Paeonol Mannich base-rhein conjugate as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses a paeonol mannich base-rhein conjugate as well as a preparation method and application thereof. The conjugate is a compound as shown in a general formula (I) or (II) or a pharmaceutically acceptable salt thereof. Compared with the clinically common antitumor drugs fluorouracil and paeonol, the conjugate provided by the invention has obviously higher in-vitro anti-human hepatoma carcinoma cell (HepG2) and human lung cancer cell (A549) proliferative activity, and the in-vitro anti-human cervical carcinoma cell (Hela), human colon cancer cell (HT29) and human osteosarcoma cell (U2OS) proliferative activity of most compounds is obviously superior to that of fluorouracil and paeonol; and the conjugate has good water solubility, is expected to be applied to treatment of various cancers such as cervical cancer, colon cancer, osteosarcoma, lung cancer or liver cancer, and has a wide clinical application prospect. # imgabs0 #

Description

Technical Field

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

[0002] According to the World Health Organization, malignant tumors remain the main cause of serious threats to human life. Despite the adoption of a series of cancer treatment strategies (such as surgery, chemotherapy, radiotherapy and immunotherapy), cancer-related mortality remains high, accounting for 13% of total human deaths. Therefore, the development of highly selective anticancer drugs with few side effects to improve the efficacy of cancer treatment remains one of the current urgent issues to be addressed (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 Paeonia suffruticosa, which has antipyretic, analgesic, anti-inflammatory, anti-tumor and anti-allergic effects (Phytomedicine, 2023, 109; Chinese Pharmacological Bulletin, 2023(06):1078-1084; Journal of Beijing Union University, 2023, 37(02):72-78.). Studies have shown that paeonol has an inhibitory effect on the growth and proliferation of cancer cells in various cell lines, including cervical cancer HeLa cells, human bladder cancer T24 and 5637 cells, non-small cell lung cancer A549 cells, hepatocellular carcinoma Hep3B, Huh-7, BEL-7404, osteosarcoma Saos-2, MG-63 cells, etc. Paeonol can effectively inhibit 5-lipoxygenase (5-LO) and stimulate cancer cell invasion and migration by upregulating the expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9); paeonol can also reduce tumor microenvironment inflammation and inhibit cancer cell migration by inhibiting STAT3 / NF-κB and TGF-β1 / Smad signaling pathways; paeonol inhibits the activation of WNT / β-catenin signaling pathway, downregulates cyclin D1 and CDK4, upregulates cyclin p21Cip1, and blocks the cell cycle in 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). Paeonol has various anti-tumor mechanisms, but its volatility, poor water solubility and easy metabolism limit its clinical application. Therefore, it is of great significance to structurally modify paeonol to enhance its anti-tumor activity, improve its physicochemical properties, and enhance its applicability, thereby providing new alternative drugs for cancer treatment. Summary of the invention

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

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

[0006]

[0007] Wherein, n is an integer of 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substituted group is substituted with a C1 to C6 alkyl group.

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

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

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

[0011] In some embodiments, the compound represented by general formula (I) or (II) is 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 formulas (4) or (5) with rhein in the presence of a base and a solvent, the reaction formula being as follows;

[0043]

[0044] Wherein, X is a halogen atom; n is an integer of 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substituted group is substituted with a C1 to 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 1:1-2.

[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 (4) or formula (5) comprises: subjecting the compound represented by one of formula (2) or formula (3) to a Williamson reaction with a dihaloalkane, the reaction formula being as follows:

[0048]

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

[0050] In some embodiments, the method for preparing the compound represented by one of formula (2) or formula (3) comprises: subjecting paeonol to a Mannich reaction with polyformaldehyde 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 auxiliary ingredient.

[0052] In a third aspect, the present invention provides use of the aforementioned conjugate or pharmaceutical composition 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.

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

[0054] The present invention designs and synthesizes a series of paeonol Mannich base-rhein conjugates with novel structures. The Mannich base structure introduced into paeonol by the Mannich reaction improves the water solubility and bioavailability of paeonol. The obtained paeonol Mannich base is further coupled with rhein to significantly enhance the anti-tumor activity. Experimental results show that compared with the commonly used clinical anti-tumor drugs fluorouracil and paeonol, the in vitro anti-proliferation activity of the conjugate of the present invention against human liver cancer cells (HepG2) and human lung cancer cells (A549) is significantly higher, and the in vitro anti-proliferation activity of most compounds against human cervical cancer cells (Hela), human colon cancer cells (HT29) and human osteosarcoma cells (U2OS) is significantly better than that of fluorouracil and paeonol, indicating that the anti-tumor effect is excellent. The conjugate of the present invention 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 prospects for clinical application. DETAILED DESCRIPTION

[0055] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0056] The synthetic route of the target compound is as follows, specifically, i: using paeonol (1) as the starting material, and carrying out Mannich reaction with polyformaldehyde and a nitrogen-containing heterocyclic compound, introducing a nitrogen-containing heterocyclic methyl group at its 3-position or 5-position to obtain the corresponding paeonol Mannich base derivatives (2, 3); ii: the paeonol Mannich base derivatives (2, 3) and the corresponding dibromoalkane are subjected to Williamson reaction to synthesize compounds (4, 5); iii: the compounds (4, 5) are coupled with rhein to obtain new paeonol Mannich base-rhein conjugates (I, II).

[0057]

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

[0059] Paeonol (498 mg, 3 mmol) and paraformaldehyde (120 mg, 4 mmol) (degree of polymerization n = 10-100) were placed in a reaction flask, 95% ethanol (20 mL) was added, and refluxed with stirring at 85°C. After 1 h, morpholine (0.30 mL, 4 mmol) was added, and the reaction was stopped after 8 h of TLC detection. The reaction solution was spin-dried, water was added, and dichloromethane was extracted. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, sealed, and allowed to stand overnight. The reaction solution after extraction 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%; of which 2a 208 mg, with a yield of 26.2%, 1 H NMR (600MHz, CDCl3) δ: 12.63 (s, 1H), 7.88 (d, J = 9.0Hz, 1H), 6.67 (d, J = 9.0Hz, 1H), 3.87 (s, 3H), 3.56 (d, J = 4.7H z,4H),3.38(s,2H),2.58(s,3H),2.44~2.35(m,4H).IR(KBr)v:3292,3021,2927,1683,1605,1460,1372,1233cm -1 HRMS calculation for C 14 H 19 NO4[M+H] + :266.1392, found266.1408; 3a 298mg, yield 37.5%.

