Pterostilbene chalcone compounds, their preparation methods and medical uses

Abstract

The present invention discloses a pterostilbene chalcone compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. The compound has a strong inhibitory effect on LPS-induced NO production in RAW264.7 cells, significantly superior to indomethacin, and can be developed into a new anti-inflammatory drug. The preparation method of the compound of the present invention is characterized by readily available raw materials, simple operation, and high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a pterostilbene chalcone compound, a preparation method thereof and medical use thereof. Background Art

[0002] Pterostibene (E-3,5-dimethoxy-4-hydroxystilbene) is a trans-stilbene compound obtained from natural plants such as blueberries, Indian jeera trees, and the sword-leaved dragon tree native to Guangxi, China. Modern research indicates that it possesses multiple effects, including anticancer, antioxidant, hypoglycemic, COX-1 and COX-2 inhibition, and antifungal properties. It is also a dimethylated derivative of resveratrol and is currently a hot topic of research.

[0003] Pterostilbene has strong anti-inflammatory activity. Studies have shown that it can downregulate the gene or protein levels of iNOS, COX-2, and PGE2 in vitro and in vivo. It also significantly downregulates TLR4 and NF-κB p65 expression in the lung tissue of mice with pulmonary fibrosis, inhibits iNOS expression, and reduces the secretion of inflammatory factors such as IL-1β and TNF-α. Paeonol is the primary active ingredient in the Ranunculaceae plant Paeonia suffruticosa and the Asclepiadaceae plant Cynanchum indica, exhibiting multiple pharmacological effects, including anti-inflammatory and anti-tumor effects. Modern research has found that paeonol can inhibit the production of inflammatory factors TNF-α, IL-1β and IL-6, as well as the excessive production of NO and PGE2 in a concentration-dependent manner to exert anti-inflammatory effects; chalcones refer to compounds containing a 1,3-diphenylpropenone structure in the molecule. As natural products with a wide range of pharmacological activities, there are many natural products with anti-inflammatory activity, such as: isoliquiritigenin can inhibit the phosphorylation of NF-κB, IKK, ERK and p38, thereby downregulating iNOS, COX-2, TNF-α and IL-6, and can also exert anti-inflammatory activity by reducing the activation of NF-κB through the IKK and MAP kinase signaling pathways; cardamom can improve colitis in mice by activating the AhR / Nrf2 / NQO1 pathway and inhibiting the activation of the NLRP3 inflammasome, downregulating the levels of L-1β, TNF-α, IL-6, NLRP3, caspase-1, ASC, and IL-1β in the colon of colitis mice.

[0004] However, the clinical applications of pterostilbene and paeonol are limited by their susceptibility to oxidation, low bioavailability, and poor water solubility. Furthermore, chalcone compounds, due to their weak activity, have also struggled to achieve significant results in anti-inflammatory settings. Therefore, combining these two compounds through pharmaceutical chemical structural modification to design and synthesize novel structural compounds with enhanced anti-inflammatory activity, improved physicochemical properties, and enhanced applicability is of great significance in providing material support for the development of anti-inflammatory drugs. Summary of the Invention

[0005] In view of the shortcomings of the existing technology, the present invention provides a pterostilbene chalcone compound, its preparation method, and medical use. The present invention uses pterostilbene as a lead compound and combines it with paeonol to design and synthesize a series of pterostilbene chalcone compounds with novel structures that have outstanding anti-inflammatory effects, good compound structural stability, and strong applicability. These compounds have very important clinical application prospects and practical value.

[0006] The first aspect of the present invention provides a pterostilbene chalcone compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

[0007]

[0008] Wherein, n is an integer of 2 to 6, and R is a nitrogen-containing group.

[0009] According to a specific embodiment of the present invention, the nitrogen-containing group is selected from a substituted or unsubstituted nitrogen-containing five-membered heterocyclic group, a nitrogen-containing six-membered heterocyclic group, and a C6-C10 aromatic amine group, and is substituted with one of C1-C6 alkyl substitution, C1-C6 alkoxy substitution, and hydroxy substitution; preferably, the nitrogen-containing group is substituted with one of C1-C3 alkyl substitution, C1-C3 alkoxy substitution, and hydroxy substitution.

[0010] According to a specific embodiment of the present invention, the nitrogen-containing group is selected from one of morpholinyl, hexahydropyridine, pyrrolidinyl, 1-methylpiperazinyl, 1-ethylpiperazinyl, 1-hydroxyethylpiperazinyl, 4-piperidinol and N-methylbenzylamino.

[0011] According to a specific embodiment of the present invention, the pterostilbene chalcone compound is selected from one of the following compounds:

[0012]

[0013] The second aspect of the present invention provides a method for preparing the aforementioned pterostilbene chalcone compound or a pharmaceutically acceptable salt thereof, comprising:

[0014] S1. In the presence of acidic chloride, pterostilbene is reacted with a formylating agent to obtain intermediate A. The reaction formula is as follows:

[0015]

[0016] S2. In the presence of an alkaline reagent, reacting intermediate A with paeonol in a solvent to obtain intermediate B. The reaction formula is as follows:

[0017]

[0018] S3. In the presence of an alkaline reagent, react intermediate B with a dihalogenated alkane in a solvent to obtain intermediate C. The reaction formula is as follows:

[0019]

[0020] Wherein, X is a halogen, and n is an integer from 2 to 6;

[0021] S4. In the presence of an alkaline reagent, react the intermediate C with a nitrogen-containing compound in a solvent to obtain a pterostilbene chalcone compound represented by the general formula (I). The reaction formula is as follows:

[0022]

[0023] Wherein, n is an integer of 2 to 6, and R is a nitrogen-containing group.

[0024] According to a specific embodiment of the present invention, in step S1, the mass volume ratio of pterostilbene to the formylating agent is 10 g:10-30 mL; preferably, the formylating agent is N,N-dimethylformamide; preferably, the reaction temperature is 35-45° C., and the reaction time is 5-7 h.

[0025] According to a specific embodiment of the present invention, in step S2, the molar ratio of intermediate A to paeonol is 1:1-3; preferably, the alkaline reagent includes pyrrolidine, and the solvent includes anhydrous ethanol; preferably, the reaction temperature is 35-45°C, and the reaction time is 30-40h.

[0026] According to a specific embodiment of the present invention, in step S3, the molar ratio of intermediate B to dihaloalkane is 1:4-6; preferably, the alkaline reagent includes potassium carbonate, and the solvent includes N,N-dimethylformamide; preferably, the reaction temperature is room temperature, and the reaction time is 7-9 hours; and / or, in step S4, the molar ratio of intermediate C to nitrogen-containing compound is 1:2-4; preferably, the alkaline reagent includes potassium carbonate, and the solvent includes anhydrous acetonitrile; preferably, the reaction temperature is 45-55°C, and the reaction time is 5-7 hours.

[0027] The third aspect of the present invention provides a pharmaceutical composition, which is composed of a therapeutically effective amount of the aforementioned pterostilbene chalcone compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0028] A fourth aspect of the present invention provides use of the aforementioned pterostilbene chalcone compounds or pharmaceutically acceptable salts thereof in the preparation of anti-inflammatory drugs.

