Paeonol Mannich base-rhein conjugate, preparation method and application thereof

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and discloses a paeonol Mannich base-rhein conjugate, a preparation method thereof and an application thereof. The conjugate is a compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof. Compared with the clinically commonly used anti-tumor drugs fluorouracil and paeonol, the conjugate of the present invention has significantly higher in vitro proliferation inhibitory activities against human liver cancer cells (HepG2) and human lung cancer cells (A549), and the in vitro proliferation inhibitory activities of most compounds against human cervical cancer cells (Hela), human colon cancer cells (HT29) and human osteosarcoma cells (U2OS) are significantly better than those of fluorouracil and paeonol, indicating excellent anti-tumor effects. Moreover, the conjugate of the present invention has good water solubility and is expected to be applied to the treatment of various cancers such as cervical cancer, colon cancer, osteosarcoma, lung cancer or liver cancer, and has broad clinical application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a paeonol Mannich base-rhein conjugate, a preparation method thereof and an application thereof. Background Art

[0002] According to the World Health Organization, malignant tumors remain the main cause seriously threatening human life. Despite a series of cancer treatment strategies (such as surgery, chemotherapy, radiotherapy and immunotherapy), the cancer-related mortality rate remains high, accounting for 13% of the total human deaths. Therefore, developing anti-cancer drugs with high selectivity and low side effects to improve the efficacy of cancer treatment is still one of the urgent problems to be solved currently (CA Cancer J.Clin. 2021, 71: 209-249; Chinese Medical Ethics, 2023, 36(05): 540-547.).

[0003] Paeonol is one of the effective active ingredients of the traditional Chinese medicine Cortex Moutan, and has effects such as antipyretic and analgesic, anti-inflammatory, anti-tumor activity, and inhibition of allergic reactions (Phytomedicine, 2023, 109; Chinese Pharmacological Bulletin, 2023(06): 1078 - 1084; Journal of Beijing Union University, 2023, 37(02): 72 - 78.). Research shows that paeonol has inhibitory effects on the growth and proliferation of cancer cells in a variety of 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, MG-63 cells, etc. Paeonol can effectively inhibit 5-lipoxygenase (5-LO), and stimulate cancer cell invasion and migration by up-regulating the expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9); paeonol can also inhibit cancer cell migration by inhibiting the STAT3 / NF-κB and TGF-β1 / Smad signaling pathways and reducing the inflammation of the tumor microenvironment; paeonol inhibits the activation of the WNT / β-catenin signaling pathway, down-regulates cyclin D1 and CDK4, up-regulates cyclin p21Cip1, and arrests the cell cycle at the G0 / G1 phase (Psychopharmacology (Berl). 2022, 239(7): 2083 - 2092.; Clin Transl Oncol. 2021, 23(3): 601 - 611; Acta Histochem. 2020, 122(1): 151455; Mol Med Rep. 2021, 23(6): 401; Cancer Manag Res. 2020, 12: 641 - 651; Int J Mol Med. 2020, 46(2): 675 - 684). The anti-tumor mechanism of paeonol is diverse, but it is volatile, has poor water solubility, and is easily metabolized, which limits its clinical application. Therefore, it is of great significance to modify the structure of paeonol to enhance its anti-tumor activity, improve its physicochemical properties, and improve its applicability, so as to provide new alternative drugs for cancer treatment. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides a paeonol Mannich base-rhein conjugate with good anti-tumor effect and good water solubility, and its preparation method and application.

[0005] In the first aspect, the present invention provides a paeonol Mannich base-rhein conjugate, and the conjugate is a compound represented by the general formula (Ⅰ) or (Ⅱ) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Among them, n is an integer from 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substitution is by a C1-C6 alkyl group.

[0008] In some embodiments, R is a substituted or unsubstituted five- or six-membered nitrogen-containing heterocyclic group.

[0009] In some embodiments, the substitution is by a C1-C3 alkyl group.

[0010] In some embodiments, R is selected from morpholinyl, piperidinyl, 4-methylpiperazinyl or 4-ethylpiperazinyl.

[0011] In some embodiments, the compounds represented by general formula (I) or (II) are selected from the following compounds:

[0012] 3-(2-Acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)propyl-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Compound No.: I1, the same below)

[0013] 4-(2-Acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)butyl-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (I2);

[0014] 5-(2-Acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)pentyl-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (I3);

[0015] 6-(2-Acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)hexyl-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (I4);

[0016] 7-(2-Acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)heptyl-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (I5);

[0017] 8-(2-Acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)octyl-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (I6);

[0018] 3-(6-Acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)propyl-4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (II1);

[0019] 4-(6-Acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)butyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ2);

[0020] 5-(6-Acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)pentyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ3);

[0021] 6-(6-Acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)hexyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ4);

[0022] 7-(6-Acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)heptyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ5);

[0023] 8-(6-Acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)octyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ6);

[0024] 3-(6-Acetyl-3-methoxy-2-(piperidin-1-ylmethyl)phenoxy)propyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ7);

[0025] 4-(6-Acetyl-3-methoxy-2-(piperidin-1-ylmethyl)phenoxy)butyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ8);

[0026] 5-(6-Acetyl-3-methoxy-2-(piperidin-1-ylmethyl)phenoxy)pentyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ9);

[0027] 6-(6-Acetyl-3-methoxy-2-(piperidin-1-ylmethyl)phenoxy)hexyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ10);

[0028] 7-(6-Acetyl-3-methoxy-2-(piperidin-1-ylmethyl)phenoxy)heptyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ11);

[0029] 8-(6-Acetyl-3-methoxy-2-(piperidin-1-ylmethyl)phenoxy)octyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ12);

[0030] 3-(2-Acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)propyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ13);

[0031] 4-(2-Acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)butyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ14);

[0032] 5-(2-Acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)pentyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ15);

[0033] 6-(2-Acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)hexyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ16);

[0034] 7-(2-Acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)heptyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ17);

[0035] 8-(2-Acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)octyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ18);

[0036] 3-(2-Acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)propyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ19);

[0037] 4-(2-Acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)butyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ20);

[0038] 5-(2-Acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)pentyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ21);

[0039] 6-(2-Acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)hexyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ22);

[0040] 7-(2-Acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)heptyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ23);

[0041] 8-(2-Acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)octyl 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate (Ⅱ24).

[0042] In a second aspect, the present invention provides a method for preparing a paeonol Mannich base-rhein conjugate represented by formula (Ⅰ) or (Ⅱ), comprising: reacting a compound represented by one of formula (4) or formula (5) with rhein in the presence of a base and a solvent, and the reaction formula is as follows;

[0043]

[0044] Wherein, X is a halogen atom; n is an integer from 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substitution is by a C1-C6 alkyl group.

[0045] In some embodiments, the molar ratio of the compound represented by one of formula (4) or formula (5) to rhein is 1:1 to 2.

[0046] In some embodiments, the reaction temperature is 60-80 °C and the reaction time is 8-10 h.

[0047] In some embodiments, the method for preparing the compound represented by one of formula (2) or formula (3) comprises: carrying out a Williamson reaction between the compound represented by one of formula (2) or formula (3) and a dihaloalkane, and the reaction formula is as follows:

[0048]

[0049] Wherein, X is a halogen atom; n is an integer from 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substitution is by a C1-C6 alkyl group.

[0050] In some embodiments, the method for preparing the compound represented by one of formula (2) or formula (3) comprises: carrying out a Mannich reaction between paeonol, paraformaldehyde and a nitrogen-containing heterocyclic compound.

[0051] In a third aspect, the present invention provides a pharmaceutical composition comprising the aforementioned conjugate as the sole or main active ingredient and a pharmaceutically acceptable carrier or adjuvant component.

[0052] In a third aspect, the present invention provides the use of the aforementioned conjugate or pharmaceutical composition in the preparation of a medicament for treating cancer, wherein the cancer is selected from cervical cancer, colon cancer, osteosarcoma, lung cancer or liver cancer.

[0053] The beneficial effects of the present invention are as follows:

[0054] The present invention designed and synthesized a series of paeonol Mannich base-rhein conjugates with novel structures. The Mannich base structure introduced into paeonol by the Mannich reaction improved the water solubility and bioavailability of paeonol. The further conjugation of the obtained paeonol Mannich base with rhein significantly enhanced the anti-tumor activity. Experimental results showed that compared with the clinically commonly used anti-tumor drugs fluorouracil and paeonol, the conjugates of the present invention had significantly higher in vitro anti-proliferation activities against human liver cancer cells (HepG2) and human lung cancer cells (A549). Moreover, the in vitro anti-proliferation activities of most compounds against human cervical cancer cells (Hela), human colon cancer cells (HT29) and human osteosarcoma cells (U2OS) were significantly better than those of fluorouracil and paeonol, indicating excellent anti-tumor effects. The conjugates of the present invention are expected to be applied to the treatment of various cancers such as cervical cancer, colon cancer, osteosarcoma, lung cancer or liver cancer, and have broad clinical application prospects. Detailed implementation manners

[0055] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Apparently, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0056] The synthetic route of the target compound is as follows. Specifically, i: Using paeonol (1) as the starting material, performing a Mannich reaction with paraformaldehyde and a nitrogen-containing heterocyclic compound to introduce a nitrogen-containing heterocyclic methyl group at the 3-position or 5-position thereof, obtaining the corresponding paeonol Mannich base derivatives (2, 3); ii: Synthesizing compounds (4, 5) from the paeonol Mannich base derivatives (2, 3) and the corresponding dibromoalkanes through the Williamson reaction; iii: Coupling compounds (4, 5) with rhein to obtain new paeonol Mannich base-rhein conjugates (Ⅰ, Ⅱ).