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

[0061] 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 refluxed at 85°C with stirring. After 1 h, piperidine (0.35 mL, 4 mmol) was added, and the reaction was stopped after TLC detection for 8 h. The reaction solution was spin-dried, water was added, and dichloromethane was extracted. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, sealed and allowed to stand overnight. The reaction solution after extraction 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%; of which 2b was 222 mg with a yield of 28.2%,1 H NMR (600MHz, CDCl3) δ: 10.70 (s, 1H), 8.36 (d, J = 9.0Hz, 1H), 6.63 (d, J = 9.0Hz, 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)v:3289,3019,2924,1681,1603,1462,1371,1231cm -1 HRMS calculation for C 15 H 21 NO3[M+H] + :264.1600, found 264.1611; 3b 264mg, yield 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 refluxed at 85°C with stirring. Methylpiperazine (0.44 mL, 4 mmol) was added after 1 h, and the reaction was stopped after TLC detection for 8 h. The reaction solution was spin-dried, water was added, and dichloromethane was extracted. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, sealed and allowed to stand overnight. The reaction solution after extraction 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 with a yield of 62.8%; of which 2c 241 mg with a yield of 27.7% 1 H NMR (600MHz, CDCl3) δ: 12.71 (s, 1H), 8.29 (d, J = 9.0Hz, 1H), 6.64 (d, J = 9.0Hz, 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)v:3291,3223,2929,1685,1603,1461,1374,1235cm -1 HRMS calculation for C 15 H 22 N2O3[M+H] + :279.1709, found279.1725; 3c 293mg, yield 35.1%.

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

[0065] 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 refluxed at 85°C with stirring. After 1 h, ethylpiperazine (0.50 mL, 4 mmol) was added, and the reaction was stopped after TLC detection for 8 h. The reaction solution was spin-dried, water was added, and dichloromethane was extracted. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, sealed and allowed to stand overnight. The reaction solution after extraction 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%; of which 2d had a yield of 233 mg and a yield of 26.5%, 1 H NMR (600MHz, CDCl3) δ: 12.85 (s, 1H), 8.13 (d, J = 9.0Hz, 1H), 6.58 (d, J = 9.0Hz, 1H), 3.84 (s, 3H), 3.56 (d, J = 4.7Hz, 4H) ,3.42~3.33(m,10H),2.60(s,3H),1.25(t,J=5.7Hz,3H).IR(KBr)v:3288,3022,2923,1684,1602,1460,1372,1231cm -1 HRMS calculation for C 16 H 24 N2O3[M+H] + :293.1865, found 293.1885; 3d 335mg, yield 38.3%.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0081] 1mmol (265mg) of compound 3a, 3mmol (120mg) of sodium hydroxide, and 6mL of DMF were added to a 50mL round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromobutane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [V (ethyl acetate): (petroleum ether) = 1:4] was used to obtain 260mg 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] 1mmol (265mg) of compound 3a, 3mmol (120mg) of sodium hydroxide, and 6mL of DMF were added to a 50mL round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromopentane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [V (ethyl acetate): (petroleum ether) = 1:4] was used to obtain 272mg 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] 1mmol (265mg) of compound 3a, 3mmol (120mg) of sodium hydroxide, and 6mL of DMF were added to a 50mL round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromohexane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [V (ethyl acetate): (petroleum ether) = 1:4] was used to obtain 283mg 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] 1mmol (265mg) of compound 3a, 3mmol (120mg) of sodium hydroxide, and 6mL of DMF were added to a 50mL round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromoheptane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [V (ethyl acetate): (petroleum ether) = 1:4] was used to obtain 294mg of yellow oil 5e, with a yield of 62.2%.

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

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

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

[0092] 1mmol (263mg) of compound 3b and 3mmol (120mg) of sodium hydroxide were added to a 50ml round-bottom flask, and 6mL of DMF was added to the 50ml round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromobutane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [V (ethyl acetate): (petroleum ether) = 1:5] was used to obtain 287mg 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)ethane-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, stirred at room temperature for 20 min, and then 3 mmol of dibromopentane was added and stirred at 35 ° C. After TLC detection, the reaction was completed, filtered, 100 mL of water was added, and 50 mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, added with an appropriate amount of anhydrous sodium sulfate, dried, filtered, and concentrated under reduced pressure. Column chromatography [V (ethyl acetate): (petroleum ether) = 1:5] was used to obtain 301 mg of 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)ethane-1-one (5j)

[0094] 1mmol (263mg) of compound 3b and 3mmol (120mg) of sodium hydroxide were added to a 50ml round-bottom flask, and 6mL of DMF was added to the 50ml round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromohexane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [V (ethyl acetate): (petroleum ether) = 1:5] was used to obtain 299mg 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)ethane-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, and 6 mL of DMF was added to the 50 mL round-bottom flask, stirred at room temperature for 20 min, and then 3 mmol of dibromoheptane was added and stirred at 35 ° C. TLC detected that the reaction was complete, filtered, 100 mL of water was added, and 50 mL of ethyl acetate was extracted three times. The organic layer was washed with a saturated sodium chloride solution, added with an appropriate amount of anhydrous sodium sulfate to dry, filtered, and concentrated under reduced pressure. Column chromatography separation [V (ethyl acetate): (petroleum ether) = 1:5] gave 333 mg of a yellow oil 5k, with a yield of 60.1%. Example 22 Synthesis of 1-(2-((8-bromooctyl)oxy)-4-methoxy-3-(piperidin-1-ylmethyl)phenyl)ethane-1-one (5l)

