A class of 10-aralkyloxy camptothecin compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions and applications thereof

Abstract

The present application relates to the technical field of anticancer drug preparation, in particular to a kind of 10-aralkyloxy camptothecin compound or its pharmaceutically acceptable salt, pharmaceutical composition and application thereof, and the 10-aralkyloxy camptothecin compound has the following general formula:

Description

Technical Field

[0001] This invention relates to the field of anticancer drug preparation technology, specifically to a class of 10-arylalkoxycamptothecin compounds or their pharmaceutically acceptable salts, pharmaceutical compositions and their applications. Background Technology

[0002] Currently, the main treatments for cancer remain surgery, radiation therapy, and drug therapy, with drug therapy still playing a significant role. Therefore, researching and developing new anti-cancer drugs is of great importance.

[0003] Over the past two decades, kinase inhibitors have become a hot topic in anti-tumor drug research, with more than 30 kinase inhibitors on the market. For example, epidermal growth factor tyrosine kinase inhibitors such as gefitinib and osimertinib, Bruton's tyrosine inhibitor ibrutinib, and BRAF inhibitor vemurafenib are used as anti-cancer drugs to treat lung cancer, leukemia, melanoma, and other cancers. However, kinase inhibitors are prone to acquired resistance, have a narrow anti-tumor spectrum, and are expensive. In particular, after several generations of treatment with kinase inhibitors, acquired tumor mutations become more dispersed, and this highly dispersed and heterogeneous mutation becomes a significant limitation for kinase inhibitors targeting tumors.

[0004] Therefore, the development of a new generation of broad-spectrum anticancer chemotherapy drugs remains necessary. Topoisomerase I is highly expressed in tumor cells, and camptothecin-based topoisomerase I inhibitors possess broad-spectrum antitumor effects. 10-hydroxycamptothecin is an alkaloid isolated from the camptotheca tree; it exhibits strong cytotoxicity and shows good efficacy against gastrointestinal tumors, liver cancer, bladder cancer, and leukemia, but it is highly toxic, poorly water-soluble, and cannot be administered orally. Therefore, the continued design, synthesis, and evaluation of camptothecin derivatives, and the discovery of novel, highly effective, and low-toxicity camptothecin-based antitumor chemotherapy drugs, remain of great significance.

[0005] In view of the above-mentioned defects, the inventors of this invention have finally obtained this invention after a long period of research and practice. Summary of the Invention

[0006] The purpose of this invention is to design, synthesize, and evaluate camptothecin derivatives, discover novel, highly effective, and low-toxic camptothecin-based antitumor chemotherapy drugs, and to provide a class of 10-arylalkoxy camptothecin compounds or their pharmaceutically acceptable salts, pharmaceutical compositions, and their applications.

[0007] To achieve the above objectives, this invention discloses a class of 10-arylalkoxycamptothecin compounds or pharmaceutically acceptable salts thereof, wherein the 10-arylalkoxycamptothecin compounds have the following general formula:

[0008] ,

[0009] R1 is hydrogen or ethyl.

[0010] R2 is any one of methyl, ethyl, propyl, or 2-carbonylethyl;

[0011] A is selected from any one of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, β-naphthyl, 2-benzofuranyl, 2-furanyl, 2-thienyl, 2-thiazolyl, 3-isopropoxyphenyl, 3-isobutoxyphenyl, 3-cyclobutoxyphenyl, 3-cyclopentoxyphenyl, 3-bromo-4-methylphenyl, 3,4-dimethylphenyl, 3-methoxy-4-methylphenyl, and 3-methyl-4-methoxyphenyl.

[0012] The 10-arylalkoxycamptothecin compound is any one of the following compounds:

[0013] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0014] The present invention also discloses a pharmaceutical composition comprising one or more therapeutically effective amounts of the 10-arylalkoxycamptothecin compound as described above or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0015] The excipients are any one or a combination of several of the following: stabilizers, solubilizers, lubricants, and disintegrants.

[0016] The excipients are any one or more combinations of starch, dextrin, glucose, lactose, cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, Twenty-80, polyvinyl alcohol, magnesium stearate, and talc.

[0017] This invention also discloses the use of the above-mentioned 10-arylalkoxycamptothecin compounds or their pharmaceutically acceptable salts in the preparation of anticancer drugs.

[0018] The dosage form of the drug is tablets, capsules, or injections.

[0019] Each of the tablets, capsules, or injections contains 10 to 50 mg of a 10-aryloxycamptothecin compound.

[0020] The 10-arylalkoxycamptothecin compounds, in combination with antimetabolites, anticancer drugs, EGFR inhibitors, or BTK inhibitors, form a drug complex.

[0021] The anticancer drugs include anti-lung cancer drugs and anti-colon cancer drugs.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] 1. The 10-arylalkoxycamptothecin-like compounds in this invention have novel structures. The compounds involved in this invention have an acetamide structural fragment attached to the 10-hydroxycamptothecin structure, which is novel. No literature reports were found after searching.

[0024] 2. The 10-arylalkoxycamptothecin-like compounds in this invention have better antitumor activity. For example, compound B22 is a derivative of 10-hydroxycamptothecin; compound C6 is a derivative of SN-38. The in vitro anti-proliferation activity of compounds B22 and C6 is stronger than that of 10-hydroxycamptothecin and SN-38, respectively.

[0025] 3. The 10-arylalkoxycamptothecin compounds in this invention have low toxicity. At the same dose, compound C6 (a derivative of SN-38) administered intravenously to mice at 2 mg / kg is more effective than N-38.

[0026] Based on the above, the 10-arylalkoxycamptothecin compounds of this invention can be used to prepare anticancer drug formulations, providing more options for the clinical treatment of cancer. Attached Figure Description

[0027] Figure 1 The inhibitory effect of compound C6 on HCT116 subcutaneous xenografts in nude mice is shown in the following figures: (A) is a representative photograph of the dissected tumor in each group; (B) is the tumor volume growth curve; (C) is the quantitative comparison of tumor weight; (D) is the mouse body weight change curve. Compared with the solvent control group, * (p<0.05) and ** (p<0.01) are shown.

[0028] Figure 2 In the image, (A) shows the hematoxylin-eosin (H&E) staining results of heart, liver, spleen, lung, and kidney tissues (magnification 20x), and (B) shows the hematoxylin-eosin (H&E) staining and Ki67 immunohistochemical staining results of tumor tissue (magnification 20x).

[0029] Figure 3 The hemolytic activity of compound C6 at different concentrations was measured. Detailed Implementation

[0030] The above-mentioned and other technical features and advantages of the present invention will be described in more detail below with reference to the accompanying drawings.

[0031] The structural formulas of the compounds involved in the following examples are shown below:

[0032] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0033] Example 1

[0034] Synthesis of compound A1:

[0035] 5 mL of DMF was added to 10-HCPT (1.0 mmol) and benzyl bromide (1.2 mmol), followed by dropwise addition of triethylamine (1.5 mmol) at room temperature. The resulting reaction solution was stirred at room temperature for 12 h, and the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, saturated brine was added to quench the reaction, and the aqueous phase was extracted three times with ethyl acetate. All organic phases were combined, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The crude product was purified by silica gel column chromatography using dichloromethane-methanol (20:1 v / v) as the eluent to obtain the target product A1.

[0036] The characterization data of compound A1 are as follows:

[0037] 1 H NMR (600 MHz, DMSO-d6) δH 8.54 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J = 19.2 Hz, 3H), 7.43 (s, 2H), 7.37 (s, 1H), 7.29 (s,1H), 6.50 (s, 1H), 5.42 (s, 2H), 5.28 (d, J = 16.6 Hz, 4H), 1.87 (s, 2H), 0.88 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δC 172.99, 157.62, 157.28, 150.68,150.51, 146.17, 144.48, 136.94, 131.02, 130.68, 130.44, 129.75, 128.99,128.55, 128.46, 123.70, 118.85, 107.90, 96.54, 72.87, 70.26, 65.71, 50.66,30.73, 8.24. ESI-MS m / z: 455.1[M+ H] + .

