Pleuromutilin compound as well as preparation method and application thereof

Abstract

The invention discloses a pleuromutilin compound as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The compound is a polysubstituted aryl amide thioether pleuromutilin derivative, and is synthesized by the following method: pleuromutilin is taken as a raw material, methylsulfonylation is performed on a C-22 side chain terminal hydroxyl group, a nucleophilic substitution reaction is performed on the pleuromutilin and a sulfydryl-containing aromatic intermediate, and nitryl is reduced to obtain a target compound. According to the pleuromutilin compound provided by the invention, key groups of a parent nucleus are reserved and optimized, the binding capacity and physicochemical properties of the compound and an action target are enhanced by introducing a thioether bond and a polysubstituted aryl amide group, and an in-vitro antibacterial activity test shows that the pleuromutilin compound has strong inhibitory activity on various pathogenic bacteria and can be used for preparing antibacterial agents. The activity of part of the compounds is superior to that of clinically common medicines tiamulin and valnemulin. The compound is suitable for preparing medicines for preventing and / or treating bacterial infectious diseases, and is used for developing novel and efficient antibacterial medicines.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically a truncated pleurotin compound, its preparation method, and its application. Background Technology

[0002] Antibiotics are a class of chemical substances produced by microorganisms during their life activities, or artificially modified and synthesized, that selectively inhibit or kill other microorganisms. The problem of bacterial resistance caused by the long-term use and abuse of antibiotics is becoming increasingly serious, posing a severe threat to human and animal health. The World Health Organization's 2022 report, "Global Antimicrobial Resistance and Use Surveillance System Report," indicated that resistance rates in common bacterial infections are as high as 50% or more. The 2024 alert list of priority pathogens included many Gram-positive bacteria with high or moderate priority, such as methicillin-resistant Staphylococcus aureus (MRSA) and macrolide-resistant Streptococcus pneumoniae (MRSA). Increasing research and development efforts on novel antibiotics is currently a crucial way to address the problem of bacterial resistance. In recent years, some pharmaceutical companies and research institutions have begun to focus on the structural modification of marketed antibacterial drugs, hoping to develop drugs with better antibacterial activity, especially those derived from natural products.

[0003] Pleuroromutilin, a tricyclic diterpenoid compound with anti-Gram-positive bacteria and mycoplasma activity, was first isolated in 1951 from the fermentation broth of *Pleurotus mutilus* and *Pleurotus passeckeranius*. Pleuroromutilin binds to the 23S rRNA of the 50S subunit of the bacterial ribosome, inhibiting bacterial protein synthesis by suppressing peptidyl transferase activity. The tricyclic nucleus in its structure is tightly fitted to the A site of the peptidyl transferase, while the C-14 side chain extends into the cavity of the P site in different conformations, thus affecting the rRNA conformation and inhibiting bacterial protein synthesis. This effective drug binding mechanism is achieved through an induced-fit mechanism, utilizing the inherent flexibility of the ribosome to allow the pleuroromutilin compound to bind tightly to the subunit pocket.

[0004] Although pleuromedullary truncated has a unique antibacterial mechanism, its physicochemical properties and antibacterial spectrum have significant drawbacks, limiting its direct clinical application. Firstly, its water solubility and oral bioavailability are low; its natural structure has extremely poor water solubility, leading to poor absorption and low bioavailability in vivo. Furthermore, the antibacterial activity of pleuromedullary truncated needs to be enhanced; its original antibacterial activity, particularly against certain Gram-negative bacteria, is insufficient to meet the demands for highly effective clinical treatment.

[0005] While existing research has confirmed that modifying the C22 side chain is an effective way to enhance activity—for example, introducing a basic group or aromatic ring can improve activity and solubility, and introducing a specific heterocycle can enhance the interaction with the target—current modification strategies mostly rely on empirical attempts and lack a systematic design of the relationship between structure, activity, and properties. For example, what type of linker can optimally improve metabolic stability while maintaining activity, and how to precisely control the polarity, charge, and spatial conformation of the side chain terminal group to simultaneously improve antibacterial efficacy, water solubility, and inhibitory effects on drug-resistant strains—these questions remain unanswered, resulting in low efficiency in the development of new derivatives and limited breakthroughs in activity. Summary of the Invention

[0006] To overcome the above-mentioned deficiencies of the prior art, the present invention aims to provide a truncated pleurotin compound, its preparation method and application. Using truncated pleurotin as a lead compound, a series of truncated pleurotin compounds with substituted aromatic amines as C22 side chains were designed and synthesized. The in vitro antibacterial activity of the compounds against a variety of Gram-positive bacteria was tested, revealing the antibacterial application effect of such compounds.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] In a first aspect, the present invention provides a truncated pleurotin compound, the structural formula of which is as follows:

[0009]

[0010] in, It is aryl, aromatic heteroyl, cycloalkyl, or heterocyclic;

[0011] R1 is H, -NH2, -OH, -SH, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, -NO2, haloalkyl, aryl, aromatic heteroyl, alkyl, heterocyclic, alkylamino, alkoxy, alkylthio, cycloalkyl, or sulfonyl.

[0012] R2 is H, -NH2, -OH, -SH, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, -NO2, haloalkyl, aryl, aromatic heteroyl, alkyl, heterocyclic, alkylamine, alkoxy, alkylthio, cycloalkyl, or sulfonyl.

[0013] X is N, O, or S;

[0014] n can be 0, 1, 2, 3, 4, or 5.

[0015] As a limitation of the present invention It is a benzene ring.

[0016] As another limitation of the present invention, one of R1 and R2 is an amino group and the other is an alkyl group or a halogen.

[0017] Secondly, the present invention also provides a pharmaceutically acceptable salt, isomer, racemate, hydrate, solvate, or isotopic label, which is prepared from one of the above-mentioned truncated pleurotin compounds.

[0018] Thirdly, the present invention also provides a method for preparing truncated pleurotin compounds, comprising the following steps performed sequentially:

[0019] S1. Starting with truncated pleurotin, it is reacted with a sulfonating agent in the presence of p-toluenesulfonyl chloride to give intermediate 1, which is methanesulfonated at C-22.

[0020] S2. The intermediate 1 is reacted with a mercapto-containing aromatic intermediate under alkaline conditions to undergo a nucleophilic substitution reaction to obtain a nitro-substituted intermediate 2;

[0021] S3. Nitro reduction reaction of intermediate 2 to obtain a truncated pleurotin compound.

[0022] As a limitation of the present invention, in step S1, the sulfonating agent is p-methylbenzenesulfonyl chloride; the reaction solvent is tetrahydrofuran; and the reaction is carried out under low temperature conditions of -5~0℃ and alkaline aqueous solution.

[0023] In step S2, the thiol-containing aromatic intermediate is 2-mercapto-O-(3-bromo-4-nitrophenyl)acetamide; the base is sodium hydroxide; and the reaction solvent is tetrahydrofuran.

[0024] In step S3, the nitro reduction reaction is carried out under reflux with iron powder, ammonium chloride and methanol solvent.

[0025] Furthermore, such truncated pleurotin compounds are preferably the following compounds:

[0026]

[0027]

[0028]

[0029] Specifically, among the compounds mentioned above, the truncated pleurotin compounds containing group A are one of P001 to P030, and have the same general skeletal formula (I) except for group A; the truncated pleurotin compounds containing group B are one of P031 to P043, and have the same general skeletal formula (II) except for group B; the truncated pleurotin compounds containing group C are one of P044 to P050, and have the same general skeletal formula (III) except for group C; and the truncated pleurotin compounds containing group D are one of P051 to P057, and have the same general skeletal formula (IV) except for group D.

[0030] Furthermore, a method for preparing the above-mentioned truncated pleurotin compounds is provided, with the following reaction equation:

[0031]

[0032] As another limitation of the present invention, it also includes a step of purifying the products obtained in steps S1 to S3, wherein the purification method is recrystallization, column chromatography, or a combination thereof.

[0033] Fourthly, the present invention provides the use of truncated pleurotin compounds in the preparation of medicaments for the prevention and / or treatment of bacterial infectious diseases.

[0034] As a limitation of the present invention, the bacterial infectious disease is caused by Gram-positive bacteria.

[0035] Fifthly, the present invention provides an antibacterial pharmaceutical composition comprising a truncated pleurotin compound or a pharmaceutically acceptable salt, isomer, racemate, hydrate, solvate or isotopic label thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0036] Furthermore, the drug can be prepared according to conventional methods in the pharmaceutical field, and the dosage form of the drug is injection, tablet, capsule, granule, suspension, emulsion, solution, sol, lyophilized powder for injection, gel, aerosol, microcapsule, microsphere, liposome, micelle, sustained-release preparation or controlled-release preparation.

[0037] The aforementioned carriers and / or excipients may include at least one of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorbent carriers, and lubricants.

[0038] By adopting the above technical solution, the technical progress achieved by this invention compared with the prior art is as follows:

[0039] This invention modifies the structure of the natural product truncated pleurotin and uses a molecular design strategy combining molecular simulation and pharmacophore construction to design and synthesize a series of truncated pleurotin compounds with multi-substituted aromatic acyl thioethers as C22 side chains. The structures were subsequently confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0040] The truncated pleurotin compounds prepared in this invention, after in vitro activity testing, showed that these compounds exhibit good bactericidal activity against a variety of pathogens, providing more candidate molecules for the development of novel antibiotics. The truncated pleurotin compounds of this invention show inhibitory effects against Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. Some of these compounds show superior antibacterial activity compared to tiamulin or voriconazole, and can be used as lead compounds in the development of novel antibiotics. Detailed Implementation

[0041] The present invention will be further described in detail below through specific embodiments. It should be understood that the described embodiments are only for explaining the present invention and are not intended to limit the present invention. The terminology used in this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms “a,” “the,” and “the” as used in the present invention and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. The term “and / or” as used herein refers to and includes any or all possible combinations of one or more of the associated listed items.

[0042] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0043] Example 1

[0044] This embodiment describes a method for preparing a truncated pleurotin compound P001, comprising the following steps performed sequentially:

[0045] S1. Starting with truncated pleurotin, it reacts with a sulfonating agent in the presence of p-toluenesulfonyl chloride to give compound 1, which is methanesulfonated at the C-22 position. The specific chemical reaction formula and reaction method are as follows:

[0046]

[0047] Pleurotus truncated (10 g, 26.4 mmol), p-toluenesulfonyl chloride (7.52 g, 39.6 mmol), and tetrahydrofuran (100 mL) were added to a four-necked round-bottom flask and stirred to dissolve. A 10% sodium hydroxide aqueous solution (20 mL) was added dropwise at -5 to 0 °C. After the reaction was complete, the solvent was removed by rotary evaporation. The residue was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with 10% dilute hydrochloric acid and saturated brine until neutral, dried over anhydrous NaSO4, filtered, and concentrated to constant weight to obtain the crude product. The crude product was recrystallized from ethyl acetate and petroleum ether (V:V = 1:1) to give a white solid, which was compound 1 (8.58 g), with a yield of 61.1%. The characterization results were as follows:

[0048] 1 H-NMR (500 MHz, CDCl3, δ: ppm) 7.83 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 6.40 (dd, J=17.5, 11.0 Hz, 1H), 5.78 (d, J=8.5 Hz, 1H), 5.34 (dd, J=11.0, 1.5 Hz, 1H), 5.20 (dd, J=17.5, 1.5 Hz, 1H), 4.49 (d, J=1.0 Hz, 2H), 3.33 (d, J=7.0 Hz, 1H), 2.46 (s, 3H), 2.26 (dd, J=13.5, 6.5 Hz, 2H), 2.20(dt, J=30.0, 10.5 Hz, 2H), 2.02 - 2.08 (m, 2H), 1.64 (s, 1H), 1.56 (s, 3H), 1.42 - 1.46 (m, 3H), 1.41 (s, 3H), 1.34 - 1.37 (m, 1H), 1.24 - 1.28 (m, 2H), 1.16 (s, 3H), 1.11 (dd, J=14.5, 4.5 Hz, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.62 (d,J=7.0 Hz, 3H).