[0096] 1mmol (263mg) of compound 3b and 3mmol (120mg) of sodium hydroxide were added to a 50ml round-bottom flask, and 6mL of DMF was added to the 50ml round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromooctane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (ethyl acetate): (petroleum ether) = 1:5] gave 337mg of a yellow oil 51, with a yield of 59.4%. Example 23 Synthesis of 1-(3-bromopropoxy)-4-methoxy-5-(4-methylpiperazin-1-yl)methyl)phenyl)ethane-1-one (5m)

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

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

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

[0100] 1mmol (276mg) of compound 3c and 3mmol (120mg) of sodium hydroxide were added to a 50ml round-bottom flask, and 6mL of DMF was added to the 50ml round-bottom flask, stirred at room temperature for 20min, and then 3mmol of dibromohexane was added and stirred at 35°C. After TLC detection, the reaction was completed, filtered, 100mL of water was added, and 50mL of ethyl acetate was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (ethyl acetate): (petroleum ether) = 1:5] gave 235mg of a yellow oil 5p, with a yield of 53.5%. Example 27 Synthesis of 1-(7-bromoheptyloxy)-4-methoxy-5-(4-methylpiperazin-1-yl)methyl)phenyl)ethane-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, and 6 mL of DMF was added to the 50 mL round-bottom flask, and stirred at room temperature for 20 min. Then 3 mmol of dibromoheptane was added and stirred at 35°C. After TLC detection, the reaction was completed, and the mixture was filtered, 100 mL of water was added, and 50 mL of ethyl acetate was extracted three times. The organic layer was washed with a saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (ethyl acetate): (petroleum ether) = 1:5] gave 245 mg of a yellow oil 5q, with a yield of 54.4%. Example 28 Synthesis of 1-(8-bromooctyloxy)-4-methoxy-5-(4-methylpiperazin-1-yl)methyl)phenyl)ethane-1-one (5r)

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

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

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

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

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

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

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

[0109] Synthesis of target compounds

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

[0111] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 4a were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 242mg, yield 41.2%; 1HNMR (600MHz, CDCl3) δ8.36(s,1H,Ar-H),7.90(s,1H,Ar-H),7.83(d,J=7.4Hz,1H,Ar-H),7.70(t,J=8.4,3 .3Hz,1H,Ar-H),7.62(d,J=8.6Hz,1H,Ar-H),7.31(d,J=8.3Hz,1H,Ar-H),6.43(d,1H,J=7.5Hz,Ar-H),4.6 2(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,-OC H2-),3.45(s,2H,-NCH2-),2.59(s,3H,-COCH3),2.43(t,J=4.6Hz,4H,-NCH2-),2.41-2.38(m,2H,-CH2-). 13 C NMR (151MHz, CDCl3) δ197.45,192.70,180.85,164.36,162.78,162.74,162.37,160.36,138.12,137.68,134.22, 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 forC 32 H 31 NO 10 ,[M+H] + :590.2026,found.590.2014.

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

[0113] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 4b were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil 4b, 242mg, with a yield of 41.2%; 1HNMR (600MHz, CDCl3) δ8.39(s,1H,Ar-H),7.92(s,1H,Ar-H),7.85(d,J=7.5Hz,1H,Ar-H),7.71(t,J=8.0H z,1H,Ar-H),7.62(d,J=8.6Hz,1H,Ar-H),7.32(d,J=8.3Hz,1H,Ar-H),6.69(d,J=6.5Hz,1H,Ar-H),4.41(t ,J=6.6Hz,2H,-COOCH2-),3.94(t,J=6.6Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.61(t,J=4.8Hz,4H,-OCH2 ),3.59(s,2H,-NCH2-),2.59(s,3H,-COCH3),2.49(t,J=4.6Hz,4H,-NCH2-),1.92-1.87(m,4H,-CH2-).13C NMR (151MHz, CDCl3) δ199.26,192.78,180.84,164.35,162.78,162.50,162.38,159.54,138.08,137.67,133.92,133.50,130.90,126.6 9,125.21,124.81,120.32,120.14,118.22,115.83,106.25,76.70,67.10,65.86,55.83,53.26,50.00,29.96,29.86,28.63,22.69.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-(morpholinylmethyl)phenoxy)pentyl-2-rhein carboxylate (I3):

[0115] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 4c were added after 1h. The reaction progress was detected by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] obtained a yellow oil, 258mg, yield 41.9%; 1 HNMR (600MHz, CDCl3) δ: 8.34 (s, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 7.81 (d, J = 7.3Hz, 1H, Ar-H), 7.69 (t, J = 7.7Hz, 1H ,Ar-H),7.62(d,J=8.6Hz,1H,Ar-H),7.29(d,J=8.0Hz,1H,Ar-H),6.69(d,J=6.5Hz,1H,Ar-H)4.41(t,J=13.2Hz, 2H,-COOCH2-),4.09(t,J=6.4Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.66(t,J=4.5Hz,4H,-OCH2-),3.44(s,2H,-N CH2-),2.55(s,3H,-COCH3),2.46(t,4H,-NCH2-),1.97-1.90(t,J=7.3Hz,4H,-CH2-),1.71-1.68(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 ,125.19,125.17,124.88,120.32,120.06,120.04,118.22,115.78,68.37,66.88,65.72,55.84,55.68,32.00,28.91,28.32,22.83.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-(morpholinylmethyl)phenoxy)hexyl-2-rhein carboxylate (I4):

[0117] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 4d were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 266mg, with a yield of 42.2%; 1 HNMR (600MHz, CDCl3) δ: 8.35 (s, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.82 (d, J = 7.4Hz, 1H, Ar-H), 7.70 (t, J = 8.0Hz, 1H ,Ar-H),7.62(d,J=8.6Hz,1H,Ar-H),7.30(d,J=8.3Hz,1H,Ar-H),6.69(d,J=6.5Hz,1H,Ar-H),4.39(t,J=6.5Hz, 2H,-COOCH2-),4.06(t,J=6.4Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.66(t,J=4.8Hz,4H,-OCH2-),3.43(s,2H,-N CH2-),2.56(s,3H,-COCH3),2.43(t,J=4.9Hz,4H,-NCH2-),1.93-1.80(m,4H,-CH2-),1.64-1.52(m,4H,-CH2-). 13 C NMR (151MHz, CDCl3) δ199.27,192.76,180.82,164.33,162.76,162.48,162.44,162.36,138.15,137.66,133.87,133.48,126.71 ,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-(morpholinylmethyl)phenoxy)heptyl-2-rhein carboxylate (I5):

