoxycarbonyl-L-methionine (249 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-histidine (255 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-glutamine (246 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-asparagine (232 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-proline (215 mg, 1.0 mmol), (R)-2-(dimethyl Except for 4-(tert-butoxycarbonyl)propionic acid (117 mg, 1.0 mmol), 3-(dimethylamino)propionic acid hydrochloride (154 mg, 1.0 mmol), 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (243 mg, 1.0 mmol), N-tert-butoxycarbonyl-1-aminocyclopropanecarboxylic acid (201 mg, 1.0 mmol) and N-tert-butoxycarbonyl-1-aminocyclobutanecarboxylic acid (215 mg, 1.0 mmol), the other preparation steps and conditions are the same as those in Example 52.

[0025] The obtained compound 53 was 14-O-(2-{[(S)-2-((S)-2-aminopropionamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 213 mg and a yield of 38%. MS (ESI) m / z: 638.3 [M+H] + Compound 54 is 14-O-(2-{[(S)-2-((S)-2-amino-3-methylbutanamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 275 mg and a yield of 47%. MS (ESI) m / z: 666.4[M+H] +Compound 55 is 14-O-(2-{[(S)-2-((S)-2-amino-3-hydroxypropionamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 241 mg and a yield of 42%. MS (ESI) m / z: 654.4 [M+H] + Compound 56 is 14-O-(2-{[(S)-2-((S)-2-amino-4-methylpentanamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 287 mg and a yield of 48%. MS (ESI) m / z: 680.4[M+H] + Compound 57 is 14-O-(2-{[(S)-2-((2S,3S)-2-amino-3-methylpentanamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 239 mg and a yield of 50%. MS (ESI) m / z: 680.4[M+H] + Compound 58 is 14-O-(2-{[(S)-2-((2S,3R)-2-amino-3-hydroxybutyramido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 206 mg and a yield of 35%. MS (ESI) m / z: 668.3[M+H] + Compound 59 is 14-O-(2-{[(S)-2-((S)-2-amino-4-(methylthio)butanamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 190 mg and a yield of 31%. MS (ESI) m / z: 698.4 [M+H] + Compound 60 is 14-O-(2-{[(S)-2-((S)-(2-amino-3-(1H-imidazol-4-yl)propionamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 161 mg and a yield of 26%. MS (ESI) m / z: 704.3 [M+H] + Compound 61 is 14-O-(2-{[(S)-2-((S)-2,5-diamino-5-oxopentanamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 134 mg and a yield of 22%. MS (ESI) m / z: 695.4 [M+H] + Compound 62 is 14-O-(2-{[(S)-2-((S)-2,4-diamino-4-oxobutanamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 177 mg and a yield of 26%. MS (ESI) m / z: 681.3 [M+H]+ Compound 63 is 14-O-(2-{[(S)-2-((S)-pyrroline-2-carboxamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 206 mg and a yield of 31%. MS (ESI) m / z: 664.3[M+H] + Compound 64 is 14-O-(2-{[(S)-2-((R)-2-(dimethylamino)propionamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 253 mg and a yield of 38%. MS (ESI) m / z: 666.4 [M+H] + Compound 65 is 14-O-(2-{[(S)-2-(3-(dimethylamino)propionamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 146 mg and a yield of 22%. MS (ESI) m / z: 666.4 [M+H] + Compound 66 is 14-O-(2-{[(S)-2-(4-aminocyclohexane-1-carboxamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 228 mg and a yield of 33%. MS (ESI) m / z: 692.4 [M+H] + Compound 67 is 14-O-(2-{[(S)-2-(1-aminocyclopropane-1-amide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 305 mg and a yield of 47%. MS (ESI) m / z: 650.3[M+H] + Compound 68 is 14-O-(2-{[(S)-2-(1-aminocyclobutane-1-amide)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 278 mg and a yield of 42%. MS (ESI) m / z: 664.3[M+H] + ; The structural formulas of compounds 53 to 68 are: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0026] Example 69 A method for preparing a pleuromutilin derivative as shown in Compound 69 comprises the following steps: Step 1: Compound 1 (500 mg, 0.88 mmol) prepared in Example 1, aqueous formaldehyde solution (357 mg, 4.40 mmol, 37%), and sodium cyanoborohydride (83 mg, 1.32 mmol) were added to a 25 mL eggplant flask equipped with a magnetic stirrer and methanol (7 mL). After stirring at room temperature for 15 minutes, glacial acetic acid was slowly added dropwise to adjust the pH of the reaction solution to 5-7, and the reaction was continued at room temperature for 8 hours. After completion of the reaction, saturated ammonium chloride solution was added to quench the reaction. The methanol was evaporated by concentration under reduced pressure. The residue was added with water (20 mL) and the pH was adjusted to 9 with 2 mol / L sodium hydroxide. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phase was washed three times with 2 mol / L sodium hydroxide solution (10 mL × 3) and then extracted with 1 mol / L hydrochloric acid solution (10 mL × 3). The combined organic phases were then adjusted to neutral pH with sodium hydroxide and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure. The crude product was purified by column chromatography using dichloromethane / methanol (v / v = 20 / 1) to afford a white solid (143 mg, 28% yield), compound 69, 14-O-(2-{[(S)-2-(methylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetraline. MS (ESI) of compound 69: m / z: 581.34130 [M+H] + .