[0029] Beneficial effects of the present invention:

[0030] This invention designs and synthesizes a series of pterostilbene chalcone compounds with novel structures. These compounds exhibit excellent anti-inflammatory effects by inhibiting the activity and expression of key inflammatory mediators, including cyclooxygenase, inducible nitric oxide synthase, and nuclear factor-κB. Experiments have shown that these compounds exhibit a strong inhibitory effect on LPS-induced NO production in RAW264.7 cells, significantly superior to indomethacin, and are promising candidates for development as new anti-inflammatory drugs. The preparation method of these compounds is characterized by readily available raw materials, simple operation, and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The cytotoxicity results of the compounds were detected by MTT assay;

[0032] Figure 2 The results of Griess method detection of the inhibitory effect of compounds on LPS-induced NO;

[0033] Figure 3 Western blot assay was used to detect the inhibitory effects of the compounds on iNOS and COX-2 protein expressions;

[0034] Figure 4 Western blot experiments were used to detect the effects of compounds on the NF-kB signaling pathway;

[0035] Figure 5 Western blot experiments were used to detect the effects of compounds on the MAPK inflammatory signaling pathway. DETAILED DESCRIPTION

[0036] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0037] Example 1

[0038] (E)-3-(2,4-dimethoxy-6-((E)-4-(2-morpholinoethoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-1)

[0039]

[0040] 1) Synthesis of intermediate A:

[0041] Pterostilbene (10.0 g, 39.0 mmol) and DMF (20 mL) were added to a 250 mL round-bottom flask and stirred to dissolve. The temperature was then cooled to 0-5°C in an ice bath. Phosphorus oxychloride (5.3 mL, 58.5 mmol) was slowly added dropwise using a constant pressure dropping funnel. After completion of the addition, the mixture was quickly transferred to 40°C and allowed to react for 6 h. TLC monitoring (PE:EA = 2:1) was performed. After completion of the reaction, the reaction mixture was slowly added to 1000 mL of ice water with stirring. 40% sodium hydroxide solution was added dropwise to adjust the pH to 5-6. A large amount of yellow solid precipitated, which was filtered and dried to obtain 9.8 g of crude product. This crude product was transferred to a 250 mL round-bottom flask, ethyl acetate (100 mL) was added, and the mixture was heated at reflux for 2 h. After cooling, the mixture was filtered and dried to obtain Intermediate A (7.9 g, 71%) as a pale yellow solid. 1 H NMR (600MHz, DMSO-d6), δ: 10.41 (s, 1H), 7.90 (d, J = 16.2Hz, 1H), 7.39 (d, J = 8.2Hz, 2H), 7.15 (d, J = 16.2 Hz,1H),6.89(d,J=2.2Hz,1H),6.80(d,J=8.2Hz,2H),6.61(d,J=2.2Hz,1H),3.92(s,3H),3.90(s,3H).

[0042] 2) Synthesis of intermediate B:

[0043] In a 250mL round-bottom flask, 5.0g (17.6mmol) of intermediate A, 3.5g (21.1mmol) of paeonol, and 100mL of anhydrous ethanol were added. After thorough stirring, 1.7mL (21.1mmol) of pyrrolidine was added dropwise. The temperature was raised to 40°C and the reaction was allowed to proceed for 36h. TLC monitoring (PE:EA=2:1) ​​was performed. As the reaction proceeded, a large amount of yellow solid appeared in the reaction solution. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with a small amount of anhydrous ethanol solution and dried to obtain 7.2g of crude product. This crude product was recrystallized using anhydrous ethanol and ethyl acetate in sequence to obtain a light red crystalline compound intermediate B (5.8g, 76%). 1 H NMR (600MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.24 (d, J = 15.5Hz, 1H), 7.67 (d, J = 9.0Hz, 1H), 7.60 (d, J = 15.5Hz, 1H), 7.49-7.46 (m, 2H), 7.33 (d,J=16.1Hz,1H),6.96–6.90(m,3H),6.71(d,J=2.3Hz,1H),6.44(m,2H),6.31(dd,J=9.0,2.3Hz,1H),3.92(s,3H),3.90(s,3H),3.87(s,3H).

[0044] 3) Synthesis of intermediate C1:

[0045] To a 100 mL round-bottom flask, add Intermediate B (2.0 g, 4.6 mmol), potassium carbonate (1.28 g, 9.2 mmol), and DMF (10 mL). Stir at room temperature for 10 minutes, then add 1,2-dibromoethane (2.4 mL, 23 mmol). Continue the reaction for 8 hours, monitored by TLC (PE:EA = 3:1). Stop the reaction when the solution turns golden yellow. Pour the solution into 200 mL of ice water and extract with ethyl acetate (20 mL x 2). The combined organic phases are washed with saturated brine and dried over anhydrous sodium sulfate. Purify by column chromatography (PE:EA = 6:1) to obtain Intermediate C1 (1.5 g, 59%) as a pale yellow solid. 1 HNMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.24 (d, J=15.5Hz, 1H), 7.68 (d, J= 9.0Hz,1H),7.61(d,J=15.5Hz,1H),7.48(d,2H),7.35(d,J=16.0Hz,1H),6.96–6.9 1(m,3H),6.73(d,J=2.4Hz,1H),6.46–6.45(m,2H),6.35(dd,J=9.0,2.5Hz,1H),4. 32(t,J=6.3Hz,2H),3.93(s,3H),3.91(s,3H),3.84(s,3H),3.66(t,J=6.3Hz,2H).

[0046] 4) Synthesis of Compound I-1:

[0047] To a 50 mL round-bottom flask, compound C1 (200 mg, 0.37 mmol), potassium carbonate (102.5 mg, 0.74 mmol), and anhydrous acetonitrile (10 mL) were added. The mixture was stirred and heated to 50°C. Morpholine (0.1 mL, 1.11 mmol) was added and allowed to react for 6 h. TLC monitoring (DCM:MeOH = 15:1) was performed. After completion of the reaction, the reaction solution was evaporated to dryness, and the residue was dissolved in DCM, extracted with water, washed with saturated brine, and dried over anhydrous sodium sulfate. Purification by column chromatography (V (dichloromethane):V (methanol) = 100:1) afforded compound I-1 (120 mg, 59%) as a pale yellow solid, mp 64.8-65.6°C. 1HNMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.24 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H ),7.61(d,J=15.5Hz,1H),7.49–7.46(m,2H),7.34(d,J=16.1Hz,1H),6.96–6.90(m,3H),6.72 (d,J=2.4Hz,1H),6.45(m,2H),6.34(dd,J=9.0,2.3Hz,1H),4.17–4.14(m,2H),3.92(s,3H),3 .90(s,3H),3.84(s,3H),3.75(t,J=4.3Hz,4H),2.82(d,J=6.0Hz,2H),2.61(d,J=5.7Hz,4H). 13 C NMR (151MHz, Chloroform-d), δ: 192.76, 166.69, 165.95, 161.92, 161.00, 158.88, 141.98, 138.52, 131.93, 131.33, 130.13, 128.16, 125. 76,123.52,116.08,115.05,114.51,107.66,103.98,101.05,97.78,67.01,65.95,57.73,55.92,55.66,55.62,54.22.ESI-HRMS(m / z):C 32 H 35 NO7[M+H] + :calcd:546.2494; found:546.2504.

[0048] Example 2

[0049] (E)-3-(2,4-dimethoxy-6-((E)-4-(2-piperidinylethoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-2)

[0050]

[0051] The preparation method is the same as that of Example 1, except that the morpholine in Example 1 is replaced by piperidine to obtain compound I-2. mp: 83.6-84.9°C. 1H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.25 (d, J = 15.4Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.6 1(d,J=15.4Hz,1H),7.46(d,J=8.7Hz,2H),7.33(d,J=16.0Hz,1H),6.96–6.90(m,3H),6.72(d,J=2 .4Hz,1H),6.46–6.44(m,2H),6.34(dd,J=9.0,2.5Hz,1H),4.14(t,J=6.1Hz,2H),3.92(s,3H),3. 90(s,3H),3.83(s,3H),2.79(t,J=6.1Hz,2H),2.53(m,4H),1.66–1.60(m,4H),1.48–1.43(m,2H). 13 C NMR (151MHz, Chloroform-d), δ: 192.73, 166.66, 165.93, 161.90, 160.98, 159.02, 142.00, 138.51, 131.97, 131.33, 129.94, 128.12, 125.63, 123 .49,116.06,115.05,114.51,107.60,103.95,101.08,97.74,66.11,57 .98,55.90,55.64,55.60,55.18,31.05,25.99,24.26.ESI-HRMS(m / z):C 33 H 37 NO6[M+H] + :calcd:544.2701; found:544.2686.

[0052] Example 3

[0053] (E)-3-(2,4-dimethoxy-6-((E)-4-(2-pyrroleethoxy)phenyl)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-3)

[0054]

[0055] The preparation method is the same as that of Example 1, except that morpholine in Example 1 is replaced by pyrrolidine to obtain compound I-3. mp: 85.6-86.3°C. 1H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H ),7.61(d,J=15.5Hz,1H),7.49–7.45(m,2H),7.33(d,J=16.0Hz,1H),6.96–6.91(m,3H),6.7 2(d,J=2.2Hz,1H),6.45(m,2H),6.34(dd,J=9.0,2.3Hz,1H),4.15(t,J=5.9Hz,2H),3.92(s, 3H), 3.90 (s, 3H), 3.83 (s, 3H), 2.93 (t, J = 5.9Hz, 2H), 2.68–2.64 (m, 4H), 1.84–1.81 (m, 4H). 13 C NMR (151MHz, Chloroform-d), δ: 192.80, 166.72, 166.00, 161.96, 161.04, 159.09, 142.03, 138.53, 132.02, 131.35, 130.10, 128.16, 125. 76,123.65,116.22,115.14,114.61,107.60,104.11,101.17,97.86,66.26,57.35,55.95,55.63,53.82,52.90,52.44.ESI-HRMS(m / z):C 32 H 35 NO6[M+H] + :calcd:530.2543; found:530.2537.