[0049] S2. Compound 1 is reacted with a thiol-containing aromatic intermediate under alkaline conditions via a nucleophilic substitution reaction to yield a nitro-substituted compound 3-1. The specific chemical reaction formula and reaction method are as follows:

[0050]

[0051] 2-Mercapto-O-(3-bromo-4-nitrophenyl)acetamide (2.78 g, 0.01 mol) was added to a THF (80 mL) solution of compound 1 (5.00 g, 0.009 mol). After dissolving with stirring at 0 °C, NaOH (0.72 g, 0.018 mol) was added in portions to the reaction solution. After the reaction was complete, part of the solvent was removed, and the residue was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with 5% HCl until neutral, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight to give 5.62 g of a dark red solid. Purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10 to 1:5) yielded a white solid compound, compound 3-1 (3.37 g, 60%). The characterization results are as follows:

[0052] 1 H-NMR (500 MHz, CDCl3, δ: ppm) 9.53 (s, 1H), 8.71 (d, J=9.2 Hz, 1H), 8.36 (d, J= 2.6 Hz, 1H), 8.21 (dd, J=9.2, 2.5 Hz, 1H), 6.47 (dd, J=17.4, 11.0Hz, 1H), 5.79 (d, J=8.5 Hz, 1H), 5.32 (dd, J=10.9, 1.4 Hz, 1H), 5.21 (dd, J=17.4, 1.5 Hz, 1H), 3.60 (s, 2H), 3.36 - 3.43 (m, 1H), 3.34 (d, J=4.3 Hz, 2H),2.34 - 2.43 (m, 1H), 2.17 - 2.29 (m, 2H), 2.09-2.17 (m, 2H), 1.77 - 1.84 (m,1H), 1.66 -1.72 (m, 2H), 1.50 - 1.58 (m, 2H), 1.48 (s, 3H), 1.32 -1.46 (m,3H), 1.19 (s, 3H), 1.15 (dd, J=14.2, 4.5 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.75 (d, J=7.0 HZ, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.85, 167.94,166.93, 143.36, 140.07, 138.99, 129.97, 128.14, 124.86, 120.34, 117.29,74.60, 70.39, 58.10, 45.47, 44.90, 44.01, 41.83, 37.34, 36.70, 36.06, 34.69,34.46, 30.41, 26.87, 26.41, 24.86, 16.97, 14.88, 11.53.

[0053] S3. Nitro reduction of compound 3-1 yields a truncated pleurotin compound P001. The specific chemical reaction formula and reaction method are as follows:

[0054]

[0055] Compound 3-1 (5.00 g, 0.008 mol) and NH4Cl (2.57 g, 0.048 mol) were added to a methanol (50 mL) solution. Iron powder (2.69 g, 0.048 mol) was added in portions, and the mixture was heated to reflux. After the reaction was complete, the iron powder and solvent were removed. The residue was dissolved in 50 mL of dichloromethane, washed first with 15 mL of 5% dilute hydrochloric acid solution, then washed with saturated sodium carbonate and saturated brine until neutral, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to constant weight to give 3.62 g of a red solid, with a crude product yield of 69.9%. The crude product was purified by column chromatography to give a white solid, P001. The characterization results are as follows:

[0056] 11H NMR (500 MHz, CDCl3, δ: ppm) 8.79 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H, C30-H), 6.74 (d, J = 2.6 Hz, 1H, C27-H), 6.62 (dd, J = 8.7, 2.5 Hz, 1H, C29-H), 6.48 (dd, J = 17.4, 11.0 Hz, 1H), 5.79 (d, J = 8.5 Hz, 1H), 5.36 (dd, J = 11.0, 1.1 Hz, 1H), 5.22 (dd, J = 17.4, 1.3 Hz, 1H), 3.50 (s, 2H, C23-H), 3.38 (d, J = 6.5 Hz, 1H), 3.34 (s, 2H, C22-H), 2.34 - 2.39 (m, 1H), 2.19 - 2.33 (m, 2H), 2.10 - 2.16 (m, 2H), 1.77 - 1.83 (m, 1H), 1.53 - 1.72 (m, 2H), 1.54 - 1.61 (m, 1H), 1.50 - 1.54 (m, 1H), 1.48 (s, 3H), 1.37 - 1.43 (m, 3H), 1.18 (s, 3H), 1.14 (dd, J = 14.1, 4.3 Hz, 1H), 0.91 (d, J = 7.0 Hz, 3H), 0.76 (d, J = 7.0 Hz, 3H). 13 13C NMR(126 MHz, CDCl3, δ: ppm) 216.96, 168.07, 165.75, 144.25, 138.97, 125.40, 25.29, 123.83, 117.36, 115.16 (C27), 114.20 (C29), 74.66, 70.04, 58.18, 45.49, 44.92, 44.01, 41.84, 36.89 (C22), 36.78 (C23), 36.06, 34.70, 34.49, 30.46, 26.88, 26.40, 24.89, 16.94, 14.93, 11.56. HRMS: m / z C 30 H 41 ClN2O5S [M + H] + 577.2425, found 577.2423.

[0057] Example 2

[0058] This embodiment describes a method for preparing truncated pleurotin compounds P002~P030. Taking the target compound P002 as an example, the specific chemical reaction formula and reaction method are as follows:

[0059]

[0060] Halogenated alkanes (1.73 mmol), anhydrous potassium carbonate (0.24 g, 1.73 mmol), and P001 (0.5 g, 0.86 mmol) were added to 10 mL of N,N-dimethylformamide and reacted at room temperature or with stirring. After the reaction was complete, 60 mL of water was added to the system, and a solid precipitated upon stirring. The solid was filtered and dried to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compounds P002-P030. The characterization results are as follows:

[0061] P002 is a white solid with a yield of 7.2%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.76 (s, 1H), 7.96 (d, J=8.9 Hz, 1H, C30-H), 6.63 (d, J=2.6 Hz, 1H, C27-H), 6.58 (dd, J=8.4, 2.6 Hz, 1H, C29-H), 6.49 (dd, J=17.5, 11.1 Hz, 1H), 5.79 (d, J=8.5 Hz,1H), 5.36 (d, J=11.0 Hz, 1H), 5.22 (dd, J=17.5, 1.3 Hz 1H), 3.50 (s, 2H, C23-H), 3.39 (s, 1H), 3.34 (s, 2H, C22-H), 3.15 (dd, J=14.3, 7.2 Hz, 2H, C31-H), 2.33 - 2.40 (m, 1H), 2.19 - 2.29 (m, 2H), 2.07 - 2.13 (m, 2H), 1.78 - 1.82(m, 1H), 1.64 -1.71 (m, 2H), 1.50 - 1.61 (m, 2H), 1.48 (s, 3H), 1.31 -1.41(m, 3H), 1.27 (t, J=7.0 Hz, 3H, C32-H), 1.19 (s, 3H), 1.14 (dd, J=14.1, 4.5Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H).13 C NMR (126 MHz, CDCl3, δ: ppm) 217.00, 168.10, 165.68, 146.39, 138.95, 125.70, 124.03,123.94, 117.39, 112.26, 112.04, 74.66, 70.00, 58.19, 45.49, 44.91, 44.01,41.84, 38.57 (C31), 36.87, 36.78, 36.06, 34.71, 34.50, 30.47, 26.88, 26.38,24.89, 16.95, 14.93, 14.73 (C32), 11.57. HRMS: m / z C 32 H 45 ClN2O5S [M+H] + 605.2738, found 605.2736.

[0062] P003 is a white solid with a yield of 7.1%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.76 (s, 1H),7.96 (d, J=8.9 Hz, 1H, C30-H), 6.64 (d, J=2.4 Hz, 1H, C27-H), 6.54 (dd, J=8.4, 2.4 Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.80 (d, J=8.4 Hz ,1H), 5.35 (d, J=11.0 Hz, 1H), 5.22 (d, J=17.4 Hz, 1H), 3.50 (s, 2H, C23-H),3.39 (s, 1H), 3.35 (s, 2H, C22-H), 3.07 (t, J=4.6 Hz, 2H, C31-H), 2.33 - 2.38(m, 1H), 2.17 - 2.31 (m, 2H), 2.08 - 2.16 (m, 2H), 1.76 - 1.82 (m, 1H), 1.68-1.73 (m, 2H), 1.53 - 1.67 (m, 2H, C32-H), 1.49 - 1.60 (m, 2H), 1.48 (s, 3H),1.32 -1.42 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.2, 4.5 Hz, 1H), 1.02 (t, J=7.4 Hz, 3H, C33-H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13 C NMR(126 MHz, CDCl3, δ: ppm) 217.00, 168.09, 165.67, 146.41, 138.97, 125.72,123.97, 123.95, 117.36, 112.25, 112.03, 74.64, 69.99, 58.18, 45.87 (C31),45.49, 44.90, 44.00, 41.84, 36.85, 36.78, 36.06, 34.70, 34.50, 30.46, 26.88,26.41, 24.88, 22.55 (C32), 16.94, 14.93, 11.61 (C33), 11.57. HRMS: m / zC 33 H 47 ClN2O5S [M+H]+ 619.2894, found 619.2880.

[0063] P004 is a white solid with a yield of 6.5%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.65 (s, 1H), 7.84 (d, J=8.9 Hz, 1H, C30-H), 6.64 (d, J=2.4 Hz, 1H, C27-H), 6.34 - 6.42 (m,2H), 5.70 (d, J=8.4 Hz,1H), 5.25 (d, J=11.0 Hz, 1H), 5.12 (d, J=17.4 Hz,1H), 3.45 - 3.54 (m, 1H, C31-H), 3.40 (s, 2H, C23-H), 3.26 - 3.32 (m, 1H),3.25 (s, 2H, C22-H), 2.23 - 2.28 (m, 1H), 2.07 - 2.21 (m, 2H), 1.98 - 2.06(m, 2H), 1.65 - 1.72 (m, 1H), 1.55 -1.63 (m, 2H), 1.40 - 1.52 (m, 2H), 1.38(s, 3H), 1.17 -1.31 (m, 3H), 1.12 (d, J=6.2 Hz, 6H, C32-H, C33-H), 1.09 (s,3H), 1.05 (dd, J=14.2, 4.5 Hz, 1H), 0.82 (d, J=7.0 Hz, 3H), 0.66 (d, J=7.0Hz, 3H). 13 C NMR (126 MHz, CDCl3, δ: ppm) 216.95, 168.09, 165.65, 145.48,138.96, 125.72, 124.01, 123.82, 117.36, 112.80, 112.47, 74.66, 70.00, 58.18,45.49, 44.91, 44.50 (C31), 44.01, 41.84, 36.86, 36.78, 36.06, 34.71, 34.49,30.47, 26.88, 26.39, 24.89, 22.86 (C32), 16.94, 14.93, 11.55. HRMS: m / zC 33 H 47ClN2O5S [M+H] + 619.2894, found 619.2897.

[0064] P005 is a white solid with a yield of 8.0%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H), 7.96 (d, J=8.9 Hz, 1H, C30-H), 6.65 (d, J=2.6 Hz, 1H, C27-H), 6.55 (dd, J=8.9, 2.6 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.90 - 5.96 (m, 1H,C32-H), 5.79 (d, J=8.5 Hz,1H), 5.36 (dd, J=11.0, 1.1 Hz, 1H), 5.29 (dd, J=17.1, 1.5 Hz, 1H), 5.18 - 5.24 (m, 2H, C33-H), 3.76 (d, J=5.3 Hz, 2H, C-31), 3.50 (s, 2H, C23-H), 3.39 (s, 1H), 3.34 (s, 2H, C22-H), 2.33 - 2.38 (m, 1H),2.19 - 2.29 (m, 2H), 2.08 - 2.14 (m, 2H), 1.77 - 1.81 (m, 1H), 1.65 -1.71 (m,2H), 1.49 - 1.57 (m, 2H), 1.47 (s, 3H), 1.30 -1.42 (m, 3H), 1.18 (s, 3H), 1.14 (dd, J=14.2, 4.5 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.75 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 217.02, 168.10, 165.73, 145.98, 138.94,134.69 (C32), 125.64, 124.30, 123.90, 117.38, 116.63 (C33), 112.60, 112.26,74.65, 70.01, 58.18, 46.48 (C31), 45.49, 44.90, 44.00, 41.84, 36.85, 36.78,36.05, 34.69, 34.49, 30.46, 26.87, 26.38, 24.88, 16.94, 14.93, 11.57. HRMS:m / z C 33 H 45 ClN2O5S [M+H] + 617.2738, found 617.2768.

[0065] P006 is a white solid with a yield of 6.7%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.76 (s, 1H),7.96 (d, J=8.8 Hz, 1H, C30-H), 6.63 (d, J=2.1 Hz, 1H, C27-H), 6.53 (d, J=10.4Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.80 (d, J=8.3 Hz ,1H), 5.37(d, J=10.9, Hz, 1H), 5.22 (d, J=17.4 Hz, 1H), 3.50 (s, 2H, C23-H), 3.39 (s,1H), 3.34 (s, 2H, C22-H), 3.10 (t, J=6.8 Hz, 2H, C31-H), 2.32 - 2.40 (m, 1H),2.19 - 2.31 (m, 2H), 2.09 - 2.17 (m, 2H), 1.78 - 1.83 (m, 1H), 1.67 -1.72 (m,2H), 1.61 - 1,66 (m, 2H), 1.55-1.60 (m, 2H, C32-H) 1.48 (s, 3H), 1.40 - 1.45(m, 2H, C33-H), 1.39 -1.40 (m, 1H), 1.31 - 1.38 (m, 2H), 1.19 (s, 3H), 1.14(dd, J=14.1, 3.4 Hz, 1H), 0.98 (t, J=7.3 Hz, 3H, C34-H), 0.91 (d, J=7.0 Hz,3H), 0.76 (d, J=7.0 Hz, 3H). 13 C NMR (126 MHz, CDCl3, δ: ppm) 216.99, 168.10,165.66, 146.47, 138.94, 125.71, 123.95, 117.40, 112.22, 112.02, 74.66, 70.00,58.19, 45.49, 44.91, 44.01, 43.77 (C31), 41.85, 36.87, 36.79, 36.06, 34.71,34.50, 31.47 (C32), 30.47, 26.88, 26.37, 24.89, 20.27 (C33), 16.95, 14.93,13.91 (C34), 11.57. HRMS: m / z C34 H 49 ClN2O5S [M+H] + 633.3051, found 633.3016.

