A kind of ionone alkaloid derivative and medical use

Abstract

The present invention provides an ionone alkaloid derivative or a pharmaceutically acceptable salt thereof having an anti-breast cancer metastasis effect, and the structure thereof is as shown in Formula I: The present invention also provides the use of the ionone alkaloid derivative in the preparation of an anti-breast cancer metastasis drug.

Description

Technical Field

[0001] The invention relates to an ionone alkaloid derivative, a preparation method and application of the ionone alkaloid derivative as an anti-breast cancer metastasis drug, and belongs to the field of pharmaceutical chemistry research. Background Art

[0002] According to the report "Global Cancer Statistics 2018" published by the Journal of Clinicians Cancer of the American Cancer Society, there will be approximately 18.1 million new cancer cases and 9.6 million cancer deaths in 2018. Nearly half of the 18.1 million new cancer cases are in Asia, and nearly 70% of the 9.6 million cancer deaths are in Asia. By 2030, the number of new cancer cases worldwide will increase by about 50%. Therefore, cancer has become one of the major diseases that seriously threaten human life and health. In a large number of clinical cases, tumor metastasis is the main cause of death in patients with malignant tumors, and the cause of death of about 90% of patients with malignant tumors is related to tumor metastasis. Therefore, in-depth understanding of the basic mechanism of tumor metastasis, seeking new strategies to inhibit tumor metastasis, and discovering anti-tumor metastasis drugs are the key to effectively prevent and treat malignant tumor metastasis.

[0003] Tumor metastasis is one of the important biological characteristics of malignant tumors. The invasion and metastasis of tumor cells is a multi-stage, multi-step, multi-factor and multi-gene coordinated process. Tumor cell metastasis is generally considered to include the following four stages: (1) The adhesion ability between tumor cells decreases, and tumor cells detach from the primary tumor focus and adhere to the basement membrane; (2) After detachment, tumor cells secrete and induce tumor stromal cells to secrete a variety of proteases to degrade the extracellular matrix and basement membrane, migrate and invade blood vessels; (3) Invade the circulatory system, migrate with the blood and adhere to the vascular endothelial cells in the new site; (4) After penetrating the blood vessel wall, tumor cells settle and proliferate locally, and finally form metastatic foci in specific tissues or organs.

[0004] At present, various anti-tumor metastasis chemical drugs under development are aimed at specific targets at a certain stage of tumor metastasis for drug discovery and development. For example, Cilengitide, which is in the phase III clinical stage, is a drug that inhibits tumor cell adhesion by targeting integrins. It acts on αvβ3 receptors and αvβ5 receptors and can inhibit angiogenesis in glial cells. Batimastat (BB-94), a drug that acts on matrix metalloproteinases (MMPs), can significantly inhibit the activity of multiple MMP subtypes, thereby inhibiting the invasion of tumor cells using MMPs and inhibiting angiogenesis. Vascular endothelial growth factor (VEGF) is a central regulator of angiogenesis. It can increase the permeability of blood vessels and provide favorable conditions for the metastasis and spread of tumor cells. Vandetanib (ZD-6474) inhibits tumor angiogenesis by acting on VEGF receptors, and also inhibits the proliferation of tumor cells.

[0005] Therefore, interfering with or blocking the process of malignant tumors spreading in the host is the most effective means to prolong survival, improve quality of life and reduce mortality. On the other hand, since the anti-tumor metastasis drug treatment after conventional primary tumor resection is a continuous, long-term administration process, the ideal anti-tumor metastasis drug not only blocks the invasion and metastasis of tumor cells in the body, but also should be a non-cytotoxic drug or have very low toxic side effects and will not cause damage to the immune system. Although tumor chemotherapy drugs can kill or inhibit tumor growth, since they are all cytotoxic drugs, while killing tumor cells, they also cause great damage to normal cells. Therefore, the ideal anti-tumor metastasis drug should be a non-cytotoxic drug with low toxic side effects.

[0006] The invention patent of this research group disclosed a herba alkaloid compounds with anti-tumor metastasis effect (Application No. 201010114809.9). Further, with the active ingredient Salignone as the lead, a series of derivatives were synthesized and the invention patent "A pregnane alkaloid derivative with anti-breast cancer metastasis effect and medical use" (Patent No. 201310749522.7) was disclosed. Our research group derived and synthesized ionone alkaloids from Chiralione chinensis and discovered the anti-tumor metastasis lead compound ION-31a [Synthesis and anti-metastatic effects of novel chiralionone alkaloid derivatives, Hai-Jun Fang, Xiao-Ai Shou, Qian Liu, Chun-Chun Gan, Hong-Quan Duan, Nan Qin, European Journal of Medicinal Chemistry 101 (2015) 245-253]. We further derived and synthesized a large number of different types of derivatives. After screening, most of the compounds showed strong anti-breast cancer metastasis activity, and the activities of compounds N2, 5, 7, 8, 10, 13, 15, 18, 19, 21, 23-27, 29, 37-39, 43, 58-61, 66, and 71 were particularly outstanding. Summary of the invention

[0007] The purpose of the present invention is to provide an ionone alkaloid derivative and the use of the compound in preparing an anti-breast cancer metastasis drug.

[0008] The present invention is achieved through the following technical solutions:

[0009] In one aspect, the present invention provides an ionone alkaloid derivative or a pharmaceutically acceptable salt thereof, the structure and synthesis route of which are shown in Formula 1-4:

[0010]

[0011] Formula 1 Synthesis route of ionone alkaloid derivatives N1-N28

[0012]

[0013] Formula 2 Synthesis route of ionone alkaloid derivatives N29-N40

[0014]

[0015] Formula 3 Synthesis route of ionone alkaloid derivatives N41-N48

[0016]

[0017] Formula 4 Synthesis route of ionone alkaloid derivatives N49-N73

[0018] In another aspect, the present invention provides a use of a pregnane alkaloid derivative or a pharmaceutically acceptable salt thereof in preparing an anti-breast cancer metastasis drug.

[0019] Firstly, the present invention carries out the cytotoxicity test on the synthesized pregnane alkaloid derivatives N1-N73, and further carries out the anti-breast cancer metastasis activity screening at a non-cytotoxic dose.

[0020] Toxic effects of each derivative on breast cancer cells

[0021] Principle of MTT colorimetric assay: This analytical method is based on the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and is a common method for detecting cell survival and growth. MTT is a universal cell stain. The succinate dehydrogenase associated with NADP exists in the mitochondria of living cells, which can reduce exogenous yellow MTT to insoluble blue-purple crystals formazane and deposit in the cells. This enzyme disappears in dead cells and MTT is not reduced. After dissolving formazane with DMSO, the change in optical density is detected at a wavelength of 550nm using a microplate reader to measure the inhibitory effect of the test drug on cell growth and thus evaluate cytotoxicity.

[0022] Experimental steps: Digest the cultured cells with 0.25% trypsin, aspirate the trypsin, and terminate the digestion with culture medium containing 10% FBS. Mix the cell suspension and count and adjust the density to 1x10 4 , add the adjusted cell suspension to a 96-well plate, 180ul per well, and culture in an incubator at 37°C, 5% CO2 for 24 hours. Add the drug after 24 hours, 5 replicate wells for each concentration, and continue to culture in an incubator at 37°C, 5% CO2 for 48 hours after adding the drug. Then add 20ul of 5mg / ml MTT to each well, and continue to culture in an incubator at 37°C, 5% CO2 for 4 hours. After 4 hours, take out the 96-well plate, aspirate the supernatant, add 100ul of DMSO to each well, and measure the absorbance at a wavelength of 570nm using an enzyme marker. Inhibition rate = (1-OD value of the drug-added group / OD value of the blank group) x 100%

[0023] Principle of Transwell chemotaxis method for evaluating anti-metastatic activity of breast cancer

[0024] In the upper chamber of the Transwell chamber, an 8μm pore filter is directly placed between the upper and lower chambers of the invasion chamber. Tumor cells move through the filter membrane by deformation. This model can be used to analyze the size of cell movement ability. When adding chemotaxis inducers (chemokine EGF) during drug screening, the size of the test drug's ability to inhibit the chemotaxis and migration of tumor cells is expressed by measuring the changes in the number of cells that chemotaxis passes through the filter membrane in tumor cells co-cultured with the test drug and tumor cells in the blank group, and then the anti-tumor metastasis activity of the test drug is evaluated. The positive controls are the reagent LY294002 (a PI3K inhibitor with anti-tumor metastasis effect) and the lead compound ION-31a.

[0025] Experimental steps:

[0026] 1. Screening of non-cytotoxic doses of samples: Use the MTT method to screen out sample concentrations with non-cytotoxic effects.

[0027] 2. Co-culture of samples and cells: The cells were plated on 6-well plates and cultured in an incubator at 37°C and 5% CO2 for 24 hours to allow them to adhere to the wall. After 24 hours, the samples were added to the 6-well plates at a determined concentration and incubated in an incubator at 37°C and 5% CO2 for 24 hours.

[0028] 3. Chemotaxis assay: The cells treated with the samples were digested with 0.25% trypsin, and then digested with a culture medium containing 10% FBS. The cell suspension was centrifuged at 1300 rpm for 5 minutes. The supernatant was poured out, 0.1% BM was added to mix the cells, and then centrifuged again for 5 minutes. The cells were counted and the cell density was adjusted to 5x10 5 , placed in the incubator for later use. Prepare the chemokine EGF on ice, add it to the lower chamber of the chemotaxis chamber, 30ul per well, spread the coated membrane on the lower chamber, put the rubber pad, fix the upper chamber, add the previously prepared cell suspension to the upper chamber, 50ul per well, 3 replicates for each sample concentration, place it in a CO2 incubator for 3.5h and then take it out, take out the lower chamber, scrape off the cells that have not been chemotactic, and then use the three-step staining reagent for fixation and staining. After staining, fix the membrane with paraffin oil and count under a microscope.

[0029] 4. Statistical calculation method: When counting, select 5 fields of view for each well and count them separately, take the average value, and then take the average of three replicate wells to get the number of chemotactic cells at the sample concentration. Data were processed using SPSS11.5 to calculate the half inhibition rate IC 50 .

[0030] Calculation formula:

[0031]

[0032]

[0033] Experimental Results

[0034] The half inhibitory concentration (IC) of each preferred derivative on the chemotaxis and migration of MB-MDA-231 (human breast cancer cells) 50 ) as shown in Table 1:

[0035] Table 1 The half inhibitory concentration (IC) of each derivative in inhibiting the chemotaxis and migration of breast cancer cells 50 )

[0036]

[0037] The evaluation of anti-breast cancer metastasis activity showed that the preferred compounds all exhibited anti-breast cancer metastasis activity at non-cytotoxic doses, among which compounds N2, 5, 7, 8, 10, 13, 15, 18, 19, 21, 23-27, 29, 37-39, 43, 58-61, 66, and 71 were particularly active. DETAILED DESCRIPTION

[0038] Example 1.

[0039] Synthesis method of compounds N1-N3:

[0040] Weigh 1.0 equivalent of intermediate 7 into a reaction bottle, add appropriate amount of acetone or DMF to dissolve, add 3.0 equivalents of anhydrous potassium carbonate and 3.0 equivalents of the corresponding bromide, react under reflux and stir, and monitor by TLC until the reaction is complete. Add 1 mol / L sodium hydroxide aqueous solution to the reaction solution and stir for 1 hour, extract with EA, combine the organic layers, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain a crude product.

[0041] Synthesis of compound N1

[0042]

[0043] Using ethyl bromoacetate as the raw material, the product was prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-8: 1, V / V) to obtain a yellow oil with a yield of 84.3%. 1H NMR (400MHz, CDCl3): δ7.27 (m, 1H, Ar-H), 7.09 (m, 2H, Ar-H), 6.93 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 4.16 (q, J =7.0Hz, 2H, OCH2), 3.77 (s, 2H, Ar-CH2), 3.31 (s, 2H, Ar-CH2), 2.63 (t, J = 6.8Hz, 2H, 9-H), 2.35 (d, J = 17.4Hz , 1H, 2-H), 2.01 (d, J=17.4Hz, 1H, 2-H), 1.95 (d, J=1.0Hz, 3H, 13-H), 1.84 (t, J=5.2Hz, 1H, 6-H), 1.72 (m, 1H, 7-H), 1.55 (m, 2H, 8-H), 1.43 (m, 1H, 7-H), 1.27 (t, J=7.0Hz, 3H, CH3), 1.04 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ 199.1 (3-C), 177.1 (CO), 165.4 (5-C), 163.0 (d, J = 244.2Hz, Ar-C), 142.0 (d, J = 6.8Hz, Ar-C), 129.8 (d, J = 8 .1Hz, Ar-C), 125.1 (4-C), 124.3 (d, J=2.6Hz, Ar-C), 115.5 (d, J=21.2Hz, Ar-C), 114.0 (d, J=21.1Hz, Ar-C), 60.3 (OCH2), 58.0 (Ar- C H2), 54.5(N- C H2), 54.2(9-C), 51.1(6-C), 47.2(2-C), 36.3(1-C), 28.8(12-C), 27.7(7-C), 27.5(8-C), 27.1(11-C), 24.7(13-C), 14.3(CH3).HR-ESIMSm / z 390.2428[M+H] + , calculate for C 23 H 33 FNO3, 390.2444.

[0044] Synthesis of compound N2

[0045]

[0046] The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-8: 1. V / V) to obtain a yellow oil with a yield of 82.7%.1 H NMR (400MHz, CDCl3): δ7.26 (m, 1H, Ar-H), 7.08 (m, 2H, Ar-H), 6.94 (m, 1H, Ar-H), 5.81 (s, 1H, 4-H), 3 .61 (s, 2H, Ar-CH2), 3.31 (d, J=2.0Hz, 2H, N-CH2), 2.54 (t, J=6.8Hz, 2H, 9-H), 2.37 (d, J=17.2Hz, 1H, 2-H), 2.26 (t, J=2.0Hz, 1H, CH), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.97 (s, 3H, 13-H), 1.86 (t, J=5.4Hz, 1 H, 6-H), 1.75 (m, 1H, 7-H), 1.58 (m, 2H, 8-H), 1.44 (m, 1H, 7-H), 1.05 (s, 3H, 11-H), 1.01 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ 199.2 (3-C), 165.4 (5-C), 162.9 (d, J = 244.2Hz, Ar-C), 141.4 (d, J = 3.9Hz, Ar-C), 129.8 (d, J = 8.2Hz, Ar- C), 125.0 (4-C), 124.5 (d, J=2.6Hz, Ar-C), 115.6 (d, J=21.1Hz, Ar-C), 114.1 (d, J=21.0Hz, Ar-C), 78.0 (C), 73.5 (CH), 57.4 (Ar- C H2), 53.5(9-C), 51.1(6-C), 47.1(2-C), 41.5(N- C H2), 36.3(1-C), 28.7(12-C), 27.8(7-C), 27.2(11-Cand 8-C), 24.7(13-C).HR-ESIMS m / z 342.2219[M+H] + , calculate for C 22 H 29 FNO, 342.2233.

[0047] Synthesis of compound N3

[0048]

[0049] The product was prepared by the above method using N-Boc-bromoethylamine as raw material and separated and purified by silica gel column chromatography (PE: EA = 6: 1-4: 1, V / V) to obtain a yellow oil with a yield of 54.8%. 1H NMR (400MHz, CDCl3): δ7.27 (m, 1H, Ar-H), 7.04 (m, 2H, Ar-H), 6.94 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.55 (s, 2H, Ar-CH2), 3.19 (m, 2H, CH2), 2.54 (t, J=6.0Hz, 2H, 9-H), 2.44 (t, J=6.6Hz, 2H, N-CH2), 2.35 (d, J= 17.2Hz, 1H, 2-H), 2.01 (d, J=17.2Hz, 1H, 2-H), 1.95 (s, 3H, 13-H), 1.82 (t, J=5.2Hz, 1H, 6-H), 1.68 (m, 1 H, 7-H), 1.53 (m, 2H, 8-H), 1.44 (s, 9H, (CH3)3), 1.35 (m, 1H, 7-H), 1.04 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ 199.2 (3-C), 165.5 (5-C), 162.9 (d, J = 244.3Hz, Ar-C), 155.9 (CO), 141.2 (d, J = 5.7Hz, Ar-C), 129.8 (d, J = 8.1Hz, Ar-C), 125.0 (4-C), 124.2 (d, J=2.1Hz, Ar-C), 115.4 (d, J=21.2Hz, Ar-C), 114.0 (d, J=21.0Hz, Ar-C), 79.1 (C), 58.2 (Ar- C H2), 54.3(N-CH2), 53.5(9-C), 51.0(6-C), 47.1(2-C), 38.0(CH2), 36.3(1-C), 28.7 (12-C), 28.4((CH3)3), 28.0(7-C), 27.2(11-C), 26.9(8-C), 24.8(13-C).HR-ESIMS m / z447.3002[M+H] + , calculate for C 26 H 40 FN2O3, 447.3023.

[0050] Example 2.

[0051] Synthesis method of compound N4

[0052]

[0053] Weigh 1.0 equivalent of compound N1 into a reaction bottle, add an appropriate amount of methanol to dissolve, add 1.3 equivalents of potassium hydroxide, stir at room temperature, and monitor by TLC until the reaction is complete. Add saturated citric acid aqueous solution to pH = 3 and stir for 30 minutes, extract with EA, combine the organic layers, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain a crude product, which is separated and purified by silica gel column chromatography (DCM: MeOH = 30: 1, V / V) to obtain a yellow oil with a yield of 86.2%. 1 H NMR (400MHz, DMSO-d6): δ12.08 (s, 1H, OH), 7.37 (m, 1H, Ar-H), 7.18 (m, 2H, Ar-H), 7.09 (m, 1H, Ar-H), 5.71 (s, 1H, 4-H) , 3.81 (s, 2H, Ar-CH2), 3.32 (s, 2H, Ar-CH2), 2.62 (t, J=6.8Hz, 2H, 9-H), 2.30 (d, J=17.2Hz, 1H, 2-H). 1.90 (m, 4H, 13-H and 2-H), 1.82 (t, J=5.4Hz, 1H, 6-H), 1.64 (m, 1H, 7-H), 1.49 (m, 2H, 8-H), 1.30 (m, 1H, 7-H), 0.96 (s, 3H, 11-H), 0.92 (s, 3H, 12-H). 13 C NMR (100MHz, DMSO-d6): δ 197.8 (3-C), 171.9 (CO), 165.6 (5-C), 162.2 (d, J = 241.7Hz, Ar-C), 141.7 (d, J = 5.9Hz, Ar-C), 130.1 (d, J=8.2Hz, Ar-C), 124.7 (d, J=2.6Hz, Ar-C), 124.2 (4-C), 115.3 (d, J=21.2Hz, Ar-C), 113.9 (d, J=20.9Hz, Ar-C), 57.2 (Ar- C H2), 54.2(N-CH2), 53.6(9-C), 50.0(6-C), 46.8(2-C), 35.9(1-C), 28.3(12-C), 26.9(7-C), 26.5(11-C), 24.0(8-C), 21.0(13-C).HR-ESIMS m / z 362.2114[M+H] + , calculate for C 21 H 29 FNO3, 362.2131.