[0056] Example 4

[0057] (E)-3-(2,4-dimethoxy-6-((E)-4-(2-(4-methylpiperazine)ethoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-4)

[0058]

[0059] The preparation method is the same as that of Example 1, except that morpholine in Example 1 is replaced by methylpiperazine to obtain compound I-4. mp: 75.7-76.6°C. 1H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.24 (d, J = 15.6Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7. 61(d,J=15.5Hz,1H),7.48–7.45(m,2H),7.34(d,J=16.1Hz,1H),6.96–6.90(m,3H),6.72(d,J=2. 4Hz,1H),6.46–6.44(m,2H),6.34(dd,J=9.0,2.6Hz,1H),4.13(t,J=5.8Hz,2H),3.92(s,3H),3.9 0(s,3H),3.83(s,3H),2.84(t,J=5.8Hz,2H),2.72–2.58(m,4H),2.57–2.43(m,4H),2.31(s,3H). 13 C NMR (151MHz, Chloroform-d), δ: 192.73, 166.65, 165.92, 161.89, 160.98, 158.94, 141.97, 138.49, 131.93, 131.31, 130.02, 128.12, 125.67, 123.46,116.04,115.03,114.49,107.61,103.95,101.05,97.74,66.11,57.20,55.90,55.63,55.60,55.07,53.57,46.03.ESI-HRMS(m / z):C 33 H 38 N2O6[M+H] + :calcd:559.2810; found:559.2797.

[0060] Example 5

[0061] (E)-3-(2,4-dimethoxy-6-((E)-4-(2-(4-ethylpiperazine)ethoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-5)

[0062]

[0063] The preparation method is the same as that of Example 1, except that morpholine in Example 1 is replaced by ethylpiperazine to obtain the target compound I-5. mp: 112.8-113.6°C. 1H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.24 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d ,J=15.5Hz,1H),7.46(d,J=8.7Hz,2H),7.34(d,J=16.0Hz,1H),6.96–6.89(m,3H),6.72(d,J=2.3Hz, 1H),6.46–6.44(m,2H),6.34(dd,J=9.0,2.5Hz,1H),4.14(t,J=5.9Hz,2H),3.92(s,3H),3.90(s,3H) ,3.83(s,3H),2.84(t,J=5.9Hz,2H),2.74–2.46(m,8H),2.44(q,J=7.2Hz,2H),1.10(t,J=7.2Hz,3H). 13 C NMR(151MHz,Chloroform-d),δ:192.81,166.72,166.00,161.96,161.04,159.14,142.05,138.53,132.04,131.36,130.07,128.16,1 25.74,123.66,116.22,115.15,114.63,107.57,104.12,101.20,97.86,67.33,55.95,55.63,55.18,54.87,23.69.ESI-HRMS(m / z):C 34 H 40 N2O6[M+H] + :calcd:573.2965; found:573.2955.

[0064] Example 6

[0065] (E)-3-(2,4-dimethoxy-6-((E)-4-(2-(4-hydroxyethylpiperazine)ethoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-6)

[0066]

[0067] The preparation method is the same as that of Example 1, except that morpholine in Example 1 is replaced by hydroxyethylpiperazine to obtain compound I-6. mp: 85.4-86.1°C. 1H NMR (600MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.24 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.2Hz, 1H) ,7.62(d,J=15.5Hz,1H),7.47(m,3H),7.34(d,J=16.0Hz,1H),6.96–6.90(m,3H),6.72(d,J=2 .4Hz,1H),6.46–6.44(m,2H),6.35(dd,J=9.3,3.0Hz,1H),4.14(t,J=4.7Hz,3H),3.93(s,3H) ,3.91(s,3H),3.84(s,3H),3.62(t,J=4.7Hz,3H),2.84(t,J=4.7Hz,2H),2.69–2.55(m,10H). 13 C NMR(151MHz,Chloroform-d),δ:192.81,166.72,166.00,161.97,161.05,159.04,142.03,138.53,132.01,131.35,130.16,128.17,125.79, 123.64,116.21,115.15,114.61,107.61,104.13,101.16,97.87,66.28,59.41,57.92,57.29,55.95,55.63,53.84,52.98.ESI-HRMS(m / z):C 34 H 40 N2O7[M+H] + :calcd:589.2914; found:589.2900.

[0068] Example 7

[0069] (E)-3-(2-((E)-4-(2-(benzyl(methyl)amino)ethoxy)phenyl)-4,6-dimethoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-7)

[0070]

[0071] The preparation method is the same as that of Example 1, except that the morpholine in Example 1 is replaced by N-methylbenzylamine to obtain compound I-7. mp: 83.8-84.4°C. 1H NMR (400MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H),7.61(d,J=15.5Hz,1H),7.46(d,J=8.4Hz,2H),7.38–7.31(m,6H),6.97–6.88(m,3H) ,6.73(d,J=2.3Hz,1H),6.45(m,2H),6.35(dd,J=9.0,2.5Hz,1H),4.15(t,J=5.9Hz,2H), 3.92(s,3H),3.91(s,3H),3.83(s,3H),3.67(s,2H),2.89(t,J=5.9Hz,2H),2.38(s,3H). 13 C NMR (151MHz, Chloroform-d), δ: 192.74, 166.67, 165.94, 161.90, 160.99, 159.05, 142.01, 138.52, 131.98, 131.33, 129.91, 129.21, 128.41, 128.13, 127.23,125.61,123.49,116.07,115.00,114.52,107.60,103.94,101.09, 97.75,66.54,62.84,55.91,55.83,55.63,55.61,43.10.ESI-HRMS(m / z):C 36 H 37 NO6[M+H] + :calcd:580.2701; found:580.2687.

[0072] Example 8: (E)-3-(2,4-dimethoxy-6-((E)-4-(2-(4-hydroxypiperidinyl)ethoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-8)

[0073]

[0074] The preparation method is the same as that of Example 1, except that morpholine in Example 1 is replaced by 4-hydroxypiperidine to obtain compound I-8. mp: 102.3-103.1°C. 1H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.24 (d, J = 15.4Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d, J = 1 5.4Hz,1H),7.49–7.46(m,2H),7.34(d,J=16.1Hz,1H),6.96–6.90(m,3H),6.73(d,J=2.3Hz,1H),6.46–6.4 4(m,2H),6.35(dd,J=9.0,2.4Hz,1H),4.14(t,J=5.9Hz,2H),3.92(s,3H),3.91(s,3H),3.84(s,3H),3.76– 3.71(m,1H),2.92–2.88(m,2H),2.83(t,J=5.9Hz,2H),2.34(s,2H),1.96–1.91(m,2H),1.65–1.62(m,2H). 13 C NMR (151MHz, Chloroform-d), δ: 192.81, 166.71, 165.99, 161.96, 161.05, 159.03, 142.03, 138.54, 132.01, 131.35, 130.13, 128.17, 125. 78,123.63,116.20,115.14,114.61,107.61,104.11,101.16,97.86,66.40,57.16,55.95,55.65,55.62,51.66,34.56.ESI-HRMS(m / z):C 33 H 37 NO7[M+H] + :calcd:560.2648; found:560.2635.