[0066] P007 is a white solid with a yield of 8.7%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H),7.98 (d, J=8.8 Hz, 1H, C30-H), 7.38 (d, J=1.5 Hz, 2H, C33-H, C37-H) 7.36 -7.38 (m, 2H, C34-H, C36-H), 7.30 -7.34 (m, 1H, C35-H), 6.69 (d, J=2.6 Hz,1H,C27-H), 6.59 (dd, J=8.8, 2.6 Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.5 Hz, 1H),5.80 (d, J=8.5 Hz,1H), 5.36 (dd, J=11.0, 1.2 Hz, 1H), 5.22 (dd, J=17.4, 1.3Hz, 1H), 4.33 (s, 2H, C31-H), 3.50 (s, 2H, C23-H), 3.38 (s, 1H), 3.34 (s, 2H,C22-H), 2.34 - 2.39 (m, 1H), 2.19 - 2.33 (m, 2H), 2.09 - 2.16 (m, 2H), 1.77- 1.83 (m, 1H), 1.55 -1.72 (m, 2H), 1.54 - 1.62 (m, 1H), 1.50 - 1.54 (m, 1H), 1.48 (s, 3H), 1.27 -1.42 (m, 3H), 1.18 (s, 3H), 1.15 (dd, J=14.1, 4.3 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.95, 168.08, 165.68, 145.80, 138.95, 138.56 (C32), 128.79 (C34),127.53, 127.50 (C33), 125.61, 124.59, 123.89, 117.39, 112.71, 112.30, 74.66,70.02, 58.18, 48.39 (C31), 45.49, 44.91, 44.01, 41.85, 36.89, 36.78, 36.06,34.71, 34.50, 30.47, 26.88, 26.38, 24.89, 16.95, 14.93, 11.56. HRMS: m / zC 37 H 47 ClN2O5S [M+H] + 667.2894, found 667.2849.

[0067] P008 is a white solid with a yield of 14.0%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H),7.99 (d, J=8.9 Hz, 1H, C30-H), 7.35 (d, J=8.4 Hz, 2H, C34-H, C36-H), 7.31 (d,J=7.1 Hz, 2H, C33-H, C37-H), 6.65 (d, J=2.2 Hz, 1H, C27-H), 6.57 (dd, J=8.7,2.1 Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.80 (d, J=8.4 Hz ,1H),5.36 (d, J=11.0 Hz, 1H), 5.22 (dd, J=17.4 Hz, 1H), 4.32 (s, 2H, C31-H), 3.50(s, 2H, C23-H), 3.39 (s, 1H), 3.34 (s, 2H, C22-H), 2.34 - 2.39 (m, 1H), 2.20- 2.31 (m, 2H), 2.03 - 2.14 (m, 2H), 1.76 -1.82 (m, 1H), 1.65 -1.72 (m, 2H),1.51 - 1.60 (m, 2H), 1.47 (s, 3H), 1.28 -1.41 (m, 3H), 1.19 (s, 3H), 1.15(dd, J=14.2, 4.5 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13 CNMR (126 MHz, CDCl3, δ: ppm) 216.98, 168.08, 165.73, 145.60, 138.95, 137.18(C32), 133.20 (C35), 128.92 (C34), 128.68 (C33), 125.63, 124.72, 123.92,117.39, 112.68, 112.26, 74.66, 70.03, 58.18, 47.61 (C31), 45.49, 44.91,44.01, 41.84, 36.88, 36.78, 36.06, 34.69, 34.50, 30.46, 26.88, 26.38, 24.89,16.95, 14.93, 11.57. HRMS: m / z C 37 H46 Cl2N2O5S [M+H] + 701.2404, found 701.2524.

[0068] P009 is a white solid with a yield of 15.8%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.78 (s, 1H), 7.98 (d, J=8.9 Hz, 1H, C30-H), 7.36 (s, 1H, C33-H), 7.23 - 7.30 (m, 3H, C35-H, C36-H, C37-H), 6.65 (d, J=2.4 Hz, 1H, C27-H), 6.56 (dd, J=8.9, 2.4 Hz, 1H,C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.4 Hz,1H), 5.35 (d, J=11.0 Hz, 1H), 5.21 (d, J=18.3 Hz, 1H), 4.32 (s, 2H, C31-H), 3.50 (s, 2H, C23-H), 3.38 (s, 1H), 3.34 (s, 2H, C22-H), 2.33 - 2.38 (m, 1H), 2.20 - 2.29 (m,2H), 2.03 - 2.14 (m, 2H), 1.76 - 1.82 (m, 1H), 1.63 -1.73 (m, 2H), 1.50 -1.59 (m, 2H), 1.48 (s, 3H), 1.31 -1.41 (m, 3H), 1.18 (s, 3H), 1.14 (dd, J=14.2, 4.4 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR(126 MHz, CDCl3, δ: ppm) 216.96, 168.09, 165.72, 145.56, 140.92 (C32),138.94, 134.70 (C36), 130.06 (C34), 127.65 (C35), 127.35 (C37), 125.64,125.37, 124.76, 123.93, 117.38, 112.68, 112.19, 77.34, 74.66, 70.04, 58.18,47.70 (C31), 45.49, 44.91, 44.01, 41.85, 36.89, 36.78, 36.06, 34.71, 34.49,30.46, 26.88, 26.38, 24.89, 16.95, 14.93, 11.56. HRMS: m / z C 37 H 42 Cl2N2O5S [M+H] + 701.2504, found 701.2511。

[0069] P010 is a white solid with a yield of 15.3%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H), 7.97 (d, J=8.9 Hz, 1H, C30-H), 7.35 - 7.43 (m, 2H, C35-H, C37-H), 7.23 - 7.27(m, 2H, C34-H, C36-H), 6.65 (d, J=2.5 Hz, 1H, C27-H), 6.57 (dd, J=8.9, 2.5Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.5 Hz, 1H), 5.35(d, J=11.0 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.43 (s, 2H, C31-H), 3.50 (s,2H, C23-H), 3.38 (s, 1H), 3.34 (s, 2H, C22-H), 2.34 - 2.38 (m, 1H), 2.18 -2.29 (m, 2H), 2.09 - 2.14 (m, 2H), 1.77 - 1.82 (m, 1H), 1.66 -1.73 (m, 2H),1.50 - 1.60 (m, 2H), 1.48 (s, 3H), 1.33 -1.42 (m, 3H), 1.19 (s, 3H), 1.14(dd, J=14.1, 4.3 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13CNMR (126 MHz, CDCl3, δ: ppm) 216.95, 168.08, 165.71, 145.60, 138.95, 135.92(C32), 133.35 (C33), 129.73 (C35), 129.01 (C34), 128.71 (C37), 127.07 (C36),125.67, 124.67, 123.94, 117.38, 112.72, 112.24, 74.66, 70.03, 58.18, 45.95(C31), 45.49, 44.91, 44.01, 41.85, 36.88, 36.78, 36.06, 34.70, 34.49, 30.47,26.88, 26.38, 24.89, 16.94, 14.93, 11.56. HRMS: m / z C37H42Cl2N2O5S [M+H]+701.2504, found 701.2515。.

[0070] P011 is a pale yellow, foamy solid with a yield of 11.8%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78(s, 1H), 8.12 (d, J=8.3 Hz, 1H, C30-H), 7.96 (d, J=8.7 Hz, 1H, C34-H), 7.59 -7.66 (m, 2H, C35-H, C37-H3), 7.48 (t, J=6.7 Hz, 1H, C36), 6.61 (s, 1H), 6.54 (d, J=8.9 Hz, 1H, C27-H), 6.47 (dd, J=17.3, 11.2 Hz, 1H, C29-H), 5.79 (d, J=8.2 Hz,1H), 5.35 (d, J=11.0, 1H), 5.21 (d, J=17.4, 1H), 4.74 (s, 2H, C31-H), 3.49 (s, 2H, C23-H), 3.38 (s, 1H), 3.33 (s, 2H, C22-H), 2.32 - 2.38 (m, 1H), 2.20 - 2.29 (m, 2H), 2.08 - 2.14 (m, 2H), 1.77 - 1.81 (m, 1H), 1.67 -1.72 (m,2H), 1.49 - 1.58 (m, 2H), 1.47 (s, 3H), 1.29 -1.41 (m, 3H), 1.18 (s, 3H),1.14 (dd, J=14.5, 4.4 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.99, 168.08, 165.78, 148.26 (C33),138.94, 134.85 (C32), 133.86 (C37), 129.75 (C35), 128.37 (C36), 125.74 (C34),125.44, 124.92, 124.02, 117.39, 112.76, 112.16, 76.83, 74.65, 70.04, 58.17,45.83 (C31), 45.49, 44.90, 44.00, 41.84, 36.85, 36.77, 36.05, 34.68, 34.50,30.46, 26.88, 26.37, 24.88, 16.95, 14.92, 11.57. HRMS: m / z C37H46ClN3O7S [M+H]+ 712.2745, found 712.2710。.

[0071] P012 is a pale yellow, foamy solid with a yield of 9.4%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77(s, 1H), 8.22 (d, J=8.7 Hz, 2H, C34-H, C36-H), 7.98 (d, J=8.8 Hz, 1H, C30-H), 7.53 (d, J=8.6 Hz, 2H, C33-H, C37-H), 6.61 (d, J=2.6 Hz, 1H, C27-H), 6.53 (dd, J=8.6, 2.3 Hz, 1H, C29-H), 6.47 (dd, J=17.4, 11.0 Hz, 1H), 5.80 (d, J=8.5 Hz ,1H), 5.33 (dd, J=11.0, 1.2 Hz, 1H), 5.20 (dd, J=17.4, 1.1 Hz, 1H),4.47 (s, 2H, C31-H), 3.49 (s, 2H, C23-H), 3.35 -3.41 (m, 1H), 3.33 (s, 2H,C22-H), 2.31 - 2.37 (m, 1H), 2.19 - 2.29 (m, 2H), 2.07 - 2.14 (m, 2H), 1.76- 1.82 (m, 1H), 1.63 -1.72 (m, 2H), 1.49 - 1.57 (m, 2H), 1.47 (s, 3H), 1.27 -1.40 (m, 3H), 1.18 (s, 3H), 1.14 (dd, J=14.2, 4.5 Hz, 1H), 0.90 (d, J=7.0 Hz, 3H), 0.75 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 217.01, 168.06,165.84, 147.35, 146.63, 145.19, 138.98, 127.71 (C33), 125.74, 125.03, 124.03(C34), 117.34, 112.74, 112.21, 74.64, 70.05, 58.17, 47.54 (C31), 45.49, 44.90, 44.00, 41.83, 36.83, 36.76, 36.05, 34.66, 34.49, 30.45, 26.87, 26.40, 24.88, 16.94, 14.92, 11.56.HRMS: m / z C37H46ClN3O7S [M+H]+ 712.2745, found712.2703。.

[0072] P013 is a pale yellow, foamy solid with a yield of 12.8%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78(s, 1H), 8.23 ​​(s, 1H, C33-H), 8.15 (d, J=8.1 Hz, 1H, C35-H), 7.97 (d, J=8.9Hz, 1H, C30-H), 7.71 (d, J=7.6, 1H, C37-H), 7.55 (t, J=8.0 Hz, 1H, C36-H), 6.63 (d, J=2.6 Hz, 1H, C27-H), 6.54 (dd, J=8.9, 2.6 Hz, 1H, C29-H), 6.47 (dd,J=17.4, 11.0 Hz, 1H), 5.78 (d, J=8.4 Hz ,1H), 5.33 (d, J=11.7, 1H), 5.20 (d,J=17.4, 1H), 4.46 (s, 2H, C31-H), 3.49 (s, 2H, C23-H), 3.35 - 3.41 (m, 1H),3.33 (s, 2H, C22-H), 2.31 - 2.38 (m, 1H), 2.19 - 2.29 (m, 2H), 2.08 - 2.14(m, 2H), 1.76 - 1.81 (m, 1H), 1.62 -1.72 (m, 2H), 1.49 - 1.55 (m, 2H), 1.47(s, 3H), 1.34 -1.41 (m, 3H), 1.17 (s, 3H), 1.15 (dd, J=14.5, 4.4 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.75 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ:ppm) 217.00, 168.08, 165.82, 148.68 (C34), 145.18, 141.26 (C32), 138.97,133.15 (C37), 129.76 (C36), 125.71, 125.05, 124.02, 122.52 (C33), 121.99 (C35), 117.32, 112.82, 112.21, 74.65, 70.06, 58.17, 47.42 (C31), 45.49,44.90, 44.00, 41.84, 36.88, 36.77, 36.06, 34.70, 34.49, 30.45, 26.88, 26.39,24.88, 16.93, 14.92, 11.55. HRMS: m / z C37H46ClN3O7S [M+H]+ 712.2745, found712.2733。.