[0027] The reaction formula of compound 69 is: Examples 70 to 76 A method for preparing pleuromutilin derivatives as shown in compounds 70 to 76, except that the formaldehyde aqueous solution and the amount used in step 1 are replaced by acetaldehyde (264 mg, 4.4 mmol), acetone (255 mg, 4.4 mmol), cyclopropylcarboxaldehyde (308 mg, 4.4 mmol), cyclobutanone (308 mg, 4.4 mmol), cyclobutylcarboxaldehyde (370 mg, 4.4 mmol), cyclopentanone (370 mg, 4.4 mmol) and azetidine-3-carboxaldehyde (374 mg, 4.4 mmol), respectively, the remaining preparation steps and conditions are the same as those in Example 69.

[0028] The obtained compound 70 is 14-O-(2-{[(S)-2-(ethylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 115 mg and a yield of 22%. MS (ESI) m / z: 595.4 [M+H]+ Compound 71 is 14-O-(2-{[(S)-2-(isopropylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 166 mg and a yield of 31%. MS (ESI) m / z: 609.3[M+H] + Compound 72 is 14-O-(2-{[(S)-2-((cyclopropylmethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 131 mg and a yield of 24%. MS (ESI) m / z: 621.4 [M+H] + Compound 73 is 14-O-(2-{[(S)-2-(cyclobutylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 153 mg and a yield of 28%. MS (ESI) m / z: 621.4 [M+H] + Compound 74 is 14-O-(2-{[(S)-2-((cyclobutylmethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 140 mg and a yield of 25%. MS (ESI) m / z: 635.3[M+H] + Compound 75 is 14-O-(2-{[(S)-2-(cyclopentylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 106 mg and a yield of 50%. MS (ESI) m / z: 635.3 [M+H] + Compound 76 is 14-O-(2-{[(S)-2-((azetidin-3-ylmethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 89 mg and a yield of 16%. MS (ESI) m / z: 636.3[M+H] + ; The structural formulas of compounds 70 to 76 are: 、 、 、 、 、 、 .