[0054] Example 3.

[0055] Synthesis method of compound N5

[0056]

[0057] Weigh 1.0 equivalent of compound N3 into a reaction bottle, add an appropriate amount of DCM to dissolve, add 3.0 equivalents of trifluoroacetic acid under ice bath, stir at room temperature, and monitor by TLC until the reaction is complete. Add 1 mol / L sodium hydroxide aqueous solution and stir, extract with DCM, combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate to obtain a yellow oil with a yield of 85.1%. 1 H NMR (400MHz, CDCl3): δ7.26 (m, 1H, Ar-H), 7.05 (m, 2H, Ar-H), 6.93 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3. 55 (s, 2H, Ar-CH2), 2.74 (t, J=5.6Hz, 2H, N-CH2), 2.50 (t, J=5.6Hz, 2H, N-CH2), 2.42 (t, J=6.8Hz, 2H, 9-H), 2.34 (d, J=17.6Hz, 1H, 2-H), 2.01 (d, J=17.6Hz, 1H, 2-H), 1.94 (s, 3H, 13-H), 1.81 (t, J=5.2Hz, 1H, 6-H), 1.66 (m, 1H, 7-H), 1.53 (m, 2H, 8-H), 1.35 (m, 1H, 7-H), 1.02 (s, 3H, 11-H), 0.99 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4 (3-C), 165.6 (5-C), 162.9 (d, J=244.0Hz, Ar-C), 142.6 (d, J=6.9Hz, Ar-C), 129.7 (d, J=8 .1Hz, Ar-C), 125.0 (4-C), 124.2 (d, J=2.6Hz, Ar-C), 115.4 (d, J=21.1Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 58.6 (Ar- C H2), 57.3(N-CH2), 54.7(9-C), 51.1(6-C), 47.1(2-C), 39.7(CH2), 36.3(1- C), 28.7(12-C), 28.0(7-C), 27.2(11-C), 27.1(8-C), 24.8(13-C).HR-ESIMS m / z 347.2480[M+H] + ,calcdfor C 21 H 32 FN2O, 347.2499.

[0058] Example 4.

[0059] Synthesis method of compound N6

[0060]

[0061] Weigh 1.0 equivalent of N5 into a reaction bottle, add an appropriate amount of DCM to dissolve, add 5.0 equivalents of pyridine and 5.0 equivalents of succinic anhydride under ice bath, stir at room temperature, and monitor by TLC until the reaction is complete. Concentrate to obtain a crude product, separate and purify by silica gel column chromatography (DCM: MeOH = 20: 1, V / V) to obtain a yellow oil with a yield of 73.5%. 1 H NMR (400MHz, DMSO-d6): δ12.08 (s, 1H, OH), 7.79 (s, 1H, NH), 7.34 (m, 1H, Ar-H), 7.15 (m, 2H, Ar-H), 7.05 (m, 1H, Ar-H), 5.70 (s, 1H, 4-H), 3.59 (s, 2H, Ar-CH2), 3.15 (q, J=6.1Hz, 2H, CH2), 2.42 (m, 6H, CH2), 2.31 (m, 3H, 2-Hand CH2), 1.91(s, 3H, 13-H), 1.86(m, 2H, 2-H and 6-H), 1.64(m, 1H, 7-H), 1.48(m, 2H, 8-H), 1.29(m, 1H, 7-H), 0.97(s, 3H, 11-H), 0.92(s, 3H, 12-H). 13 C NMR (100MHz, DMSO-d6): δ 197.8 (3-C), 173.7 (CO), 170.8 (CO), 165.6 (5-C), 162.2 (d, J = 241.5Hz, Ar-C), 143.0 (d, J = 6.3Hz, Ar-C), 129.9 (d, J=8.2Hz, Ar-C), 124.4 (d, J=2.6Hz, Ar-C), 124.1 (4-C), 115.0 (d, J=21.1Hz, Ar-C), 113.5 (d, J=20.7Hz, Ar-C), 57.5 (Ar- C H2), 53.8(N-CH2), 53.0(9-C), 50.2(6-C), 46.9(2-C), 39.7(CH2), 36.6(CH2), 35.9(1-C), 30 .0(CH2), 29.2(CH2), 28.3(12-C), 27.2(7-C), 26.5(11-C), 26.4(8-C), 24.0(13-C).HR-ESIMS m / z 447.2638[M+H] + , calculate for C 25 H 36FN2O4, 447.2659.

[0062] Example 5.

[0063] Synthesis method of compounds N7-N28:

[0064] Weigh 1.0 equivalent of intermediate 7 and 3.0 equivalent of the corresponding aldehyde into a reaction bottle, add an appropriate amount of methanol to dissolve, add 0.2 mL of water, then add 0.5 equivalent of zinc chloride and 1.5 equivalent of sodium cyanoborohydride dissolved in methanol, stir the reaction at 30°C, and monitor the reaction by TLC until the end. The methanol is spin-dried, water and DCM are added and extracted, the organic layers are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product.

[0065] Synthesis of compound N7

[0066]

[0067] Pyridine-4-carboxaldehyde was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 77.3%. 1 H NMR (600MHz, CDCl3): δ8.55 (d, J=5.4Hz, 2H, Ar-H), 7.29 (d, J=5.4Hz, 2H, Ar-H), 7.27 (m, 1H, Ar-H), 7.09 (m, 2H, Ar-H), 6.95 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.55 (s, 4H, Ar-CH2), 2.42 (t, J=6.9Hz, 2H, 9 -H), 2.33 (d, J=17.4Hz, 1H, 2-H), 2.02 (d, J=17.4Hz, 1H, 2-H), 1.90 (s, 3H, 13-H), 1.80 (t, J=5.4Hz, 1 H, 6-H), 1.66 (m, 1H, 7-H), 1.55 (m, 2H, 8-H), 1.35 (m, 1H, 7-H), 1.01 (s, 3H, 11-H), 0.99 (s, 3H, 12-H). 13CNMR (150MHz, CDCl3): δ 199.3 (3-C), 165.4 (5-C), 163.0 (d, J = 244.4Hz, Ar-C), 149.8 (C), 148.9 (C), 141.8 (d, J = 7.1Hz, Ar-C), 129.9 ( d, J=8.1Hz, Ar-C), 125.2 (4-C), 124.1 (d, J=2.6Hz, Ar-C), 123.6 (C), 115.3 (d, J=21.2Hz, Ar-C), 114.1 (d, J=21.0Hz, Ar-C), 58.3 (Ar- C H2), 57.7(9-C), 54.4(N- C H2-Ar), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.2(8-C), 26.9(11-C), 24.8(13-C).HR-ESIMS m / z 395.2479[M+H] + , calculate for C 25 H 32 FN2O, 395.2499.

[0068] Synthesis of compound N8

[0069]

[0070] Thiophene-2-carboxaldehyde was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 78.6%. 1 H NMR (600MHz, CDCl3): δ7.26 (m, 1H, Ar-H), 7.23 (m, 1H, Ar-H), 7.12 (m, 2H, Ar-H), 6.91 (m, 2H, Ar-H), 6 .89 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.77 (s, 2H, Ar-CH2), 3.57 (s, 2H, Ar-CH2), 2.45 (t, J=6.6Hz, 2H, 9-H), 2.35 (d, J=17.4Hz, 1H, 2-H), 2.01 (d, J=17.4Hz, 1H, 2-H), 1.92 (s, 3H, 13-H), 1.80 (t, J=5.4Hz, 2H, 6-H), 1.72 (m, 1H, 7-H), 1.56 (m, 2H, 8-H), 1.37 (m, 1H, 7-H), 1.03 (s, 3H, 11-H), 0.99 (s, 3H, 12-H). 13C NMR (150MHz, CDCl3): δ 199.5 (3-C), 165.8 (5-C), 163.0 (d, J = 243.9Hz, Ar-C), 142.8 (d, J = 7.5Hz, Ar-C), 142.3 (C), 129.7 (d, J = 8.1Hz, Ar-C ), 126.5(C), 125.5(C), 125.1(4-C), 124.9(C), 124.2(d, J=2.0Hz, Ar-C), 115.4(d, J=21.2Hz, Ar-C), 113.9(d, J=21.0Hz, Ar-C), 57.8(Ar- C H2), 53.7(9-C), 52.8(N- C H2-Ar), 51.0(6-C), 47.2(2-C), 36.4(1-C), 28.8(12-C), 27.9(7-C), 27.2(8-C), 27.0(11-C), 24.8(13-C).HR-ESIMS m / z 400.2102[M+H] + , calculate for C 24 H 31 FNOS, 400.2110.

[0071] Synthesis of compound N9

[0072]

[0073] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 81.6%. 1 H NMR (400MHz, CDCl3): δ7.27 (m, 2H, Ar-H), 7.09 (m, 4H, Ar-H), 6.93 (m, 2H, Ar-H), 5.79 ( s, 1H, 4-H), 3.53 (s, 4H, Ar-CH2), 2.41 (t, J=6.8Hz, 2H, 9-H), 2.33 (d, J=10.8Hz, 3H, 13 -H), 2.03 (d, J=10.8Hz, 3H, 13-H), 1.90 (s, 3H, 13-H), 1.78 (t, J=5.4Hz, 1H, 6-H), 1.66 (m, 1H, 7-H), 1.54 (m, 2H, 8-H), 1.33 (m, 1H, 7-H), 1.01 (s, 3H, 11-H), 0.98 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.3 (3-C), 165.6 (5-C), 163.0 (d, J=244.2Hz, Ar-C), 142.3 (d, J=6.9Hz, Ar-C), 129.8 (d, J=8 .2Hz, Ar-C), 125.1 (4-C), 124.2 (d, J=2.4Hz, Ar-C), 115.4 (d, J=21.2Hz, Ar-C), 113.9 (d, J=21.0Hz, Ar-C), 58.2 (Ar- C H2), 54.1(9-C), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 28.0(7-C), 27.2(11-C), 26.9(8-C), 24.8(13-C).HR-ESIMS m / z 412.2437[M+H] + , calculate for C 26 H 32 F2NO, 412.2452.

[0074] Synthesis of compound N10

[0075]

[0076] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 83.5%. 1 H NMR (400MHz, CDCl3): δ7.29 (m, 1H, Ar-H), 7.19 (m, 1H, Ar-H), 7.11 (m, 4H, Ar-H), 6.96 (m, 1H, Ar- H), 5.82 (s, 1H, 4-H), 3.54 (s, 2H, Ar-CH2), 3.51 (s, 2H, Ar-CH2), 2.41 (t, J=6.8Hz, 2H, 9-H), 2.3 4(d, J=17.4Hz, 1H, 2-H), 2.03 (d, J=17.4Hz, 1H, 2-H), 1.93 (s, 3H, 13-H), 1.81 (t, J=5.4Hz, 1H, 6 -H), 1.66(m, 1H, 7-H), 1.56(m, 2H, 8-H), 1.36(m, 1H, 7-H), 1.03(s, 3H, 11-H), 1.00(s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.4 (3-C), 165.6 (5-C), 163.0 (d, J=244.2Hz, Ar-C), 150.3 (dd, J1=246.3Hz, J 2=12.7Hz, Ar-C), 149.4 (dd, J1=245.4Hz, J2=12.8Hz, Ar-C), 142.1 (d, J=4.0Hz, Ar-C), 136.6 (d, J=2.4 Hz, Ar-C), 129.8 (d, J = 8.1 Hz, Ar-C), 125.1 (4-C), 124.3 (), 124.1 (d, J = 2.6 Hz, Ar-C), 117.3 (d, J = 17, 2 Hz, Ar-C), 117.0 (d, J=16.9Hz, Ar-C), 115.3 (d, J=21.2Hz, Ar-C), 114.2 (d, J=21.1Hz, Ar-C), 58.1 (Ar- C H2), 57.7(9-C), 54.0(Ar- C H2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.2(8-C), 26.8(11-C), 24.8(13-C).HR-ESIMS m / z 430.2341[M+H] + , calculate for C 26 H 31 F3NO,430.2358.

[0077] Synthesis of compound N11

[0078]

[0079] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 75.3%. 1H NMR (400MHz, CDCl3): δ7.57 (d, J=8.0Hz, 2H, Ar-H), 7.46 (d, J=8.0Hz, 2H, Ar-H), 7.26 (m, 1H, Ar-H), 7 .08 (m, 2H, Ar-H), 6.93 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.60 (s, 2H, Ar-CH2), 3.54 (s, 2H, Ar-CH2), 2.4 2(t, J=6.8Hz, 2H, 9-H), 2.32 (d, J=17.6Hz, 1H, 2-H), 2.01 (d, J=17.6Hz, 1H, 2-H), 1.89 (s, 3H, 13-H), 1.78 (t, J=5.4Hz, 1H, 6-H), 1.64 (m, 2H, 7-H), 1.54 (m, 2H, 8-H), 1.00 (s, 3H, 12-H), 0.98 (s, 3H, 11-H). 13 C NMR (100MHz, CDCl3): δ 199.1 (3-C), 165.2 (5-C), 163.0 (d, J = 244.3Hz, Ar-C), 142.8 (Ar-C), 142.1 (d, J = 6.9Hz, Ar-C), 129.8 (d, J = 7.8Hz, Ar-C), 128.8 ( Ar-C), 125.3 (Ar-C), 125.2 (4-C), 124.2 (q, J=270.2Hz, CF3), 124.1 (d, J=2. 5Hz, Ar-C), 115.4 (d, J=21.2Hz, Ar-C), 114.0 (d, J=21.1Hz, Ar-C), 58.4 (Ar- C H2), 54.3(Ar- C H2), 51.1(6-C), 47.2(2-C), 36.3(1-C), 28.7(12-C), 28.0(7-C), 27.1(8-C), 27.0(11-C), 24.7(13-C).HR-ESIMS m / z 462.2403[M+H] + , calculate for C 27 H 32 F4NO,462.2420.

[0080] Synthesis of compound N12

[0081]

[0082] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 78.9%.1 H NMR (400MHz, CDCl3): δ7.22 (m, 3H, Ar-H), 7.10 (m, 4H, Ar-H), 6.90 (m, 1H, Ar-H), 5.78 (s, 1H, 4-H), 3.51 (s, 4H, Ar-CH2), 2.39 (t, J=6.8Hz, 2H, 9-H), 2.33 (s, 3H, CH3), 2.32 ( d, J=17.2Hz, 1H, 2-H), 1.99 (d, J=17.2Hz, 1H, 2-H), 1.89 (s, 3H, 13-H), 1.76 (t, J=5.6H z, 1H, 6-H), 1.64 (m, 2H, 7-H), 1.52 (m, 2H, 8-H), 1.00 (s, 3H, 12-H), 0.97 (s, 3H, 11-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 165.7(5-C), 163.0(d, J=243.9Hz, Ar-C), 142.8(d, J=6.8Hz, Ar-C), 136.6(Ar-C), 136.2(Ar-C), 129.6(d, J=8.1Hz, Ar-C), 129.2(Ar-C), 12 9.0(Ar-C), 128.7(Ar-C), 127.1(Ar-C), 125.1(4-C), 124.2(d, J=2.1Hz, Ar-C), 115.4( d, J=21.1Hz, Ar-C), 113.7 (d, J=21.1Hz, Ar-C), 58.4 (Ar-CH2), 58.1 (Ar-CH2), 53.9 (Ar- C H2), 51.1(6-C), 47.2(2-C), 36.3(1-C), 28.7(12-C), 28.0(7-C), 27.2(8-C), 26.9(11-C), 24.8(13-C), 21.1(CH3).HR-ESIMS m / z 408.2682[M+H] + , calculate for C 27 H 35 FNO, 408.2703.

[0083] Synthesis of compound N13

[0084]

[0085] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 77.2%. 1H NMR (400MHz, CDCl3): δ7.25 (m, 3H, Ar-H), 7.08 (m, 2H, Ar-H), 6.91 (m, 2H, Ar-H), 6.85 (d, J=8.4Hz, 1H, Ar-H), 5.79 (s, 1H, 4-H), 3.79 (s, 3H, OCH3), 3.51 (s, 2H, Ar-CH2), 3.49 (s, 2H, Ar-CH2), 2.39 (t, J=6.8Hz, 2H, 9-H), 2.32 (d, J=17.2Hz, 1H, 2-H), 2.00 (d, J=17.2Hz, 1H, 2-H), 1.89 (s, 3H, 13-H), 1. 77 (t, J=5.6Hz, 1H, 6-H). 1.64 (m, 2H, 7-H), 1.54 (m, 2H, 8-H), 1.00 (s, 3H, 12-H), 0.98 (s, 3H, 11-H). 13 C NMR (100MHz, CDCl3): δ 199.3 (3-C), 165.6 (5-C), 163.0 (d, J = 243.9Hz, Ar-C), 158.7 (Ar-C), 142.8 (d, J = 6.4Hz, Ar-C), 129.9 (Ar-C), 129.6 (d, J = 8.9Hz, A r-C), 125.1 (4-C), 124.2 (d, J=2.6Hz, Ar-C), 115.3 (d, J=21.3Hz, Ar-C), 113 .7(d, J=20.8Hz, Ar-C), 113.7(Ar-C), 58.1(Ar-CH2), 55.2(OCH3), 53.9(Ar- C H2), 51.1(6-C), 47.16(2-C), 36.3(1-C), 28.7(12-C), 28.0(7-C), 27.2(8-C), 26.9(11-C), 24.8(13-C).HR-ESIMS m / z 424.2630[M+H] + , calculate for C 27 H 35 FNO2,424.2652.

[0086] Synthesis of compound N14

[0087]

[0088] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 76.4%. 11H NMR (400 MHz, CDCl3): δ 7.19 (m, 3H, Ar-H), 7.01 (m, 2H, Ar-H), 6.84 (m, 1H, Ar-H), 6.77 (d, J = 8.4 Hz, 1H, Ar-H), 5.71 (s, 1H, 4-H), 3.95 (q, J = 6.8 Hz, 2H, OCH2), 3.43 (s, 2H, Ar-CH2), 3.41 (s, 2H, Ar-CH2), 2.31 (t, J = 6.8 Hz, 2H, 9-H), 2.25 (d, J = 17.6 Hz, 1H, 2-H), 1.92 (d, J = 17.6 Hz, 1H, 2-H), 1.82 (s, 3H, 13-H), 1.69 (t, J = 5.4 Hz, 1H, 6-H), 1.56 (m, 2H, 7-H), 1.46 (m, 2H, 8-H), 1.33 (t, J = 6.8 Hz, 3H, CH3), 0.93 (s, 3H, 12-H), 0.90 (s, 3H, 11-H). 13 13C NMR (100 MHz, CDCl3): δ 199.3 (3-C), 165.6 (5-C), 163.0 (d, J = 243.7 Hz, Ar-C), 157.2 (Ar-C), 143.2 (d, J = 6.8 Hz, Ar-C), 130.1 (Ar-C), 129.5 (d, J = 8.1 Hz, Ar-C), 127.8 (Ar-C), 127.6 (Ar-C), 125.0 (4-C), 124.1 (d, J = 2.0 Hz, Ar-C), 120.3 (Ar-C), 115.4 (d, J = 21.2 Hz, Ar-C), 113.6 (d, J = 21.1 Hz, Ar-C), 111.4 (Ar-C), 64.1 (OCH2), 62.4 (Ar-CH2), 57.0 (Ar- C H2), 52.8 (Ar- C H2), 50.1 (6-C), 46.1 (2-C), 35.3 (1-C), 27.7 (12-C), 27.0 (7-C), 26.12 (8-C), 25.9 (11-C), 23.7 (13-C), 13.9 (CH3). HR-ESIMS m / z 438.2775 [M+H] + , calcd for C 28 H 37 FNO2, 438.2808.