[0073] P014 is a white solid with a yield of 11.2%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H), 7.97 (d, J=8.9 Hz, 1H, C30-H), 7.33 (t, J=8.2 Hz, 2H, C33-H, C37-H), 7.06 (t,J=8.6 Hz, 2H, C34-H, C36-H), 6.65 (d, J=2.4 Hz, 1H, C27-H), 6.56 (dd, J=8.9,2.4 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.4 Hz ,1H),5.35 (d, J=11.0 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.30 (s, 2H, C31-H), 3.49(s, 2H, C23-H), 3.38 (s, 1H), 3.34 (s, 2H, C22-H), 2.32 - 2.40 (m, 1H), 2.19- 2.29 (m, 2H), 2.07 - 2.15 (m, 2H), 1.77 - 1.82 (m, 1H), 1.65 - 1.72 (m,2H), 1.50 - 1.61 (m, 2H), 1.48 (s, 3H), 1.26 -1.42 (m, 3H), 1.18 (s, 3H),1.14 (dd, J=14.2, 4.3 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.97, 168.08, 165.73, 145.78, 138.97,134.37, 129.03 (C33), 128.97, 125.65, 124.60, 123.94, 117.36, 115.71 (C34),115.54, 112.63, 112.20, 74.66, 70.04, 58.18, 47.59 (C31), 45.49, 44.91, 44.01, 41.85, 36.86, 36.78, 36.06, 34.69, 34.49, 30.46, 26.88, 26.40, 24.89, 16.94, 14.93, 11.56.HRMS: m / z C37H46ClFN2O5S [M+H]+ 685.2800, found685.2812。.

[0074] P015 is a white solid with a yield of 17.1%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78 (s, 1H),7.98 (d, J=8.9 Hz, 1H, C30-H), 7.36 (t, J=7.6 Hz, 1H, C35-H), 7.26 -7.31 (m,1H, C34-H), 7.07 - 7.16 (m, 2H, C36-H, C37-H), 6.68 (d, J=2.6 Hz, 1H, C27-H), 6.58 (dd, J=8.9, 2.6 Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d,J=8.5 Hz,1H), 5.35 (dd, J=11.0, 1.0 Hz, 1H), 5.21 (dd, J=17.4, 1.3 Hz 1H), 4.40 (s, 2H, C31-H), 3.50 (s, 2H, C23-H), 3.39 (s, 1H), 3.35 (s, 2H, C22-H),2.32 - 2.37 (m, 1H), 2.20 - 2.29 (m, 2H), 2.08 - 2.14 (m, 2H), 1.79 - 1.82(m, 1H), 1.65 -1.72 (m, 2H), 1.49 - 1.60 (m, 2H), 1.48 (s, 3H), 1.29 -1.41(m, 3H), 1.19 (s, 3H), 1.14 (dd, J=14.1, 4.4 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.98, 168.09,165.70, 145.66, 138.93, 129.40, 129.37, 129.18, 129.11(C37), 125.63, 124.66(C36), 124.35 (C35), 123.90, 117.39, 115.62, 115.45 (C34), 112.72, 112.23, 74.66, 70.02, 58.18, 45.49, 44.90, 44.01, 41.98, 41.84, 36.88, 36.78, 36.06, 34.70, 34.50, 30.47, 26.88, 26.37, 24.89, 16.95, 14.93, 11.57. HRMS: m / zC37H46ClFN2O5S [M+H]+ 685.2800, found 685.2813。.

[0075] P016 is a white solid with a yield of 16.1%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78 (s, 1H),7.98 (d, J=8.9 Hz, 1H, C30-H), 7.32 - 7.36 (m, 1H, C36-H), 7.15 (d, J=7.6 Hz,1H, C37-H), 7.08 (d, J=9.7 Hz, 1H, C33-H), 6.97 - 7.02 (m, 1H, C35-H), 6.65 (d, J=2.6 Hz, 1H, C27-H), 6.56 (dd, J=8.9, 2.6 Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.80 (d, J=8.4 Hz,1H), 5.36 (dd, J=11.0, 1.2 Hz, 1H), 5.21 (dd, J=17.4, 1.4 Hz, 1H), 4.35 (s, 2H, C31-H), 3.50 (s, 2H, C23-H), 3.39(s, 1H), 3.34 (s, 2H, C22-H), 2.34 - 2.38 (m, 1H), 2.18 - 2.30 (m, 2H), 2.09- 2.14 (m, 2H), 1.78 - 1.82 (m, 1H), 1.65 -1.72 (m, 2H), 1.50 - 1.61 (m, 2H),1.48 (s, 3H), 1.32 -1.42 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.0, 4.7 Hz,1H), 0.92 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.94, 168.08, 165.70, 145.61, 138.95, 130.34, 125.62, 124.74 (C38),123.91, 122.74, 117.37, 114.44, 114.27, 114.20, 114.02, 112.66, 112.20,74.66, 70.03, 58.18, 47.72 (C31), 45.49, 44.91, 44.01, 41.85, 36.90, 36.78,36.06, 34.71, 34.49, 30.47, 26.88, 26.37, 24.89, 16.94, 14.93, 11.55. HRMS:m / z C37H46ClFN2O5S [M+H]+ 685.2800, found 685.2815。.

[0076] P017 is a white solid with a yield of 19.4%.1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H),7.93 (d, J=8.8 Hz, 1H, C30-H), 7.63 (d, J=7.8 Hz, 2H, C34-H, C36-H), 7.48 (d,J= 7.7 Hz, 2H, C33-H, C37-H), 6.64 (s, 1H, C27-H), 6.55 (d, J=8.4 Hz, 1H,C29-H), 6.48 (dd, J=17.3, 11.0 Hz, 1H), 5.79 (d, J=8.3 Hz ,1H), 5.35 (d, J=11.0 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.42 (s, 2H, C31-H), 3.50 (s, 2H, C23-H), 3.38 (s, 1H), 3.33 (s, 2H, C22-H), 2.32 - 2.39 (m, 1H), 2.18 - 2.30 (m,2H), 2.03 - 2.16 (m, 2H), 1.76 - 1.84 (m, 1H), 1.64 -1.72 (m, 2H), 1.50 -1.60 (m, 2H), 1.48 (s, 3H), 1.32 -1.41 (m, 3H), 1.18 (s, 3H), 1.14 (dd, J=14.4, 4.1 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR(126 MHz, CDCl3, δ: ppm) 216.96, 168.07, 165.77, 145.49, 142.94, 138.96,127.44, 125.74, 125.71, 125.68, 124.85 (C38), 123.98, 117.35, 112.70, 112.20,74.65, 70.05, 58.18, 47.75, 45.49, 44.91, 44.01, 41.84, 36.86, 36.77, 36.06,34.68, 34.49, 30.46, 26.88, 26.39, 24.88, 16.94, 14.92, 11.55. HRMS: m / zC38H46ClF3N2O5S [M+H]+ 735.2768, found 735.2774.。

[0077] P018 is a white solid with a yield of 18.3%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.79 (s, 1H), 7.99 (d, J=8.9 Hz, 1H, C30-H), 7.64 (s, 1H, C33-H), 7.57 (t, J=6.6 Hz, 2H,C35-H, C37-H), 7.49 (t, J=7.6 Hz, 1H, C36-H), 6.66 (d, J=2.2 Hz, 1H, C27-H), 6.56 (dd, J=8.6, 2.3 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d,J=8.4 Hz,1H), 5.35 (d, J=11.0 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.40 (s, 2H,C31-H), 3.50 (s, 2H, C23-H), 3.38 (s, 1H), 3.34 (s, 2H, C22-H), 2.33 - 2.38(m, 1H), 2.17 - 2.29 (m, 2H), 2.03 - 2.15 (m, 2H), 1.77 - 1.83 (m, 1H), 1.65-1.73 (m, 2H), 1.50 - 1.62 (m, 2H), 1.48 (s, 3H), 1.27 -1.41 (m, 3H), 1.18(s, 3H), 1.15 (dd, J=14.1, 4.3 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.96, 168.08, 165.74, 145.52,139.87, 138.95, 130.60 (C34), 129.27, 125.65, 124.89, 124.37, 124.34, 124.05,124.02 (C38), 123.94, 117.35, 112.74, 112.20, 74.65, 70.04, 58.18, 47.86(C31), 45.49, 44.91, 44.01, 41.84, 36.88, 36.78, 36.06, 34.70, 34.49, 30.46,26.88, 26.38, 24.88, 16.94, 14.92, 11.55. HRMS: m / z C38H46ClF3N2O5S [M+H]+735.2768, found 735.2772.

[0078] P019 is a white solid with a yield of 15.3%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H), 7.97 (d, J=8.9 Hz, 1H, C30-H), 7.72 (d, J=7.9 Hz, 1H, C34-H), 7.59 (d, J=5.4Hz, 1H, C36-H), 7.53 (t, J=7.6 Hz, 1H, C35-H), 7.41 (t, J=7.6 Hz, 1H, C37-H), 6.64 (d, J= 2.5 Hz, 1H, C27-H), 6.54 (dd, J=8.9, 2.6 Hz, 1H, C29-H), 6.48(dd, J=17.3, 11.0 Hz, 1H), 5.79 (d, J=8.5 Hz,1H), 5.35 (d, J=11.1 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.56 (s, 2H, C31-H), 3.50 (s, 2H, C23-H), 3.38 (s,1H), 3.34 (s, 2H, C22-H), 2.34 - 2.39 (m, 1H), 2.20 - 2.31 (m, 2H), 2.08 -2.16 (m, 2H), 1.78 - 1.82 (m, 1H), 1.65 -1.72 (m, 2H), 1.51 - 1.62 (m, 2H),1.48 (s, 3H), 1.32 -1.42 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.2, 4.4 Hz,1H), 0.92 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3,δ: ppm) 216.95, 168.08, 165.73, 145.46, 138.94, 137.30, 132.27, 128.64,127.37, 126.28, 126.23, 125.72, 124.76 (C38), 124.00, 117.37, 112.65, 112.12,74.66, 70.04, 58.18, 45.49, 44.91 (C31), 44.56, 44.01, 41.85, 36.87, 36.78,36.06, 34.69, 34.49, 30.46, 26.88, 26.37, 24.89, 16.94, 14.92, 11.55. HRMS:m / z C38H46ClF3N2O5S [M+H]+ 735.2768, found 735.2736。.

[0079] P020 is a white solid with a yield of 12.4%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.80 (s, 1H), 7.99 (d, J=8.7 Hz, 1H, C30-H), 7.66 (s, 1H, C33-H), 7.60 (t, J=6.3 Hz, 2H,C35-H, C36-H), 7.50 (d, J=7.5 Hz, 1H, C37-H), 6.62 (s, 1H, C27-H), 6.54 (d, J=8.1 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.1 Hz, 1H), 5.79 (d, J=8.3 Hz ,1H),5.34 (d, J=10.9 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.40 (s, 2H, C31-H), 3.50(s, 2H, C23-H), 3.35 (s, 1H), 3.34 (s, 2H, C22-H), 2.31 - 2.39 (m, 1H), 2.20- 2.31 (m, 2H), 2.06 - 2.18 (m, 2H), 1.74 - 1.85 (m, 1H), 1.65 -1.71 (m, 2H), 1.50 - 1.61 (m, 2H), 1.48 (s, 3H), 1.27 -1.42 (m, 3H), 1.18 (s, 3H), 1.14(dd, J=14.2, 3.6 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.74 (d, J=7.0 Hz, 3H). 13CNMR (126 MHz, CDCl3, δ: ppm) 217.01, 168.08, 165.80, 145.13, 140.50, 138.96,131.57, 131.18, 130.62, 129.60, 125.68, 125.08, 123.98, 118.75 (C38), 117.35,112.89, 112.81, 112.24, 74.65, 70.06, 58.17, 47.41 (C31), 45.49, 44.90,44.01, 41.84, 36.89, 36.77, 36.06, 34.70, 34.50, 30.46, 26.88, 26.40, 24.88,16.95, 14.93, 11.57.HRMS: m / z C38H46ClN3O5S [M+H]+ 692.2847, found 692.2899。.