[0029] Example 77 to Example 101 A method for preparing pleuromutilin derivatives as shown in compounds 77 to 101, except that the compound 1-1 indole compound used in step 1 and the amount thereof are replaced by (S)-[1-(5-fluoro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.12 g, 6.9 mmol), (S)-[1-(5-chloro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.24 g, 6.9 mmol), (S)-[1-(5-bromo-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.54 g, 6.9 mmol), (S)-[1-(5-methyl- tert-Butyl (S)-[1-(5-methoxy-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamate (2.21 g, 6.9 mmol), tert-Butyl (S)-3-(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-5-((tert-butoxycarbonyl)oxy)-1H-indole-1-carboxylate (3.5 g, 6.9 mmol), tert-Butyl (S)-[1-(5-cyano-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamate (2.17 g, 6.9 mmol), tert-Butyl (S)-[1-(5-methoxy-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamate (2.21 g, 6.9 mmol), tert-Butyl (S)-3-(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-5-((tert-butoxycarbonyl)oxy)-1H-indole-1-carboxylate (3.5 g, 6.9 mmol), tert-Butyl (S)-[1-(5-cyano-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamate (2.17 g, 6.9 mmol), -1H-indol-3-yl)-3-hydroxypropyl-2-yl]carbamic acid tert-butyl ester (2.31 g, 6.9 mmol), (S)-5-((tert-butyloxycarbonyl)amino)-3-(2-((tert-butyloxycarbonyl)amino)-3-hydroxypropyl)-1H-indole-1-carboxylate (3.49 g, 6.9 mmol), (S)-[1-(5-trifluoromethyl-1H-indol-3-yl)-3-hydroxypropyl-2-yl]carbamate (2.47 g, 6.9 mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propan-2-yl]carbamate (2.00 g, 6.9 mmol), (S )-tert-Butyl (1-hydroxy-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamate (2.00 g, 6.9 mmol), (S)-tert-Butyl (1-hydroxy-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propan-2-yl)carbamate (2.00 g, 6.9 mmol), (S)-tert-Butyl (1-hydroxy-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propan-2-yl)carbamate (2.00 g, 6.9 mmol), (S)-tert-Butyl (1-hydroxy-3-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)propan-2-yl)carbamate (2.01 g, 6.9 mmol).9mmol), (S)-(1-hydroxy-3-(1H-pyrrolo[2,3-d]pyridazin-3-yl)propan-2-yl)carbamic acid tert-butyl ester (0.20g, 0.69mmol), (S)-(1-hydroxy-3-(5H-pyrrolo[2,3-b]pyrazin-7-yl)propan-2-yl)carbamic acid tert-butyl ester (0.20g, 0.69mmol), (S)-(1-hydroxy-3-(4,5,6,7 -tetrahydro-1H-indol-3-yl)propan-2-yl)carbamic acid tert-butyl ester (0.20 g, 0.69 mmol), (S)-(1-(benzothiophen-3-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester (2.12 g, 6.9 mmol), (S)-(1-(benzofuran-3-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester (2.01 g, 6.9 mmol), (S)-(1- tert-Butyl (hydroxy-3-(1H-indazol-3-yl)propan-2-yl)carbamate (0.2 g, 0.69 mmol), tert-butyl (S)-(1-hydroxy-3-(1-methyl-1H-indol-3-yl)propan-2-yl)carbamate (2.10 g, 6.9 mmol), tert-butyl (S)-(1-(1-((tert-butoxycarbonyl)amino)-1H-indol-3-yl)-3-hydroxypropan-2-yl)carbamate Except for the addition of tert-butyl (S)-(1-hydroxy-3-(2-methyl-1H-indol-3-yl)propan-2-yl)carbamate (0.21 g, 0.69 mmol), and tert-butyl (S)-(1-(2-cyano-1H-indol-3-yl)-3-hydroxypropyl-2-yl)carbamate (0.22 g, 0.69 mmol), the remaining preparation steps and conditions were the same as those in Example 1.