[0038] Example 2

[0039] Synthesis of compound A2:

[0040] The difference between this embodiment and Example 1 is that (2-bromoethyl)benzene is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound A2 are as follows:

[0041] 1 H NMR (600 MHz, DMSO-d6) δH 8.49 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.46 (dd, J = 9.2, 2.8 Hz, 1H), 7.39 (d, J = 7.0Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.26 (d, J = 10.9 Hz, 2H), 6.51 (s, 1H), 5.41 (s, 2H), 5.23 (s, 2H), 4.36 (t, J = 7.0 Hz, 2H), 3.19 – 3.12 (m, 3H),1.86 (dp, J = 21.3, 7.1 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δC 157.71, 157.30, 150.55, 150.53, 146.19, 144.41, 138.60, 130.94,130.60, 130.43, 129.87, 129.51, 128.86, 126.87, 123.59, 118.79, 107.42,96.55, 72.87, 69.23, 65.70, 50.65, 49.07, 35.25, 30.73, 8.23. ESI-MS m / z:469.1 [M+ H] + .

[0042] Example 3

[0043] Synthesis of compound A3:

[0044] The difference between this embodiment and Example 1 is that (3-bromopropyl)benzene is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound A3 are as follows:

[0045] 1 H NMR (600 MHz, DMSO-d6) δ H 8.47 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.48 (dd, J = 9.2, 2.7 Hz, 1H), 7.45 (s, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.27(d, J = 5.6 Hz, 3H), 7.20 (t, J = 7.2 Hz, 1H), 6.50 (s, 1H), 5.41 (s, 2H), 5.21 (s, 2H), 4.13 (t, J = 6.4 Hz, 2H), 2.80 (t, J = 7.7 Hz, 2H), 2.12 (p, J= 6.7 Hz, 2H), 1.87 (dp, J = 21.3, 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6) δ C173.00, 157.91, 157.26, 150.50, 146.19, 144.40,141.77, 130.93, 130.54, 130.34, 129.84, 128.84, 126.36, 123.61, 118.78,107.24, 96.49, 72.87, 67.76, 65.71, 50.62, 31.94, 30.74, 30.68, 8.24. ESI-MSm / z: 483.1 [M+ H] + .

[0046] Example 4

[0047] Synthesis of compound A4:

[0048] The difference between this embodiment and Example 1 is that 2-bromoacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound A4 are as follows:

[0049] 1 H NMR (600 MHz, DMSO-d6) δH 8.47 (s, 1H), 8.15 – 8.00 (m, 3H), 7.73(t, J = 7.4 Hz, 1H), 7.61 (q, J = 6.7, 5.5 Hz, 3H), 7.55 (s, 1H), 7.28 (s,1H), 6.51 (s, 1H), 5.80 (s, 2H), 5.41 (s, 2H), 5.23 (s, 2H), 1.87 (dp, J =21.2, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δC194.39, 172.99, 157.29, 157.26, 150.80, 150.52, 146.18, 144.53, 134.84,134.38, 130.98, 130.69, 130.45, 129.67, 129.36, 128.40, 123.36, 118.89,108.12, 96.56, 72.87, 71.02, 65.71, 50.69, 30.74, 8.25. ESI-MS m / z: 483.1 [M+H] + .

[0050] Example 5

[0051] Synthesis of compound B1:

[0052] The difference between this embodiment and Example 1 is that 2-bromo-1-(2-fluorophenyl)ethyl ketone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B1 are as follows:

[0053] 1 H NMR (600 MHz, DMSO-d6) δ H 8.47 (s, 1H), 8.13 – 8.04 (m, 2H), 7.94(d, J = 7.9 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.55(d, J = 7.1 Hz, 2H), 7.28 (s, 1H), 6.51 (s, 1H), 5.61 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 1.87 (dp, J = 21.1, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6) δ C 193.82, 172.99, 157.29, 157.05, 150.89, 150.75,150.51, 146.15, 144.58, 139.47, 131.04, 130.73, 130.46, 129.94, 129.63,124.38, 123.28, 118.92, 108.23, 96.60, 72.87, 71.41, 65.71, 50.70, 30.74,8.25. ESI-MS m / z: 501.1 [M+ H] + .

[0054] Example 6

[0055] Synthesis of compound B2:

[0056] The difference between this embodiment and Example 1 is that 2-bromo-1-(3-fluorophenyl)ethyl ketone was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B2 are as follows:

[0057] 1 H NMR (600 MHz, DMSO-d6) δ H8.52 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.73 (q, J = 7.4 Hz, 1H), 7.67 – 7.62 (m, 3H), 7.34 (s, 1H), 6.56 (s, 1H), 5.85 (s, 2H), 5.47 (s, 2H), 5.29 (s, 2H), 1.92 (dd, J = 13.6, 7.0 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6) δ C 193.49, 172.99, 163.50, 161.88, 157.29, 157.15, 150.85, 150.52, 146.18, 144.56, 136.95, 136.91, 131.64, 131.59, 131.00, 130.73, 130.45, 129.66, 124.61, 123.32, 121.32, 121.18, 118.90, 115.13, 114.98, 108.18, 96.58, 72.87, 71.15, 65.71, 50.71, 30.74, 8.25. ESI-MS m / z:501.1 [M+ H] + .

[0058] Example 7

[0059] Synthesis of compound B3:

[0060] The difference between this embodiment and Example 1 is that 2-bromo-1-(4-fluorophenyl)ethyl ketone was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B3 are as follows:

[0061] 1 H NMR (600 MHz, DMSO-d6) δ H8.45 (s, 1H), 8.21 – 8.13 (m, 2H), 8.07(d, J = 9.2 Hz, 1H), 7.58 (d, J = 9.5 Hz, 1H), 7.54 (s, 1H), 7.45 (t, J = 7.9Hz, 2H), 7.28 (s, 1H), 6.51 (s, 1H), 5.77 (s, 2H), 5.41 (s, 2H), 5.22 (s,2H), 1.87 (dp, J = 21.4, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150MHz, DMSO-d6) δ C 193.05, 172.99, 166.71, 165.04, 157.28, 157.20, 150.79,150.51, 146.15, 144.52, 131.62, 131.60, 131.52, 131.45, 130.97, 130.67,130.42, 129.63, 123.31, 118.89, 116.50, 116.36, 108.11, 96.56, 72.87, 70.94,65.71, 50.67, 30.75, 8.25. ESI-MS m / z: 501.1 [M+ H] + .

[0062] Example 8

[0063] Synthesis of compound B4:

[0064] The difference between this embodiment and Example 1 is that 2-bromo-1-(2-chlorophenyl)ethyl ketone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B4 are as follows:

[0065] 1 H NMR (600 MHz, DMSO-d6) δ H8.54 (s, 1H), 8.13 (d, J = 9.1 Hz, 1H), 7.97 (d, J = 7.1 Hz, 1H), 7.67 (d, J = 3.2 Hz, 2H), 7.62 – 7.57 (m, 3H), 7.34(s, 1H), 6.56 (s, 1H), 5.64 (s, 2H), 5.47 (s, 2H), 5.29 (s, 2H), 1.92 (dp, J= 21.2, 7.2 Hz, 2H), 1.28 (s, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 197.24, 172.99, 157.29, 156.84, 150.95, 150.51, 146.13, 144.59,135.93, 133.53, 131.10, 131.08, 130.81, 130.77, 130.53, 130.18, 129.57,127.86, 123.22, 118.94, 108.20, 96.61, 72.87, 72.58, 65.71, 50.69, 30.74,8.25. ESI-MS m / z: 517.1 [M+ H] + .

[0066] Example 9

[0067] Synthesis of compound B5:

[0068] The difference between this embodiment and Example 1 is that 2-bromo-1-(3-chlorophenyl)ethyl ketone was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B5 are as follows:

[0069] 1 H NMR (600 MHz, DMSO-d6) δ H8.47 (s, 1H), 8.10 (d, J = 13.5 Hz, 2H), 8.02 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.29 (s, 1H), 6.51 (s, 1H), 5.81 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 1.88 (dp, J = 13.3, 6.5 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6) δ C 193.46, 172.99, 157.27, 157.11, 150.80, 150.51,146.15, 144.53, 136.63, 134.27, 134.01, 131.34, 130.97, 130.66, 130.41,129.63, 128.16, 127.00, 123.29, 118.89, 108.15, 96.57, 72.87, 65.71, 50.68,30.75, 8.25. ESI-MS m / z: 517.1 [M+ H] + .

