A pleuromutilin derivative, preparation method and application thereof

Abstract

The present application relates to a pleuromutilin derivative, a preparation method and application thereof. The pleuromutilin derivative is a compound as shown in formula (I) and stereoisomers, tautomers or pharmaceutically acceptable salts thereof. The present application also provides a preparation method of the pleuromutilin derivative. The present application also provides application of the pleuromutilin derivative in preparation of antibacterial and / or anti-mycoplasma drugs. The present application provides a new drug which exhibits good antibacterial activity in vivo and in vitro, thereby solving the problem of drug resistance of existing antibiotics.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a pleuromutilin derivative, a preparation method and application thereof. BACKGROUND

[0002] Antimicrobial resistance (AMR) has become a global public health crisis. Its development speed far exceeds the development of new antibiotics, leading to difficult treatment of common infections, prolonged hospitalization, increased costs and increased mortality. Methicillin-resistant Staphylococcus aureus (MRSA) is listed as one of the 12 most deadly pathogens by the World Health Organization, which is resistant to all known beta-lactam antibiotics, and is the main cause of global hospital and community-acquired infections, and is also the main factor leading to increased morbidity and mortality. Some clinical methicillin-resistant Staphylococcus aureus strains have also been reported to be resistant to vancomycin, linezolid and daptomycin. The development of antibiotics is mainly derived from natural products in microorganisms. So far, about 28000 antimicrobial active compounds have been isolated and purified from microorganisms, and about 200 compounds have been directly used for the treatment of infectious diseases. Further modification of the skeletons of these compounds has led to the development of another 200-300 antibiotics, which is more than synthetic antibiotics, which shows that semi-synthesis of natural products still has great potential in the discovery of new antibiotics.

[0003] Pleuromutilin is a unique tricyclic diterpenoid natural product with good activity against gram-positive bacteria. So far, there are four kinds of pleuromutilin antibiotics on the market, which are veterinary drugs fusaric acid timomycin and hydrochloric acid vancomycin, and human drugs rethamol and raphi second line. Compared with sulfonamides, fluoroquinolones, beta-lactams and oxazolinones antibacterial drugs developed based on the same parent nucleus structure, the development of pleuromutilin antibiotics is relatively slow. SUMMARY

[0004] Therefore, the purpose of the present application is to provide a pleuromutilin derivative, a preparation method and application thereof, so as to provide a new drug which exhibits good antibacterial activity in vitro and in vivo, and to solve the problem of drug resistance of existing antibiotics.

[0005] In order to achieve the above purpose, the technical scheme adopted by the present application is as follows: a pleuromutilin derivative, the structure of which is a compound as shown in formula (I) and stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

[0006]

[0007] 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 0 to 5 substituents are present on the cycloalkyl, aryl or heteroaryl; Z is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and 0 to 5 substituents are present on the cycloalkyl, aryl or heteroaryl, the substituents being selected from H, F, Cl, Br, CN, OH, NH2, NO2, CF3, OCF3, C 1-4 alkyl or C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C , R is selected from CH3or CN; cycloalkyl is a monocyclic or bicyclic hydrocarbon radical of 3 to 10 ring carbon atoms, i.e. C 3-10 cycloalkyl, bicyclic hydrocarbon radical is a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common atoms; heterocyclyl means a C 2-11 heterocyclyl; and is a saturated or partially saturated monocyclic or bicyclic heterocyclic radical, 1, 2 or 3 of the ring atoms being a heteroatom from the group consisting of N, O and S, the remaining ring atoms being carbon; bicyclic heterocyclic radical means a heterocyclic ring consisting of two rings having two common ring atoms, the bridge separating the two rings being a single bond, a chain of one ring atom or a chain of two ring atoms, or the two rings being connected by a common ring atom in a spiro ring; aryl means a monocyclic, bicyclic or tricyclic carbocyclic ring system, and at least one ring is aromatic, the whole being a C 6-14 aryl; heteroaryl means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system, and at least one ring is aromatic, containing 1 to 4 heteroatoms, the whole being a C 5-11 aryl; heteroaryl means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system, and at least one ring is aromatic, containing 1 to 4 heteroatoms, the whole being a C 1-4 alkyl means a saturated straight-chain or branched hydrocarbon radical having 1 to 4 carbon atoms; C 1-4 alkoxy means an alkoxy radical having a total of 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom; aminoacyl means an amino-substituted acyl radical derived from an amino acid by removal of the carboxylic acid hydroxyl group.

[0008] Preferably, cycloalkyl is a saturated monocyclic hydrocarbon radical of 3 to 8 ring carbon atoms, i.e. C 3-8 cycloalkyl. Cycloalkyl is a monocyclic hydrocarbon radical of 3 to 6 ring carbon atoms, i.e. C 3- 6 cycloalkyl. Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Preferably, heterocyclyl means a C 3-9 heterocyclyl. Preferably, heterocyclyl means a C 3-5- heterocyclyl. Preferably, the heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,6-diazaspiro[3.4]octanyl, 1,7- diazaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2- oxa-7-azaspiro[3.5]nonanyl, 2-oxa-8-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 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 is selected from phenyl, naphthyl, indanyl or anthryl. Preferably, the heteroaryl is selected from C 5-9 - heteroaryl. Preferably, the heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furanyl, indolyl or quinolinyl. Preferably, the C 1-4 - alkyl. Preferably, the alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Preferably, the C 1-4 - alkoxy. Preferably, the alkoxy is selected from methoxy, ethoxy, propoxy or tert-butoxy. Preferably, the pharmaceutically acceptable salt is a salt of an acid and a lone pair electron containing nitrogen 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.

[0009] Preferably, the compound of formula (I) is selected from compound (I-a), (I-b), (I-c), (I-d) or (I-e); the structures of the compounds (I-a), (I-b), (I-c), (I-d) and (I-e) are shown as follows:

[0010] , , , , .

[0011] The present application also provides a preparation method of the truncated pleuromutilin derivative according to the present application, comprising the following steps:

[0012] .

