TBC1D2-targeted aromatic methylene matrine derivative as well as preparation method and application thereof

Abstract

The invention discloses a TBC1D2-targeted aromatic methenyl matrine derivative as well as a preparation method and application thereof, and relates to the technical field of chemical medicines. A series of aromatic methylene matrine derivatives containing a naphthalene ring, an indole ring, an azaindole ring and a benzene ring are synthesized, and by introducing a special structure formed by the aromatic rings, the in-vitro anti-tumor activity of matrine can be greatly improved. The TBC1D2-targeted aromatic methenyl matrine derivative provided by the invention can be used for preparing antitumor drugs, the raw materials are easy to obtain, and the synthesis steps are simple. In-vitro biological experiments show that the derivatives have brand-new action targets and action mechanisms; in-vitro antitumor activity researches show that the derivatives are antitumor drugs with development prospects, and the derivatives can be applied to clinical treatment of tumors.

Description

Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, and in particular to an aromatic methenomatrine derivative targeting TBC1D2, its preparation method, and its application. Background Technology

[0002] Cancer, a complex disease characterized by abnormal cell proliferation and metastasis, has become one of the major public health problems worldwide. Current cancer treatments include surgery, radiotherapy, targeted therapy, immunotherapy, antibody-drug conjugates (ADCs), and CAR-T cell therapy. However, cancer research still faces many challenges: tumor heterogeneity and drug resistance evolution, unclear metastasis mechanisms, uneven distribution of medical resources, and the quality of life of long-term survivors. Developing anticancer drugs with novel mechanisms of action can provide new opportunities to address these challenges.

[0003] TBC1D2 is a member of the TBC (Tre-2 / Bub2 / Cdc16) domain protein family, primarily involved in regulating cell migration, invasion, and metabolism. It is abnormally highly expressed in various cancers, such as ovarian and breast cancer. TBC1D2 catalyzes the hydrolysis of rabbit7a-GTP to rabbit7a-GDP. The inactivated rabbit7a-GDP facilitates the dissociation of mitochondria from lysosomes, inhibiting the formation of late-stage autophagic lysosomes. Therefore, TBC1D2 inhibitors can inhibit cancer progression by inducing autophagy. Currently, there are no drugs specifically targeting TBC1D2, thus this type of drug has significant application value and broad application prospects. Summary of the Invention

[0004] The purpose of this invention is to provide an aromatic methene matrine derivative targeting TBC1D2, its preparation method, and its application, in order to solve the problems existing in the prior art.

[0005] To achieve the above objectives, the present invention provides the following solution: One of the technical solutions of the present invention is an aromatic methenomatrine derivative targeting TBC1D2, having a structure as shown in general formula I, general formula II or general formula III: ; In general formula I, R = 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3,4-difluorophenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3,5-dimethoxyphenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-di-tert-butylphenyl or 2-naphthyl; In general formula II, R = 3-chlorophenyl, 2,4-difluorophenyl, 4-bromophenyl, 3,4-difluorophenyl or 4-tert-butylphenyl; In general formula III, X = C or N; when X = C, R = allyl, 3-phenoxypropyl, 4-phenoxybutyl or 4-(2-naphthoxy)butyl; when X = N, R = benzyl, 3-fluorobenzyl, 3-chlorobenzyl or 4-bromobenzyl.

[0006] The second technical solution of the present invention: a method for preparing the above-mentioned aromatic methylene matrine derivative targeting TBC1D2, comprising the following steps: Using one of the compounds shown in Formulas IV-VI and one of the compounds shown in Formulas VII-X as reactants, an aromatic aldehyde is obtained through a substitution reaction under alkaline conditions; using the aromatic aldehyde and matrine as reactants, and NaH as a condensing agent, the aromatic methylene matrine derivative targeting TBC1D2 is obtained through a condensation reaction. , , , , , , ; In Formula IV, R = 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3,4-difluorophenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3,5-dimethoxyphenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-di-tert-butylphenyl or 2-naphthyl; In formula V, R = allyl, 3-phenoxypropyl, 4-phenoxybutyl, benzyl, 3-fluorobenzyl, 3-chlorobenzyl, or 4-bromobenzyl; In formula VI, R = 4-(2-naphthoxy)butyl.

[0007] Furthermore, the molar ratio of one of the compounds shown in formulas IV-VI to one of the compounds shown in formulas VII-X is 2:3.

[0008] Furthermore, the substitution reaction is carried out at a temperature of 60°C for a time of 1-4 hours.

[0009] Furthermore, the molar ratio of the aromatic aldehyde and matrine is 2:3.

[0010] Furthermore, the reaction procedure for the condensation reaction is as follows: first react at 23-27℃ for 1 hour, and then react at 60-100℃ for 20 minutes to 1 hour.

[0011] The third technical solution of the present invention: the application of the above-mentioned aromatic methene matrine derivative targeting TBC1D2 in the preparation of TBC1D2 inhibitors.

[0012] The fourth technical solution of the present invention: the application of the above-mentioned aromatic methylene matrine derivative targeting TBC1D2 in the preparation of anticancer drugs.

[0013] In this invention, an immunoassay was used to identify the target of a synthesized aromatic methylene matrine derivative. Immunoassay is a biochemical detection technique based on the principle of specific binding between antigens and antibodies, utilizing highly selective reactions to achieve quantitative or qualitative analysis of target substances in biological samples. By leveraging the competitive nature of compounds and specific antibodies against antigenic epitopes, the change in fluorescence intensity of fluorescently labeled antibodies can identify targeted drugs against specific targets. This invention used immunoassay to identify the designed and synthesized aromatic methylene matrine derivative as a TBC1D2 inhibitor. Specifically, the aromatic methylene matrine derivative synthesized in this invention competitively binds to anti-TBC1D2 antibodies, causing the fluorescently labeled antibody to become free, thereby weakening the fluorescence intensity.

[0014] Furthermore, TBC1D2 catalyzes the hydrolysis of rabbit7a-GTP to rabbit7a-GDP. Rabbit7a-GTP is located on the lysosomal membrane, while rabbit7a-GDP is located in the cytoplasm. TBC1D2 inhibitors can inhibit the hydrolysis of rabbit7a-GTP, leading to the accumulation of rabbit7a on the lysosomal membrane and promoting lysosomal maturation and autophagy. This characteristic was utilized in this invention to further identify the synthesized aromatic methene matrine derivative as a TBC1D2 inhibitor.

[0015] The present invention discloses the following technical effects: This invention synthesizes a series of aromatic methenic matrine derivatives containing naphthalene rings, indole rings, azaindole rings, and benzene rings. The special structures formed by introducing these aromatic rings can significantly increase the in vitro antitumor activity of matrine. The aromatic methenic matrine derivatives synthesized in this invention have been identified as a class of TBC1D2 inhibitors with strong antitumor activity.

[0016] The aromatic methenomatrine derivatives targeting TBC1D2 provided by this invention can be used to prepare antitumor drugs, with readily available raw materials and simple synthesis steps. In vitro biological experiments show that these derivatives have novel targets and mechanisms of action; in vitro antitumor activity studies have shown that these derivatives are promising antitumor drugs and can be applied to the clinical treatment of tumors. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 This is a schematic diagram illustrating the principle of target identification using immunoassay in this invention.

[0019] Figure 2 The target identification results for HKY-55.

[0020] Figure 3 The results show the inhibitory activity of HDY-55. Detailed Implementation

[0021] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0022] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0023] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0024] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0025] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0026] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0027] In the following embodiments and test examples of the present invention, room temperature refers specifically to 25±2℃.

[0028] All raw materials and reagents used in the following embodiments and test examples of this invention are commercially available products.

[0029] In the following embodiments of the present invention, the synthetic routes of the aromatic methylene matrine derivatives in Examples 1-19 are as follows: .

[0030] The synthetic routes of the aromatic methylene matrine derivatives in Examples 20-32 are similar to those in Examples 1-19, except that the reactants in the first step reaction (i.e., substitution reaction) are replaced accordingly.