[0070] Example 10

[0071] Synthesis of compound B6:

[0072] The difference between this embodiment and Example 1 is that 2-bromo-1-(4-chlorophenyl)ethyl ketone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B6 are as follows:

[0073] 1 H NMR (600 MHz, DMSO-d6) δ H8.45 (s, 1H), 8.08 (t, J = 8.5 Hz, 3H), 7.69 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 9.2 Hz, 1H), 7.55 (s, 1H), 7.27 (s,1H), 6.50 (s, 1H), 5.77 (s, 2H), 5.41 (s, 2H), 5.22 (s, 2H), 1.87 (dp, J =21.2, 7.2 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.51, 172.99, 157.27, 157.15, 150.80, 150.51, 146.15, 144.53, 139.25,133.51, 130.98, 130.67, 130.42, 130.34, 129.62, 129.46, 123.30, 118.89,108.12, 96.57, 72.87, 71.01, 65.71, 50.68, 30.75, 8.25. ESI-MS m / z: 517.1 [M+H] + .

[0074] Example 11

[0075] Synthesis of compound B7:

[0076] The difference between this embodiment and Example 1 is that 2-bromo-1-(2-bromophenyl)ethyl ketone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B7 are as follows:

[0077] 1 H NMR (600 MHz, DMSO-d6) δ H 8.55 (s, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.66 – 7.55 (m, 4H), 7.34(s, 1H), 6.56 (s, 1H), 5.61 (s, 2H), 5.47 (s, 2H), 5.30 (s, 2H), 1.93 (dp, J= 20.4, 7.2 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ C 198.21, 172.98, 157.29, 156.80, 150.97, 150.51, 146.13, 144.61, 138.02,134.22, 133.43, 131.09, 130.78, 130.56, 129.98, 129.57, 123.24, 119.07,118.95, 108.25, 96.61, 72.87, 72.34, 65.71, 50.69, 30.74, 8.25. ESI-MS m / z:561.1 [M+ H] + .

[0078] Example 12

[0079] Synthesis of compound B8:

[0080] The difference between this embodiment and Example 1 is that 2-bromo-1-(3-bromophenyl)ethyl ketone was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B8 are as follows:

[0081] 1 H NMR (600 MHz, DMSO-d6) δ H 8.49 (s, 1H), 8.23 ​​(s, 1H), 8.08 (dd, J =26.4, 8.5 Hz, 2H), 7.93 (d, J = 7.1 Hz, 1H), 7.66 – 7.55 (m, 3H), 7.29 (s,1H), 6.50 (s, 1H), 5.81 (s, 2H), 5.42 (s, 2H), 5.25 (s, 2H), 1.87 (dp, J =21.0, 7.5 Hz, 2H), 0.89 (d, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C193.41, 172.99, 157.28, 157.12, 150.80, 150.51, 146.16, 144.54, 136.91,136.84, 131.58, 131.00, 130.67, 130.42, 129.64, 127.36, 123.30, 122.72,118.89, 108.17, 96.58, 72.87, 71.07, 65.71, 50.68, 30.75, 8.26. ESI-MS m / z:561.1 [M+ H] + .

[0082] Example 13

[0083] Synthesis of compound B9:

[0084] The difference between this embodiment and Example 1 is that 2-bromo-1-(4-bromophenyl)ethyl ketone was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B9 are as follows:

[0085] 1 H NMR (600 MHz, DMSO-d6) δ H 8.46 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 9.3 Hz, 1H), 7.55 (s, 1H), 7.28 (s, 1H), 6.50 (s, 1H), 5.76 (s, 2H), 5.41 (s, 2H), 5.23(s, 2H), 1.88 (dp, J = 20.3, 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.74, 172.99, 157.28, 157.16, 150.83, 150.51, 146.16,144.54, 133.83, 132.41, 130.99, 130.70, 130.42, 129.64, 128.46, 123.31,118.90, 108.14, 96.57, 72.87, 70.99, 65.71, 50.69, 30.74, 8.25. ESI-MS m / z:561.1 [M+ H]+ .

[0086] Example 14

[0087] Synthesis of compound B10:

[0088] The difference between this embodiment and Example 1 is that 2-bromo-2'-(trifluoromethyl)acetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B10 are as follows:

[0089] 1 H NMR (600 MHz, DMSO-d6) δ H 8.49 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.97 (t, J = 7.5 Hz, 1H), 7.79 – 7.74 (m, 1H), 7.59 (d, J = 11.4 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.29 (s, 1H), 6.50 (s, 1H), 5.61 (s, 2H), 5.42(s, 2H), 5.24 (s, 2H), 1.87 (dp, J = 21.4, 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz,3H). 13 C NMR (150 MHz, DMSO-d6) δ C 198.50, 172.99, 157.29, 156.71, 150.03,150.51, 146.13, 144.63, 136.37, 133.09, 132.23, 131.09, 130.84, 130.51,129.55, 129.08, 123.20, 118.96, 108.23, 96.62, 72.87, 72.38, 65.71, 50.71,30.73, 8.24. ESI-MS m / z: 551.1 [M+ H] + .

[0090] Example 15

[0091] Synthesis of compound B11:

[0092] The difference between this embodiment and Example 1 is that 2-bromo-3'-(trifluoromethyl)acetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B11 are as follows:

[0093] 1H NMR (600 MHz, DMSO-d6) δ H 8.49 (s, 1H), 8.36 (d, J = 10.0 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 7.90 – 7.83 (m, 1H), 7.67 – 7.58 (m, 2H), 7.29 (s,1H), 6.51 (s, 1H), 5.89 (s, 2H), 5.42 (s, 2H), 5.25 (s, 2H), 1.87 (dp, J =20.1, 7.3 Hz, 2H), 0.89 (t, J = 7.5 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 195.02, 172.99, 159.78, 157.39, 157.31, 150.75, 150.54, 146.23, 144.49,135.47, 130.96, 130.65, 130.51, 130.37, 129.70, 124.95, 123.39, 121.26,118.87, 113.18, 107.90, 96.55, 74.11, 72.87, 65.71, 56.56, 50.67, 30.73,8.25. ESI-MS m / z: 551.1 [M+ H] + .

[0094] Example 16

[0095] Synthesis of compound B12:

[0096] The difference between this embodiment and Example 1 is that 2-bromo-4'-(trifluoromethyl)acetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B12 are as follows:

[0097] 1 H NMR (600 MHz, DMSO-d6) δ H8.45 (s, 1H), 8.28 (s, 2H), 8.08 (d, J =9.1 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.62 – 7.57 (m, 2H), 7.28 (s, 1H), 6.50 (s, 1H), 5.84 (s, 2H), 5.41 (s, 2H), 5.22 (s, 2H), 1.87 (dp, J = 21.5,7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.01,172.99, 157.28, 157.09, 150.84, 150.51, 146.15, 144.56, 138.04, 133.64,133.43, 131.01, 130.69, 130.43, 129.63, 129.30, 126.31, 126.29, 123.28,118.90, 108.16, 96.58, 72.87, 71.26, 65.71, 50.68, 30.75, 8.25. ESI-MS m / z:551.1 [M+ H] + .

[0098] Example 17

[0099] Synthesis of compound B13:

[0100] The difference between this embodiment and Example 1 is that 2-bromo-2'-nitroacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B13 are as follows:

[0101] 1 H NMR (600 MHz, DMSO-d6) δ H8.48 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.94 (t, J = 7.5 Hz, 1H), 7.89 – 7.82 (m, 2H), 7.57(s, 1H), 7.42 (d, J = 12.0 Hz, 1H), 7.27 (s, 1H), 6.51 (s, 1H), 5.42 (d, J =6.5 Hz, 4H), 5.24 (s, 2H), 1.87 (dp, J = 21.2, 7.1 Hz, 2H), 0.88 (t, J = 7.3Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 198.26, 172.98, 157.27, 156.40, 150.09,150.49, 146.97, 146.08, 144.63, 135.21, 133.62, 132.75, 131.12, 130.83,130.56, 129.48, 129.45, 124.70, 122.93, 118.98, 108.30, 96.64, 72.86, 72.34,65.71, 50.70, 30.74, 8.24. ESI-MS m / z: 528.1 [M+ H] + .