[0013] Preferably, the preparation method of the pleuromutilin derivative comprises the following steps: S1, dissolving the compound shown in formula (II), triphenylphosphine and thioacetic acid in an organic solvent, adding dropwise diisopropyl azodicarboxylate at 0 DEG C, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, concentrating the crude product, and subjecting to silica gel column chromatography to obtain the compound shown in formula (III); or dissolving the compound shown in formula (II) and a base in an organic solvent, adding dropwise p-toluenesulfonyl chloride or methanesulfonyl chloride at 0 DEG C, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, concentrating, and chromatographing to obtain a first intermediate; dissolving the first intermediate in an organic solvent, adding dropwise potassium thioacetate at 0 DEG C, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, concentrating the crude product, and subjecting to silica gel column chromatography to obtain the compound shown in formula (III); or dissolving the compound shown in formula (II), triphenylphosphine and carbon tetrahalide in an organic solvent, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, concentrating, and chromatographing to obtain a second intermediate; dissolving the second intermediate in an organic solvent, adding dropwise potassium thioacetate at 0 DEG C, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, concentrating the crude product, and subjecting to silica gel column chromatography to obtain the compound shown in formula (III); S2, dissolving the compound shown in formula (III) in an organic solvent, adding a base at 0 DEG C, heating to reflux temperature to perform a reflux reaction for 2-16 hours, then adding the compound shown in formula (IV), stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, concentrating, and chromatographing to obtain a third intermediate; dissolving the third intermediate in an organic solvent, adding an acid at 0 DEG C, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, and concentrating the solvent under reduced pressure to obtain the compound shown in formula (V); S3, dissolving the compound shown in formula (V) in an organic solvent, adding chloroacetyl chloride, a heterocyclic compound and a base at 0 DEG C, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, concentrating the crude product, and subjecting to silica gel column chromatography to obtain the compound shown in formula (VI); or dissolving the compound shown in formula (V) in an organic solvent, adding a 2-bromo-acetamide derivative and a base at 0 DEG C, stirring at room temperature, monitoring the reaction by TLC, adding water after the reaction is completed, extracting with an organic solvent, combining the organic phases, concentrating the crude product, and subjecting to silica gel column chromatography to obtain the compound shown in formula (VII).Alternatively, the compound of formula (V) is dissolved in an organic solvent, an amino acid, a condensing agent and a base are added at a temperature of 0°C, stirring at room temperature, TLC monitoring of the reaction, after the reaction is completed, water is added and extracted with an organic solvent, the organic phase is combined, the concentrated crude product is subjected to silica gel column chromatography to obtain the compound of formula (VIII); or the compound of formula (V) is dissolved in an organic solvent, an aldehyde and a reducing agent are slowly added dropwise at a temperature of 0°C, TLC monitoring of the reaction, after the reaction is completed, water is added to quench the reaction, extracted with an organic solvent, the organic phase is combined, the concentrated crude product is subjected to silica gel column chromatography to obtain the compound of formula (IX).

[0014] 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-dimethylpyridine, 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 pleuromutilins inhibit 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 on C14 of the pleuromutilin structure molecule can penetrate into the hydrophobic group of the ribosomal subunit, thereby improving its antibacterial activity. At the same time, pleuromutilins do not interact with mammalian ribosomes and do not interfere with protein synthesis in eukaryotic cells. The ingenious mechanism of action, unique chemical structure and ease of modification of the C14 side chain of pleuromutilins make it important to conduct in-depth research on pleuromutilins.

[0015] The present application also provides a use of the pleuromutilin derivative in the preparation of an antibiotic and / or an anti-mycoplasma drug. The present application also provides a use of the pleuromutilin derivative in the preparation of an anti-Gram-positive bacteria and / or an anti-Mycoplasma pneumoniae drug.

[0016] The present application provides a novel pleuromutilin derivative with a 2-amino-3-(1H-indol-3-yl)propane-1-thiol side chain, which has good water solubility and low cytotoxicity. In vivo and in vitro antibacterial activity studies show that the antibacterial activity of the pleuromutilin derivative is better than that of the marketed antibacterial products tylosin furoate and voriconazole hydrochloride. The synthesis process conditions are simple and mild, and the production cost is low, so the pleuromutilin derivative is suitable for development into an animal or human resistant bacteria antibiotic, thereby effectively solving the problem of antibiotic resistance. The pleuromutilin derivative can be used as a potential new antibacterial drug for the treatment of local or systemic infections in animals and humans, and has promotional application value in the field of medicinal chemistry. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 is a mass spectrum of compound 1; Figure 2 is a mass spectrum of compound 7; Figure 3 is a mass spectrum of compound 38; Figure 4 is a mass spectrum of compound 52; Figure 5 is a mass spectrum of compound 87. DETAILED DESCRIPTION

[0018] The present application will be described in detail below with reference to preferred embodiments, and other advantages and effects of the present application can be easily understood by those skilled in the art from the disclosure herein. The present application can also be implemented or applied by other different specific embodiments, and various modifications or changes can be made to the details in the specification based on different views and applications without departing from the spirit of the present application. It should be understood that the preferred embodiments are only for illustrating the present application, but not for limiting the protection scope of the present application.

[0019] Example 1: A preparation method of a pleuromutilin derivative as shown in compound 1, comprising the following steps:

[0020] Step 1, Compound 1-1 (CAS: 82689-19-8) (2.0 g, 6.9 mmol) was added to a 50 mL flask with a magnetic stirrer and anhydrous tetrahydrofuran (20 mL), and triphenylphosphine (3.6 g, 13.8 mmol) and diisopropyl azodicarboxylate (2.8 g, 13.8 mmol) were added under stirring at a temperature of 0 °C. After 2 hours of reaction at a temperature of 0 °C, thioacetic acid (1.0 g, 13.8 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 16 hours. After thin layer chromatography (TLC) showed that the raw material point completely disappeared, the solution was concentrated under reduced pressure, and then ethyl acetate (20 mL) and water (50 mL) were added in sequence. The organic phase was extracted and the organic phase was washed with saturated brine 3 times, dried with anhydrous sodium sulfate, and filtered under reduced pressure. The organic phase was concentrated under reduced pressure. The crude product was added to ethanol (15 mL) to form a large amount of suspension, and the solid was filtered under reduced pressure. The filter cake was washed with ether, methyl tert-butyl ether and water in sequence, and dried under reduced pressure to obtain white solid 1-2 (3.94 g, yield 82%);