[0075] Example 9

[0076] (E)-3-(2,4-dimethoxy-6-((E)-4-(3-morpholinopropyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-9)

[0077]

[0078] The preparation method is the same as that in Example 1, except that 1,2-dibromoethane in Example 1 is replaced by 1,3-dibromopropane to obtain compound I-9. 1H NMR (600MHz, Chloroform-d), δ: 13.67 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 8.9Hz, 1H) ,7.62(d,J=15.5Hz,1H),7.49–7.45(m,2H),7.34(d,J=16.0Hz,1H),6.97–6.89(m,3H),6.73 (d,J=2.3Hz,1H),6.47–6.44(m,2H),6.35(dd,J=8.9,2.6Hz,1H),4.06(t,J=6.3Hz,2H),3.9 3(s,3H),3.91(s,3H),3.84(s,3H),3.76–3.72(m,4H),2.59–2.47(m,6H),2.04–1.97(m,2H). 13 C NMR(101MHz,Chloroform-d),δ:192.79,166.72,165.96,161.94,161.03,159.21,142.04,138.55,132.02,131.35,129.94,128.17,125.64, 123.55,116.12,114.97,114.55,107.66,104.00,101.08,97.80,66.98,66.29,55.95,55.70,55.67,55.64,53.83,26.13.ESI-HRMS(m / z):C 33 H 37 NO7[M+H] + :calcd:560.2648; found:560.2626.

[0079] Example 10

[0080] (E)-3-(2,4-dimethoxy-6-((E)-4-(3-piperidinylpropyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-10)

[0081]

[0082] The preparation method is the same as that of Example 9, except that the morpholine in Example 9 is replaced by piperidine to obtain compound I-10. mp: 115.8-116.2°C. 1H NMR (600MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.6Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d, J =15.6Hz,1H),7.46(d,J=8.6Hz,2H),7.33(d,J=16.0Hz,1H),6.96–6.89(m,3H),6.73(d,J=2.2Hz,1H),6 .46–6.43(m,2H),6.35(dd,J=9.0,2.3Hz,1H),4.03(t,J=6.4Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s, 3H), 2.48 (t, J = 7.5Hz, 2H), 2.45–2.36 (m, 4H), 2.01–1.97 (m, 2H), 1.63–1.57 (m, 4H), 1.47–1.42 (m, 2H). 13 C NMR(101MHz,Chloroform-d),δ:192.78,166.69,165.96,161.93,161.01,159.32,142.05,138.55,132.05,131.35,129.81,128.14,125.56,123 .55,116.12,115.00,114.56,107.61,103.97,101.12,97.78,66.74,56 .09,55.93,55.65,55.63,54.77,26.88,26.03,24.52.ESI-HRMS(m / z):C 34 H 39 NO6[M+H] + :calcd:558.2856; found:558.2833.

[0083] Example 11

[0084] (E)-3-(2,4-dimethoxy-6-((E)-4-(3-pyrrolopropoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-11)

[0085]

[0086] The preparation method is the same as that of Example 9, except that morpholine in Example 9 is replaced by pyrrolidine to obtain compound I-11. mp: 118.8-119.6°C. 1H NMR (600MHz, Chloroform-d), δ: 13.67 (s, 1H), 8.25 (d, J = 15.4Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61(d,J=15.4Hz,1H),7.46(d,J=8.2Hz,2H),7.33(d,J=15.9Hz,1H),6.96–6.89(m,3H),6.7 3(d,J=2.3Hz,1H),6.47–6.43(m,2H),6.35(dd,J=9.0,2.6Hz,1H),4.06(t,J=6.2Hz,2H),3.9 2(s,3H),3.91(s,3H),3.84(s,3H),2.75–2.60(m,6H),2.11–2.05(m,2H),1.87–1.82(m,4H). 13 C NMR(101MHz,Chloroform-d),δ:192.78,166.69,165.95,161.93,161.01,159.20,142.04,138.54,132.03,131.35,129.90,128.15,125.60, 123.53,116.11,114.97,114.56,107.61,103.99,101.11,97.79,66.46,55.93,55.65,55.62,54.35,53.30,28.61,23.61.ESI-HRMS(m / z):C 33 H 37 NO6[M+H] + :calcd:544.2699; found:544.2674.

[0087] Example 12

[0088] (E)-3-(2,4-dimethoxy-6-((E)-4-(3-(4-methylpiperazine)propoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-12)

[0089]

[0090] The preparation method is the same as that of Example 9, except that morpholine in Example 9 is replaced by methylpiperazine to obtain compound I-12. mp: 110.3-111.3°C. 1H NMR (400MHz, Chloroform-d), δ: 13.68 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H ),7.62(d,J=15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.97–6.87(m,3H),6. 73(d,J=2.2Hz,1H),6.47–6.43(m,2H),6.35(dd,J=9.0,2.4Hz,1H),4.04(t,J=6.3Hz,2H), 3.92(s,3H),3.91(s,3H),3.84(s,3H),2.75–2.42(m,10H),2.35(s,3H),2.03–1.96(m,2H). 13 C NMR (101MHz, Chloroform-d), δ: 192.77, 166.69, 165.95, 161.92, 161.01, 159.28, 142.04, 138.53, 132.03, 131.34, 129.84, 128.14, 125.56, 123 .53,116.10,114.98,114.55,107.61,103.98,101.10,97.77,66.50,55 .92,55.64,55.62,55.25,55.22,53.30,46.14,26.90.ESI-HRMS(m / z):C 34 H 40 N2O6[M+H] + :calcd:573.2965; found:573.2943.

[0091] Example 13

[0092] (E)-3-(2,4-dimethoxy-6-((E)-4-(3-(4-ethylpiperazine)propoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-13)

[0093]

[0094] The preparation method is the same as that of Example 9, except that morpholine in Example 9 is replaced by ethylpiperazine to obtain compound I-13. mp: 84.7-85.1°C. 1H NMR (400MHz, Chloroform-d), δ: 13.68 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61(d,J=15.5Hz,1H),7.49–7.44(m,2H),7.33(d,J=16.0Hz,1H),6.97–6.88(m,3H),6.72(d ,J=2.3Hz,1H),6.46–6.43(m,2H),6.35(dd,J=9.0,2.4Hz,1H),4.04(t,J=6.4Hz,2H),3.92(s ,3H),3.91(s,3H),3.83(s,3H),2.79–2.34(m,12H),2.03–1.95(m,2H),1.10(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d), δ: 192.77, 166.69, 165.95, 161.92, 161.01, 159.29, 142.04, 138.54, 132.04, 131.34, 129.83, 128.13, 125.56, 123.54 ,116.11,114.99,114.55,107.62,103.97,101.10,97.77,66.55,55.93,5 5.65,55.62,55.29,53.36,52.95,52.46,26.92,12.10.ESI-HRMS(m / z):C 35 H 42 N2O6[M+H] + :calcd:587.3121; found:587.3105.

[0095] Example 14

[0096] (E)-3-(2,4-dimethoxy-6-((E)-4-(3-(4-hydroxyethylpiperazine)propoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-14)

[0097]

[0098] The preparation method is the same as that of Example 9, except that morpholine in Example 9 is replaced by hydroxyethylpiperazine to obtain compound I-14. mp: 100.8-101.7°C. 1H NMR (600MHz, Chloroform-d), δ: 13.67 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7 .62(d,J=15.5Hz,1H),7.47(d,J=8.2Hz,2H),7.34(d,J=16.0Hz,1H),6.96–6.89(m,3H),6.73( d,J=2.3Hz,1H),6.47–6.44(m,2H),6.35(dd,J=9.0,2.5Hz,1H),4.05(t,J=6.3Hz,2H),3.93(s ,3H),3.91(s,3H),3.84(s,3H),3.63(t,J=5.2Hz,2H),2.64–2.50(m,12H),2.01–1.97(m,2H). 13 C NMR(101MHz,Chloroform-d),δ:192.80,166.69,165.96,161.93,161.02,159.24,142.05,138.56,132.04,131.35,129.89,128.15,125.58,123.53 ,116.10,114.98,114.55,107.65,103.99,101.09,97.79,66.42,59.40,5 7.81,55.94,55.66,55.63,55.20,53.30,52.95,26.85.ESI-HRMS(m / z):C 35 H 42 N2O7[M+H] + :calcd:603.3072; found:603.3058.