[0119] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 4e were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 278mg, yield 43.1%; 1 HNMR (600MHz, CDCl3) δ: 8.35 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.82 (d, J = 7.4Hz, 1H, Ar-H), 7.69 (t, J = 8.0Hz, 1H, Ar-H),7.62(d,J=8.6Hz,1H,Ar-H),7.30(d,J=8.3Hz,1H,Ar-H),6.69(d,J=6.5Hz,1H,Ar-H),4.39(t,J=6.5Hz,2H ,-COOCH2-),4.06(t,J=6.4Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.66(t,J=4.8Hz,4H,-OCH2-),3.43(s,2H,-NCH2 -),2.56(s,3H,-COCH3),2.43(t,J=4.9Hz,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-(morpholinylmethyl)phenoxy)octyl-2-rhein carboxylate (I6):

[0121] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 4f were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 288mg, yield 43.7%; 1 HNMR (600MHz, CDCl3) δ8.36(s,1H,Ar-H),7.88(s,1H,Ar-H),7.82(d,J=7.3Hz,1H,Ar-H),7.69(t,J=9.5Hz,1H,Ar-H) ,7.59(d,J=8.9Hz,1H,Ar-H),7.29(d,J=8.2Hz,1H,Ar-H),6.67(d,J=8.5Hz,1H,Ar-H),4.36(t,J=6.5Hz,2H,-COOCH2- ),3.86(t,J=5.6Hz,2H,-OCH2-),3.82(s,3H,-OCH3),3.62(t,J=4.8Hz,4H,-OCH2-),3.56(s,2H,-NCH2-),2.57(s,3H ,-COCH3),2.48(t,J=4.8Hz,4H,-NCH2),1.81-1.76(m,4H,-CH2-),1.48-1.43(m,4H,-CH2-),1.41-1.36(m,4H,-CH2). 13 C NMR (151MHz, CDCl3) δ192.73,180.84,164.36,162.73,162.49,162.33,159.70,138.18,137.67,133.82,133.43,130.85,126.69,1 25.21,124.80,120.30,120.15,106.20,67.11,66.13,55.83,53.23,49.94,30.27,29.87,29.64,29.42,29.16,28.53,25.89.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-(morpholinylmethyl)phenoxy)propyl-2-rhein carboxylate (II1)

[0123] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5a were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 250mg, yield 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=6.5H z,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) δ197.24,192.69,180.80,164.22,162.81,162.58,162.34,159.44,137.76,137.64,133.92,133.66,133.39,12 5.24,124.93,120.34,120.20,120.02,118.44,118.31,115.77,95.35,66.96,65.24,62.77,55.84,55.76,55.73,31.97,28.77.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-(morpholinylmethyl)phenoxy)butyl-2-rhein carboxylate (II2)

[0125] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5b were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 257mg, yield 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,-NC H2-),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) δ197.40,192.75,180.86,164.32,162.81,162.57,162.36,159.73,137.83,137.75,133.92,133.66,133.4 4,125.21,124.91,120.35,120.06,118.27,115.80,95.20,68.00,66.93,65.44,55.83,55.66,53.32,32.00,26.05,25.58.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-(morpholinylmethyl)phenoxy)pentyl-2-rhein carboxylate (II3)

[0127] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70°C, and after 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5c were added. TLC was used to monitor the reaction progress. After the reaction was completed, the mixture was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was used for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave 266mg 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) δ197.43,192.70,180.85,164.32,162.78,162.60,162.34,159.93,137.95,137.71,133.88,133.67,133.44,133.42,1 25.19,125.17,124.88,120.32,120.06,120.04,118.22,95.21,68.37 ,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-(morpholinylmethyl)phenoxy)hexyl-2-rhein carboxylate (II4)

[0129] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5d were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 274mg, yield 43.5%; 1 H NMR (600MHz, CDCl3) δ8.35(s,1H,Ar-H),7.88(s,1H,Ar-H),7.82(d,J=7.4Hz,1H,Ar-H),7.75(s,1H,Ar-H), 7.70(t,J=8.0Hz,1H,Ar-H),7.30(d,J=8.3Hz,1H,Ar-H),6.37(s,1H,Ar-H),4.39(t,J=6.5Hz,2H,-COOCH2- ),4.06(t,J=6.4Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.66(t,J=4.8,4.4Hz,4H,-NCH2-),3.44(s,2H,-NCH2 -),2.56(s,3H,-COCH3),2.43(t,J=4.9Hz,4H,-NCH2-),1.93-1.81(m,4H,-CH2-),1.63-1.51(m,4H,-CH2-). 13 C NMR (151MHz, CDCl3) δ197.56,192.67,180.82,164.32,162.76,162.58,162.33,159.84,137.91,137.71,133.85,133.59,133.39,1 25.18,124.88,120.32,120.04,118.20,115.76,95.11,68.33,65.73,55.66,55.60,55.26,32.00,29.63,28.90,28.31,22.82.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-(morpholinylmethyl)phenoxy)heptyl-2-rhein carboxylate (II5)