[0021] Step 2, Compound 1-2 (3.9 g, 11.2 mmol) was added to a 50 mL flask with a magnetic stirrer and methanol (20 mL), and potassium tert-butoxide (18.8 g, 16.8 mmol) was added under stirring at room temperature. After refluxing the reaction solution for 16 hours, compound 1-3 (6.0 g, 11.2 mmol) was added. The reaction was stirred at room temperature overnight. After thin layer chromatography showed that the raw material point completely disappeared, the reaction solution was concentrated under reduced pressure, and then water (10 mL) and ethyl acetate (10 mL) were added. The extraction was performed again, and the organic phase was extracted with ethyl acetate 3 times (20 mL x 3). The organic phase was combined and washed with saturated brine 3 times, dried with anhydrous sodium sulfate, and filtered under reduced pressure. The organic phase was concentrated under reduced pressure. The crude product was dissolved in acetonitrile (12 mL), and water (10 mL) was slowly added dropwise under stirring at a temperature of 0 °C. The suspension was filtered, and the filter cake was washed with petroleum ether (10 mL) and water (20 mL), and dried under reduced pressure to obtain a first white solid (4.92 g, yield 66%). The first white solid (4.9 g, 7.36 mmol) was dissolved in 1,4-dioxane (20 mL), and 4 mol / L hydrochloric acid / 1,4-dioxane (7.5 mL) was slowly added dropwise under stirring at a temperature of 0 °C. The reaction solution was stirred at room temperature for 16 hours. After thin layer chromatography showed that the raw material point completely disappeared, the reaction solution was concentrated under reduced pressure to obtain compound 1 (4.36 g, yield 100%), which was 14-O-({[(S)-2-amino-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommirin. The mass spectrum of compound 1 is shown as follows: Figure 1 MS (ESI) m / z: 567.32565 [M+H] + .

[0022] The reaction equation of compound 1 is as follows:

[0023]

[0024] Example 2: A preparation method of a pleuromutilin derivative as shown in compound 2, comprising the following steps:

[0025] Step 1: Compound 1 (10.0 g, 17.7 mmol) in Example 1 was added to a flask equipped with a magnetic stirrer and dry dichloromethane (150 mL), followed by the addition of triethylamine (2.7 g, 26.6 mmol) and chloroacetyl chloride (2.4 g, 21.2 mmol) at a temperature of 0 °C. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with water (75 mL x 3), the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The crude product was purified by column chromatography, eluted with petroleum ether / ethyl acetate (V / V = 3 / 1~1 / 1) to obtain a gray-white solid 1-4 (7.2 g, yield 63%).

[0026] Step 2: Compound 1-4 (500 mg, 0.78 mmol) was added to a flask equipped with a magnetic stirrer and acetonitrile (10 mL), followed by the addition of potassium carbonate (161 mg, 1.2 mmol) and piperidine hydrochloride (113 mg, 0.94 mmol) at a temperature of 0 °C. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, water (15 mL) was added to the reaction solution, extracted with ethyl acetate (15 mL x 3), the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The crude product was purified by column chromatography, eluted with dichloromethane / methanol (V / V = 18 / 1) to obtain a gray-white solid (226 mg, yield 42%), which was compound 2, 14-O-({[(S)-2-(2-(piperidin-1-yl)acetamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl)mutilin. The mass spectrum MS (ESI) m / z of compound 2: 692.40972 [M+H] + .

[0027] The reaction equation of compound 2 is as follows:

[0028]

[0029] Examples 3 to 37

[0030] A preparation method of a pleuromutilin derivative as shown in compounds 3-37, wherein the piperidine hydrochloride used for carrying out nucleophilic substitution in step 2 is replaced by 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)methanone (145 mg, 0.94 mmol), 1-(oxetan-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), 4-fluoropiperidine (97 mg, 0.94 mmol), 4-phenylpiperidine (151 mg, 0.94 mmol), 1,4'-bipiperidine (158 mg, 0.94 mmol), 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (253 mg, 0.94 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (172 mg, 0.94 mmol), 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-diazaspiro[3.5]nonane (119 mg, 0.94 mmol), 2-oxa-8-diazaspiro[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), respectively.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.