[0057]

[0058] Reaction conditions and reagents i: 95% EtOH, (CH2O) n, Morpholine / Piperidine / N-Methylpiperazine / N-Ethylpiperazine, 85 °C; ii: DMF, NaOH, Br(CH2) n Br, 35 °C; iii: DMF, K2CO3, KI, TBAB, 70 °C. Synthesis of Paeonol Mannich Bases 2a and 3a in Example 1

[0059] Paeonol (498 mg, 3 mmol) and paraformaldehyde (120 mg, 4 mmol) (degree of polymerization n = 10 - 100) were added into a reaction flask, and 95% ethanol (20 mL) was added. The mixture was refluxed and stirred at 85 °C. After 1 h, morpholine (0.30 mL, 4 mmol) was added. The reaction was monitored by TLC and stopped after 8 h. The reaction solution was concentrated by rotary evaporation, water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, sealed with a film and left to stand overnight. The extracted reaction solution was filtered, concentrated under reduced pressure, and separated by column chromatography [V(ethyl acetate):(petroleum ether) = 1:8] to obtain 506 mg of a white solid with a yield of 63.7%; among which 208 mg of 2a with a yield of 26.2%, 1 1H NMR (600 MHz, CDCl3) δ: 12.63 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 6.67 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J = 4.7 Hz, 4H), 3.38 (s, 2H), 2.58 (s, 3H), 2.44 - 2.35 (m, 4H). IR (KBr) ν: 3292, 3021, 2927, 1683, 1605, 1460, 1372, 1233 cm -1 。HRMS calcd for C 14 H 19 NO4[M + H] + : 266.1392, found 266.1408; 298 mg of 3a with a yield of 37.5%.

[0060] Synthesis of Paeonol Mannich Bases 2b and 3b in Example 2

[0061] Referring to the synthesis method of 2a, paeonol (498 mg, 3 mmol) and paraformaldehyde (120 mg, 4 mmol) were added into a reaction flask, and 95% ethanol (20 mL) was added. The mixture was refluxed and stirred at 85 °C. After 1 h, piperidine (0.35 mL, 4 mmol) was added. The reaction was monitored by TLC and stopped after 8 h. The reaction solution was concentrated by rotary evaporation, water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, sealed with a film and left to stand overnight. The extracted reaction solution was filtered, concentrated under reduced pressure, and separated by column chromatography [V(ethyl acetate):(petroleum ether) = 1:6] to obtain 486 mg of a white solid with a yield of 61.6%; among which 222 mg of 2b with a yield of 28.2%,1 1H NMR (600 MHz, CDCl3) δ: 10.70 (s, 1H), 8.36 (d, J = 9.0 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H), 4.13 (s, 2H), 3.89 (s, 3H), 3.35 - 3.26 (m, 4H), 2.62 (s, 3H), 1.85 - 1.66 (m, 6H). IR (KBr) ν: 3289, 3019, 2924, 1681, 1603, 1462, 1371, 1231 cm -1 。HRMS calcd for C 15 H 21 NO3[M + H] + : 264.1600, found 264.1611; 3b 264 mg, the yield was 33.4%.

[0062] Example 3 Synthesis of Paeonol Mannich Bases 2c and 3c

[0063] Referring to the synthesis method of 2a, paeonol (498 mg, 3 mmol) and paraformaldehyde (120 mg, 4 mmol) were put into a reaction flask, 95% ethanol (20 mL) was added, and the mixture was refluxed and stirred at 85 °C. After 1 h, methylpiperazine (0.44 mL, 4 mmol) was added. The reaction was stopped after 8 h by TLC detection. The reaction solution was evaporated to dryness, water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, sealed with a film and left standing overnight. The extracted reaction solution was filtered, concentrated under reduced pressure, and separated by column chromatography [V (ethyl acetate): (petroleum ether) = 1:10] to obtain 534 mg of a white solid, and the yield was 62.8%; among them, 2c was 241 mg, and the yield was 27.7% 1 1H NMR (600 MHz, CDCl3) δ: 12.71 (s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 9.0 Hz, 1H), 3.89 (s, 3H), 3.60 (s, 2H), 3.45 - 3.37 (m, 7H), 2.79 (s, 3H), 2.62 - 2.54 (m, 4H). IR (KBr) ν: 3291, 3223, 2929, 1685, 1603, 1461, 1374, 1235 cm -1 。HRMS calcd for C 15 H 22 N2O3[M + H] + : 279.1709, found 279.1725; 3c was 293 mg, and the yield was 35.1%.

[0064] Example 4 Synthesis of Paeonol Mannich Bases 2d and 3d

[0065] According to the synthesis method of 2a, paeonol (498 mg, 3 mmol) and paraformaldehyde (120 mg, 4 mmol) were added into a reaction flask, 95% ethanol (20 mL) was added, and the mixture was refluxed and stirred at 85 °C. After 1 h, ethyl piperazine (0.50 mL, 4 mmol) was added, and the reaction was monitored by TLC. The reaction was stopped after 8 h. The reaction solution was concentrated by rotary evaporation, water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, sealed with a film, and left standing overnight. The extracted reaction solution was filtered, concentrated under reduced pressure, and separated by column chromatography [V(ethyl acetate):(petroleum ether) = 1:9] to obtain 568 mg of a white solid with a yield of 64.8%; among them, 233 mg of 2d with a yield of 26.5%, 1 1H NMR (600 MHz, CDCl3) δ: 12.85 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H), 3.56 (d, J = 4.7 Hz, 4H), 3.42 - 3.33 (m, 10H), 2.60 (s, 3H), 1.25 (t, J = 5.7 Hz, 3H). IR (KBr) ν: 3288, 3022, 2923, 1684, 1602, 1460, 1372, 1231 cm -1 。HRMS calcd for C 16 H 24 N2O3 [M + H] + : 293.1865, found 293.1885; 335 mg of 3d with a yield of 38.3%.

[0066] Example 5 Synthesis of 1-(2-(3-bromopropoxy)-4-methoxy-3-morpholinomethylphenyl)ethan-1-one (4a)

[0067] 1 mmol (265 mg) of compound 2a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of 1,3-dibromopropane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After the reaction was completed, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After separation by column chromatography [V(ethyl acetate):(petroleum ether) = 1:4], 228 mg of a yellow oil 4a was obtained with a yield of 54.6%.

[0068] Example 6 Synthesis of 1-(2-(4-bromobutoxy)-4-methoxy-3-morpholinomethylphenyl)ethan-1-one (4b)

[0069] 1 mmol (265 mg) of compound 2a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromobutane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 263 mg of yellow oil 4b was obtained, with a yield of 61.1%.

[0070] Example 7 Synthesis of 1-(2-(5-bromopentyloxy)-4-methoxy-3-morpholinomethylphenyl)ethan-1-one (4c)

[0071] 1 mmol (265 mg) of compound 2a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromopentane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 280 mg of yellow oil 4c was obtained, with a yield of 62.9%.

[0072] Example 8 Synthesis of 1-(2-(6-bromohexyloxy)-4-methoxy-3-morpholinomethylphenyl)ethan-1-one (4d)

[0073] 1 mmol (265 mg) of compound 2a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromohexane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 277 mg of yellow oil 3d was obtained, with a yield of 60.4%.

[0074] Example 9 Synthesis of 1-(2-(7-bromoheptyloxy)-4-methoxy-3-morpholinomethylphenyl)ethan-1-one (4e)

[0075] 1 mmol (265 mg) of compound 2a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromoheptane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion, then filtered by suction. 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 291 mg of yellow oil 3e was obtained, with a yield of 61.4%.

[0076] Example 10 Synthesis of 1-(2-(8-bromooctyloxy)-4-methoxy-3-morpholinomethylphenyl)ethan-1-one (4f)

[0077] 1 mmol (265 mg) of compound 2a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromooctane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion, then filtered by suction. 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 304 mg of yellow oil 4f was obtained, with a yield of 62.3%.

[0078] Example 11 Synthesis of 1-(2-(3-bromopropoxy)-4-methoxy-5-morpholinomethylphenyl)ethan-1-one (5a)

[0079] 1 mmol (265 mg) of compound 3a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromopropane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion, then filtered by suction. 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 247 mg of yellow oil 5a was obtained, with a yield of 59.3%.

[0080] Example 12 Synthesis of 1-(2-(4-bromobutoxy)-4-methoxy-5-morpholinomethylphenyl)ethan-1-one (5b)

[0081] 1 mmol (265 mg) of compound 3a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromobutane was added, and the stirring was continued at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4] gave 260 mg of yellow oil 5b with a yield of 60.4%.

[0082] Example 13 Synthesis of 1-(2-(5-bromopentyloxy)-4-methoxy-5-morpholinomethylphenyl)ethan-1-one (5c)

[0083] 1 mmol (265 mg) of compound 3a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromopentane was added, and the stirring was continued at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4] gave 272 mg of yellow oil 5c with a yield of 61.1%.

[0084] Example 14 Synthesis of 1-(2-(6-bromohexyloxy)-4-methoxy-5-morpholinomethylphenyl)ethan-1-one (5d)

[0085] 1 mmol (265 mg) of compound 3a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromohexane was added, and the stirring was continued at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4] gave 283 mg of yellow oil 5d with a yield of 61.8%.

[0086] Example 15 Synthesis of 1-(2-(7-bromoheptyloxy)-4-methoxy-5-morpholinomethylphenyl)ethan-1-one (5e)

[0087] 1 mmol (265 mg) of compound 3a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromoheptane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 294 mg of yellow oil 5e was obtained, with a yield of 62.2%.

[0088] Example 16 Synthesis of 1-(2-(8-bromooctyloxy)-4-methoxy-5-morpholinomethylphenyl)ethan-1-one (5f)

[0089] 1 mmol (265 mg) of compound 3a, 3 mmol (120 mg) of sodium hydroxide, and 6 mL of DMF were added to a 50 mL round-bottom flask, stirred at room temperature for 20 min, then 3 mmol of dibromooctane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:4], 296 mg of yellow oil 5f was obtained, with a yield of 60.8%.