[0102] Example 18

[0103] Synthesis of compound B14:

[0104] The difference between this embodiment and Example 1 is that 2-bromo-3'-nitroacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B14 are as follows:

[0105] 1 H NMR (600 MHz, DMSO-d6) δ H8.78 (s, 1H), 8.56 (d, J = 8.2 Hz, 1H), 8.52 – 8.47 (m, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.95 – 7.91 (m, 1H), 7.64 (d,J = 10.7 Hz, 2H), 7.29 (s, 1H), 6.51 (s, 1H), 5.90 (s, 2H), 5.42 (s, 2H), 5.25 (s, 2H), 1.87 (dp, J = 21.5, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6) δ C 193.20, 172.99, 157.28, 157.05, 150.86, 150.51,148.52, 146.14, 144.56, 136.01, 134.68, 131.17, 131.01, 130.69, 130.43,129.62, 128.45, 123.26, 122.87, 118.91, 108.25, 96.60, 72.87, 71.29, 65.71,50.69, 30.75, 8.25. ESI-MS m / z: 528.1 [M+ H] + .

[0106] Example 19

[0107] Synthesis of compound B15:

[0108] The difference between this embodiment and Example 1 is that 2-bromo-4'-nitroacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B15 are as follows:

[0109] 1 H NMR (600 MHz, DMSO-d6) δ H8.46 (s, 1H), 8.43 (d, J = 7.1 Hz, 2H), 8.31 (d, J = 7.1 Hz, 2H), 8.09 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 11.0 Hz, 2H), 7.28 (s, 1H), 6.51 (s, 1H), 5.85 (s, 2H), 5.41 (s, 2H), 5.23 (s, 2H), 1.87 (dp, J = 21.2, 7.3 Hz, 2H), 0.91 – 0.88 (m, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.26, 172.99, 157.31, 157.10, 150.93, 150.53, 148.54, 146.19, 144.60,136.04, 134.70, 131.19, 131.04, 130.79, 129.68, 128.47, 123.32, 122.89,118.93, 108.32, 96.60, 72.87, 71.31, 65.71, 50.73, 30.72, 8.24. ESI-MS m / z:528.1 [M+ H] + .

[0110] Example 20

[0111] Synthesis of compound B16:

[0112] The difference between this embodiment and Example 1 is that 2-bromo-3'-cyanoacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B16 are as follows:

[0113] 1 H NMR (600 MHz, DMSO-d6) δ H8.58 (s, 1H), 8.48 (s, 1H), 8.33 (d, J =8.0 Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.83 (s,1H), 7.62 (d, J = 9.9 Hz, 2H), 7.30 (s, 1H), 6.51 (s, 1H), 5.84 (s, 2H), 5.42(s, 2H), 5.26 (s, 2H), 1.88 (d, J = 16.6 Hz, 2H), 0.89 (s, 3H). 13 C NMR (150MHz, DMSO-d6) δ C 198.50, 172.99, 157.28, 156.70, 150.00, 150.51, 146.11,144.62, 136.37, 133.09, 132.23, 131.08, 130.81, 130.49, 129.53, 129.08,126.85, 126.64, 123.19, 118.95, 108.20, 96.62, 72.87, 72.38, 65.71, 50.70,30.74, 8.24. ESI-MS m / z: 508.1 [M+ H] + .

[0114] Example 21

[0115] Synthesis of compound B17:

[0116] The difference between this embodiment and Example 1 is that 2-bromo-4'-cyanoacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B17 are as follows:

[0117] 1 H NMR (600 MHz, DMSO-d6) δ H8.45 (s, 1H), 8.22 (d, J = 8.1 Hz, 2H), 8.10 (dd, J = 15.2, 8.5 Hz, 3H), 7.60 (dd, J = 12.1, 3.1 Hz, 2H), 7.28 (s,1H), 6.51 (s, 1H), 5.82 (s, 2H), 5.41 (s, 2H), 5.23 (s, 2H), 1.87 (dp, J =21.2, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.97, 172.99, 157.28, 157.07, 150.86, 150.51, 146.15, 144.56, 138.01,133.35, 131.01, 130.71, 130.44, 129.63, 129.08, 123.27, 118.91, 118.59,116.17, 108.19, 96.59, 72.87, 71.30, 65.71, 50.70, 30.74, 8.25. ESI-MS m / z:508.1 [M+ H] + .

[0118] Example 22

[0119] Synthesis of compound B18:

[0120] The difference between this embodiment and Example 1 is that 2-bromo-2'-methylacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B18 are as follows:

[0121] 1 H NMR (600 MHz, DMSO-d6) δ H8.53 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.62 – 7.56 (m, 3H), 7.47 – 7.41 (m, 2H), 7.32 (s,1H), 6.56 (s, 1H), 5.67 (s, 2H), 5.46 (s, 2H), 5.27 (s, 2H), 2.49 (s, 3H), 1.92 (dp, J = 21.2, 7.2 Hz, 2H), 0.94 (td, J = 7.3, 1.5 Hz, 3H). 13 C NMR (150MHz, DMSO-d6) δ C 198.18, 172.99, 157.28, 157.16, 150.79, 150.52, 146.16,144.51, 138.29, 135.25, 132.55, 132.32, 130.98, 130.69, 130.42, 129.65,129.27, 126.40, 123.33, 118.89, 107.99, 96.56, 72.87, 72.03, 65.71, 50.67,30.74, 21.08, 8.25. ESI-MS m / z: 497.1 [M+ H] + .

[0122] Example 23

[0123] Synthesis of compound B19:

[0124] The difference between this embodiment and Example 1 is that 2-bromo-3'-methylacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B19 are as follows:

[0125] 1 H NMR (600 MHz, DMSO-d6) δ H8.46 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 13.2 Hz, 2H), 7.59 (d, J = 12.0 Hz, 1H), 7.54 (d, J = 10.1 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 7.28 (s, 1H), 6.50 (s, 1H), 5.77 (s, 2H), 5.41(s, 2H), 5.22 (s, 2H), 2.43 (s, 3H), 1.87 (dp, J = 21.5, 7.2 Hz, 2H), 0.89(t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.39, 172.99, 157.28,157.25, 150.77, 150.52, 146.17, 144.52, 138.79, 134.96, 134.86, 130.96,130.67, 130.42, 129.65, 129.24, 128.71, 125.61, 123.35, 118.88, 108.08,96.56, 72.87, 70.99, 65.71, 50.68, 30.74, 21.36, 8.25. ESI-MS m / z: 497.1 [M+H] + .

[0126] Example 24

[0127] Synthesis of compound B20:

[0128] The difference between this embodiment and Example 1 is that 2-bromo-4'-methylacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B20 are as follows:

[0129] 1 H NMR (600 MHz, DMSO-d6) δ H8.44 (s, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 6.5 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J= 7.8 Hz, 2H), 0.88 (t, J = 7.3Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.83, 172.99, 157.27, 150.74, 150.51,146.15, 144.88, 144.50, 132.34, 130.95, 130.63, 130.40, 129.86, 129.63,128.48, 123.33, 118.87, 108.05, 96.56, 72.87, 70.89, 65.71, 50.66, 30.75,21.74, 8.25. ESI-MS m / z: 497.1 [M+ H] + .

[0130] Example 25

[0131] Synthesis of compound B21:

[0132] The difference between this embodiment and Example 1 is that 2-bromo-2'-methoxyacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B21 are as follows:

[0133] 1 H NMR (600 MHz, DMSO-d6) δ H8.50 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 4.9 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.50 (s,1H), 5.52 (s, 2H), 5.41 (s, 2H), 5.24 (s, 2H), 4.01 (s, 3H), 1.87 (dp, J =21.4, 14.2, 7.3 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6)δ C 194.11, 172.99, 157.29, 157.12, 154.43, 150.84, 150.52, 149.65, 146.16,144.56, 135.91, 131.00, 130.70, 130.45, 130.43, 129.64, 124.52, 123.29,118.90, 108.20, 96.59, 72.87, 71.16, 65.71, 50.69, 30.74, 8.25. ESI-MS m / z:513.1 [M+ H] + .