[0031] 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 was 14-O-({[(S)-2-(2-(3,5-dimethylpiperazin-l-yl)acetylamino)-3-(lH-indol-3- yl)propyl]thio}-acetyl)mitorin, yield 314 mg, yield 56%, MS (ESI) m / z: 721.4 [M+H] + ; Compound 11 was 14-O-({[(S)-2-(2-((S)-3-methylpiperazin-l-yl)acetylamino)-3-(lH-indol-3- yl)propyl]thio}-acetyl)mitorin, yield 231 mg, yield 42%, MS (ESI) m / z: 707.4 [M+H] + ; Compound 12 was 14-O-({[(S)-2-(2-(4-acetylpiperazin-l-yl)acetylamino)-3-(lH-indol-3- yl)propyl]thio}-acetyl)mitorin, yield 384 mg, yield 67%, MS (ESI) m / z: 735.4 [M+H] + ; Compound 13 was 14-O-({[(S)-2-(2-(4-cyclopropanecarbonyl)piperazin-l-yl)acetylamino)-3-(lH- indol-3-yl)propyl]thio}-acetyl)mitorin, yield 380 mg, yield 64%, MS (ESI) m / z: 761.4 [M+H] + ; Compound 14 was 14-O-({[(S)-2-(2-(4-(oxetan-3-yl)piperazin-l-yl)acetylamino)-3-(lH-indol-3- yl)propyl]thio}-acetyl)mitorin, yield 286 mg, yield 49%, MS (ESI) m / z: 749.4 [M+H] + ; Compound 15 was 14-O-({[(S)-2-(2-(4-cyclopropylpiperazin-l-yl)acetylamino)-3-(lH-indol-3- yl)propyl]thio}-acetyl)mitorin, yield 297 mg, yield 52%, MS (ESI) m / z: 733.4 [M+H] + ; Compound 16 was 14-O-({[(S)-2-(2-(4-cyclopropylmethylpiperazin-l-yl)acetylamino)-3-(lH-indol- 3-yl)propyl]thio}-acetyl)mitorin, yield 338 mg, yield 58%, MS (ESI) m / z: 747.4 [M+H] + ; Compound 17 was 14-O-({[(S)-2-(2-(4-(pyridin-4-yl)piperazin-l-yl)acetylamino)-3-(lH-indol-3- yl)propyl]thio}-acetyl)mitorin, yield 276 mg, yield 46%, MS (ESI) m / z: 770.4 [M+H]+ ; compound 18 is 14-0-({[(S)-2-(2-(4-(6-nitropyridin-3-yl)piperazin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommitrin, yield 241 mg, yield 20%, MS (ESI) m / z: 815.4 [M+H] + ; compound 19 is 14-0-({[(S)-2-(2-(4-fluoropiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommitrin, yield 360 mg, yield 65%, MS (ESI) m / z: 710.4 [M+H] + ; compound 20 is 14-0-({[(S)-2-(2-(4-phenylpiperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommitrin, yield 359 mg, yield 60%, MS (ESI) m / z: 768.4 [M+H] + ; compound 21 is 14-0-({[(S)-2-(2-([1,4'-bipiperidin]-1'-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommitrin, yield 326 mg, yield 54%, MS (ESI) m / z: 775.5 [M+H] + ; compound 22 is 14-0-({[(S)-2-(2-(4-(piperazin-1-yl)piperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommitrin, yield 326 mg, yield 54%, MS (ESI) m / z: 776.4 [M+H] + ; compound 23 is 14-0-({[(S)-2-(2-(4-methylpiperazin-1-yl)piperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommitrin, yield 234 mg, yield 38%, MS (ESI) m / z: 790.5 [M+H] + ; compound 24 is 14-0-({[(S)-2-(2-(4-(dimethylamino)piperidin-1-yl)acetylamino)-3-(1H-indol-3-yl)propyl]thio}-acetyl)myrtucommitrin, yield 378 mg, yield 66%, MS (ESI) m / z: 735.4 [M+H] +; compound 25 is 14-O-({[(S)-2-(2-(4-hydroxypiperidin-l-yl)acetamido)-3-(lH- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 248 mg, 45% yield, MS (ESI) m / z: 708.3 [M+H] + ; compound 26 is 14-O-({[(S)-2-(2-(4-aminopiperidin-l-yl)acetamido)-3-(lH- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 281 mg, 51% yield, MS (ESI) m / z: 707.4 [M+H] + ; compound 27 is 14-O-({[(S)-2-(2-(3,5-dimethylpiperidin-l-yl)acetamido)-3-(lH- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 320 mg, 57% yield, MS (ESI) m / z: 720.4 [M+H] + ; compound 28 is 14-O-({[(S)-2-(2-(4,4-dimethylpiperidin-l-yl)acetamido)-3-(lH- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 354 mg, 63% yield, MS (ESI) m / z: 720.3 [M+H] + ; compound 29 is 14-O-({[(S)-2-(2-(2,6-dimethylpiperidin-l-yl)acetamido)-3-(lH- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 309 mg, 51% yield, MS (ESI) m / z: 720.4 [M+H] + ; compound 30 is 14-O-({[(S)-2-(2-(morpholin-l-yl)acetamido)-3-(lH-indol-3- yl)propyl]thio}-acetyl)myrtucommirin, yield 352 mg, 65% yield, 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-(lH- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 206 mg, 36% yield, 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-(lH- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 206 mg, 36% yield, MS (ESI) m / z: 733.4 [M+H] +; compound 33 is 14-O-({[(S)-2-(2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)acetamido)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 303 mg, yield 36%, MS (ESI) m / z: 734.3 [M+H] + ; compound 34 is 14-O-({[(S)-2-(2-(2-oxa-8-azaspiro[4.5]dec-8-yl)acetamido)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 402 mg, yield 69%, MS (ESI) m / z: 748.4 [M+H] + ; compound 35 is 14-O-({[(S)-2-(2-(2-hydroxycyclopentyl)amino)acetamido)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 116 mg, yield 21%, MS (ESI) m / z: 708.4 [M+H] + ; compound 36 is 14-O-({[(S)-2-(2-(2-hydroxycyclohexyl)amino)acetamido)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 135 mg, yield 24%, MS (ESI) m / z: 722.4 [M+H] + ; compound 37 is 14-O-({[(S)-2-(2-(2-(piperazin-1-yl)ethyl)amino)acetamido)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 103 mg, yield 18%, MS (ESI) m / z: 736.4 [M+H] + ;

[0032] The structural formula of compounds 3~37 are respectively as follows: , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 .

[0033] Example 38 A method for preparing a pleuromutilin derivative as shown in compound 38, comprising the following steps:

[0034] Step 1, compound 1 (500 mg, 0.88 mmol) prepared in example 1 was added to a 25 mL tomato 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 under stirring at room temperature, after mixing, the reaction solution was reacted at room temperature for 3 hours. After the reaction was completed, water (15 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL x 3), the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, reduced pressure filtration, the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography, eluted with dichloromethane / methanol (V / V=20 / 1) to obtain a gray-white solid (357 mg, yield 65%), which was compound 38, 14-O-({[(S)-2-((2-amino-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin. The mass spectrum of compound 38 is shown in Figure 3 MS (ESI) m / z: 624.34712 [M+H] + .

[0035] The reaction equation of compound 38 is as follows:

[0036]

[0037] Examples 39 to 51

[0038] A preparation method of a pleuromutilin derivative as shown in compounds 39-51, wherein the 2-bromoacetamide used in step 1 and the amount 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) respectively, and the rest of the preparation steps and conditions are the same as those in Example 38.

[0039] The prepared compound 39 is 14-O-({[(S)-2-(2-((methylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin, with a yield of 381 mg and a yield of 68%, MS (ESI) m / z: 638.3 [M+H] + ; the compound 40 is 14-O-({[(S)-2-(2-(ethylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin, with a yield of 326 mg and a yield of 57%, MS (ESI) m / z: 652.2 [M+H] + ; the compound 41 is 14-O-({[(S)-2-(2-(isopropylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin, with a yield of 363 mg and a yield of 62%, MS (ESI) m / z: 666.4 [M+H] + ; the compound 42 is 14-O-({[(S)-2-((2-(cyclopropylamino)-2-oxoethyl)amino)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin, with a yield of 338 mg and a yield of 58%, MS (ESI) m / z: 664.3 [M+H] +; compound 43 was 14-O-({[(S)-2-((2-(cyclobutylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 292 mg, yield 49%, MS (ESI) m / z: 678.3 [M+H] + ; compound 44 was 14-O-({[(S)-2-((2-(cyclopentylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 334 mg, yield 55%, MS (ESI) m / z: 692.4 [M+H] + ; compound 45 was 14-O-({[(S)-2-((2-(cyclohexylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 423 mg, yield 60%, MS (ESI) m / z: 706.3 [M+H] + ; compound 46 was 14-O-({[(S)-2-((2-(pyridin-4-ylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 238 mg, yield 34%, MS (ESI) m / z: 701.2 [M+H] + ; compound 47 was 14-O-({[(S)-2-((2-(1 H-imidazol-2-ylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 324 mg, yield 47%, MS (ESI) m / z: 690.3 [M+H] + ; compound 48 was 14-O-({[(S)-2-((2-(thiazol-2-ylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 311 mg, yield 44%, MS (ESI) m / z: 707.2 [M+H] + ; compound 49 was 14-O-({[(S)-2-((2-(oxazol-2-ylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 242 mg, yield 35%, MS (ESI) m / z: 691.3 [M+H] + ; compound 50 was 14-O-({[(S)-2-((2-(pyrimidin-2-ylamino)-2-oxoethyl)amino)-3-(1 H- indol-3-yl)propyl]thio}-acetyl)myrtucommirin, yield 225 mg, yield 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) mupirocin, yield 267 mg, yield 38%, MS (ESI) m / z: 702.4 [M+H] + ;

[0040] The structural formula of compound 39-51 is respectively as follows: , , , , , , , , , , , , .