[0099] Example 15

[0100] (E)-3-(2-((E)-4-(2-(benzyl(methyl)amino)propyloxy)phenylvinyl)-4,6-dimethoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-15)

[0101]

[0102] The preparation method is the same as that of Example 9, except that the morpholine in Example 9 is replaced by N-methylbenzylamine to obtain compound I-15. mp: 59.7-60.5°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.26 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H) ,7.62(d,J=15.5Hz,1H),7.49–7.44(m,2H),7.37–7.29(m,6H),6.98–6.87(m,3H),6.73(d,J= 2.3Hz,1H),6.47–6.44(m,2H),6.35(dd,J=9.0,2.4Hz,1H),4.05(t,J=6.4Hz,2H),3.93(s,3H ),3.91(s,3H),3.83(s,3H),3.53(s,2H),2.63–2.52(m,2H),2.24(s,3H),2.06–1.98(m,2H). 13 C NMR(101MHz,Chloroform-d),δ:192.79,166.70,165.96,161.93,161.02,15 9.30,142.07,138.56,132.08,131.36,129.80,129.19,128.41,128.14,127 .23,125.53,123.56,116.12,114.99,114.56,107.62,103.98,101.12,97.7 8,66.32,62.45,55.94,55.65,55.64,53.92,42.27,27.25.ESI-HRMS(m / z):C 37 H 39 NO6[M+H] + :calcd:594.2856; found:594.2837.

[0103] Example 16

[0104] (E)-3-(2,4-dimethoxy-6-((E)-4-(3-(4-hydroxypiperidinyl)propoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-16)

[0105]

[0106] The preparation method is the same as that of Example 9, except that morpholine in Example 9 is replaced by 4-hydroxypiperidine to obtain compound I-16. mp: 93.3-94.3°C. 1H NMR (400MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d, J = 15.5Hz, 1H),7.46(d,J=8.4Hz,2H),7.33(d,J=16.0Hz,1H),6.97–6.88(m,3H),6.73(d,J=2.3Hz,1H),6.46–6.43(m,2H),6 .35(dd,J=9.0,2.3Hz,1H),4.04(t,J=6.3Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),3.79–3.71(m,1H),2.88 –2.79(m,2H),2.56(t,J=7.4Hz,2H),2.31–2.16(m,2H),2.05–1.99(m,2H),1.97–1.91(m,2H),1.66–1.60(m,2H). 13 C NMR (101MHz, Chloroform-d), δ: 192.77, 166.66, 165.94, 161.92, 161.01, 159.25, 142.04, 138.54, 132.02, 131.33, 129.84, 128.13, 125.54, 123.47,116.06,114.97,114.54,107.61,103.98,101.09,97.76,66.52,55.91,55.64,55.60,55.15,51.26,34.55,27.12.ESI-HRMS(m / z):C 34 H 39 NO7[M+H] + :calcd:574.2805; found:574.2789.

[0107] Example 17

[0108] (E)-3-(2,4-dimethoxy-6-((E)-4-(4-morpholinobutyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-17)

[0109]

[0110] The preparation method is the same as that of Example 1, except that 1,2-dibromoethane in Example 1 is replaced by 1,4-dibromobutane to obtain compound I-17. mp: 127.8-128.4°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d,J=15.5Hz,1H),7.49–7.45(m,2H),7.34(d,J=16.0Hz,1H),6.97–6.87(m,3H),6.73(d,J=2.3Hz ,1H),6.47–6.43(m,2H),6.35(dd,J=9.0,2.4Hz,1H),4.01(t,J=6.3Hz,2H),3.92(s,3H),3.91(s, 3H),3.84(s,3H),3.73(t,J=4.6Hz,4H),2.52–2.37(m,6H),1.87–1.80(m,2H),1.73–1.66(m,2H). 13 CNMR(101MHz,DMSO-d6),δ:192.07,165.70,165.56,161.96,161.01,158.80,141.92,138.06,132.41,131.69,129.32,128.20,124.41,122.3 8,114.80,114.48,113.99,107.50,104.29,101.08,97.84,67.40,66. 26,57.81,56.10,55.76,55.62,53.35,26.55,22.40.ESI-HRMS(m / z):C 34 H 39 NO7[M+H] + :calcd:574.2805; found:574.2806.

[0111] Example 18

[0112] (E)-3-(2,4-dimethoxy-6-((E)-4-(4-piperidinylbutyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-18)

[0113]

[0114] The preparation method is the same as that of Example 17, except that the morpholine in Example 17 is replaced by piperidine to obtain compound I-18. mp: 178.9-179.6°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.23 ​​(d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.63 (d, J = 15. 5Hz,1H),7.46(d,J=8.3Hz,2H),7.33(d,J=16.0Hz,1H),6.96–6.84(m,3H),6.72(d,J=2.3Hz,1H),6.46–6.4 3(m,2H),6.35(dd,J=9.0,2.5Hz,1H),4.02(t,J=5.3Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),3.60–3 .51(m,2H),3.08–2.98(m,2H),2.71–2.58(m,2H),2.37–2.25(m,2H),2.20–2.08(m,2H),1.94–1.79(m,6H). 13 C NMR (101MHz, Chloroform-d), δ: 192.80, 166.68, 165.96, 161.96, 161.04, 158.76, 142.02, 138.53, 131.97, 131.34, 130.22, 128.23, 125.74, 123.42 ,116.03,114.89,114.52,107.64,104.03,101.07,97.84,67.09,57.36,5 5.93,55.68,55.63,53.36,26.74,22.68,22.29,20.95.ESI-HRMS(m / z):C 35 H 41 NO6[M+H] + :calcd:572.3012; found:572.2993.

[0115] Example 19

[0116] (E)-3-(2,4-dimethoxy-6-((E)-4-(4-pyrrolidinyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-19)

[0117]

[0118] The preparation method is the same as that of Example 17, except that morpholine in Example 17 is replaced by pyrrolidine to obtain compound I-19. mp: 98.8-99.7°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz ,1H),7.61(d,J=15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.97–6.87(m, 3H),6.73(d,J=2.3Hz,1H),6.47–6.43(m,2H),6.35(dd,J=9.0,2.4Hz,1H),4.01(t,J=6 .3Hz,2H),3.92(s,3H),3.91(s,3H),3.83(s,3H),2.59–2.51(m,6H),1.87–1.71(m,8H). 13 C NMR (101MHz, Chloroform-d), δ: 192.78, 166.69, 165.96, 161.93, 161.01, 159.34, 142.06, 138.55, 132.07, 131.35, 129.78, 128.14, 125.53, 123 .55,116.12,114.98,114.57,107.60,103.99,101.12,97.78,67.99,56 .29,55.93,55.65,55.62,54.34,27.52,25.67,23.58.ESI-HRMS(m / z):C 34 H 39 NO6[M+H] + :calcd:558.2856; found:558.2836.

[0119] Example 20

[0120] (E)-3-(2,4-dimethoxy-6-((E)-4-(4-(4-methylpiperazine)butoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-20)

[0121]

[0122] The preparation method is the same as that of Example 17, except that morpholine in Example 17 is replaced by methylpiperazine to obtain compound I-20. mp: 80.2-81.1°C. 1H NMR (400MHz, Chloroform-d), δ: 13.68 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7. 62(d,J=15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.97–6.87(m,3H),6.73(d,J=2 .3Hz,1H),6.47–6.43(m,2H),6.35(dd,J=9.0,2.5Hz,1H),4.00(t,J=6.3Hz,2H),3.92(s,3H),3 .91(s,3H),3.83(s,3H),2.73–2.42(m,10H),2.33(s,3H),1.84–1.78(m,2H),1.75–1.68(m,2H). 13 C NMR (151MHz, Chloroform-d), δ: 192.76, 166.68, 165.94, 161.91, 161.00, 159.29, 142.05, 138.54, 132.04, 131.34, 129.77, 128.14, 125.51, 123.51 ,116.08,114.94,114.53,107.62,103.95,101.08,97.75,67.94,58.34,5 5.92,55.65,55.62,55.27,53.30,46.18,27.41,23.60.ESI-HRMS(m / z):C 35 H 42 N2O6[M+H] + :calcd:587.3121; found:587.3090.

