Aloe-emodin piperazine derivative as well as preparation method and application thereof

Abstract

The invention relates to an aloe-emodin piperazine derivative as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The aloe-emodin piperazine derivative is obtained by taking aloe-emodin as a raw material, substituting 15-site alcoholic hydroxyl of the aloe-emodin with piperazine and then connecting the 15-site alcoholic hydroxyl with a natural compound with anti-tumor activity and a derivative of the natural compound by utilizing different connecting arms. In-vitro anti-tumor experiments of the aloe-emodin piperazine derivative show that the aloe-emodin piperazine derivative has good anti-tumor activity on human cervical cancer cells (HeLa), human liver cancer cells (HepG2), human lung cancer cells (A549) and human osteosarcoma cells (U2OS), is expected to be developed into drugs for treating cervical cancer, osteosarcoma, lung cancer or liver cancer and other cancers, and has wide clinical application prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to an aloe-emodin piperazine derivative, its preparation method, and its application. Background Technology

[0002] Aloe-emodin is one of the main active ingredients of rhubarb, a traditional Chinese medicine. It is widely found in the leaves of aloe (Liliaceae family), the rhizomes of rhubarb (Polygonaceae family), and plants such as hyacinth bean. Aloe-emodin possesses a wide range of pharmacological effects, including antiviral, anti-inflammatory, antibacterial, antiparasitic, antitumor, neuroprotective, and hepatoprotective properties (Eur J Pharm Biopharm, 2016, 10797-109; J Ethnopharmacol, 2014, 153(3), 846-853; Eur J Pharmacol, 2014, 738, 125-132; Bioorg Med Chem Lett, 2014, 24(23), 5385-5389; Planta Med, 1998, 64(2), 176-178; Pharmacol Toxico, 2002, 90(4), 193-198). Aloe-emodin has a large conjugated structure with three coplanar rings and an active hydroxyl group on the aromatic ring, sharing the same pharmacophore as the antitumor drug doxorubicin. Studies have shown that aloe-emodin has significant antitumor activity against lung cancer, gastric cancer, liver cancer, melanoma, breast cancer, and colon cancer (Eur J Pharmacol, 2001, 431(3): 287-295; Cancer Biol Ther, 2007, 6(1): 85-88; Life Sci, 2002, 71(16): 1879-1892; Anti-cancer Agents Med Chem, 2016, 16(6): 763-770; e CAM, 2013, 2013: 1-12; Phytother Res, 2020, 34(2): 270-281; ​​Chem PharmBull (Tokyo), 2008, 56(4): 497-503.), and its mechanisms of action are diverse. Aloe-emodin can cause DNA breaks in human lung cancer cell line CH27, leading to irreversible cell death; it can induce apoptosis in lung cancer cell line CH27 by activating caspase family proteases; it can inhibit cell proliferation by arresting the cell cycle of human gastric cancer cells; it can inhibit tumor cell proliferation by inducing the expression of p53 and p21 (tumor suppressor genes) in HepG-2 and Hep3B (human liver cancer cell lines); it can inhibit the proliferation, adhesion, migration, and invasion of breast cancer MCF-7 cells and induce apoptosis; and it can inhibit the transcriptional activation of ERα by downregulating the level of estrogen receptor α (ERα) protein (nucleocytoplasmic shuttle protein) in human breast cancer cell lines (MCF-7 and MDA-MB-453).(Eur J Pharmacol, 2001, 431(3): 287-295; Cancer Biol Ther, 2007, 6(1): 85-88; Life Sci, 2002, 71(16): 1879-1892; Anti-cancer Agents Med Chem, 2016, 16(6): 763-770; Phytother Res, 2020, 34(2):270-281.) To this end, pharmaceutical researchers have used aloe-emodin as a lead compound to modify and transform its structure, thereby obtaining novel antitumor drugs with novel structures, higher activity and good drug-like properties, which have high research and development value.

[0003] Paeonol is one of the effective active ingredients of the traditional Chinese medicine peony bark, and it has antipyretic, analgesic, anti-inflammatory, antitumor, and anti-allergic effects (Phytomedicine, 2023, 109;). middleChinese Journal of Pharmacology, 2023(06): 1078-1084; Journal of Beijing Union University, 2023, 37(02): 72-78). Studies have shown that paeonol has an inhibitory effect on the growth and proliferation of cancer cells in various cell lines, including cervical cancer HeLa cells, human bladder cancer T24 and 5637 cells, non-small cell lung cancer A549 cells, hepatocellular carcinoma Hep3B, Huh-7, BEL-7404, osteosarcoma Saos-2, and MG-63 cells (Psychopharmacology (Berl). 2022, 239(7): 2083-2092; Clin Transl Oncol, 2021,23(3): 601-611; Acta Histochem, 2020, 122(1): 151455). Coumarin compounds possess a variety of physiological activities, including antibacterial, anticoagulant, antioxidant, anti-inflammatory, and antitumor effects (Brit J Clin Pharmaco, 2014, 77(4):626-641; Eur J Med Chem, 2015, 102: 611-630; Curr Pharm Design, 2004, 10(30):3813-3833). Some natural coumarin compounds can selectively act on tumor cells while exhibiting low toxicity to normal cells, such as psoralen, daphne, scopolamine, and neomycin. Studies have shown that compounds with coumarin skeletons obtained through total synthesis or structural modification can enhance their antitumor activity and have diverse mechanisms of action. They can inhibit the proliferation of tumor cells by regulating the cell cycle, inducing apoptosis, inhibiting microtubule polymerization, or affecting various enzymes and signaling pathways (Bioorg Chem, 2019, 87: 838-850; Eur J Med Chem, 2019, 165: 309-322; Bioorg Chem, 2020. 95103, 530-103 536; Eur J Med Chem, 2019, 166470-479).

[0004] Piperazine possesses good biological activity and low toxicity, making it frequently used in medicinal chemistry. Its two opposing nitrogen atoms on the ring have a large polar surface area, relatively rigid structure, and more hydrogen bond acceptors and donors, allowing it to participate in hydrogen bond formation in organisms, increasing the affinity and selectivity of drugs to receptors. These properties typically result in greater water solubility, oral bioavailability, and improved target affinity and specificity. Therefore, it is used in many drugs, especially as an anti-tumor drug, showing great development potential and application prospects. Many research groups have applied piperazine to the development of anti-tumor drugs. Currently, several piperazine-containing anti-tumor drugs have been developed, such as entrectinib, flumatinib mesylate, and giretinib. Aloe-emodin has significant anti-tumor activity with diverse mechanisms of action. However, its low water solubility, poor intestinal absorption, short elimination half-life, and low bioavailability affect its anti-tumor activity. Similarly, paeonol and coumarin also have anti-tumor effects, but their anti-tumor activity is weak, limiting their clinical application. Summary of the Invention

[0005] To address the above problems, this invention provides an aloe-emodin piperazine derivative, its preparation method, and its application.

[0006] The first object of the present invention is to provide a pharmaceutically acceptable salt of an aloe-emodin piperazine derivative, such as the compound represented by general formula I. I In Equation I, n is an integer from 1 to 6; R includes , , , .

[0007] Furthermore, n is an integer from 2 to 6.