[0030] The obtained compound 77 is 14-O-({[(S)-2-amino-3-(5-fluoro-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 1.21 g and a yield of 30%. MS (ESI) m / z: 585.3 [M+H] + Compound 78 is 14-O-({[(S)-2-amino-3-(5-chloro-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.86 g and a yield of 21%. MS (ESI) m / z: 601.2 [M+H] + Compound 79 is 14-O-({[(S)-2-amino-3-(5-bromo-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 1.51 g and a yield of 34%. MS (ESI) m / z: 645.1[M+H] +Compound 80 is 14-O-({[(S)-2-amino-3-(5-methyl-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.72 g and a yield of 18%. MS (ESI) m / z: 581.3 [M+H] + Compound 81 is 14-O-({[(S)-2-amino-3-(5-methoxy-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 1.64 g and a yield of 40%. MS (ESI) m / z: 597.3 [M+H] + Compound 82 is 14-O-({[(S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.60 g and a yield of 15%. MS (ESI) m / z: 583.3 [M+H] + Compound 83 is 14-O-({[(S)-2-amino-3-(5-cyano-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 1.06 g and a yield of 26%. MS (ESI) m / z: 592.1[M+H] + Compound 84 is 14-O-({[(S)-2-amino-3-(5-nitro-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.59 g and a yield of 14%. MS (ESI) m / z: 612.2 [M+H] + Compound 85 is 14-O-({[(S)-2-amino-3-(5-amino-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.68 g and a yield of 17%. MS (ESI) m / z: 582.1[M+H] + Compound 86 is 14-O-({[(S)-2-amino-3-(5-trifluoromethyl-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 1.05 g and a yield of 24%. MS (ESI) m / z: 635.1[M+H] + Compound 87 is 14-O-({[(S)-2-amino-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 0.78 g and a yield of 20%. The mass spectrum is as follows: Figure 5 As shown, MS (ESI) m / z: 568.3[M+H] +Compound 88 is 14-O-({[(S)-2-amino-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.86 g and a yield of 22%. MS (ESI) m / z: 568.3 [M+H] + Compound 89 is 14-O-({[(S)-2-amino-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.70 g and a yield of 18%. MS (ESI) m / z: 568.3[M+H] + Compound 90 is 14-O-({[(S)-2-amino-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.98 g and a yield of 25%. MS (ESI) m / z: 568.3 [M+H] + Compound 91 is 14-O-({[(S)-2-amino-3-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.71 g and a yield of 20%. MS (ESI) m / z: 569.3 [M+H] + Compound 92 is 14-O-({[(S)-2-amino-3-(7H-pyrrolo[2,3-d]pyridazin-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.063 g and a yield of 16%. MS (ESI) m / z: 569.3 [M+H] + Compound 93 is 14-O-({[(S)-2-amino-3-(5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.055 g and a yield of 14%. MS (ESI) m / z: 569.3[M+H] + Compound 94 is 14-O-({[(S)-2-amino-3-(4,5,6,7-tetrahydro-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.102 g and a yield of 18%. MS (ESI) m / z: 571.3 [M+H] + Compound 95 is 14-O-({[(S)-2-amino-3-(benzothiophen-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 1.13 g and a yield of 28%. MS (ESI) m / z: 584.2 [M+H] +Compound 96 is 14-O-({[(S)-2-amino-3-(benzofuran-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 1.33 g and a yield of 34%. MS (ESI) m / z: 568.2 [M+H] + Compound 97 is 14-O-({[(S)-2-amino-3-(1H-indazol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.098 g and a yield of 25%. MS (ESI) m / z: 568.3 [M+H] + Compound 98 is 14-O-({[(S)-2-amino-3-(1-methyl-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 1.00 g and a yield of 25%. MS (ESI) m / z: 581.1 [M+H] + Compound 99 is 14-O-({[(S)-2-amino-3-(1-amino-1H-indol-3-yl)propyl]thio}-acetyl)tetramethyleneimine, with a yield of 0.056 g and a yield of 14%. MS (ESI) m / z: 582.3 [M+H] + Compound 100 is 14-O-({[(S)-2-amino-3-(2-methyl-1H-indol-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 0.15 g and a yield of 37%, MS (ESI) m / z: 581.2[M+H] + Compound 101 is 14-O-({[(S)-2-amino-3-(2-cyano-1H-indol-3-yl)propyl]thio}-acetyl) tert-butyl ester, with a yield of 0.09 g and a yield of 24%, MS (ESI) m / z: 592.3[M+H] + ; The structural formulas of compounds 77 to 101 are: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0031] Biological activity test The inhibitory activity of the pleuromutilin derivatives (1-101) prepared in Examples 1-101 against drug-resistant Gram-positive strains (such as methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300)) and Mycoplasma hyopneumoniae (Mhp, ATCC 25934) was tested based on the broth microdilution method recommended by NCCLS. The data were expressed as the minimum inhibitory concentration (MIC, in μg / mL) required to inhibit the growth of the pathogens. The readings were read at 600 nm and 450 nm using a microplate reader. The results are shown in Table 1.