[0131] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF and stirred at 70℃. After 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI and 1mmol of compound 5e were added. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:40] gave a yellow oil, 257mg, with a yield of 44.1%. 1 H NMR (600MHz, CDCl3) δ8.35(s,1H,Ar-H),7.88(s,1H,Ar-H),7.82(d,J=7.4Hz,1H,Ar-H),7.75(s,1H,Ar-H), 7.70(t,J=8.0Hz,1H,Ar-H),7.30(d,J=8.3Hz,1H,Ar-H),6.37(s,1H,Ar-H),4.39(t,J=6.5Hz,2H,-COOCH2- ),4.06(t,J=6.4Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.66(t,J=4.8,4.4Hz,4H,-NCH2-),3.44(s,2H,-NCH2 -),2.56(s,3H,-COCH3),2.43(t,J=4.9Hz,4H,-NCH2-),1.93-1.81(m,4H,-CH2-),1.63-1.51(m,4H,-CH2-). 13C NMR (151MHz, CDCl3) δ197.56,192.67,180.82,164.32,162.76,162.58,162.33,159.84,137.91,137.71,133.85,133.59,133.39,1 25.18,124.88,120.32,120.04,118.20,115.76,95.11,68.33,65.73,55.66,55.60,55.26,32.00,29.63,28.90,28.31,22.82.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-(morpholinylmethyl)phenoxy)octyl-2-rhein carboxylate (II6)

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

[0134] 1H NMR (600MHz, CDCl3) δ8.36(s,1H,Ar-H),7.89(s,1H,Ar-H),7.81(d,J=7.4Hz,1H,Ar-H),7.74(s,1H,Ar-H),7. 69(t,J=7.9Hz,1H,Ar-H),7.29(d,J=8.4Hz,1H,Ar-H),6.36(s,1H,Ar-H),4.37(t,J=6.7Hz,2H,-COOCH2-),4. 04(t,J=6.5Hz,2H,-OCH2-),3.84(s,3H,-OCH3),3.66(t,J=4.7Hz,4H,-NCH2-),3.43(s,2H,-NCH2),2.56(s,3 H,-COCH3),2.47(t,J=4.9Hz,4H,-NCH2-),1.83(m,4H,-CH2-),1.49(m,4H,-CH2-),1.44-1.37(m,4H,-CH2-). 13 C NMR (151MHz, CDCl3) δ197.63,192.68,180.85,164.36,162.74,162.61,162.32,160.12,138.13,137.67,133.82,133.65,133.63,133.40,130. 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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5g were added after 1h. The reaction progress was detected by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:20] obtained a yellow oil, 257mg, yield 41.2%.

[0137] 1 H NMR (600MHz, CDCl3) δ8.33(s,1H,Ar-H),7.87(s,1H,Ar-H),7.81(d,J=7.5Hz,1H,Ar-H),7.75(s,1H,Ar- H),7.69(t,J=8.1Hz,1H,Ar-H),7.29(d,J=8.3Hz,1H,Ar-H),6.42(s,1H,Ar-H),4.61(t,J=6.1Hz,2H,-C OOCH2-),4.25(t,J=6.1Hz,2H,-OCH2-),3.86(s,3H,-OCH3),3.46(s,2H,-NCH2-),2.58(s,3H,-COCH3), 2.47(t,J=4.9Hz,4H,-NCH2-),2.24(m,2H,-CH2-),1.59-1.47(m,4H,-CH2-),1.41-1.31(m,2H,-CH2-). 13 C NMR (151MHz, CDCl3) δ197.28,192.63,180.76,164.21,162.80,162.64,162.35,159.40,137.72,137.64,133.90,133.37,125.2 4,124.90,120.30,120.13,119.99,118.28,115.76,95.38,65.24,62.80,55.99,55.72,54.05,31.88,28.77,25.66,24.12.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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5h were added after 1h. The reaction progress was detected by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted 3 times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:20] obtained a yellow oil, 257mg, yield 44.5%.

[0140] 1 H NMR (600MHz, CDCl3) δ8.41(s,1H,Ar-H),7.91(s,1H,Ar-H),7.88(d,J=7.5Hz,1H,Ar-H),7.79(s,1H,A r-H),7.73(t,J=7.6Hz,1H,Ar-H),7.35(d,J=9.6Hz,1H,Ar-H),6.42(s,1H,Ar-H),4.49(t,J=9.4Hz,2H ,-COOCH2-),4.21(t,J=6.1Hz,2H,-OCH2-),3.93(s,3H,-OCH3),3.64(s,2H,-NCH2-),2.61(s,3H,-CO CH3),2.08(t,J=5.2Hz,4H,-NCH2-),1.70(m,4H,-CH2-)1.42(m,4H,-CH2-),1.29-1.24(m,2H,-CH2-). 13 C NMR (151MHz, CDCl3) δ197.31,192.66,180.76,164.28,162.79,162.64,162.36,159.78,137.82,137.70,134.03,133.88,133.41,130.81,1 28.79,125.18,124.87,120.29,120.08,119.99,118.22,95.26,68.03 ,65.46,55.80,55.66,53.86,31.90,29.63,26.06,25.58,23.99.HRMS calcd forC 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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF and stirred at 70℃. After 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI and 1mmol of compound 5i were added. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with 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, 257mg, with a yield of 43.8%.

[0143] 1 H NMR (600MHz, CDCl3) δ8.41(s,1H,Ar-H),7.95(s,1H,Ar-H),7.87(d,J=7.5Hz,1H,Ar-H),7.77(s,1H,Ar-H), 7.73(t,J=8.0Hz,1H,Ar-H),7.34(d,J=8.4Hz,1H,Ar-H),6.41(s,1H,Ar-H),4.44(t,J=6.4Hz,2H,-COOCH2- ),4.12(t,J=6.3Hz,2H,-OCH2-),3.89(s,3H,-OCH3),3.60((s,2H,-NCH2-),2.66(s,3H,-COCH3),2.08(t,J =5.2Hz,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 CNMR(151MHz, CDCl3)δ162.86,162.59,162.39,159.54,137.77,133.67,133.63,132.65,125.28,124.95,120.37,120.24 ,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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF and stirred at 70℃. After 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI and 1mmol of compound 5j were added. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with 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, 257mg, with a yield of 44.6%.