[0008] Furthermore, the aloe-emodin-piperazine derivative is selected from any one of the following compounds I1-I20: I1: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)ethyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I2: 3-((4-(3-(2-acetyl-5-methoxyphenoxy)propyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I3: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)butyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I4: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)pentyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I5: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)hexyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I6: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)ethyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I7: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)propyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I8: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I9: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)pentyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I10: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)hexyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I11: 3-((4-(3-((3-acetyl-2-oxo-2H-chromen-7-yl)oxy)ethyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I12: 3-((4-(3-((3-acetyl-2-oxo-2H-chromen-7-yl)oxy)propyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I13: 3-((4-(3-((3-acetyl-2-oxo-2H-chromen-7-yl)oxo)butyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I14: 3-((4-(3-((3-acetyl-2-oxo-2H-chromen-7-yl)oxo)pentyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I15: 3-((4-(3-((3-acetyl-2-oxo-2H-chromen-7-yl)oxo)hexyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I16: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)ethyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I17: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)propyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I18: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I19: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)pentyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I20: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)hexyl)piperazin-1-yl)methyl)anthracene-9,10-dione.

[0009] The target compounds of I1-I20 can all be purified using conventional separation techniques and, if necessary, converted into addition salts with pharmaceutically acceptable acids.

[0010] The second objective of this invention is to provide a method for preparing an aloe-emodin piperazine derivative, comprising: Hydrogen-containing compounds and dihalogenated straight-chain alkanes undergo substitution reactions to yield halogenated compounds; 15-piperazine aloe-emodin and halogenated compounds undergo a nitrogen-hydrocarbonation reaction to yield aloe-emodin piperazine derivatives. The chemical formula of the dihalo-substituted straight-chain alkane is X(CH2). n X, n are integers from 2 to 6; The hydrogen-containing compound is one of paeonol, 7-hydroxy-4-methylcoumarin, 7-hydroxy-3-acetylcoumarin, and paeonolacetic acid.

[0011] Furthermore, the preparation of the 15-piperazine aloe-emodin includes: Piperazine, a second organic solvent, potassium iodide, tetrabutylammonium bromide, and chloroaloe-emodin were mixed and reacted to obtain 15-piperazine aloe-emodin.

[0012] Furthermore, the molar ratio of piperazine to halogenated aloe-emodin is 1.2-2:1; the temperature of the mixing reaction is 20-30℃; and the time of the mixing reaction is 6-48h.

[0013] Furthermore, the second organic solvent is preferably dichloromethane (DCM).

[0014] Furthermore, the molar mass of potassium iodide added is 0.1-0.3 times the molar mass of halogenated aloe-emodin added, preferably 0.3 times.

[0015] Furthermore, the molar mass of the added tetrabutylammonium bromide is 0.05-0.25 times that of the added molar mass of the added halogenated aloe-emodin, preferably 0.1 times.

[0016] Furthermore, the acquisition of the chlorinated aloe-emodin includes: Aloe-emodin, a third organic solvent, and a halogenating agent were mixed evenly and subjected to a halogenation reaction to obtain halogenated aloe-emodin.

[0017] Furthermore, the third organic solvent is preferably N,N-dimethylformamide (DMF).

[0018] Furthermore, the halogenation reaction is carried out at a temperature of 20-40°C for a time of 12-48 hours.

[0019] Furthermore, the halogenating agent is thionyl chloride.

[0020] Furthermore, obtaining the halogenated compound includes: A hydrogen-containing compound, a dihalogenated straight-chain alkane, a first organic solvent, and a basic reagent are mixed and heated to carry out a substitution reaction, yielding a halogenated compound.

[0021] Furthermore, the alkaline reagent is sodium hydroxide or potassium carbonate.

[0022] Furthermore, the reaction temperature of the substitution reaction is 20-50℃, and the reaction time is 4-24h; the molar ratio of the hydrogen-containing compound and the dihalo-substituted straight-chain alkane is 1:1-4.

[0023] Furthermore, the first organic solvent is preferably N,N-dimethylformamide (DMF).

[0024] Furthermore, the dihalo-substituted straight-chain alkane is one of 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, and 1,6-dibromohexane.

[0025] A third objective of the present invention is to provide a pharmaceutical composition comprising the aloe-emodin-piperazine derivative described above or an aloe-emodin-piperazine derivative prepared by the method described above.

[0026] The fourth objective of this invention is to provide the application of the aloe-emodin-piperazine derivative prepared by the method described above in the preparation of a tumor treatment drug.

[0027] Furthermore, the tumor is one of liver cancer, osteosarcoma, cervical cancer, or lung cancer.

[0028] The beneficial effects of this invention are: This invention discloses an aloe-emodin piperazine derivative, its preparation method, and its application. Using aloe-emodin as a substrate and piperazine as a linker, different natural compounds and their derivatives with antitumor activity are linked to aloe-emodin, resulting in an aloe-emodin piperazine derivative with a unique structure. Because the aloe-emodin piperazine derivative not only contains the structure of aloe-emodin but also the structures of natural compounds and their derivatives with antitumor activity, the antitumor activity of aloe-emodin is enhanced.

[0029] The in vitro antitumor experiments of the aloe-emodin piperazine derivative described in this invention have demonstrated that it has good antitumor activity against human cervical cancer cells (HeLa), human liver cancer cells (HepG2), human lung cancer cells (A549), and human osteosarcoma cells (U2OS). It is expected to be developed into a therapeutic drug for various cancers such as cervical cancer, osteosarcoma, lung cancer, or liver cancer, and has broad prospects for clinical application.

[0030] Furthermore, the IC50 of the obtained aloe-emodin-piperazine derivative... 50 The value of IC50 is higher than that of aloe-emodin. 50 Much lower, compared to the IC50 of aloe-emodin. 50 The IC50 value of the obtained aloe-emodin piperazine derivative. 50 The value decreased by at least 31%, and the IC of I2 against HepG2 was reduced. 50 The value even decreased by 79.4%.

[0031] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. The objects and other advantages of the invention may be realized and obtained by means of the structures pointed out in the description, claims and drawings. Attached Figure Description

[0032] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0033] Figure 1 A roadmap for preparing an aloe-emodin piperazine derivative according to an embodiment of the present invention is shown. Detailed Implementation

[0034] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0035] like Figure 1 As shown, a method for preparing an aloe-emodin-piperazine derivative according to certain embodiments of the present invention includes: Hydrogen-containing compounds (4a-4d) and dihalo-chain alkanes undergo substitution reaction (iii) to yield halo compounds (5a-5d). 15-piperazine aloe-emodin (3) and halogenated compounds (5a-5d) were subjected to a nitrogen-hydrocarbonation reaction (iv) to obtain aloe-emodin piperazine derivatives (I1-I20). The chemical formula of the dihalo-substituted straight-chain alkane is X(CH2). n X, n are integers from 1 to 6; The hydrogen-containing compounds (4a-4d) are one of paeonol, 7-hydroxy-4-methylcoumarin, 7-hydroxy-3-acetylcoumarin, and paeonolacetic acid.