[0032] Table 1 Antibacterial and antimycoplasma activities of compounds 1-101 As can be seen from the data in Table 1, the pleuromutilin derivatives having indole analog side chains provided by the present invention have good antibacterial and antimycoplasma activities, which are superior to the marketed drugs tylosin fumarate and valnemulin hydrochloride, and have potential development value in the application field of antibiotic drugs for anti-resistant bacteria in animals and humans.

[0033] In summary, the pleuromutilin derivatives of the present invention are a novel class of pleuromutilin derivatives containing 2-amino-3-(1H-indol-3-yl)propane-1-thiol, as demonstrated by in vitro antibacterial and antimycoplasma activity tests. These derivatives exhibit excellent antibacterial and antimycoplasma effects, with their inhibitory effects against clinically drug-resistant and virulent mycoplasma strains exceeding those of the marketed pleuromutilin antibiotics, tylosin fumarate and valnemulin hydrochloride. This demonstrates that the pleuromutilin derivatives of the present invention can serve as potential novel antibacterial and antimycoplasma agents for treating localized or systemic infections in animals and humans, exhibiting excellent antibacterial and antimycoplasma activity and possessing potential value for new drug development.

[0034] The above embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Any equivalent substitution or modification made by those skilled in the art based on the present invention is within the protection scope of the present invention.

Claims

1. A pleuromutilin derivative, characterized in that: The structure is a compound as described in formula (I) and its stereoisomers, tautomers or pharmaceutically acceptable salts; In formula (I), Y is selected from 、 ,H,C 1-4 Alkyl, cycloalkyl or aminoacyl, wherein A is selected from heterocyclic or H, B is selected from alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, and the cycloalkyl, aryl or heteroaryl has 0 to 5 substituents selected from H, F, Cl, Br, CN, OH, NH2, NO2, CF3, OCF3, C 1-4 Alkyl or C 1-4 alkoxy; Z is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, and the cycloalkyl, aryl or heteroaryl has 0 to 5 substituents selected from H, F, Cl, Br, CN, OH, NH2, NO2, CF3, OCF3, C 1-4 Alkyl or C 1-4 alkoxy; X is selected from N, O or S; Q is selected from NH2, C 1-4 Alkyl, C 1-4 Alkoxy, tert-butoxyacyl, p-toluenesulfonyl, benzyl or 2-(trimethylsilyl)ethoxymethyl; G is selected from N or , wherein R is selected from CH3 or CN; The cycloalkyl group refers to a monocyclic or bicyclic hydrocarbon group with 3 to 10 ring carbon atoms, wherein the bicyclic hydrocarbon group is a cycloalkyl portion consisting of two saturated carbon rings with two common atoms; The heterocyclic group refers to a C 2-11 -heterocyclyl; and is a saturated or partially saturated monocyclic or bicyclic heterocyclyl, 1, 2 or 3 of the ring atoms are heteroatoms selected from the group consisting of N, O and S, and the remaining ring atoms are carbon; the bicyclic heterocyclyl refers to a heterocycle consisting of two rings with two common ring atoms, the bridge separating the two rings is a single bond, a chain of one ring atom or a chain of two ring atoms, or the two rings are connected by a common ring atom to form a spirocycle; The aryl group refers to a monocyclic, bicyclic or tricyclic carbon ring system, wherein at least one ring is aromatic and the whole is a C 6-14 -aryl; The heteroaryl group refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system, wherein at least one ring is aromatic, contains 1 to 4 heteroatoms, and the whole is a C 5-11 -heteroaryl; the heteroatom is O, S or N; The C 1-4 Alkyl refers to a saturated straight-chain or branched hydrocarbon group having 1 to 4 carbon atoms; The C 1-4 Alkoxy refers to an alkoxy group having a total of 1 to 4 carbon atoms attached to the rest of the molecule through an oxygen atom; The aminoacyl group refers to the amino group substituted acyl group of an amino acid after removing the carboxylic acid hydroxyl group.