[0146] 1 H NMR (600MHz, CDCl3) δ8.39(s,1H,Ar-H),7.92(s,1H,Ar-H),7.83(d,J=7.5Hz,1H,Ar-H),7.75(s,1H,Ar-H),7 .71(t,J=8.0Hz,1H,Ar-H),7.31(d,J=8.5Hz,1H,Ar-H),6.37(s,1H,Ar-H),4.39(t,J=6.6Hz,2H,-COOCH2-), 4.06(t,J=9.4,6.3Hz,2H,-OCH2-),3.86(s,3H,-OCH3),3.52(s,2H,-NCH2-),2.57(s,3H,-COCH3),2.50(t,J =5.2Hz,4H,-NCH2-),1.97-1.84(m,4H,-CH2-),1.60(m,4H,-CH2-),1.55(m,2H,-CH2-),1.39(m,4H,-CH2-). 13C NMR (151MHz, CDCl3) δ192.73,180.90,164.37,162.70,162.65,162.39,160.15,138.03,137.69,137.64,134.07,133.46,125.23,125.1 9,124.87,124.83,120.29,120.25,120.09,120.05,95.24,68.52,55.80,53.78,31.95,29.63,29.11,29.07,28.48,25.27,23.85.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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5k were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography separation [V (methanol): (dichloromethane) = 1:20] gave 257mg of yellow oil, with a yield of 45.8%.

[0149] 1H NMR (600MHz, CDCl3) δ8.35(s,1H,Ar-H),7.88(s,1H,Ar-H),7.81(d,J=7.4Hz,1H,Ar-H),7.75(s,1H,Ar-H),7.70(t, J=8.0Hz,1H,Ar-H),7.29(d,J=8.4Hz,1H,Ar-H),6.36(s,1H,Ar-H),4.37(t,J=6.8Hz,2H,-COOCH2-),4.05(t,J=6.5H z,2H,-OCH2-),3.85(s,3H,-OCH3),3.53(s,2H,-NCH2-),2.56(s,3H,-COCH3),2.48(t,J=5.2Hz,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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF and stirred at 70℃. After 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI and 1mmol of compound 51 were added. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with 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, 257mg, with a yield of 46.2%.

[0152] 1H NMR (600MHz, CDCl3) δ8.38(s,1H,Ar-H),7.91(s,1H,Ar-H),7.83(d,J=7.5Hz,1H,Ar-H),7.76(s,1H,Ar-H),7.70(t, J=9.8Hz,1H,Ar-H),7.31(d,J=8.3Hz,1H,Ar-H),6.37(s,1H,Ar-H),4.37(t,J=6.8Hz,2H,-COOCH2-),4.05(t,J=6.5H z,2H,-OCH2-),3.85(s,3H,-OCH3),3.55(s,2H,-NCH2-),2.56(s,3H,-COCH3),2.48(t,J=6.3Hz,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 C NMR (151MHz, CDCl3) δ192.74,164.38,162.80,162.72,162.38,137.66,134.16,130.82,128.82,128.79,125.25,125.22,124.86,120 .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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5m were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:10] obtained a yellow oil, 257mg, yield 42.2%. 1 H NMR (600MHz, CDCl3) δ8.37(s,1H,Ar-H),7.90(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),7.31(d,J=8.4Hz,1H,Ar-H),6.41(s,1H,Ar-H),4.61(t, J=6.3Hz,2H,-COOCH2-),4.25(t,J=6.0Hz,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 C NMR (151MHz, CDCl3) δ197.26,192.72,180.83,164.23,162.83,162.54,162.38,159.40,137.75,137.68,133.96,133.59,133.43,12 5.26,124.92,120.34,120.04,118.54,118.34,115.80,95.38,65.26,62.77,55.72,55.10,54.86,52.29,45.63,31.91,29.63.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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF and stirred at 70℃. After 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI and 1mmol of compound 5n were added. TLC was used to monitor the reaction progress. After the reaction was completed, the mixture was filtered, 100mL of water was added to the filtrate, and the mixture was extracted 3 times with 50mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:10] gave a yellow oil, 257mg, with a yield of 42.7%. 1 H NMR (600MHz, CDCl3) δ8.33(s,1H,Ar-H),7.87(s,1H,Ar-H),7.81(d,J=5.4Hz,1H,Ar-H),7.73(s ,1H,Ar-H),7.69(t,J=7.9Hz,1H,Ar-H),7.29(d,J=8.3Hz,1H,Ar-H),6.36(s,1H,Ar-H),4.46(t, J=5.2Hz,2H,-COOCH2-),4.14(t,J=5.0Hz,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 (151MHz, CDCl3) δ197.48,192.64,180.78,164.29,162.76,162.56,162.32,159.69,137.73,133.84,133.64,133.36,12 5.19,124.89,120.32,120.00,118.21,115.74,95.16,67.99,65.48,55.66,55.60,55.24,54.91,45.81,32.01,25.57.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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5o were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:10] obtained a yellow oil, 257mg, yield 43.6%. 1 H NMR (600MHz, CDCl3) δ8.34(s,1H,Ar-H),7.87(s,1H,Ar-H),7.82(d,J=7.4Hz,1H,Ar-H),7.73(s,1H,Ar-H) ,7.69(t,J=7.9Hz,1H,Ar-H),7.29(d,J=8.4Hz,1H,Ar-H),6.36(s,1H,Ar-H),4.41(t,J=6.4Hz,2H,-COOCH 2-),4.08(t,J=6.2Hz,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 (151MHz, CDCl3) δ197.56,192.67,180.82,164.32,162.76,162.58,162.33,159.84,137.91,137.71,133.85,133.59,133.39,125. 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 (II)16 )