[0089] Synthesis of Compound N15

[0090]

[0091] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 78.3%. 1 H NMR (400MHz, CDCl3): δ7.23 (m, 2H.Ar-H), 7.09 (m, 2H, Ar-H), 6.91 (m, 3H, Ar-H), 6.85 (d, J=7.2Hz, 1H , Ar-H), 5.79 (s, 1H, 4-H), 4.02 (q, J=7.2Hz, 2H, OCH2), 3.53 (s, 2H, Ar-CH2), 3.52 (s, 2H, Ar-CH2), 2. 41 (t, J=6.8Hz, 2H, 9-H), 2.32 (d, J=17.2Hz, 1H, 2-H), 1.90 (s, 3H, 13-H), 1.77 (t, J=5.2Hz, 1H, 6-H), 1.66 (m, 2H, 7-H), 1.53 (m, 2H, 8-H), 1.41 (t, J=7.2Hz, 3H, CH3), 1.01 (s, 3H, 12-H), 0.98 (s, 3H, 11-H). 13 C NMR (100MHz, CDCl3): δ199.2(3-C), 165.5(5-C), 163.0(d, J=244.0Hz, Ar-C), 159.1(Ar -C), 142.7 (d, J=6.9Hz, Ar-C), 141.1 (Ar-C), 129.6 (d, J=8.1Hz, Ar-C), 129.0 (Ar-C), 1 25.1(4-C), 124.2(d, J=2.4Hz, Ar-C), 120.9(Ar-C), 115.4(d, J=21.3Hz, Ar-C), 115.0( Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 112.9 (Ar-C), 63.3 (OCH2), 58.8 (Ar-CH2), 58.3 (Ar- C H2), 54.1(Ar- C H2), 51.2(6-C), 47.2(2-C), 36.3(1-C), 28.7(12-C), 28.0(7-C), 27.1(8-C), 27.1(11-C), 24.7(13-C), 14.9(CH3).HR-ESIMS m / z 438.2787[M+H] + , calculate for C 28 H 37 FNO2,438.2808.

[0092] Synthesis of compound N16

[0093]

[0094] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 75.4%. 1 H NMR (400MHz, CDCl3): δ7.43 (d, J=6.8Hz, 1H, Ar-H), 7.23 (m, 2H, Ar-H), 7.11 (m, 2H, Ar-H), 6.93 (m, 2H, Ar-H), 6.83 ( d, J=8.0Hz, 1H, Ar-H), 5.78 (s, 1H, 4-H), 4.02 (q, J=6.8Hz, 2H, OCH2), 3.62 (s, 2H, Ar-CH2), 3.57 (s, 2H, Ar-CH2), 2. 43 (t, J=6.8Hz, 2H, 9-H), 2.32 (d, J=17.2Hz, 1H, 2-H), 1.99 (d, J=17.2Hz, 1H, 2-H), 1.89 (s, 3H, 13-H), 1.76 (t, J=5. 2Hz, 1H, 6-H), 1.64 (m, 2H, 7-H), 1.54 (m, 2H, 8-H), 1.40 (t, J=6.8Hz, 3H, CH3), 0.99 (s, 3H, 12-H), 0.97 (s, 3H, 11-H). 13 C NMR (100MHz, CDCl3): δ198.4 (3-C), 164.7 (5-C), 162.0 (d, J=243.9Hz, Ar-C), 150. 1(Ar-C), 141.8(d, J=7.1Hz, Ar-C), 130.1(Ar-C), 127.9(Ar-C), 128.6(d, J=8.1Hz, Ar-C), 127.6 (Ar-C), 124.0 (4-C), 123.1 (d, J=2.0Hz, Ar-C), 114.3 (d, J=21.3Hz, Ar -C), 113.5 (Ar-C), 113.2 (Ar-C), 112.7 (d, J=21.2Hz, Ar-C), 63.6 (OCH2), 58.6 (Ar- C H2), 54.3(Ar- C H2), 52.2(Ar-CH2), 51.2(6-C), 47.2(2-C), 36.3(1-C), 28.7(12-C), 28.0(7-C), 27.2(8-C), 27.1(11-C), 24.7(13-C), 14.9(CH3).HR-ESIMS m / z 438.2776[M+H] +, calculate for C 28 H 37 FNO2,438.2808.

[0095] Synthesis of compound N17

[0096]

[0097] The crude product was separated and purified by silica gel column chromatography (PE: EA = 12: 1-8: 1, V / V) to obtain a yellow oil with a yield of 78.2%. 1 H NMR (400MHz, CDCl3): δ7.27 (m, 3H, Ar-H), 7.11 (d, J=8.0Hz, 2H, Ar-H), 6.94 (m, 1H, Ar-H), 6.87 (d, J=8.0Hz, 2 H, Ar-H), 5.82 (s, 1H, 4-H), 3.97 (t, J=6.4Hz, 2H, OCH2), 3.53 (s, 2H, Ar-CH2), 3.50 (s, 2H, Ar-CH2), 3.41 (t, J =6.6Hz, 2H, 9-H), 2.37 (d, J = 17.2Hz, 1H, 2-H), 2.02 (d, J = 17.2Hz, 1H, 2-H), 1.92 (s, 3H, 13-H), 1.78 (m, 3H, 6- H, CH2), 1.67 (m, 1H, 7-H), 1.53 (m, 4H, 8-H, CH2), 1.32 (m, 1H, 7-H), 1.03 (s, 3H, 12-H), 0.99 (m, 6H, 11-H, CH3). 13 C NMR (100MHz, CDCl3): δ199.5 (3-C), 165.8 (5-C), 163.0 (d, J=243.7Hz, Ar-C), 15 8.3 (Ar-C), 142.8 (d, J=6.9Hz, Ar-C), 131.0 (Ar-C), 129.9 (Ar-C), 129.6 (d, J=8 .1Hz, Ar-C), 125.0 (4-C), 124.2 (d, J=2.0Hz, Ar-C), 115.3 (d, J=21.3Hz, Ar-C), 114.2 (Ar-C), 113.7 (d, J=21.2Hz, Ar-C), 67.7 (OCH2), 58.0 (Ar-CH2), 53.8 (Ar- CH2), 51.1(6-C), 47.1(2-C), 36.3(1-C), 31.4(CH2), 28.7(12-C), 28.0(7-C), 27.2(8-C), 26.9(11-C), 24.8(13-C), 19.3(CH2), 13.9(CH3).HR-ESIMS m / z 466.3110[M+H] + ,calcdfor C 30 H 41 FNO2,466.3121.

[0098] Synthesis of compound N18

[0099]

[0100] The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-6: 1, V / V) to obtain a yellow oil with a yield of 76.2%. 1 H NMR (400MHz, CDCl3): δ7.63 (d, J=7.6Hz, 2H, Ar-H), 7.45 (d, J=7.6Hz, 2H, Ar-H), 7.29 (m, 1H, Ar-H), 7.08 ( m, 2H, Ar-H), 6.96 (m, 1H, Ar-H), 5.82 (s, 1H, 4-H), 3.60 (s, 2H, Ar-CH2), 3.55 (s, 2H, Ar-CH2), 2.42 (t, J=6 .4Hz, 2H, 9-H), 2.34 (d, J=17.4Hz, 1H, 2-H), 2.04 (d, J=17.4Hz, 1H, 2-H), 1.92 (s, 3H, 13-H), 1.81 (t, J=5. 2Hz, 1H, 6-H), 1.64(m, 1H, 7-H), 1.55(m, 2H, 8-H), 1.36(m, 1H, 7-H), 1.02(s, 3H, 11-H), 1.00(s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ 199.4 (3-C), 165.5 (5-C), 163.0 (d, J=244.5Hz, Ar-C), 145.4 (Ar-C), 141.8 (d, J=6.6Hz, Ar-C), 132.2 (Ar-C), 129.9 (d, J=8 .0Hz, Ar-C), 129.4(Ar-C), 125.2(4-C), 124.1(Ar-C), 118.9(CN), 115.3(d, J=21.0Hz, Ar-C), 114.1(d, J=21.1Hz, Ar-C), 110.9(Ar-C), 58.4(Ar- C H2), 58.3(9-C), 54.3(Ar- C H2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.8(12-C), 27.9(7-C), 27.1(8-C), 26.8(11-C), 24.8(13-C).HR-ESIMS m / z 419.2477[M+H] + , calculate for C 27 H 32 FN2O, 419.2499.

[0101] Synthesis of compound N19

[0102]

[0103] Using 4-nitrobenzaldehyde as raw material, the product was prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-6: 1, V / V) to obtain a yellow oil with a yield of 71.6%. 11H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 7.6 Hz, 2H, Ar-H), 7.53 (d, J = 7.6 Hz, 2H, Ar-H), 7.29 (m, 1H, Ar-H), 7.09 (m, 2H, Ar-H), 6.96 (m, 1H, Ar-H), 5.82 (s, 1H, 4-H), 3.65 (s, 2H, Ar-CH2), 3.57 (s, 2H, Ar-CH2), 2.44 (t, J = 6.4 Hz, 2H, 9-H), 2.34 (d, J = 17.4 Hz, 1H, 2-H), 2.03 (d, J = 17.4 Hz, 1H, 2-H), 1.92 (s, 3H, 13-H), 1.82 (t, J = 5.2 Hz, 1H, 6-H), 1.64 (m, 1H, 7-H), 1.56 (m, 2H, 8-H), 1.36 (m, 1H, 7-H), 1.02 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13 13C NMR (100 MHz, CDCl3): δ 199.4 (3-C), 165.5 (5-C), 163.0 (d, J = 244.5 Hz, Ar-C), 147.5 (Ar-C), 147.1 (Ar-C), 141.8 (d, J = 6.8 Hz, Ar-C), 129.9 (d, J = 8.2 Hz, Ar-C), 129.1 (Ar-C), 125.2 (4-C), 124.1 (d, J = 2.6 Hz, Ar-C), 123.6 (Ar-C), 115.3 (d, J = 21.2 Hz, Ar-C), 114.2 (d, J = 21.1 Hz, Ar-C), 58.3 (Ar- C CH2), 58.1 (9-C), 54.3 (Ar- C CH2), 51.0 (6-C), 47.1 (2-C), 36.3 (1-C), 28.8 (12-C), 27.9 (7-C), 27.2 (8-C), 26.8 (11-C), 24.8 (13-C). HR-ESIMS m / z 439.2374 [M+H] + , calcd for C 26 H 32 FN2O3, 439.2397.

[0104] Synthesis of Compound N20

[0105]

[0106] The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-8: 1, V / V) to obtain a yellow oil with a yield of 76.8%. 1 H NMR (400MHz, CDCl3): δ7.28 (m, 3H, Ar-H), 7.20 (d, J=7.6Hz, 2H, Ar-H), 7.12 (d, J=7.6Hz, 2H, Ar-H), 6.94 (m , 1H, Ar-H), 5.82 (s, 1H, 4-H), 3.54 (s, 4H, Ar-CH2), 2.91 (m, 1H, CH), 2.42 (t, J=6.0Hz, 1H, 9-H), 2.35 (d, J=1 7.2Hz, 1H, 2-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.91 (s, 3H, 13-H), 1.79 (t, J=5.2Hz, 1H, 6-H), 1.66 (m, 1H, 7-H ), 1.55 (m, 2H, 8-H), 1.37 (m, 1H, 7-H), 1.26 (d, J=6.8Hz, 6H, (CH3)2), 1.03 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.6 (3-C), 166.0 (5-C), 163.0 (d, J=243.7Hz, Ar-C), 14 7.8 (Ar-C), 142.8 (d, J=6.6Hz, Ar-C), 136.7 (Ar-C), 129.6 (d, J=8.4Hz, Ar-C), 1 28.7(Ar-C), 127.3(Ar-C), 126.8(Ar-C), 126.3(Ar-C), 125.0(4-C), 124.2(d,J =2.1Hz, Ar-C), 115.4 (d, J = 21.3Hz, Ar-C), 113.7 (d, J = 20.9Hz, Ar-C), 58.4 (Ar- C H2), 58.2(9-C), 54.0(Ar- C H2), 51.1(6-C), 47.1(2-C), 36.3(1-C), 33.8( C H), 28.7(12-C), 27.9(7-C), 27.2(8-C), 26.9(11-C), 24.8(13-C), 24.1(( C H3)2).HR-ESIMS m / z436.2904[M+H] + , calculate for C 29 H 39 FNO, 436.3016.

[0107] Synthesis of compound N21

[0108]

[0109] The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-8: 1, V / V) to obtain a yellow oil with a yield of 73.2%. 1 H NMR (400MHz, CDCl3): δ7.26 (m, 1H, Ar-H), 7.20 (d, J=7.6Hz, 2H, Ar-H), 7.11 (d, J=7.6Hz, 2H, Ar-H), 6.93 (m, 1H, Ar -H), 6.73 (d, J=7.4Hz, 2H, Ar-H), 5.81 (s, 1H, 4-H), 3.52 (s, 2H, Ar-CH2), 3.49 (s, 2H, Ar-CH2), 2.96 (s, 6H, N (CH3) 2), 2.41 (t, J=6.4Hz, 2H, 9-H), 2.34 (d, J=17.2Hz, 1H, 2-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.93 (s, 3H, 13-H), 1.80 ( t, J=5.2Hz, 1H, 6-H), 1.68 (m, 1H, 7-H), 1.55 (m, 2H, 8-H), 1.36 (m, 1H, 7-H), 1.03 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.6 (3-C), 166.0 (5-C), 162.9 (d, J=244.0Hz, Ar-C), 149.8 (Ar-C), 143.0 (d, J=7.3Hz, Ar-C), 129.7 (Ar-C), 129.5 (d, J=8 .3Hz, Ar-C), 126.9 (Ar-C), 125.0 (4-C), 124.1 (d, J=2.1Hz, Ar-C), 115.3 (d, J=21.1Hz, Ar-C), 113.6 (d, J=21.0Hz, Ar-C), 112.5 (Ar-C), 58.0 (Ar- C H2), 57.9(9-C), 53.7(Ar- C H2), 51.1(6-C), 47.1(2-C), 40.7(N( CH3)2), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.2(8-C), 26.9(11-C), 24.8(13-C).HR-ESIMS m / z 437.2948[M+H] + , calculate for C 28 H 38 FN2O, 437.2968.

[0110] Synthesis of compound N22

[0111]

[0112] The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-8: 1, V / V) to obtain a yellow oil with a yield of 72.6%. 1 H NMR (400MHz, CDCl3): δ7.26 (m, 1H, Ar-H), 7.17 (d, J=7.6Hz, 2H, Ar-H), 7.11 (d, J=7.6Hz, 2H, Ar-H), 6.93 (m, 1H, Ar-H), 6.66 (d, J=7.4Hz, 2H, Ar-H), 5.82 (s, 1H, 4-H), 3.53 (s, 2H, Ar-CH2), 3.47 (s, 2H, Ar-CH2), 3.36 (q, J=6.8Hz, 4H, (CH2)2), 2.39 (m, 3H, 9-H and 2-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.93 (s, 3H, 13-H), 1.80 (t, J=5.2Hz, 1H, 6-H), 1.69 (m, 1H, 7-H), 1. 56 (m, 2H, 8-H), 1.36 (m, 1H, 7-H), 1.17 (t, J=6.8Hz, 6H, (CH3)2), 1.03 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ 199.6 (3-C), 166.1 (5-C), 162.9 (d, J=243.6Hz, Ar-C), 146.9 (Ar-C), 143.1 (d, J=6.7Hz, Ar-C), 129.9 (Ar-C), 129.5 (d, J=8 .2Hz, Ar-C), 125.5 (Ar-C), 124.9 (4-C), 124.2 (d, J=2.1Hz, Ar-C), 115.3 (d, J=21.1Hz, Ar-C), 113.6 (d, J=21.1Hz, Ar-C), 111.6 (Ar-C), 58.0 (Ar-C H2), 57.7(9-C), 53.7(Ar- C H2), 51.1(6-C), 47.1(2-C), 44.4(( C H2)2), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.2(8-C), 26.9(11-C), 24.8(13-C), 12.6(( C H3)2).HR-ESIMS m / z 465.3265[M+H] + , calculate for C 30 H 42 FN2O, 465.3281.

[0113] Synthesis of compound N23

[0114]

[0115] The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-6: 1, V / V) to obtain a yellow oil with a yield of 78.6%. 1 H NMR (400MHz, CDCl3): δ7.64 (s, 1H, Ar-H), 7.59 (m, 1H, Ar-H), 7.54 (m, 1H, Ar-H), 7.43 (m, 1H, Ar-H), 7.28 (m, 1H , Ar-H), 7.08 (m, 2H, Ar-H), 6.94 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.57 (s, 2H, Ar-CH2), 3.55 (s, 2H, Ar-CH2), 2. 42 (t, J=6.8Hz, 2H, 9-H), 2.32 (t, J=17.2Hz, 1H, 2-H), 2.01 (d, J=17.2Hz, 1H, 2-H), 1.92 (s, 3H, 13-H), 1.80 (t, J=5.2Hz, 1H, 6-H), 1.65 (m, 1H, 7-H), 1.55 (m, 2H, 8-H), 1.34 (m, 1H, 7-H), 1.02 (s, 3H, 11-H), 0.99 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.3(3-C), 165.4(5-C), 162.9(d, J=243.3Hz, Ar-C), 141. 8(d, J=6.7Hz, Ar-C), 141.2(Ar-C), 133.1(Ar-C), 132.1(Ar-C), 130.8(Ar-C), 129. 9(d, J=8.1Hz, Ar-C), 129.2(Ar-C), 125.2(4-C), 124.2(d, J=4.3Hz, Ar-C), 118.9( Ar-C), 115.4 (d, J=21.2Hz, Ar-C), 114.1 (d, J=21.0Hz, Ar-C), 112.4 (CN), 58.3 (Ar- C H2), 58.0(Ar- C H2), 54.2(9-C), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.2(11-C), 26.8(8-C), 24.8(13-C).HR-ESIMS m / z 419.2479[M+H] + , calculate for C 27 H 32 FN2O, 419.2499.