[0031] Example 1 The preparation of an aromatic methene matrine derivative (HKY-55) targeting TBC1D2 is as follows: (1) Take 10 mmol of 6-hydroxy-2-naphthaldehyde and excess K2CO3 (35 mmol) and place them in a 250 mL flask. Add 100 mL of acetonitrile to dissolve them. Add 15 mmol of 4-trifluoromethoxybenzyl bromide dropwise at 60 °C. After the addition is complete, continue the reaction for 2 h. After the reaction is complete, cool to room temperature, filter and concentrate the filtrate to reduce the volume. Then precipitate and filter with petroleum ether. The white solid obtained is 6-[4-(trifluoromethoxy)benzyl]-2-naphthaldehyde, which can be used directly in the next step of the reaction without purification. (2) Dissolve 10 mmol of 6-[4-(trifluoromethoxy)benzyl]-2-naphthylcarboxaldehyde and 15 mmol of matrine in 20 mL of anhydrous 1,4-dioxane. Add excess NaH (50 mmol) at room temperature. After stirring the reaction mixture at room temperature for 1 h, react at 80 °C for 30 min. Monitor the reaction by TLC. After the reaction is complete, add ice water dropwise at 0 °C to quench the excess NaH. Add excess ice water, then extract with ethyl acetate. Dry the organic phase with Na2SO4, concentrate, and purify the resulting oily substance by silica gel column chromatography using petroleum ether / ethyl acetate (volume ratio 1:4) as eluent. Then recrystallize with ethanol-water to obtain 14-(6-[4-(trifluoromethoxy)benzyloxy]-2-naphthylmethylyl)matrine (abbreviated as HKY-55), which is a white solid with a yield of 31%. The spectroscopic characterization data of HKY-55 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.72(s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.43 (dd, J =8.5, 1.7 Hz, 1H), 7.26 (s, 1H), 7.25 (s, 1H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H),7.19 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 4.53 (dd, J = 12.8, 4.4 Hz, 1H), 3.98(ddd, J = 10.9, 8.0, 5.2 Hz, 1H), 3.24 (t, J = 12.7 Hz, 1H), 2.97 (ddd, J =15.0, 7.3, 3.8 Hz, 1H), 2.86 (d, J = 10.5 Hz, 1H), 2.81 (d, J = 11.9 Hz, 1H),2.58 (dddd, J = 14.9, 10.7, 4.0, 2.0 Hz, 1H), 2.14 (t, J = 3.1, 1.4 Hz, 1H),2.13 – 2.08 (m, 1H), 1.99 (qd, J = 12.6, 2.8 Hz, 2H), 1.89 (d, J = 13.1 Hz,1H), 1.84 – 1.76 (m, 2H), 1.75 – 1.71 (m, 1H), 1.70 – 1.61 (m, 1H), 1.59 –1.50 (m, 3H), 1.49 – 1.38 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.04, 157.10, 149.07, 135.62, 134.63,133.92, 132.10, 130.78, 130.04, 129.06, 128.94, 128.87, 128.25, 126.77,121.29, 119.43, 107.19, 69.28, 63.94, 57.43, 57.39, 53.00, 42.98, 42.74,35.80, 27.94, 26.58, 26.00, 23.44, 21.36, 20.96. 19 F NMR (565 MHz, CDCl3) δ -57.83. HRMS (ESI) m / z calculated for C 34 H 36 F3N2O3 + [M+H] + : 577.2678, found:577.2680. Example 2 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 3,5-di(trifluoromethyl)benzyl bromide. The final product obtained in this example was 14-(6-[3,5-di-(trifluoromethyl)benzyloxy]-2-naphthylmethylene)matrine (abbreviated as HKY-2), which was a white solid with a yield of 23%. The spectroscopic characterization data of HKY-2 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.96 (s, 2H), 7.87 (s, 1H), 7.85 (s, 1H),7.79 (d, J = 9.0 Hz, 1H), 7.73 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.44 (dd, J= 8.5, 1.9 Hz, 1H), 7.26 (dd, J = 8.9, 2.5 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H),5.28 (s, 2H), 4.53 (dd, J = 12.7, 4.4 Hz, 1H), 3.98 (s, 1H), 3.24 (t, J =12.7 Hz, 1H), 2.97 (dddd, J = 15.0, 7.3, 3.9, 1.5 Hz, 1H), 2.86 (d, J = 9.0Hz, 1H), 2.82 (d, J = 10.3 Hz, 1H), 2.59 (dddd, J = 14.9, 10.7, 4.0, 2.1 Hz,1H), 2.17 – 2.08 (m, 2H), 1.99 (q, J = 12.9, 11.8, 10.7 Hz, 2H), 1.89 (d, J =14.1 Hz, 1H), 1.85 – 1.78 (m, 1H), 1.77 – 1.71 (m, 2H), 1.69 – 1.64 (m, 1H),1.60 – 1.51 (m, 3H), 1.50 – 1.38 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.00, 156.62, 139.58, 134.53, 133.81,132.45, 132.39, 132.23, 132.01, 131.78, 130.95, 130.27, 129.16, 128.86,128.39, 127.46, 127.43, 126.83, 124.28, 122.47, 122.11, 122.08, 119.18,107.25, 68.59, 63.92, 57.38, 53.00, 42.98, 42.74, 35.80, 27.93, 26.58, 25.99,23.43, 21.34, 20.96. 19F NMR (565 MHz, CDCl3) δ -62.84. HRMS (ESI) m / z calculated for C 35 H 35 F6N2O2 + [M+H] + : 629.2603, found:629.2592. Example 3 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 2-chlorobenzyl bromide. The final product obtained in this example was 14-(6-(2-chlorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-5), which was a white solid with a yield of 35%. The spectroscopic characterization data of HKY-5 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.73– 7.69 (m, 2H), 7.64 – 7.58 (m, 1H), 7.43 (dt, J = 8.5, 2.1 Hz, 2H), 7.32 –7.27 (m, 2H), 7.26 (dd, J = 8.9, 2.4 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 5.29(s, 2H), 4.53 (dd, J = 12.7, 4.4 Hz, 1H), 3.98 (ddd, J = 10.7, 8.1, 5.1 Hz,1H), 3.24 (t, J = 12.8 Hz, 1H), 2.99 – 2.94 (m, 1H), 2.86 (d, J = 10.8 Hz,1H), 2.81 (d, J = 11.1 Hz, 1H), 2.62 – 2.55 (m, 1H), 2.14 (t, J = 3.3 Hz, 1H), 2.12 – 2.09 (m, 1H), 2.02 – 1.95 (m, 2H), 1.89 (d, J = 13.6 Hz, 1H), 1.84 – 1.78 (m, 2H), 1.74 (d, J = 13.4 Hz, 1H), 1.69 – 1.66 (m, 1H), 1.59 –1.52 (m, 3H), 1.49 – 1.40 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 165.05, 157.07, 134.66, 134.64, 133.96,132.82, 132.07, 130.76, 130.00, 129.58, 129.21, 128.96, 128.86, 128.19,127.15, 126.84, 119.42, 107.34, 67.30, 63.94, 57.46, 57.41, 53.01, 42.98,42.75, 35.82, 27.95, 26.61, 26.00, 23.45, 21.38, 20.99. HRMS (ESI) m / z calculated for C 33 H 36 ClN2O2 + [M+H] + : 527.2465, found:527.2458. Example 4 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 2-bromomethylnaphthalene. The final product obtained in this example was 14-(6-(2-naphthylmethoxy)-2-naphthylmethyl)matrine (abbreviated as HKY-7), which was a light yellow solid with a yield of 21%. The spectroscopic characterization data of HKY-7 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.94 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.87– 7.84 (m, 3H), 7.76 (d, J = 8.9 Hz, 1H), 7.72 (s, 1H), 7.70 (d, J = 8.5 Hz,1H), 7.59 (dd, J = 8.4, 1.8 Hz, 1H), 7.51 – 7.48 (m, 2H), 7.42 (dd, J = 8.5,1.9 Hz, 1H), 7.28 (dd, J = 8.8, 2.5 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 5.35(s, 2H), 4.54 (dd, J = 12.8, 4.4 Hz, 1H), 4.01 – 3.94 (m, 1H), 3.24 (t, J =12.6 Hz, 1H), 2.99 – 2.93 (m, 1H), 2.90 – 2.85 (m, 1H), 2.84 – 2.80 (m, 1H),2.61 – 2.55 (m, 1H), 2.15 (s, 1H), 2.13 – 2.08 (m, 1H), 2.03 – 1.95 (m, 2H),1.89 (d, J = 13.8 Hz, 1H), 1.84 – 1.79 (m, 2H), 1.74 (d, J = 13.3 Hz, 1H),1.67 (d, J = 12.5 Hz, 1H), 1.58 – 1.52 (m, 3H), 1.49 – 1.39 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.07, 157.42, 134.72, 134.35, 133.99,133.44, 133.24, 131.93, 130.65, 129.94, 128.87, 128.58, 128.13, 128.11,128.09, 127.88, 126.78, 126.54, 126.41, 126.25, 125.42, 119.60, 107.31,70.35, 63.92, 57.35, 52.96, 42.94, 42.70, 35.77, 27.89, 26.52, 25.97, 23.41,21.32, 20.91. HRMS (ESI) m / z calculated for C 37 H 39 N2O2 + [M+H] + : 543.3012, found:543.3010. Example 5 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 2-fluorobenzyl bromide. The final product obtained in this example was 14-(6-(2-fluorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-9), which was a white solid with a yield of 30%. The spectroscopic characterization data of HKY-9 are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 7.78 – 7.69 (m, 3H), 7.62 – 7.53 (m, 1H), 7.45 – 7.40 (m, 2H), 7.29 (m, 2H), 7.25 – 7.21 (m, 1H), 7.19 –7.08 (m, 1H), 5.27 (d, J = 16.3 Hz, 2H), 4.53 (dd, J = 12.9, 4.4 Hz, 1H), 4.00 – 3.96 (m, 1H), 3.24 (t, J = 12.8 Hz, 1H), 3.01 – 2.92 (m, 1H), 2.83(dd, J = 22.3, 10.0 Hz, 1H), 2.58 (t, J = 13.0 Hz, 1H), 2.17 – 1.39 (m, 15H). 13C NMR (126 MHz, CDCl3) δ 165.03, 159.64, 157.12, 157.06, 134.61,133.95, 132.80, 132.03, 130.72, 129.99, 129.95, 129.88, 129.86, 129.82,129.56, 129.20, 128.94, 128.91, 128.85, 128.16, 127.13, 126.82, 124.45,124.42, 124.12, 124.00, 119.46, 119.40, 115.60, 115.43, 107.32, 107.19, 67.28, 63.94, 63.87, 63.83, 57.39, 52.98, 42.94, 42.71, 35.79, 27.93, 26.56, 25.99, 23.42, 21.35, 20.95. 19 F NMR (565 MHz, CDCl3) δ -118.62. HRMS (ESI) m / z calculated for C 33 H 36 FN2O2 + [M+H] + : 511.2761, found:511.2756. Example 6 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 4-isopropylbenzyl bromide. The final product obtained in this example was 14-(6-(4-isopropylbenzyloxy)-2-naphthylmethyl)matrine (abbreviated as HKY-51), which was a light yellow solid with a yield of 25%. The spectroscopic characterization data of HKY-51 are as follows: 11H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 7.99 (dd, J = 8.7, 1.8 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.0 Hz, 3H), 7.29 – 7.21 (m, 4H), 5.15 (d, J = 8.6 Hz, 2H), 4.67 – 4.62 (m, 1H), 4.48 (dd, J = 12.7, 4.3 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.14 (t, J = 13.1 Hz, 1H), 2.98 – 2.89 (m, 1H), 2.88 – 2.77 (m, 2H), 2.24 – 1.39 (m, 15H), 1.32 – 1.21 (m, 7H). 13 13C NMR (126 MHz, CDCl3) δ 198.20, 166.97, 166.36, 159.31, 159.11, 149.18, 149.14, 137.49, 137.33, 133.86, 133.78, 131.52, 131.50, 130.96, 130.95, 128.01, 127.99, 127.37, 127.14, 126.90, 126.88, 126.85, 125.50, 125.22, 120.23, 120.00, 107.07, 107.01, 70.26, 70.22, 63.72, 57.29, 53.45, 50.48, 43.63, 42.89, 41.77, 35.46, 34.03, 25.72, 24.10, 23.18, 23.02, 22.77. HRMS (ESI) m / z calculated for C 36 H 42 N2O2 + [M] + : 534.3246, found: 534.3262. Example 7 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 3-chlorobenzyl bromide. The final product obtained in this example was 14-(6-(3-chlorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-52), which was a white solid with a yield of 37%. The spectroscopic characterization data of HKY-52 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.71(s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.42 (dd, J =8.5, 1.7 Hz, 1H), 7.36 – 7.28 (m, 3H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H), 7.16(d, J = 2.5 Hz, 1H), 5.14 (s, 2H), 4.53 (dd, J = 12.7, 4.4 Hz, 1H), 3.97(ddd, J = 10.8, 8.0, 5.1 Hz, 1H), 3.23 (t, J = 12.7 Hz, 1H), 2.96 (dddd, J =15.0, 7.3, 3.8, 1.4 Hz, 1H), 2.88 – 2.83 (m, 1H), 2.82 – 2.78 (m, 1H), 2.57(dddd, J = 14.8, 10.8, 4.0, 2.0 Hz, 1H), 2.12 (t, J = 3.1 Hz, 1H), 2.11 –2.07 (m, 1H), 1.97 (qd, J = 12.6, 2.8 Hz, 2H), 1.88 (dt, J = 14.0, 2.6 Hz,1H), 1.83 – 1.75 (m, 2H), 1.75 – 1.71 (m, 1H), 1.65 (qt, J = 14.6, 4.1 Hz,1H), 1.58 – 1.50 (m, 3H), 1.48 – 1.37 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 164.97, 157.02, 138.94, 134.65, 134.57,133.87, 132.05, 130.74, 130.00, 129.99, 128.90, 128.82, 128.26, 128.18,127.56, 126.75, 125.50, 119.39, 107.19, 69.26, 63.87, 57.40, 57.36, 52.96,42.94, 42.69, 35.77, 27.91, 26.55, 25.93, 23.40, 21.33, 20.93. HRMS (ESI) m / z calculated for C 33 H 36 ClN2O2 + [M+H] + : 527.2465, found:527.2464. Example 8 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 3-fluorobenzyl bromide. The final product obtained in this example was 14-(6-(3-fluorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-66), which was a white solid with a yield of 36%. The spectroscopic characterization data of HKY-66 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.71(d, J = 1.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.5, 1.9 Hz,1H), 7.35 (td, J = 8.0, 5.8 Hz, 1H), 7.25 – 7.18 (m, 3H), 7.16 (d, J = 2.7Hz, 1H), 7.01 (td, J = 8.5, 3.0 Hz, 1H), 5.16 (s, 2H), 4.53 (dd, J = 12.7,4.4 Hz, 1H), 3.97 (ddd, J = 10.7, 8.0, 5.1 Hz, 1H), 3.23 (t, J = 12.7 Hz,1H), 2.95 (dddd, J = 15.0, 6.0, 3.9, 1.9 Hz, 1H), 2.85 (dd, J = 10.8, 2.9 Hz,1H), 2.80 (d, J = 12.8 Hz, 0H), 2.57 (dddd, J = 14.9, 10.7, 4.0, 2.1 Hz, 1H),2.12 (t, J = 3.3 Hz, 1H), 2.11 – 2.07 (m, 1H), 1.97 (qd, J = 12.5, 2.9 Hz,2H), 1.88 (d, J = 13.8 Hz, 1H), 1.83 – 1.75 (m, 2H), 1.72 (dd, J = 14.0, 2.8Hz, 1H), 1.69 – 1.60 (m, 1H), 1.58 – 1.49 (m, 3H), 1.48 – 1.37 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 164.96, 163.90, 162.27, 157.01, 139.48,139.46, 139.43, 134.55, 133.86, 132.01, 130.71, 130.28, 130.22, 129.95,128.87, 128.83, 128.80, 128.15, 126.73, 122.86, 122.84, 119.38, 115.02,114.89, 114.41, 114.27, 107.19, 69.27, 69.26, 63.84, 57.37, 57.33, 52.94, 42.92, 42.67, 35.76, 27.88, 26.52, 25.91, 23.38, 21.30, 20.91. 19 F NMR (565 MHz, CDCl3) δ -112.65. HRMS (ESI) m / z calculated for C 33 H 36 FN2O2 + [M+H] + : 511.2761, found:511.2761. Example 9 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 4-bromobenzyl bromide in equal molar amounts. The final product obtained in this example was 14-(6-(4-bromobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-67), which was a white solid with a yield of 23%. The spectroscopic characterization data of HKY-67 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.84 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.71(s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 – 7.50 (m, 2H), 7.42 (dd, J = 8.5,1.7 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.21 (dd, J = 8.9, 2.5 Hz, 1H), 7.16(d, J = 2.5 Hz, 1H), 5.13 (s, 2H), 4.53 (dd, J = 12.7, 4.4 Hz, 1H), 3.97(ddd, J = 10.7, 7.9, 5.2 Hz, 1H), 3.23 (t, J = 12.7 Hz, 1H), 2.99 – 2.93 (m,1H), 2.86 (d, J = 10.3 Hz, 1H), 2.81 (d, J = 11.4 Hz, 1H), 2.58 (dddd, J =14.8, 10.7, 4.0, 2.0 Hz, 1H), 2.14 (t, J = 2.7 Hz, 1H), 2.12 – 2.08 (m, 1H),1.98 (qd, J = 12.6, 2.8 Hz, 2H), 1.89 (d, J = 12.9 Hz, 1H), 1.84 – 1.74 (m,3H), 1.66 (qt, J = 14.5, 3.9 Hz, 1H), 1.59 – 1.50 (m, 3H), 1.49 – 1.38 (m,3H). 13 C NMR (151 MHz, CDCl3) δ 165.02, 157.09, 135.93, 134.62, 133.90,132.07, 131.89, 130.76, 130.00, 129.26, 128.91, 128.85, 128.21, 126.76,122.10, 119.44, 107.24, 69.42, 63.91, 57.44, 57.40, 53.00, 42.98, 42.73,35.81, 27.94, 26.58, 25.98, 23.43, 21.36, 20.97. HRMS (ESI) m / z calculated for C33 H 36 BrN2O2 + [M+H] + : 571.1960, found:571.1954. Example 10 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 2-bromo-4-fluorobenzyl bromide. The final product obtained in this example was 14-(6-(2-bromo-4-fluorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-69), which was a light yellow solid with a yield of 21%. The spectroscopic characterization data of HKY-69 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.74– 7.70 (m, 2H), 7.55 (dd, J = 8.8, 5.1 Hz, 1H), 7.43 (dd, J = 8.5, 1.8 Hz,1H), 7.37 (dd, J = 9.3, 3.1 Hz, 1H), 7.26 (dd, J = 8.9, 2.5 Hz, 1H), 7.18 (d,J = 2.7 Hz, 1H), 6.93 (td, J = 7.9, 3.1 Hz, 1H), 5.21 (s, 2H), 4.53 (dd, J =12.7, 4.5 Hz, 1H), 4.01 – 3.95 (m, 1H), 3.24 (t, J = 12.7 Hz, 1H), 3.00 –2.93 (m, 1H), 2.86 (d, J = 9.7 Hz, 1H), 2.82 (d, J = 10.6 Hz, 1H), 2.58(dddd, J = 14.9, 10.7, 4.0, 2.1 Hz, 1H), 2.16 – 2.09 (m, 2H), 1.99 (q, J =11.6 Hz, 2H), 1.89 (d, J = 13.3 Hz, 1H), 1.84 – 1.74 (m, 3H), 1.70 – 1.62 (m,1H), 1.60 – 1.50 (m, 3H), 1.50 – 1.38 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 165.04, 163.22, 161.58, 156.64, 138.60,138.54, 134.61, 133.95, 133.90, 133.88, 132.22, 130.84, 130.15, 129.07,128.85, 128.27, 126.86, 119.25, 116.50, 116.35, 116.05, 115.89, 115.87,115.85, 107.40, 69.00, 63.93, 57.43, 57.39, 53.01, 42.98, 42.74, 35.81, 27.93, 26.58, 26.00, 23.44, 21.36, 20.96. 