[0080] P021 is a white solid with a yield of 13.9%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78 (s, 1H), 7.97 (d, J=8.8 Hz, 1H, C30-H), 7.70 (d, J=10.1 Hz, 1H, C34-H), 7.58 (t, J=7.7Hz, 1H, C36-H), 7.53 (d, J=7,8 Hz, 1H, C35-H), 7.40 (t, J=7.5 Hz, 1H, C37-H), 6.65 (s, 1H, C27-H), 6.55 (d, J=8.8 Hz, 1H, C29-H), 6.48 (dd, J=17.3, 11.1Hz, 1H), 5.79 (d, J=8.4 Hz,1H), 5.34 (d, J=11.0 Hz, 1H), 5.20 (d, J=17.4 Hz,1H), 4.57 (s, 2H, C31-H), 3.49 (s, 2H, C23-H), 3.38 (s, 1H), 3.33 (s, 2H,C22-H), 2.30 - 2.39 (m, 1H), 2.18 - 2.29 (m, 2H), 2.08 - 2.15 (m, 2H), 1.76 -1.83 (m, 1H), 1.64 -1.71 (m, 2H), 1.50 - 1.58 (m, 2H), 1.48 (s, 3H), 1.27 -1.41 (m, 216.99, 168.08,165.79, 145.06, 142.79, 138.95, 133.31, 133.17, 128.20, 127.94, 125.71,125.01, 123.98, 117.46, 117.36 (C38), 112.85, 112.18, 111.34, 74.65, 70.04,58.17, 46.39 (C31), 45.49, 44.90, 44.01, 41.84, 36.86, 36.77, 36.06, 34.68,34.50, 30.46, 26.88, 26.39, 24.88, 16.94, 14.93, 11.57. HRMS: m / zC38H46ClN3O5S [M+H]+ 692.2847, found 692.2855。.

[0081] P022 is a white solid with a yield of 12.4%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78 (s, 1H), 7.97 (d, J=8.9 Hz, 1H, C30-H), 7.66 (d, J=8.3 Hz, 2H, C34-H, C36-H), 7.47 (d,J=8.3 Hz, 2H, C33-H, C37-H), 6.61 (d, J=2.6 Hz, 1H, C27-H), 6.52 (dd, J=8.9,2.6 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.78 (d, J=8.4 Hz ,1H),5.34 (dd, J=11.0, 1.2 Hz, 1H), 5.21 (d, J=17.4, 1.4 Hz, 1H), 4.43 (s, 2H,C31-H), 3.49 (s, 2H, C23-H), 3.37 - 3.41 (m, 1H), 3.33 (s, 2H, C22-H), 2.32 -2.37 (m, 1H), 2.18 - 2.30 (m, 2H), 2.07 - 2.14 (m, 2H), 1.76 - 1.82 (m, 1H),1.63 -1.71 (m, 2H), 1.50 - 1.57 (m, 2H), 1.48 (s, 3H), 1.26 -1.40 (m, 3H),1.18 (s, 3H), 1.14 (dd, J=14.7, 4.5 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.75 (d,J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.98, 168.06, 165.81,145.25, 144.54, 138.98, 132.60, 127.70, 125.71, 124.99, 124.02, 118.77 (C38),117.34, 112.72, 112.18, 111.28, 77.35, 74.65, 70.06, 58.17, 47.74 (C31),45.49, 44.91, 44.01, 41.84, 36.84, 36.77, 36.06, 34.67, 34.49, 30.45, 26.88,26.41, 24.88, 16.94, 14.92, 11.56.HRMS: m / z C38H46ClN3O5S [M+H]+ 692.2847,found 692.2842。.

[0082] P023 is a white solid with a yield of 19.8%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H),7.98 (d, J=8.9 Hz, 1H, C30-H), 7.26 (t, J=7.5 Hz, 1H, C36-H), 7.11 -7.19 (m,3H, C33-H, C35-H, C37-H), 6.67 (d, J=2.6 Hz, 1H, C27-H), 6.58 (dd, J=8.9, 2.5Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.5 Hz, 1H), 5.35(d, J=11.0, Hz, 1H), 5.21 (d, J=17.4 Hz 1H), 4.28 (s, 2H, C31-H), 3.50 (s,2H, C23-H), 3.39 (s, 1H), 3.35 (s, 2H, C22-H), 2.38 (s, 3H, C38-H), 2.33 -2.37 (m, 1H), 2.18 - 2.29 (m, 2H), 2.09 - 2.15 (m, 2H), 1.78 - 1.82 (m, 1H),1.65 -1.72 (m, 2H), 1.51 - 1.61 (m, 2H), 1.49 (s, 3H), 1.29 -1.42 (m, 3H),1.19 (s, 3H), 1.14 (dd, J=14.1, 4.3 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d,J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.99, 168.10, 165.71,146.10, 138.95, 138.61, 138.48, 128.68, 128.26, 128.22, 125.67, 124.53,124.36, 123.94, 117.38, 112.53, 112.21, 112.14, 74.66, 70.02, 58.19, 48.29(C31), 45.50, 44.91, 44.01, 41.85, 36.87, 36.79, 36.06, 34.71, 34.50, 30.47,26.89, 26.39, 24.89, 21.48 (C38), 16.95, 14.94, 11.57. HRMS: m / zC38H49ClN2O5S [M+H]+ 681.3051, found 681.3047。.

[0083] P024 is a white solid with a yield of 19.5%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H),7.97 (d, J=8.9 Hz, 1H, C30-H), 7.31 (d, J=7.2 Hz, 1H, C37-H), 7.18 -7.27 (m,3H, C34-H, C35-H, C36-H), 6.68 (d, J=2.5 Hz, 1H, C27-H), 6.57 (dd, J=8.9, 2.5Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.4 Hz, 1H), 5.37(d, J=11.0 Hz, 1H), 5.22 (d, J=17.4 Hz, 1H), 4.27 (s, 2H, C31-H), 3.50 (s,2H, C23-H), 3.39 (s, 1H), 3.35 (s, 2H, C22-H), 2.38 (s, 3H, C38-H), 2.34 -2.37 (m, 1H), 2.21 - 2.29 (m, 2H), 2.10 - 2.16 (m, 2H), 1.77 - 1.84 (m, 1H),1.65 -1.72 (m, 2H), 1.50 - 1.62 (m, 2H), 1.49 (s, 3H), 1.27 -1.43 (m, 3H),1.19 (s, 3H), 1.14 (dd, J=14.1, 4.3 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.76 (d,J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.97, 168.10, 165.70,146.19, 138.97, 136.35, 136.28, 130.58, 128.17, 127.69, 126.28, 125.74,124.33, 124.02, 117.38, 112.31, 111.99, 74.66, 70.03, 58.19, 46.39 (C31),45.50, 44.92, 44.02, 41.85, 36.87, 36.79, 36.07, 34.71, 34.50, 30.47, 26.89,26.40, 24.90, 18.96 (C38), 16.95, 14.94, 11.57. HRMS: m / z C38H49ClN2O5S [M+H]+ 681.3051, found 681.3047。.

[0084] P025 is a white solid with a yield of 17.0%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H),7.97 (d, J=8.9 Hz, 1H, C30-H), 7.26 (d, J=7.9 Hz, 2H, C34-H, C36-H), 7.19 (d,J=7.9 Hz, 2H, C33-H, C37-H), 6.67 (d, J=2.6 Hz, 1H, C27-H), 6.57 (dd, J=8.9,2.6 Hz, 1H, C29-H), 6.49 (dd, J=17.4, 11.0 Hz, 1H), 5.80 (d, J=8.4 Hz ,1H),5.35 (dd, J=11.0, 1.2 Hz, 1H), 5.21 (dd, J=17.4, 1.3 Hz, 1H), 4.28 (s, 2H,C31-H), 3.50 (s, 2H, C23-H), 3.39 (s, 1H), 3.35 (s, 2H, C22-H), 2.38 (s, 3H,C38-H), 2.35 - 2.37 (m, 1H), 2.20 - 2.30 (m, 2H), 2.10 - 2.15 (m, 2H), 1.78 -1.83 (m, 1H), 1.67 -1.72 (m, 2H), 1.50 - 1.61 (m, 2H), 1.49 (s, 3H), 1.33 -1.42 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.0, 4.3 Hz, 1H), 0.92 (d, J=7.0 Hz,3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.96, 168.09,165.66, 146.07, 138.95, 137.18, 135.60, 129.45, 127.47, 125.63, 124.37,123.91, 117.38, 112.54, 112.16, 76.84, 74.66, 70.02, 58.19, 48.06 (C31),45.50, 44.92, 44.01, 41.85, 36.88, 36.79, 36.07, 34.71, 34.50, 30.47, 26.89,26.39, 24.90, 21.15 (C38), 16.95, 14.94, 11.57. HRMS: m / z C38H49ClN2O5S [M+H]+ 681.3051, found 681.3066。.

[0085] P026 is a white solid with a yield of 15.0%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.76 (s, 1H), 7.97 (d, J=8.9 Hz, 1H, C30-H), 7.49 (d, J=8.4 Hz, 2H, C34-H, C36-H), 7.24 (d,J=8.3 Hz, 2H, C33-H, C37-H), 6.64 (d, J=2.5 Hz, 1H, C27-H), 6.55 (dd, J=8.9,2.5 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.5 Hz ,1H),5.35 (d, J=11.0 Hz, 1H), 5.21 (dd, J=17.2, 0.9 Hz, 1H), 4.29 (s, 2H, C31-H), 3.49 (s, 2H, C23-H), 3.38 (s, 1H), 3.34 (s, 2H, C22-H), 2.33 - 2.38 (m, 1H),2.20 - 2.29 (m, 2H), 2.07 - 2.15 (m, 2H), 1.77 - 1.82 (m, 1H), 1.64 -1.72 (m,2H), 1.50 - 1.62 (m, 2H), 1.48 (s, 3H), 1.29 -1.42 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.1, 3.4 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.75 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.95, 168.07, 165.73, 145.53, 138.96,137.70, 131.86 (C34), 129.03 (C33), 125.63, 124.77, 123.92, 121.25, 117.36,112.73, 112.29, 74.66, 70.04, 58.18, 47.68 (C31), 45.49, 44.92, 44.01, 41.85, 36.88, 36.78, 36.06, 34.70, 34.49, 30.46, 26.88, 26.40, 24.89, 16.94, 14.93, 11.56.HRMS: m / z C37H46BrClN2O5S [M+H]+ 745.1999, found 745.1917。.

[0086] P027 is a white solid with a yield of 12.3%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H, C30-H), 7.52 (s, 1H, C33-H), 7.43 (d, J = 7.9 Hz, 1H, C35-H), 7.29 (d, J = 3.6 Hz, 1H, C36-H), 7.23 (t, J = 7.8 Hz, 1H, C37-H), 6.65 (d, J = 2.6 Hz, 1H, C27-H), 6.56 (dd, J = 8.9, 2.6 Hz, 1H, C29-H), 6.48 (dd, J = 17.4, 11.3 Hz, 1H), 5.79 (d, J = 8.5 Hz, 1H), 5.35 (dd, J = 11.0, 1.1 Hz, 1H), 5.21 (dd, J = 17.4, 1.4 Hz, 1H), 4.31 (s, 2H, C31-H), 3.50 (s, 2H, C23-H), 3.39 (s, 1H), 3.34 (s, 2H, C22-H), 2.34 - 2.39 (m, 1H), 2.19 - 2.29 (m, 2H), 2.06 - 2.14 (m, 2H), 1.76 - 1.84 (m, 1H), 1.66 - 1.73 (m, 2H), 1.50 - 1.62 (m, 2H), 1.48 (s, 3H), 1.31 - 1.44 (m, 3H), 1.18 (s, 3H), 1.15 (dd, J = 14.1, 4.3 Hz, 1H), 0.92 (d, J = 7.0 Hz, 3H), 0.76 (d, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.95, 168.09, 165.72, 145.57, 141.22, 138.94, 130.59 (C35), 130.35 (C36), 130.27 (C33), 125.85, 125.64, 124.75 (C37), 123.93, 122.92, 117.37, 112.66, 112.18, 74.66, 70.04, 58.18, 47.64, 45.49, 44.91, 44.01, 41.85, 36.90, 36.78, 36.06, 34.72, 34.50, 30.47, 26.88, 26.38, 24.89, 16.95, 14.93,11.56. HRMS: m / z C37H46BrClN2O5S [M+H]+ 745.1999, found 745.1961。.