2. The pleuromutilin derivative according to claim 1, characterized in that The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and / or the heterocyclyl group is selected from azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,6-diazaspiro[3.4]octane, 1,7-diazaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[3.5]nonane, 7-oxa-2-azaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.5]nonane, morpholinyl or thiomorpholinyl; and / or, the aryl group is selected from phenyl, naphthyl, indanyl or anthracenyl; and / or, the heteroaryl group is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furanyl, indolyl or quinolinyl; and / or, the C 1-4 Alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and / or, the C 1-4 The alkoxy group is selected from methoxy, ethoxy, propoxy or tert-butoxy.

3. The pleuromutilin derivative according to claim 1, characterized in that The pharmaceutically acceptable salt is a salt formed by an acid and a nitrogen containing a lone pair of electrons in compound (I); the acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, trifluoroacetic acid, tartaric acid, lactic acid, maleic acid, fumaric acid, malic acid, citric acid, benzenesulfonic acid, p-toluenesulfonic acid, glucuronic acid, taurine, glutamic acid or aspartic acid.

4. The pleuromutilin derivative according to claim 1, characterized in that The compound of formula (I) is selected from compound (Ia), (Ib), (Ic), (Id) or (Ie); the structural formulas of compounds (Ia), (Ib), (Ic), (Id) and (Ie) are shown below: ， ， ， ， 。 5. The pleuromutilin derivative according to claim 1, characterized in that The compound of formula (I) is selected from any one of the following compounds: 14-O-({[(S)-2-amino-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(azetidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(pyrrolidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(pyrrolidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, (S)-2-(2-(3-hydroxypyrrolidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(piperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-methylpiperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-ethylpiperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) 1H-indol-3-yl) propyl] thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-isopropylpiperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl] thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(3,5-dimethylpiperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl] thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-((S)-3-methylpiperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl] thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-acetylpiperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl] thio}-acetyl) emthioline, 1-({[(S)-2-(2-(4-cyclopropanecarbonyl)piperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-(oxetan-3-yl)piperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-(oxetan-3-yl)piperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline,14-O-({[(S)-2-(2-(4-cyclopropylmethylpiperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-(pyridin-4-yl)piperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-(6-nitropyridin-3-yl)piperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-(6-nitropyridin-3-yl)piperazin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-phenylpiperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-([1,4'-bipiperidin-1'-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-piperazin-1-yl)piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-methylpiperazin-1-yl)piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 1-yl)piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-(dimethylamino)piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-hydroxypiperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-aminopiperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(4-aminopiperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, Euterpe, 14-O-({[(S)-2-(2-(4,4-dimethylpiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) euterpe, 14-O-({[(S)-2-(2-(2,6-dimethylpiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) euterpe, 14-O-({[(S)-2-(2-(2,6-dimethylpiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) euterpe,14-O-({[(S)-2-(2-(2,7-diazaspiro[3.5]non-7-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(2,7-diazaspiro[3.5]non-2-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(7-oxa-2-azaspiro[3.5]non-2-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(2-oxa-8-azaspiro[4 .5]decane-8-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(2-hydroxycyclopentyl)amino)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(2-hydroxycyclohexyl)amino)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(2-hydroxycyclohexyl)amino)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(2-(piperazin-1-yl)ethyl)amino)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-( {[(S)-2-((2-amino-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-((methylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(ethylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-(2-(isopropylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-( {[(S)-2-((2-(Cyclopropylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(Cyclobutylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(Cyclopentylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(Cyclohexylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline,14-O-({[(S)-2-(2-(pyridin-4-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(1H-imidazol-2-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(thiazol-2-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(oxazol-2-ylamino)-2-oxoethyl)amino)-3-( 1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(pyrimidin-2-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-((2-(pyrimidin-4-ylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(2-aminoacetamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-2-aminopropionamido)-3- (1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-2-amino-3-methylbutanamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-2-amino-3-hydroxypropionamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-2-amino-4-methylpentanamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((2S,3S)-2-amino 1-{[(S)-2-((2S,3R)-2-amino-3-hydroxybutyramido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-2-amino-4-(methylthio)butyramido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-(2-amino-3-(1H-imidazol-4-yl)propionamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline,14-O-(2-{[(S)-2-((S)-2,5-diamino-5-oxopentanamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-2,4-diamino-4-oxobutanamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-pyrroline-2-carboxamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((R)-2-(dimethylamino)propionamide)-3-(1H-indol-3-yl)propionamide 1-{[(S)-2-(4-aminocyclohexane-1-carboxamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(1-aminocyclopropane-1-carboxamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(1-aminocyclopropane-1-carboxamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(1-aminocyclobutane-1-carboxamide)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(methylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(ethylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(isopropylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((cyclopropylmethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(cyclobutylamino)-3-( 1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((cyclobutylmethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-(cyclopentylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline and 14-O-(2-{[(S)-2-((azetidin-3-ylmethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(5-fluoro-1H-indol-3-yl)propyl]thio}-acetyl) emthioline,14-O-({[(S)-2-amino-3-(5-chloro-1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(5-bromo-1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(5-methyl-1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(5-methoxy-1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propyl]thio}-acetyl) Tetramethylenete ... )propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]thio}-acetyl) emthioline, 14-O-({[( 14-O-({[(S)-2-amino-3-(5H-pyrrolo[2,3-b]pyrazin-7-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(4,5,6,7-tetrahydro-1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(benzothiophen-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(benzothiophen-3-yl)propyl]thio}-acetyl) emthioline,14-O-({[(S)-2-amino-3-(1H-indole-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(1-methyl-1H-indole-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(1-amino-1H-indole-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(2-methyl-1H-indole-3-yl)propyl]thio}-acetyl) emthioline, 14-O-({[(S)-2-amino-3-(2-cyano-1H-indole-3-yl)propyl]thio}-acetyl) emthioline.