19 F NMR (565 MHz, CDCl3) δ -113.84. HRMS (ESI) m / z calculated for C 33 H 35 BrFN2O2 + [M+H] + : 589.1866, found:589.1863. Example 11 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 4-tert-butylbenzyl bromide. The final product obtained in this example was 14-(6-(4-tert-butylbenzyloxy)-2-naphthylmethyl)matrine (abbreviated as HKY-71), which was a white solid with a yield of 24%. The spectroscopic characterization data of HKY-71 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.72– 7.69 (m, 2H), 7.45 – 7.41 (m, 5H), 7.24 – 7.21 (m, 2H), 5.15 (s, 2H), 4.53(dd, J = 12.7, 4.4 Hz, 1H), 3.98 (ddd, J = 10.7, 7.9, 5.1 Hz, 1H), 3.24 (t, J= 12.7 Hz, 1H), 2.97 (dddd, J = 14.9, 7.2, 3.9, 1.4 Hz, 1H), 2.86 (d, J =10.4 Hz, 1H), 2.81 (d, J = 11.6 Hz, 1H), 2.59 (dddd, J = 14.8, 10.7, 4.0, 2.0Hz, 1H), 2.14 (t, J = 3.1 Hz, 1H), 2.13 – 2.08 (m, 1H), 2.03 – 1.95 (m, 2H),1.93 – 1.87 (m, 1H), 1.84 – 1.76 (m, 2H), 1.75 – 1.71 (m, 1H), 1.66 (dddd, J= 18.0, 14.3, 10.8, 4.1 Hz, 1H), 1.60 – 1.51 (m, 3H), 1.50 – 1.38 (m, 3H),1.34 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 165.06, 157.52, 151.28, 134.72, 134.01,133.80, 131.86, 130.63, 129.85, 128.86, 128.79, 128.11, 127.68, 126.75,125.72, 119.66, 107.06, 70.07, 63.92, 57.44, 57.40, 53.00, 42.97, 42.72,35.81, 34.74, 31.47, 27.94, 26.59, 25.98, 23.44, 21.36, 20.97. HRMS (ESI) m / z calculated for C 37 H 45 N2O2 + [M+H]+ : 549.3481, found:549.3469. Example 12 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 3,5-di(tert-butyl)benzyl bromide. The final product obtained in this example was 14-(6-[3,5-di(tert-butyl)benzyloxy]-2-naphthylmethylene)matrine (abbreviated as HKY-72), which was a white solid with a yield of 23%. The spectroscopic characterization data of HKY-72 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.89 (s, 1H), 7.78 (d, J = 9.7 Hz, 1H), 7.76– 7.73 (m, 2H), 7.48 – 7.44 (m, 2H), 7.37 (d, J = 1.8 Hz, 2H), 7.31 – 7.26(m, 2H), 5.18 (s, 2H), 4.57 (dd, J = 12.7, 4.4 Hz, 1H), 4.01 (ddd, J = 10.8,7.9, 5.1 Hz, 1H), 3.27 (t, J = 12.7 Hz, 1H), 3.01 (dddd, J = 14.8, 7.2, 3.7,1.3 Hz, 1H), 2.89 (d, J = 10.0 Hz, 1H), 2.84 (d, J = 11.1 Hz, 1H), 2.62(dddd, J = 14.8, 10.7, 3.9, 2.0 Hz, 1H), 2.17 (t, J = 2.9 Hz, 1H), 2.16 –2.11 (m, 1H), 2.01 (qd, J = 12.5, 2.8 Hz, 2H), 1.92 (d, J = 11.9 Hz, 1H), 1.87 – 1.79 (m, 2H), 1.79 – 1.75 (m, 1H), 1.69 (dtt, J = 17.8, 8.3, 4.1 Hz,1H), 1.63 – 1.54 (m, 3H), 1.52 – 1.42 (m, 3H), 1.38 (s, 18H). 13C NMR (151 MHz, CDCl3) δ 165.04, 157.68, 151.23, 135.76, 134.72,134.03, 131.81, 130.58, 129.78, 128.86, 128.78, 128.08, 126.74, 122.44,122.40, 119.74, 107.04, 71.09, 63.90, 57.42, 57.38, 52.97, 42.96, 42.70,35.79, 35.00, 31.59, 27.92, 26.57, 25.96, 23.43, 21.34, 20.95. HRMS (ESI) m / z calculated for C 41 H 53 N2O2 + [M+H] + : 605.4107, found:605.4098. Example 13 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 3,5-di(methoxy)benzyl bromide. The final product obtained in this example was 14-(6-[3,5-di(methoxy)benzyloxy]-2-naphthylmethyl)matrine (abbreviated as HKY-75), which was a white solid with a yield of 19%. The spectroscopic characterization data of HKY-75 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.84 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.71(s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.5, 1.7 Hz, 1H), 7.23 (dd,J = 8.9, 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.63 (d, J = 2.3 Hz, 2H),6.42 (t, J = 2.3 Hz, 1H), 5.11 (s, 2H), 4.52 (dd, J = 12.7, 4.4 Hz, 1H), 3.97(ddd, J = 10.7, 8.0, 5.2 Hz, 1H), 3.80 (s, 6H), 3.23 (t, J = 12.7 Hz, 1H),2.99 – 2.93 (m, 1H), 2.85 (d, J = 10.3 Hz, 1H), 2.80 (d, J = 11.5 Hz, 1H),2.57 (dddd, J = 14.8, 10.7, 4.0, 2.0 Hz, 1H), 2.12 (t, J = 3.3, 2.7 Hz, 1H),2.11 – 2.07 (m, 1H), 2.01 – 1.93 (m, 2H), 1.88 (d, J = 12.8 Hz, 1H), 1.83 –1.75 (m, 2H), 1.75 – 1.70 (m, 1H), 1.70 – 1.60 (m, 1H), 1.58 – 1.50 (m, 3H),1.48 – 1.37 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 164.99, 161.13, 157.26, 139.22, 134.62,133.93, 131.89, 130.64, 129.85, 128.81, 128.08, 126.74, 119.50, 107.21,100.00, 70.09, 63.86, 57.39, 57.35, 55.46, 52.95, 42.93, 42.68, 35.77, 27.90,26.54, 25.92, 23.39, 21.32, 20.92. HRMS (ESI) m / z calculated for C 35 H 41 N2O4 + [M+H] + : 553.3066, found:553.3057. Example 14 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 4-fluorobenzyl bromide in equal molar amounts. The final product obtained in this example was 14-(6-(4-fluorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-76), which was a white solid with a yield of 24%. The spectroscopic characterization data of HKY-76 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.72(s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.47 – 7.44 (m, 2H), 7.42 (dd, J = 8.5,1.9 Hz, 1H), 7.21 (dd, J = 8.8, 2.5 Hz, 1H), 7.19 (d, J = 2.7 Hz, 1H), 7.12 –7.06 (m, 2H), 5.14 (s, 2H), 4.53 (dd, J = 12.7, 4.4 Hz, 1H), 3.98 (ddd, J =10.7, 8.0, 5.1 Hz, 1H), 3.24 (t, J = 12.7 Hz, 1H), 3.00 – 2.93 (m, 1H), 2.86 (d, J = 10.2 Hz, 1H), 2.81 (d, J = 11.6 Hz, 1H), 2.58 (dddd, J = 14.9, 10.7,4.0, 2.1 Hz, 1H), 2.14 (t, J = 3.2 Hz, 1H), 2.10 (dt, J = 9.2, 3.9 Hz, 1H), 1.98 (qd, J = 12.6, 2.9 Hz, 2H), 1.89 (d, J = 13.8 Hz, 1H), 1.84 – 1.76 (m,2H), 1.75 – 1.71 (m, 1H), 1.66 (qt, J = 14.4, 4.2 Hz, 1H), 1.59 – 1.50 (m,3H), 1.50 – 1.38 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.03, 163.50, 161.87, 157.21, 134.64,133.93, 132.64, 132.62, 132.02, 130.73, 129.96, 129.57, 129.54, 129.51,128.88, 128.85, 128.19, 126.75, 119.50, 115.75, 115.61, 107.19, 69.52, 63.91,57.43, 57.39, 53.00, 42.97, 42.94, 42.73, 35.81, 27.93, 26.58, 25.97, 23.43, 21.36, 20.96. 19 F NMR (565 MHz, CDCl3) δ -114.07. HRMS (ESI) m / z calculated for C 33 H 36 FN2O2 + [M+H] + : 511.2761, found: 511.2759. Example 15 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 3,4-difluorobenzyl bromide. The final product obtained in this example was 14-(6-(3,4-difluorobenzyloxy)-2-naphthylmethyl)matrine (abbreviated as HKY-77), which was a white solid with a yield of 23%. The spectroscopic characterization data of HKY-77 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.84 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.71(s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.5, 1.7 Hz, 1H), 7.34 –7.28 (m, 1H), 7.20 (dd, J = 8.9, 2.5 Hz, 1H), 7.19 – 7.14 (m, 3H), 5.11 (s,2H), 4.52 (dd, J = 12.7, 4.4 Hz, 1H), 3.97 (ddd, J = 10.8, 8.0, 5.2 Hz, 1H),3.23 (t, J = 12.7 Hz, 1H), 2.95 (dddd, J = 15.0, 7.3, 3.8, 1.4 Hz, 1H), 2.85(d, J = 10.2 Hz, 1H), 2.80 (d, J = 11.4 Hz, 1H), 2.57 (dddd, J = 14.8, 10.7,4.0, 2.0 Hz, 1H), 2.12 (t, J = 3.1 Hz, 1H), 2.11 – 2.07 (m, 1H), 1.97 (qd, J= 12.7, 2.8 Hz, 2H), 1.88 (d, J = 16.1 Hz, 1H), 1.83 – 1.70 (m, 2H), 1.73 (d,J = 13.4 Hz, 1H), 1.65 (qt, J = 14.5, 4.0 Hz, 1H), 1.59 – 1.48 (m, 3H), 1.48– 1.36 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 164.96, 156.86, 151.42, 151.34, 150.99, 150.91, 149.77, 149.69, 149.35, 149.26, 134.52, 133.95, 133.92, 133.88,133.83, 132.12, 130.80, 130.03, 128.94, 128.81, 128.23, 126.74, 123.48,123.45, 123.44, 123.41, 119.32, 117.56, 117.45, 116.65, 116.54, 107.20, 68.83, 63.86, 57.40, 57.35, 52.96, 42.94, 42.70, 35.78, 27.90, 26.54, 25.93, 23.40, 21.32, 20.93. 19 F NMR (565 MHz, CDCl3) δ -137.19, -137.23, -138.70, -138.74. HRMS (ESI) m / z calculated for C 33 H 35 F2N2O2 + [M+H] + : 529.2667, found:529.2665. Example 16 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 2-bromobenzyl bromide. The final product obtained in this example was 14-(6-(2-bromobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-88), which was a white solid with a yield of 37%. The spectroscopic characterization data of HKY-88 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.79 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.69– 7.65 (m, 2H), 7.57 (dd, J = 8.0, 1.2 Hz, 1H), 7.54 (dd, J = 7.7, 1.7 Hz,1H), 7.36 (dd, J = 8.6, 1.6 Hz, 1H), 7.30 (td, J = 7.5, 1.2 Hz, 1H), 7.21(dd, J = 8.9, 2.5 Hz, 1H), 7.18 – 7.13 (m, 2H), 5.19 (s, 2H), 4.67 (dd, J =13.9, 4.6 Hz, 1H), 4.48 (ddd, J = 11.3, 8.1, 5.2 Hz, 1H), 3.67 (t, J = 13.5Hz, 1H), 3.51 (d, J = 11.4 Hz, 1H), 3.46 (d, J = 11.7 Hz, 1H), 3.22 (d, J =8.4 Hz, 1H), 2.93 (dt, J = 15.3, 4.9 Hz, 1H), 2.75 – 2.61 (m, 3H), 2.34 –2.21 (m, 2H), 2.21 – 2.14 (m, 1H), 2.07 (dt, J = 12.9, 4.3 Hz, 1H), 2.00 (d,J = 14.5 Hz, 1H), 1.86 (d, J = 14.0 Hz, 1H), 1.80 – 1.65 (m, 4H), 1.59 (tt, J= 14.5, 4.3 Hz, 1H), 1.50 – 1.40 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 165.24, 157.04, 135.95, 135.47, 133.98,132.70, 131.41, 129.95, 129.70, 129.43, 129.03, 128.92, 128.78, 127.86,127.65, 126.89, 122.48, 119.42, 107.24, 69.47, 64.30, 56.27, 56.18, 51.87,41.61, 41.58, 34.39, 26.18, 25.80, 24.27, 22.86, 18.95, 18.67. HRMS (ESI) m / z calculated for C 33 H 36 BrN2O2 + [M+H] + : 571.1960, found:571.1966. Example 17 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 4-trifluoromethylbenzyl bromide. The final product obtained in this example was 14-(6-(4-trifluoromethylbenzyloxy)-2-naphthylmethyl)matrine (abbreviated as HKY-92), which was a white solid with a yield of 36%. The spectroscopic characterization data of HKY-92 are as follows: 1H NMR (500 MHz, CDCl3) δ 7.85 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.72(s, 1H), 7.71 – 7.65 (m, 3H), 7.62 – 7.58 (m, 2H), 7.42 (dd, J = 8.4, 1.7 Hz,1H), 7.23 (dd, J = 8.9, 2.5 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 5.25 (s, 2H),4.53 (dd, J = 12.7, 4.4 Hz, 1H), 3.98 (ddd, J = 11.4, 7.7, 4.8 Hz, 1H), 3.24(t, J = 12.7 Hz, 1H), 3.01 – 2.92 (m, 1H), 2.87 (d, J = 11.1 Hz, 1H), 2.82(d, J = 11.4 Hz, 1H), 2.58 (dddd, J = 14.9, 10.9, 4.1, 2.1 Hz, 1H), 2.17 –2.13 (m, 1H), 2.13 – 2.07 (m, 1H), 1.99 (q, J = 11.7, 10.4 Hz, 2H), 1.89 (d,J = 13.7 Hz, 1H), 1.85 – 1.78 (m, 1H), 1.70 (dt, J = 38.8, 8.7 Hz, 3H), 1.53(ddd, J = 11.7, 7.6, 3.8 Hz, 3H), 1.49 – 1.37 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 164.99, 156.95, 140.98, 134.56, 133.87,132.16, 130.83, 130.43, 130.21, 130.08, 128.97, 128.84, 128.26, 127.55,126.77, 125.74, 125.72, 125.70, 125.67, 125.10, 123.30, 119.35, 107.25,69.26, 63.90, 57.43, 57.39, 52.99, 42.97, 42.73, 35.80, 27.93, 26.58, 25.97,23.43, 21.35, 20.96. 19 F NMR (565 MHz, CDCl3) δ -62.53. HRMS (ESI) m / z calculated for C 34 H 36 F3N2O2 + [M+H] + : 561.2729, found:561.2725. Example 18 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 4-chlorobenzyl bromide. The final product obtained in this example was 14-(6-(4-chlorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-93), which was a white solid with a yield of 41%. The spectroscopic characterization data of HKY-93 are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.72(s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.43 – 7.40 (m, 3H), 7.39 – 7.35 (m, 2H),7.21 (dd, J = 8.9, 2.5 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.53(dd, J = 12.8, 4.4 Hz, 1H), 4.02 – 3.93 (m, 1H), 3.24 (t, J = 12.7 Hz, 1H), 3.00 – 2.92 (m, 1H), 2.85 (d, J = 10.4 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.58 (dddd, J = 14.8, 10.8, 3.9, 2.0 Hz, 1H), 2.13 (s, 1H), 2.12 – 2.08 (m,1H), 1.98 (q, J = 13.6, 11.9 Hz, 2H), 1.89 (d, J = 13.9 Hz, 1H), 1.84 – 1.78(m, 1H), 1.75 (d, J = 7.6 Hz, 2H), 1.66 (d, J = 13.0 Hz, 1H), 1.59 – 1.49 (m,3H), 1.49 – 1.36 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 165.02, 157.11, 135.39, 134.63, 133.98,133.91, 132.05, 130.75, 129.99, 128.96, 128.94, 128.90, 128.85, 128.20,126.76, 119.45, 107.23, 69.39, 63.92, 57.42, 57.38, 52.98, 42.96, 42.72,35.79, 27.92, 26.57, 25.98, 23.43, 21.34, 20.95. HRMS (ESI) m / z calculated for C 33 H 36 ClN2O2 + [M+H] + : 527.2465, found:527.2457. Example 19 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced equimolarly with 4-bromo-2-fluorobenzyl bromide. The final product obtained in this example was 14-(6-(4-bromo-2-fluorobenzyloxy)-2-naphthylmethylene)matrine (abbreviated as HKY-105), which was a white solid with a yield of 32%. The spectroscopic characterization data of HKY-105 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.84 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.71(s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.44 – 7.40 (m, 2H), 7.32 – 7.28 (m, 2H),7.21 – 7.17 (m, 2H), 5.18 (s, 2H), 4.53 (dd, J = 12.7, 4.4 Hz, 1H), 3.97(ddd, J = 10.8, 8.0, 5.1 Hz, 1H), 3.23 (t, J = 12.7 Hz, 1H), 2.95 (dddd, J =14.8, 7.1, 3.8, 1.6 Hz, 1H), 2.86 (d, J = 10.1 Hz, 1H), 2.81 (d, J = 11.4 Hz,1H), 2.57 (dddd, J = 14.8, 10.7, 3.9, 2.0 Hz, 1H), 2.13 (t, J = 3.0 Hz, 1H),2.12 – 2.07 (m, 1H), 1.98 (qd, J = 12.5, 2.8 Hz, 2H), 1.88 (d, J = 13.2 Hz,1H), 1.84 – 1.75 (m, 2H), 1.73 (dt, J = 13.1, 1.7 Hz, 1H), 1.70 – 1.60 (m,1H), 1.58 – 1.50 (m, 3H), 1.48 – 1.37 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 164.98, 161.08, 159.42, 156.80, 134.56,133.89, 133.84, 132.12, 130.83, 130.80, 130.77, 130.02, 128.96, 128.89,128.81, 128.21, 127.80, 127.78, 126.79, 123.39, 123.29, 122.30, 122.24,119.27, 119.11, 107.17, 63.87, 63.33, 63.31, 57.39, 57.35, 52.96, 42.94,42.69, 35.77, 27.90, 26.54, 25.94, 23.40, 21.32, 20.92. 19 F NMR (565 MHz, CDCl3) δ -115.72. HRMS (ESI) m / z calculated for C 33 H 35 BrFN2O2 + [M+H] + : 589.1866, found:589.1861. Example 20 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 3,4-difluorobenzyl bromide in equal molar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 4-hydroxy-1-naphthaldehyde in equal molar amounts. The final product obtained in this example was 14-(4-(3,4-difluorobenzyloxy)-1-naphthylmethylene)matrine (abbreviated as HKY-78), which was a white solid with a yield of 32%. The spectroscopic characterization data of HKY-78 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.35 – 8.32 (m, 1H), 8.14 (s, 1H), 7.98 –7.95 (m, 1H), 7.56 – 7.48 (m, 2H), 7.36 (ddd, J = 11.0, 7.6, 1.9 Hz, 1H),7.25 – 7.17 (m, 3H), 6.82 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 4.56 (dd, J =12.7, 4.4 Hz, 1H), 3.96 (ddd, J = 10.8, 8.3, 5.3 Hz, 1H), 3.25 (t, J = 12.7Hz, 1H), 2.85 (dd, J = 10.7, 2.8 Hz, 1H), 2.81 (d, J = 11.4 Hz, 1H), 2.70(dddd, J = 14.9, 6.9, 3.7, 1.3 Hz, 1H), 2.37 (dddd, J = 14.9, 11.2, 3.9, 2.0Hz, 1H), 2.14 (t, J = 3.1 Hz, 1H), 2.06 (dddd, J = 13.5, 6.9, 5.3, 3.8 Hz,1H), 2.02 – 1.93 (m, 2H), 1.87 – 1.72 (m, 4H), 1.63 (qt, J = 14.0, 3.9 Hz,1H), 1.59 – 1.53 (m, 2H), 1.50 – 1.36 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 164.94, 154.13, 151.48, 151.39, 151.02, 150.94, 149.83, 149.75, 149.37, 149.29, 134.12, 134.09, 134.06, 133.16,132.43, 132.14, 127.00, 126.96, 126.60, 125.70, 125.66, 125.02, 123.38,123.36, 123.34, 123.32, 122.38, 117.63, 117.52, 116.56, 116.44, 104.56, 69.01, 63.92, 57.40, 57.37, 53.13, 42.92, 42.75, 35.76, 27.93, 26.52, 26.36, 23.64, 21.34, 21.26, 20.92. 19 F NMR (565 MHz, CDCl3) δ -137.15, -137.18, -138.71, -138.75. HRMS (ESI) m / z calculated for C 33 H 35 F2N2O2 + [M+H] + : 529.2667, found:529.2660. Example 21 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 3-chlorobenzyl bromide in equal molar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 4-hydroxy-1-naphthaldehyde in equal molar amounts. The final product obtained in this example was 14-(4-(3-chlorobenzyloxy)-1-naphthylmethyl)matrine (abbreviated as HKY-81), which was a white solid with a yield of 28%. The spectroscopic characterization data of HKY-81 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.38 – 8.33 (m, 1H), 8.15 (d, J = 1.4 Hz,1H), 7.99 – 7.94 (m, 1H), 7.56 – 7.49 (m, 3H), 7.39 (dt, J = 6.9, 1.9 Hz,1H), 7.36 – 7.30 (m, 2H), 7.21 (dd, J = 7.9, 1.1 Hz, 1H), 6.82 (d, J = 8.0Hz, 1H), 5.22 (s, 2H), 4.56 (dd, J = 12.7, 4.4 Hz, 1H), 3.95 (ddd, J = 10.7,8.2, 5.3 Hz, 1H), 3.25 (t, J = 12.7 Hz, 1H), 2.87 – 2.83 (m, 1H), 2.81 (dp, J= 11.5, 2.1 Hz, 1H), 2.70 (dddd, J = 14.9, 6.9, 3.7, 1.2 Hz, 1H), 2.37 (dddd,J = 14.9, 11.1, 3.9, 2.0 Hz, 1H), 2.13 (t, J = 3.1 Hz, 1H), 2.05 (dddd, J =13.5, 6.9, 5.3, 3.8 Hz, 1H), 2.01 – 1.93 (m, 2H), 1.86 – 1.81 (m, 2H), 1.81 –1.72 (m, 2H), 1.63 (qt, J = 13.5, 3.6 Hz, 1H), 1.59 – 1.52 (m, 2H), 1.49 –1.34 (m, 4H). 