[0087] P028 is a white solid with a yield of 16.9%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H), 7.98 (d, J=8.8 Hz, 1H, C30-H), 7.29 (t, J=7.7 Hz, 1H, C36-H), 6.96 (d, J=7.4Hz, 1H, C37-H), 6.92 (s, 1H, C33-H), 6.85 (dd, J=8.2, 1.7Hz, 1H, C35-H), 6.67 (d, J= 2.3 Hz, 1H, C27-H), 6.57 (dd, J=8.9, 2.3 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.4 Hz,1H), 5.36 (d, J=11.0 Hz, 1H), 5.21 (d,J=17.7 Hz, 1H), 4.31 (s, 2H, C31-H), 3.83 (s, 3H, C38-H), 3.50 (s, 2H, C23-H), 3.39 (s, 1H), 3.34 (s, 2H, C22-H), 2.32 - 2.39 (m, 1H), 2.22 - 2.31 (m,2H), 2.08 - 2.14 (m, 2H), 1.78 - 1.82 (m, 1H), 1.67 -1.72 (m, 2H), 1.50 -1.62 (m, 2H), 1.49 (s, 3H), 1.30 -1.42 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.1, 4.2 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.75 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.96, 168.09, 165.68, 160.02, 145.95, 140.38,138.94, 129.82, 125.61, 124.49, 123.89, 119.65, 117.38, 113.06, 112.81,112.59, 112.19, 74.66, 70.02, 58.18, 55.28 (C38), 48.26 (C31), 45.49, 44.91,44.01, 41.85, 36.89, 36.78, 36.06, 34.71, 34.49, 30.47, 26.88, 26.38, 24.89,16.95, 14.93, 11.56. HRMS: m / z C38H39ClN2O6S [M+H]+ 697.3000, found 697.3012。.

[0088] P029 is a white solid with a yield of 15.5%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.78 (s, 1H), 7.98 (d, J=8.9 Hz, 1H, C30-H), 7.39 (d, J=8.6 Hz, 2H, C34-H, C36-H), 7.22 (d,J=8.1 Hz, 2H, C33-H, C37-H), 6.65 (d, J=2.6 Hz, 1H, C27-H), 6.56 (dd, J=8.9,2.6 Hz, 1H, C29-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 5.79 (d, J=8.5 Hz ,1H),5.36 (d, J=11.0 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.34 (s, 2H, C31-H), 3.50(s, 2H, C23-H), 3.39 (s, 1H), 3.34 (s, 2H, C22-H), 2.33 - 2.39 (m, 1H), 2.21- 2.31 (m, 2H), 2.08 - 2.16 (m, 2H), 1.76 - 1.82 (m, 1H), 1.67 -1.72 (m, 2H), 1.49 - 1.62 (m, 2H), 1.48 (s, 3H), 1.30 -1.43 (m, 3H), 1.19 (s, 3H), 1.15(dd, J=14.1, 4.4 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13CNMR (126 MHz, CDCl3, δ: ppm) 216.95, 168.07, 165.74, 148.53, 145.63, 138.96,137.45, 129.87 (C38), 128.67 (C34), 125.67, 124.75, 123.96, 121.31 (C33),117.36, 112.66, 112.18, 74.66, 70.04, 58.18, 47.52 (C31), 45.49, 44.91,44.01, 41.84, 36.87, 36.78, 36.06, 34.69, 34.49, 30.46, 26.88, 26.38, 24.88,16.94, 14.92, 11.55.HRMS: m / z C38H46ClF3N2O6S [M+H]+ 751.2717, found751.2733。.

[0089] P030 is a white solid with a yield of 16.4%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.77 (s, 1H), 7.97 (d, J=8.9 Hz, 1H, C30-H), 6.65 (d, J=2.5 Hz, 1H, C27-H), 6.56 (dd, J=8.9, 2.5 Hz, 1H, C29-H), 6.52 (d, J=2.1 Hz, 1H, C35-H), 6.48 (dd, J=17.5,11.1 Hz, 1H), 6.37 - 6.40 (m, 2H, C33-H, C37-H), 5.79 (d, J=8.4 Hz, 1H), 5.35(d, J=11.0 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.26 (s, 2H, C31-H), 3.80 (s,6H, C38-H, C39-H), 3.48 (s, 2H, C23-H), 3.38 (s, 1H), 3.34 (s, 2H, C22-H),2.32 - 2.39 (m, 1H), 2.19 - 2.30 (m, 2H), 2.08 - 2.16 (m, 2H), 1.75 - 1.83(m, 1H), 1.65 -1.73 (m, 2H), 1.50 - 1.62 (m, 2H), 1.48 (s, 3H), 1.31 -1.43(m, 3H), 1.18 (s, 3H), 1.15 (dd, J=14.1, 4.2 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.97, 168.10,165.68, 161.18, 145.97, 141.28, 138.95, 125.61, 124.47, 123.89, 117.36,112.57, 112.16, 105.27, 99.22, 74.65, 70.02, 58.18, 55.39 (C38), 48.39 (C31),45.49, 44.91, 44.01, 41.84, 36.89, 36.78, 36.06, 34.71, 34.49, 30.46, 26.88,26.39, 24.89, 16.94, 14.93, 11.56.HRMS: m / z C39H51ClN2O7S [M+H]+ 727.3106, found 727.3112. .

[0090] Example 3

[0091] This embodiment describes a method for preparing a truncated pleurotin compound P031. The specific chemical reaction formula and reaction method are as follows:

[0092]

[0093] 2-Mercapto-O-(3-methyl-5-nitrophenyl)acetamide (2.04 g, 0.009 mol) was added to a THF (80 mL) solution of compound 1 (5.00 g, 0.009 mol). After dissolving by stirring at 0 °C, NaOH (0.72 g, 0.018 mol) was added to the reaction solution. After the reaction was completed, the solvent was removed, and the residue was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with 5% HCl until neutral, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to constant weight to give 4.95 g of dark red solid. The crude product yield was 93.8%.

[0094] Further synthesis is performed according to the following chemical reaction formula and reaction method:

[0095]

[0096] Compound 3-2 (5.00 g, 0.009 mol) and NH4Cl (2.89 g, 0.054 mol) were added to a methanol (50 mL) solution. Iron powder (3.02 g, 0.054 mol) was added in portions, and the mixture was heated to reflux. After the reaction was complete, the iron powder and solvent were removed. The residue was dissolved in 50 mL of dichloromethane. The solution was first washed with 15 mL of 5% dilute hydrochloric acid solution, and then washed with saturated sodium carbonate and saturated brine until neutral. The solution was dried, filtered, and concentrated to constant weight to give 4.02 g of a red solid, with a crude product yield of 80.2%. The crude product was purified by column chromatography to give a white, foamy solid, which was PO31. The characterization results are as follows:

[0097] 11H NMR (500 MHz, CDCl3, δ: ppm) 8.58 (s, 1H), 7.50 (d, J = 1.8 Hz, 1H, C30-H), 6.97 (d, J = 8.1 Hz, 1H, C27-H), 6.43 - 6.49 (m, 2H, C29-H, C19-H), 5.77 (d, J = 8.5 Hz, 1H), 5.32 (d, J = 11.0 Hz, 1H), 5.20 (d, J = 17.4 Hz, 1H), 3.48 (s, 2H, C23-H), 3.38 (d, J = 6.5 Hz, 1H), 3.32 (d, J = 3.4 Hz, 2H, C22-H), 2.31 - 2.35 (m, 1H), 2.23 - 2.30 (m, 2H), 2.21 (s, 3H, C31-H), 2.08 - 2.15 (m, 2H), 1.76 - 1.82 (m, 1H), 1.64 - 1.72 (m, 2H), 1.48 - 1.60 (m, 2H), 1.47 (s, 3H), 1.28 - 1.45 (m, 3H), 1.18 (s, 3H), 1.14 (dd, J = 14.1, 4.4 Hz, 1H), 0.91 (d, J = 7.0 Hz, 3H), 0.75 (d, J = 7.0 Hz, 3H). 13 13C NMR (126 MHz, CDCl3, δ: ppm) 216.96, 168.25, 165.90, 145.22, 138.97, 136.18, 131.05, 117.65, 117.32, 111.88, 108.64, 74.61, 70.23, 58.13, 45.48, 44.89, 44.02, 41.84, 37.30, 36.74 (C23), 36.05 (C22), 34.94, 34.49, 30.44, 26.88, 26.41, 24.87, 16.97, 16.88 (C31), 14.91, 11.58. HRMS: m / z C 31 1 44 1H1N2O5S [M + H] + 557.2971, found 557.3050。

[0098] Example 4

[0099] This embodiment describes a method for preparing truncated pleurotin compounds PO32-PO43. Taking the target compound PO32 as an example, the specific chemical reaction formula and reaction method are as follows:

[0100]

[0101] Halogenated alkanes (1.73 mmol), anhydrous potassium carbonate (0.24 g, 1.73 mmol), and PO31 (0.5 g, 0.86 mmol) were added to a solution of N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature or heated. After the reaction was complete, 60 mL of water was added, and a solid precipitated. The solid was filtered and dried to obtain the crude product. The crude product was purified by chromatography to obtain compounds PO32-PO43. The characterization results are as follows:

[0102] P032 is a slightly yellow solid with a yield of 19.5%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.56 (s, 1H), 7.42 (d, J=2.3 Hz, 1H, C30-H), 7.00 (d, J=8.2 Hz, 1H, C27-H), 6.47 (dd, J=17.4, 11.0 Hz, 1H, C29-H), 6.39 (dd, J=8.2, 2.3 Hz, 1H), 5.78 (d, J=8.5 Hz,1H), 5.33(dd, J=11.4, 1.2 Hz, 1H), 5.22 (dd, J=17.4, 1.4 Hz, 1H), 3.49 (s,2H, C23-H), 3.35 - 3.41 (m, 1H), 3.33 (d, J=3.2 Hz, 2H, C22-H), 3.17 (dd, J=14.3, 7.2 Hz, 2H, C32-H), 2.31 - 2.38 (m, 1H), 2.24- 2.31 (m, 2H), 2.23 (s,3H, C31-H), 2.07 - 2.16 (m, 2H), 1.77 - 1.83 (m, 1H), 1.65 -1.73(m, 2H), 1.50- 1.60 (m, 2H), 1.49 (s, 3H), 1.33 -1.49(m, 3H), 1.26 (t, J=7.2 Hz, 3H, C33-H), 1.18 (s, 3H), 1.15 (dd, J=14.1, 4.4 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H).13 C NMR (126 MHz, CDCl3, δ: ppm) 216.92, 168.23, 165.79,147.49, 138.94, 136.20, 130.98, 117.37, 116.33, 109.40, 106.57, 74.63, 70.18,58.15, 45.48, 44.90, 44.02, 41.84, 38.80 (C32), 37.33, 36.75, 36.05, 34.93,34.49, 30.45, 26.89, 26.38, 24.88, 16.97, 16.81 (C31), 14.91, 14.89 (C33),11.57. HRMS: m / z C 33 H 48 N₂O₅S [M+H] + 585.3284, found 585.3360.

[0103] P033 is a slightly yellow solid with a yield of 16.9%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.55 (s, 1H),7.42 (d, J=2.0 Hz, 1H, C30-H), 6.99 (d, J=8.2 Hz, 1H, C27-H), 6.47 (dd, J=17.4, 11.0 Hz, 1H), 6.29 (dd, J=8.2, 2.1 Hz, 1H, C29-H), 5.78 (d, J=8.4 Hz ,1H), 5.33(d, J=11.4 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 3.48 (s, 2H, C23-H),3.35 - 3.41 (m, 1H), 3.32 (d, J=3.1 Hz, 2H, C22-H), 3.09 (t, J=7.1 Hz, 2H,C32-H), 2.32 - 2.39 (m, 1H), 2.23- 2.31 (m, 2H), 2.21 (s, 3H, C31-H), 2.08 -2.14 (m, 2H), 1.76 - 1.82 (m, 1H), 1.62 -1.70 (m, 4H), 1.50 - 1.57 (m, 2H),1.48 (s, 3H), 1.30 -1.47(m, 3H), 1.18 (s, 3H), 1.14 (dd, J=14.1, 4.3 Hz, 1H),1.00 (t, J=7.4 Hz, 3H, C34-H). 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz,3H). 13 C NMR (126 MHz, CDCl3, δ: ppm) 216.92, 168.22, 165.80, 147.58, 138.95,136.21, 130.96, 117.35, 116.13, 109.29, 106.47, 74.63, 70.18, 58.14, 46.07(C32), 45.48, 44.90, 44.02, 41.84, 37.32, 36.75, 36.05, 34.92, 34.48, 30.44,26.88, 26.40, 24.88, 22.73 (C33), 16.96, 16.79 (C31), 14.91, 11.69 (C34),11.57. HRMS: m / z C 34 H 50N₂O₅S [M+H] + 599.3440, found 599.3503.