[0036] The names of aloe-emodin piperazine derivatives I1-I20 are as follows: I1: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)ethyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I2: 3-((4-(3-(2-acetyl-5-methoxyphenoxy)propyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I3: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)butyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I4: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)pentyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I5: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)hexyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione (I5); I6: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)ethyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I7: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)propyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I8: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I9: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)pentyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I10: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I11: (4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)ethyl 2-(2-acetyl-5-methoxyphenoxy)acetate; I12: (4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)propyl 2-(2-acetyl-5-methoxyphenoxy)acetate; I13: 2-(4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)butyl-2-(2-acetyl-5-methoxyphenoxy)acetate; I14: 2-(4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)pentyl-2-(2-acetyl-5-methoxyphenoxy)acetate; I15: 2-(4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)hexyl-2-(2-acetyl-5-methoxyphenoxy)acetate; I16: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)ethyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I17: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)propyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I18: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I19: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)pentyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I20: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)hexyl)piperazin-1-yl)methyl)anthracene-9,10-dione.

[0037] In some embodiments of the present invention, the dihalo-substituted straight-chain alkane is one of 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, and 1,6-dibromohexane.

[0038] In some embodiments of the present invention, obtaining the chlorinated aloe-emodin (i) includes: Aloe-emodin, a third organic solvent, and a halogenating agent were mixed evenly and subjected to a halogenation reaction to obtain halogenated aloe-emodin.

[0039] In some embodiments of the present invention, the preparation (ii) of the 15-piperazine aloe-emodin includes: Piperazine, a second organic solvent, potassium iodide, tetrabutylammonium bromide, and chloroaloe-emodin were mixed and reacted to obtain 15-piperazine aloe-emodin.

[0040] Synthesis of intermediate 2 Add 5.40 g (10 mmol) of aloe-emodin to a 100 mL round-bottom flask, add 20 mL of LDM, stir at room temperature, and slowly add 20 mL (50 mmol) of thionyl chloride. Continue stirring and monitor the reaction progress by thin-layer chromatography (TLC). The reaction is complete in about 30 hours. Stop the reaction, slowly pour the reaction solution into 200 mL of ice water while stirring, let it stand for two hours, filter, and wash with water. 4.77 g of product is obtained, with a yield of 85%.

[0041] Synthesis of intermediate 3 6.88 g (0.8 mol) of anhydrous piperazine was placed in a round-bottom flask, and 150 mL of dichloromethane was added and stirred at room temperature. 322 mg (1 mmol) of TABA and 498 mg (0.3 mmol) of KI were added, followed by the addition of 2.89 g (0.01 mol) of chloroaloemodin (added in portions), and stirring continued. The reaction was monitored by thin-layer chromatography (TLC), and was completed in approximately 24 hours. The reaction was stopped, concentrated, and water was added. The pH was adjusted to approximately 3 with dilute hydrochloric acid, and the mixture was filtered to recover unreacted β-ethyl. The pH of the filtrate was then adjusted to 9-10 with potassium carbonate, and the mixture was filtered again. The filter cake was washed with water and dried to obtain 31.14 g of the compound, with a yield of 45%.

[0042] Synthesis of intermediate 5a 1.992 g (12 mmol) of paeonol was placed in a 250 mL round-bottom flask, and 15 mL of LDM was added. The mixture was heated and stirred at 35 °C until dissolved. Then, 1.44 g (36 mmol) of sodium hydroxide was added, and stirring was continued for half an hour. 3.1 mL (36 mmol) of 1,2-dibromoethane was added dropwise, and stirring was continued. Thin-layer chromatography (TLC) was used to monitor the reaction until it was completed in about 6 hours. The reaction was stopped, 150 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:10) to obtain product 5a, with a yield of about 60%.

[0043] Synthesis of intermediate 5b 1.992 g (12 mmol) of paeonol was placed in a 250 mL round-bottom flask, and 15 mL of LDM was added. The mixture was heated and stirred at 35 °C until dissolved. Then, 1.44 g (36 mmol) of sodium hydroxide was added, and stirring was continued for half an hour. 3.7 mL (36 mmol) of 1,3-dibromopropane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 6 hours. The reaction was stopped, 150 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:10) to obtain product 5b, with a yield of about 70%.

[0044] Synthesis of intermediate 5c 1.992 g (12 mmol) of paeonol was placed in a 250 mL round-bottom flask, and 15 mL of LDM was added. The mixture was heated and stirred at 35 °C until dissolved. Then, 1.44 g (36 mmol) of sodium hydroxide was added, and stirring was continued for half an hour. 4.3 mL (36 mmol) of 1,4-dibromobutane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 6 hours. The reaction was then stopped. 150 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:10) to obtain product 5c, with a yield of approximately 75%.

[0045] Synthesis of intermediate 5d 1.992 g (12 mmol) of paeonol was placed in a 250 mL round-bottom flask, and 15 mL of LDM was added. The mixture was heated and stirred at 35 °C until dissolved. Then, 1.44 g (36 mmol) of sodium hydroxide was added, and stirring was continued for half an hour. 4.9 mL (36 mmol) of 1,5-dibromopentane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 6 hours. The reaction was then stopped. 150 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:10) to obtain the product 5d, with a yield of approximately 75%.

[0046] Synthesis of intermediate 5e 1.992 g (12 mmol) of paeonol was placed in a 250 mL round-bottom flask, and 15 mL of LDM was added. The mixture was heated and stirred at 35 °C until dissolved. Then, 1.44 g (36 mmol) of sodium hydroxide was added, and stirring was continued for half an hour. 5.8 mL (36 mmol) of 1,6-dibromohexane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 6 hours. The reaction was then stopped. 150 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:10) to obtain product 5e, with a yield of approximately 75%.

[0047] Synthesis of intermediate 5f 880 mg (5 mmol) of 7-hydroxy-4-methylcoumarin was placed in a 100 mL round-bottom flask, 20 mL of LDM was added, and the mixture was stirred until dissolved. Then, 2.76 g (20 mmol) of potassium carbonate was added, the temperature was raised to 65 °C, and stirring was continued for half an hour. 0.8 mL (10 mmol) of 1,2-dibromoethane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was then stopped. 200 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:3) to obtain product 5f, with a yield of approximately 55%.

[0048] Synthesis of 5g intermediate 880 mg (5 mmol) of 7-hydroxy-4-methylcoumarin was placed in a 100 mL round-bottom flask, 20 mL of LDM was added, and the mixture was stirred until dissolved. Then, 2.76 g (20 mmol) of potassium carbonate was added, the temperature was raised to 65 °C, and stirring was continued for half an hour. 1.06 mL (10 mmol) of 1,3-dibromopropane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was then stopped. 200 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether at a ratio of 1:3) to obtain 5 g of the product, with a yield of approximately 55%.

[0049] Synthesis of intermediate 5h 880 mg (5 mmol) of 7-hydroxy-4-methylcoumarin was placed in a 100 mL round-bottom flask, 20 mL of LDM was added, and the mixture was stirred until dissolved. Then, 2.76 g (20 mmol) of potassium carbonate was added, the temperature was raised to 65 °C, and stirring was continued for half an hour. 1.3 mL (10 mmol) of 1,4-dibromobutane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was stopped. 200 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether at a ratio of 1:3) to obtain the product, with a yield of about 65%.