[0116] Synthesis of compound N24

[0117]

[0118] The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-6: 1, V / V) to obtain a yellow oil with a yield of 75.4%. 11H NMR (400 MHz, CDCl3): δ 7.59 (m, 1H, Ar-H), 7.44 (m, 1H, Ar-H), 7.28 (m, 2H, Ar-H), 7.07 (m, 2H, Ar-H), 6.94 (m, 1H, Ar-H), 5.81 (s, 1H, 4-H), 3.67 (s, 2H, Ar-CH2), 3.58 (s, 2H, Ar-CH2), 2.44 (t, J = 6.8 Hz, 2H, 9-H), 2.32 (t, J = 17.2 Hz, 1H, 2-H), 2.01 (d, J = 17.2 Hz, 1H, 2-H), 1.92 (s, 3H, 13-H), 1.80 (t, J = 5.2 Hz, 1H, 6-H), 1.65 (m, 1H, 7-H), 1.57 (m, 2H, 8-H), 1.35 (m, 1H, 7-H), 1.02 (s, 3H, 11-H), 0.99 (s, 3H, 12-H). 13 13C NMR (100 MHz, CDCl3): δ 199.3 (3-C), 165.4 (5-C), 162.9 (d, J = 244.3 Hz, Ar-C), 160.6 (d, J = 248.4 Hz, Ar-C), 141.7 (d, J = 6.6 Hz, Ar-C), 132.6 (d, J = 14.0 Hz, Ar-C), 131.7 (d, J = 4.7 Hz, Ar-C), 129.9 (d, J = 8.2 Hz, Ar-C), 128.1 (d, J = 3.6 Hz, Ar-C), 125.2 (4-C), 124.1 (d, J = 4.3 Hz, Ar-C), 119.1 (Ar-C), 118.9 (CN), 117.6 (d, J = 2.6 Hz, Ar-C), 115.3 (d, J = 21.2 Hz, Ar-C), 114.1 (d, J = 21.1 Hz, Ar-C), 112.1 (d, J = 9.4 Hz, Ar-C), 58.4 (Ar- C CH2), 54.5 (9-C), 51.0 (6-C), 47.1 (2-C), 36.3 (1-C), 28.7 (12-C), 27.9 (7-C), 27.2 (11-C), 26.8 (8-C), 24.8 (13-C). HR-ESIMS m / z 437.2387 [M + H] + , calcd for C 27 H 31 F2N2O, 437.2404.

[0119] Synthesis of Compound N25

[0120]

[0121] The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-6: 1, V / V) to obtain a yellow oil with a yield of 76.5%. 1 H NMR (400MHz, CDCl3): δ7.58 (m, 2H, Ar-H), 7.29 (m, 1H, Ar-H), 7.18 (m, 1H, Ar-H), 7.06 (m, 2H, Ar -H), 6.95 (m, 1H, Ar-H), 5.81 (s, 1H, 4-H), 3.54 (s, 4H, Ar-CH2), 2.41 (t, J=6.8Hz, 2H, 9-H), 2.32 (t, J=17.2Hz, 1H, 2-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.93 (s, 3H, 13-H), 1.81 (t, J=5.2Hz, 1H, 6- H), 1.64(m, 1H, 7-H), 1.56(m, 2H, 8-H), 1.34(m, 1H, 7-H), 1.02(s, 3H, 11-H), 1.00(s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.3 (3-C), 165.4 (5-C), 163.0 (d, J=244.7Hz, Ar-C), 162.2 (d, J=256.8Hz, Ar-C).141.7 (d, J=6.6Hz, Ar-C), 136.8 (d, J=14.0Hz, Ar-C), 135.1 (d, J=7.7Hz, Ar-C), 133.1 (Ar-C )-129.9 (d, J=8.1Hz, Ar-C), 125.2 (4-C), 124.1 (d, J=4.3Hz, Ar-C), 116.4 (d, J=19.4Hz, Ar-C), 115 .3 (d, J=21.3Hz, Ar-C), 114.3 (d, J=21.1Hz, Ar-C), 114.1 (CN), 101.2 (d, J=15.5Hz, Ar-C), 58.2 (Ar- C H2), 57.2(Ar- C H2), 54.5(9-C), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.2(11-C), 26.8(8-C), 24.8(13-C).HR-ESIMS m / z 437.2387[M+H] + , calculate for C 27 H 31 F2N2O, 437.2404.

[0122] Synthesis of compound N26

[0123]

[0124] The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-6: 1, V / V) to obtain a yellow oil with a yield of 77.4%. 1 H NMR (400MHz, CDCl3): δ7.81 (d, J=7.6Hz, 1H, Ar-H), 7.58 (d, J=7.6Hz, 1H, Ar-H), 7.37 (m, 1H, Ar-H), 7.27 (m, 1H , Ar-H), 7.07 (m, 2H, Ar-H), 6.94 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.71 (s, 2H, Ar-CH2), 3.60 (s, 2H, Ar-CH2), 2. 45 (t, J=6.8Hz, 2H, 9-H), 2.31 (t, J=17.2Hz, 1H, 2-H), 2.01 (d, J=17.2Hz, 1H, 2-H), 1.91 (s, 3H, 13-H), 1.79 (t, J=5.2Hz, 1H, 6-H), 1.64 (m, 1H, 7-H), 1.55 (m, 2H, 8-H), 1.32 (m, 1H, 7-H), 1.00 (s, 3H, 11-H), 0.99 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.3(3-C), 165.4(5-C), 162.9(d, J=244.5Hz, Ar-C), 141. 7(d, J=6.8Hz, Ar-C), 139.2(Ar-C), 136.0(Ar-C), 134.4(Ar-C), 132.6(Ar-C), 129. 9(d, J=8.1Hz, Ar-C), 127.1(Ar-C), 125.2(4-C), 124.1(d, J=4.3Hz, Ar-C)-116.2( Ar-C), 115.3 (d, J=21.4Hz, Ar-C), 114.2 (d, J=21.0Hz, Ar-C), 114.0 (CN), 58.6 (Ar- C H2), 55.4(Ar- CH2), 54.7(9-C), 51.0(6-C), 47.0(2-C), 36.3(1-C), 28.7(12-C), 28.0(7-C), 27.2(11-C), 26.9(8-C), 24.8(13-C).HR-ESIMS m / z453.1994[M+H] + , calculate for C 27 H 31 ClFN2O, 453.2019.

[0125] Synthesis of compound N27

[0126]

[0127] Using 4-formyl-biphenyl-3-carboxylic acid methyl ester as raw material, the product was prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 76.5%. 1 H NMR (400MHz, CDCl3): δ8.28 (m, 1H, Ar-H), 8.00 (m, 1H, Ar-H), 7.78 (m, 1H, Ar-H), 7.59 (d, J=8.0Hz, 2H, Ar-H), 7.50 (m, 1H, Ar-H), 7 .43 (d, J=8.0Hz, 2H, Ar-H), 7.27 (m, 1H, Ar-H), 7.11 (m, 2H, Ar-H), 6.93 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.94 (s, 3H, OCH3), 3.60 (s , 2H, Ar-CH2), 3.56 (s, 2H, Ar-CH2), 2.44 (t, J=6.8Hz, 2H, 9-H), 2.34 (d, J=17.2Hz, 1H, 2-H), 2.01 (d, J=17.2Hz, 1H, 2-H), 1.90 (s, 3H, 13-H), 1.79 (t, J=5.4Hz, 1H, 6-H), 1.67 (m, 1H, 7-H), 1.56 (m, 2H, 8-H), 1.36 (m, 1H, 7-H), 1.02 (s, 3H, 11-H), 0.98 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.4(3-C), 167.0(CO), 165.7(5-C), 162.9(d, J=244.1Hz, Ar-C), 142.5( d, J=6.8Hz, Ar-C), 141.1 (Ar-C), 139.1 (Ar-C), 138.8 (Ar-C), 131.4 (Ar-C), 130.6 (Ar-C), 129.6 ( d, J=8.2Hz, Ar-C), 129.2 (Ar-C), 128.9 (Ar-C), 128.3 (Ar-C), 128.1 (Ar-C), 127.0 (Ar-C), 125.0 (4-C), 124.1 (d, J=2.4Hz, Ar-C), 115.3 (d, J=21.1Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 58.3 (Ar- C H2), 58.2(Ar- C H2), 54.0(9-C), 52.2(O C H3), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.1(11-C), 26.9(8-C), 24.8(13-C).HR-ESIMS m / z 528.2883[M+H] + , calculate for C 34 H 39 FNO3,528.2914.

[0128] Synthesis of compound N28

[0129]

[0130] Using 1-methyl-3-phenyl-1H-pyrazole-5-carbaldehyde as raw material, the product was prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 6: 1-2: 1, V / V) to obtain a yellow oil with a yield of 76.8%. 11H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.2 Hz, 2H, Ar-H), 7.37 (m, 2H, Ar-H), 7.28 (m, 2H, Ar-H), 7.04 (m, 2H, Ar-H), 6.95 (m, 1H, Ar-H), 6.45 (s, 1H), 5.79 (s, 1H, 4-H), 3.84 (s, 3H, N-CH3), 3.56 (s, 4H, Ar-CH2), 2.44 (t, J = 6.8 Hz, 2H, 9-H), 2.31 (d, J = 17.2 Hz, 1H, 2-H), 2.00 (d, J = 17.2 Hz, 1H, 2-H), 1.89 (s, 3H, 13-H), 1.77 (t, J = 5.2 Hz, 1H, 6-H), 1.60 (m, 1H, 7-H), 1.53 (m, 2H, 8-H), 1.31 (m, 1H, 7-H), 0.99 (s, 3H, 11-H), 0.97 (s, 3H, 12-H). 13 13C NMR (100 MHz, CDCl3): δ 199.3 (3-C), 165.5 (5-C), 162.8 (d, J = 244.6 Hz, Ar-C), 149.8 (C), 141.6 (d, J = 6.7 Hz, Ar-C), 140.6 (Ar-C), 133.3 (C), 129.8 (d, J = 8.3 Hz, Ar-C), 128.6 (Ar-C), 127.5 (Ar-C), 125.3 (Ar-C), 125.1 (4-C), 124.4 (d, J = 2.5 Hz, Ar-C), 115.5 (d, J = 21.1 Hz, Ar-C), 114.1 (Ar-C), 104.3 (CH), 58.4 (Ar- C CH2), 54.2 (9-C), 50.9 (Ar- C CH2), 49.5 (6-C), 47.0 (2-C), 36.8 (N-CH3), 36.3 (1-C), 28.7 (12-C), 27.9 (7-C), 27.1 (11-C), 26.6 (8-C), 24.8 (13-C). HR-ESIMS m / z 474.2895 [M + H] + , calcd for C 30 H 37 FN3O, 474.2921.

[0131] Example 6.

[0132] Synthesis method of compounds N29 - N40:

[0133] 1.0 equivalent of intermediate 7 and 3.0 equivalent of the corresponding aldehyde (8A-8L) were weighed into a reaction bottle, dissolved in an appropriate amount of methanol, and then 0.2 mL of water was added, followed by 0.5 equivalent of zinc chloride and 1.5 equivalent of sodium cyanoborohydride dissolved in methanol. The reaction was stirred at 30°C and monitored by TLC until the reaction was completed. The methanol was spin-dried, water and DCM were added and extracted, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product.

[0134] Synthesis of compound N29

[0135]

[0136] Compound 8A was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 90.2%. 1 H NMR (400MHz, CDCl3): δ7.38 (m, 2H, Ar-H), 7.25 (m, 3H, Ar-H), 7.14 (m, 3H, Ar-H), 7.01 (m, 2H, Ar-H), 6.91 ( m, 1H, Ar-H), 5.79 (s, 1H, 4-H)-3.78 (s, 3H, OCH3), 3.69 (s, 2H, Ar-CH2), 3.59 (s, 2H, Ar-CH2), 2.45 (t, J=6 .8Hz, 2H, 9-H), 2.33 (d, J=17.2Hz, 1H, 2-H), 2.00 (d, J=17.2Hz, 1H, 2-H), 1.89 (s, 3H, 13-H), 1.78 (t, J=5. 2Hz, 1H, 9-H), 1.67(m, 1H, 7-H), 1.58(m, 2H, 8-H), 1.35(m, 1H, 7-H), 1.00(s, 3H, 11-H), 0.97(s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ 199.5 (3-C), 165.9 (5-C), 162.9 (d, J = 243.9Hz, Ar-C), 158.5 (d, J = 246.6Hz, Ar-C), 156.8 (Ar-C), 142.7 (d, J=6.8Hz, Ar-C), 131.2 (Ar-C), 130.6 (d, J=3.5Hz, Ar-C), 130.1 (d, J=4.5Hz, Ar-C), 129.6 (d, J=8.2Hz, Ar-C), 1 29.3 (Ar-C), 126.2 (d, J=17.1Hz, Ar-C), 125.7 (d, J=15.5Hz, Ar-C), 125.1 (4-C), 124.9 (Ar-C), 124.1 (d, J=2.1Hz, Ar-C) , 123.4 (d, J=3.9Hz, Ar-C), 120.5 (Ar-C), 115.3 (d, J=21.2Hz, Ar-C)-113.8 (d, J=21.1Hz, Ar-C), 111.0 (Ar-C), 58.2 (Ar- C H2), 55.6 (OCH3), 54.0 (9-C), 51.4 (d, J=1.8Hz, Ar- C H2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.1(11-C), 27.0(8-C), 24.7(13-C).HR-ESIMS m / z 518.2841[M+H] + , calculate for C 33 H 38 F2NO2, 518.2871.

[0137] Synthesis of compound N30

[0138]

[0139] Compound 8B was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 89.2%. 1H NMR(400MHz,CDCl3):δ7.41(m,1H,Ar-H),7.26(m-4H,Ar-H),7.16(m,5H,Ar-H),6.92(m,1H,Ar-H),6.92(m,1H,Ar-H) m,1H,Ar-H),5.79(s,1H,4-H),3.68(s,2H,Ar-CH2), 3.59(s,2H,Ar-CH2),2.45(t,J=6.8Hz,2H,9-H),2.3 3(d,J=17.6Hz,1H,2-H)-2.19(s,3H,CH3),2.00(d,J 17.6Hz,1H,2-H),1.90(s,3H,13-H),1.78(t,J=5.2) Hz,1H,9-H)-1.66(m,1H,7-H),1.57(m,2H,8-H),1.3 4(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H). 13 C NMR(100MHz,CDCl3):δ199.5(3-C),165.8(5-C),162.9(d =243.8Hz,Ar-C),158.1(d,J=246.6Hz,Ar-C),142.6(d, J=7.0Hz,Ar-C),136.5(Ar-C),135.8(Ar-C),130.3(d,J)=8 .9Hz,Ar-C),130.3(Ar-C)\129.9(d\J=9.6Hz,Ar-C),129. 6(d,J=8.2Hz,Ar-C),129.2(d,J=7.8Hz,Ar-C),127.9(Ar-C) C),125.9(d,J=15.4Hz,Ar-C),125.6(4-C),125.0(Ar-C), 124.1(d,J=2.2Hz,Ar-C),123.6(d,J=4.0Hz,Ar-C),115.3 (d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar- C H2),54.1(9-C),51.4(Ar- C H2),51.1(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27 .1(11-C),27.0(8-C),24.8(13-C),20.0(d,J=2.6Hz,CH3).HR-ESIMS m / z502.2903[M+H] + ,calcd for C 33 H 38F2NO, 502.2921.

[0140] Synthesis of compound N31

[0141]

[0142] Compound 8C was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 87.9%. 1 H NMR (400MHz, CDCl3): δ7.46 (m, 2H, Ar-H), 7.32 (m, 3H, Ar-H), 7.25 (m, 1H, Ar-H), 7.19 (m, 2H, Ar-H), 7.11 ( m, 2H, Ar-H), 6.92 (m, 1H, Ar-H), 5.79 (s, 1H, 4-H), 3.69 (s, 2H, Ar-CH2), 3.60 (s, 2H, Ar-CH2), 2.46 (t, J=6 .8Hz, 2H, 9-H), 2.33 (d, J=17.6Hz, 1H, 2-H), 2.00 (d, J=17.6Hz, 1H, 2-H), 1.90 (s, 3H, 13-H), 1.78 (t, J=5. 2Hz, 1H, 6-H), 1.67(m, 1H, 7-H), 1.57(m, 2H, 8-H), 1.34(m, 1H, 7-H), 1.00(s, 3H, 11-H), 0.97(s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ 199.5 (3-C), 165.9 (5-C), 162.9 (d, J = 243.8Hz, Ar-C), 158.1 (d, J = 246.4Hz, Ar-C), 142.5 (d, J =7.0Hz, Ar-C), 135.0 (Ar-C), 133.6 (Ar-C), 131.5 (Ar-C), 131.0 (d, J = 4.6Hz, Ar-C), 130.2 (d, J = 3.2Hz, Ar-C), 129.6 (d, J=8.1Hz, Ar-C), 129.5 (Ar-C), 126.9 (d, J=16.9Hz, Ar-C), 126.6 (Ar-C), 126.1 (d, J=15.1Hz, Ar-C), 125.0 (4-C), 124.1 (d, J=2.4Hz, Ar-C), 123.5 (d, J=4.1Hz, Ar-C), 115.3 (d, J=21.2Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 58.3 (Ar- C H2), 54.0(9-C), 51.2(Ar- CH2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C).27.2(11-C), 27.0(8-C), 24.8(13-C).HR-ESIMS m / z 522.2346[M+H] + , calculate for C 32 H 35 ClF2NO, 522.2375.

[0143] Synthesis of compound N32

[0144]

[0145] Compound 8D was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 89.4%. 1 H NMR (400MHz, CDCl3): δ7.62 (s, 1H, Ar-H), 7.50 (d, J=8.4Hz, 1H, Ar-H), 7.45 (m, 1H, Ar-H), 7.36 (m, 1H, Ar-H), 7.27 (m, 2H, Ar-H), 7.19 (m, 1H-Ar-H), 7.10 (m, 1H, Ar-H), 6.92 (m, 1H, Ar-H), 5.80 (s, 1H, 4-H), 3.69 (s, 2H, Ar-CH2), 3.59 (s, 2 H, Ar-CH2), 2.45 (t, J=6.8Hz, 2H, 9-H), 2.33 (d, J=17.2Hz, 1H, 2-H), 2.00 (d, J=17.2Hz, 1H, 2-H), 1.91 (s, 3H, 13-H), 1 .79 (t, J=5.4Hz, 1H, 6-H), 1.67 (m, 1H, 7-H), 1.58 (m, 2H, 8-H), 1.35 (m, 1H, 7-H), 1.01 (s, 3H, 11-H), 0.97 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ 199.5 (3-C), 165.9 (5-C), 162.9 (d, J = 243.8Hz, Ar-C), 158.1 (d, J = 246.4Hz, Ar-C), 142.5 (d, J =7.0Hz, Ar-C), 135.0 (Ar-C), 133.6 (Ar-C), 131.5 (Ar-C), 131.0 (d, J = 4.6Hz, Ar-C), 130.2 (d, J = 3.2Hz, Ar-C), 129.6 (d, J=8.1Hz, Ar-C), 129.5 (Ar-C), 126.9 (d, J=16.9Hz, Ar-C), 126.6 (Ar-C), 126.1 (d, J=15.1Hz, Ar-C), 125.0 (4-C), 124.1 (d, J=2.4Hz, Ar-C), 123.5 (d, J=4.1Hz, Ar-C)-115.3 (d, J=21.2Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 58.3 (Ar- C H2), 54.0(9-C), 51.2(Ar- C H2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.2(11-C), 27.0(8-C), 24.8(13-C).HR-ESIMS m / z 556.1963[M+H] + , calculate for C 32 H 34 Cl2F2NO, 556.1986.