[0090] Example 17 Synthesis of 1-(2-((3-bromopropyl)oxy)-4-methoxy-3-(piperidin-1-ylmethyl)phenyl)ethan-1-one (5g)

[0091] 1 mmol (263 mg) of compound 3b and 3 mmol (120 mg) of sodium hydroxide were added to a 50 mL round-bottom flask, and 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromopropane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):V(petroleum ether) = 1:5], 277 mg of yellow oil 5g was obtained, with a yield of 55.6%. Example 18 Synthesis of 1-(2-((4-bromobutyl)oxy)-4-methoxy-3-(piperidin-1-ylmethyl)phenyl)ethan-1-one (5h)

[0092] 1 mmol (263 mg) of compound 3b and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask, and 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromobutane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5] gave 287 mg of a yellow oil 5h with a yield of 56.1%. Example 19 Synthesis of 1-(2-((5-bromopentyl)oxy)-4-methoxy-3-(piperidin-1-ylmethyl)phenyl)ethan-1-one (5i)

[0093] 1 mmol (263 mg) of compound 3b and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask, and 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromopentane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5] gave 301 mg of a yellow oil 5i with a yield of 57.3%. Example 20 Synthesis of 1-(2-((6-bromohexyl)oxy)-4-methoxy-3-(piperidin-1-ylmethyl)phenyl)ethan-1-one (5j)

[0094] 1 mmol (263 mg) of compound 3b and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask, and 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromohexane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5] gave 299 mg of a yellow oil 5j with a yield of 55.4%. Example 21 Synthesis of 1-(2-((7-bromoheptyl)oxy)-4-methoxy-3-(piperidin-1-ylmethyl)phenyl)ethan-1-one (5k)

[0095] 1 mmol (263 mg) of compound 3b and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. Stir at room temperature for 20 min, then add 3 mmol of dibromoheptane and stir at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 333 mg of yellow oil 5k was obtained with a yield of 60.1%. Example 22 Synthesis of 1-(2-((8-bromooctyl)oxy)-4-methoxy-3-(piperidin-1-ylmethyl)phenyl)ethan-1-one (5l)

[0096] 1 mmol (263 mg) of compound 3b and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. Stir at room temperature for 20 min, then add 3 mmol of dibromooctane and stir at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 337 mg of yellow oil 5l was obtained with a yield of 59.4%. Example 23 Synthesis of 1-(3-bromopropoxy)-4-methoxy-5-(4-methylpiperazin-1-yl)methyl)phenyl)ethan-1-one (5m)

[0097] 1 mmol (276 mg) of compound 3c and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. Stir at room temperature for 20 min, then add 3 mmol of dibromopropane and stir at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 199 mg of yellow oil 5m was obtained with a yield of 50.2%. Example 24 Synthesis of 1-(4-bromobutoxy)-4-methoxy-5-(4-methylpiperazin-1-yl)methyl)phenyl)ethan-1-one (5n)

[0098] 1 mmol (276 mg) of compound 3c and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromobutane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, filtration was carried out under suction. 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 212 mg of yellow oil 5n was obtained, with a yield of 51.6%. Example 25 Synthesis of 1-(5-bromopentyloxy)-4-methoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl)ethan-1-one (5o)

[0099] 1 mmol (276 mg) of compound 3c and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromopentane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, filtration was carried out under suction. 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 218 mg of yellow oil 5o was obtained, with a yield of 51.3%. Example 26 Synthesis of 1-(6-bromohexyloxy)-4-methoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl)ethan-1-one (5p)

[0100] 1 mmol (276 mg) of compound 3c and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromohexane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, filtration was carried out under suction. 100 mL of water was added, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 235 mg of yellow oil 5p was obtained, with a yield of 53.5%. Example 27 Synthesis of 1-(7-bromoheptyloxy)-4-methoxy-5-(4-methylpiperazin-1-ylmethyl)phenyl)ethan-1-one (5q)

[0101] 1 mmol (276 mg) of compound 3c and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromoheptane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 245 mg of yellow oil 5q was obtained with a yield of 54.4%. Example 28 Synthesis of 1-(8-bromooctyloxy)-4-methoxy-5-((4-methylpiperazin-1-yl)methyl)phenyl)ethan-1-one (5r)

[0102] 1 mmol (276 mg) of compound 3c and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromooctane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 256 mg of yellow oil 5r was obtained with a yield of 54.8%. Example 29 Synthesis of 1-(2-(3-bromopropoxy)-5-((4-ethylpiperazin-1-yl)methyl)-4-methoxyphenyl)ethan-1-one (5s)

[0103] 1 mmol (292 mg) of compound 3d and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromopropane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 216 mg of yellow oil 5s was obtained with a yield of 50.6%. Example 30 Synthesis of 1-(2-(4-bromobutoxy)-5-((4-ethylpiperazin-1-yl)methyl)-4-methoxyphenyl)ethan-1-one (5t)

[0104] 1 mmol (292 mg) of compound 3d and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask, and 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromobutane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 229 mg of yellow oil 5t was obtained with a yield of 55.7%. Example 31 Synthesis of 1-(2-(5-bromopentoxy)-5-(4-ethylpiperazin-1-yl)methyl)-4-methoxyphenyl)ethan-1-one (5u)

[0105] 1 mmol (292 mg) of compound 3d and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask, and 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromopentane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 239 mg of yellow oil 5u was obtained with a yield of 56.1%. Example 32 Synthesis of 1-(2-(6-bromohexyloxy)-5-(4-ethylpiperazin-1-yl)methyl)-4-methoxyphenyl)ethan-1-one (5v)

[0106] 1 mmol (292 mg) of compound 3d and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask, and 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromohexane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC until completion. The mixture was filtered by suction, 100 mL of water was added, and the mixture was extracted 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5], 252 mg of yellow oil 5v was obtained with a yield of 57.3%. Example 33 Synthesis of 1-(2-(7-bromoheptyloxy)-5-(4-ethylpiperazin-1-yl)methyl)-4-methoxyphenyl)ethan-1-one (5w)

[0107] 1 mmol (292 mg) of compound 3d and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromoheptane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, filtration was carried out. 100 mL of water was added, and extraction was performed 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5] gave 266 mg of a yellow oil 5w with a yield of 58.6%. Example 34 Synthesis of 1-(2-(8-bromooctyloxy)-5-(4-ethylpiperazin-1-yl)methyl)-4-methoxyphenyl)ethan-1-one (5x)

[0108] 1 mmol (292 mg) of compound 3d and 3 mmol (120 mg) of sodium hydroxide were added to a 50 ml round-bottom flask. 6 mL of DMF was added to the 50 mL round-bottom flask. The mixture was stirred at room temperature for 20 min, then 3 mmol of dibromooctane was added, and the mixture was stirred at 35 °C. The reaction was monitored by TLC. After completion of the reaction, filtration was carried out. 100 mL of water was added, and extraction was performed 3 times with 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(ethyl acetate):(petroleum ether) = 1:5] gave 278 mg of a yellow oil 5x with a yield of 59.5%.

[0109] Synthesis of the target compound

[0110] Example 35 Synthesis of 3-(6-acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)propyl-2-rhein carboxylate (I1):

[0111] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF. The mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 4a were added. The reaction process was monitored by TLC. After completion of the reaction, filtration was carried out. The filtrate was added with 100 mL of water, and extraction was performed 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):(dichloromethane) = 1:40] gave 242 mg of a yellow oil with a yield of 41.2%; 1HNMR (600 MHz, CDCl3) δ 8.36 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.83 (d, J = 7.4 Hz, 1H, Ar-H), 7.70 (t, J = 8.4, 3.3 Hz, 1H, Ar-H), 7.62 (d, J = 8.6 Hz, 1H, Ar-H), 7.31 (d, J = 8.3 Hz, 1H, Ar-H), 6.43 (d, 1H, J = 7.5 Hz, Ar-H), 4.62 (t, J = 6.5 Hz, 2H, -COOCH2-), 4.26 (t, J = 6.2 Hz, 2H, -OCH2-), 3.88 (s, 3H, -OCH3), 3.66 (t, J = 4.8 Hz, 4H, -OCH2-), 3.45 (s, 2H, -NCH2-), 2.59 (s, 3H, -COCH3), 2.43 (t, J = 4.6 Hz, 4H, -NCH2-), 2.41 - 2.38 (m, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 197.45, 192.70, 180.85, 164.36, 162.78, 162.74, 162.37, 160.36, 138.12, 137.68, 134.22, 133.87, 133.43, 125.20, 124.86, 120.29, 120.08, 118.17, 115.79, 68.68, 66.03, 53.66, 44.92, 32.00, 29.09. HRMS calcd for C 32 H 31 NO 10 , [M + H] + : 590.2026, found. 590.2014。

[0112] Example 36 Synthesis of 4-(6-acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)butyl-2-rhein carboxylate (I2):

[0113] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 4b were added. The reaction progress was monitored by TLC. After the reaction was completed, it was filtered by suction. The filtrate was added to 100 mL of water and extracted 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):(dichloromethane) = 1:40] gave 242 mg of a yellow oil 4b, with a yield of 41.2%; 1HNMR (600 MHz, CDCl3) δ 8.39 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.85 (d, J = 7.5 Hz, 1H, Ar-H), 7.71 (t, J = 8.0 Hz, 1H, Ar-H), 7.62 (d, J = 8.6 Hz, 1H, Ar-H), 7.32 (d, J = 8.3 Hz, 1H, Ar-H), 6.69 (d, J = 6.5 Hz, 1H, Ar-H), 4.41 (t, J = 6.6 Hz, 2H, -COOCH2-), 3.94 (t, J = 6.6 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.61 (t, J = 4.8 Hz, 4H, -OCH2), 3.59 (s, 2H, -NCH2-), 2.59 (s, 3H, -COCH3), 2.49 (t, J = 4.6 Hz, 4H, -NCH2-), 1.92 - 1.87 (m, 4H, -CH2-). 13C NMR (151 MHz, CDCl3) δ 199.26, 192.78, 180.84, 164.35, 162.78, 162.50, 162.38, 159.54, 138.08, 137.67, 133.92, 133.50, 130.90, 126.69, 125.21, 124.81, 120.32, 120.14, 118.22, 115.83, 106.25, 76.70, 67.10, 65.86, 55.83, 53.26, 50.00, 29.96, 29.86, 28.63, 22.69. HRMS calcd for C 33 H 33 NO 10 , [M+H] + : 604.2183, found. 604.2165。

[0114] Example 37 Synthesis of 5-(6-acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)pentyl 2-rhein carboxylate (I3):

[0115] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 4c were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out, the filtrate was added with 100 mL of water, extracted with 50 mL of dichloromethane three times, the organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane)=1:40] gave a yellow oil, 258 mg, yield 41.9%; 1 1H NMR (600 MHz, CDCl3) δ: 8.34 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.81 (d, J = 7.3 Hz, 1H, Ar-H), 7.69 (t, J = 7.7 Hz, 1H, Ar-H), 7.62 (d, J = 8.6 Hz, 1H, Ar-H), 7.29 (d, J = 8.0 Hz, 1H, Ar-H), 6.69 (d, J = 6.5 Hz, 1H, Ar-H) 4.41 (t, J = 13.2 Hz, 2H, -COOCH2-), 4.09 (t, J = 6.4 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.66 (t, J = 4.5 Hz, 4H, -OCH2-), 3.44 (s, 2H, -NCH2-), 2.55 (s, 3H, -COCH3), 2.46 (t, 4H, -NCH2-), 1.97 - 1.90 (t, J = 7.3 Hz, 4H, -CH2-), 1.71 - 1.68 (m, 2H, -CH2-). 13 13C NMR (151 MHz, CDCl3) δ 197.43, 192.70, 180.85, 164.32, 162.78, 162.60, 162.34, 159.93, 137.95, 137.71, 133.88, 133.67, 133.44, 133.42, 125.19, 125.17, 124.88, 120.32, 120.06, 120.04, 118.22, 115.78, 68.37, 66.88, 65.72, 55.84, 55.68, 32.00, 28.91, 28.32, 22.83. HRMS calcd for C 34 H 35 NO 10 , [M + H] + : 618.2339, found 618.2322.