13 C NMR (151 MHz, CDCl3) δ 164.93, 154.26, 139.12, 134.64, 133.13,132.45, 132.03, 130.04, 128.25, 127.43, 127.00, 126.94, 126.43, 125.67,125.63, 125.40, 124.95, 122.46, 104.54, 69.41, 63.88, 63.76, 57.38, 57.34,53.10, 42.89, 42.72, 35.73, 27.91, 26.49, 26.33, 23.61, 21.32, 20.90. HRMS (ESI) m / z calculated for C 33 H 36 ClN2O2 + [M+H] + : 527.2465, found:527.2461. Example 22 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 4-bromobenzyl bromide in equal molar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 4-hydroxy-1-naphthaldehyde in equal molar amounts. The final product obtained in this example was 14-(4-(4-bromobenzyloxy)-1-naphthylmethylene)matrine (abbreviated as HKY-84), which was a white solid with a yield of 41%. The spectroscopic characterization data of HKY-84 are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.34 (dd, J = 7.8, 1.8 Hz, 1H), 8.14 (s,1H), 7.96 (dd, J = 7.8, 1.6 Hz, 1H), 7.56 – 7.48 (m, 4H), 7.41 – 7.38 (m,2H), 7.21 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 5.21 (s, 2H), 4.56(dd, J = 12.9, 4.4 Hz, 1H), 3.97 (s, 1H), 3.25 (t, J = 12.6 Hz, 1H), 2.88 –2.79 (m, 2H), 2.71 (ddd, J = 14.9, 6.9, 3.6 Hz, 1H), 2.37 (t, J = 13.9, 12.7Hz, 1H), 2.15 (s, 1H), 2.09 – 2.03 (m, 1H), 2.03 – 1.93 (m, 2H), 1.89 – 1.79 (m, 4H), 1.76 (d, J = 13.0 Hz, 1H), 1.69 – 1.53 (m, 3H), 1.51 – 1.37 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 165.01, 154.34, 136.11, 133.16, 132.56,132.03, 131.91, 129.13, 127.04, 126.97, 126.41, 125.72, 125.64, 124.99,122.48, 122.05, 104.59, 69.54, 63.95, 57.38, 53.13, 42.92, 42.75, 35.75,27.92, 26.51, 26.39, 23.64, 21.33, 20.91. HRMS (ESI) m / z calculated for C 33 H 36 BrN2O2 + [M+H] + : 571.1960, found: 571.1946. Example 23 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 2,4-difluorobenzyl bromide in equal molar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 4-hydroxy-1-naphthaldehyde in equal molar amounts. The final product obtained in this example was 14-(4-(2,4-difluorobenzyloxy)-1-naphthylmethylene)matrine (abbreviated as HKY-89), which was a white solid with a yield of 35%. The spectroscopic characterization data of HKY-89 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.31 (dd, J = 8.0, 1.6 Hz, 1H), 8.15 (s,1H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 7.58 (td, J = 8.4, 6.4 Hz, 1H), 7.55 –7.47 (m, 2H), 7.23 (dd, J = 7.8, 1.0 Hz, 1H), 6.93 (td, J = 8.4, 7.9, 2.2 Hz,1H), 6.91 – 6.85 (m, 2H), 5.27 (s, 2H), 4.56 (dd, J = 12.7, 4.4 Hz, 1H), 3.96(ddd, J = 10.6, 8.2, 5.2 Hz, 1H), 3.25 (t, J = 12.6 Hz, 1H), 2.85 (dt, J =11.4, 2.6 Hz, 1H), 2.81 (dt, J = 11.5, 2.1 Hz, 1H), 2.74 – 2.68 (m, 1H), 2.38(dddd, J = 14.9, 11.2, 3.8, 1.9 Hz, 1H), 2.13 (t, J = 3.0 Hz, 1H), 2.09 –2.03 (m, 1H), 1.97 (tdd, J = 11.4, 7.5, 2.6 Hz, 2H), 1.87 – 1.81 (m, 2H),1.80 – 1.72 (m, 2H), 1.63 (qt, J = 14.0, 3.7 Hz, 1H), 1.59 – 1.52 (m, 2H),1.50 – 1.35 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 164.94, 163.80, 163.72, 162.15, 162.07,161.59, 161.51, 159.93, 159.85, 154.18, 133.14, 132.44, 132.07, 130.83,130.80, 130.77, 130.73, 127.01, 126.92, 126.52, 125.69, 125.60, 124.96,122.41, 120.24, 120.22, 120.15, 120.12, 111.72, 111.69, 111.58, 111.56, 104.51, 104.21, 104.04, 103.87, 63.89, 63.59, 63.56, 57.40, 57.36, 53.11, 42.90, 42.74, 35.75, 27.92, 26.51, 26.34, 23.62, 21.33, 20.91. 19 F NMR (565 MHz, CDCl3) δ -109.99, -110.00, -114.25, -114.26. HRMS (ESI) m / z calculated for C 33 H 35 F2N2O2 + [M+H] + : 529.2667, found:529.2661. Example 24 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 4-tert-butylbenzyl bromide in equal molar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 4-hydroxy-1-naphthaldehyde in equal molar amounts. The final product obtained in this example was 14-(4-(4-tert-butylbenzyloxy)-1-naphthylmethyl)matrine (abbreviated as HKY-91), which was a white solid with a yield of 28%. The spectroscopic characterization data of HKY-91 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.38 (dd, J = 8.1, 1.1 Hz, 1H), 8.16 (s,1H), 7.97 (dd, J = 7.8, 1.2 Hz, 1H), 7.54 – 7.44 (m, 6H), 7.23 (dd, J = 7.9,1.0 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 5.23 (s, 2H), 4.57 (dd, J = 12.7, 4.4Hz, 1H), 3.96 (ddd, J = 10.6, 8.2, 5.2 Hz, 1H), 3.25 (t, J = 12.7 Hz, 1H),2.88 – 2.84 (m, 1H), 2.82 (d, J = 11.4 Hz, 1H), 2.73 (dddd, J = 14.8, 6.8,3.7, 1.2 Hz, 1H), 2.39 (dddd, J = 14.9, 11.2, 3.8, 1.9 Hz, 1H), 2.14 (t, J =3.0 Hz, 1H), 2.10 – 2.04 (m, 1H), 1.98 (tdd, J = 11.4, 7.9, 2.7 Hz, 2H), 1.88– 1.82 (m, 2H), 1.81 – 1.73 (m, 2H), 1.69 – 1.60 (m, 1H), 1.60 – 1.53 (m,2H), 1.50 – 1.37 (m, 4H), 1.36 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 165.06, 154.82, 151.18, 134.06, 133.14,132.66, 131.88, 127.43, 127.19, 126.86, 126.06, 125.83, 125.67, 125.47,124.90, 122.72, 104.48, 70.16, 63.95, 57.44, 57.40, 53.15, 42.93, 42.77,35.78, 34.75, 31.50, 27.96, 26.64, 26.55, 26.40, 23.66, 21.37, 20.95. HRMS (ESI) m / z calculated for C 37 H 45N2O2 + [M+H] + : 549.3481, found:549.3472. Example 25 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 3-bromopropene in equimolar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with indole-3-carboxaldehyde in equimolar amounts. The final product obtained in this example was 14-(1-N-allyl-3-indolomenyl)matrine (abbreviated as HKY-43), which is a light yellow solid with a yield of 18%. The spectroscopic characterization data of HKY-43 are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.05 (t, J = 2.1 Hz, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.33 – 7.28 (m, 1H), 7.27 – 7.23 (m, 1H), 7.22 (s, 1H), 7.19 (ddd, J= 8.1, 6.9, 1.2 Hz, 1H), 6.00 (ddt, J = 17.1, 10.5, 5.4 Hz, 1H), 5.23 (dq, J= 10.3, 1.6 Hz, 1H), 5.12 (dq, J = 17.1, 1.7 Hz, 1H), 4.75 (dt, J = 5.4, 1.7Hz, 2H), 4.52 (dd, J = 12.7, 4.5 Hz, 1H), 3.98 (ddd, J = 11.6, 7.3, 4.9 Hz,1H), 3.22 (t, J = 12.7 Hz, 1H), 2.88 – 2.79 (m, 3H), 2.58 (dddd, J = 15.6,9.4, 4.5, 2.1 Hz, 1H), 2.18 – 2.11 (m, 2H), 2.02 – 1.94 (m, 2H), 1.93 – 1.89(m, 1H), 1.85 – 1.76 (m, 2H), 1.75 – 1.70 (m, 1H), 1.70 – 1.63 (m, 2H), 1.62– 1.58 (m, 1H), 1.54 (tt, J = 13.6, 4.7 Hz, 1H), 1.48 – 1.38 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 165.47, 136.02, 133.02, 128.76, 128.15,126.11, 125.80, 122.66, 120.43, 119.74, 117.90, 112.43, 109.74, 64.04, 64.00,57.47, 57.43, 52.80, 49.20, 43.19, 42.07, 35.89, 27.96, 26.71, 25.26, 24.30,21.39, 21.01. HRMS (ESI) m / z calculated for C 27 H 34 N3O + [M+H] + : 416.2702, found:416.2698. Example 26 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced in equimolar amounts with 3-phenoxybromopropane, and 6-hydroxy-2-naphthaldehyde was replaced in equimolar amounts with indole-3-carboxaldehyde. The final product obtained in this example was 14-(1-N-(3-phenoxypropyl)-3-indolemethylenyl)matrine (abbreviated as HKY-49), which was a white solid with a yield of 22%. The spectroscopic characterization data of HKY-49 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.35(d, J = 8.1 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.24 (ddd, J = 8.2, 6.9, 1.2 Hz,1H), 7.20 – 7.18 (m, 1H), 7.17 (s, 2H), 6.95 (tt, J = 7.4, 1.2 Hz, 1H), 6.90– 6.87 (m, 2H), 4.49 (dd, J = 12.7, 4.5 Hz, 1H), 4.41 (t, J = 6.5 Hz, 2H),3.93 – 3.88 (m, 1H), 3.87 – 3.81 (m, 2H), 3.19 (t, J = 12.6 Hz, 1H), 2.86 (d,J = 11.1 Hz, 1H), 2.80 (d, J = 11.3 Hz, 1H), 2.55 (dddd, J = 14.8, 8.2, 4.4,1.7 Hz, 1H), 2.34 – 2.30 (m, 1H), 2.30 – 2.26 (m, 2H), 2.12 (t, J = 3.0 Hz,1H), 2.02 – 1.91 (m, 3H), 1.88 – 1.83 (m, 1H), 1.81 – 1.74 (m, 2H), 1.74 –1.68 (m, 1H), 1.68 – 1.61 (m, 1H), 1.56 – 1.52 (m, 2H), 1.51 – 1.49 (m, 1H),1.49 – 1.42 (m, 2H), 1.41 – 1.37 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 165.41, 158.64, 135.66, 129.63, 128.89,128.80, 125.88, 125.63, 122.62, 121.04, 120.34, 119.70, 114.51, 112.07,109.43, 63.96, 63.78, 57.42, 57.38, 52.67, 43.15, 43.00, 41.86, 35.84, 29.46,27.91, 26.67, 25.04, 24.05, 21.35, 20.93. HRMS (ESI) m / z calculated for C 33 H 40 N3O2 + [M+H] + : 510.3121, found:510.3118. Example 27 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced in equimolar amounts with 4-phenoxybromobutane, and 6-hydroxy-2-naphthaldehyde was replaced in equimolar amounts with indole-3-carboxaldehyde. The final product obtained in this example was 14-(1-N-(4-phenoxybutyl)-3-indolemethylenyl)matrine (abbreviated as HKY-53), which was a light yellow solid with a yield of 26%. The spectroscopic characterization data of HKY-53 are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.30 – 7.24 (m, 4H), 7.19 (ddd, J = 8.0, 7.0, 1.0 Hz,1H), 6.94 (tt, J = 7.3, 1.1 Hz, 1H), 6.89 – 6.85 (m, 2H), 4.52 (dd, J = 12.7,4.5 Hz, 1H), 4.24 (t, J = 7.1 Hz, 2H), 4.01 – 3.97 (m, 1H), 3.96 (t, J = 6.1Hz, 2H), 3.23 (t, J = 12.7 Hz, 1H), 2.89 – 2.79 (m, 3H), 2.59 (dddd, J =15.4, 9.2, 4.4, 1.9 Hz, 1H), 2.16 – 2.11 (m, 2H), 2.07 (dq, J = 9.3, 7.1 Hz, 2H), 2.02 – 1.94 (m, 2H), 1.91 (d, J = 14.1 Hz, 1H), 1.83 – 1.76 (m, 4H), 1.75 – 1.71 (m, 1H), 1.70 – 1.63 (m, 2H), 1.63 – 1.58 (m, 1H), 1.54 (tt, J =13.5, 4.7 Hz, 1H), 1.48 – 1.39 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 165.49, 158.88, 135.88, 129.59, 128.73,128.19, 126.17, 125.58, 122.58, 120.90, 120.31, 119.78, 114.53, 112.15,109.53, 67.29, 64.02, 57.45, 57.41, 52.78, 46.53, 43.20, 42.03, 35.88, 27.95,27.21, 26.79, 26.73, 26.69, 25.22, 24.31, 21.37, 20.99. HRMS (ESI) m / z calculated for C 34 H 42 N3O2 + [M+H] + : 524.3277, found:524.3273. Example 28 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced in equimolar amounts with 4-(2-naphthoxy)chlorobutane, and 6-hydroxy-2-naphthoaldehyde was replaced in equimolar amounts with indole-3-carboxaldehyde. The final product obtained in this example was 14-(1-N-[4-(2-naphthoxy)butyl]-3-indolemethylenyl)matrine (abbreviated as HKY-63), which was a white solid with a yield of 21%. The spectroscopic characterization data of HKY-63 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.06 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 7.6Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 8.6Hz, 1H), 7.43 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.33(ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.29 – 7.25 (m, 2H), 7.20 (ddd, J = 8.0,6.9, 1.0 Hz, 1H), 7.12 (dd, J = 8.9, 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H),4.53 (dd, J = 12.7, 4.5 Hz, 1H), 4.27 (t, J = 7.0 Hz, 2H), 4.08 (t, J = 6.1Hz, 2H), 3.97 (ddd, J = 11.5, 7.2, 4.9 Hz, 1H), 3.23 (t, J = 12.7 Hz, 1H),2.89 – 2.79 (m, 3H), 2.58 (dddd, J = 15.4, 9.2, 4.4, 1.9 Hz, 1H), 2.16 – 2.08(m, 4H), 1.98 (qd, J = 12.0, 2.8 Hz, 2H), 1.92 – 1.85 (m, 3H), 1.84 – 1.76(m, 2H), 1.76 – 1.70 (m, 1H), 1.69 – 1.61 (m, 2H), 1.61 – 1.57 (m, 1H), 1.54(tt, J = 13.5, 4.8 Hz, 1H), 1.49 – 1.37 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 165.51, 156.86, 135.92, 134.65, 129.58,129.10, 128.78, 128.21, 127.77, 126.83, 126.55, 126.19, 125.66, 123.80,122.63, 120.37, 119.85, 118.89, 112.23, 109.56, 106.75, 67.45, 64.05, 57.47,57.43, 52.79, 46.57, 43.20, 42.07, 35.90, 27.97, 27.26, 26.78, 26.70, 25.26, 24.34, 21.39, 21.01. HRMS (ESI) m / z calculated for C 38 H 44 N3O + [M+H] + : 574.3434, found:574.3430. Example 29 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 3-fluorobenzyl bromide in equimolar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 7-azaindole-3-carboxaldehyde in equimolar amounts. The final product obtained in this example was 14-(1-N-(3-fluorobenzyl)-7-azaindole-3-methylene)matrine (abbreviated as HKY-56), which was a white solid with a yield of 18%. The spectroscopic characterization data of HKY-56 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.38 (dd, J = 4.7, 1.5 Hz, 1H), 8.11 (dd, J= 7.9, 1.5 Hz, 1H), 7.94 (s, 1H), 7.29 (s, 1H), 7.28 – 7.24 (m, 1H), 7.16(dd, J = 7.9, 4.7 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.95 (td, J = 8.5, 2.6Hz, 1H), 6.89 (dt, J = 9.6, 2.2, 2.1 Hz, 1H), 5.57 – 5.46 (m, 2H), 4.49 (dd,J = 12.7, 4.5 Hz, 1H), 4.00 – 3.94 (m, 1H), 3.22 (t, J = 12.6 Hz, 1H), 2.84(d, J = 11.1 Hz, 1H), 2.82 – 2.75 (m, 2H), 2.57 – 2.51 (m, 1H), 2.17 – 2.08(m, 2H), 1.97 (qd, J = 12.3, 2.9 Hz, 2H), 1.89 (d, J = 13.8 Hz, 1H), 1.82 –1.74 (m, 2H), 1.71 (d, J = 15.1 Hz, 1H), 1.68 – 1.61 (m, 2H), 1.60 – 1.49 (m,2H), 1.48 – 1.36 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.06, 163.97, 162.33, 147.61, 144.27,140.07, 140.02, 130.52, 130.47, 128.14, 127.64, 127.32, 125.04, 122.96,122.93, 120.71, 116.89, 114.91, 114.77, 114.48, 114.33, 111.49, 63.95, 57.44,57.40, 52.81, 47.61, 43.22, 42.12, 35.90, 27.94, 26.69, 25.18, 24.26, 21.36,20.97. 19 F NMR (565 MHz, CDC l3) δ -112.37. HRMS (ESI) m / z calculated for C 30 H 34 FN4O + [M+H] + : 485.2717, found:485.2717. Example 30 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 3-chlorobenzyl bromide in equimolar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 7-azaindole-3-carboxaldehyde in equimolar amounts. The final product obtained in this example was 14-(1-N-(3-chlorobenzyl)-7-azaindole-3-methylene)matrine (abbreviated as HKY-60), which was a white solid with a yield of 29%. The spectroscopic characterization data of HKY-60 are as follows: 1H NMR (600 MHz, CDCl3) δ 8.38 (dd, J = 4.7, 1.5 Hz, 1H), 8.11 (dd, J= 7.9, 1.5 Hz, 1H), 7.94 (s, 1H), 7.29 (s, 1H), 7.25 – 7.22 (m, 2H), 7.21 (s,1H), 7.17 (dd, J = 7.9, 4.7 Hz, 1H), 7.07 (dt, J = 6.7, 1.9 Hz, 1H), 5.55 –5.44 (m, 2H), 4.50 (dd, J = 12.7, 4.5 Hz, 1H), 3.97 (ddd, J = 11.4, 7.2, 5.0Hz, 1H), 3.22 (t, J = 12.7 Hz, 1H), 2.85 (dt, J = 11.3, 2.3 Hz, 1H), 2.82 –2.75 (m, 2H), 2.54 (dddd, J = 15.5, 9.3, 4.4, 1.9 Hz, 1H), 2.16 – 2.10 (m,2H), 1.97 (qd, J = 12.4, 2.9 Hz, 2H), 1.89 (dt, J = 13.7, 2.2 Hz, 1H), 1.82 –1.79 (m, 1H), 1.76 (dt, J = 13.1, 4.0 Hz, 1H), 1.72 (dd, J = 15.3, 2.4 Hz,1H), 1.69 – 1.61 (m, 2H), 1.58 (dd, J = 10.9, 3.0 Hz, 1H), 1.53 (tt, J =13.5, 4.8 Hz, 1H), 1.48 – 1.37 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.06, 147.61, 144.28, 139.54, 134.80,130.24, 128.15, 128.13, 127.58, 127.56, 127.37, 125.58, 125.04, 120.72,116.92, 111.54, 63.96, 57.44, 57.41, 52.82, 47.55, 43.23, 42.13, 35.91,27.94, 26.70, 25.19, 24.28, 21.37, 20.98. HRMS (ESI) m / z calculated for C 30 H 34 ClN4O + [M+H] + : 501.2421, found:501.2413. Example 31 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with 4-bromobenzyl bromide in equimolar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 7-azaindole-3-carboxaldehyde in equimolar amounts. The final product obtained in this example was 14-(1-N-(4-bromobenzyl)-7-azaindole-3-methylene)matrine (abbreviated as HKY-62), which was a white solid with a yield of 24%. The spectroscopic characterization data of HKY-62 are as follows: 1 H NMR (600 MHz, CDCl3) δ 8.36 (dd, J = 4.7, 1.5 Hz, 1H), 8.09 (dd, J= 7.9, 1.5 Hz, 1H), 7.93 (t, J = 1.8, 1.1 Hz, 1H), 7.43 – 7.39 (m, 2H), 7.27(s, 1H), 7.15 (dd, J = 7.9, 4.7 Hz, 1H), 7.09 – 7.06 (m, 2H), 5.52 – 5.40 (m,2H), 4.48 (dd, J = 12.7, 4.5 Hz, 1H), 3.96 (ddd, J = 10.7, 7.2, 4.9 Hz, 1H), 3.21 (t, J = 12.7 Hz, 1H), 2.83 (ddt, J = 11.5, 4.3, 1.9 Hz, 1H), 2.81 – 2.72(m, 2H), 2.52 (dddd, J = 15.5, 9.4, 4.4, 2.0 Hz, 1H), 2.15 – 2.08 (m, 2H), 1.96 (qd, J = 12.4, 2.9 Hz, 2H), 1.88 (dt, J = 13.8, 2.2 Hz, 1H), 1.81 – 1.73(m, 2H), 1.72 – 1.68 (m, 1H), 1.67 – 1.59 (m, 2H), 1.59 – 1.49 (m, 2H), 1.47– 1.36 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 165.03, 147.55, 144.20, 136.49, 132.01,129.15, 128.08, 127.52, 127.25, 124.99, 121.83, 120.71, 116.85, 111.43,63.90, 57.40, 57.37, 52.77, 47.50, 43.19, 43.11, 42.09, 35.87, 27.91, 26.66,25.16, 24.23, 21.33, 20.94. HRMS (ESI) m / z calculated for C 30 H 34 BrN4O + [M+H] + : 545.1916, found:545.1915. Example 32 Same as Example 1, except that 4-trifluoromethoxybenzyl bromide was replaced with benzyl bromide in equimolar amounts, and 6-hydroxy-2-naphthaldehyde was replaced with 7-azaindole-3-carboxaldehyde in equimolar amounts. The final product obtained in this example was 14-(1-N-benzyl-7-azaindole-3-methylene)matrine (abbreviated as HKY-79), which was a white solid with a yield of 36%. The spectroscopic characterization data of HKY-79 are as follows: 1H NMR (500 MHz, CDCl3) δ 8.38 (dd, J = 4.7, 1.6 Hz, 1H), 8.10 (dd, J= 7.8, 1.6 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.33 – 7.26 (m, 4H), 7.22 –7.19 (m, 2H), 7.15 (dd, J = 7.8, 4.7 Hz, 1H), 5.57 – 5.49 (m, 2H), 4.49 (dd,J = 12.7, 4.5 Hz, 1H), 3.96 (dt, J = 11.8, 6.6 Hz, 1H), 3.21 (t, J = 12.6 Hz,1H), 2.84 (d, J = 11.0 Hz, 1H), 2.82 – 2.71 (m, 2H), 2.52 (dddd, J = 15.5,9.2, 4.4, 2.0 Hz, 1H), 2.16 – 2.06 (m, 2H), 2.01 – 1.91 (m, 2H), 1.88 (d, J =15.6 Hz, 1H), 1.82 – 1.73 (m, 2H), 1.71 (d, J = 13.2 Hz, 1H), 1.67 – 1.60 (m,2H), 1.60 – 1.48 (m, 2H), 1.48 – 1.36 (m, 3H). 13 C NMR (126 MHz, CDCl3) δ 165.13, 147.69, 144.11, 137.43, 128.91,127.99, 127.87, 127.49, 126.98, 125.19, 120.73, 116.73, 111.18, 63.95, 57.42,57.39, 52.78, 48.09, 43.19, 42.09, 35.88, 27.92, 26.67, 25.18, 24.21, 21.34,20.96. HRMS (ESI) m / z calculated for C 30 H 35 N4O + [M+H] + : 467.2811, found:467.2799. The structural formulas of the aromatic methylene matrine derivatives prepared in each embodiment are shown in Table 1-2.