[0146] Synthesis of compound N33

[0147]

[0148] Compound 8E was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1-V / V) to obtain a yellow oil with a yield of 88.6%. 1H NMR(400MHz,CDCl3):δ7.40(m,1H,Ar-H),7.25(m,1H,Ar-H),7.15(m,6H,Ar-H),7.05(m,1H,Ar-H),6.92(m,1H,Ar-H),5.80(s,1H,4-H),3.58(m,4H,Ar-CH2),2.45(t,J=6.4Hz,2H,9-H),2.34(s,3H,Ar-CH3),2.33(d,J=17.2Hz,1H,2-H),2.07(s,3H,Ar-CH3),2.00(d,J=17.2Hz,1H,2-H),1.90(s,3H,13-H),1.78(t,J=5.2Hz,1H,6-H)-1.67(m,1H,7-H),1.57(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H). 13 C NMR(100MHz,CDCl3):δ199.4(3-C),165.8(5-C),162.9(d,J=243.8Hz,Ar-C),158.1(d,J=244.5Hz,Ar-C),142.6(d,J=6.9Hz,Ar-C),136.9(Ar-C),135.9(Ar-C),135.0(Ar-C),130.4(d,J=3.2Hz,Ar-C),130.1(d,J=4.4Hz,Ar-C),129.7(d,J=17.5Hz,Ar-C),129.5(d,J=10.5Hz,Ar-C),127.8(Ar-C),125.8(d,J=15.5Hz,Ar-C),125.2(Ar-C),125.0(4-C),124.1(d,J=2.3Hz,Ar-C),123.5(d,J=4.1Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),58.3(Ar- C H2),54.1(9-C),51.4(Ar- C H2),51.1(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),27.0(8-C),24.8(13-C),20.0(CH3),16.7(CH3).HR-ESIMS m / z 516.3050[M+H] + ,calcd for C 34 H 40F2NO, 516.3078.

[0149] Synthesis of compound N34

[0150]

[0151] Compound 8F was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 86.3%. 1 H NMR (400MHz, CDCl3): δ7.44 (m, 1H, Ar-H), 7.26 (m, 2H, Ar-H), 7.15 (m, 4H, Ar-H), 7.00 (m, 1H, Ar-H), 6.92 (m, 2H , Ar-H), 5.79 (s, 1H, 4-H), 3.92 (s, 3H, OCH3), 3.69 (m, 2H, Ar-CH2), 3.60 (s, 2H, Ar-CH2), 2.45 (t, J=6.6Hz, 2H, 9 -H), 2.34 (d, J=17.2Hz, 1H, 2-H), 2.07 (s, 3H, Ar-CH3), 2.00 (d, J=17.2Hz, 1H, 2-H), 1.90 (s, 3H, 13-H), 1.78 (t, J=5.2Hz, 1H, 6-H), 1.67 (m, 1H, 7-H), 1.57 (m, 2H, 8-H), 1.34 (m, 1H, 7-H), 1.00 (s, 3H, 11-H), 0.97 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ 199.6 (3-C), 166.0 (5-C), 162.9 (d, J = 244.0Hz, Ar-C), 158.2 (d, J = 247.6Hz, Ar-C), 150.9 (Ar-C), 148.4 (Ar-C), 141.9 (d, J=11.1Hz, Ar-C), 142.5 (d, J=7.0Hz, Ar-C), 130.9 (d, J=4.6Hz, Ar-C), 130.3 (Ar-C), 129.6 (d, J=3 .2Hz, Ar-C), 126.2 (d, J=15.2Hz, Ar-C), 124.9 (4-C), 124.4 (d, J=13.2Hz, Ar-C), 124.1 (d, J=2.2Hz, Ar-C), 123.7 (Ar-C) , 123.3 (d, J=16.8Hz, Ar-C), 122.7 (Ar-C), 115.3 (d, J=21.2Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 112.9 (Ar-C), 58.3 (Ar- CH2), 56.3(OCH3), 54.0(9-C), 51.3(d, J=1.8Hz, Ar- C H2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.1(11-C), 27.0(8-C), 24.7(13-C).HR-ESIMS m / z 536.2744[M+H] + , calculate for C 33 H 37 F3NO2, 536.2776.

[0152] Synthesis of compound N35

[0153]

[0154] Compound 8G was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 87.8%. 1 H NMR (400MHz, CDCl3): δ7.48 (m, 1H, Ar-H), 7.26 (m, 2H, Ar-H), 7.20 (m, 2H, Ar-H), 7.13 (m, 4H, Ar-H), 6 .92 (m, 1H, Ar-H), 5.79 (s, 1H, 4-H), 3.70 (s, 2H, Ar-CH2), 3.60 (s, 2H, Ar-CH2), 2.46 (t, J=6.7Hz, 2H, 9-H), 2.34 (d, J=17.2Hz, 1H, 2-H), 2.00 (d, J=17.2Hz, 1H, 2-H), 1.90 (s, 3H, 13-H), 1.79 (t, J=5.2Hz, 1H, 6-H), 1.66 (m, 1H, 7-H), 1.58 (m, 2H, 8-H), 1.34 (m, 1H, 7-H), 1.00 (s, 3H, 11-H), 0.98 (s, 3H, 12-H). 13CNMR (100MHz, CDCl3): δ199.5 (3-C), 165.8 (5-C), 163.0 (d, J=243.9Hz, Ar-C), 158.2 (d, J=248.0Hz, Ar-C), 150.8 (dd, J1=246.5Hz, J2=13.1Hz, A r-C), 148.0 (dd, J1=248.7Hz, J2=12.9Hz, Ar-C), 142.4 (d, J=6.7Hz, Ar-C), 131.4 (d, J=4.6Hz, Ar-C), 130.1 (Ar-C), 129.6 (d, J=8.1Hz, Ar-C), 12 6.5 (d, J=15.1Hz, Ar-C), 126.2 (d, J=1.3Hz, Ar-C), 125.9 (d, J=12.4Hz, Ar-C), 125.0 (4-C), 124.1 (d, J=2.0Hz, Ar-C), 123.9 (dd, J1=4.7Hz, J2=6 .9Hz, Ar-C), 122.3 (dd, J1=2.5Hz, J2=16.6Hz, Ar-C), 116.8 (d, J=17.1Hz, Ar-C), 115.3 (d, J=21.2Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 58.3 (Ar- C H2), 54.0(9-C), 51.3(d, J=1.9Hz, Ar- C H2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.1(11-C), 27.0(8-C), 24.7(13-C).HR-ESIMS m / z 524.2547[M+H] + , calculate for C 32 H 34 F4NO, 524.2577.

[0155] Synthesis of compound N36

[0156]

[0157] Compound 8H was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 89.5%. 1H NMR(400MHz,CDCl3):δ7.43(m,1H,Ar-H),7.25(m,3H,Ar-H),7.17(m,3H,Ar-H),7.10(m,3H,Ar-H),6.92(m,1H,Ar-H),5.79(s,1H,4-H),3.69(s,2H,Ar-CH2),3.60(s,2H,Ar-CH2),2.46(t,J=6.7Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.33(s,3H,CH3),1.99(d,J=17.2Hz,1H,2-H),1.89(s,3H,13-H),1.78(t,J=5.2Hz,1H,6-H),1.67(m,1H,7-H),1.57(m,2H,8-H),1.34(m,1H,7-H),1.00(s,3H,11-H),0.97(s,3H,12-H). 13 C NMR(100MHz,CDCl3):δ199.5(3-C),166.0(5-C),163.0(d,J=244.0Hz,Ar-C),158.4(d,J=247.0Hz,Ar-C),158.3(d,J=245.5Hz,Ar-C),142.6(d,J=6.9Hz,Ar-C),131.3(d,J=5.1Hz,Ar-C),130.8(d,J=4.6Hz,Ar-C),130.4(d,J=2.2Hz,Ar-C),129.7(d,J=8.1Hz,Ar-C),128.9(d,J=2.0Hz,Ar-C),126.2(d,J=15.2Hz,Ar-C),152.2(d,J=17.7Hz,Ar-C),125.0(4-C),124.2125.0(d,J=23.8Hz,Ar-C),123.9(d,J=23.0Hz,Ar-C),123.7(d,J=4.0Hz,Ar-C),123.6(d,J=4.3Hz,Ar-C),123.3(d,J=16.6Hz,Ar-C),115.4(d,J=21.2Hz,Ar-C),113.9(d,J=21.1Hz,Ar-C),58.4(Ar- C H2),54.0(9-C),51.4(d,J=1.7Hz,Ar- CH2), 51.1(6-C), 47.1(2-C), 36.4(1-C), 28.7(12-C), 28.0(7-C), 27.2(11-C), 27.0(8-C), 24.8(13-C), 14.8(d, J=4.3Hz, CH3).HR-ESIMS m / z 520.2814[M+H] + , calculate for C 33 H 37 F3NO, 520.2827.

[0158] Synthesis of compound N37

[0159]

[0160] Compound 8I was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 84.9%. 1 H NMR (400MHz, CDCl3): δ7.44 (m, 1H, Ar-H), 7.27 (m, 2H, Ar-H), 7.18 (m, 2H, Ar-H), 7.11 (m, 2H, Ar-H), 6.98 (m, 1H, Ar- H), 6.92 (m, 2H, Ar-H), 5.79 (s, 1H, 4-H), 3.94 (s, 3H, OCH3), 3.60 (s, 2H, Ar-CH2), 3.60 (s, 2H, Ar-CH2), 2.46 (t, J=6. 6Hz, 2H, 9-H), 2.33 (d, J=17.2Hz, 1H, 2-H), 2.33 (s, 3H, Ar-CH3), 1.99 (d, J=17.2Hz, 1H, 2-H), 1.90 (s, 3H, 13-H), 1. 78 (t, J=5.2Hz, 1H, 6-H), 1.66 (m, 1H, 7-H), 1.57 (m, 2H, 8-H), 134 (m, 1H, 7-H), 1.00 (s, 3H, 11-H), 0.97 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ 199.6 (3-C), 166.0 (5-C), 163.0 (d, J = 243.8Hz, Ar-C), 158.0 (d, J = 246.3Hz, Ar-C), 155.3 (Ar-C), 142.6 (d, J=6.9Hz, Ar-C), 136.7 (Ar-C), 131.0 (d, J=4.5Hz, Ar-C), 130.1 (d, J=2.8Hz, Ar-C), 129.7 (d, J=8.1Hz, Ar-C), 1 27.1 (d, J=17.0Hz, Ar-C), 127.0 (Ar-C), 126.1 (d, J=15.1Hz, Ar-C), 125.0 (4-C), 124.2 (d, J=2.4Hz, Ar-C), 123.5 (d, J=4 .0Hz, Ar-C), 123.3 (Ar-C), 122.2 (Ar-C), 115.3 (d, J=21.2Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 111.4 (Ar-C), 58.2 (Ar- C H2), 56.3(OCH3), 54.0(9-C), 51.3(Ar- C H2), 51.0(6-C), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.1(11-C), 27.0(8-C), 24.8(13-C).HR-ESIMS m / z 552.2465[M+H] + , calculate for C 33 H 37 ClF2NO2, 552.2481.

[0161] Synthesis of compound N38

[0162]

[0163] Compound 8J was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 83.6%. 1H NMR(400MHz,CDCl3):δ7.77(d,J=8.4Hz,1H,Ar-H),7.66(m,1H,Ar-H),7.50(m,3H,Ar-H),7.26(m,3H,Ar-H),7.11(m,2H,Ar-H),6.92(m,1H,Ar-H),5.79(s,1H,4-H),3.71(s,2H,Ar-CH2),3.62(s,2H,Ar-CH2),2.48(t,J=6.8Hz,2H,9-H),2.34(d.J=17.2Hz,1H,2-H),1.99(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.80(t,J=5.2Hz,1H,6-H),1.67(m,1H,7-H),1.58(m,2H,8-H),1.35(m,1H,7-H),1.01(s,3H,11-H),0.98(s,3H,12-H). 13 C NMR(100MHz,CDCl3):δ199.4(3-C),165.7(5-C),163.0(d,J=244.0Hz,Ar-C),157.9(d,J=247.1Hz,Ar-C),142.4(d,J=7.8Hz,Ar-C),139.7(Ar-C),133.1(Ar-C),132.6(Ar-C),132.0(d,J=4.8Hz,Ar-C),130.9(Ar-C),130.0(d,J=2.3Hz,Ar-C),129.6(d,J=8.1Hz,Ar-C),128.2(Ar-C),126.7(d,J=15.1Hz,Ar-C),125.9(d,J=16.1Hz,Ar-C),125.0(4-C),124.2(d,J=2.5Hz,Ar-C),124.0(d,J=6.2Hz,Ar-C),118.0(CN),115.3(d,J=21.2Hz,Ar-C),113.8(d,J=21.1Hz,Ar-C),113.0(Ar-C),58.3(Ar- C H2),54.1(9-C),51.2(Ar- C H2),51.0(6-C),47.2(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.1(11-C),27.0(8-C),24.8(13-C).HR-ESIMS m / z 513.2695[M+H] + ,calcd forC 33 H35 F2N2O, 513.2717.

[0164] Synthesis of compound N39

[0165]

[0166] Compound 8K was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 80.7%. 1 H NMR (400MHz, CDCl3): δ8.05 (m, 1H, Ar-H), 7.68 (m, 1H, Ar-H), 7.55 (m, 1H, Ar-H), 7.45 (m, 2H, Ar-H), 7.25 (m, 3H, Ar- H), 7.10 (m, 2H, Ar-H), 6.92 (m, 1H, Ar-H), 5.78 (s, 1H, 4-H), 3.64 (s, 2H, Ar-CH2), 3.58 (s, 2H, Ar-CH2), 3.60 (s, 2H, N -CH2), 2.43 (t, J=6.8Hz, 2H, 9-H), 2.34 (d, J=17.2Hz, 1H, 2-H), 1.99 (d, J=17.2Hz, 1H, 2-H), 1.91 (s, 3H, 13-H), 1.8 0 (t, J=5.4Hz, 1H, 6-H), 1.67 (m, 1H, 7-H), 1.56 (m, 2H, 8-H), 1.33 (m, 1H, 7-H), 1.00 (s, 3H, 11-H), 0.98 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ 199.5 (3-C), 165.9 (5-C), 162.9 (d, J = 243.8Hz, Ar-C), 157.8 (d, J = 245.2Hz, Ar-C), 149.1 (Ar-C), 142.4 (d, J=6.9Hz, Ar-C), 132.9 (Ar-C), 132.5 (Ar-C), 131.5 (d, J=4.5Hz, Ar-C), 130.8 (Ar-C), 129.6 (d, J=8.2Hz, Ar-C) , 128.9 (Ar-C), 128.8 (d, J=2.7Hz, Ar-C), 126.0 (d, J=15.0Hz, Ar-C), 125.6 (d, J=16.9Hz, Ar-C), 125.0 (4-C), 124.5 (Ar- C), 124.3 (d, J=4.0Hz, Ar-C), 124.1 (d, J=2.5Hz, Ar-C), 115.3 (d, J=21.2Hz, Ar-C), 113.8 (d, J=21.1Hz, Ar-C), 58.3 (Ar- C H2), 54.0(9-C), 51.1(6-C), 51.0(Ar- C H2), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.9(7-C), 27.1(11-C), 27.0(8-C), 24.7(13-C).HR-ESIMS m / z 533.2485[M+H] + ,calcdfor C 32 H 35 F2N2O3, 533.2616.

[0167] Synthesis of compound N40

[0168]

[0169] Compound 8L was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 10: 1-6: 1, V / V) to obtain a yellow oil with a yield of 86.2%. 1H NMR(400MHz,CDCl3):δ7.65(m,2H,Ar-H),7.52(m,1H,Ar-H),7.35(m,1H,Ar-H),7.25(m,3H,Ar-H),7.10(m,2H,Ar-H),6.93(m,1H,Ar-H),5.79(s,1H,4-H),3.70(s,3H,Ar-CH3),3.60(s,2H,Ar-CH2),3.60(s,2H,N-CH2),2.47(t,J=6.7Hz,2H,9-H),2.34(d,J=17.2Hz,1H,2-H),2.00(d,J=17.2Hz,1H,2-H),1.91(s,3H,13-H),1.80(t,J=5.4Hz,1H,6-H),1.67(m,1H,7-H),1.58(m,2H,8-H),1.35(m,1H,7-H),1.00(s,3H,11-H),0.98(s,3H,12-H). 13 C NMR(100MHz,CDCl3):δ199.3(3-C),165.7(5-C),163.0(d,J=243.9Hz,Ar-C),159.1(d,J=259.4Hz,Ar-C),158.0(d,J=248.2Hz,Ar-C),142.3(d,J=6.8Hz,Ar-C),136.5(d,J=3.0Hz,Ar-C),131.1(Ar-C),129.9(Ar-C),129.6(d,J=8.1Hz,Ar-C),126.8(d,J=14.8Hz,Ar-C),125.2(d,J=14.5Hz,Ar-C),125.0(4-C),124.7(d,J=4.3Hz,Ar-C),124.1(d,J=4.0Hz,Ar-C),121.3(d,J=16.4Hz,Ar-C),115.3(d,J=21.2Hz,Ar-C),113.9(d,J=21.1Hz,Ar-C),113.8(CN),102.1(d,J=16.6Hz,Ar-C),58.4(Ar- C H2),54.3(9-C),51.3(Ar- C H2).51.0(6-C),47.1(2-C),36.3(1-C),28.7(12-C),27.9(7-C),27.2(11-C),27.0(8-C),24.8(13-C).HR-ESIMS m / z 531.2613[M+H] + ,calcd forC 33 H34 F3N2O, 531.2623.

[0170] Example 7.

[0171] Synthesis method of compounds N41-N48:

[0172] Weigh 1.0 equivalent of the compound and 3.0 equivalents of the corresponding intermediate (10A-10H) into a reaction bottle, add appropriate amount of DCM to dissolve, add 5.0 equivalents of triethylamine dropwise under ice bath conditions, stir at room temperature, monitor by TLC until the reaction is completed, and concentrate to obtain a crude product.

[0173] Synthesis of compound N41

[0174]

[0175] Compound 10A was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-4: 1, V / V) to obtain a yellow oil with a yield of 74.3%. 1 H NMR (400MHz, CDCl3): δ7.80 (m, 2H, Ar-H), 7.30 (m, 1H, Ar-H), 7.14 (m, 4H, Ar-H), 6.97 (m, 1H, Ar-H), 6. 40 (s, 1H, CH), 5.82 (s, 1H, 4-H), 3.81 (s, 2H, Ar-CH2), 3.66 (s, 2H, Ar-CH2), 2.54 (t, J=6.8Hz, 2H, 9-H), 2.36 (d, J=17.2Hz, 1H, 2-H), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.96 (d, J=0.6Hz, 3H, 13-H), 1.84 (t, J=5.2Hz , 1H, 6-H), 1.72 (m, 1H, 7-H), 1.61 (m, 2H, 8-H), 1.42 (m, 1H, 7-H), 1.04 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.4(3-C), 170.6(C), 165.5(5-C), 163.8(d, J=248.5Hz, Ar-C), 163. 0 (d, J=244.4Hz, Ar-C), 161.4 (C), 141.5 (d, J=7.0Hz, Ar-C), 130.0 (d, J=8.1Hz, Ar-C), 128.7 ( d, J=8.3Hz, Ar-C), 125.2 (d, J=3.7Hz, Ar-C), 125.1 (4-C), 124.2 (d, J=2.6Hz, Ar-C), 116.1 (d, J=21.8Hz, Ar-C), 115.4 (d, J=21.2Hz, Ar-C), 114.3 (d, J=21.1Hz, Ar-C), 101.2 (CH), 58.0 (Ar- C H2), 54.1(9-C), 51.0(6-C), 48.4(Ar- C H2), 47.1(2-C), 36.3(1-C), 28.8(12-C), 27.8(7-C), 27.2(8-C), 27.1(11-C), 24.8(13-C).HR-ESIMS m / z 479.2489[M+H] + , calculate for C 29 H 33 F2N2O2, 479.2510.