[0116] Example 38 Synthesis of 6-(6-acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)hexyl 2-rhein carboxylate (I4):

[0117] Add 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate to 10 mL of DMF, stir at 70 °C, after 1 h add 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 4d. Monitor the reaction progress by TLC. After the reaction is complete, filter by suction, add 100 mL of water to the filtrate, extract with 50 mL of dichloromethane three times, wash the organic layer with saturated sodium chloride solution, add an appropriate amount of anhydrous sodium sulfate for drying, filter, and concentrate under reduced pressure. Separate by column chromatography [V(methanol):V(dichloromethane) = 1:40] to obtain a yellow oil, 266 mg, yield 42.2%; 1 1H NMR (600 MHz, CDCl3) δ: 8.35 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.82 (d, J = 7.4 Hz, 1H, Ar-H), 7.70 (t, J = 8.0 Hz, 1H, Ar-H), 7.62 (d, J = 8.6 Hz, 1H, Ar-H), 7.30 (d, J = 8.3 Hz, 1H, Ar-H), 6.69 (d, J = 6.5 Hz, 1H, Ar-H), 4.39 (t, J = 6.5 Hz, 2H, -COOCH2-), 4.06 (t, J = 6.4 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.66 (t, J = 4.8 Hz, 4H, -OCH2-), 3.43 (s, 2H, -NCH2-), 2.56 (s, 3H, -COCH3), 2.43 (t, J = 4.9 Hz, 4H, -NCH2-), 1.93 - 1.80 (m, 4H, -CH2-), 1.64 - 1.52 (m, 4H, -CH2-). 13 13C NMR (151 MHz, CDCl3) δ 199.27, 192.76, 180.82, 164.33, 162.76, 162.48, 162.44, 162.36, 138.15, 137.66, 133.87, 133.48, 126.71, 125.20, 124.79, 120.29, 120.14, 118.16, 115.81, 106.23, 76.91, 65.98, 62.67, 55.83, 49.95, 29.83, 26.81, 26.01, 25.41. HRMS calcd for C 35 H 37 NO 10 , [M + H] +: 632.2496, found 632.2475.

[0118] Example 39 Synthesis of 7-(6-acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)heptyl-2-rhein carboxylate (I5):

[0119] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 4e were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out under suction. The filtrate was added to 100 mL of water, and extracted 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:40] gave a yellow oil, 278 mg, with a yield of 43.1%; 1 HNMR (600 MHz, CDCl3) δ: 8.35 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.82 (d, J = 7.4 Hz, 1H, Ar-H), 7.69 (t, J = 8.0 Hz, 1H, Ar-H), 7.62 (d, J = 8.6 Hz, 1H, Ar-H), 7.30 (d, J = 8.3 Hz, 1H, Ar-H), 6.69 (d, J = 6.5 Hz, 1H, Ar-H), 4.39 (t, J = 6.5 Hz, 2H, -COOCH2-), 4.06 (t, J = 6.4 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.66 (t, J = 4.8 Hz, 4H, -OCH2-), 3.43 (s, 2H, -NCH2-), 2.56 (s, 3H, -COCH3), 2.43 (t, J = 4.9 Hz, 4H, -NCH2-), 1.93 - 1.80 (m, 4H, -CH2-), 1.54 - 1.48 (m, 2H, -CH2-). HRMS calcd for C 36 H 38 NO 10 , [M + H] + : 646.2652, found 646.2645.

[0120] Example 40 Synthesis of 8-(6-acetyl-3-methoxy-2-(morpholinomethyl)phenoxy)octyl-2-rhein carboxylate (I6):

[0121] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 4f were added. The reaction progress was monitored by TLC. After completion of the reaction, filtration was carried out under suction, the filtrate was added with 100 mL of water, extracted 3 times with 50 mL of dichloromethane, the organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:40] gave a yellow oil, 288 mg, yield 43.7%; 1 1H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.82 (d, J = 7.3 Hz, 1H, Ar-H), 7.69 (t, J = 9.5 Hz, 1H, Ar-H), 7.59 (d, J = 8.9 Hz, 1H, Ar-H), 7.29 (d, J = 8.2 Hz, 1H, Ar-H), 6.67 (d, J = 8.5 Hz, 1H, Ar-H), 4.36 (t, J = 6.5 Hz, 2H, -COOCH2-), 3.86 (t, J = 5.6 Hz, 2H, -OCH2-), 3.82 (s, 3H, -OCH3), 3.62 (t, J = 4.8 Hz, 4H, -OCH2-), 3.56 (s, 2H, -NCH2-), 2.57 (s, 3H, -COCH3), 2.48 (t, J = 4.8 Hz, 4H, -NCH2), 1.81 - 1.76 (m, 4H, -CH2-), 1.48 - 1.43 (m, 4H, -CH2-), 1.41 - 1.36 (m, 4H, -CH2). 13 13C NMR (151 MHz, CDCl3) δ 192.73, 180.84, 164.36, 162.73, 162.49, 162.33, 159.70, 138.18, 137.67, 133.82, 133.43, 130.85, 126.69, 125.21, 124.80, 120.30, 120.15, 106.20, 67.11, 66.13, 55.83, 53.23, 49.94, 30.27, 29.87, 29.64, 29.42, 29.16, 28.53, 25.89. HRMS calcd for C 37 H 41 NO 10 , [M + H] + : 660.2809, found 660.2796.

[0122] Example 41 Synthesis of 3-(2-acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)propyl 2-rhein carboxylate (Ⅱ1)

[0123] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5a were added. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and extracted with 50 mL of dichloromethane three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane)=1:40] gave a yellow oil, 250 mg, with a yield of 42.6%; 1 HNMR(600MHz,CDCl3)δ8.36(s,1H,Ar-H),7.90(s,1H,Ar-H),7.83(d,J=7.4Hz,1H,Ar-H),7.78(s,1H,Ar-H),7.70(t,J=8.6Hz,1H,Ar-H),7.31(d,J=8.3Hz,1H,Ar-H),6.43(s,1H,Ar-H),4.62(t,J=6.5Hz,2H,-COOCH2-),4.26(t,J=6.2Hz,2H,-OCH2-),3.88(s,3H,-OCH3),3.66(t,J=4.8Hz,4H,-NCH2-),3.45(s,2H,-NCH2-),2.59(s,3H,-COCH3),2.43(t,J=4.9Hz,4H,-NCH2-),2.41-2.38(m,2H,-CH2-). 13 C NMR(151MHz,CDCl3)δ197.24,192.69,180.80,164.22,162.81,162.58,162.34,159.44,137.76,137.64,133.92,133.66,133.39,125.24,124.93,120.34,120.20,120.02,118.44,118.31,115.77,95.35,66.96,65.24,62.77,55.84,55.76,55.73,31.97,28.77.HRMS calcd forC 32 H 31 NO 10 ,[M+H] + :590.2026,found.590.2008。

[0124] Example 42 Synthesis of 4-(2-acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)butyl-2-rhein carboxylate (Ⅱ2)

[0125] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5b were added. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and extracted three times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:40] gave a yellow oil, 257 mg, with a yield of 42.7%; 1 HNMR(600MHz,CDCl3)δ8.38(s,1H,Ar-H),7.91(s,1H,Ar-H),7.84(d,J=7.5Hz,1H,Ar-H),7.77(s,1H,Ar-H),7.71(t,J=8.0Hz,1H,Ar-H),7.32(d,J=8.5Hz,1H,Ar-H),6.39(s,1H,Ar-H),4.47(t,J=5.3Hz,2H,-COOCH2-),4.15(t,J=5.1Hz,2H,-OCH2-),3.86(s,3H,-OCH3),3.67(t,J=4.6Hz,4H,-NCH2-),3.43(s,2H,-NCH2-),2.59(s,3H,-COCH3),2.43(t,J=4.7Hz,4H,-NCH2-),2.06(m,4H,-CH2). 13 C NMR(151MHz,CDCl3)δ197.40,192.75,180.86,164.32,162.81,162.57,162.36,159.73,137.83,137.75,133.92,133.66,133.44,125.21,124.91,120.35,120.06,118.27,115.80,95.20,68.00,66.93,65.44,55.83,55.66,53.32,32.00,26.05,25.58.HRMS calcd for C 33 H 33 NO 10 ,[M+H] + :604.2183,found.604.2164。

[0126] Example 43 Synthesis of 5-(2-acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)pentyl 2-rhein carboxylate (Ⅱ3)

[0127] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5c were added. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and extracted with 50 mL of dichloromethane three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane)=1:40] gave 266 mg of a yellow oil, with a yield of 43.2%; 1 HNMR(600MHz,CDCl3)δ8.34(s,1H,Ar-H),7.87(s,1H,Ar-H),7.81(d,J=7.3Hz,1H,Ar-H),7.74(s,1H,Ar-H),7.69(t,J=7.7Hz,1H,Ar-H),7.29(d,J=8.0Hz,1H,Ar-H),6.38(s,1H,Ar-H),4.41(t,J=6.7Hz,2H,-COOCH2-),4.09(t,J=6.4Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.66(t,J=4.5Hz,4H,-NCH2-),3.44(s,2H,-NCH2-),2.55(s,3H,-COCH3),2.46(t,J=4.7Hz,4H,-NCH2-),1.93(m,4H,-CH2-),1.69(m,2H,-CH2-). 13 C NMR(151MHz,CDCl3)δ197.43,192.70,180.85,164.32,162.78,162.60,162.34,159.93,137.95,137.71,133.88,133.67,133.44,133.42,125.19,125.17,124.88,120.32,120.06,120.04,118.22,95.21,68.37,66.88,65.72,55.84,55.68,53.28,32.00,28.91,28.32,22.83.HRMS calcd for C 34 H 35 NO 10 ,[M+H] +: 618.2339, found 618.2322.