[0050] Synthesis of intermediate 5i 880 mg (5 mmol) of 7-hydroxy-4-methylcoumarin was placed in a 100 mL round-bottom flask, 20 mL of LDM was added, and the mixture was stirred until dissolved. Then, 2.76 g (20 mmol) of potassium carbonate was added, the temperature was raised to 65 °C, and stirring was continued for half an hour. 1.35 mL (10 mmol) of 1,5-dibromopentane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was stopped. 200 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:3) to obtain product 5i, with a yield of about 65%.

[0051] Synthesis of intermediate 5j 880 mg (5 mmol) of 7-hydroxy-4-methylcoumarin was placed in a 100 mL round-bottom flask, 20 mL of LDM was added, and the mixture was stirred until dissolved. Then, 2.76 g (20 mmol) of potassium carbonate was added, the temperature was raised to 65 °C, and stirring was continued for half an hour. 1.52 mL (10 mmol) of 1,6-dibromohexane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was stopped. 200 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:3) to obtain product 5j, with a yield of about 65%.

[0052] Synthesis of intermediate 5k 1.02 g (5 mmol) of 3-acetyl-7-hydroxycoumarin was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.38 g (10 mmol) of potassium carbonate was added, and the mixture was heated to 50 °C and stirred for half an hour. 1.29 mL (15 mmol) of 1,2-dibromoethane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was then stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, and the mixture was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then a suitable amount of petroleum ether was added and stirred. Crystallization was carried out at low temperature, and the crystals were filtered and dried. The product 5k was obtained, with a yield of about 40%.

[0053] Synthesis of intermediate 5l 1.02 g (5 mmol) of 3-acetyl-7-hydroxycoumarin was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.38 g (10 mmol) of potassium carbonate was added, the mixture was heated to 50 °C, and stirring was continued for half an hour. 1.57 mL (15 mmol) of 1,3-dibromopropane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then a suitable amount of petroleum ether was added and stirred. Crystallization was carried out at low temperature, filtered, and the filter cake was dried. 5 μL of product was obtained, with a yield of about 60%.

[0054] Synthesis of intermediate 5m 1.02 g (5 mmol) of 3-acetyl-7-hydroxycoumarin was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.38 g (10 mmol) of potassium carbonate was added, and the mixture was heated to 50 °C and stirred for half an hour. 1.82 mL (15 mmol) of 1,4-dibromobutane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was then stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, and the mixture was dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then a suitable amount of petroleum ether was added and stirred. Crystallization was carried out at low temperature, and the crystals were filtered and dried. 5 mL of the product was obtained, with a yield of about 60%.

[0055] Synthesis of intermediate 5n 1.02 g (5 mmol) of 3-acetyl-7-hydroxycoumarin was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.38 g (10 mmol) of potassium carbonate was added, the temperature was raised to 50 °C, and stirring was continued for half an hour. 2.04 mL (15 mmol) of 1,5-dibromopentane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then a suitable amount of petroleum ether was added and stirred. Crystallization was carried out at low temperature, filtered, and the filter cake was dried. Product 5n was obtained, with a yield of about 60%.

[0056] Synthesis of intermediate 5o 1.02 g (5 mmol) of 3-acetyl-7-hydroxycoumarin was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.38 g (10 mmol) of potassium carbonate was added, the temperature was raised to 50 °C, and stirring was continued for half an hour. 2.29 mL (15 mmol) of 1,6-dibromohexane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 8 hours. The reaction was stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then petroleum ether was added and stirred. Crystallization was carried out at low temperature, filtered, and the filter cake was dried. Product 5O was obtained, with a yield of about 50%.

[0057] Synthesis of intermediate 5p 1.12 g (5 mmol) of paeonol acetic acid was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.035 g (7.5 mmol) of potassium carbonate was added, the mixture was heated to 60 °C, and stirring was continued for half an hour. 1.75 mL (20 mmol) of 1,2-dibromoethane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 4 hours. The reaction was then stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:5) to obtain product 5p, with a yield of approximately 85%.

[0058] Synthesis of intermediate 5q 1.12 g (5 mmol) of paeonol acetic acid was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.035 g (7.5 mmol) of potassium carbonate was added, the mixture was heated to 60 °C, and stirring was continued for half an hour. 2.03 mL (20 mmol) of 1,3-dibromopropane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 4 hours. The reaction was then stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:5) to obtain product 5q, with a yield of approximately 90%.

[0059] Synthesis of intermediate 5r 1.12 g (5 mmol) of paeonol acetic acid was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.035 g (7.5 mmol) of potassium carbonate was added, the mixture was heated to 60 °C, and stirring was continued for half an hour. 2.42 mL (20 mmol) of 1,4-dibromobutane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 4 hours. The reaction was then stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:5) to obtain product 5r, with a yield of approximately 90%.

[0060] Synthesis of intermediate 5s 1.12 g (5 mmol) of paeonol acetic acid was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.035 g (7.5 mmol) of potassium carbonate was added, and the mixture was heated to 60 °C and stirred for half an hour. 2.71 mL (20 mmol) of 1,5-dibromopentane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 4 hours. The reaction was then stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:5) to obtain the product 5s, with a yield of approximately 90%.

[0061] Synthesis of intermediate 5t 1.12 g (5 mmol) of paeonol acetic acid was placed in a 100 mL round-bottom flask, 10 mL of LDM was added, and the mixture was stirred until dissolved. Then, 1.035 g (7.5 mmol) of potassium carbonate was added, the temperature was raised to 60 °C, and stirring was continued for half an hour. 3.05 mL (20 mmol) of 1,6-dibromobutane was added dropwise, and stirring was continued. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was completed in about 4 hours. The reaction was stopped. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dehydrated with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluting agent: ethyl acetate: petroleum ether = 1:5) to obtain 5 μL of product, with a yield of approximately 90%.