[0032] Table 1 Table 2 Test Example 1 (1) Target identification experiment (immunoassay, schematic diagram as follows) Figure 1 As shown, the specific detection principle is as follows: after the drug binds to the antigenic epitope of the antibody, the fluorescence intensity weakens or disappears, thereby identifying the drug target. HeLa cell lines were taken, revived, and passaged. After 24 hours, the cells reached the logarithmic growth phase. The cells were then digested with trypsin to prepare 2×10⁶ cells / cells. 4 Cell suspension was seeded at 500 μL per well in 24-well plates with coverslips and cultured until 60% confluence. Cells were fixed with 4 wt% paraformaldehyde at room temperature for 20 min, permeabilized with 0.2 wt% Trinton X-100, incubated with 1 wt% BSA solution at 37°C for 40 min, and then incubated at 4°C for 12 h in TBC1D2 antibody solution (commercially available TBC1D2 antibody diluted 1 wt% BSA solution at a volume ratio of 1:200). Under light-protected conditions, the samples were incubated at 37°C for 40 min in a secondary antibody solution conjugated with Alexa Fluor 488 (commercially available secondary antibody conjugated with Alexa Fluor 488 diluted 1 wt% BSA solution at a volume ratio of 1:200). After thorough washing, the samples were mounted with 10 μL of anti-fluorescence quenching mounting medium containing DAPI (nuclear dye, concentration 1 μg / mL). The stability of fluorescence intensity over 30 minutes was observed using a fluorescence microscope as a blank control group. An appropriate amount of the compound (HKY-55, 4 μg) was taken and a compound solution was prepared using 10 μL of anti-fluorescence decay mounting medium as a solvent. This solution was used to seal the sample and served as the test sample group. The decay of fluorescence intensity over 30 minutes was observed using a fluorescence microscope. The test results are as follows: Figure 2 As shown. By Figure 2 It can be seen that the fluorescence intensity of the tested sample group decreased significantly compared to the blank control group within 30 minutes, proving that HDY-55 competitively binds to the antigenic epitope of the TBC1D2 antibody, thus TBC1D2 is the target of the compound. Furthermore, using the same method, the other compounds in Table 1 produced similar phenomena to HDY-55, indicating that the target of the other compounds in Table 1 is also TBC1D2.