[0128] Example 44 Synthesis of 6-(2-Acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)hexyl 2-rhein carboxylate (II4)

[0129] Add 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate to 10 mL of DMF, stir at 70 °C. After 1 h, add 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of Compound 5d. Monitor the reaction progress by TLC. After the reaction is complete, filter by suction. Add 100 mL of water to the filtrate and extract with 50 mL of dichloromethane three times. Wash the organic layer with saturated sodium chloride solution, add an appropriate amount of anhydrous sodium sulfate for drying, filter, and concentrate under reduced pressure. Separate by column chromatography [V(methanol):V(dichloromethane) = 1:40] to obtain a yellow oil, 274 mg, with a yield of 43.5%; 1 1H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.82 (d, J = 7.4 Hz, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.70 (t, J = 8.0 Hz, 1H, Ar-H), 7.30 (d, J = 8.3 Hz, 1H, Ar-H), 6.37 (s, 1H, Ar-H), 4.39 (t, J = 6.5 Hz, 2H, -COOCH2-), 4.06 (t, J = 6.4 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.66 (t, J = 4.8, 4.4 Hz, 4H, -NCH2-), 3.44 (s, 2H, -NCH2-), 2.56 (s, 3H, -COCH3), 2.43 (t, J = 4.9 Hz, 4H, -NCH2-), 1.93 - 1.81 (m, 4H, -CH2-), 1.63 - 1.51 (m, 4H, -CH2-). 13 13C NMR (151 MHz, CDCl3) δ 197.56, 192.67, 180.82, 164.32, 162.76, 162.58, 162.33, 159.84, 137.91, 137.71, 133.85, 133.59, 133.39, 125.18, 124.88, 120.32, 120.04, 118.20, 115.76, 95.11, 68.33, 65.73, 55.66, 55.60, 55.26, 32.00, 29.63, 28.90, 28.31, 22.82. HRMS calcd for C 35 H37 NO 10 , [M+H] + : 632.2496, found 632.2475.

[0130] Example 45 Synthesis of 7-(2-acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)heptyl 2-rhein carboxylate (II5)

[0131] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5e were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out under suction. The filtrate was added to 100 mL of water, and extracted 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:40] gave a yellow oil, 257 mg, with a yield of 44.1%. 1 1H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.82 (d, J = 7.4 Hz, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.70 (t, J = 8.0 Hz, 1H, Ar-H), 7.30 (d, J = 8.3 Hz, 1H, Ar-H), 6.37 (s, 1H, Ar-H), 4.39 (t, J = 6.5 Hz, 2H, -COOCH2-), 4.06 (t, J = 6.4 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.66 (t, J = 4.8, 4.4 Hz, 4H, -NCH2-), 3.44 (s, 2H, -NCH2-), 2.56 (s, 3H, -COCH3), 2.43 (t, J = 4.9 Hz, 4H, -NCH2-), 1.93 - 1.81 (m, 4H, -CH2-), 1.63 - 1.51 (m, 4H, -CH2-). 1313C NMR (151 MHz, CDCl3) δ 197.56, 192.67, 180.82, 164.32, 162.76, 162.58, 162.33, 159.84, 137.91, 137.71, 133.85, 133.59, 133.39, 125.18, 124.88, 120.32, 120.04, 118.20, 115.76, 95.11, 68.33, 65.73, 55.66, 55.60, 55.26, 32.00, 29.63, 28.90, 28.31, 22.82. HRMS calcd for C 35 H 37 NO 10 , [M+H] + : 632.2496, found 632.2475。

[0132] Example 46 Synthesis of 8-(2-acetyl-5-methoxy-4-(morpholinomethyl)phenoxy)octyl 2-rhein carboxylate (II6)

[0133] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of Compound 5f were added. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and extracted three times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane)=1:40] gave a yellow oil, 257 mg, with a yield of 43.2%.

[0134] 11H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.81 (d, J = 7.4 Hz, 1H, Ar-H), 7.74 (s, 1H, Ar-H), 7.69 (t, J = 7.9 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 6.36 (s, 1H, Ar-H), 4.37 (t, J = 6.7 Hz, 2H, -COOCH2-), 4.04 (t, J = 6.5 Hz, 2H, -OCH2-), 3.84 (s, 3H, -OCH3), 3.66 (t, J = 4.7 Hz, 4H, -NCH2-), 3.43 (s, 2H, -NCH2), 2.56 (s, 3H, -COCH3), 2.47 (t, J = 4.9 Hz, 4H, -NCH2-), 1.83 (m, 4H, -CH2-), 1.49 (m, 4H, -CH2-), 1.44 - 1.37 (m, 4H, -CH2-). 13 13C NMR (151 MHz, CDCl3) δ 197.63, 192.68, 180.85, 164.36, 162.74, 162.61, 162.32, 160.12, 138.13, 137.67, 133.82, 133.65, 133.63, 133.40, 130.85, 128.79, 125.20, 124.84, 120.27, 120.10, 119.92, 95.10, 66.92, 55.88, 55.65, 53.30, 32.10, 32.07, 30.54, 29.64, 29.19, 29.14, 29.05. HRMS calcd for C 37 H 41 NO 10 , [M + H] + : 660.2809, found 660.2796。

[0135] Example 47 Synthesis of 3-(2-Acetyl-5-methoxy-4-(piperidin-1-ylmethyl)phenoxy)propyl 2-rhein carboxylate (II7)

[0136] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 5 g were added. The reaction process was monitored by TLC. After the reaction was completed, filtration was carried out by suction, 100 mL of water was added to the filtrate, and extraction was performed 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:20] gave a yellow oil, 257 mg, with a yield of 41.2%.

[0137] 1 H NMR (600 MHz, CDCl3) δ 8.33 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.81 (d, J = 7.5 Hz, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.69 (t, J = 8.1 Hz, 1H, Ar-H), 7.29 (d, J = 8.3 Hz, 1H, Ar-H), 6.42 (s, 1H, Ar-H), 4.61 (t, J = 6.1 Hz, 2H, -COOCH2-), 4.25 (t, J = 6.1 Hz, 2H, -OCH2-), 3.86 (s, 3H, -OCH3), 3.46 (s, 2H, -NCH2-), 2.58 (s, 3H, -COCH3), 2.47 (t, J = 4.9 Hz, 4H, -NCH2-), 2.24 (m, 2H, -CH2-), 1.59 - 1.47 (m, 4H, -CH2-), 1.41 - 1.31 (m, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 197.28, 192.63, 180.76, 164.21, 162.80, 162.64, 162.35, 159.40, 137.72, 137.64, 133.90, 133.37, 125.24, 124.90, 120.30, 120.13, 119.99, 118.28, 115.76, 95.38, 65.24, 62.80, 55.99, 55.72, 54.05, 31.88, 28.77, 25.66, 24.12. HRMS calcd for C 33 H 33 NO9, [M + H] + : 588.2234, found. 588.2217。

[0138] Example 48 Synthesis of 4-(2-acetyl-5-methoxy-4-(piperidin-1-ylmethyl)phenoxy)butyl 2-rhein carboxylate (II8)

[0139] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of Compound 5 were added, and the reaction was carried out for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and extracted with 50 mL of dichloromethane three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:20] gave a yellow oil, 257 mg, with a yield of 44.5%.

[0140] 1 1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.88 (d, J = 7.5 Hz, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.73 (t, J = 7.6 Hz, 1H, Ar-H), 7.35 (d, J = 9.6 Hz, 1H, Ar-H), 6.42 (s, 1H, Ar-H), 4.49 (t, J = 9.4 Hz, 2H, -COOCH2-), 4.21 (t, J = 6.1 Hz, 2H, -OCH2-), 3.93 (s, 3H, -OCH3), 3.64 (s, 2H, -NCH2-), 2.61 (s, 3H, -COCH3), 2.08 (t, J = 5.2 Hz, 4H, -NCH2-), 1.70 (m, 4H, -CH2-) 1.42 (m, 4H, -CH2-), 1.29 - 1.24 (m, 2H, -CH2-). 13 13C NMR (151 MHz, CDCl3) δ 197.31, 192.66, 180.76, 164.28, 162.79, 162.64, 162.36, 159.78, 137.82, 137.70, 134.03, 133.88, 133.41, 130.81, 128.79, 125.18, 124.87, 120.29, 120.08, 119.99, 118.22, 95.26, 68.03, 65.46, 55.80, 55.66, 53.86, 31.90, 29.63, 26.06, 25.58, 23.99. HRMS calcd for C 34 H 35NO9, [M+H]+: 602.2390, found 602.2373.

[0141] Example 49 Synthesis of 5-(2-acetyl-5-methoxy-4-(piperidin-1-ylmethyl)phenoxy)pentyl 2-rhein carboxylate (Ⅱ9)

[0142] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5i were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was performed by suction. The filtrate was added to 100 mL of water, and extracted 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:20] gave a yellow oil, 257 mg, with a yield of 43.8%.