[0134] Example 26

[0135] Synthesis of compound B22:

[0136] The difference between this embodiment and Example 1 is that 2-bromo-3'-methoxyacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B22 are as follows:

[0137] 1 H NMR (600 MHz, DMSO-d6) δ H8.48 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.57 – 7.52 (m, 3H), 7.30 (d, J = 13.8 Hz, 2H), 6.51 (s, 1H), 5.79 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 3.86 (s, 3H), 1.87 (dp, J = 21.5, 7.2 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13 CNMR (150 MHz, DMSO-d6) δ C 194.23, 172.99, 159.99, 157.31, 157.26, 150.84,150.53, 146.20, 144.55, 136.15, 130.99, 130.73, 130.58, 130.48, 129.68,123.37, 120.82, 120.27, 118.90, 113.08, 108.17, 96.57, 72.87, 71.09, 65.71,55.94, 50.71, 40.53, 30.73, 8.25. ESI-MS m / z: 513.1 [M+ H] + .

[0138] Example 27

[0139] Synthesis of compound B23:

[0140] The difference between this embodiment and Example 1 is that 2-bromo-4'-methoxyacetophenone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B23 are as follows:

[0141] 1 H NMR (600 MHz, DMSO-d6) δ H8.45 (s, 1H), 8.06 (t, J = 9.7 Hz, 3H), 7.57 (d, J = 9.5 Hz, 1H), 7.50 (s, 1H), 7.28 (s, 1H), 7.12 (d, J = 7.2 Hz, 2H), 6.50 (s, 1H), 5.70 (s, 2H), 5.41 (s, 2H), 5.21 (s, 2H), 3.88 (s, 3H), 1.87 (dp, J = 20.5, 6.9, 6.3 Hz, 2H), 0.91 – 0.87 (m, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 192.67, 172.99, 164.13, 157.33, 157.27, 150.74, 150.51, 146.17,144.50, 130.95, 130.75, 130.64, 130.41, 129.63, 127.73, 123.35, 118.87,114.57, 108.05, 96.55, 72.87, 70.72, 65.71, 56.13, 50.66, 30.75, 8.25. ESI-MSm / z: 484.1 [M+ H] + .

[0142] Example 28

[0143] Synthesis of compound B24:

[0144] The difference between this embodiment and Example 1 is that 2-(2-bromoacetyl)pyridine is used instead of benzyl bromide, while other process conditions remain the same. The characterization data of the obtained compound B24 are as follows:

[0145] 1 H NMR (600 MHz, DMSO-d6) δ H8.82 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 8.08 (t, J = 9.6 Hz, 2H), 8.02 (d, J = 7.8 Hz, 1H), 7.79 – 7.75 (m, 1H), 7.59(d, J = 9.3 Hz, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 6.50 (s, 1H), 5.91 (s, 2H), 5.41 (s, 2H), 5.21 (s, 2H), 1.86 (dp, J = 21.1, 7.2 Hz, 2H), 0.91 – 0.86 (m,3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.90, 172.98, 157.28, 150.89, 150.73,150.52, 149.80, 146.19, 144.52, 138.33, 130.96, 130.60, 130.51, 129.72,129.02, 123.46, 121.99, 118.87, 107.89, 96.55, 72.87, 70.96, 65.71, 50.65,30.75, 8.25. ESI-MS m / z: 484.1 [M+ H] + .

[0146] Example 29

[0147] Synthesis of compound B25:

[0148] The difference between this embodiment and Example 1 is that 3-(2-bromoacetyl)pyridine is used instead of benzyl bromide, while other process conditions remain the same. The characterization data of the obtained compound B25 are as follows:

[0149] 1 H NMR (600 MHz, DMSO-d6) δ H9.31 (s, 1H), 8.93 (d, J = 4.7 Hz, 1H), 8.51 (s, 1H), 8.45 (d, J = 9.9 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.72 – 7.69(m, 1H), 7.66 (d, J = 10.8 Hz, 2H), 7.33 (s, 1H), 6.56 (s, 1H), 5.88 (s, 2H), 5.46 (s, 2H), 5.28 (s, 2H), 1.92 (dp, J = 21.2, 7.2 Hz, 2H), 0.94 (t, J = 7.3Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.50, 172.99, 157.30, 157.15, 150.86,150.53, 146.19, 144.56, 136.64, 134.27, 134.02, 131.36, 131.00, 130.73,130.47, 129.68, 128.17, 127.01, 123.33, 118.91, 108.21, 96.58, 72.87, 71.12,65.71, 50.71, 30.73, 8.25. ESI-MS m / z: 484.1 [M+ H] + .

[0150] Example 30

[0151] Synthesis of compound B26:

[0152] The difference between this embodiment and Example 1 is that 2-bromo-2-acetylnaphthalene is used instead of benzyl bromide, while other process conditions remain the same. The characterization data of the obtained compound B26 are as follows:

[0153] 1 H NMR (600 MHz, DMSO-d6) δ H8.83 (s, 1H), 8.48 (s, 1H), 8.17 (d, J =8.1 Hz, 1H), 8.11 (dd, J = 9.0, 5.1 Hz, 2H), 8.08 – 8.04 (m, 2H), 7.72 (t, J= 7.5 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.60 (s, 1H), 7.29 (s, 1H), 6.51 (s, 1H), 5.94 (s, 2H), 5.42 (s, 2H), 5.23 (s, 2H), 1.87 (dp, J = 21.2, 7.1 Hz, 2H),0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.30, 172.99, 157.33, 157.30, 150.82, 150.53, 146.19, 144.56, 135.83, 132.60, 132.13, 131.02, 130.72, 130.46, 130.38, 130.06, 129.70, 129.43, 128.98, 128.29, 127.65, 123.81, 123.40, 118.89, 108.17, 96.57, 72.88, 71.08, 65.71, 50.70, 30.74, 8.25. ESI-MS m / z: 533.1 [M+ H] + .

[0154] Example 31

[0155] Synthesis of compound B27:

[0156] The difference between this embodiment and Example 1 is that 1-(1-benzofuran-2-yl)-2-bromoethylone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B27 are as follows:

[0157] 1 H NMR (600 MHz, DMSO-d6) δ H8.48 (s, 1H), 8.13 – 8.07 (m, 2H), 7.92 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.64 – 7.59 (m, 2H), 7.57 (d,J = 2.8 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.28 (s, 1H), 6.52 (s, 1H), 5.69(s, 2H), 5.41 (s, 2H), 5.21 (s, 2H), 1.87 (dp, J = 21.2, 7.1 Hz, 2H), 0.89(t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 185.22, 172.99, 157.28,157.06, 155.41, 150.86, 150.52, 150.36, 146.12, 144.58, 131.05, 130.67,130.51, 129.60, 129.37, 127.07, 124.76, 124.35, 123.26, 118.91, 115.26,112.78, 108.07, 96.63, 72.87, 70.43, 65.70, 50.65, 30.75, 8.24. ESI-MS m / z:523.1 [M+ H] + .

[0158] Example 32

[0159] Synthesis of compound B28:

[0160] The difference between this embodiment and Example 1 is that 2-bromo-1-(2-furan)-1-ethylone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B28 are as follows:

[0161] 1 H NMR (600 MHz, DMSO-d6) δ H8.50 (s, 1H), 8.15 – 8.06 (m, 2H), 7.68(d, J = 3.6 Hz, 1H), 7.60 (d, J = 9.4 Hz, 1H), 7.53 (s, 1H), 7.28 (s, 1H),6.83 (d, J = 3.8 Hz, 1H), 6.50 (s, 1H), 5.54 (s, 2H), 5.42 (s, 2H), 5.24 (s,2H), 1.87 (dp, J = 21.3, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150MHz, DMSO-d6) δ C 183.07, 172.99, 157.29, 157.16, 150.90, 150.52, 150.24,148.78, 146.16, 144.58, 131.05, 130.74, 130.53, 129.63, 123.27, 119.83,118.93, 113.16, 108.07, 96.59, 72.87, 70.03, 65.71, 50.69, 30.73, 8.25. ESI-MS m / z: 473.1 [M+ H] + .