6. A method for preparing a pleuromutilin derivative according to any one of claims 1 to 5, characterized in that: The following steps are involved: 。 7. The method for preparing a pleuromutilin derivative according to claim 6, characterized in that: The following steps are involved: S1. Dissolve the compound represented by formula (II), triphenylphosphine and thioacetic acid in an organic solvent, add diisopropyl azodicarboxylate dropwise at 0°C, stir at room temperature, and monitor the reaction using a thin layer plate. After the reaction is completed, add water and extract with an organic solvent. Combine the organic phases, concentrate the crude product, and chromatograph on a silica gel column to obtain the compound represented by formula (III); Alternatively, the compound represented by formula (II) and a base are dissolved in an organic solvent, p-toluenesulfonyl chloride or methanesulfonyl chloride is added dropwise at 0°C, stirred at room temperature, and the reaction is monitored by thin-layer plate. After the reaction is completed, water is added and extracted with an organic solvent. The organic phases are combined, concentrated, and chromatographed to obtain a first intermediate. The first intermediate is dissolved in an organic solvent, potassium thioacetate is added dropwise at 0°C, stirred at room temperature, and the reaction is monitored by thin-layer plate. After the reaction is completed, water is added and extracted with an organic solvent. The organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain a compound represented by formula (III). Alternatively, the compound represented by formula (II), triphenylphosphine and carbon tetrabromide are dissolved in an organic solvent, stirred at room temperature, and the reaction is monitored by thin-layer plate. After the reaction is completed, water is added and the mixture is extracted with an organic solvent. The organic phases are combined, concentrated, and subjected to chromatography to obtain a second intermediate. The second intermediate is dissolved in an organic solvent, potassium thioacetate is added dropwise at 0°C, stirred at room temperature, and the reaction is monitored by thin-layer plate. After the reaction is completed, water is added and the mixture is extracted with an organic solvent. The organic phases are combined, and the concentrated crude product is subjected to silica gel column chromatography to obtain a compound represented by formula (III). S2. Dissolve the compound represented by formula (III) in an organic solvent, add a base at 0°C, raise the temperature to reflux temperature and carry out reflux reaction for 2 to 16 hours, then add the compound represented by formula (IV), stir at room temperature, and monitor the reaction by thin layer plate. After the reaction, add water and extract with an organic solvent. Combine the organic phases, concentrate, and chromatograph to obtain a third intermediate; dissolve the third intermediate in an organic solvent, add an acid at 0°C, stir at room temperature, and monitor the reaction by thin layer plate. After the reaction, concentrate the solvent under reduced pressure to obtain a compound represented by formula (V); S3. Dissolve the compound represented by formula (V) in an organic solvent, add chloroacetyl chloride, a heterocyclic compound, and a base at 0°C, stir at room temperature, and monitor the reaction using a thin layer plate. After the reaction is completed, add water and extract with an organic solvent. Combine the organic phases, concentrate the crude product, and chromatograph on a silica gel column to obtain the compound represented by formula (VI); Alternatively, the compound represented by formula (V) is dissolved in an organic solvent, and a 2-bromoacetamide derivative and a base are added at 0°C. The mixture is stirred at room temperature and the reaction is monitored by thin-layer plate. After the reaction is completed, water is added and the mixture is extracted with an organic solvent. The organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain the compound represented by formula (VII). Alternatively, the compound represented by formula (V) is dissolved in an organic solvent, and an amino acid, a condensing agent, and a base are added at 0°C. The mixture is stirred at room temperature and the reaction is monitored by thin-layer plate. After the reaction is completed, water is added and the mixture is extracted with an organic solvent. The organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain the compound represented by formula (VIII). Alternatively, the compound represented by formula (V) is dissolved in an organic solvent, and aldehyde and a reducing agent are added dropwise at 0°C. The reaction is monitored by thin-layer plate. After the reaction is completed, water is added to quench the reaction, and the organic phases are extracted with an organic solvent. The organic phases are combined, and the concentrated crude product is chromatographed on a silica gel column to obtain the compound represented by formula (IX).

8. The method for preparing a pleuromutilin derivative according to claim 7, characterized in that: The organic solvent is selected from at least one of pyridine, chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, chlorobenzene, toluene, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide; The base is selected from at least one of sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, potassium carbonate, sodium bicarbonate and sodium carbonate; The acid is selected from one or both of trifluoroacetic acid and hydrochloric acid; The condensing agent is selected from at least one of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and N,N′-dicyclohexylcarbodiimide (DCC); The reducing agent is selected from at least one of lithium aluminum hydride (LiAlH4), sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OAc)3).

9. Use of a pleuromutilin derivative prepared by the method according to any one of claims 6 to 8 in the preparation of antibiotics and / or antimycoplasma drugs.

10. Use of a pleuromutilin derivative prepared by the method according to any one of claims 6 to 8 in the preparation of anti-Gram-positive bacteria and / or anti-Mycoplasma pneumoniae drugs.

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