[0104] P034 is a slightly yellow solid with a yield of 14.7%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.56 (s, 1H), 7.43 (d, J=2.1 Hz, 1H, C30-H), 6.99 (d, J=8.2 Hz, 1H, C27-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 6.38 (dd, J=8.2, 2.2 Hz, 1H, C29-H), 5.78 (d, J=8.5 Hz,1H), 5.33(dd, J=11.0, 1.0 Hz, 1H), 5.22 (dd, J=17.4, 1.2 Hz, 1H), 3.49 (s,2H, C23-H), 3.35 - 3.41 (m, 1H), 3.33 (d, J=3.1 Hz, 2H, C22-H), 3.12 (t, J=7.1 Hz, 2H, C32-H), 2.32 - 2.38 (m, 1H), 2.23- 2.31 (m, 2H), 2.22 (s, 3H,C31-H), 2.08 - 2.16 (m, 2H), 1.77 - 1.82 (m, 1H), 1.66 -1.73 (m, 2H), 1.59 -1.64 (m, 2H, C33-H), 1.49 - 1.57 (m, 2H), 1.48 (s, 3H), 1.43 -1.47 (m, 2H,C34-H), 1.27 -1.42(m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.1, 4.6 Hz, 1H), 0.97(t, J=7.4 Hz, 3H, C35-H), 0.92 (d, J=7.0 Hz, 3H), 0.77 (d, J=7.0 Hz, 3H). 13CNMR (126 MHz, CDCl3, δ: ppm) 216.92, 168.22, 165.78, 147.62, 138.93, 136.21,130.96, 117.37, 116.11, 109.27, 106.44, 74.63, 70.18, 58.15, 45.48, 44.90,44.02, 43.95 (C32), 41.84, 37.33, 36.75, 36.05, 34.92, 34.48, 31.68 (C33),30.45, 26.89, 26.38, 24.88, 20.33 (C34), 16.97, 16.80 (C31), 14.91, 13.98(C35), 11.57. HRMS: m / z C 35 H 52 N₂O₅S [M+H] + 613.3597, found 613.3670.

[0105] P035 is a slightly yellow solid with a yield of 15.2%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.58 (s, 1H),7.51 (d, J=2.1 Hz, 1H, C30-H), 7.32 (s, 4H, C34-H, C35-H, C37-H, C38-H), 6.98(d, J=8.2 Hz, 1H, C27-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 6.34 (dd J=8.2, 2.2Hz, 1H, C29-H), 5.79 (d, J=8.5 Hz ,1H), 5.33 (d, J=11.0 Hz, 1H), 5.22 (dd, J=17.4, 1.2 Hz, 1H), 4.32 (s, 2H, C32-H), 3.48 (s, 2H, C23-H), 3.36 - 3.40 (m,1H), 3.32 (d, J=3.3 Hz, 2H, C22-H), 2.32 - 2.37 (m, 1H), 2.23 - 2.31 (m, 2H),2.22 (s, 3H, C31-H), 2.10 - 2.19 (m, 2H), 1.78 - 1.83 (m, 1H), 1.66 -1.72 (m,2H), 1.50 - 1.59 (m, 2H), 1.49 (s, 3H), 1.32 -1.46(m, 3H), 1.18 (s, 3H), 1.15(dd, J=14.4, 4.4 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13 CNMR (126 MHz, CDCl3, δ: ppm) 216.89, 168.23, 165.85, 146.84, 138.95, 138.07,136.31, 132.84, 131.04, 128.81 (C35), 128.75 (C34), 117.35, 116.77, 109.27,106.61, 74.63, 70.22, 58.14, 47.77, 45.48, 44.91, 44.02, 41.85, 37.34, 36.74,36.06, 34.93, 34.49, 30.45, 26.89, 26.40, 24.89, 16.97, 16.81 (C31), 14.91,11.57. HRMS: m / z C 38H 49 ClN2O5S [M+H] + 681.3051, found 681.3085.

[0106] P036 is a slightly yellow solid with a yield of 18.6%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.58 (s, 1H),7.50 (s, 1H, C30-H), 7.38 (s, 1H, C34-H), 7.22 - 7.31 (m, 3H, C36-H, C37-H,C38-H), 6.98 (d, J=8.1 Hz, 1H, C29-H), 6.47 (dd, J=17.4, 10.5 Hz, 1H), 6.34(d, J=6.9 Hz, 1H, C28-H), 5.77 (d, J=7.4 Hz,1H), 5.32 (d, J=11.0 Hz, 1H),5.20 (d, J=17.4 Hz, 1H), 4.32 (s, 2H, C32-H), 3.48 (s, 2H, C23-H), 3.36 -3.41 (m, 1H), 3.32 (d, J=3.1 Hz, 2H, C22-H), 2.31 - 2.38 (m, 1H), 2.23 - 2.30(m, 2H), 2.22 (s, 3H, C31-H), 2.07 - 2.15 (m, 2H), 1.76 - 1.82 (m, 1H), 1.63-1.72 (m, 2H), 1.51 - 1.60 (m, 2H), 1.48 (s, 3H), 1.27 -1.46(m, 3H), 1.17 (s,3H), 1.14 (dd, J=14.5, 4.1 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.75 (d, J=7.0Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.95, 168.25, 165.89, 146.79,141.82, 138.96, 136.30, 134.48, 131.06, 129.90, 127.45, 127.34, 125.54,117.33, 116.89, 109.22, 106.70, 74.62, 70.22, 58.14, 47.88 (C32), 45.48,44.89, 44.02, 41.85, 37.32, 36.75, 36.06, 34.95, 34.49, 30.44, 26.89, 26.41,24.89, 16.97, 16.83 (C31), 14.92, 11.58. HRMS: m / z C 38 H 49 ClN2O5S [M+H] + 681.3051, found 681.3116.

[0107] P037 is a slightly yellow solid with a yield of 26.9%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.58 (s, 1H),7.53 (d, J=2.1 Hz, 1H, C30-H), 7.45 (t, J=3.8 Hz, 1H, C35-H), 7.37 - 7.41 (m,1H, C38-H), 7.23 (t, J=4.1 Hz, 2H, C36-H, C37-H), 6.98 (d, J=8.2 Hz, 1H, C27-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 6.35 (dd, J=8.2, 2.2 Hz, 1H, C29-H), 5.79(d, J=8.5 Hz ,1H), 5.33(d, J=11.0 Hz, 1H), 5.21 (dd, J=17.4, 1.3 Hz, 1H),4.45 (s, 2H, C32-H), 3.49 (s, 2H, C23-H), 3.37 - 3.41 (m, 1H), 3.33 (d, J=3.3Hz, 2H, C22-H), 2.32 - 2.38 (m, 1H), 2.23 - 2.31 (m, 2H), 2.22 (s, 3H, C31-H), 2.08 - 2.17 (m, 2H), 1.78 - 1.83 (m, 1H), 1.64 -1.74 (m, 2H), 1.50 - 1.60(m, 2H), 1.49 (s, 3H), 1.24 -1.47(m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.2, 4.4Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.92, 168.24, 165.84, 146.73, 138.93, 136.69, 136.28,133.35, 131.07, 129.55, 129.29, 128.43, 126.95, 117.37, 116.87, 109.18,106.85, 74.63, 70.21, 58.14, 46.09 (C32), 45.48, 44.90, 44.02, 41.85, 37.33,36.75, 36.05, 34.95, 34.49, 30.45, 26.89, 26.38, 24.88, 16.98, 16.84 (C31),14.92, 11.58. HRMS: m / z C 38 H 49 ClN2O5S [M+H] + 681.3051, found 681.3110.

[0108] P038 is a slightly yellow solid with a yield of 11.3%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.57 (s, 1H),7.51 (s, 1H, C30-H), 7.28 (d, J=7.8 Hz, 2H, C35-H, C37-H), 7.17 (d, J=7.7 Hz,2H, C34-H, C38-H), 6.99 (d, J=8.1 Hz, 1H, C27-H), 6.48 (dd, J=17.4, 11.0 Hz,1H), 6.40 (d J=7.7 Hz, 1H, C29-H), 5.79 (d, J=8.1 Hz ,1H), 5.34 (d, J=11.0Hz, 1H), 5.22 (d, J=17.4 Hz, 1H), 4.30 (s, 2H, C32-H), 3.49 (s, 2H, C23-H),3.37 - 3.40 (m, 1H), 3.33 (d, J=3.0 Hz, 2H, C22-H), 2.37 (s, 3H, C39-H), 2.32- 2.35 (m, 1H), 2.23 - 2.31 (m, 2H), 2.22 (s, 3H, C31-H), 2.10 - 2.17 (m,2H), 1.78 - 1.82 (m, 1H), 1.65 -1.73 (m, 2H), 1.50 - 1.58 (m, 2H), 1.49 (s,3H), 1.29 -1.47 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.1, 4.0 Hz, 1H), 0.92(d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm)216.94, 168.25, 165.83, 147.18, 138.93, 136.85, 136.33, 136.22, 131.02,129.32 (C35), 127.61 (C34), 117.38, 116.69, 109.38, 106.73, 74.63, 70.19,58.15, 48.30 (C32), 45.49, 44.90, 44.02, 41.85, 37.32, 36.75, 36.05, 34.94,34.50, 30.45, 26.89, 26.39, 24.89, 21.17 (C39), 16.98, 16.85 (C31), 14.92,11.59. HRMS: m / z C 39 H 52 N₂O₅S [M+H] + 661.3597, found 661.3662.

[0109] P039 is a slightly yellow solid with a yield of 10.6%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.57 (s, 1H),7.49 (s, 1H, C30-H), 7.25 (t, J=7.5 Hz, 1H), 7.19 (t, J=8.8 Hz, 2H), 7.10 (d,J=7.3 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H, C27-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H),6.39 (d, J=7.9 Hz, 1H, C29-H), 5.79 (d, J=8.4 Hz ,1H), 5.34 (d, J=11.0 Hz,1H), 5.21 (d, J=17.4 Hz, 1H), 4.30 (s, 2H, C32-H), 3.49 (s, 2H, C23-H), 3.37- 3.39 (m, 1H), 3.34 (d, J=2.9 Hz, 2H, C22-H), 2.38 (s, 3H, C39-H), 2.31 -2.36 (m, 1H), 2.23 - 2.30 (m, 2H), 2.23 (s, 3H, C31-H), 2.09 - 2.16 (m, 2H),1.77 - 1.83 (m, 1H), 1.65 -1.72 (m, 2H), 1.52 - 1.61 (m, 2H), 1.49 (s, 3H),1.27 -1.46 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.1, 4.0 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.93,168.25, 165.84, 147.29, 139.41, 138.96, 138.28, 136.22, 131.03, 128.54,128.36, 127.99, 124.67, 117.36, 116.66, 109.28, 106.73, 74.63, 70.20, 58.15,48.53 (C32), 45.49, 44.91, 44.03, 41.85, 37.31, 36.76, 36.06, 34.94, 34.49,30.45, 26.90, 26.42, 24.89, 21.49 (C39), 16.97, 16.84 (C31), 14.92, 11.58.HRMS: m / z C 39 H 52 N₂O₅S [M+H] + 661.3597, found 661.3664.

[0110] P040 is a slightly yellow solid with a yield of 17.3%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.59 (s, 1H),7.51 (d, J=2.0 Hz, 1H, C30-H), 7.35 (d, J=7.0 Hz, 1H), 7.18 - 7.24 (m, 3H),7.01 (d, J=8.2 Hz, 1H, C27-H), 6.48 (dd, J=17.4, 11.0 Hz, 1H), 6.39 (dd, J=8.2, 2.1 Hz, 1H, C29-H), 5.79 (d, J=8.5 Hz ,1H), 5.34 (d, J=11.1, 1H), 5.22(d, J=17.4 Hz, 1H), 4.29 (s, 2H, C32-H), 3.49 (s, 2H, C23-H), 3.37 - 3.41 (m,1H), 3.34 (d, J=3.1 Hz, 2H, C22-H), 2.39 (s, 3H, C39-H), 2.32 - 2.38 (m, 1H),2.26 - 2.31 (m, 1H), 2.24 (s, 3H, C31-H), 2.17 - 2.23 (m, 1H), 2.03 - 2.15(m, 2H), 1.77 - 1.83 (m, 1H), 1.66 -1.73 (m, 2H), 1.51 - 1.63 (m, 2H), 1.49(s, 3H), 1.27 -1.47 (m, 3H), 1.19 (s, 3H), 1.15 (dd, J=14.3, 4.3 Hz, 1H),0.92 (d, J=7.0 Hz, 3H), 0.77 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ:ppm) 216.90, 168.24, 165.82, 147.37, 138.93, 137.06, 136.41, 136.28, 131.05,130.43, 128.31, 127.43, 126.16, 117.38, 116.54, 109.13, 106.44, 74.64, 70.20,58.15, 46.56 (C32), 45.49, 44.91, 44.03, 41.85, 37.34, 36.75, 36.06, 34.95,34.49, 30.45, 26.90, 26.38, 24.89, 19.00 (C39), 16.98, 16.84 (C31), 14.92,11.58. HRMS: m / z C 39 H 52 N₂O₅S [M+H] + 661.3597, found 661.3670.