[0162] Example 33

[0163] Synthesis of compound B29:

[0164] The difference between this embodiment and Example 1 is that 2-bromo-1-(2-thiophene)-1-ethylone is used instead of benzyl bromo, while other process conditions remain the same. The characterization data of the obtained compound B29 are as follows:

[0165] 1 H NMR (600 MHz, DMSO-d6) δ H8.47 (s, 1H), 8.20 (d, J = 3.8 Hz, 1H), 8.13 (d, J = 4.9 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.53 (s, 1H), 7.36 (s, 1H), 7.27 (s, 1H), 6.50 (s, 1H), 5.67 (s, 2H), 5.41(s, 2H), 5.22 (s, 2H), 1.87 (dp, J = 21.2, 7.2 Hz, 2H), 0.91 – 0.87 (m, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 187.82, 172.99, 157.27, 157.13, 150.86, 150.51,146.13, 144.56, 140.87, 135.97, 134.27, 131.05, 130.70, 130.49, 129.58,129.42, 123.23, 118.91, 108.08, 96.59, 72.87, 70.70, 65.71, 50.67, 30.75,8.25. ESI-MS m / z: 489.1 [M+ H] + .

[0166] Example 34

[0167] Synthesis of compound B30:

[0168] The difference between this embodiment and Example 1 is that 2-bromo-1-(1,3-thiazolyl-2-yl)ethyl ketone was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B30 are as follows:

[0169] 1 H NMR (600 MHz, DMSO-d6) δ H8.51 (s, 1H), 8.35 (d, J = 3.0 Hz, 1H), 8.27 (d, J = 3.0 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 9.1 Hz, 2H), 7.29 (s, 1H), 6.51 (s, 1H), 5.85 (s, 2H), 5.41 (s, 2H), 5.23 (s, 2H), 1.87(dp, J = 21.3, 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 187.68, 172.98, 164.21, 157.29, 157.04, 150.90, 150.52, 146.17, 145.78,144.60, 131.03, 130.68, 130.59, 129.68, 128.75, 123.32, 118.92, 108.07,96.60, 70.45, 65.71, 50.67, 30.74, 8.25. ESI-MS m / z: 490.1 [M+ H] + .

[0170] Example 35

[0171] Synthesis of compound B31:

[0172] The difference between this embodiment and Example 1 is that 2-bromo-1-(3-isopropoxyphenyl)ethane-1-one was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B31 are as follows:

[0173] 1 H NMR (600 MHz, DMSO-d6) δ H8.47 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.64 – 7.58 (m, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.28(d, J = 5.2 Hz, 2H), 6.50 (s, 1H), 5.78 (s, 2H), 5.41 (s, 2H), 5.23 (s, 2H), 4.75 (d, J = 6.0 Hz, 1H), 1.87 (dp, J = 21.4, 7.3 Hz, 2H), 1.31 (d, J = 6.0Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.24,172.99, 158.16, 157.30, 157.25, 150.79, 150.52, 146.19, 144.53, 136.25,130.96, 130.69, 130.61, 130.45, 129.67, 123.36, 121.41, 120.41, 118.89,115.12, 108.15, 96.56, 72.87, 71.07, 70.04, 65.71, 50.69, 30.74, 22.19, 8.25.ESI-MS m / z: 541.1 [M+ H] + .

[0174] Example 36

[0175] Synthesis of compound B32:

[0176] The difference between this embodiment and Example 1 is that 2-bromo-1-(3-isobutoxyphenyl)ethane-1-one was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B32 are as follows:

[0177] 1 H NMR (600 MHz, DMSO-d6) δ H8.46 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.57 – 7.48 (m, 3H), 7.29(d, J = 15.2 Hz, 2H), 6.50 (s, 1H), 5.78 (s, 2H), 5.41 (s, 2H), 5.21 (s, 2H), 3.84 (d, J = 6.3 Hz, 2H), 1.86 (dp, J = 21.4, 7.2 Hz, 2H), 1.01 (d, J = 6.7Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.21,172.99, 159.50, 157.27, 157.22, 150.76, 150.51, 146.16, 144.51, 136.13,130.95, 130.64, 130.42, 129.63, 123.33, 120.61, 120.56, 118.87, 113.80,108.12, 96.56, 74.52, 72.87, 71.08, 65.71, 50.66, 30.75, 28.19, 19.51, 8.25.ESI-MS m / z: 555.2 [M+ H] + .

[0178] Example 37

[0179] Synthesis of compound B33:

[0180] The difference between this embodiment and Example 1 is that 2-bromo-1-(3-cyclobutoxyphenyl)ethane-1-one was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B33 are as follows:

[0181] 1 H NMR (600 MHz, DMSO-d6) δ H8.46 (s, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.54 (s, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 7.20 (d, J = 9.7 Hz, 1H), 6.50 (s,1H), 5.76 (s, 2H), 5.41 (s, 2H), 5.22 (s, 2H), 4.80 (p, J = 7.2 Hz, 1H), 2.47(d, J = 11.9 Hz, 2H), 2.08 (q, J = 8.5, 7.2 Hz, 2H), 1.94 – 1.78 (m, 3H), 1.68 (p, J = 9.4 Hz, 1H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6)δ C 194.15, 172.99, 157.76, 157.28, 157.22, 150.77, 150.51, 146.16, 144.52,136.19, 130.95, 130.65, 130.42, 129.64, 123.33, 120.73, 120.68, 118.88,114.25, 108.10, 96.56, 72.87, 71.45, 71.05, 65.71, 50.67, 30.75, 30.47,13.26, 8.25. ESI-MS m / z: 555.1 [M+ H] + .

[0182] Example 38

[0183] Synthesis of compound B34:

[0184] The difference between this embodiment and Example 1 is that 2-bromo-1-(3-cyclopentoxyphenyl)ethane-1-one was used instead of benzyl bromo, while other process conditions remained the same. The characterization data of the obtained compound B34 are as follows:

[0185] 1 H NMR (600 MHz, DMSO-d6) δ H8.46 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.55 – 7.49 (m, 3H), 7.27 (d, J = 12.0 Hz, 2H), 6.50 (s, 1H), 5.77 (s, 2H), 5.41 (s, 2H), 5.22 (s, 2H), 4.93 (t, J = 6.1 Hz,1H), 2.00 – 1.93 (m, 2H), 1.86 (dp, J = 21.3, 7.0 Hz, 2H), 1.74 (d, J = 11.4Hz, 4H), 1.61 (d, J = 9.4 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.20, 172.99, 158.33, 157.28, 157.23, 150.76, 150.52, 146.17,144.52, 136.16, 130.95, 130.65, 130.55, 130.42, 129.65, 123.34, 121.17,120.32, 118.87, 114.97, 108.12, 96.56, 79.50, 72.87, 71.06, 65.71, 50.67,32.67, 30.75, 24.07, 8.25. ESI-MS m / z: 567.2 [M+ H] + .

[0186] Example 39

[0187] Synthesis of compound C1:

[0188] The difference between this embodiment and Example 1 is that SN38 is used instead of 10-HCPT, and 2-bromo-1-(3-bromophenyl)ethyl ketone is used instead of benzyl bromo. All other process conditions remain the same. The characterization data of compound C1 obtained are as follows:

[0189] 1 H NMR (600 MHz, DMSO-d6) δ H8.23 (s, 1H), 8.09 (dd, J = 17.2, 8.5 Hz, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.60 (q, J = 8.5, 7.9 Hz, 2H), 7.54 (s, 1H), 7.28 (s, 1H), 6.50 (s, 1H), 5.87 (s, 2H), 5.43 (s, 2H), 5.28 (s, 2H), 3.15(d, J = 7.8 Hz, 2H), 1.87 (dp, J = 21.5, 7.1 Hz, 2H), 1.24 (t, J = 7.6 Hz,3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.00, 173.01, 157.31, 157.20, 150.53, 150.31, 146.73, 145.02, 144.43, 136.99, 136.92, 131.94, 131.61, 131.00, 128.85, 128.17, 127.41, 122.71, 122.58, 118.80, 104.58, 96.54, 72.87, 71.02, 65.72, 55.38, 49.97, 30.73, 22.64, 13.92, 8.24.