[0033] (2) Inhibitory activity identification: The above HeLa cell suspension was seeded at 500 μL per well into 24-well plates with coverslips. After cell adhesion, different concentrations of drug-treated groups and a blank control group were set up. After drug treatment, the cells were cultured until 60% confluence. The cells were fixed with 4 wt% paraformaldehyde at room temperature for 20 min, permeabilized with 0.2 wt% Trinton X-100, incubated with 1 wt% BSA solution at 37°C for 40 min, and then incubated with Rab7a antibody solution (commercially available Rab7a antibody diluted with 1 wt% BSA solution at a volume ratio of 1:200) at 4°C for 12 h. Under light-protected conditions, samples were incubated at 37°C for 40 min in a secondary antibody solution conjugated with Alexa Fluor 488 (commercially available secondary antibody conjugated with Alexa Fluor 488 diluted with 1 wt% BSA solution at a volume ratio of 1:200). After thorough washing, the samples were mounted with anti-fluorescence quenching mounting medium containing DAPI (concentration of 1 μg / mL) and observed and photographed under a fluorescence microscope. The results are as follows: Figure 3 As shown, a magnified view of the white box in group rabbit7a is provided. Figure 3 It can be seen that with the increase of the drug concentration, rab7a is enriched on the lysosomal membrane, and the lysosomal volume increases at the same time, proving that compound HKY-55 has TBC1D2 inhibitory activity.