[0111] P041 is a pale yellow solid with a yield of 20.0%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.54 (s, 1H),7.60 (s, 1H, C30-H), 7.54 (d, J=7.6 Hz, 1H), 7.47 - 7.51 (m, 2H), 7.41 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H C27-H), 6.42 (dd, J=17.4, 11.1 Hz, 1H),6.30 (d, J=8.1 Hz, 1H, C29-H), 5.73 (d, J=8.4 Hz ,1H), 5.27(d, J=11.0 Hz,1H), 5.16 (d, J=17.4 Hz, 1H), 4.35 (s, 2H, C32-H), 3.43 (s, 2H, C23-H), 3.30- 3.37 (m, 1H), 3.27 (d, J=3.1 Hz, 2H, C22-H), 2.27 - 2.32 (m, 1H), 2.18 -2.26 (m, 2H), 2.18 (s, 3H, C31-H), 2.04 - 2.12 (m, 2H), 1.71 - 1.78 (m, 1H),1.58 -1.68 (m, 2H), 1.52 - 1.45 (m, 2H), 1.43 (s, 3H), 1.21 -1.41(m, 3H),1.12 (s, 3H), 1.09 (dd, J=14.3, 4.3 Hz, 1H), 0.86 (d, J=7.0 Hz, 3H), 0.70 (d,J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.88, 168.19, 165.85,146.68, 140.63, 138.90, 136.28, 131.03, 130.73, 129.03, 124.13, 124.10,124.03, 124.00, 117.28, 116.94, 109.15, 106.67, 74.57, 70.17, 58.08, 48.02(C32), 45.43, 44.84, 43.97, 41.79, 37.27, 36.69, 36.00, 34.87, 34.43, 30.38,26.83, 26.33, 24.83, 16.91, 16.76 (C31), 14.85, 11.51. HRMS: m / z C 39 H 49 F3N2O5S[M+H] + 715.3314, found 715.3377.

[0112] P042 is a slightly yellow solid with a yield of 16.0%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.59 (s, 1H),7.53 (d, J=1.8 Hz, 1H, C30-H), 7.41 (d, J=8.5 Hz, 2H, C35-H, C37-H), 7.20 (d,J=8.2 Hz, 2H, C34-H, C38-H), 6.99 (d, J=8.2 Hz, 1H, C27-H), 6.48 (dd, J=17.4,11.0 Hz, 1H), 6.35 (dd, J=8.2, 2.0 Hz, 1H, C29-H), 5.79 (d, J=8.6 Hz ,1H),5.32(d, J=11.1 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.45 (s, 2H, C32-H), 3.48(s, 2H, C23-H), 3.36 - 3.42 (m, 1H), 3.32 (d, J=3.3 Hz, 2H, C22-H), 2.32 -2.37 (m, 1H), 2.23 - 2.32 (m, 2H), 2.22 (s, 3H, C31-H), 2.09 - 2.16 (m, 2H),1.76 - 1.83 (m, 1H), 1.64 -1.73 (m, 2H), 1.51 - 1.60 (m, 2H), 1.49 (s, 3H),1.29 -1.47(m, 3H), 1.18 (s, 3H), 1.15 (dd, J=14.2, 4.3 Hz, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.76 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.92,168.23, 165.90, 148.32, 146.79, 138.96, 138.30, 136.33, 131.07, 128.79 (C35),121.15 (C34), 117.33, 116.86, 109.24, 106.65, 76.86, 74.62, 70.22, 58.14,47.71 (C32), 45.48, 44.90, 44.02, 41.84, 37.31, 36.74, 36.06, 34.90, 34.48,30.44, 26.89, 26.40, 24.88, 16.96, 16.81 (C31), 14.90, 11.56. HRMS: m / zC 39 H 49 F3N2O5S [M+H] + 715.3314, found 715.3385.

[0113] P043 is a slightly yellow solid with a yield of 23.9%. 1H NMR (500 MHz, CDCl3, δ: ppm) 8.59 (s, 1H),7.69 (d, J=7.3 Hz, 1H, C30-H), 7.65 (d, J=7.8 Hz, 1H), 7.47 - 7.52 (m, 2H),7.37 (t, J=7.6 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H, C27-H), 6.47 (dd, J=17.4, 11.1Hz, 1H), 6.29 (dd, J=8.1, 2.0 Hz, 1H, C29-H), 5.78 (d, J=8.4 Hz ,1H), 5.32(d,J=11.1 Hz, 1H), 5.20 (d, J=17.4 Hz, 1H), 4.56 (s, 2H, C32-H), 3.48 (s, 2H,C23-H), 3.36 - 3.41 (m, 1H), 3.32 (d, J=3.3 Hz, 2H, C22-H), 2.32 - 2.37 (m,1H), 2.23- 2.31 (m, 2H), 2.22 (s, 3H, C31-H), 2.09 - 2.16 (m, 2H), 1.76 -1.83 (m, 1H), 1.64 -1.73 (m, 2H), 1.50 - 1.57 (m, 2H), 1.48 (s, 3H), 1.29 -1.47(m, 3H), 1.18 (s, 3H), 1.14 (dd, J=14.2, 4.3 Hz, 1H), 0.91 (d, J=7.0 Hz,3H), 0.75 (d, J=7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3, δ: ppm) 216.92, 168.24,165.87, 146.63, 138.94, 138.17, 136.30, 132.16, 131.12, 128.89, 127.05,126.06, 126.01, 117.35, 116.95, 108.82, 106.89, 74.63, 70.22, 58.14, 45.48(C32), 44.90, 44.66, 44.02, 41.84, 37.30, 36.74, 36.05, 34.94, 34.48, 30.44,26.88, 26.38, 24.88, 16.96, 16.82 (C31), 14.90, 11.57. HRMS: m / z C 39 H 49 F3N2O5S[M+H] + 715.3314, found 715.3385.

[0114] Example 5

[0115] This embodiment provides a test and results of the antibacterial activity of truncated pleurotin compounds. Specifically, the tested bacteria included Staphylococcus aureus (S. aureus, ATCC 6538), methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300), and pyogenic coccus (ATCC 12314).

[0116] The positive control drugs were tiamulin and vorimidrine.

[0117] This invention employs a micro-broth dilution method to determine the MIC value of a compound. 100 μL of distilled water is pipetted into wells 1-12 of a sterile 96-well plate. Then, 100 μL of the test solution is pipetted into well 1, and after thorough mixing, 100 μL is pipetted from well 1 and added to well 2. This mixture is then repeated, with 100 μL added from well 2 to well 3, and so on, serially diluting up to well 10. The 100 μL mixture aspirated from well 10 is discarded. Finally, 100 μL of a solution with a concentration of approximately 10 is added to each of wells 1-10. 6The test bacterial solution at CFU / mL was mixed thoroughly. At this point, the drug concentrations in wells 1 through 10 were 32 μg / mL, 16 μg / mL, 8 μg / mL, 4 μg / mL, 2 μg / mL, 1 μg / mL, 0.5 μg / mL, 0.25 μg / mL, 0.125 μg / mL, and 0.0625 μg / mL, respectively. 100 μL of the solution was added to well 11, resulting in a concentration of approximately 10... 6 The test bacterial culture at CFU / mL was used as a positive control, and 100 μL of blank culture medium was added to well 12 as a negative control. The 96-well plate was incubated at 37℃ for 24 h, and the OD value was measured and the MIC value was recorded. Each compound was measured in triplicate. The test results are shown in Table 2.

[0118] Table 2. Antibacterial activity test data of each compound

[0119] The results above show that the truncated pleurotin compounds listed in the examples have good inhibitory activity against MRSA and MSSA, but their inhibitory activity against pyogeniccoccus is not as good as that against tiamulin. P002 has the best inhibitory activity against MRSA, which is significantly better than that against tiamulin. P033 has the best inhibitory activity against MSSA, which is better than that against tiamulin and comparable to that against vornimulin.

[0120] In other embodiments, the reaction temperature in step S1 of the method for preparing truncated pleurotin compounds can also be carried out in the range of 0-5°C; the alkaline aqueous solution that can be used for the sulfonation reaction also includes potassium hydroxide or sodium carbonate solution; the reaction solvent can also be dichloromethane or N,N-dimethylformamide.

[0121] In step S2, the alkaline conditions can also be provided by potassium hydroxide or sodium carbonate; the reaction solvent can be replaced by dichloromethane, N,N-dimethylformamide or acetonitrile; the reaction temperature can be carried out in the range of 0-30°C.

[0122] In step S3, the nitro reduction reaction can also use hydrogen / Pd-C catalytic hydrogenation or stannous chloride / hydrochloric acid system; the reaction solvent can be ethanol or isopropanol; the heating reflux temperature can be adjusted between 60-80℃ depending on the selected solvent.

[0123] Furthermore, in the purification methods described in steps S1-S3, the solvent combination used for recrystallization can be ethyl acetate / petroleum ether, methanol / water, or ethanol / water; the ratio of the mobile phase in column chromatography can be adjusted within a certain range, for example, the volume ratio of petroleum ether to ethyl acetate can vary between 10:1 and 1:1.

[0124] Pleurotus truncated compounds can be used to prepare drugs for treating skin, soft tissue, or respiratory tract infections caused by Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae. Pharmaceutical compositions based on truncated pleurotus truncated compounds can be formulated into dosage forms such as tablets, capsules, injections, or topical ointments as needed.

[0125] It should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art can still modify the technical solutions described in the above embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A truncated pleurotin compound, characterized in that, Its general structural formula is as follows: in, It is aryl, aromatic heteroyl, cycloalkyl, or heterocyclic; R1 is H, -NH2, -OH, -SH, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, -NO2, haloalkyl, aryl, aromatic heteroyl, alkyl, heterocyclic, alkylamino, alkoxy, alkylthio, cycloalkyl, or sulfonyl. R2 is H, -NH2, -OH, -SH, -F, -Cl, -Br, -I, -CN, -CHO, -COOH, -NO2, haloalkyl, aryl, aromatic heteroyl, alkyl, heterocyclic, alkylamine, alkoxy, alkylthio, cycloalkyl, or sulfonyl. X is N, O, or S; n can be 0, 1, 2, 3, 4, or 5.

2. The truncated pleurotin compound according to claim 1, characterized in that, It is a benzene ring.

3. The truncated pleurotin compound according to claim 1, characterized in that, One of R1 and R2 is an amino group, and the other is an alkyl group or a halogen.

4. A pharmaceutically acceptable salt, isomer, racemate, hydrate, solvate, or isotope label, characterized in that, It is prepared from a truncated pleurotin compound according to any one of claims 1 to 3.

5. A method for preparing a truncated pleurotin compound according to any one of claims 1 to 3, characterized in that, This includes the following steps performed sequentially: S1. Starting with truncated pleurotin, it is reacted with a sulfonating agent in the presence of p-toluenesulfonyl chloride to give intermediate 1, which is methanesulfonated at C-22. S2. The intermediate 1 is reacted with a mercapto-containing aromatic intermediate under alkaline conditions to undergo a nucleophilic substitution reaction to obtain a nitro-substituted intermediate 2; S3. Nitro reduction reaction of intermediate 2 to obtain a truncated pleurotin compound.

6. The method for preparing a truncated pleurotin compound according to claim 5, characterized in that, In step S1, the sulfonating agent is p-methylbenzenesulfonyl chloride; the reaction solvent is tetrahydrofuran; and the reaction is carried out under low temperature conditions of -5~0℃ and alkaline aqueous solution. In step S2, the thiol-containing aromatic intermediate is 2-mercapto-O-(3-bromo-4-nitrophenyl)acetamide; the base is sodium hydroxide; and the reaction solvent is tetrahydrofuran. In step S3, the nitro reduction reaction is carried out under reflux with iron powder, ammonium chloride and methanol solvent.

7. A method for preparing a truncated pleurotin compound according to claim 5 or 6, characterized in that, It also includes a step of purifying the products obtained in steps S1 to S3, wherein the purification method is recrystallization, column chromatography, or a combination thereof.

8. The use of the truncated pleurotin compound according to any one of claims 1 to 3 in the preparation of a medicament for the prevention and / or treatment of bacterial infectious diseases.

9. The application according to claim 8, characterized in that, The bacterial infectious diseases are caused by Gram-positive bacteria.

10. An antibacterial pharmaceutical composition, characterized in that, It comprises a truncated pleurotin compound as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer, racemate, hydrate, solvate, or isotopic label thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

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