[0190] Example 40

[0191] Synthesis of compound C2:

[0192] The difference between this embodiment and Example 1 is that SN38 is used instead of 10-HCPT, and 2-bromo-1-(4-methylphenyl)ethyl ketone is used instead of benzyl bromo. All other process conditions remain the same. The characterization data of compound C2 are as follows:

[0193] 1 H NMR (600 MHz, DMSO-d6) δ H8.08 (d, J = 9.2 Hz, 1H), 7.89 (s, 2H),7.62 – 7.48 (m, 4H), 7.27 (s, 1H), 6.50 (s, 1H), 5.82 (s, 2H), 5.42 (s, 2H),5.25 (s, 2H), 3.11 (d, J = 7.8 Hz, 2H), 2.42 (s, 3H), 1.87 (dp, J = 22.1,15.0, 7.8 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.98, 173.00, 157.29, 150.52, 150.24, 146.72, 144.97,144.31, 138.79, 135.02, 134.96, 131.90, 129.25, 128.79, 128.68, 128.14,125.67, 122.57, 118.77, 104.49, 96.51, 72.87, 70.95, 65.73, 49.94, 30.74,22.64, 21.37, 13.86, 8.24. ESI-MS m / z: 525.2 [M+ H] + .

[0194] Example 41

[0195] Synthesis of compound C3:

[0196] The difference between this embodiment and Example 1 is that SN38 is used instead of 10-HCPT, and 2-bromo-1-(3-methoxyphenyl)ethyl ketone is used instead of benzyl bromo. All other process conditions remain the same. The characterization data of compound C3 obtained are as follows:

[0197] 1 H NMR (600 MHz, DMSO-d6) δ H8.14 (d, J = 9.2 Hz, 1H), 7.74 (d, J =7.6 Hz, 1H), 7.66 – 7.55 (m, 4H), 7.36 (d, J = 8.3 Hz, 1H), 7.32 (s, 1H), 6.55 (s, 1H), 5.88 (s, 2H), 5.48 (s, 2H), 5.30 (s, 2H), 3.91 (s, 3H), 3.17(q, J = 7.6 Hz, 2H), 1.92 (dp, J = 21.6, 7.2 Hz, 2H), 1.28 (t, J = 7.6 Hz,3H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.77, 173.00,159.97, 157.29, 157.25, 150.52, 150.25, 146.71, 144.98, 144.33, 136.30,131.90, 130.58, 128.79, 128.14, 122.59, 120.81, 120.15, 118.78, 113.18,104.49, 96.52, 72.87, 71.03, 65.73, 55.92, 49.94, 30.74, 22.64, 13.86, 8.24.ESI-MS m / z: 541.1 [M+ H] + .

[0198] Example 42

[0199] Synthesis of compound C4:

[0200] The difference between this embodiment and Example 1 is that SN38 is used instead of 10-HCPT, and 2-bromo-1-(3-bromo-4-methylphenyl)ethyl-1-one is used instead of benzyl bromo. All other process conditions remain the same. The characterization data of compound C4 obtained are as follows:

[0201] 1 H NMR (600 MHz, DMSO-d6) δ H8.24 (s, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.52 (s, 1H), 7.27 (s,1H), 6.50 (s, 1H), 5.83 (s, 2H), 5.43 (s, 2H), 5.27 (s, 2H), 3.14 (q, J = 7.7Hz, 2H), 2.46 (s, 3H), 1.87 (dp, J = 21.5, 7.2 Hz, 2H), 1.23 (t, J = 7.5 Hz,3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.57, 173.00,157.29, 157.21, 150.52, 150.27, 146.71, 145.00, 144.37, 144.21, 134.58,131.97, 131.92, 131.86, 128.81, 128.15, 127.64, 125.08, 122.55, 118.79,104.54, 96.53, 72.87, 70.92, 65.73, 49.95, 30.74, 23.23, 22.64, 13.90, 8.24.ESI-MS m / z: 603.1 [M+ H] + .

[0202] Example 43

[0203] Synthesis of compound C5:

[0204] The difference between this embodiment and Example 1 is that SN38 is used instead of 10-HCPT, and 2-bromo-1-(3,4-dimethylphenyl)ethyl-1-one is used instead of benzyl bromo. All other process conditions are the same. The characterization data of compound C5 obtained are as follows:

[0205] 1 H NMR (600 MHz, DMSO-d6) δ H8.08 (d, J = 9.2 Hz, 1H), 7.87 – 7.81 (m,2H), 7.58 (d, J = 9.6 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.27(s, 1H), 6.50 (s, 1H), 5.78 (s, 2H), 5.42 (s, 2H), 5.25 (s, 2H), 3.11 (q, J =7.7 Hz, 2H), 2.33 (s, 6H), 1.87 (dp, J = 21.5, 14.2, 7.2 Hz, 2H), 1.21 (t, J= 7.6 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.53,173.01, 157.33, 157.30, 150.53, 150.24, 146.72, 144.96, 144.30, 143.72,137.45, 132.84, 131.89, 130.32, 129.19, 128.80, 128.14, 126.13, 122.58,118.77, 104.47, 96.51, 72.87, 70.84, 65.72, 49.94, 30.73, 22.64, 20.16,19.83, 13.85, 8.24. ESI-MS m / z: 539.2 [M+ H] + .

[0206] Example 44

[0207] Synthesis of compound C6:

[0208] The difference between this embodiment and Example 1 is that SN38 is used instead of 10-HCPT, and 2-bromo-1-(3-methoxy-4-methylphenyl)ethyl-1-one is used instead of benzyl bromo. All other process conditions remain the same. The characterization data of compound C6 obtained are as follows:

[0209] 1 H NMR (600 MHz, DMSO-d6) δ H8.08 (d, J = 9.2 Hz, 1H), 7.67 (d, J =7.6 Hz, 1H), 7.59 (d, J = 12.0 Hz, 1H), 7.49 (s, 2H), 7.38 (d, J = 7.6 Hz,1H), 7.26 (s, 1H), 6.50 (s, 1H), 5.80 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 3.88 (s, 3H), 3.10 (q, J = 5.9, 4.3 Hz, 2H), 2.25 (s, 3H), 1.87 (dp, J =21.5, 7.3 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 194.43, 173.01, 158.00, 157.29, 150.51, 150.24, 146.70,144.95, 144.27, 134.17, 133.26, 131.90, 131.10, 128.77, 128.11, 122.53,121.19, 118.77, 108.96, 104.53, 96.52, 72.87, 70.92, 65.73, 55.93, 49.93,30.74, 22.64, 16.80, 13.83. ESI-MS m / z: 555.2 [M+ H] + .

[0210] Example 45

[0211] Synthesis of compound C7:

[0212] The difference between this embodiment and Example 1 is that SN38 is used instead of 10-HCPT, and 2-bromo-1-(3-methyl-4-methoxyphenyl)ethyl-1-one is used instead of benzyl bromo. All other process conditions remain the same. The characterization data of compound C7 obtained are as follows:

[0213] 1 H NMR (600 MHz, DMSO-d6) δ H8.08 (d, J = 9.2 Hz, 1H), 7.98 (d, J =8.5 Hz, 1H), 7.88 (s, 1H), 7.58 (d, J = 9.4 Hz, 1H), 7.48 (s, 1H), 7.27 (s,1H), 7.12 (d, J = 8.6 Hz, 1H), 6.50 (s, 1H), 5.75 (s, 2H), 5.42 (s, 2H), 5.26(s, 2H), 3.91 (s, 3H), 3.10 (q, J = 7.6 Hz, 2H), 2.23 (s, 3H), 1.87 (dp, J =21.4, 7.2 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO-d6) δ C 193.33, 173.01, 162.34, 157.39, 157.30, 150.53, 150.23,146.73, 144.95, 144.27, 131.88, 130.63, 128.89, 128.80, 128.15, 127.39,126.57, 122.58, 118.77, 110.61, 104.47, 96.51, 72.87, 70.64, 65.72, 56.28,49.95, 30.73, 22.65, 16.49, 13.83, 8.23. ESI-MS m / z: 555.2 [M+ H] + .

[0214] 1. Validation of in vitro anticancer activity:

[0215] To verify the anticancer activity of 10-arylalkoxycamptothecin compounds, 10-hydroxycamptothecin (10-HPCT) and 10-hydroxy-7-ethylcamptothecin (SN-38) were used as positive control drugs. The growth inhibitory effect of compound A1-C7 on human lung cancer cells A549, human liver cancer cells HepG2, and human colon cancer cells HCT116 was determined by in vitro MTT assay.