[0041] Example 52 A preparation method of a pleuromutilin derivative as shown in compound 52, comprising the following steps:

[0042] Step 1, compound 1 (500 mg, 0.88 mmol) and N-tert-butoxycarbonyl-L- glycine (175 mg, 1.0 mmol) prepared in example 1 were added into a 25 mL flask with magnetic stirring bar and anhydrous N,N-dimethylformamide (10 mL), HATU (456 mg, 1.2 mmol) and triethylamine (133 mg, 1.32 mmol) were added under ice-bath stirring. After 30 minutes of ice-bath stirring, the reaction solution was transferred to room temperature and reacted for 6 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography, eluted with dichloromethane / methanol (V / V = 30 / 1) to obtain a gray-white solid (337 mg, yield 53%). The above gray-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 dropwise addition was completed, the reaction was carried out 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 fully dissolving, saturated sodium bicarbonate was added dropwise to adjust the pH to 7-8, and then ethyl acetate (5 mL x 3) was used for extraction. The organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography, eluted with dichloromethane / methanol (V / V = 15 / 1) to obtain a gray-white solid (180 mg, yield 62%), which was compound 52, 14-O- (2-{[ (S) -2- (2-aminoacetamide) -3- (1H-indol-3-yl) propyl]thio} -acetyl) myrtucommine. The mass spectrum of compound 52 is shown in Figure 4 + .

[0043] The reaction equation of compound 52 is as follows:

[0044]

[0045] Examples 53 to 68

[0046] ​A preparation method of a pleuromutilin derivative as shown in compounds 53-68, wherein, in step 1, N-tert-butoxycarbonyl-L-glycine used and the amount are replaced by N-tert-butoxycarbonyl-L-alanine (189 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-valine (217 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-serine (205 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-leucine (231 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-isoleucine (231 mg, 1.0 mmol), N-tert-butoxycarbonyl-L-threonine (219 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-(dimethylamino)propanoic acid (117 mg, 1.0 mmol), 3-(dimethylamino)propanoic acid hydrochloride (154 mg, 1.0 mmol), 4-tert-butoxycarbonylamino-cyclohexylacetic acid (243 mg, 1.0 mmol), N-tert-butoxycarbonyl-1-aminocyclopropaneacetic acid (201 mg, 1.0 mmol), and N-tert-butoxycarbonyl-1-aminocyclobutaneacetic acid (215 mg, 1.0 mmol), and the rest of the preparation steps and conditions are the same as in Example 52.

[0047] The prepared compound 53 is 14-O-(2-{[(S)-2-((S)-2-aminopropanoyl)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin, with a yield of 213 mg and a yield of 38%, MS (ESI) m / z: 638.3 [M+H] + ; the compound 54 is 14-O-(2-{[(S)-2-((S)-2-amino-3-methylbutanoyl)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin, with a yield of 275 mg and a yield of 47%, MS (ESI) m / z: 666.4 [M+H] + ; the compound 55 is 14-O-(2-{[(S)-2-((S)-2-amino-3-hydroxypropanoyl)-3-(1H-indol-3-yl)propyl]thio}-acetyl) pleuromutilin, with a yield of 241 mg and a yield of 42%, MS (ESI) m / z: 654.4 [M+H] +; compound 56 was 14-0-(2-{[(S)-2-((S)-2-amino-4-methylpentanoyl)-3-(1H- indol-3-yl)propyl]thio}-acetyl)mutilin, yield 287 mg, yield 48%, MS (ESI) m / z: 680.4 [M+H] + ; compound 57 was 14-0-(2-{[(S)-2-((2S,3S)-2-amino-3-methylpentanoyl)-3-(1H- indol-3-yl)propyl]thio}-acetyl)mutilin, yield 239 mg, yield 50%, MS (ESI) m / z: 680.4 [M+H] + ; compound 58 was 14-0-(2-{[(S)-2-((2S,3R)-2-amino-3-hydroxybutanoyl)-3-(1H- indol-3-yl)propyl]thio}-acetyl)mutilin, yield 206 mg, yield 35%, MS (ESI) m / z: 668.3 [M+H] + ; compound 59 was 14-0-(2-{[(S)-2-((S)-2-amino-4-(methylthio)butanoyl)-3-(1H- indol-3-yl)propyl]thio}-acetyl)mutilin, yield 190 mg, yield 31%, MS (ESI) m / z: 698.4 [M+H] + ; compound 60 was 14-0-(2-{[(S)-2-((S)-(2-amino-3-(1H-imidazol-4-yl)propanoyl)-3- (1H-indol-3-yl)propyl]thio}-acetyl)mutilin, yield 161 mg, yield 26%, MS (ESI) m / z: 704.3 [M+H] + ; compound 61 was 14-0-(2-{[(S)-2-((S)-2,5-diamino-5-oxopentanoyl)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 134 mg, yield 22%, MS (ESI) m / z: 695.4 [M+H] + ; compound 62 was 14-0-(2-{[(S)-2-((S)-2,4-diamino-4-oxobutanoyl)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 177 mg, yield 26%, MS (ESI) m / z: 681.3 [M+H] + ; compound 63 was 14-0-(2-{[(S)-2-((S)-pyrrolidine-2-carboxamide)-3-(1H-indol-3- yl)propyl]thio}-acetyl)mutilin, yield 206 mg, yield 31%, MS (ESI) m / z: 664.3 [M+H]+ ; compound 64 is 14-O- (2-{[ (S) -2- ( (R) -2- (dimethylamino) propanamide) -3- (1H- indol-3-yl) propyl]thio} -acetyl) mitragyna, yield 253 mg, yield 38%, MS (ESI) m / z: 666.4 [M+H] + ; compound 65 is 14-O- (2-{[ (S) -2- (3- (dimethylamino) propanamide) -3- (1H- indol-3-yl) propyl]thio} -acetyl) mitragyna, yield 146 mg, yield 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) mitragyna, yield 228 mg, yield 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) mitragyna, yield 305 mg, yield 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) mitragyna, yield 278 mg, yield 42%, MS (ESI) m / z: 664.3 [M+H] + ;

[0048] The structural formula of compound 53~68 is respectively as follows: , , , , , , , , , , , , , , , .