[0062] Synthesis of target compound I1 169 mg (0.5 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, compound 5a (0.6 mmol), 69 mg (0.5 mmol) of anhydrous potassium carbonate, and 8.3 mg (0.05 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure. An appropriate amount of water was added to the residue, and the mixture was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I1. Compound I1 was a yellow oil, 102 mg in quantity, with a yield of 38.5%. 1H NMR(600 MHz, Chloroform-d) δ 12.09 (s, 1H), 12.04 (s, 1H), 7.83 (d, J = 3.7 Hz,1H), 7.82 (d, J = 5.0 Hz, 1H), 7.80 (s, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.32(s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 8.7, 2.2 Hz, 1H), 6.43 (d, J= 2.1 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 3.84 – 3.83 (m, 3H), 3.58 (s, 2H),2.88 (t, J = 5.8 Hz, 2H), 2.60 (s, 9H); 13C NMR (151 MHz, Chloroform-d) δ197.82, 192.65, 181.92, 164.45, 162.80, 162.49, 160.21, 149.84, 137.12,133.67, 133.49, 132.69, 124.63, 124.05, 121.35, 120.62, 120.03, 115.88,114.81, 105.39, 99.06, 66.41, 62.28, 56.94, 55.55, 53.53, 53.17, 32.15; HRMS, m / z: C30H30N2O7, [M+H]+: theoretical value 531.2087, measured value 531.2119. Synthesis of target compound I2 169 mg (0.5 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, compound 5b (0.6 mmol), 69 mg (0.5 mmol) of anhydrous potassium carbonate, and 8.3 mg (0.05 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure. An appropriate amount of water was added to the residue, and the mixture was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I2. Compound I2 was a yellow oil, 106 mg in quantity, with a yield of 38.9%. 1H NMR(600 MHz, Chloroform-d) δ 12.09 (s, 1H), 12.04 (s, 1H), 7.83 (s, 1H), 7.82(d, J = 3.3 Hz, 1H), 7.80 (s, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.32 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 8.7, 2.1 Hz, 1H), 6.44 (d, J = 2.1Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.59 (s, 2H), 2.58 (s, 11H),2.06 (q, J = 6.7 Hz, 2H); 13C NMR (151 MHz, Chloroform-d) δ 197.70, 192.65,181.93, 164.48, 162.80, 162.49, 160.43, 149.85, 137.13, 133.67, 133.48,132.70, 124.63, 124.05, 121.19, 120.62, 120.03, 115.88, 114.80, 105.05,98.99, 66.79, 62.27, 55.55, 55.23, 53.18, 53.06, 32.13, 26.56; HRMS, m / z:C31H32N2O7, [M+H]+: Theoretical value 545.2243, measured value 545.2217. Synthesis of target compound I3 169 mg (0.5 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, compound 5c (0.6 mmol), 69 mg (0.5 mmol) of anhydrous potassium carbonate, and 8.3 mg (0.05 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure. An appropriate amount of water was added to the residue, and the mixture was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was concentrated under reduced pressure and purified by thin-layer chromatography to obtain product I3. Compound I3 was a yellow oil, 118 mg in quantity, with a yield of 42.3%. 1H NMR (600 MHz, Chloroform-d) δ 12.09 (s, 1H), 12.04 (s, 1H), 7.84 – 7.82 (m, 1H), 7.81 (d, J = 3.8 Hz, 1H), 7.80 – 7.73 (m, 1H), 7.70 – 7.66 (m, 1H), 7.32 (d,J = 10.4 Hz, 1H), 7.31 – 7.27 (m, 1H), 6.50 (td, J = 5.7, 2.7 Hz, 1H), 6.42(dd, J = 5.1, 2.0 Hz, 1H), 4.05 (q, J = 6.2 Hz, 2H), 3.84 (s, 3H), 3.57 (d, J= 18.5 Hz, 2H), 3.02 – 2.78 (m, 2H), 2.58 (s, 5H), 2.47 – 2.39 (m, 4H), 1.91– 1.88 (m, 2H), 1.71 (dd, J = 14.9, 7.6 Hz, 2H); 13C NMR (151 MHz, Chloroform-d) δ 197.75, 192.65, 181.93, 164.47, 162.79, 162.55, 160.46,149.82, 137.13, 133.67, 133.48, 132.70, 124.63, 124.06, 121.37, 120.61, 120.03, 115.88, 114.80, 105.02, 99.02, 68.22, 62.24, 55.54, 55.53, 53.58, 53.05, 32.09, 27.16, 27.03; HRMS, m / z: C32H34N2O7, [M+H]+: theoretical value 559.2400, measured value 559.2440. Synthesis of target compound I4 169 mg (0.5 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, 5 d (0.6 mmol) of compound, 69 mg (0.5 mmol) of anhydrous potassium carbonate, and 8.3 mg (0.05 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by thin-layer chromatography to obtain product I4. Compound I4 was a yellow oil, 125 mg in quantity, with a yield of 43.8%. 1H NMR(600 MHz, Chloroform-d) δ 12.10 (s, 1H), 12.04 (s, 1H), 7.83 (d, J = 2.1 Hz,1H), 7.82 (d, J = 4.1 Hz, 1H), 7.80 (s, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.32(s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 8.7, 2.1 Hz, 1H), 6.41 (d, J= 2.1 Hz, 1H), 4.03 (t, J = 6.3 Hz, 2H), 3.84 (s, 3H), 3.59 (s, 2H), 2.58 (s,11H), 1.90 – 1.86 (m, 2H), 1.61 – 1.57 (m, 2H), 1.55 – 1.50 (m, 2H); 13C NMR (151 MHz, Chloroform-d) δ 197.82, 192.66, 181.95, 164.48, 162.79, 162.49,160.56, 149.90, 137.12, 133.68, 133.47, 132.69, 124.63, 124.07, 121.17,120.64, 120.03, 115.89, 114.79, 105.01, 98.84, 68.33, 62.29, 58.36, 55.53, 53.13, 53.06, 32.14, 29.07, 26.51, 24.26; HRMS, m / z: C33H36N2O7, [M+H]+: theoretical value 573.2556, measured value 573.2593. Synthesis of target compound I5 169 mg (0.5 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, compound 5e (0.6 mmol), 69 mg (0.5 mmol) of anhydrous potassium carbonate, and 8.3 mg (0.05 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I5. Compound I5 was a yellow oil, 113 mg in quantity, with a yield of 38.5%. 1H NMR(600 MHz, Chloroform-d) δ 12.09 (s, 1H), 12.03 (s, 1H), 7.83 (s, 1H), 7.81(d, J = 2.3 Hz, 1H), 7.80 (s, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 8.7, 2.1 Hz, 1H), 6.41 (d, J = 1.9Hz, 1H), 4.00 (s, 2H), 3.83 (s, 3H), 3.58 (s, 2H), 2.58 (s, 9H), 2.40 – 2.37(m, 2H), 1.86 (d, J = 7.0 Hz, 2H), 1.53 (s, 4H), 1.39 (q, J = 7.7 Hz, 2H);13C NMR (151 MHz, Chloroform-d) δ197.87, 192.65, 181.93, 164.48, 162.78,162.48, 160.59, 149.85, 137.12, 133.67, 133.47, 132.67, 124.63, 124.07,121.17, 120.63, 120.03, 115.88, 114.79, 104.97, 98.86, 68.41, 62.26, 58.45, 55.52, 53.07, 52.95, 32.12, 29.07, 27.25, 26.57, 26.17; HRMS, m / z:C34H38N2O7, [M+H]+: Theoretical value 587.2713, measured value 587.2748. Synthesis of target compound I6 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, compound 5f (1 mmol), 207 mg (1.5 mmol) of anhydrous potassium carbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I6. Compound I6 was a yellow-black solid, 120 mg in quantity, with a yield of 22.2%. 