[0160] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5p were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:10] obtained a yellow oil, 257mg, yield 43.9%. 1 H NMR (600MHz, CDCl3) δ8.34(s,1H,Ar-H),7.87(s,1H,Ar-H),7.81(d,J=7.5Hz,1H,Ar-H),7.73(s,1H,Ar-H ),7.69(t,J=8.0Hz,1H,Ar-H),7.29(d,J=8.4Hz,1H,Ar-H),6.35(s,1H,Ar-H),4.38(t,J=6.6Hz,2H,-COOC H2-),4.05(t,J=6.3Hz,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 C NMR (151MHz, CDCl3) δ197.55,192.73,180.82,164.35,164.33,162.80,1 62.78,162.54,138.10,138.08,137.68,137.66,133.86,125.21,125.19, 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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF and stirred at 70℃. After 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI and 1mmol of compound 5q were added. TLC was used to monitor the reaction progress. After the reaction was completed, the mixture was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was used for extraction 3 times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:10] was performed to obtain a yellow oil, 257mg, with a yield of 44.8%. 1 H NMR (600MHz, CDCl3) δ8.34(s,1H,Ar-H),7.87(s,1H,Ar-H),7.80(d,J=7.5Hz,1H,Ar-H),7.73(s,1H,Ar-H), 7.69(t,J=8.0Hz,1H,Ar-H),7.29(d,J=8.4Hz,1H,Ar-H),6.35(s,1H,Ar-H),4.38(t,J=6.4Hz,2H,-COOCH2- ),4.03(t,J=6.3Hz,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 H 42 N2O9,[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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF and stirred at 70℃. After 1h, 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI and 1mmol of compound 5r were added. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:10] obtained 257mg of yellow oil, with a yield of 45.7%. 1 H NMR (600MHz, CDCl3) δ8.35(s,1H,Ar-H),7.88(s,1H,Ar-H),7.80(d,J=7.1Hz,1H,Ar-H),7.72(s,1H,Ar-H),7.6 8(t,J=7.9Hz,1H,Ar-H),7.28(d,J=8.6Hz,1H,Ar-H),6.33(s,1H,Ar-H),4.36(t,J=6.4Hz,2H,-COOCH2-),4.03 (t,J=6.3Hz,2H,-OCH2-),3.82(s,3H,-OCH3),3.45(s,2H,-NCH2-),2.54(s,3H,-COCH3),2.53-2.30(m,8H,-NC H2-),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 (151MHz, CDCl3) δ197.55,192.68,180.81,164.33,162.75,162.54,162. 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 forC 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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5s were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:15] obtained a yellow oil, 257mg, yield 43.4%. 1 H NMR (600MHz, CDCl3) δ8.34(s,1H,Ar-H),7.88(s,1H,Ar-H),7.81(d,J=7.5Hz,1H,Ar-H),7.75(s,1H,A r-H),7.69(t,J=9.6Hz,1H,Ar-H),7.29(d,J=8.4Hz,1H,Ar-H),6.41(s,1H,Ar-H),4.61(t,J=6.2Hz,2H ,-COOCH2-),4.24(t,J=4.9Hz,2H,-OCH2-),3.85(s,3H,-OCH3),3.48(s,2H,-NCH2-),2.58(s,3H,-CO CH3),2.56-2.39(m,8H,-NCH2-),2.39(m,2H,-NCH2-),2.37(m,2H,-CH2-),1.04(,J=7.1Hz,3H,-CH3). 13 C NMR (151MHz, CDCl3) δ197.34,192.61,180.78,164.21,162.76,162.59,162.32,159.42,137.75,137.58,133.85,133.67,133.32,125.2 6,124.95,120.34,120.01,118.45,118.26,115.72,95.25,65.16,62.78,55.66,55.22,52.64,52.48,52.20,32.02,28.72,11.79.HRMS calcd for C 34 H 36 N2O9,[MH]+: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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5t were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:15] obtained a yellow oil, 257mg, yield 43.8%. 1 H NMR (600MHz, CDCl3) δ8.32(s,1H,Ar-H),7.86(s,1H,Ar-H),7.81(d,J=7.4Hz,1H,Ar-H),7.72(s,1H,A r-H),7.69(t,J=8.0Hz,1H,Ar-H),7.29(d,J=8.4Hz,1H,Ar-H),6.36(s,1H,Ar-H),4.45(t,J=6.2Hz,2H ,-COOCH2-),4.13(t,J=4.7Hz,2H,-OCH2-),3.83(s,3H,-OCH3),3.45(s,2H,-NCH2-),2.56(s,3H,-CO CH3),2.56-2.40(m,8H,-NCH2-),2.40(m,2H,-NCH2-),2.08(m,4H,-CH2),1.05(t,J=7.2Hz,3H,-CH3). 13 C NMR (151MHz, CDCl3) δ197.38,192.64,180.73,164.26,162.77,162.54,162.34,159.65,137.81,137.69,133.85,133.59,133.39,125.16,124. 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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5u were added after 1h. The reaction progress was detected by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:15] obtained yellow oil 7u, 257mg, yield 44.1%. 1H NMR (600MHz, CDCl3) δ8.36(s,1H,Ar-H),7.89(s,1H,Ar-H),7.83(d,J=7.4Hz,1H,Ar-H),7.73(s,1H,Ar-H) ,7.70(t,J=8.1Hz,1H,Ar-H)),7.31(d,J=8.4Hz,1H,Ar-H),6.36(s,1H,Ar-H),4.42(t,J=6.6Hz,2H,-COOCH 2-),4.08(t,J=9.5Hz,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=7.2Hz,3H,-CH3).13C NMR (151MHz, CDCl3) δ197.56,192.71,180.86,164.34,162.78,162.59,1 62.36,159.82,137.94,137.71,133.88,133.65,133.62,133.42,130.85, 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,[MH]+: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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5v were added after 1h. The reaction progress was monitored by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:15] obtained a yellow oil, 257mg, yield 44.6%. 1 H NMR (600MHz, CDCl3) δ8.34(s,1H,Ar-H),7.87(s,1H,Ar-H),7.80(d,J=7.3Hz,1H,Ar-H),7.72(s,1H,Ar-H ),7.69(t,J=7.9Hz,1H,Ar-H),7.29(d,J=8.2Hz,1H,Ar-H),6.35(s,1H,Ar-H),4.38(t,J=6.6Hz,2H,-COOC H2-),4.05(t,J=6.3Hz,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=7.1Hz,3H,-CH3). 13 C NMR (151MHz, CDCl3) δ197.63,192.66,180.82,164.34,162.74,162.59,162 .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 Calculate for C 37 H 42 N2O9, [MH]+: 657.2817, found. 657.2823. Example 63 Synthesis of 7-(2-acetyl-4-((4-ethylpiperazin-1-yl)methyl)-5-methoxyphenoxy)heptyl-2-rhein carboxylate (II)23 )