[0123] Example 21

[0124] (E)-3-(2,4-dimethoxy-6-((E)-4-(4-(4-ethylpiperazine)butoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-21)

[0125]

[0126] The preparation method is the same as that of Example 17, except that morpholine in Example 17 is replaced by ethylpiperazine to obtain compound I-21. mp: 121.8-122.6°C. 1H NMR (600MHz, Chloroform-d), δ: 13.64 (s, 1H), 8.23 ​​(d, J = 15.4Hz, 1H), 7.67 (d, J = 9.0Hz, 1H), 7.60 (d, J = 15 .4Hz,1H),7.46–7.43(m,2H),7.32(d,J=16.0Hz,1H),6.93(d,J=16.0Hz,1H),6.89–6.86(m,2H),6.71(d,J =2.3Hz,1H),6.45–6.42(m,2H),6.33(dd,J=9.0,2.5Hz,1H),3.99(t,J=6.4Hz,2H),3.91(s,3H),3.89(d,J =2.0Hz,3H),3.82(s,3H),2.64–2.33(m,12H),1.82–1.79(m,2H),1.70–1.65(m,2H),1.08(t,J=7.3Hz,3H). 13 C NMR(151MHz,Chloroform-d),δ:192.80,166.71,165.97,161.94,161.02,1 59.31,142.07,138.56,132.07,131.36,129.80,128.16,125.54,123.55,11 6.11,114.96,114.56,107.64,103.97,101.10,97.78,67.94,58.30,55.93, 55.66,55.63,53.12,52.79,52.36,27.41,23.55,11.95.ESI-HRMS:(m / z):C 36 H 44 N2O6[M+H] + :calcd:601.3278; found:601.3257.

[0127] Example 22

[0128] (E)-3-(2,4-dimethoxy-6-((E)-4-(4-(4-hydroxyethylpiperazine)butoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-22)

[0129]

[0130] The preparation method is the same as that of Example 17, except that morpholine in Example 17 is replaced by hydroxyethylpiperazine to obtain compound I-22. mp: 132.4-133.7°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d,J=15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.97–6.87(m,3H),6.73(d,J=2.3Hz ,1H),6.47–6.43(m,2H),6.35(dd,J=9.0,2.5Hz,1H),4.01(t,J=6.3Hz,2H),3.93(s,3H),3.91(s, 3H), 3.84 (s, 3H), 3.62 (t, J = 5.4Hz, 2H), 2.72–2.39 (m, 12H), 1.86–1.79 (m, 2H), 1.73–1.67 (m, 2H). 13 CNMR(151MHz,Chloroform-d),δ:192.78,166.68,165.94,161.92,161.01,1 59.28,142.06,138.54,132.05,131.34,129.79,128.15,125.51,123.49,11 6.07,114.94,114.54,107.63,103.97,101.08,97.76,67.92,59.34,58.32, 57.83,55.92,55.65,55.62,53.38,52.99,27.39,23.58.ESI-HRMS:(m / z):C 36 H 44 N2O7[M+H] + :calcd:617.3227; found:617.3201.

[0131] Example 23

[0132] (E)-3-(2-((E)-4-(4-(benzyl(methyl)amino)butoxy)phenyl)-4,6-dimethoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-23)

[0133]

[0134] The preparation method is the same as that of Example 17, except that the morpholine in Example 17 is replaced by N-methylbenzylamine to obtain compound I-23. mp: 53.5-54.2°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.26 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d, J=15.5Hz,1H),7.49–7.44(m,2H),7.36–7.30(m,6H),6.95(d,J=16.0Hz,1H),6.91–6.86(m,2H),6.73( d,J=2.2Hz,1H),6.47–6.44(m,2H),6.35(dd,J=9.0,2.4Hz,1H),3.98(t,J=6.3Hz,2H),3.93(s,3H),3 .91(s,3H),3.83(s,3H),3.51(s,2H),2.45(t,2H),2.22(s,3H),1.87–1.80(m,2H),1.76–1.68(m,2H). 13 CNMR(151MHz,Chloroform-d),δ:192.78,166.70,165.96,161.93,161.01,159 .35,142.07,138.56,132.08,131.36,129.76,129.22,128.36,128.15,127.11 ,125.51,123.55,116.12,114.98,114.55,107.63,103.96,101.11,97.77,67. 97,62.43,56.99,55.94,55.66,55.64,42.27,27.17,23.94.ESI-HRMS:(m / z):C 38 H 41 NO6[M+H] + :calcd:608.3012; found:608.2993.

[0135] Example 24

[0136] Synthesis of (E)-3-(2,4-dimethoxy-6-((E)-4-(4-(4-hydroxypiperidinyl)butoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-24):

[0137]

[0138] The preparation method is the same as that of Example 17, except that morpholine in Example 17 is replaced by 4-hydroxypiperidine to obtain compound I-24. mp: 108.8-109.6°C. 1H NMR (400MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5 Hz,1H),7.46(d,J=8.3Hz,2H),7.34(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.89(d,J=8.3Hz,2H),6.73(d, J=2.3Hz1H),6.47–6.43(m,2H),6.35(dd,J=9.0,2.6Hz,1H),4.01(t,J=6.1Hz,2H),3.92(s,3H),3.90(s,6H), 3.83(s,3H),3.79–3.72(m,1H),2.88–2.80(m,2H),2.47(m,2H),2.24(m,2H),1.85–1.79(m,2H),1.64(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:192.81,166.69,165.96,161.93,161.02,159.29,142.08,138.58,132.07,131.36,129.80,128.16,125.52,123 .51,116.09,114.96,114.55,107.65,103.97,101.09,97.78,67.94,58. 26,55.94,55.67,55.64,51.24,34.62,27.44,23.84.ESI-HRMS:(m / z):C 35 H 41 NO7[M+H] + :calcd:588.2961; found:588.2940

[0139] Example 25

[0140] (E)-3-(2,4-dimethoxy-6-((E)-4-(5-morpholinopentyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-25)

[0141]

[0142] The preparation method is the same as that of Example 1, except that 1,2-dibromoethane in Example 1 is replaced by 1,5-dibromopentane to obtain compound I-25. mp: 108.8-109.6°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d, J =15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.95(d,J=16.0Hz,1H),6.91–6.87(m,2H),6. 73(d,J=2.3Hz,1H),6.46–6.44(m,2H),6.35(dd,J=9.0,2.6Hz,1H),3.99(t,J=6.4Hz,2H),3.93(s,3H) ,3.91(s,3H),3.84(s,3H),3.77–3.70(m,4H),2.50–2.35(m,6H),1.86–1.79(m,2H),1.56–1.46(m,2H). 13 C NMR (151MHz, Chloroform-d), δ: 192.75, 166.66, 165.92, 161.90, 160.99, 159.29, 142.04, 138.52, 132.02, 131.32, 129.76, 128.13, 125.48, 123.43 ,116.03,114.90,114.52,107.60,103.95,101.06,97.72,67.98,67.10,5 9.09,55.90,55.63,55.59,53.91,29.27,26.43,24.12.ESI-HRMS:(m / z):C 35 H 41 NO7[M+H] + :calcd:588.2961; found:588.2945.

[0143] Example 26

[0144] (E)-3-(2,4-dimethoxy-6-((E)-4-(5-piperidinyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-26)

[0145]

[0146] The preparation method is the same as that of Example 25, except that the morpholine in Example 25 is replaced by piperidine to obtain compound I-26. mp: 99.3-100.5°C. 1H NMR (400MHz, Chloroform-d), δ: 13.68 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.95(d,J=16.0Hz,1H),6.91–6.86(m,2H),6.73 (d,J=2.4Hz,1H),6.46–6.43(m,2H),6.35(dd,J=9.0,2.5Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3. 91(s,3H),3.84(s,3H),2.37(d,J=24.1Hz,6H),1.85–1.78(m,2H),1.63–1.57(m,6H),1.51–1.43(m,4H). 13 C NMR(151MHz,Chloroform-d),δ:192.76,166.67,165.93,161.91,160.99,1 59.34,142.05,138.53,132.05,131.34,129.72,128.13,125.47,123.48,11 6.06,114.93,114.53,107.59,103.94,101.09,97.74,68.04,59.49,55.91, 55.64,55.61,54.75,29.31,26.73,25.99,24.53,24.33.ESI-HRMS:(m / z):C 36 H 43 NO6[M+H] + :calcd:586.3169; found:586.3141.

[0147] Example 27

[0148] (E)-3-(2,4-dimethoxy-6-((E)-4-(5-pyrrolopentyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-27)

[0149]

[0150] The preparation method is the same as that of Example 25, except that morpholine in Example 25 is replaced by pyrrolidine to obtain compound I-27. mp: 189.3-190.7°C. 1H NMR (400MHz, Chloroform-d), δ: 13.68 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.62 (d, J =15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,2H),6.91–6.86(m,2H),6. 73(d,J=2.3Hz,1H),6.46–6.44(m,2H),6.35(dd,J=9.0,2.6Hz,1H),3.99(t,J=6.5Hz,2H),3.92(s,3H) ,3.91(s,3H),3.83(s,3H),2.61–2.50(m,6H),1.86–1.80(m,6H),1.68–1.61(m,2H),1.56–1.49(m,2H). 13 C NMR (151MHz, Chloroform-d), δ: 192.79, 166.64, 165.93, 161.94, 161.02, 159.04, 142.06, 138.53, 132.03, 131.33, 129.93, 128.17, 125.53, 123.34 ,115.96,114.88,114.50,107.61,103.98,101.06,97.77,67.43,55.91,5 5.66,55.62,55.59,53.71,28.70,25.55,23.68,23.49.ESI-HRMS:(m / z):C 35 H 41 NO6[M+H] + :calcd:572.3012; found:572.3020.