1H NMR (600 MHz, Chloroform-d) δ 12.10 (s, 1H), 12.05 (s, 1H), 8.49 (d, J = 4.4 Hz, 1H), 7.84 (dd, J = 7.5, 1.1 Hz, 1H), 7.81 (s, 1H), 7.69 (dd, J = 8.3, 7.6 Hz, 1H), 7.57 – 7.54 (m, 1H), 7.32 (d, J = 1.3 Hz, 1H), 7.30 (dd, J = 8.4, 1.1Hz, 1H), 6.90 (dd, J = 8.7, 2.4 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.19 (dd,J = 7.3, 5.0 Hz, 2H), 3.60 (s, 2H), 2.73 – 2.45 (m, 13H); 13C NMR (151 MHz, Chloroform-d) δ 195.49, 192.59, 181.88, 164.23, 162.72, 162.44, 159.67,157.63, 147.70, 137.09, 133.58, 133.44, 131.54, 131.44, 124.60, 123.99,120.67, 120.52, 119.98, 115.80, 114.77, 113.92, 112.08, 100.86, 66.69, 62.12, 60.94, 56.57, 53.44, 53.36, 52.83, 29.63; HRMS, m / z: C31H28N2O7, [M+H]+: theoretical value 541.1975, measured value 541.1956. Synthesis of target compound I7 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, 5 g (1 mmol) of the compound, 207 mg (1.5 mmol) of anhydrous potassium carbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure. An appropriate amount of water was added to the residue, and the mixture was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I7. Compound I7 was a yellow-black solid, 190 mg in quantity, with a yield of 42%. 1H NMR (600MHz, Chloroform-d) δ 12.08 (s, 2H), 8.48 (s, 1H), 7.82 (dd, J = 7.5, 1.0 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.69 – 7.66 (m, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.32 – 7.30 (m, 1H), 7.29 (dd, J = 8.4, 1.0 Hz, 1H), 6.87 (dd, J = 8.7, 2.3Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.04 (t, J = 6.4 Hz, 2H), 3.59 (s, 2H),2.69 (s, 13H), 1.87 – 1.84 (m, 2H); 13C NMR (151 MHz, Chloroform-d) δ 195.70,192.76, 182.04, 164.91, 162.90, 162.61, 159.94, 157.92, 147.97, 137.26,133.77, 133.60, 131.63, 131.61, 124.76, 124.17, 120.72, 120.62, 120.15,115.98, 114.92, 114.32, 112.04, 100.83, 68.88, 62.35, 58.42, 58.03, 53.07, 53.18, 53.02, 28.88, 24.05; HRMS, m / z: C32H30N2O7, [M+H]+: theoretical value 555.2131, measured value 555.2106. Synthesis of target compound I8 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, 1 mmol of compound 5h, 207 mg (1.5 mmol) of anhydrous potassium carbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I8. Compound I8 was a yellow-black solid, 204 mg in quantity, with a yield of 45%. 1H NMR (600MHz, Chloroform-d) δ 12.19 – 11.87 (m, 2H), 8.47 (s, 1H), 7.81 (dd, J = 7.5,1.1 Hz, 1H), 7.79 (t, J = 1.6 Hz, 1H), 7.67 (dd, J = 8.3, 7.6 Hz, 1H), 7.51(d, J = 8.7 Hz, 1H), 7.31 – 7.29 (m, 1H), 7.28 (dd, J = 8.4, 1.1 Hz, 1H), 6.86 (dt, J = 8.7, 1.9 Hz, 1H), 6.79 (dd, J = 7.6, 2.3 Hz, 1H), 4.05 (dt, J =21.2, 6.4 Hz, 2H), 3.58 (s, 2H), 2.69 (d, J = 1.1 Hz, 13H), 1.87 – 1.83 (m,2H), 1.57 – 1.47 (m, 2H); 13C NMR (151 MHz, Chloroform-d) δ 195.70, 192.73,182.02, 164.86, 162.87, 162.58, 159.92, 157.91, 147.96, 137.23, 133.75,133.56, 131.60, 131.59, 124.74, 124.16, 120.73, 120.60, 120.13, 115.96, 114.88, 114.34, 112.04, 100.81, 68.80, 62.37, 58.58, 58.05, 53.20, 53.06, 50.91, 28.91, 26.97, 23.30; HRMS, m / z: C33H32N2O7, [M+H]+: theoretical value 569.2288, measured value 569.2266. Synthesis of target compound I9 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, compound 5i (1 mmol), 207 mg (1.5 mmol) of anhydrous potassium carbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The solution was then concentrated under reduced pressure and purified by TLC to obtain product I9. Compound I9 was a yellow-black solid, 200 mg in quantity, with a yield of 43%. 1H NMR (600MHz, Chloroform-d) δ 12.15 – 11.91 (m, 2H), 8.47 (s, 1H), 7.83 – 7.80 (m,1H), 7.80 – 7.78 (m, 1H), 7.68 – 7.65 (m, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.30(s, 1H), 7.29 – 7.27 (m, 1H), 6.86 (dd, J = 8.7, 2.3 Hz, 1H), 6.78 (d, J =2.1 Hz, 1H), 4.04 (t, J = 6.4 Hz, 2H), 3.58 (s, 2H), 2.69 (s, 13H), 1.87 –1.83 (m, 2H), 1.50 (q, J = 7.7 Hz, 2H), 1.35 – 1.21 (m, 2H); 13C NMR (151MHz, Chloroform-d) δ 195.67, 192.74, 182.02, 164.90, 162.88, 162.59, 159.92,157.91, 147.95, 137.24, 133.76, 133.57, 131.63, 131.60, 124.75, 124.16,120.71, 120.60, 120.13, 115.97, 114.98, 114.32, 112.03, 100.82, 68.88, 62.36, 58.43, 58.43, 53.56, 53.20, 53.08, 30.72, 28.88, 26.45, 24.05; HRMS, m / z:C34H34N2O7, [M+H]+: Theoretical value 583.2444, measured value 583.2421. Synthesis of target compound I10 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, and 10 mL of acetonitrile was added. The mixture was heated and stirred at 70 °C. Then, 5 mg (1 mmol) of compound Ij, 207 mg (1.5 mmol) of anhydrous potassium carbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I10. Compound I10 was a yellow-black solid, 240 mg in quantity, with a yield of 50%.1H NMR (600 MHz, Chloroform-d) δ 12.21 – 11.92 (m, 2H), 8.47 (s, 1H), 7.84 – 7.80 (m, 1H), 7.80 – 7.76 (m, 1H), 7.68 – 7.65 (m, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.30 (s, 1H), 7.29 – 7.27 (m, 1H), 6.86 (dd, J = 8.7, 2.3 Hz, 1H), 6.79 (dd,J = 7.9, 2.1 Hz, 1H), 4.07 – 4.02 (m, 2H), 3.58 (s, 2H), 2.70 – 2.37 (m,13H), 1.82 (dt, J = 14.3, 6.6 Hz, 2H), 1.51 (ddt, J = 30.2, 15.2, 7.7 Hz,4H), 1.38 (p, J = 7.4 Hz, 2H); 13C NMR (151 MHz, Chloroform-d) δ 95.66,192.73, 182.01, 164.95, 162.88, 162.58, 159.92, 157.92, 147.95, 137.23,133.76, 133.55, 131.58, 131.58, 124.73, 124.15, 120.71, 120.57, 120.12, 115.96, 114.87, 114.35, 112.00, 100.81, 69.00, 62.38, 58.60, 58.06, 53.56, 53.23, 53.15, 30.72, 28.92, 27.36, 26.74, 25.98; HRMS, m / z: C35H36N2O7, [M+H]+: theoretical value 597.2601, measured value 597.2576. Synthesis of target compound I11 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, 5 kJ of compound 5 (1 mmol), 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by thin-layer chromatography to obtain product I11. Compound I11 was a yellow-black solid, 192 mg in quantity, with a yield of 42.3%. 