[0049] Example 69 A preparation method of a pleuromutilin derivative as shown in compound 69, comprising the following steps:

[0050] Step 1: Into a 25 mL round bottom flask equipped with a magnetic stir bar and methanol (7 mL), was placed compound 1 (500 mg, 0.88 mmol) prepared in Example 1, formaldehyde aqueous solution (357 mg, 4.40 mmol, 37%), and sodium cyanoborohydride (83 mg, 1.32 mmol). After stirring at room temperature for 15 min, glacial acetic acid was added to adjust the pH of the reaction solution to 5-7, and the reaction was continued at room temperature for 8 h. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution, and the methanol was removed by concentration under reduced pressure. The residue was added with water (20 mL) and adjusted to pH 9 with 2 mol / L sodium hydroxide solution. The mixture was extracted with ethyl acetate (15 mL x 3), and the organic phase was washed with 2 mol / L sodium hydroxide solution (10 mL x 3) and 1 mol / L hydrochloric acid solution (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane / methanol (V / V=20 / 1) as the eluent to obtain compound 69, 14-O- (2-{[ (S) -2- (methylamino) -3- (1H-indol-3-yl) propyl]thio} -acetyl) pleuromutilin, as a white solid (143 mg, 28% yield). The mass spectrum MS (ESI) m / z of compound 69: 581.34130 [M+H] + .

[0051] The reaction equation of compound 69 is as follows:

[0052]

[0053] Example 70 to Example 76 A method for preparing a pleuromutilin derivative as shown in compounds 70-76, except that the formaldehyde aqueous solution and the amount used in step 1 are replaced with 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 azetidin-3-carboxaldehyde (374 mg, 4.4 mmol), respectively, and the remaining preparation steps and conditions are the same as those of Example 69.

[0054] The prepared compound 70 is 14-O- (2-{[ (S) -2- (ethylamino) -3- (1H-indol-3-yl) propyl]thio} -acetyl) pleuromutilin, with a yield of 115 mg and a yield of 22%, and MS (ESI) m / z: 595.4 [M+H] +; Compound 71 was 14-O- (2-{[ (S) -2- (isopropylamino) -3- (1H-indol-3- yl) propyl]thio} -acetyl) myriocin, yield 166 mg, yield 31%, MS (ESI) m / z: 609.3 [M+H] + ; Compound 72 was 14-O- (2-{[ (S) -2- ((cyclopropylmethyl) amino) -3- (1H-indol-3- yl) propyl]thio} -acetyl) myriocin, yield 131 mg, yield 24%, MS (ESI) m / z: 621.4 [M+H] + ; Compound 73 was 14-O- (2-{[ (S) -2- (cyclobutylamino) -3- (1H-indol-3- yl) propyl]thio} -acetyl) myriocin, yield 153 mg, yield 28%, MS (ESI) m / z: 621.4 [M+H] + ; Compound 74 was 14-O- (2-{[ (S) -2- ((cyclobutylmethyl) amino) -3- (1H-indol-3- yl) propyl]thio} -acetyl) myriocin, yield 140 mg, yield 25%, MS (ESI) m / z: 635.3 [M+H] + ; Compound 75 was 14-O- (2-{[ (S) -2- (cyclopentylamino) -3- (1H-indol-3- yl) propyl]thio} -acetyl) myriocin, yield 106 mg, yield 50%, MS (ESI) m / z: 635.3 [M+H] + ; Compound 76 was 14-O- (2-{[ (S) -2- ((azetidin-3-ylmethyl) amino) -3- (1H-indol-3- yl) propyl]thio} -acetyl) myriocin, yield 89 mg, yield 16%, MS (ESI) m / z: 636.3 [M+H] + ;

[0055] The structural formula of Compound 70~76 was respectively as follows: , , , , , , .

[0056] Examples 77 to 101

[0057] A preparation method of a pleuromutilin derivative as shown in compounds 77-101, wherein the compound 1-1 indole compound and the amount used in step 1 are replaced by (S)-[1-(5-fluoro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.12g, 6.9mmol), (S)-[1-(5-chloro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.24g, 6.9mmol), (S)-[1-(5-bromo-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.54g, 6.9mmol), (S)-[1-(5-methyl-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.1g, 6.9mmol), (S)-[1-(5-methoxy-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.21g, 6.9mmol), (S)-3-(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-5-((tert-butoxycarbonyl)oxy)-1H-indole-1-carboxylic acid tert-butyl ester (3.5g, 6.9mmol), (S)-[1-(5-cyano-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.17g, 6.9mmol), (S)-[1-(5-nitro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.31g, 6.9mmol), (S)-5-((tert-butoxycarbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-1H-indole-1-carboxylic acid tert-butyl ester (3.49g, 6.9mmol), (S)-[1-(5-trifluoromethyl-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.47g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propan-2-yl]carbamic acid tert-butyl ester (2.00g, 6.9mmol), (S)-(1-hydroxy-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamic acid tert-butyl ester (2.00g, 6.9mmol), (S)-(1-hydroxy-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propan-2-yl)carbamic acid tert-butyl ester (2.00g, 6.9mmol), (S)-(1-hydroxy-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propan-2-yl)carbamic acid tert-butyl ester (2.00g, 6.9mmol), (S)-[1-hydroxy-3-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[2,3-d]pyrimidin-5-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-2-yl]carbamic acid tert-butyl ester (2.01g, 6.9mmol) and step 2 is replaced by (S)-[1-(5-fluoro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.12g, 6.9mmol), (S)-[1-(5-chloro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.24g, 6.9mmol), (S)-[1-(5-bromo-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.54g, 6.9mmol), (S)-[1-(5-methyl-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.1g, 6.9mmol), (S)-[1-(5-methoxy-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.21g, 6.9mmol), (S)-3-(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-5-((tert-butoxycarbonyl)oxy)-1H-indole-1-carboxylic acid tert-butyl ester (3.5g, 6.9mmol), (S)-[1-(5-cyano-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.17g, 6.9mmol), (S)-[1-(5-nitro-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.31g, 6.9mmol), (S)-5-((tert-butoxycarbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-1H-indole-1-carboxylic acid tert-butyl ester (3.49g, 6.9mmol), (S)-[1-(5-trifluoromethyl-1H-indol-3-yl)-3-hydroxypropan-2-yl]carbamic acid tert-butyl ester (2.47g, 6.9mmol), (S)-[1-hydroxy-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propan-2-yl]carbamic acid tert-butyl ester (2.00g, 6.9mmol), (S)-(1-hydroxy-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)propan-2-yl)carbamic acid tert-butyl ester (2.00g, 6.9mmol), (S)-(1-hydroxy-3-(1H-pyrrolo[3,29 mmol), (S)-(1-hydroxy-3-(1 H-pyrrolo[2,3-d]pyridazin-3-yl)propan-2-yl)carbamic acid tert-butyl ester (0.20 g, 0.69 mmol), (S)-(1-hydroxy-3-(5H-pyrrolo[2,3-b]pyrazin-7-yl)propan-2-yl)carbamic acid tert-butyl ester (0.20 g, 0.69 mmol), (S)-(1-hydroxy-3-(4,5,6,7-tetrahydro-1 H-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-hydroxy-3-(1 H-indazol-3-yl)propan-2-yl)carbamic acid tert-butyl ester (0.2 g, 0.69 mmol), (S)-(1-hydroxy-3-(1-methyl-1 H-indol-3-yl)propan-2-yl)carbamic acid tert-butyl ester (2.10 g, 6.9 mmol), (S)-(1-(1-((tert-butoxycarbonyl)amino)-1 H-indol-3-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester (0.28 g, 0.69 mmol), (S)-(1-hydroxy-3-(2-methyl-1 H-indol-3-yl)propan-2-yl)carbamic acid tert-butyl ester (0.21 g, 0.69 mmol), and (S)-(1-(2-cyano-1 H-indol-3-yl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester (0.22 g, 0.69 mmol), the rest of the preparation steps and conditions are the same as Example 1.