[0143] 1 H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.87 (d, J = 7.5 Hz, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.73 (t, J = 8.0 Hz, 1H, Ar-H), 7.34 (d, J = 8.4 Hz, 1H, Ar-H), 6.41 (s, 1H, Ar-H), 4.44 (t, J = 6.4 Hz, 2H, -COOCH2-), 4.12 (t, J = 6.3 Hz, 2H, -OCH2-), 3.89 (s, 3H, -OCH3), 3.60 ((s, 2H, -NCH2-), 2.66 (s, 3H, -COCH3), 2.08 (t, J = 5.2 Hz, 4H, -NCH2-), 1.97 - 1.86 (m, 4H, -CH2-), 1.69 (m, 4H, -CH2-), 1.41 (m, 2H, -CH2-), 1.28 (m, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 162.86, 162.59, 162.39, 159.54, 137.77, 133.67, 133.63, 132.65, 125.28, 124.95, 120.37, 120.24, 120.07, 118.27, 95.92, 95.46, 69.78, 65.25, 62.75, 55.84, 55.80, 55.75, 55.72, 32.11, 31.98, 31.94, 31.82, 28.78. HRMS calcd for C35 H 37 NO9, [M+H]+: 616.2547, found 616.2530.

[0144] Example 50 Synthesis of 6-(2-acetyl-5-methoxy-4-(piperidin-1-ylmethyl)phenoxy)hexyl 2-rhein carboxylate (II 10 )

[0145] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5j were added. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and extracted with 50 mL of dichloromethane three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:20] gave a yellow oil, 257 mg, with a yield of 44.6%.

[0146] 1 H NMR (600 MHz, CDCl3) δ 8.39 (s, 1H, Ar-H), 7.92 (s, 1H, Ar-H), 7.83 (d, J = 7.5 Hz, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.71 (t, J = 8.0 Hz, 1H, Ar-H), 7.31 (d, J = 8.5 Hz, 1H, Ar-H), 6.37 (s, 1H, Ar-H), 4.39 (t, J = 6.6 Hz, 2H, -COOCH2-), 4.06 (t, J = 9.4, 6.3 Hz, 2H, -OCH2-), 3.86 (s, 3H, -OCH3), 3.52 (s, 2H, -NCH2-), 2.57 (s, 3H, -COCH3), 2.50 (t, J = 5.2 Hz, 4H, -NCH2-), 1.97 - 1.84 (m, 4H, -CH2-), 1.60 (m, 4H, -CH2-), 1.55 (m, 2H, -CH2-), 1.39 (m, 4H, -CH2-). 1313C NMR (151 MHz, CDCl3) δ 192.73, 180.90, 164.37, 162.70, 162.65, 162.39, 160.15, 138.03, 137.69, 137.64, 134.07, 133.46, 125.23, 125.19, 124.87, 124.83, 120.29, 120.25, 120.09, 120.05, 95.24, 68.52, 55.80, 53.78, 31.95, 29.63, 29.11, 29.07, 28.48, 25.27, 23.85. HRMS calcd for C 36 H 39 NO9, [M + H]+: 630.2703, found 630.2684。

[0147] Example 51 Synthesis of 7-(2-acetyl-5-methoxy-4-(piperidin-1-ylmethyl)phenoxy)heptyl 2-rhein carboxylate (II 11 )

[0148] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5k were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out under suction. The filtrate was added to 100 mL of water and extracted 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane) = 1:20] gave 257 mg of a yellow oil, with a yield of 45.8%.

[0149] 11H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.81 (d, J = 7.4 Hz, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.70 (t, J = 8.0 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 6.36 (s, 1H, Ar-H), 4.37 (t, J = 6.8 Hz, 2H, -COOCH2-), 4.05 (t, J = 6.5 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.53 (s, 2H, -NCH2-), 2.56 (s, 3H, -COCH3), 2.48 (t, J = 5.2 Hz, 4H, -NCH2-), 1.90 - 1.80 (m, 4H, -CH2-), 1.64 (m, 4H, -CH2-), 1.57 (m, 2H, -CH2-), 1.51 - 1.46 (m, 4H, -CH2-), 1.40 - 1.37 (m, 2H, -CH2-). HRMS calcd for C 36 H 39 NO9, [M + H]+: 644.2860, found. 644.2855。

[0150] Example 52 Synthesis of 8-(2-acetyl-5-methoxy-4-(piperidin-1-ylmethyl)phenoxy)octyl 2-rhein carboxylate (II 12 )

[0151] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5l were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out by suction. The filtrate was added to 100 mL of water, and extracted 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):(dichloromethane) = 1:20] gave a yellow oil, 257 mg, with a yield of 46.2%.

[0152] 11H NMR (600 MHz, CDCl3) δ 8.38 (s, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.83 (d, J = 7.5 Hz, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.70 (t, J = 9.8 Hz, 1H, Ar-H), 7.31 (d, J = 8.3 Hz, 1H, Ar-H), 6.37 (s, 1H, Ar-H), 4.37 (t, J = 6.8 Hz, 2H, -COOCH2-), 4.05 (t, J = 6.5 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.55 (s, 2H, -NCH2-), 2.56 (s, 3H, -COCH3), 2.48 (t, J = 6.3 Hz, 4H, -NCH2-), 1.88 - 1.79 (m, 4H, -CH2-), 1.64 - 1.59 (m, 4H, -CH2), 1.54 (m, 2H, -CH2-), 1.49 - 1.43 (m, 4H, -CH2-), 1.43 - 1.40 (m, 4H, -CH2-). 13 13C NMR (151 MHz, CDCl3) δ 192.74, 164.38, 162.80, 162.72, 162.38, 137.66, 134.16, 130.82, 128.82, 128.79, 125.25, 125.22, 124.86, 120.30, 120.27, 120.12, 118.18, 95.24, 68.75, 66.11, 66.08, 55.72, 32.00, 30.59, 30.55, 29.66, 29.29, 29.21, 29.12, 28.54, 23.84. HRMS calcd for C 38 H 42 NO9, [M + H]+: 658.3016, found 658.3010。

[0153] Example 53 Synthesis of 3-(2-acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)propyl 2-rhein carboxylate (II 13 )

[0154] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, 1 mmol of compound 5m were added. The reaction process was monitored by TLC. After the reaction was completed, filtration was carried out by suction, the filtrate was added with 100 mL of water, extracted 3 times with 50 mL of dichloromethane, the organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separation by thin layer chromatography [V(methanol):V(dichloromethane)=1:10] gave a yellow oil, 257 mg, yield 42.2%. 1 1H NMR (600 MHz, CDCl3) δ 8.37 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.84 (d, J = 7.5 Hz, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 7.71 (t, J = 8.0 Hz, 1H, Ar-H), 7.31 (d, J = 8.4 Hz, 1H, Ar-H), 6.41 (s, 1H, Ar-H), 4.61 (t, J = 6.3 Hz, 2H, -COOCH2-), 4.25 (t, J = 6.0 Hz, 2H, -OCH2-), 3.86 (s, 3H, -OCH3), 3.49 (s, 2H, -NCH2-), 2.59 (s, 3H, -COCH3), 2.56 - 2.38 (m, 8H, -NCH2-), 2.41 - 2.35 (m, 2H, -CH2-), 2.29 (s, 3H, -CH3). 13 13C NMR (151 MHz, CDCl3) δ 197.26, 192.72, 180.83, 164.23, 162.83, 162.54, 162.38, 159.40, 137.75, 137.68, 133.96, 133.59, 133.43, 125.26, 124.92, 120.34, 120.04, 118.54, 118.34, 115.80, 95.38, 65.26, 62.77, 55.72, 55.10, 54.86, 52.29, 45.63, 31.91, 29.63. HRMS calcd for C 33 H 34 N2O9, [M + H]+: 603.2343, found 603.2337。

[0155] Example 54 Synthesis of 4-(2-acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)butyl 2-rhein carboxylate (Ⅱ 14 )

[0156] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 5n were added. The reaction progress was monitored by TLC. After completion of the reaction, filtration was carried out, the filtrate was added to 100 mL of water, extracted with 50 mL of dichloromethane three times, the organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V(methanol):V(dichloromethane)=1:10] gave a yellow oil, 257 mg, yield 42.7%. 1 H NMR (600 MHz, CDCl3) δ 8.33 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.81 (d, J = 5.4 Hz, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.69 (t, J = 7.9 Hz, 1H, Ar-H), 7.29 (d, J = 8.3 Hz, 1H, Ar-H), 6.36 (s, 1H, Ar-H), 4.46 (t, J = 5.2 Hz, 2H, -COOCH2-), 4.14 (t, J = 5.0 Hz, 2H, -OCH2-), 3.83 (s, 3H, -OCH3), 3.43 (s, 2H, -NCH2-), 2.57 (s, 3H, -COCH3), 2.54 - 2.28 (m, 8H, -NCH2-), 2.24 (s, 3H, -CH3), 2.07 - 2.00 (m, 4H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 197.48, 192.64, 180.78, 164.29, 162.76, 162.56, 162.32, 159.69, 137.73, 133.84, 133.64, 133.36, 125.19, 124.89, 120.32, 120.00, 118.21, 115.74, 95.16, 67.99, 65.48, 55.66, 55.60, 55.24, 54.91, 45.81, 32.01, 25.57. HRMS calcd for C 34 H 36 N2O9, [M + H]+: 617.2499, found 617.2480。

[0157] Example 55 Synthesis of 5-(2-acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)pentyl 2-rhein carboxylate (Ⅱ 15 )

[0158] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, and after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5o were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was performed by suction, 100 mL of water was added to the filtrate, and extraction was carried out 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V(methanol):V(dichloromethane)=1:10] gave a yellow oil, 257 mg, with a yield of 43.6%. 1 H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.82 (d, J = 7.4 Hz, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.69 (t, J = 7.9 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 6.36 (s, 1H, Ar-H), 4.41 (t, J = 6.4 Hz, 2H, -COOCH2-), 4.08 (t, J = 6.2 Hz, 2H, -OCH2-), 3.84 (s, 3H, -OCH3), 3.45 (s, 2H, -NCH2-), 2.54 (s, 3H, -COCH3), 2.52 - 2.29 (m, 8H, -NCH2-), 2.24 (s, 3H, -CH3), 1.99 (m, 2H, -CH2-), 1.92 (m, 2H, -CH2-), 1.71 - 1.66 (m, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 197.56, 192.67, 180.82, 164.32, 162.76, 162.58, 162.33, 159.84, 137.91, 137.71, 133.85, 133.59, 133.39, 125.18, 124.88, 120.32, 120.04, 118.20, 115.76, 95.11, 68.33, 65.73, 55.66, 55.60, 55.26, 52.55, 45.81, 32.00, 29.63, 28.90, 22.82. HRMS calcd for C 35 H 38 N2O9, [M + H]+: 631.2656, found 631.2631。