1H NMR (600MHz, Chloroform-d) δ 12.05 (d, J = 25.0 Hz, 2H), 7.81 (dd, J = 7.5, 1.0 Hz,1H), 7.79 (d, J = 1.4 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.33 – 7.30 (m, 1H), 7.28 (dd, J = 8.4, 1.0 Hz, 1H), 6.85 (dd, J = 8.8, 2.5Hz, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.14 – 6.10 (m, 1H), 4.15 (t, J = 5.7 Hz, 2H), 3.59 (s, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.70 – 2.36 (m, 11H); 13C NMR (151 MHz, Chloroform-d) δ 192.74, 182.01, 162.89, 162.59, 161.86, 161.42,155.34, 152.65, 149.96, 137.24, 133.76, 133.58, 125.64, 124.74, 124.15,120.71, 120.13, 115.97, 114.89, 113.80, 112.81, 112.15, 101.64, 66.59, 62.37, 56.96, 53.70, 53.57, 53.17, 50.96, 18.80; HRMS, m / z: C32H28N2O8, [M+H]+: theoretical value 569.1924, measured value 569.1917. Synthesis of target compound I12 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, 5 L (1 mmol) of the compound, 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I12. Compound I12 was a yellow-black solid, 133 mg in quantity, with a yield of 28.7%. 1H NMR (600MHz, Chloroform-d) δ 12.05 (d, J = 31.3 Hz, 2H), 7.84 – 7.80 (m, 1H), 7.80 –7.77 (m, 1H), 7.69 – 7.65 (m, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H),7.30 – 7.27 (m, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz,1H), 6.12 – 6.11 (m, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.59 (s, 2H), 2.60 – 2.38(m, 13H), 2.02 – 1.99 (m, 2H); 13C NMR (151 MHz, Chloroform-d) δ 192.74,182.01, 162.89, 162.59, 162.17, 161.46, 155.38, 152.69, 150.00, 137.23,133.76, 133.56, 125.60, 124.73, 124.15, 120.72, 120.12, 115.97, 114.88,113.62, 112.74, 112.01, 101.52, 66.88, 62.37, 59.38, 54.96, 53.57, 53.25, 53.19, 26.54, 18.80; HRMS, m / z: C33H30N2O8, [M+H]+: theoretical value 583.2080, measured value 584.5596. Synthesis of target compound I13 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, 5 mL (1 mmol) of the compound, 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by thin-layer chromatography to obtain product I13. Compound I13 was a yellow-black solid, 163 mg in quantity, with a yield of 34.4%. 1H NMR (600MHz, Chloroform-d) δ 12.05 (d, J = 39.1 Hz, 2H), 7.81 (dd, J = 7.5, 1.1 Hz,1H), 7.78 (d, J = 1.5 Hz, 1H), 7.66 (dd, J = 8.4, 7.5 Hz, 1H), 7.46 (d, J =8.8 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H), 7.28 (dd, J = 8.4, 1.1 Hz, 1H), 6.82(dd, J = 8.8, 2.5 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.11 (d, J = 1.1 13C NMR (151 MHz, Chloroform-d) δ 192.72,181.99, 162.87, 162.57, 162.18, 161.49, 155.38, 152.72, 149.98, 137.21,133.74, 133.54, 125.59, 124.71, 124.15, 120.71, 120.11, 115.95, 114.86, 113.57, 112.78, 111.96, 101.41, 68.35, 62.36, 58.14, 58.09, 53.14, 53.14, 52.12, 27.08, 23.31, 18.79; HRMS, m / z: C34H32N2O8, [M+H]+: theoretical value 597.2237, measured value 597.2228. Synthesis of target compound I14 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, compound 5n (1 mmol), 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I14. Compound I14 was a yellow-black solid, 160 mg in quantity, with a yield of 32.8%.1H NMR (600MHz, Chloroform-d) δ 12.04 (d, J = 30.6 Hz, 2H), 7.81 (dd, J = 7.5, 1.0 Hz,1H), 7.78 (d, J = 1.4 Hz, 1H), 7.66 (dd, J = 8.3, 7.6 Hz, 1H), 7.46 (d, J =8.8 Hz, 1H), 7.31 – 7.29 (m, 1H), 7.28 (dd, J = 8.4, 1.0 Hz, 1H), 6.83 – 6.81(m, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.11 – 6.10 (m, 1H), 4.01 – 3.99 (m, 2H), 3.58 (s, 2H), 2.54 – 2.37 (m, 13H), 1.82 (d, J = 7.7 Hz, 2H), 1.58 (d, J =7.4 Hz, 2H), 1.51 – 1.48 (m, 2H); 13C NMR (151 MHz, Chloroform-d) δ 192.12,182.00, 162.86, 162.56, 162.24, 161.51, 155.37, 152.74, 149.96, 137.22,133.74, 133.54, 125.59, 124.72, 124.15, 120.71, 120.11, 115.95, 114.86, 113.55, 112.75, 111.92, 101.42, 68.46, 62.36, 59.36, 58.49, 53.20, 53.10, 50.88, 28.98, 26.52, 24.09, 18.78; HRMS, m / z: C35H34N2O8, [M+H]+: Theoretical value 611.2393, measured value 611.2386. Synthesis of target compound I15 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, compound 5O (1 mmol), 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was stopped after approximately 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I15. Compound I15 was a yellow-black solid, 189 mg in quantity, with a yield of 37.8%.1H NMR (600MHz, Chloroform-d) δ 12.06 (d, J = 24.3 Hz, 2H), 7.82 (dd, J = 7.5, 1.0 Hz,1H), 7.80 (d, J = 1.2 Hz, 1H), 7.69 – 7.66 (m, 1H), 7.52 (d, J = 8.7 Hz, 1H),7.32 – 7.30 (m, 1H), 7.29 (dd, J = 8.4, 1.0 Hz, 1H), 6.87 (dd, J = 8.7, 2.3Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.11 – 6.10 (m, 1H), 4.04 (t, J = 13C NMR (151 MHz, Chloroform-d) δ192.76, 182.04, 162.90, 162.60, 162.30, 161.52, 155.41, 152.73, 150.03,137.23, 133.78, 133.57, 125.59, 124.73, 124.17, 120.74, 120.14, 115.98, 114.88, 113.54, 112.81, 111.94, 101.44, 68.58, 62.40, 58.64, 58.63, 53.6, 53.22, 53.16, 29.04, 27.41, 26.76, 26.04, 18.80; HRMS, m / z: C36H36N2O8, [M+H]+: theoretical value 625.2550, measured value 625.2540. Synthesis of target compound I16 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, 5 p (1 mmol) of compound, 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and an appropriate amount of water was added to the residue. The residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The solution was concentrated under reduced pressure and purified by thin-layer chromatography to obtain product I16. Compound I16 was a yellow-black solid, 216 mg in quantity, with a yield of 46.0%.