[0151] Example 28

[0152] (E)-3-(2,4-dimethoxy-6-((E)-4-(5-(4-methylpiperazine)pentyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-28)

[0153]

[0154] The preparation method is the same as that of Example 25, except that morpholine in Example 25 is replaced by methylpiperazine to obtain compound I-28. mp: 92.4-93.7°C. 1H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d, J = 15 .5Hz,1H),7.47–7.45(m,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.90–6.87(m,2H),6.73(d,J =2.2Hz,1H),6.46–6.44(m,2H),6.35(dd,J=9.0,2.4Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.90(s,3 H),3.83(s,3H),2.61–2.35(m,10H),2.29(s,3H),1.84–1.80(m,2H),1.60–1.56(m,2H),1.51–1.47(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:192.76,166.67,165.93,161.91,160.99,1 59.32,142.05,138.53,132.04,131.34,129.74,128.14,125.48,123.49,11 6.06,114.92,114.53,107.61,103.94,101.08,97.74,68.01,58.68,55.91, 55.64,55.61,55.25,53.36,46.17,29.30,26.79,24.22.ESI-HRMS:(m / z):C 36 H 44 N2O6[M+H] + :calcd:601.3278; found:601.3257.

[0155] Example 29

[0156] (E)-3-(2,4-dimethoxy-6-((E)-4-(5-(4-ethylpiperazine)pentyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-29)

[0157]

[0158] The preparation method is the same as that of Example 25, except that morpholine in Example 25 is replaced by ethylpiperazine to obtain compound I-29. mp: 85.5-86.2°C. 1H NMR (400MHz, Chloroform-d), δ: 13.68 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz,1H),7.49–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.90–6.86(m,2H),6.73( d,J=2.3Hz,1H),6.45(m,2H),6.35(dd,J=9.0,2.5Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.91(s,3 H),3.83(s,3H),2.71–2.25(m,12H),1.82(m,2H),1.64–1.54(m,3H),1.50(m,2H),1.09(t,J=7.2Hz,3H). 13 C NMR(151MHz,Chloroform-d),δ:192.75,166.67,165.93,161.90,160.99,159 .32,142.05,138.53,132.04,131.33,129.73,128.13,125.47,123.48,116.0 5,114.91,114.52,107.61,103.92,101.07,97.73,68.01,58.75,55.91,55.6 5,55.61,53.37,52.93,52.46,29.30,26.81,24.23,12.09.ESI-HRMS:(m / z):C 37 H 46 N2O6[M+H] + :calcd:615.3436; found:615.3435.

[0159] Example 30

[0160] (E)-3-(2,4-dimethoxy-6-((E)-4-(5-(4-hydroxyethylpiperazine)pentyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-30)

[0161]

[0162] The preparation method is the same as that of Example 25, except that morpholine in Example 25 is replaced by hydroxyethylpiperazine to obtain compound I-30. mp: 93.5-94.3°C. 1H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz, 1H ),7.48–7.44(m,2H),7.34(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.92–6.84(m,3H),6.73(d,J=2.3Hz,1H),6.4 6–6.44(m,2H),6.35(dd,J=9.0,2.6Hz,1H),3.98(t,J=6.4Hz,2H),3.92(s,3H),3.91(s,3H),3.84(s,3H),3.64(t, J=5.3Hz,2H),2.76–2.55(m,10H),2.44(t,J=7.7Hz,2H),1.85–1.78(m,2H),1.65–1.58(m,2H),1.54–1.47(m,2H). 13 C NMR (151MHz, Chloroform-d), δ: 192.75, 166.66, 165.91, 161.90, 160.99, 159. 29,142.04,138.52,132.03,131.33,129.73,128.13,125.46,123.43,116.02,1 14.90,114.51,107.61,103.93,101.06,97.72,67.98,59.34,58.64,57.81,55. 90,55.64,55.60,53.38,52.92,29.81,29.27,26.75,24.19.ESI-HRMS:(m / z):C 37 H 46 N2O7[M+H] + :calcd:631.3383; found:631.3361.

[0163] Example 31

[0164] (E)-3-(2-((E)-4-(5-(benzyl(methyl)amino)pentyloxy)phenyl)-4,6-dimethoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-31)

[0165]

[0166] The preparation method is the same as that of Example 25, except that the morpholine in Example 25 is replaced by N-methylbenzylamine to obtain compound I-31. mp: 57.4-58.4°C. 1 H NMR (400MHz, Chloroform-d), δ: 13.69 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d, J = 1 5.5Hz,1H),7.49–7.45(m,2H),7.36–7.31(m,6H),6.95(d,J=16.0Hz,1H),6.91–6.87(m,2H),6.73(d,J=2 .3Hz,1H),6.45(m,2H),6.35(dd,J=9.0,2.5Hz,1H),3.98(t,J=6.5Hz,2H),3.93(s,3H),3.91(s,3H),3.8 3(s,3H),3.52(s,2H),2.42(t,2H),2.22(s,3H),1.84–1.76(m,2H),1.64–1.59(m,2H),1.54–1.47(m,2H). 13 C NMR(151MHz,Chloroform-d)δ192.76,166.67,165.93,161.91,160.99,159.35, 142.05,138.54,132.05,131.34,129.72,129.25,128.36,128.14,127.14,125. 47,123.48,116.06,114.93,114.53,107.61,103.93,101.08,97.73,68.09,62. 41,57.36,55.91,55.64,55.61,42.28,31.06,29.27,24.01.ESI-HRMS:(m / z):C 39 H 43 NO6[M+H] + :calcd:622.3169; found:622.3150.

[0167] Example 32

[0168] (E)-3-(2,4-dimethoxy-6-((E)-4-(5-(4-hydroxypiperidinyl)pentyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-32)

[0169]

[0170] The preparation method is the same as that of Example 25, except that morpholine in Example 25 is replaced by 4-hydroxypiperidine to obtain compound I-32. mp: 104.5-105.1°C. 1 H NMR (400MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz, 1H), 7.46 ( d,J=8.4Hz,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.88(d,J=8.3Hz,2H),6.73(d,J=2.3Hz,1H),6.47–6.43(m ,2H),6.35(dd,J=9.0,2.5Hz,1H),3.98(t,J=6.4Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),3.77–3.70(m,1H),2.86–2 .78(m,2H),2.41(t,J=7.5Hz,2H),2.31–2.16(m,2H),2.01–1.92(m,2H),1.86–1.79(m,2H),1.63(m,4H),1.52–1.46(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:192.76,166.64,165.92,161.90,160.99,1 59.29,142.05,138.53,132.04,131.33,129.73,128.13,125.45,123.41,11 6.01,114.90,114.50,107.61,103.93,101.06,97.72,67.97,58.55,55.90, 55.64,55.60,51.17,34.42,31.05,29.24,26.91,24.23.ESI-HRMS:(m / z):C 36 H 43 NO7[M+H] + :calcd:602.3118; found:602.3102.

[0171] Example 33

[0172] (E)-3-(2,4-dimethoxy-6-((E)-4-(6-morpholinohexyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-33)

[0173]

[0174] The preparation method is the same as that of Example 1, except that 1,2-dibromoethane in Example 1 is replaced by 1,6-dibromohexane to obtain compound I-33. mp: 97.1-98.5°C. 1 H NMR (400MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz, 1H), 7. 46(d,J=8.5Hz,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.89(d,J=8.5Hz,2H),6.73(d,J=2.3Hz,1H),6.47–6 .43(m,2H),6.35(dd,J=9.0,2.5Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),3.78–3.72(m,4H ),2.54–2.43(m,4H),2.38(t,J=7.8Hz,2H),1.86–1.74(m,2H),1.61–1.53(m,2H),1.54–1.44(m,2H),1.43–1.35(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:192.76,166.67,165.93,161.91,161.00,159 .34,142.05,138.53,132.04,131.34,129.74,128.14,125.48,123.46,116.0 4,114.93,114.52,107.61,103.94,101.07,97.73,68.07,67.06,59.19,55.9 1,55.65,55.61,53.88,31.06,29.31,27.39,26.55,26.13.ESI-HRMS:(m / z):C 36 H 43 NO7[M+H] + :calcd:602.3118; found:602.3102.