[0176] Synthesis of compound N42

[0177]

[0178] Compound 10B was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-4: 1, V / V) to obtain a yellow oil with a yield of 75.2%. 11H NMR (400 MHz, CDCl3): δ 7.80 (m, 2H, Ar-H), 7.30 (m, 1H, Ar-H), 7.14 (m, 4H, Ar-H), 6.97 (m, 1H, Ar-H), 6.40 (s, 1H, CH), 5.82 (s, 1H, 4-H), 3.81 (s, 2H, Ar-CH2), 3.66 (s, 2H, Ar-CH2), 2.54 (t, J = 6.8 Hz, 2H, 9-H), 2.36 (d, J = 17.2 Hz, 1H, 2-H), 2.03 (d, J = 17.2 Hz, 1H, 2-H), 1.96 (d, J = 0.6 Hz, 3H, 13-H), 1.84 (t, J = 5.2 Hz, 1H, 6-H), 1.72 (m, 1H, 7-H), 1.61 (m, 2H, 8-H), 1.42 (m, 1H, 7-H), 1.04 (s, 3H, 11-H), 1.01 (s, 3H, 12-H). 13 13C NMR (100 MHz, CDCl3): δ 199.4 (3-C), 170.6 (C), 165.5 (5-C), 163.8 (d, J = 248.5 Hz, Ar-C), 163.0 (d, J = 244.4 Hz, Ar-C), 161.4 (C), 141.5 (d, J = 7.0 Hz, Ar-C), 130.0 (d, J = 8.1 Hz, Ar-C), 128.7 (d, J = 8.3 Hz, Ar-C), 125.2 (d, J = 3.7 Hz, Ar-C), 125.1 (4-C), 124.2 (d, J = 2.6 Hz, Ar-C), 116.1 (d, J = 21.8 Hz, Ar-C), 115.4 (d, J = 21.2 Hz, Ar-C), 114.3 (d, J = 21.1 Hz, Ar-C), 101.2 (CH), 58.0 (Ar- C CH2), 54.1 (9-C), 51.0 (6-C), 48.4 (Ar- C CH2), 47.1 (2-C), 36.3 (1-C), 34.1 (CH), 28.8 (12-C), 27.8 (7-C), 27.2 (8-C), 27.1 (11-C), 24.8 (13-C). HR-ESIMS m / z 495.2198 [M + H] + , calcd for C 29 H 33 ClFN2O2, 495.2215.

[0179] Synthesis of Compound N43

[0180]

[0181] Compound 10C was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 75.6%. 1 H NMR (400MHz, CDCl3): δ7.96 (d, J=8.4Hz, 2H, Ar-H), 7.77 (d, J=8.4Hz, 2H, Ar-H), 7.30 (m, 1H, Ar-H), 7.12 (m, 2H, Ar-H), 6.98 (m, 1H, Ar-H), 6.47 (s, 1H, CH), 5.82 (s, 1H, 4-H), 3.83 (s, 2H, Ar-CH2), 3.66 (s, 2H, Ar-CH2), 2.54 (t, J=6.8Hz, 2H, 9-H), 2.36 (d, J=17.2Hz, 1H, 2-H), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.96 (d, J=1.0Hz, 3H, 13-H), 1.85 (t , J=5.2Hz, 1H, 6-H), 1.72 (m, 1H, 7-H), 1.61 (m, 2H, 8-H), 1.42 (m, 1H, 7-H), 1.05 (s, 3H, 11-H), 1.01 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.3(3-C), 171.6(C), 165.4(5-C), 163.0(d, J=244.4Hz , Ar-C), 160.8 (C), 141.4 (d, J = 6.9Hz, Ar-C), 132.8 (Ar-C), 130.0 (d, J = 8.3Hz, Ar -C), 127.4 (Ar-C), 125.2 (4-C), 124.1 (d, J=2.0Hz, Ar-C), 118.3 (CN), 115.4 (d, J=21.5Hz, Ar-C), 114.3 (d, J=20.7Hz, Ar-C), 113.6 (Ar-C), 101.2 (CH), 58.0 (Ar- C H2), 54.2(9-C), 51.0(6-C), 48.5(Ar- C H2), 47.1(2-C), 36.3(1-C), 34.1( C H), 28.8(12-C), 27.9(7-C), 27.3(8-C), 27.1(11-C), 24.8(13-C).HR-ESIMS m / z486.2523[M+H] + , calculate for C 30 H 33 FN3O2, 486.2557.

[0182] Synthesis of compound N44

[0183]

[0184] Compound 10D was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 5: 1-3: 1, V / V) to obtain a yellow oil with a yield of 76.3%. 1 H NMR (400MHz, CDCl3): δ7.00 (d, J=8.0Hz, 2H, Ar-H), 7.29 (m, 3H, Ar-H), 7.12 (m, 2H, Ar-H), 6.96 (m, 1H, Ar-H ), 6.41 (s, 1H, CH), 5.81 (s, 1H, 4-H), 3.79 (s, 2H, Ar-CH2), 3.65 (s, 2H, Ar-CH2), 2.53 (t, J=7.0Hz, 2H, 9-H), 2.40 (s, 3H, CH3), 2.36 (d, J=17.6Hz, 1H, 2-H), 2.02 (d, J=17.6Hz, 1H, 2-H), 1.95 (s, 3H, 13-H), 1.84 (t, J=5 .2Hz, 1H, 6-H), 1.72(m, 1H, 7-H), 1.61(m, 2H, 8-H), 1.42(m, 1H, 7-H), 1.04(s, 3H, 11-H), 1.00(s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 170.2(C), 165.5(5-C), 163.0(d, J=244.3Hz, Ar-C), 162.2 (C), 141.6 (d, J=7.0Hz, Ar-C), 140.2 (Ar-C), 129.9 (d, J=8.1Hz, Ar- C), 129.6 (Ar-C), 126.6 (Ar-C), 126.1 (Ar-C), 125.1 (4-C), 124.2 (d, J=2.5Hz, Ar -C), 115.4 (d, J=21.3Hz, Ar-C), 114.2 (d, J=21.1Hz, Ar-C), 101.2 (CH), 58.0 (Ar- C H2), 54.0(9-C), 51.0(6-C), 48.4(Ar- C H2), 47.1(2-C), 36.3(1-C), 28.7(12-C), 27.7(7-C), 27.2(8-C), 27.1(11-C), 24.7(13-C), 21.4(CH3).HR-ESIMS m / z 475.2745[M+H]+ ,calcdfor C 30 H 36 FN2O2, 475.2761.

[0185] Synthesis of compound N45

[0186]

[0187] Compound 10E was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-4: 1, V / V) to obtain a yellow oil with a yield of 75.8%. 1 H NMR (400MHz, CDCl3): δ7.74 (d, J=8.0Hz, 2H, Ar-H), 7.29 (m, 1H, Ar-H), 7.13 (d, J=8.0Hz, 2H, Ar-H), 6.96 (m, 3 H, Ar-H), 6.38 (s, 1H, CH), 5.81 (s, 1H, 4-H), 3.85 (s, 3H, OCH3), 3.79 (s, 2H, Ar-CH2), 3.65 (s, 2H, Ar-CH2), 2.5 3(t, J=6.8Hz, 2H, 9-H), 2.36 (d, J=17.2Hz, 1H, 2-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.95 (s, 3H, 13-H), 1.84 (t, J =5.4Hz, 1H, 6-H), 1.72(m, 1H, 7-H), 1.61(m, 2H, 8-H), 1.42(m, 1H, 7-H), 1.04(s, 3H, 11-H), 1.00(s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 170.2(C), 165.6(5-C), 163.0(d, J=244.3Hz, Ar- C), 161.9(C), 161.0(Ar-C), 141.6(d, J=6.9Hz, Ar-C), 140.2(Ar-C), 129.9(d, J=8.3 Hz, Ar-C), 128.2 (Ar-C), 125.1 (4-C), 124.2 (d, J=2.4Hz, Ar-C), 121.5 (Ar-C), 115.4 (d, J=21.3Hz, Ar-C), 114.3 (Ar-C), 114.2 (d, J=21.1Hz, Ar-C), 101.1 (CH), 58.0 (Ar- C H2), 55.4(OCH3), 54.1(9-C), 51.0(6-C), 48.4(Ar- CH2), 47.1(2-C), 36.3(1-C), 28.8(12-C), 27.8(7-C), 27.2(8-C), 27.1(11-C), 24.8(13-C).HR-ESIMS m / z 491.2679[M+H] + , calculate for C 30 H 36 FN2O3, 491.2710.

[0188] Synthesis of Compound N46

[0189]

[0190] Compound 10F was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-6: 1, V / V) to obtain a yellow oil with a yield of 71.4%. 1 H NMR (400MHz, CDCl3): δ8.34 (d, J=8.8Hz, 2H, Ar-H), 7.99 (d, J=8.8Hz, 2H, Ar-H), 7.31 (m, 1H, Ar-H), 7.12 (m, 2 H, Ar-H), 6.96 (m, 1H, Ar-H), 6.51 (s, 1H, CH), 5.83 (s, 1H, 4-H), 3.84 (s, 2H, Ar-CH2), 3.67 (s, 2H, Ar-CH2), 2.5 6 (t, J=6.8Hz, 2H, 9-H), 2.36 (d, J=17.2Hz, 1H, 2-H), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.96 (s, 3H, 13-H), 1.86 (t, J =5.2Hz, 1H, 6-H), 1.72(m, 1H, 7-H), 1.62(m, 2H, 8-H), 1.43(m, 1H, 7-H), 1.05(s, 3H, 11-H), 1.01(s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.3(3-C), 171.8(C), 165.4(5-C), 163.1(d, J=244.4Hz, Ar-C), 160.5(C), 148.7(Ar-C), 141.3(d, J=6.9Hz, Ar-C), 135.1(Ar-C), 130.0(d , J=8.1Hz, Ar-C), 127.7 (Ar-C), 125.2 (4-C), 124.3 (Ar-C), 124.1 (d, J=2.4Hz, Ar -C), 115.4 (d, J=21.2Hz, Ar-C), 114.4 (d, J=21.1Hz, Ar-C), 101.4 (CH), 58.0 (Ar- C H2), 54.3(9-C), 51.0(6-C), 48.5(Ar- C H2), 47.1(2-C), 36.3(1-C), 28.8(12-C), 27.8(7-C), 27.2(8-C), 27.1(11-C), 24.8(13-C).HR-ESIMS m / z506.2433[M+H] + ,calcdfor C 29 H 33 FN3O4, 506.2455.

[0191] Synthesis of compound N47

[0192]

[0193] Compound 10G was used as the raw material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-4: 1, V / V) to obtain a yellow oil with a yield of 75.7%. The yield was 71.6%. 11H NMR (400 MHz, CDCl3): δ 7.57 (m, 2H, Ar-H), 7.46 (m, 1H, Ar-H), 7.32 (m, 1H, Ar-H), 7.15 (m, 3H, Ar-H), 6.99 (m, 1H, Ar-H), 6.44 (s, 1H, CH), 5.84 (s, 1H, 4-H), 3.83 (s, 2H, Ar-CH2), 3.68 (s, 2H, Ar-CH2), 2.56 (t, J = 6.8 Hz, 2H, 9-H), 2.38 (d, J = 17.2 Hz, 1H, 2-H), 2.05 (d, J = 17.2 Hz, 1H, 2-H), 1.98 (d, J = 0.6 Hz, 3H, 13-H), 1.87 (t, J = 5.2 Hz, 1H, 6-H), 1.74 (m, 1H, 7-H), 1.63 (m, 2H, 8-H), 1.44 (m, 1H, 7-H), 1.07 (s, 3H, 11-H), 1.03 (s, 3H, 12-H). 13 13C NMR (100 MHz, CDCl3): δ 199.4 (3-C), 170.9 (C), 165.4 (5-C), 163.1 (d, J = 244.5 Hz, Ar-C), 163.0 (d, J = 245.3 Hz, Ar-C), 161.4 (C), 141.5 (d, J = 7.0 Hz, Ar-C), 131.1 (d, J = 8.6 Hz, Ar-C), 130.6 (d, J = 8.2 Hz, Ar-C), 129.9 (d, J = 7.9 Hz, Ar-C), 125.2 (4-C), 124.2 (d, J = 2.6 Hz, Ar-C), 122.5 (d, J = 2.5 Hz, Ar-C), 117.0 (d, J = 21.4 Hz, Ar-C), 115.4 (d, J = 21.2 Hz, Ar-C), 114.3 (d, J = 21.0 Hz, Ar-C), 113.8 (d, J = 23.0 Hz, Ar-C), 101.3 (CH), 58.0 (Ar- C CH2), 54.1 (9-C), 51.0 (6-C), 48.4 (Ar- C CH2), 47.1 (2-C), 36.3 (1-C), 29.7 (12-C), 28.8 (7-C), 27.8 (8-C), 27.2 (11-C), 24.8 (13-C). HR-ESIMS m / z 479.2474 [M + H] + , calcd for C 29 H 33 F2N2O2, 479.2510.

[0194] Synthesis of Compound N48

[0195]

[0196] Compound 10H was used as the starting material and prepared according to the above method. The crude product was separated and purified by silica gel column chromatography (PE: EA = 8: 1-4: 1, V / V) to obtain a yellow oil with a yield of 73.6%. 1 H NMR (400MHz, CDCl3): δ7.73 (d, J=8.0Hz, 2H, Ar-H), 7.32 (d, J=8.0Hz, 2H, Ar-H), 7.28 (m, 1H, Ar-H), 7.12 (m, 2H, Ar-H), 6. 96 (m, 1H, Ar-H), .41 (s, 1H, CH), 5.83 (s, 1H, 4-H), 3.80 (s, 2H, Ar-CH2), 3.65 (s, 2H, Ar-CH2), 2.95 (m, 1H, CH), 2.53 (t, J=6 .8Hz, 2H, 9-H), 2.36 (d, J=17.2Hz, 1H, 2-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.95 (s, 3H, 13-H), 1.84 (t, J=5.2Hz, 1H, 6-H), 1 .72 (m, 1H, 7-H), 1.61 (m, 2H, 8-H), 1.43 (m, 1H, 7-H), 1.28 (d, J=6.8Hz, 6H, (CH3)2), 1.04 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 170.2(C), 165.6(5-C), 163.0(d, J=244.3Hz, Ar-C), 162.2 (C), 151.1 (Ar-C), 141.6 (d, J=6.8Hz, Ar-C), 129.9 (d, J=8.1Hz, Ar- C), 127.1 (Ar-C), 126.8 (Ar-C), 126.5 (Ar-C), 125.1 (4-C), 124.2 (d, J=2.5Hz, Ar -C), 115.4 (d, J=21.4Hz, Ar-C), 114.2 (d, J=21.0Hz, Ar-C), 101.3 (CH), 58.0 (Ar- C H2), 54.0(9-C), 51.0(6-C), 48.4(Ar- CH2), 47.2(2-C), 36.3(1-C), 34.1(CH), 28.8(12-C), 27.7(7-C), 27.2(8-C), 27.1(11-C), 24.8(13-C), 23.9((CH3)2).HR-ESIMS m / z 503.3044[M+H] + , calculate for C 27 H 35 FN2O2, 503.3074.

[0197] Example 8.

[0198] Synthesis method of compounds N49 and N62-N73

[0199] Weigh 1.0 equivalent of compound 16 into a bottle, add appropriate amount of DCM to dissolve, add 1.0 equivalent of anhydrous potassium carbonate, slowly drop 1.1 equivalent of benzyl bromide in an ice bath, then stir in an ice bath, monitor by TLC until the reaction is complete, slowly drop 1 mol / L sodium hydroxide aqueous solution to quench the reaction, extract three times with DCM, combine the organic layers, dry with anhydrous magnesium sulfate, filter, and concentrate to obtain a crude product.

[0200] Synthesis of compound N49

[0201]

[0202] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 92.6%. 1 H NMR (400MHz, CDCl3): δ7.47 (m, 1H, Ar-H), 7.12 (m, 1H, Ar-H), 6.97 (m, 1H, Ar-H), 5 .82(s, 1H, 4-H), 3.42(s, 2H, Ar-CH2), 2.37(m, 3H, 2-H, 9-H), 2.17(s, 3H, 10-H), 2. 03 (d, J=17.2Hz, 1H, 2-H), 1.98 (s, 3H, 13-H), 1.86 (t, J=5.4Hz, 1H, 6-H), 1.74 (m, 1 H, 7-H), 1.57 (m, 2H, 8-H), 1.43 (m, 1H, 7-H), 1.05 (s, 3H, 11-H), 1.02 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ 199.3 (3-C), 165.5 (5-C), 159.0 (d, J = 245.7Hz, Ar-C), 141.4 (d, J = 6.5Hz, Ar-C), 133.1 ( Ar-C), 125.4 (d, J=3.1Hz, Ar-C), 125.1 (4-C), 116.6 (d, J=22.0Hz, Ar-C), 107.1 (d, J=20.8Hz, Ar-C), 61.5 (Ar- C H2), 57.7(9-C), 51.1(6-C), 47.2(2-C), 42.2(10-C), 36.3(1-C), 28.8(12-C), 27.8(7-C), 27.2(8-C), 27.1(11-C), 24.7(13-C).HR-ESIMS m / z 396.1337[M+H] + , calculate for C 20 H 28 BrFNO, 396.1338.

[0203] Synthesis of compound N62

[0204]

[0205] Using 4-(trifluoromethyl)benzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ7.58 (s, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 7.44 (m, 2H, Ar-H), 5.82 (br s, 1H), 3.45 (br s, 2H), 2.39 (m, 3H), 2.20 (m, 3H), 2.02 (d, J=15.4Hz, 1H), 1.97 (s, 3H), 1.8 6(m, 1H), 1.72(m, 1H), 1.60(m, 2H), 1.42(m, 1H), 1.12(s, 3H), 1.05(s, 3H). 13C NMR (100 MHz, CDCl3): δ 199.4, 165.6, 159.0 (d, J = 220.7 Hz), 143.4, 129.1 (d, J = 5.7 Hz), 125.3 (d, J = 8.3 Hz), 125.2, 125.1 (d, J = 2.8 Hz), 124.0 (d, J = 19.9 Hz), 62.0, 57.7, 51.1, 47.1, 36.2, 29.7, 28.8, 27.5, 27.2, 27.1, 24.7. FAB-MS showed molecular ion peak m / z: 367 [M+H] + , molecular formula is C 21 H 28 F3NO.