[0173] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5w were added after 1h. The reaction progress was detected by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:15] obtained a yellow oil, 257mg, yield 44.7%. 1 H NMR (600MHz, CDCl3) δ8.42(s,1H,Ar-H),7.94(s,1H,Ar-H),7.88(d,J=7.4Hz,1H,Ar-H),7.76(s,1H,Ar-H),7.74( t,J=8.4Hz,1H,Ar-H),7.34(d,J=8.4Hz,1H,Ar-H),6.38(s,1H,Ar-H),4.40(t,J=6.6Hz,2H,-COOCH2-),4.07(t,J =6.4Hz,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=7.2Hz,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] 1.5mmol (284mg) of rhein and 2mmol (276mg) of potassium carbonate were added to 10mL of DMF, stirred at 70℃, and 0.5mmol (161mg) of TBAB, 1mmol (166mg) of KI, and 1mmol of compound 5x were added after 1h. The reaction progress was detected by TLC. After the reaction was completed, the filtrate was filtered, 100mL of water was added to the filtrate, and 50mL of dichloromethane was extracted three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin layer chromatography separation [V (methanol): (dichloromethane) = 1:15] obtained a yellow oil, 257mg, yield 45.1%. 1 H NMR (600MHz, CDCl3) δ8.36(s,1H,Ar-H),7.89(s,1H,Ar-H),7.81(d,J=7.5Hz,1H,Ar-H),7.72(s,1H,Ar-H),7.68(t ,J=7.7Hz,1H,Ar-H),7.29(d,J=8.1Hz,1H,Ar-H),6.34(s,1H,Ar-H),4.36(t,J=5.3Hz,2H,-COOCH2-),4.03(t,J=6. 3Hz,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=5.5Hz,3H,-CH3). 13 C NMR (151MHz, CDCl3) δ197.72,192.69,180.88,164.38,162.75,162.61,162.34 ,160.05,138.14,137.67,133.83,133.66,133.41,125.22,124.83,120.29,12 0.12,119.92,118.14,117.87,115.77,95.05,68.68,66.11,55.61,55.55,55. 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] Example 65 Pharmacological Experimental Study on Anti-Proliferation Activity of the Compounds of the Invention on Cancer Cells

[0178] Compound I was tested by MTT assay using 5-FU and paeonol, two commonly used anti-tumor drugs in clinical practice, as positive controls. 1-6 , Ⅱ 1-24 In vitro anti-cell proliferation activity 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 were routinely cultured in an incubator at 37°C and 5% CO2 saturated humidity. Cancer cells in good growth state during the logarithmic growth phase were digested with 0.25% trypsin to make the adherent cells fall off, and the cell count was (2-3)×10 4 / mL, then inoculate about 5000 cells per well into a 96-well plate and incubate in an incubator for 24 hours. Replace the culture medium, add the test drug (0.1-25.0μmol / L, 5 concentrations), 100μL per well, and continue to culture in an incubator at 37°C, 5% CO2 saturated humidity for 72 hours. Add MTT reagent to a 96-well plate, 20μL per well, and incubate in an incubator for 4 hours. Aspirate the supernatant, add DMSO, 120μL per well, shake on a flat shaker for 10 minutes, and use an enzyme-linked immunosorbent assay to measure the absorbance of each well at a wavelength of 495nm. All experiments were repeated 3 times under the same conditions to calculate the cell inhibition rate.

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

[0181] IC was calculated using SPSS (Staffstical Package for the Social Science) 17.0 using the probability unit weighted regression method (Bliss method). 50 Some experimental results are shown in Table 1.

[0182] Table 1 Experimental results

[0183]

[0184]

[0185] From the above results, it can be seen that compared with the commonly used clinical anti-tumor drugs fluorouracil and paeonol, the in vitro anti-proliferation activity of the conjugates of the present invention is significantly higher against human liver cancer cells (HepG2) and human lung cancer cells (A549), and the in vitro anti-proliferation activity of most compounds against human cervical cancer cells (Hela), human colon cancer cells (HT29) and human osteosarcoma cells (U2OS) is significantly better than that of fluorouracil and paeonol, indicating that the anti-tumor effect is excellent.

[0186] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of 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 general formula (I) or (II) or a pharmaceutically acceptable salt thereof: Wherein, n is an integer of 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substitution is substitution with a C1 to C6 alkyl group.

2. The paeonol Mannich base-rhein conjugate according to claim 1, characterized in that: The R is a substituted or unsubstituted five-membered or six-membered nitrogen-containing heterocyclic group.

3. The paeonol Mannich base-rhein conjugate according to claim 1, characterized in that: The substitution is substitution with a C1-C3 alkyl group.

4. The paeonol Mannich base-rhein conjugate according to claim 1, characterized in that: The R is selected from morpholinyl, piperidinyl, 4-methylpiperazinyl or 4-ethylpiperazinyl.

5. A method for preparing a paeonol Mannich base-rhein conjugate represented by formula (I) or (II), characterized in that: The preparation method comprises: 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 of 3 to 8; R is a substituted or unsubstituted nitrogen-containing heterocyclic group, and the substitution is substitution with a C1 to C6 alkyl group.

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

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

8. The preparation method according to claim 7, characterized in that: The preparation method of the compound represented by one of the formula (2) or formula (3) comprises: subjecting paeonol to a Mannich reaction with paraformaldehyde and a nitrogen-containing heterocyclic compound.

9. A pharmaceutical composition, characterized in that: The pharmaceutical composition is composed of the conjugate according to any one of claims 1 to 4 as the sole or main active ingredient and a pharmaceutically acceptable carrier or auxiliary ingredient.

10. Use of the conjugate according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 9 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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