[0058] The prepared compound 77 is 14-O-({[(S)-2-amino-3-(5-fluoro-1 H-indol-3-yl)propyl]thio}-acetyl)myrtucommirin, the yield is 1.21 g, the yield is 30%, MS (ESI) m / z: 585.3 [M+H] + ; compound 78 is 14-O-({[(S)-2-amino-3-(5-chloro-1 H-indol-3-yl)propyl]thio}-acetyl)myrtucommirin, the yield is 0.86 g, the yield is 21%, MS (ESI) m / z: 601.2 [M+H] + ; compound 79 is 14-O-({[(S)-2-amino-3-(5-bromo-1 H-indol-3-yl)propyl]thio}-acetyl)myrtucommirin, the yield is 1.51 g, the yield is 34%, MS (ESI) m / z: 645.1 [M+H] +; Compound 80 was 14-O-({[(S)-2-amino-3-(5-methyl-lH-indol-3- yl)propyl]thio}-acetyl)myriocin with yield of 0.72 g, yield of 18%, MS (ESI) m / z: 581.3 [M+H] + ; Compound 81 was 14-O-({[(S)-2-amino-3-(5-methoxy-lH-indol-3- yl)propyl]thio}-acetyl)myriocin with yield of 1.64 g, yield of 40%, MS (ESI) m / z: 597.3 [M+H] + ; Compound 82 was 14-O-({[(S)-2-amino-3-(5-hydroxy-lH-indol-3- yl)propyl]thio}-acetyl)myriocin with yield of 0.60 g, yield of 15%, MS (ESI) m / z: 583.3 [M+H] + ; Compound 83 was 14-O-({[(S)-2-amino-3-(5-cyano-lH-indol-3- yl)propyl]thio}-acetyl)myriocin with yield of 1.06 g, yield of 26%, MS (ESI) m / z: 592.1 [M+H] + ; Compound 84 was 14-O-({[(S)-2-amino-3-(5-nitro-lH-indol-3- yl)propyl]thio}-acetyl)myriocin with yield of 0.59 g, yield of 14%, MS (ESI) m / z: 612.2 [M+H] + ; Compound 85 was 14-O-({[(S)-2-amino-3-(5-amino-lH-indol-3- yl)propyl]thio}-acetyl)myriocin with yield of 0.68 g, yield of 17%, MS (ESI) m / z: 582.1 [M+H] + ; Compound 86 was 14-O-({[(S)-2-amino-3-(5-trifluoromethyl-lH-indol-3- yl)propyl]thio}-acetyl)myriocin with yield of 1.05 g, yield of 24%, MS (ESI) m / z: 635.1 [M+H] + ; Compound 87 was 14-O-({[(S)-2-amino-3-(lH-pyrrolo[2,3-b]pyridin-3- yl)propyl]thio}-acetyl)myriocin with yield of 0.78 g, yield of 20%, mass spectrum as shown in Figure 5 ; Compound 87 was 14-O-({[(S)-2-amino-3-(lH-pyrrolo[2,3-b]pyridin-3- yl)propyl]thio}-acetyl)myriocin with yield of 0.78 g, yield of 20%, mass spectrum as shown in +; Compound 88 was 14-O-({[(S)-2-amino-3-(lH-pyrrolo[2,3-c]pyridin-3- yl)propyl]thio}-acetyl)mitrin, yield 0.86 g, yield 22%, MS (ESI) m / z: 568.3 [M+H] + ; Compound 89 was 14-O-({[(S)-2-amino-3-(lH-pyrrolo[3,2-c]pyridin-3- yl)propyl]thio}-acetyl)mitrin, yield 0.70 g, yield 18%, MS (ESI) m / z: 568.3 [M+H] + ; Compound 90 was 14-O-({[(S)-2-amino-3-(lH-pyrrolo[3,2-b]pyridin-3- yl)propyl]thio}-acetyl)mitrin, yield 0.98 g, yield 25%, MS (ESI) m / z: 568.3 [M+H] + ; Compound 91 was 14-O-({[(S)-2-amino-3-(7H-pyrrolo[2,3-d]pyrimidin-5- yl)propyl]thio}-acetyl)mitrin, yield 0.71 g, yield 20%, MS (ESI) m / z: 569.3 [M+H] + ; Compound 92 was 14-O-({[(S)-2-amino-3-(7H-pyrrolo[2,3-d]pyridazin-3- yl)propyl]thio}-acetyl)mitrin, yield 0.063 g, yield 16%, MS (ESI) m / z: 569.3 [M+H] + ; Compound 93 was 14-O-({[(S)-2-amino-3-(5H-pyrrolo[2,3-b]pyrazin-7- yl)propyl]thio}-acetyl)mitrin, yield 0.055 g, yield 14%, MS (ESI) m / z: 569.3 [M+H] + ; Compound 94 was 14-O-({[(S)-2-amino-3-(4,5,6,7-tetrahydro-lH-indol-3- yl)propyl]thio}-acetyl)mitrin, yield 0.102 g, yield 18%, MS (ESI) m / z: 571.3 [M+H] + ; Compound 95 was 14-O-({[(S)-2-amino-3-(benzothiophen-3-yl)propyl]thio}- acetyl)mitrin, yield 1.13 g, yield 28%, MS (ESI) m / z: 584.2 [M+H] +; Compound 96 was 14-O-({[(S)-2-amino-3-(benzofuran-3-yl)propyl]thio}- acetyl)myriocin, the yield was 1.33 g, the yield was 34%, MS (ESI) m / z: 568.2 [M+H] + ; Compound 97 was 14-O-({[(S)-2-amino-3-(1H-indazol-3-yl)propyl]thio}- acetyl)myriocin, the yield was 0.098 g, the yield was 25%, MS (ESI) m / z: 568.3 [M+H] + ; Compound 98 was 14-O-({[(S)-2-amino-3-(1-methyl-1H-indol-3-yl)propyl]thio}- acetyl)myriocin, the yield was 1.00 g, the yield was 25%, MS (ESI) m / z: 581.1 [M+H] + ; Compound 99 was 14-O-({[(S)-2-amino-3-(1-amino-1H-indol-3-yl)propyl]thio}- acetyl)myriocin, the yield was 0.056 g, the yield was 14%, MS (ESI) m / z: 582.3 [M+H] + ; Compound 100 was 14-O-({[(S)-2-amino-3-(2-methyl-1H-indol-3-yl)propyl]thio}- acetyl)myriocin, the yield was 0.15 g, the yield was 37%, MS (ESI) m / z: 581.2 [M+H] + ; Compound 101 was 14-O-({[(S)-2-amino-3-(2-cyano-1H-indol-3-yl)propyl]thio}- acetyl)myriocin, the yield was 0.09 g, the yield was 24%, MS (ESI) m / z: 592.3 [M+H] + ;