[0206] Synthesis of compound N63

[0207]

[0208] The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 48%. 1 H NMR (400MHz, CDCl3): δ8.36 (s, 1H, Ar-H), 8.16 (s, 1H, Ar-H), 7.18 (s, 1H, Ar-H), 5.83 (br s, 1H), 3.60 (br s, 2H), 2.41 (d, J = 16.7Hz, 1H), 2.40 (d, 2H), 2.00 (s, 3H), 1.88 (d, J = 15.6Hz, 1H) , 1.97(s, 3H), 1.76(m, 1H), 1.61(m, 2H), 1.45(m, 2H), 1.12(s, 3H), 1.06(s, 3H). 13 C NMR (100 MHz, CDCl3): δ 198.8, 164.3, 163.8, 139.2 (d, J = 9.5 Hz), 137.1, 128.1, 125.7, 120.4, 120.2, 56.2, 50.5, 46.8, 39.4, 36.3, 31.9, 29.7, 28.6, 27.4, 25.2, 24.9. FAB-MS showed molecular ion peak m / z: 362 [M+H] + , molecular formula is C 20 H 27 FN2O3.

[0209] Synthesis of compound N64

[0210]

[0211] Using 2-fluoro-4-cyanobenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 51%. 1 H NMR (400MHz, CDCl3): δ7.46 (s, 1H, Ar-H), 7.44 (m, 1H, Ar-H), 7.33 (s, 1H, Ar-H), 5.82 (br s, 1H), 3.61 (br s, 2H), 2.35 (d, J=17.6Hz, 1H), 2.23 (m, 3H), 2.05 (m, 2H), 2.02 (s, 1H), 1.98 (s, 3H ), 1.86(m, 1H), 1.72(m, 1H), 1.63(m, 2H), 1.42(m, 1H), 1.05(s, 3H), 1.01(s, 3H). 13 C NMR (100 MHz, CDCl3): 13 C NMR (100 MHz, CDCl3): δ 198.4, 171, 165.3, 161.8, 159.6 (d, J = 6.9 Hz), 132.1, 128.0 (d, J = 8.1 Hz), 125.1, 119.1 (d, J = 2.7 Hz), 118.9, 60.3, 59.8, 57.8, 54.8, 42.5, 36.3, 30.8, 28.9, 27.8, 24.5, 14.1. FAB-MS showed molecular ion peak m / z: 342 [M+H] + , molecular formula is C 21 H 27 FN2O.

[0212] Synthesis of compound N65

[0213]

[0214] Using 3,4-difluorobenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ7.21 (s, 1H, Ar-H), 7.10 (m, 2H, Ar-H), 5.82 (br s, 1H), 3.54 (br s, 2H), 2.40 (m, 2H), 2.36 (d, J=16.0Hz 1H), 2.25(s, 3H), 2.02(s, J=16.5Hz, 1H), 1.98(s, 3H), 1.86(m, 1H), 1.72(m, 1H), 1.65(m, 1H), 1.42(m, 2H), 1.06(s, 3H), 1.02(s, 3H).13 C NMR (100 MHz, CDCl3): δ 199.4, 165.3, 151.5 (d, J = 11.0 Hz), 149.0 (d, J = 13.4 Hz), 125.1 (d, J = 10.0 Hz), 118.1 (d, J = 20.0 Hz), 117.8, 117.1 (d, J = 18.2 Hz), 117.0, 67.0, 54.7, 53.2, 51.2, 47.2, 41.3, 36.3, 28.8, 27.9, 26.6, 24.7. FAB-MS showed molecular ion peak m / z: 335 [M+H] + , molecular formula is C 20 H 27 F2NO.

[0215] Synthesis of compound N66

[0216]

[0217] Using 3,4-dichlorobenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400 MHz, CDCl3): 1 H NMR (400MHz, CDCl3): δ7.46 (s, 1H, Ar-H), 7.41 (d, 1H, J = 8.7Hz, Ar-H), 7.23 (m, 1H, Ar-H), 5.82 (br s, 1H), 3.50 (br s, 2H), 2.44 (m, 2H), 2.31 (d, J=17.3Hz, 1H), 2.30 (s, 3H), 2.02 (s, J=17.4Hz, 1H), 1.98 (s, 3H), 1.86 (m, 1H), 1.72 (m, 1H), 1.65 (m, 2H), 1.41 (m, 2H), 1.06 (s, 3H), 1.02 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.4, 165.4, 136.4, 132.4, 130.9, 130.5, 128.4, 125.1, 60.7, 57.7, 51.2, 47.2, 41.3, 36.3, 29.7, 28.8, 27.9, 27.3, 26.6, 24.7. FAB-MS showed molecular ion peak m / z: 368 [M+H] + , molecular formula is C 20 H 27 Cl2NO.

[0218] Synthesis of compound N67

[0219]

[0220] The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ8.20 (s, 1H, Ar-H), 8.18 (s, 1H, Ar-H), 7.53 (m, 1H, Ar-H), 7.27 (m, 1H, Ar-H), 5.83 (br s, 1H), 3.58 (br s, 2H), 2.37 (m, 3H), 2.22 (m, 3H), 2.05 (d, J=17.4Hz, 1H), 1.99 (s, 3H), 1.8 7(m, 1H), 1.74(m, 2H), 1.61(m, 1H), 1.41(m, 2H), 1.06(s, 3H), 1.01(s, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.4, 169.9, 165.3, 147.2, 129.4, 125.9, 123.5, 117.6, 61.7, 57.8, 51.2, 47.2, 37.5, 36.3, 29.7, 28.8, 27.9, 27.3, 26.5, 24.8. FAB-MS showed molecular ion peak m / z: 344 [M+H] + , molecular formula is C 20 H 28 N2O3

[0221] Synthesis of compound N68

[0222]

[0223] Using 4-nitrobenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ8.19 (m, 2H, Ar-H), 7.50 (m, 2H, Ar-H), 5.83 (br s, 1H), 3.60 (br s, 2H), 2.37 (m, 2H), 2.19 (m, 2H), 2.04 (d, J=17.0Hz, 1H), 1.99 (s, 3H), 1.8 8(m, 1H), 1.73(m, 2H), 1.60(m, 2H), 1.45(m, 2H), 1.06(s, 3H), 1.02(s, 3H). 13C NMR (100 MHz, CDCl3): δ 199.3, 165.3, 147.1, 129.3, 125.2, 120.6, 57.8, 51.0, 47.1, 42.2, 36.3, 34.3, 28.7, 27.8, 27.2, 27.0, 24.8. FAB-MS showed molecular ion peak m / z: 344 [M+H] + , molecular formula is C 20 H 28 N2O3.

[0224] Synthesis of compound N69

[0225]

[0226] Using 4-bromobenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 49%. 1 H NMR (400MHz, CDCl3): δ7.46 (s, 1H, Ar-H), 7.44 (s, 1H, Ar-H), 7.22 (s, 1H, Ar-H), 7.20 (s, 1H, Ar-H), 5.82 (br s, 1H), 3.48 (br s, 2H), 2.35 (m, 2H), 2.21 (s, 1H), 2.17 (s, 3H), 2.02 (d, J=17.2Hz, 1H), 1.97 (s, 3H ), 1.84(m, 1H), 1.71(m, 1H), 1.57(m, 2H), 1.41(m, 1H), 1.04(s, 3H), 1.00(s, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.4, 165.6, 163.0 (d, J = 243.7 Hz), 142.0 (d, J = 6.9 Hz), 129.6 (d, J = 8.1 Hz), 125.1, 124.3 (d, J = 2.7 Hz), 115.6 (d, J = 21.1 Hz), 113.8 (d, J = 21.1 Hz), 62.0, 57.7, 51.2, 47.2, 42.3, 36.3, 28.8, 27.9, 27.3, 27.2.24.7. FAB-MS showed molecular ion peak m / z: 378 [M+H] + , molecular formula is C 20 H 28 BrNO.

[0227] Synthesis of compound N70

[0228]

[0229] Using 2-bromo-4-methoxybenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ7.51 (s, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 6.86 (s, 1H, Ar-H), 5.82 (br s, 1H), 3.89 (s, 3H), 3.41 (br s, 2H), 2.41 (m, 2H), 2.37 (s, 1H), 2.23 (s, 3H), 2.06 (d, 1H), 2.00 (s, 3H), 1. 87(m, 1H), 1.72(m, 1H), 1.62(m, 2H), 1.41(m, 1H), 1.07(s, 3H), 1.03(s, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.4, 165.5, 155.3, 139.1, 129.4, 125.1, 111.8, 111.3, 60.1, 57.1, 56.3, 51.1, 47.1, 41.6, 36.3, 29.7, 28.7, 27.8, 27.0, 26.7, 24.8. FAB-MS showed molecular ion peak m / z: 408 [M+H] + , molecular formula is C 21 H 30 BrNO2.

[0230] Synthesis of compound N71

[0231]

[0232] The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1H NMR (400MHz, CDCl3): δ7.44 (s, 1H, Ar-H), 7.42 (s, 1H, Ar-H), 7.38 (s, 1H, Ar-H), 7.36 (d, J=8.0Hz, 2H, Ar-H), 6.82 (m, 2H, Ar-H), 6.79 (m, 1H, Ar-H), 5.81 (br s, 1H), 5.15 (s, 2H), 3.93 (s, 3H), 3.47 (s, 3H), 2.42 (s, 2H), 2.34 (d, J=16.8Hz, 1H), 2.03 (d, J=16.9 Hz, 1H), 1.97 (s, 3H), 1.86 (m, 1H), 1.76 (m, 2H), 1.72 (m, 2H), 1.37 (m, 2H), 1.04 (s, 3H), 1.01 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.4, 165.6, 150.0, 148.2, 142.0, 136.9, 128.8, 128.5, 127.9, 127.2, 125.3, 122.1, 113.5 (d, J = 21.1 Hz), 70.0, 61.3, 56.3, 50.8, 50.7, 47.0, 42.3, 36.3, 28.8, 27.9, 27.3, 27.2, 24.7. FAB-MS showed molecular ion peak m / z: 435 [M+H] + , molecular formula is C 28 H 37 NO3

[0233] Synthesis of compound N72

[0234]

[0235] Using 4-chlorobenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ7.31 (s, 1H, Ar-H), 7.29 (m, 2H, Ar-H), 7.26 (s, 1H, Ar-H), 5.82 (br s, 1H), 3.48 (br s, 2H), 2.38 (m, 2H), 2.03 (d, J = 18.4Hz, 1H), 2.23 (s, 3H), 2.08 (d, J = 17.2Hz, 1H), 1.98 (s, 3H), 1.85 (m, 1H), 1.71 (m, 1H), 1.63 (m, 2H), 1.41 (m, 1H), 1.04 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 199.3, 165.5, 130.5, 129.8, 128.5, 125.2, 60.3, 57.5, 51.1, 47.1, 41.8, 36.3, 29.7, 28.7, 27.8, 26.8, 24.8. FAB-MS showed molecular ion peak m / z: 334 [M+H] + , molecular formula is C 20 H 28 ClNO.

[0236] Synthesis of compound N73

[0237]

[0238] Using 3-fluoro-4-nitrobenzyl bromide as the raw material, the product was prepared according to the above method. The crude product was separated and purified by gel column chromatography (DCM: MeOH = 2: 1, V / V) to obtain a yellow oil with a yield of 50%. 1 H NMR (400MHz, CDCl3): δ7.96 (s, 1H, Ar-H), δ7.50 (s, 1H, Ar-H), δ7.49 (s, 1H, Ar-H), 5.82 (br s, 1H), 3.75 (br s, 2H), 2.55 (s, 2H), 2.38 (s, 1H), 2.34 (s, 3H), 2.06 (d, J=17.2Hz, 1H), 1.98 (s, 3H ), 1.87(m, 1H), 1.71(m, 1H), 1.68(m, 2H), 1.46(m, 1H), 1.06(s, 3H), 1.02(s, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.2, 165.2, 139.3, 134.6, 131.9, 130.5, 125.3, 117.9, 111.1, 57.8, 51.0, 47.1, 41.9, 36.3, 29.7, 28.7, 27.8, 27.2, 26.7, 24.8. FAB-MS showed molecular ion peak m / z: 344 [M+H] + , molecular formula is C 20 H 27 FN2O3.

[0239] Example 9.

[0240] Synthesis method of compounds N50-N61

[0241] Weigh 1 equivalent of compound N49, add appropriate amount of 1,4-dioxane: water (5:1) to dissolve, add 1.8 equivalents of substituted phenylboronic acid, then add 5 equivalents of anhydrous potassium carbonate and 0.1 equivalent of tetrakis(triphenylphosphine)palladium, stir under reflux, monitor by TLC until the reaction is complete. Dry the solvent, add DCM and water and extract, combine the organic layers and dry with anhydrous magnesium sulfate, filter and concentrate to obtain a crude product.

[0242] Synthesis of compound N50

[0243]

[0244] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 74.6%. 1 H NMR (400MHz, CDCl3): δ7.26 (m, 3H, Ar-H), 7.19 (m, 2H, Ar-H), 7.11 (m, 2H, Ar-H), 5.83 (s, 1H, 4-H), 3.51 (s, 2H, Ar-CH2), 2.40 (m, 3H, 9-H and 2-H), 2.23 (s, 3H, 10-H), 2.20 (s, 3H, CH3), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.99 (s, 3H, 13-H), 1.88 (t, J=5.2 Hz, 1H, 6-H), 1.76 (m, 1H, 7-H), 1.62 (m, 2H, 8-H), 1.45 (m, 1H, 7-H), 1.07 (s, 3H, 11-H), 1.02 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 165.6(5-C), 159.5(d, J=244.3Hz, Ar-C), 14 1.0 (d, J=6.5Hz, Ar-C), 136.6 (Ar-C), 135.6 (Ar-C), 131.2 (d, J=4.2Hz, Ar-C), 1 30.1(Ar-C), 129.9(Ar-C), 127.9(Ar-C), 127.7(d, J=16.9Hz, Ar-C), 125.6(Ar- C), 125.0 (4-C), 124.2 (d, J=2.9Hz, Ar-C), 115.8 (d, J=22.4Hz, Ar-C), 61.8 (Ar- CH2), 57.7(9-C), 51.1(6-C), 47.1(2-C), 42.4(10-C), 36.3(1-C), 28.8(12-C), 27 .9(7-C), 27.3(8-C), 27.2(11-C), 24.8(13-C), 19.9(d, J=2.9Hz, CH3).HR-ESIMS m / z 408.2703[M+H] + , calculate for C 27 H 35 FNO, 408.2703.

[0245] Synthesis of compound N51

[0246]

[0247] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 79.3%. 1 H NMR (400MHz, CDCl3): δ7.48 (m, 1H, Ar-H), 7.31 (m, 3H, Ar-H), 7.25 (m, 1H, Ar-H), 7.14 (m, 2H, Ar -H), 5.83 (s, 1H, 4-H), 3.52 (s, 2H, Ar-CH2), 2.40 (t, J=6.8Hz, 1H, 9-H), 2.39 (d, J=17.2Hz, 1H, 2 -H), 2.24 (s, 3H, 10-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.99 (s, 3H, 13-H), 1.88 (t, J=5.2Hz, 1H, 6- H), 1.75 (m, 1H, 7-H), 1.61 (m, 2H, 8-H), 1.44 (m, 1H, 7-H), 1.07 (s, 3H, 11-H), 1.02 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.5 (3-C), 165.7 (5-C), 159.6 (d, J=245.6Hz, Ar-C), 14 1.8 (d, J=6.4Hz, Ar-C), 134.8 (Ar-C), 133.6 (Ar-C), 131.7 (Ar-C), 131.2 (d, J=3 .5Hz, Ar-C), 129.6 (Ar-C), 129.2 (Ar-C), 126.6 (Ar-C), 125.5 (d, J=16.0Hz, Ar- C), 125.0 (4-C), 124.1 (d, J=3.1Hz, Ar-C), 115.7 (d, J=22.6Hz, Ar-C), 61.8 (Ar- C H2), 57.8(9-C), 51.1(6-C), 47.1(2-C), 42.3(10-C), 36.3(1-C), 28.8(12-C), 27.9(7-C).27.3(8-C), 27.1(11-C), 24.8(13-C).HR-ESIMS m / z 428.2154[M+H] + , calculate for C 26 H 32 ClFNO, 428.2156.

[0248] Synthesis of compound N52

[0249]

[0250] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 76.2%. 1 H NMR (400MHz, CDCl3): δ7.64 (m, 1H, Ar-H), 7.50 (d, J=8.4Hz, 1H, Ar-H), 7.36 (m, 2H , Ar-H), 7.15 (m, 2H, Ar-H), 5.83 (s, 1H, 4-H), 3.50 (s, 2H, Ar-CH2), 2.39 (m, 3H, 9-H and 2-H), 2.21 (s, 3H, 10-H), 2.02 (d, J=17.2Hz, 1H, 2-H), 1.99 (s, 3H, 13-H), 1.88 (t, J=5.2Hz, 1H, 6 -H), 1.75(m, 1H, 7-H), 1.61(m, 2H, 8-H), 1.44(m, 1H, 7-H), 1.07(s, 3H, 11-H), 1.02(s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.4(3-C), 165.6(5-C), 159.5(d, J=247.3Hz, Ar-C), 1 42.1 (d, J=6.2Hz, Ar-C), 135.6 (Ar-C), 132.5 (Ar-C), 131.7 (Ar-C), 130.7 (d, J= 3.4Hz, Ar-C), 130.3 (Ar-C), 130.1 (Ar-C), 130.0 (Ar-C), 128.2 (d, J=3.1Hz, Ar- C), 125.1 (4-C), 124.8 (d, J=3.0Hz, Ar-C), 116.4 (d, J=22.7Hz, Ar-C), 61.6 (Ar- C H2), 57.7(9-C), 51.1(6-C), 47.1(2-C), 42.2(10-C), 36.3(1-C), 28.8(12-C), 27.9(7-C), 27.2(8-C and 11-C), 24.8(13-C).HR-ESIMS m / z 462.1764[M+H] + , calculate for C 26 H 31 Cl2FNO, 462.1767.

[0251] Synthesis of compound N53

[0252]

[0253] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 78.1%. 1 H NMR (400MHz, CDCl3): δ7.18 (m, 3H, Ar-H), 7.09 (m, 3H, Ar-H), 5.83 (s, 1H, 4-H), 3.52 (s, 2H, Ar-CH2), 2.40 (m, 3H, 9-H and 2-H), 2.34 (s, 3H, CH3), 2.24 (s, 3H, 10-H), 2.09 (s, 3H, CH3), 2.04 (d, J=17.2Hz, 1H, 2-H), 1.99 (s, 3H, 13-H), 1.87 (t, J=5.4Hz, 1H, 6-H), 1.75 (m, 1H, 7-H), 1.62 (m, 2H, 8-H), 1.44 (m, 1H, 7-H), 1.07 (s, 3H, 11-H), 1.02 (s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.5(3-C), 165.7(5-C), 159.6(d, J=244.2Hz, Ar-C), 141.4(d, J=6.2Hz, Ar-C), 136.9(Ar-C), 135.7(Ar-C), 135.2(Ar-C), 133.1135 .2(Ar-C), 131.3(d, J=4.1Hz, Ar-C), 129.5(Ar-C), 127.9(Ar-C), 125.3(Ar-C ), 125.0 (4-C), 124.2 (d, J = 2.8Hz, Ar-C), 115.6 (d, J = 22.7Hz, Ar-C), 61.7 (Ar- C H2), 57.7(9-C), 51.1(6-C), 47.1(2-C), 42.3(10-C), 36.3(1-C), 28.8(12-C), 27.9(7-C), 27.2(8-C and 11-C), 24.8(13-C), 20.6(CH3), 16.7(CH3).HR-ESIMS m / z 422.2857[M+H] + , calculate for C 28 H 37 FNO, 422.2859.