[0034] Test Example 2 In vitro cytotoxicity assay: The in vitro antitumor activity of the aromatic methenic matrine derivative targeting TBC1D2 prepared in this invention was studied. Normal cells were human bronchial epithelial cells BEAS-2B, which were used for drug toxicity testing. Tumor cells were cervical cancer cells HeLa, liver cancer cells HepG2, and lung cancer cells A549, all of which were purchased.

[0035] This experiment used the MTT assay to determine the inhibitory activity of the compound on cancer cell proliferation and its toxicity to normal cells. The main procedure is as follows: Target cancer cell lines were obtained, resuscitated, and passaged. After the cells reached the logarithmic growth phase, they were digested with trypsin and prepared into 2×10⁻⁶ cells / cells. 4Cells were seeded at a density of 100 μL per well in 96-well plates. The experimental setup included a blank control (culture medium only), a negative control (cells with drug-free solvent), and different concentrations of drug-treated cells, with three replicates per group. The 96-well plates were incubated at 37°C, 5 vol% CO2 for 24 h to allow cell adhesion. After adhesion, the original culture medium in each well was aspirated. For the drug-treated cells, 150 μL of a serially diluted solution of different compound solutions (containing 0.05 wt% DMSO) was added to each well. The control group was replaced with an equal volume of fresh culture medium containing the corresponding concentration of DMSO. The blank control group was only replaced with fresh culture medium. Incubation continued for 48 h. After drug treatment, 10 μL of MTT solution (5 mg / mL) was added to each well, and incubation continued for 4 h. The supernatant in each well was carefully aspirated, and 100 μL of DMSO was added to each well. The plates were shaken slowly for 10 min to fully dissolve the resulting purple formazan crystals. Finally, the absorbance (OD value) of each well was measured using an ELISA reader with 490 nm as the detection wavelength (570 nm as the reference wavelength for dual-wavelength measurement).