[0059] The structural formulas of compounds 77~101 were as follows, respectively: , , , , , , , , , , , , , , , , , , , , , 、 、 、 .

[0060] Biological activity test

[0061] 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, ATCC 43300)) and Mycoplasma hyopneumoniae (Mhp, ATCC 25934) was tested based on the broth microdilution method recommended by NCCLS, and the data was expressed by the minimum inhibitory concentration (MIC, unit: μg / mL) required for inhibiting the growth of the pathogens, and the readings were taken at 600 nm and 450 nm, respectively, by using a microplate reader, and the results are shown in Table 1.

[0062] Antibacterial and anti-mycoplasma activity of compounds 1-101

[0063]

[0064]

[0065] As can be seen from the data in Table 1, the pleuromutilin derivatives provided by the present application having an indole analogue side chain have good antibacterial and anti-mycoplasma activity, which is superior to the marketed drugs tylosin furoate and voriconazole hydrochloride, and has potential development value in the field of animal and human use of antibiotics against drug-resistant bacteria.

[0066] In summary, the pleuromutilin derivatives of the present application are a class of novel structures, and the in vitro antibacterial and anti-mycoplasma activity tests show that the pleuromutilin derivatives containing 2-amino-3-(1H-indol-3-yl)propane-1-thiol have good bacteriostatic and mycoplasma inhibiting effects, and the inhibiting effect on clinical drug-resistant strains and mycoplasma virulent strains is better than that of the marketed pleuromutilin antibiotic tylosin furoate and voriconazole hydrochloride. It is proved that the pleuromutilin derivatives of the present application can be used as potential new antibacterial and anti-mycoplasma drugs for treating local or systemic infections of animals and humans, and exhibit good antibacterial and anti-mycoplasma activity, and have potential new drug development value.

[0067] The above examples are only preferred examples for fully illustrating the present application, and the protection scope of the present application is not limited thereto. Any equivalent substitution or transformation made by the person skilled in the art based on the present application is within the protection scope of the present application.

Claims

1. A pleuromutilin derivative, characterized in that: The structure is a compound as described in formula (I) and its stereoisomers or pharmaceutically acceptable salts; In formula (I), Y is selected from 、 ,H,C 1-4 Alkyl or cycloalkyl, wherein A is selected from heterocyclyl or H, and B is selected from cycloalkyl or heteroaryl; Z is selected from cycloalkyl, aryl or heteroaryl, and there are 0 to 5 substituents on the aryl, and the substituents are selected from H, F, Cl, Br, CN, OH, NH2, NO2, CF3, C 1-4 Alkyl or C 1-4 alkoxy; X is selected from N, O or S; Q is selected from NH2 or C 1-4 alkyl; G is selected from N or , wherein R is selected from CH3 or CN; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; The heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,7-diazaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-8-azaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.5]nonyl or morpholinyl; The aryl group is selected from phenyl; The heteroaryl group is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furanyl, indolyl or quinolinyl; The C 1-4 Alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; The C 1-4 The alkoxy group is selected from methoxy, ethoxy, propoxy or tert-butoxy.

2. 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.

3. The pleuromutilin derivative according to claim 1, characterized in that The compound of formula (I) is selected from compounds (Ia), (Ib), and (Ib); the structural formulas of the compounds (Ia) and (Ib) are as follows: ， ， Wherein, A, B and Z have the definitions as described in claim 1.

4. 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- 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, 1-[[(S)-2-[[(S)-2-[[(S)-2-aminopropionamido]-3-(1H-indol-3-yl)propyl]thio}-acetyl]] ester, 14-O-(2-{[(S)-2-((S)-2-aminopropionamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl] ester, 14-O-(2-{[(S)-2-((S)-2-aminopropionamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl] ester, 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-3-methylpentanamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((2S,3R)-2-amino-3-hydroxybutanamido)-3-(1H-indol-3-yl)propyl]thio}-acetyl) emthioline, 14-O-(2-{[(S)-2-((S)-2-amino-4-(methylthio)butanamido)-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.

5. A method for preparing a pleuromutilin derivative according to any one of claims 1 to 4, characterized in that: The following steps are involved: ； Wherein, A, B, Z, X, Q and G have the definitions as described in claim 1.

6. The method for preparing a pleuromutilin derivative according to claim 5, 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).

7. The method for preparing a pleuromutilin derivative according to claim 6, 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.

8. Use of a pleuromutilin derivative prepared by the method according to any one of claims 5 to 7 in the preparation of antibiotics and / or antimycoplasma drugs.

9. Use of a pleuromutilin derivative prepared by the method according to any one of claims 5 to 7 in the preparation of anti-Gram-positive bacteria and / or anti-Mycoplasma pneumoniae drugs.

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