[0254] Synthesis of compound N54

[0255]

[0256] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 79.4%. 1 H NMR (400MHz, CDCl3): δ7.32 (m, 1H, Ar-H), 7.16 (m, 5H, Ar-H), 5.83 (s, 1H, 4-H), 3.52 (s, 2H, Ar-CH2), 2.39 (m, 3H, 9-H and 2-H), 2.22 (s, 3H, 10-H), 2.04 (d, J=17.2Hz, 1H, 2-H), 1.99 (s, 3H, 13-H), 1.88 (t, J=5.4Hz, 1H, 6 -H), 1.74(m, 1H, 7-H), 1.60(m, 2H, 8-H), 1.45(m, 1H, 7-H), 1.07(s, 3H, 11-H), 1.02(s, 3H, 12-H). 13C NMR (100MHz, CDCl3): δ199.4 (3-C), 165.7 (5-C), 159.7 (d, J=247.8Hz, Ar-C), 150.9 (dd, J1=246.5Hz, J2=13.1Hz, Ar-C) , 148.0 (dd, J1=248.7Hz, J2=13.0Hz, Ar-C), 142.6 (d, J=7.2Hz, Ar-C), 131.1 (dd, J1=1.7Hz, J2=3.1Hz, Ar-C), 126.2 (dd, J1=1.7Hz, J2=3.3Hz, Ar-C), 125.7(d, J=12.2Hz, Ar-C), 125.0(4-C), 124.4(d, J=3.0Hz, Ar-C), 123.9(dd, J1=4.8Hz, J2 =7.0Hz, Ar-C), 120.8 (dd, J1 = 2.6Hz, J2 = 15.7Hz, Ar-C), 116.7 (d, J = 17.1Hz, Ar-C), 116.0 (d, J = 22.4Hz, Ar-C), 61.7 (Ar- C H2), 57.8(9-C), 51.1(6-C), 47.1(2-C), 42.3(10-C), 36.3(1-C), 28.8(12-C), 27.9(7-C), 27.3(8-C), 27.2(11-C), 24.7(13-C).HR-ESIMS m / z 430.2356[M+H] + , calculate for C 26 H 31 F3NO,430.2358.

[0257] Synthesis of compound N55

[0258]

[0259] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 81.7%. 11H NMR (400 MHz, CDCl3): δ 7.31 (m, 1H, Ar-H), 7.14 (m, 5H, Ar-H), 5.82 (s, 1H, 4-H), 3.51 (s, 2H, Ar-CH2), 2.39 (m, 3H, 9-H and 2-H), 2.33 (s, 3H, CH3), 2.23 (s, 3H, 10-H), 2.03 (d, J = 17.2 Hz, 1H, 2-H), 1.98 (s, 3H, 13-H), 1.87 (t, J = 5.4 Hz, 1H, 6-H), 1.75 (m, 1H, 7-H), 1.61 (m, 2H, 8-H), 1.44 (m, 1H, 7-H), 1.06 (s, 3H, 11-H), 1.01 (s, 3H, 12-H). 13 13C NMR (100 MHz, CDCl3): δ 199.4 (3-C), 165.7 (5-C), 159.8 (d, J = 246.9 Hz, Ar-C), 158.3 (d, J = 245.7 Hz, Ar-C), 141.6 (d, J = 7.1 Hz, Ar-C), 131.3 (d, J = 2.0 Hz, Ar-C), 131.1 (d, J = 5.1 Hz, Ar-C), 128.9 (d, J = 1.3 Hz, Ar-C), 125.1 (d, J = 18.0 Hz, Ar-C), 125.0 (4-C), 124.2 (d, J = 3.0 Hz, Ar-C), 123.5 (d, J = 4.2 Hz, Ar-C), 123.1 (d, J = 16.3 Hz, Ar-C), 122.3 (d, J = 15.8 Hz, Ar-C), 115.8 (d, J = 22.5 Hz, Ar-C), 61.8 (Ar- C CH2), 57.7 (9-C), 51.1 (6-C), 47.1 (2-C), 42.3 (10-C), 36.3 (1-C), 28.7 (12-C), 27.8 (7-C), 27.2 (8-C), 27.1 (11-C), 24.7 (13-C), 14.7 (d, J = 4.4 Hz, CH3). HR-ESIMS m / z 426.2608 [M + H] + , calcd for C 27 H 34 F2NO, 426.2608.

[0260] Synthesis of Compound N56

[0261]

[0262] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 83.6%. 1 H NMR (400MHz, CDCl3): δ7.35 (m, 3H, Ar-H), 7.28 (m, 2H, Ar-H), 7.10 (m, 2H, Ar-H), 7.01 ( m, 2H, Ar-H), 5.82 (s, 1H, 4-H), 3.80 (s, 3H, OCH3), 3.50 (s, 2H, Ar-CH2), 2.39 (m, 3H, 9-H and 2-H), 2.23 (s, 3H, 10-H), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.99 (s, 3H, 13-H), 1.87 (t, J=5.2Hz, 1H, 6 -H), 1.73(m, 1H, 7-H), 1.62(m, 2H, 8-H), 1.44(m, 1H, 7-H), 1.06(s, 3H, 11-H), 1.02(s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 165.7(5-C), 159.9(d, J=246.1Hz, Ar-C), 15 6.9 (Ar-C), 140.7 (d, J=7.0Hz, Ar-C), 131.5 (d, J=3.9Hz, Ar-C), 131.2 (Ar-C), 1 29.2(Ar-C), 125.0(4-C), 123.8(Ar-C), 124.7(d, J=16.1Hz, Ar-C), 124.0(d, J= 3.0Hz, Ar-C), 120.5 (Ar-C), 115.6 (d, J=22.7Hz, Ar-C), 111.0 (Ar-C), 61.8 (Ar- C H2), 57.6(9-C), 55.6(OCH3), 51.1(6-C), 47.1(2-C), 42.3(10-C), 36.3(1- C), 28.7(12-C), 27.8(7-C), 27.2(8-C), 27.1(11-C), 24.7(13-C).HR-ESIMS m / z 424.2651[M+H] + , calculate for C 27 H 34 FNO2,424.2652.

[0263] Synthesis of compound N57

[0264]

[0265] The crude product was separated and purified by silica gel column chromatography (PE: EA = 4: 1-2: 1, V / V) to obtain a yellow oil with a yield of 76.5%. 1 H NMR (400MHz, CDCl3): δ7.32 (m, 1H, Ar-H), 7.13 (m, 3H, Ar-H), 6.97 (m, 2H, Ar-H), 5.82 (s, 1H, 4-H), 3.92 (s, 3H, OCH3), 3.51 (s, 2H, Ar-CH2), 2.39 (m, 3H, 9-H and 2-H), 2.23 (s, 3H, 10-H), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.98 (s, 3H, 13-H), 1.87 (t, J=5.2Hz, 1H, 6 -H), 1.75(m, 1H, 7-H), 1.61(m, 2H, 8-H), 1.44(m, 1H, 7-H), 1.06(s, 3H, 11-H), 1.01(s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 165.7(5-C), 159.9(d, J=246.1Hz, Ar-C), 15 6.9 (Ar-C), 140.7 (d, J=7.0Hz, Ar-C), 131.5 (d, J=3.9Hz, Ar-C), 131.2 (Ar-C), 1 29.2(Ar-C), 125.0(4-C), 123.8(Ar-C), 124.7(d, J=16.1Hz, Ar-C), 124.0(d, J= 3.0Hz, Ar-C), 120.5 (Ar-C), 115.6 (d, J=22.7Hz, Ar-C), 111.0 (Ar-C), 61.7 (Ar- C H2), 57.7(9-C), 56.3(OCH3), 51.1(6-C), 47.1(2-C), 42.3(10-C), 36.3(1- C), 28.7(12-C), 27.8(7-C), 27.2(8-C), 27.1(11-C), 24.7(13-C).HR-ESIMS m / z442.2556[M+H] + , calculate for C 27 H 34 F2NO2, 442.2558.

[0266] Synthesis of compound N58

[0267]

[0268] The crude product was separated and purified by silica gel column chromatography (PE: EA = 3: 1-1: 1, V / V) to obtain a yellow oil with a yield of 78.2%. 1 H NMR (400MHz, CDCl3): δ7.26 (m, 2H, Ar-H), 7.14 (m, 2H, Ar-H), 6.96 (m, 2H, Ar-H), 5.82 (s, 1H, 4-H), 3.94 (s, 3H, OCH3), 3.51 (s, 2H, Ar-CH2), 2.40 (m, 3H, 9-H and 2-H), 2.23 (s, 3H, 10-H), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.99 (d, J=1.0Hz, 3H, 13-H), 1.87 (t, J=5.2Hz, 1H, 6-H), 1.75 (m, 1H, 7-H), 1.61 (m, 2H, 8-H), 1.45 (m, 1H, 7-H), 1.06 (s, 3H, 11-H), 1.01 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 165.7(5-C), 159.5(d, J=246.2Hz, Ar-C), 15 5.3 (Ar-C), 141.9 (d, J=7.1Hz, Ar-C), 136.4 (Ar-C), 131.1 (d, J=3.5Hz, Ar-C), 1 26.9 (Ar-C), 125.5 (d, J=16.1Hz, Ar-C), 125.0 (4-C), 124.0 (d, J=3.0Hz, Ar-C), 123.4(Ar-C), 122.2(Ar-C), 115.7(d, J=22.1Hz, Ar-C), 111.3(Ar-C), 61.8(Ar- C H2), 57.7(9-C), 56.3(OCH3), 51.1(6-C), 47.1(2-C), 42.4(10-C), 36.3(1- C), 28.8(12-C), 27.8(7-C), 27.3(8-C), 27.2(11-C), 24.7(13-C).HR-ESIMS m / z458.2265[M+H] + , calculate for C 27 H 34 ClFNO2, 458.2262.

[0269] Synthesis of compound N59

[0270]

[0271] The crude product was separated and purified by silica gel column chromatography (PE: EA = 3: 1-1: 1, V / V) to obtain a yellow oil with a yield of 79.5%. 1 H NMR (400MHz, CDCl3): δ7.78 (d, J=7.2Hz, 1H, Ar-H), 7.66 (m, 1H, Ar-H), 7.49 (m, 2H, Ar-H), 7 .37 (m, 1H, Ar-H), 7.21 (m, 2H, Ar-H), 5.83 (s, 1H, 4-H), 3.53 (s, 2H, Ar-CH2), 2.41 (m, 3H, 9-H and 2-H), 2.23 (s, 3H, 10-H), 2.04 (d, J=17.2Hz, 1H, 2-H), 2.00 (s, 3H, 13-H), 1.88 (t, J=5.2Hz, 1H, 6 -H), 1.76(m, 1H, 7-H), 1.62(m, 2H, 8-H), 1.46(m, 1H, 7-H), 1.07(s, 3H, 11-H), 1.02(s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ 199.5 (3-C), 165.8 (5-C), 159.4 (d, J = 247.1Hz, Ar-C), 143.2 (d, J = 6.8Hz, Ar-C), 139.5 (Ar-C), 133.3 (Ar-C), 132.6 (Ar-C), 131.0 (Ar-C), 128.1 (Ar-C), 125.1 (4-C), 124.6 (d, J=3.2Hz, Ar-C), 124.3 (d, J=15 .1Hz, Ar-C), 118.2 (CN), 116.2 (d, J=22.2Hz, Ar-C), 112.8 (Ar-C), 61.7 (Ar- C H2), 57.8(9-C), 51.1(6-C), 47.1(2-C), 42.3(10-C), 36.3(1-C), 28.8(12-C), 27.8(7-C), 27.3(8-C), 27.2(11-C), 24.8(13-C).HR-ESIMS m / z 419.2497[M+H] + , calculate for C 27 H 32 FN2O, 419.2499.

[0272] Synthesis of compound N60

[0273]

[0274] The crude product was separated and purified by silica gel column chromatography (PE: EA = 3: 1-1: 1, V / V) to obtain a yellow oil with a yield of 76.3%. 1 H NMR (400MHz, CDCl3): δ7.66 (m, 1H, Ar-H), 7.49 (m, 2H, Ar-H), 7.33 (m, 1H, Ar-H), 7.20 (m, 2H, Ar-H), 5.83 (s, 1H, 4-H), 3.53 (s, 2H, Ar-CH2), 2.40 (m, 3H, 9-H and 2-H), 2.23 (s, 3H, 10-H), 2.04 (d, J=17.2Hz, 1H, 2-H), 2.00 (d, J=1.0Hz, 3H, 13-H), 1.88 (t, J=5.2Hz, 1H, 6-H), 1.76 (m, 1H, 7-H), 1.60 (m, 2H, 8-H), 1.47 (m, 1H, 7-H), 1.07 (s, 3H, 11-H), 1.02 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.4(3-C), 165.7(5-C), 160.3(d, J=259.4Hz, Ar-C), 159.6(d, J=248.3Hz , Ar-C), 143.4 (d, J=6.6Hz, Ar-C), 136.6 (d, J=1.8Hz, Ar-C), 136.5 (d, J=1.7Hz, Ar-C), 133.0 (Ar-C ), 130.9 (d, J=4.5Hz, Ar-C), 125.1 (4-C), 124.8 (d, J=4.4Hz, Ar-C), 124.6 (d, J=3.1Hz, Ar-C), 119 .7 (d, J=15.4Hz, Ar-C), 116.1 (d, J=22.0Hz, Ar-C), 114.0 (CN), 102.1 (d, J=6.5Hz, Ar-C), 61.7 (Ar- C H2), 57.8(9-C), 51.1(6-C), 47.1(2-C), 42.3(10-C), 36.3(1-C), 28.8(12-C), 27.9(7-C), 27.3(8-C and 11-C), 24.8(13-C).HR-ESIMS m / z 437.2404[M+H] + , calculate for C 27 H 31 F2N2O, 437.2404.

[0275] Synthesis of compound N61

[0276]

[0277] The crude product was separated and purified by silica gel column chromatography (DCM: MeOH = 50: 1-30: 1, V / V) to obtain a yellow oil with a yield of 73.4%. 1 H NMR (400MHz, CDCl3): δ8.19 (s, 1H, Ar-H), 7.68 (s, 1H, Ar-H), 7.58 (m, 1H, Ar-H), 7.35 (m, 2H, Ar- H), 7.27 (m, 1H, Ar-H), 7.11 (m, 1H, Ar-H), 5.82 (s, 1H, 4-H), 3.49 (s, 2H, Ar-CH2), 2.39 (m, 3H, 9-H and 2-H), 2.22 (s, 3H, 10-H), 2.17 (s, 3H, CH3), 2.03 (d, J=17.2Hz, 1H, 2-H), 1.98 (s, 3H, 13-H), 1.87 (t, J=5.2 Hz, 1H, 6-H), 1.73 (m, 1H, 7-H), 1.58 (m, 2H, 8-H), 1.42 (m, 1H, 7-H), 1.05 (s, 3H, 11-H)-1.01 (s, 3H, 12-H). 13 C NMR (100MHz, CDCl3): δ199.7(3-C), 168.8(CO), 166.3(5-C), 159.6(d, J=246.5Hz, Ar-C), 141.0 (d, J=7.3Hz, Ar-C), 138.3 (Ar-C), 136.3 (Ar-C), 130.4 (d, J=3.5Hz, A r-C), 128.9 (Ar-C), 127.2 (Ar-C), 127.1 (Ar-C), 124.9 (4-C), 124.7 (d, J=2.5Hz, A r-C), 120.4 (d, J=2.6Hz, Ar-C), 119.2 (Ar-C), 116.3 (d, J=22.8Hz, Ar-C), 61.7 (Ar- C H2), 57.6(9-C), 51.1(6-C), 47.1(2-C), 42.4(10-C), 36.3(1-C), 28.7(12- C), 27.9(7-C), 27.3(8-C), 27.2(11-C), 24.8(13-C), 24.5(CH3).HR-ESIMS m / z 451.2764[M+H] + , calculate for C 28 H 36 FN2O2, 451.2761.

[0278] Example 10.

[0279] Evaluation of the anti-breast cancer metastasis activity of each derivative

[0280] The specific experimental methods and steps are as described above, and the experimental results are shown in Table 2:

[0281] Table 2 The half inhibitory concentration (IC50) of each derivative in inhibiting the chemotaxis and migration of breast cancer cells

[0282]

[0283] The inventor believes that researchers have been looking for compounds with anti-tumor metastasis activity, and each type of compound structure with an acceptable level of activity is of great significance for the preparation of anti-tumor metastasis drugs. The present invention is based on the lead compound ION-31a discovered by the research group in the early stage, and a large number of derivatives with different substituents and different substituted structural fragments have been designed and synthesized. The synthesized 73 derivatives are all derivatives synthesized for the first time by the research group. Further through cytotoxicity and anti-breast cancer metastasis activity screening experiments, 26 active derivatives were selected, and 7 strong active derivatives were further selected, whose anti-breast cancer metastasis activity was equivalent to or close to that of the positive control LY294002.

[0284] It is difficult for a person skilled in the art to obtain the compounds claimed in the present invention based on the structures of common ionone alkaloids disclosed in the prior art, after such a large number of structural modifications, and then to select substituents and limit them to a smaller range. That is, the structures of the compounds of the present invention are not obvious to a person skilled in the art.

[0285] Furthermore, since the present invention is first screened for cytotoxicity and cytotoxic derivatives are eliminated, the derivatives tested for activity all show anti-breast cancer metastasis effects at non-cytotoxic doses, and the activities of 7 representative derivatives are comparable to the positive control LY294002 (among the existing anti-tumor metastasis drugs on the market, there are no small molecule synthetic drugs for anti-tumor metastasis on the market). This non-cytotoxic anti-breast cancer metastasis active compound can meet the long-term administration requirements for clinical prevention and treatment of cancer metastasis, which shows that the present invention has made significant progress. The compound of the present invention has unexpected technical effects, and relative to the anti-tumor metastasis active compound in the general sense, the present invention has more important application value.

Claims

1. An ionone alkaloid derivative or a pharmaceutically acceptable salt thereof, the structure of which is shown in general formula I: 。 2. The ionone alkaloid derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from compounds N2, N7, N8, N10, N18, N26, and N43.

3. The ionone alkaloid derivative or a pharmaceutically acceptable salt thereof according to claim 2, which is selected from compounds N8, N18, and N43.

4. Use of the ionone alkaloid derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of an anti-breast cancer metastasis drug.

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