[0036] The cell proliferation inhibition rate is calculated using the following formula: Inhibition rate (%) = [(OD)] 对照组 - OD 给药组 ) / (OD 对照组 -OD 空白组 )]×100%.

[0037] Calculate the half-maximal inhibitory concentration (IC50) of the compound after 48 hours of treatment. 50 The results were expressed as mean ± standard deviation, and all experiments were independently repeated 3 times. Table 3 shows the results.

[0038] Table 3 As shown in Table 3, most of the aromatic methenomatrine derivatives targeting TBC1D2 synthesized in this invention have good antitumor activity. When matrine was used as a control drug for drug administration tests, the inhibition rates of these compounds were compared and found that HKY-9, HKY-52, HKY-55, HKY-76, HKY-89, HKY-93, and HKY-105 had strong inhibitory effects on tumor cells and exhibited highly efficient antitumor inhibitory activity.

[0039] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. An aromatic methene matrine derivative targeting TBC1D2, characterized in that, It has a structure as shown in general formula I, general formula II or general formula III: ； In general formula I, R = 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3,4-difluorophenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3,5-dimethoxyphenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-di-tert-butylphenyl or 2-naphthyl; In general formula II, R = 3-chlorophenyl, 2,4-difluorophenyl, 4-bromophenyl, 3,4-difluorophenyl or 4-tert-butylphenyl; In general formula III, X = C or N; when X = C, R = allyl, 3-phenoxypropyl, 4-phenoxybutyl or 4-(2-naphthoxy)butyl; when X = N, R = benzyl, 3-fluorobenzyl, 3-chlorobenzyl or 4-bromobenzyl.

2. A method for preparing an aromatic methene matrine derivative targeting TBC1D2 as described in claim 1, characterized in that, Includes the following steps: Using one of the compounds shown in Formulas IV-VI and one of the compounds shown in Formulas VII-X as reactants, an aromatic aldehyde is obtained through a substitution reaction under alkaline conditions; using the aromatic aldehyde and matrine as reactants, and NaH as a condensing agent, the aromatic methylene matrine derivative targeting TBC1D2 is obtained through a condensation reaction. 、 、 、 、 、 、 ； In Formula IV, R = 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromo-4-fluorophenyl, 4-bromo-2-fluorophenyl, 3,4-difluorophenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3,5-dimethoxyphenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-di-tert-butylphenyl or 2-naphthyl; In formula V, R = allyl, 3-phenoxypropyl, 4-phenoxybutyl, benzyl, 3-fluorobenzyl, 3-chlorobenzyl, or 4-bromobenzyl; In formula VI, R = 4-(2-naphthoxy)butyl.

3. The method for preparing the aromatic methene matrine derivative targeting TBC1D2 as described in claim 2, characterized in that, The molar ratio of one of the compounds shown in Formulas IV-VI to one of the compounds shown in Formulas VII-X is 2:

3.

4. The method for preparing the aromatic methene matrine derivative targeting TBC1D2 as described in claim 2, characterized in that, The substitution reaction was carried out at a temperature of 60°C for 1-4 hours.

5. The method for preparing the aromatic methene matrine derivative targeting TBC1D2 as described in claim 2, characterized in that, The molar ratio of the aromatic aldehyde to matrine is 2:

3.

6. The method for preparing the aromatic methene matrine derivative targeting TBC1D2 as described in claim 2, characterized in that, The reaction procedure for the condensation reaction is as follows: first react at 23-27℃ for 1 hour, then react at 60-100℃ for 20 minutes to 1 hour.

7. The use of an aromatic methene matrine derivative targeting TBC1D2 as described in claim 1 in the preparation of a TBC1D2 inhibitor.

8. The use of an aromatic methene matrine derivative targeting TBC1D2 as described in claim 1 in the preparation of an anticancer drug.

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