[0216] Validation methods: HCT116 cells were cultured in McCoy's 5A complete medium containing 10% fetal bovine serum and 1% penicillin-streptomycin, A549 cells were cultured in F-12K medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution, and HepG2 cells were cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution. All cells were incubated at 37°C in a 5% CO2 incubator. Different drugs were added to the drug-treated groups, with three parallel wells per group. The control group was added with an equal volume of solvent as the drug and incubated at 37°C in a 5% CO2 incubator for 48 h. After the culture medium was discarded, 10 μL of 5 mg / mL solution was added to each well. -1 After incubating with MTT solution for 4 hours, the supernatant was discarded, and 100 μL of DMSO was added to each well. After gentle shaking, the optical density (OD) was measured at 490 nm using a microplate reader.

[0217] Result Calculation: Using tumor cells treated with solvent as the control group, the drug's inhibition rate on tumor cell proliferation was calculated according to the following formula:

[0218] Cell viability (%) = (absorbance of drug-treated group - absorbance of blank group) / (absorbance of control group - absorbance of blank group) × 100%. (Each group has 3 replicates, and the average value is taken).

[0219] Based on the inhibition rate, the IC50 values ​​of different compounds inhibiting the proliferation of human lung cancer cells (A549), human liver cancer cells (HepG2), and human colon cancer cells (HCT116) were calculated using linear regression, as shown in Tables 1-3.

[0220] Table 1. Growth inhibitory effects of compounds A1-A4 on three types of human tumor cell lines (IC50, μmol / L)

[0221]

[0222] Table 2. Growth inhibitory effects of compounds B1-B34 on three types of human tumor cell lines (IC50, μmol / L)

[0223]

[0224] Table 3. Growth inhibitory effects of compounds C1-C7 on three types of human tumor cell lines (IC50, μmol / L)

[0225]

[0226] As shown in Tables 1-3, the new substituents attached to the 10 position of camptothecin have a significant impact on the activity of the compound.

[0227] 2. Verification of in vivo anticancer activity:

[0228] Using the HCT116 colon cancer mouse model, the in vivo anticancer activity of compound C6 was investigated by intraperitoneal injection.

[0229] Validation method: Male mice, weighing 19-22g. HCT116 cells and a 1:1 suspension of Matrigel were inoculated intraperitoneally into the mice. 0.2 mL of the suspension was subcutaneously injected into the right axilla of each mouse using a syringe. On day 5 after inoculation, the mice were randomly divided into 3 groups of 7 mice each:

[0230] (1) Solvent group (DMSO / PEG400 / 5% glucose injection);

[0231] (2) High-dose group of compound C6 (5 mg·kg) -1 );

[0232] (3) Low-dose group of compound C6 (2 mg·kg) -1 );

[0233] (4) Positive control drug Topotecan (TPT) (2 mg·kg -1 ).

[0234] Day 5 post-inoculation (tumor volume approximately 100mm) 3 The mice were administered the drug via intraperitoneal injection according to the above-described dosing regimen, with a volume of 0.2 mL, every other day for a total of 8 administrations. The mice's weight was recorded before administration. The mice were sacrificed the day after drug withdrawal, and the tumor mass and major organs were dissected. The tumor tissue was subjected to HE staining and Ki67 immunohistochemistry.

[0235] Result: As Figures 1-2 It was found that, compared with the control group, C6 at doses of 2 mg / kg and 5 mg / kg significantly inhibited tumor growth. The tumor growth inhibition rates of C6 in the low-dose group and the high-dose group reached 41.20% and 67.06%, respectively, and it showed no significant toxicity to major organs such as the heart, liver, spleen, lungs, and kidneys in mice. Therefore, compound C6 has a significant inhibitory effect on the growth of HCT116 colon cancer xenografts.

[0236] 3. Safety evaluation:

[0237] Four mL of sterile defibrinated sheep blood was collected and centrifuged at 2000 rpm for 10 minutes at 4°C, and the supernatant was discarded. Red blood cells were washed with phosphate-buffered saline (PBS) until the supernatant was clear, and then resuspended in PBS to prepare a 5% red blood cell suspension. Compound C6 was serially diluted to concentrations of 0.406, 0.812, 1.625, 3.25, 6.25, 12.5, 25, 50, 100, 200, 400, and 800 μg / mL, and mixed with an equal volume of the 5% red blood cell suspension. The mixture was incubated at 37°C for 1 hour. 0.1% Triton X-100 was used as a positive control, and PBS as a negative control. After incubation, the mixture was centrifuged at 3000 rpm for 5 minutes, and 200 μL of the supernatant was added to a 96-well plate. The absorbance (OD) at 540 nm was measured using a microplate reader. 540 Calculate the hemolysis rate using the following formula:

[0238] Hemolysis rate = (OD2 – OD1) / (OD3 – OD1) × 100%;

[0239] Result: As Figure 3 As shown, the values ​​meet the safety limit of less than 5% for hemolysis rate in ISO 10993-4, indicating that the compound has almost no adverse effect on the stability of red blood cell membranes.

[0240] In summary, the 10-arylalkoxycamptothecin compounds or their pharmaceutical compositions described in this invention can be used to prepare anticancer drug formulations, which may be capsules, oral liquids, granules, or injections. These formulations can be prepared according to conventional preparation processes for various formulations, wherein the content of the active ingredient is 10-100 mg, preferably 5-40 mg.

[0241] The oral formulations involved in this invention may contain pharmaceutical excipients, including stabilizers, solubilizers, lubricants, etc., such as glucose, lactose, cellulose, polyvinylpyrrolidone, crospped polyvinylpyrrolidone, starch, pectin, cyclodextrin, Twenty-80, polyvinyl alcohol, magnesium stearate, talc, etc.

[0242] The above description is merely a preferred embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalents can be made within the spirit and scope defined by the claims of the present invention, all of which will fall within the protection scope of the present invention.

Claims

1. A class of 10-arylalkoxycamptothecin compounds or pharmaceutically acceptable salts thereof, characterized in that, The 10-arylalkoxycamptothecin compounds have the following general formula: R1 is hydrogen or ethyl. R2 is any one of methyl, ethyl, propyl, or 2-carbonylethyl; A is selected from any one of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, β-naphthyl, 2-benzofuranyl, 2-furanyl, 2-thienyl, 2-thiazolyl, 3-isopropoxyphenyl, 3-isobutoxyphenyl, 3-cyclobutoxyphenyl, 3-cyclopentoxyphenyl, 3-bromo-4-methylphenyl, 3,4-dimethylphenyl, 3-methoxy-4-methylphenyl, and 3-methyl-4-methoxyphenyl.

2. The class of 10-arylalkoxycamptothecin compounds or their pharmaceutically acceptable salts as described in claim 1, characterized in that, The 10-arylalkoxycamptothecin compound is any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、#imgpt45#。 3. A pharmaceutical composition, characterized in that, It includes one or more therapeutically effective amounts of the 10-arylalkoxycamptothecin compound as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

4. The pharmaceutical composition according to claim 3, characterized in that, The excipients are any one or a combination of several of the following: stabilizers, solubilizers, lubricants, and disintegrants.

5. The pharmaceutical composition according to claim 3, characterized in that, The excipients are any one or more combinations of starch, dextrin, glucose, lactose, cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, Twenty-80, polyvinyl alcohol, magnesium stearate, and talc.

6. The use of a 10-arylalkoxycamptothecin compound or a pharmaceutically acceptable salt thereof as described in claim 1 or 2 in the preparation of an anticancer drug.

7. The use of a 10-arylalkoxycamptothecin compound or a pharmaceutically acceptable salt thereof as described in claim 6 in the preparation of an anticancer drug, characterized in that, The drug is available in tablet, capsule, or injection form.

8. The use of a 10-arylalkoxycamptothecin compound or a pharmaceutically acceptable salt thereof as described in claim 7 in the preparation of an anticancer drug, characterized in that, Each of the tablets, capsules, or injections contains 10 to 50 mg of a 10-aryloxycamptothecin compound.

9. The use of a 10-arylalkoxycamptothecin compound or a pharmaceutically acceptable salt thereof as described in claim 6 in the preparation of an anticancer drug, characterized in that, The 10-arylalkoxycamptothecin compounds, in combination with antimetabolites, anticancer drugs, EGFR inhibitors, or BTK inhibitors, form a drug complex.

10. The use of a 10-arylalkoxycamptothecin compound or a pharmaceutically acceptable salt thereof as described in claim 6 in the preparation of an anticancer drug, characterized in that, The anticancer drugs include anti-lung cancer drugs and anti-colon cancer drugs.

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