[0063] Synthesis of target compound I17 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, compound 5q (1 mmol), 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I17. Compound I17 was a yellow-black solid, 158 mg in quantity, with a yield of 32.9%.

[0064] Synthesis of target compound I18 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, compound 5r (1 mmol), 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I18. Compound I18 was a yellow-black solid, 167 mg in quantity, with a yield of 33.9%.

[0065] Synthesis of target compound I19 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, compound 5r (1 mmol), 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by TLC to obtain product I19. Compound I19 was a yellow-black solid, 206 mg in quantity, with a yield of 40.9%.

[0066] Synthesis of target compound I20 270 mg (0.8 mmol) of 15-piperazine aloe-emodin was placed in a 50 mL round-bottom flask, 10 mL of LDM was added, and the mixture was heated and stirred at 70 °C. Then, compound 5r (1 mmol), 168 mg (2 mmol) of sodium bicarbonate, and 16.6 mg (0.1 mmol) of potassium iodide were added to initiate the reaction. The reaction progress was monitored by thin-layer chromatography (TLC). The reaction was completed in approximately 24 hours, at which point the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (with a small amount of methanol) until the aqueous phase was essentially colorless. The extract was then concentrated under reduced pressure and purified by thin-layer chromatography to obtain product I20. Compound I20 was a yellow-black solid, 195 mg in quantity, with a yield of 37.9%.

[0067] Example 27 Pharmacological experiments testing the antiproliferative activity of the compounds of the present invention against cancer cells. The in vitro anti-cell proliferation activity of the test drug compound I1-20 against human cervical cancer cells (HeLa), human liver cancer cells (HepG2), human lung cancer cells (A549), and human osteosarcoma cells (U2OS) was tested using the MTT assay.

[0068] Experimental Methods: Cells were routinely cultured in an incubator at 37 ℃ and 5% CO2 saturated humidity. Cancer cells in good logarithmic growth phase were digested with 0.25% trypsin to detach adherent cells. Cell count was (2-3) × 10⁴ cells / mL, and approximately 5000 cells per well were seeded into 96-well plates and incubated for 24 h. The culture medium was changed, and the test drug (0.1-25.0 μmol / L, 5 concentrations) was added at 100 μL per well. The plates were then incubated at 37 ℃ and 5% CO2 saturated humidity for another 72 h. MTT reagent was added to each well at 20 μL, and the plates were incubated for 4 h. The supernatant was removed, and DMSO was added at 120 μL per well. The plates were shaken on a shaker for 10 min, and the absorbance at 495 nm was measured using an enzyme-linked immunosorbent assay (ELISA) reader. All experiments were repeated three times under the same conditions, and the cell inhibition rate was calculated.

[0069] Cell inhibition rate = [(OD value of negative control group – OD value of test group) / (OD value of negative control group – OD value of blank group)] × 100% Experimental data were analyzed using GraphPad Prism 8.0 and IC was calculated through nonlinear regression analysis. 50 Some of the experimental results are shown in Table 1.

[0070] Table 1

[0071] a IC 50 The value refers to the half-maximal inhibitory concentration required to inhibit cell growth.

[0072] The results above show that the aloe-emodin piperazine derivatives involved in this invention have certain inhibitory effects on the proliferation of different tumor cells. Among them, some target compounds have strong anti-tumor activity against osteosarcoma cells and human cervical cancer cells, which are significantly better than the positive control drug 5-Fu.

[0073] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An aloe-emodin-piperazine derivative, characterized in that, Pharmaceutically acceptable salts of compounds represented by general formula I; I In Equation I, n is an integer from 1 to 6; R includes , , , .

2. The aloe-emodin-piperazine derivative according to claim 1, characterized in that, Its features are, The n is an integer between 2 and 6.

3. The aloe-emodin-piperazine derivative according to claim 1, characterized in that, The aloe-emodin-piperazine derivatives mentioned above are selected from any one of the following compounds I1-I20: I1: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)ethyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I2: 3-((4-(3-(2-acetyl-5-methoxyphenoxy)propyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I3: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)butyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I4: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)pentyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I5: 3-((4-(2-(2-acetyl-5-methoxyphenoxy)hexyl)piperazin-1-yl)methyl)-1,8-dihydroxyanthracene-9,10-dione; I6: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)ethyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I7: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)propyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I8: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I9: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)pentyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I10: 1,8-Dihydroxy-3-((4-(2-((2-methylene-3-(1-propen-2-yl)-2H-chromene-7-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I11: (4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)ethyl 2-(2-acetyl-5-methoxyphenoxy)acetate; I12: (4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)propyl 2-(2-acetyl-5-methoxyphenoxy)acetate; I13: 2-(4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)butyl-2-(2-acetyl-5-methoxyphenoxy)acetate; I14: 2-(4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)pentyl-2-(2-acetyl-5-methoxyphenoxy)acetate; I15: 2-(4-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)methyl)piperazin-1-yl)hexyl-2-(2-acetyl-5-methoxyphenoxy)acetate; I16: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)ethyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I17: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)propyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I18: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)butyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I19: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)pentyl)piperazin-1-yl)methyl)anthracene-9,10-dione; I20: 1,8-Dihydroxy-3-((4-(2-((5-methyl-7-methylene-7,8-dihydronaphth-2-yl)oxy)hexyl)piperazin-1-yl)methyl)anthracene-9,10-dione.

4. A method for preparing an aloe-emodin-piperazine derivative according to any one of claims 1-3, characterized in that, include: Hydrogen-containing compounds and dihalogenated straight-chain alkanes undergo substitution reactions to yield halogenated compounds; 15-piperazine aloe-emodin and halogenated compounds undergo a nitrogen-hydrocarbonation reaction to yield aloe-emodin piperazine derivatives. The chemical formula of the dihalo-substituted straight-chain alkane is X(CH2). n X, n are integers from 1 to 6; The hydrogen-containing compound is one of paeonol, 7-hydroxy-4-methylcoumarin, 7-hydroxy-3-acetylcoumarin, and paeonolacetic acid.

5. The method for preparing an aloe-emodin-piperazine derivative according to claim 4, characterized in that, The preparation of the 15-piperazine aloe-emodin includes: Piperazine, a second organic solvent, potassium iodide, tetrabutylammonium bromide, and chloroaloe-emodin were mixed and reacted to obtain 15-piperazine aloe-emodin.

6. The method for preparing an aloe-emodin-piperazine derivative according to claim 5, characterized in that, The molar ratio of piperazine to halogenated aloe-emodin is 1.2-2:1; the temperature of the mixing reaction is 20-30℃; and the time of the mixing reaction is 6-48h.

7. A method for preparing an aloe-emodin-piperazine derivative according to any one of claims 4-6, characterized in that, The acquisition of the halogenated compound includes: A hydrogen-containing compound, a dihalogenated straight-chain alkane, a first organic solvent, and a basic reagent are mixed and heated to carry out a substitution reaction, yielding a halogenated compound.

8. The method for preparing an aloe-emodin-piperazine derivative according to claim 7, characterized in that, The alkaline reagent is sodium hydroxide or potassium carbonate; The substitution reaction is carried out at a temperature of 20-50°C for 4-24 hours; the molar ratio of the hydrogen-containing compound to the dihalogenated straight-chain alkane is 1:1-4.

9. A pharmaceutical composition, characterized in that, Includes an aloe-emodin-piperazine derivative as described in any one of claims 1-3, or an aloe-emodin-piperazine derivative prepared by the method described in any one of claims 4-7.

10. The use of an aloe-emodin-piperazine derivative according to any one of claims 1-3, or an aloe-emodin-piperazine derivative prepared by any one of claims 4-7, in the preparation of a tumor-treating drug, characterized in that, The tumor is one of the following: liver cancer, osteosarcoma, cervical cancer, or lung cancer.

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