[0159] Example 56 Synthesis of 6-(2-acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)hexyl 2-rhein carboxylate (Ⅱ16 )

[0160] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 5p were added. The reaction process was monitored by TLC. After the reaction was completed, filtration was carried out by suction, the filtrate was added with 100 mL of water, and extracted 3 times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V(methanol):V(dichloromethane)=1:10] gave a yellow oil, 257 mg, with a yield of 43.9%. 1 1H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.81 (d, J = 7.5 Hz, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.69 (t, J = 8.0 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 6.35 (s, 1H, Ar-H), 4.38 (t, J = 6.6 Hz, 2H, -COOCH2-), 4.05 (t, J = 6.3 Hz, 2H, -OCH2-), 3.83 (s, 3H, -OCH3), 3.43 (s, 2H, -NCH2-), 2.55 (s, 3H, -COCH3), 2.52 - 2.32 (m, 8H, -NCH2-), 2.23 (s, 3H, -CH3), 1.92 (m, 2H, -CH2-), 1.86 (m, 2H, -CH2-), 1.61 - 1.53 (m, 4H, -CH2). 13 13C NMR (151 MHz, CDCl3) δ 197.55, 192.73, 180.82, 164.35, 164.33, 162.80, 162.78, 162.54, 138.10, 138.08, 137.68, 137.66, 133.86, 125.21, 125.19, 124.86, 124.83, 120.27, 120.12, 118.31, 115.80, 95.23, 68.56, 68.54, 55.63, 55.61, 55.06, 52.68, 45.94, 32.38, 32.00, 31.98, 29.15, 29.13. HRMS calcd for C 36 H 40 N2O9, [M + H]+: 645.2812, found 645.2789。

[0161] Example 57 Synthesis of 7-(2-acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)heptyl 2-rhein carboxylate (II 17 )

[0162] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5q were added. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and the mixture was extracted three times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was separated by thin-layer chromatography [V(methanol):V(dichloromethane) = 1:10] to obtain a yellow oil, 257 mg, with a yield of 44.8%. 1 1H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.80 (d, J = 7.5 Hz, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.69 (t, J = 8.0 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 6.35 (s, 1H, Ar-H), 4.38 (t, J = 6.4 Hz, 2H, -COOCH2-), 4.03 (t, J = 6.3 Hz, 2H, -OCH2-), 3.83 (s, 3H, -OCH3), 3.45 (s, 2H, -NCH2-), 2.55 (s, 3H, -COCH3), 2.52 - 2.30 (m, 8H, -NCH2-), 2.23 (s, 3H, -CH3), 1.90 (m, 2H, -CH2-), 1.84 (m, 2H, -CH2-), 1.51 - 1.44 (m, 2H, -CH2-). HRMS calcd for C 37 1H 42 19N2O9, [M + H]+: 659.2969, found 659.3091.

[0163] Example 58 Synthesis of 8-(2-acetyl-5-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenoxy)octyl 2-rhein carboxylate (II 18 )

[0164] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 5r were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out, the filtrate was added to 100 mL of water, and extracted with 50 mL of dichloromethane three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V(methanol):V(dichloromethane) = 1:10] gave 257 mg of a yellow oil, with a yield of 45.7%. 1 H NMR (600 MHz, CDCl3) δ 8.35 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.80 (d, J = 7.1 Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.68 (t, J = 7.9 Hz, 1H, Ar-H), 7.28 (d, J = 8.6 Hz, 1H, Ar-H), 6.33 (s, 1H, Ar-H), 4.36 (t, J = 6.4 Hz, 2H, -COOCH2-), 4.03 (t, J = 6.3 Hz, 2H, -OCH2-), 3.82 (s, 3H, -OCH3), 3.45 (s, 2H, -NCH2-), 2.54 (s, 3H, -COCH3), 2.53 - 2.30 (m, 8H, -NCH2-), 2.26 (s, 3H, -CH3), 1.88 (m, 2H, -CH2-), 1.82 (m, 2H, -CH2), 1.54 (m, 4H, -CH2-), 1.43 - 1.39 (m, 4H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 197.55, 192.68, 180.81, 164.33, 162.75, 162.54, 162.34, 160.00, 138.16, 137.64, 133.83, 133.50, 133.43, 128.78, 125.18, 124.81, 120.24, 120.08, 118.13, 117.99, 115.77, 95.17, 68.71, 66.08, 55.60, 55.20, 54.92, 52.41, 45.74, 32.00, 30.55, 29.62, 29.19, 29.12, 29.03, 28.50. HRMS calcd for C 38 H 44 N2O9, [M + H]+: 673.3125, found. 673.3106。

[0165] Example 59 Synthesis of 3-(2-acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)propyl 2-rhein carboxylate (Ⅱ 19 )

[0166] Dissolve 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate in 10 mL of DMF, stir at 70 °C, add 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of Compound 5s after 1 h. Monitor the reaction progress by TLC. After the reaction is completed, filter by suction, add 100 mL of water to the filtrate, extract with 50 mL of dichloromethane three times, wash the organic layer with saturated sodium chloride solution, dry over an appropriate amount of anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Separate by thin-layer chromatography [V(methanol):V(dichloromethane)=1:15] to obtain a yellow oil, 257 mg, with a yield of 43.4%. 1 1H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.81 (d, J = 7.5 Hz, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.69 (t, J = 9.6 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 6.41 (s, 1H, Ar-H), 4.61 (t, J = 6.2 Hz, 2H, -COOCH2-), 4.24 (t, J = 4.9 Hz, 2H, -OCH2-), 3.85 (s, 3H, -OCH3), 3.48 (s, 2H, -NCH2-), 2.58 (s, 3H, -COCH3), 2.56 - 2.39 (m, 8H, -NCH2-), 2.39 (m, 2H, -NCH2-), 2.37 (m, 2H, -CH2-), 1.04 (, J = 7.1 Hz, 3H, -CH3). 13 13C NMR (151 MHz, CDCl3) δ 197.34, 192.61, 180.78, 164.21, 162.76, 162.59, 162.32, 159.42, 137.75, 137.58, 133.85, 133.67, 133.32, 125.26, 124.95, 120.34, 120.01, 118.45, 118.26, 115.72, 95.25, 65.16, 62.78, 55.66, 55.22, 52.64, 52.48, 52.20, 32.02, 28.72, 11.79. HRMS calcd for C 34 H 36 N2O9, [M-H]+: 615.2348, found 615.2351。

[0167] Example 60 Synthesis of 4-(2-acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)butyl 2-rhein carboxylate (II 20 )

[0168] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of Compound 5t were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out by suction. The filtrate was added to 100 mL of water, and extracted three times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V(methanol):V(dichloromethane)=1:15] gave a yellow oil, 257 mg, with a yield of 43.8%. 1 H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.81 (d, J = 7.4 Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.69 (t, J = 8.0 Hz, 1H, Ar-H), 7.29 (d, J = 8.4 Hz, 1H, Ar-H), 6.36 (s, 1H, Ar-H), 4.45 (t, J = 6.2 Hz, 2H, -COOCH2-), 4.13 (t, J = 4.7 Hz, 2H, -OCH2-), 3.83 (s, 3H, -OCH3), 3.45 (s, 2H, -NCH2-), 2.56 (s, 3H, -COCH3), 2.56 - 2.40 (m, 8H, -NCH2-), 2.40 (m, 2H, -NCH2-), 2.08 (m, 4H, -CH2), 1.05 (t, J = 7.2 Hz, 3H, -CH3). 13 C NMR (151 MHz, CDCl3) δ 197.38, 192.64, 180.73, 164.26, 162.77, 162.54, 162.34, 159.65, 137.81, 137.69, 133.85, 133.59, 133.39, 125.16, 124.85, 120.28, 120.09, 119.98, 118.25, 118.20, 115.75, 95.21, 68.02, 65.46, 55.60, 55.16, 52.61, 52.39, 52.18, 31.92, 26.05, 25.57, 11.68. HRMS calcd for C 35 H 38N2O9, [M+H]+: 629.2504, found 629.2509.

[0169] Example 61 Synthesis of 5-(2-acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)pentyl 2-rhein carboxylate (II 21 )

[0170] 1.5 mmol (284 mg) of rhein and 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, and the mixture was stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5u were added. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered by suction. The filtrate was added to 100 mL of water, and extracted with 50 mL of dichloromethane three times. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was separated by thin-layer chromatography [V(methanol):V(dichloromethane) = 1:15] to obtain 257 mg of a yellow oil 7u, with a yield of 44.1%. 11H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.83 (d, J = 7.4 Hz, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.70 (t, J = 8.1 Hz, 1H, Ar-H)), 7.31 (d, J = 8.4 Hz, 1H, Ar-H), 6.36 (s, 1H, Ar-H), 4.42 (t, J = 6.6 Hz, 2H, -COOCH2-), 4.08 (t, J = 9.5 Hz, 2H, -OCH2-), 3.88 (s, 3H, -OCH3), 3.47 (s, 2H, -NCH2-), 2.55 (s, 3H, -COCH3), 2.49 (m, 8H, -NCH2-), 2.38 (m, 2H, -NCH2-), 1.93 (m, 4H, -CH2-), 1.69 (m, 2H, -CH2-), 1.04 (t, J = 7.2 Hz, 3H, -CH3). 13C NMR (151 MHz, CDCl3) δ 197.56, 192.71, 180.86, 164.34, 162.78, 162.59, 162.36, 159.82, 137.94, 137.71, 133.88, 133.65, 133.62, 133.42, 130.85, 125.20, 124.90, 124.86, 120.33, 120.07, 120.01, 95.11, 68.34, 65.74, 55.66, 55.59, 55.31, 55.27, 52.20, 31.98, 29.64, 28.91, 22.82, 11.83. HRMS calcd for C 36 H 40 N2O9, [M-H]+: 643.2661, found. 643.2669。

[0171] Example 62 Synthesis of 6-(2-acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)hexyl 2-rhein carboxylate (Ⅱ 22 )

[0172] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 5v were added. The reaction process was monitored by TLC. After the reaction was completed, it was filtered by suction, the filtrate was added with 100 mL of water, extracted 3 times with 50 mL of dichloromethane, the organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separated by thin layer chromatography [V(methanol):V(dichloromethane) = 1:15] to obtain a yellow oil, 257 mg, yield 44.6%. 1 H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.80 (d, J = 7.3 Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.69 (t, J = 7.9 Hz, 1H, Ar-H), 7.29 (d, J = 8.2 Hz, 1H, Ar-H), 6.35 (s, 1H, Ar-H), 4.38 (t, J = 6.6 Hz, 2H, -COOCH2-), 4.05 (t, J = 6.3 Hz, 2H, -OCH2-), 3.88 (m, 3H, -OCH3), 3.46 (s, 2H, -NCH2-), 2.55 (s, 3H, -COCH3), 2.49 (m, 8H, -NCH2-), 2.38 (m, 2H, -NCH2-), 1.96 (m, 4H, -CH2-), 1.63 (m, 4H, -CH2-), 1.04 (t, J = 7.1 Hz, 3H, -CH3). 13 C NMR (151 MHz, CDCl3) δ 197.63, 192.66, 180.82, 164.34, 162.74, 162.59, 162.32, 159.96, 138.02, 137.68, 133.82, 133.65, 133.61, 133.39, 125.22, 125.19, 124.88, 124.83, 120.28, 120.06, 119.95, 95.09, 68.51, 65.92, 55.63, 55.56, 55.24, 52.45, 52.17, 32.05, 32.01, 29.64, 29.11, 28.47, 11.75. HRMS calcd for C 37 H 42 N2O9, [M-H]+: 657.2817, found. 657.2823. Example 63 Synthesis of 7-(2-acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)heptyl-2-rhein carboxylate (II23 )

[0173] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C, after 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI and 1 mmol of compound 5w were added. The reaction progress was monitored by TLC. After completion of the reaction, filtration was carried out, the filtrate was added with 100 mL of water, extracted 3 times with 50 mL of dichloromethane, the organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V(methanol):V(dichloromethane) = 1:15] gave a yellow oil, 257 mg, yield 44.7%. 1 H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H, Ar-H), 7.94 (s, 1H, Ar-H), 7.88 (d, J = 7.4 Hz, 1H, Ar-H), 7.76 (s, 1H, Ar-H), 7.74 (t, J = 8.4 Hz, 1H, Ar-H), 7.34 (d, J = 8.4 Hz, 1H, Ar-H), 6.38 (s, 1H, Ar-H), 4.40 (t, J = 6.6 Hz, 2H, -COOCH2-), 4.07 (t, J = 6.4 Hz, 2H, -OCH2-), 3.86 (s, 3H, -OCH3), 3.48 (s, 2H, -NCH2-), 2.59 (s, 3H, -COCH3), 2.58 - 2.41 (m, 8H, -NCH2-), 2.41 (m, 2H, -NCH2-), 1.91 (m, 4H, -CH2-), 1.58 - 1.55 (m, 2H, -CH2-), 1.54 - 1.49 (m, 4H, -CH2-), 1.07 (t, J = 7.2 Hz, 3H,

[0174] -CH3). HRMS calcd for C 38 H 44 N2O9, [M + H]+: 673.3119, found. 673.3133.

[0175] Example 64 Synthesis of 8-(2-acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)octyl 2-rhein carboxylate (Ⅱ 24 )

[0176] 1.5 mmol (284 mg) of rhein, 2 mmol (276 mg) of potassium carbonate were added to 10 mL of DMF, stirred at 70 °C. After 1 h, 0.5 mmol (161 mg) of TBAB, 1 mmol (166 mg) of KI, and 1 mmol of compound 5x were added. The reaction progress was monitored by TLC. After the reaction was completed, filtration was carried out by suction. The filtrate was added to 100 mL of water, and extracted three times with 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separation by thin-layer chromatography [V(methanol):V(dichloromethane) = 1:15] gave a yellow oil, 257 mg, with a yield of 45.1%. 1 1H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 7.81 (d, J = 7.5 Hz, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 7.68 (t, J = 7.7 Hz, 1H, Ar-H), 7.29 (d, J = 8.1 Hz, 1H, Ar-H), 6.34 (s, 1H, Ar-H), 4.36 (t, J = 5.3 Hz, 2H, -COOCH2-), 4.03 (t, J = 6.3 Hz, 2H, -OCH2-), 3.82 (s, 3H, -OCH3), 3.47 (s, 2H, -NCH2-), 2.54 (s, 3H, -COCH3), 2.51 - 2.42 (m, 8H, -NCH2-), 2.40 (m, 2H, -NCH2-), 1.90 (m, 4H, -CH2-), 1.55 - 1.44 (m, 4H, -CH2-), 1.44 - 1.35 (m, 4H, -CH2-), 1.04 (d, J = 5.5 Hz, 3H, -CH3). 13 13C NMR (151 MHz, CDCl3) δ 197.72, 192.69, 180.88, 164.38, 162.75, 162.61, 162.34, 160.05, 138.14, 137.67, 133.83, 133.66, 133.41, 125.22, 124.83, 120.29, 120.12, 119.92, 118.14, 117.87, 115.77, 95.05, 68.68, 66.11, 55.61, 55.55, 55.28, 52.50, 52.18, 32.07, 30.54, 29.19, 29.13, 29.05, 28.50, 25.84, 11.80. HRMS calcd for C 39 H 46 N2O9, [M + H]+: 687.3282, found 687.3254。

[0177] Pharmacological Experimental Study on the Anti-Proliferative Activity of the Compounds of the Invention Against Cancer Cells - Example 65

[0178] Using the clinically common anti-tumor drug fluorouracil (5-FU) and paeonol as positive controls, the MTT method was used to test Compounds I 1-6 , II 1-24 for their in vitro anti-cell proliferation activities against human cervical cancer cells (Hela), human colon cancer cells (HT29), human liver cancer cells (HepG2), human lung cancer cells (A549), and human osteosarcoma cells (U2OS).

[0179] Experimental method: The cells used were routinely cultured in an incubator at 37°C with 5% CO2 saturated humidity. Cancer cells in the logarithmic growth phase with good growth state were taken and digested with 0.25% trypsin to make the adherent cells detached. The cell count was (2 - 3)×10 4 cells / mL, and then about 5000 cells per well were inoculated into a 96-well plate and incubated in the incubator for 24 h. The culture medium was changed, and the test drugs (0.1 - 25.0 μmol / L, 5 concentrations) were added, 100 μL per well, and the cells were continuously cultured in an incubator at 37°C with 5% CO2 saturated humidity for 72 h. MTT reagent was added to the 96-well plate, 20 μL per well, and incubated in the incubator for 4 h. The supernatant was aspirated, and DMSO was added, 120 μL per well. The plate was shaken on a plate shaker for 10 min, and the absorbance of each well at a wavelength of 495 nm was measured using an enzyme-linked immunosorbent assay detector. All experiments were repeated 3 times under the same conditions, and the cell inhibition rate was calculated.

[0180] Cell inhibition rate = [(OD value of the negative control group - OD value of the test substance group) / (OD value of the negative control group - OD value of the blank group)]×100%

[0181] SPSS (Statistical Package for the Social Science) 17.0 was used to calculate the IC 50 . Some experimental results are shown in Table 1.

[0182] Table 1 Experimental Results

[0183]

[0184]

[0185] As can be seen from the above results, compared with the clinically common anti-tumor drugs fluorouracil and paeonol, the conjugate of the present invention has significantly higher in vitro anti-proliferation activities against human liver cancer cells (HepG2) and human lung cancer cells (A549), and the in vitro anti-proliferation activities of most compounds against human cervical cancer cells (Hela), human colon cancer cells (HT29) and human osteosarcoma cells (U2OS) are significantly better than those of fluorouracil and paeonol, indicating excellent anti-tumor effects.

[0186] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A paeonol Mannich base-rhein conjugate, characterized in that, The conjugate is a compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof: Wherein, n is an integer from 3 to 8; R is a substituted or unsubstituted five- or six-membered nitrogen-containing heterocyclic group, and the substitution is by a C1-C6 alkyl group.

2. The paeonol Mannich base-rhein conjugate according to claim 1, wherein The substitution is by a C1-C3 alkyl group.

3. The paeonol Mannich base-rhein conjugate according to claim 1, wherein R is selected from morpholinyl, piperidinyl, 4-methylpiperazinyl or 4-ethylpiperazinyl.

4. A method for preparing a paeonol Mannich base-rhein conjugate represented by formula (I) or (II), characterized in that, The preparation method includes: reacting a compound represented by one of formula (4) or formula (5) with rhein in the presence of a base and a solvent, and the reaction formula is as follows; Wherein, X is a halogen atom; n is an integer from 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substitution is by a C1-C6 alkyl group.

5. The preparation method according to claim 4, characterized in that, The molar ratio of the compound represented by one of formula (4) or formula (5) to rhein is 1:1 to 2; the temperature of the reaction is 60 to 80 °C, and the reaction time is 8 to 10 h.

6. The preparation method according to claim 4 or 5, characterized in that The preparation method of the compound represented by one of formula (4) or formula (5) includes: carrying out a Williamson reaction on a compound represented by one of formula (2) or formula (3) and a dihaloalkane, and the reaction formula is as follows: Wherein, X is a halogen atom; n is an integer from 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substitution is by a C1-C6 alkyl group.

7. The preparation method according to claim 6, characterized in that, The preparation method of the compound represented by one of formula (2) or formula (3) includes: carrying out a Mannich reaction on paeonol, paraformaldehyde and a nitrogen-containing heterocyclic compound.

8. A pharmaceutical composition, characterized in that: The pharmaceutical composition is composed of the conjugate according to any one of claims 1 to 3 as the sole or main active ingredient and a pharmaceutically acceptable carrier or adjuvant ingredient.

9. Use of the conjugate according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating cancer, wherein the cancer is selected from cervical cancer, colon cancer, osteosarcoma, lung cancer or liver cancer.

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