[0175] Example 34

[0176] (E)-3-(2,4-dimethoxy-6-((E)-4-(6-piperidinylhexyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-34)

[0177]

[0178] The preparation method is the same as that of Example 33, except that the morpholine in Example 33 is replaced by piperidine to obtain compound I-34. mp: 81.4-82.7°C. 1 H NMR (400MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d, J = 15.5H z,1H),7.46(d,J=8.3Hz,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.89(d,J=8.3Hz,2H),6.73(d,J= 2.3Hz,1H),6.46–6.43(m,2H),6.35(dd,J=9.0,2.5Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.90(s,3H),3. 83(s,3H),2.56–2.41(m,4H),2.37(t,J=7.9Hz,2H),1.84–1.76(m,2H),1.70–1.43(m,10H),1.42–1.35(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:δ192.74,166.65,165.92,161.89,160.98,15 9.34,142.04,138.52,132.04,131.33,129.69,128.12,125.44,123.43,116.0 2,114.92,114.51,107.57,103.92,101.07,97.71,68.08,59.47,55.89,55.6 3,55.60,54.64,31.04,29.29,27.57,26.10,25.79,24.40.ESI-HRMS:(m / z):C 37 H 45 NO6[M+H] + :calcd:600.3325; found:600.3309.

[0179] Example 35

[0180] (E)-3-(2,4-dimethoxy-6-((E)-4-(6-pyrrolehexyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-35)

[0181]

[0182] The preparation method is the same as that of Example 33, except that morpholine in Example 33 is replaced by pyrrolidine to obtain compound I-35. mp: 92.5-93.6°C. 1 H NMR (400MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz, 1H), 7. 46(d,J=8.4Hz,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.89(d,J=8.4Hz,2H),6.73(d,J=2.3Hz,1H),6.47–6 .42(m,2H),6.35(dd,J=9.0,2.6Hz,1H),3.98(t,J=6.4Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),2.77–2.64(m,4H ),2.59(t,J=8.0Hz,2H),1.93–1.83(m,4H),1.83–1.76(m,2H),1.71–1.61(m,2H),1.55–1.48(m,2H),1.46–1.37(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:192.76,166.65,165.93,161.91,160.99,1 59.33,142.06,138.53,132.05,131.34,129.72,128.13,125.46,123.45,11 6.03,114.93,114.52,107.60,103.93,101.08,97.73,68.04,56.49,55.91, 55.65,55.61,54.22,31.06,29.26,27.43,26.05,23.51.ESI-HRMS:(m / z):C 36 H 43 NO6[M+H] + :calcd:586.3170; found:586.3154.

[0183] Example 36

[0184] (E)-3-(2,4-dimethoxy-6-((E)-4-(6-(4-methylpiperazine)hexyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-36)

[0185]

[0186] The preparation method is the same as that of Example 33, except that morpholine in Example 33 is replaced by methylpiperazine to obtain compound I-36. mp: 76.2-77.1°C. 1 H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.25 (d, J = 15.6Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d, J = 15.6Hz ,1H),7.48–7.44(m,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.91–6.87(m,2H),6.73(d,J=2.2Hz,1 H),6.46–6.44(m,2H),6.35(dd,J=9.0,2.4Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.91(s,3H),3.83(s,3H ),2.65–2.33(m,10H),2.29(s,3H),1.82–1.78(m,2H),1.56–1.52(m,2H),1.51–1.47(m,2H),1.41–1.36(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:192.81,166.71,165.98,161.95,161.04,1 59.43,142.08,138.54,132.10,131.36,129.81,128.15,125.56,123.62,11 6.19,115.02,114.62,107.57,104.08,101.17,97.83,68.18,58.79,55.94, 55.64,55.29,53.38,46.16,29.36,27.52,26.98,26.16.ESI-HRMS:(m / z):C 37 H 46 N2O6[M+H] + :calcd:615.3434; found:615.3433.

[0187] Example 37

[0188] (E)-3-(2,4-dimethoxy-6-((E)-4-(6-(4-ethylpiperazine)hexyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-37)

[0189]

[0190] The preparation method is the same as that of Example 33, except that morpholine in Example 33 is replaced by ethylpiperazine to obtain compound I-37. mp: 63.5-64.2°C. 1 H NMR (600MHz, Chloroform-d), δ: 13.65 (s, 1H), 8.24 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.61 (d, J = 15.5Hz, 1H), 7.4 6(d,J=8.3Hz,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.89(d,J=8.3Hz,2H),6.73(d,J=2.2Hz,1H),6.46–6.4 4(m,2H),6.34(dd,J=9.0,2.4Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),2.65–2.42(m,10H), 2.37(t,J=7.9Hz,2H),1.82–1.78(m,2H),1.56–1.52(m,2H),1.51–1.47(m,2H),1.41–1.35(m,2H),1.09(t,J=7.2Hz,3H). 13 C NMR (151MHz, Chloroform-d), δ: 192.82, 166.71, 165.98, 161.96, 161.05, 159. 42,142.09,138.55,132.11,131.36,129.82,128.16,125.56,123.60,116.18,1 15.02,114.62,107.58,104.08,101.17,97.83,68.17,59.39,58.77,57.91,55. 94,55.64,55.62,53.46,53.03,29.35,27.51,26.98,26.15.ESI-HRMS:(m / z):C 38 H 48 N2O6[M+H] +:calcd:629.3592; found:629.3572.

[0191] Example 38

[0192] (E)-3-(2,4-dimethoxy-6-((E)-4-(6-(4-hydroxyethylpiperazine)hexyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-38)

[0193]

[0194] The preparation method is the same as that of Example 33, except that morpholine in Example 33 is replaced by hydroxyethylpiperazine to obtain compound I-38. mp: 68.3-69.1°C. 1 H NMR (600MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz, 1H), 7. 48–7.45(m,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.90–6.88(m,2H),6.73(d,J=2.2Hz,1H),6.46–6.43(m ,2H),6.35(dd,J=9.0,2.4Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),3.61(t,J=5.4Hz,2H), 2.59–2.46(m,10H),2.34(t,J=7.8Hz,2H),1.81–1.78(m,2H),1.54–1.51(m,2H),1.50–1.47(m,2H),1.39–1.35(m,2H). 13 C NMR (151MHz, Chloroform-d), δ: 192.82, 166.71, 165.98, 161.96, 161.05, 159. 42,142.09,138.55,132.11,131.36,129.82,128.16,125.56,123.60,116.18,1 15.02,114.62,107.58,104.08,101.17,97.83,68.17,59.39,58.77,57.91,55. 94,55.64,55.62,53.46,53.03,29.35,27.51,26.98,26.15.ESI-HRMS:(m / z):C38 H 48 N2O7[M+H] + :calcd:645.3542; found:645.3519.

[0195] Example 39

[0196] (E)-3-(2-((E)-4-(6-(benzyl(methyl)amino)hexyloxy)phenyl)-4,6-dimethoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-39)

[0197]

[0198] The preparation method is the same as that of Example 33, except that the morpholine in Example 33 is replaced by N-methylbenzylamine to obtain compound I-39. mp: 56.3-57.2°C. 1 H NMR (600MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.69 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz, 1 H),7.48–7.45(m,2H),7.36–7.30(m,6H),6.95(d,J=16.0Hz,1H),6.91–6.88(m,2H),6.73(d,J=2.2Hz,1H),6.47–6 .44(m,2H),6.35(dd,J=9.0,2.4Hz,1H),3.97(t,J=6.5Hz,2H),3.92(s,3H),3.91(s,3H),3.83(s,3H),3.50(s,2H ),2.39(t,J=7.4Hz,2H),2.20(s,3H),1.83–1.77(m,2H),1.59–1.55(m,2H),1.50–1.45(m,2H),1.42–1.38(m,2H). 13C NMR (151MHz, Chloroform-d), δ: 192.83, 166.72, 166.00, 161.97, 161.05, 159. 46,142.10,138.56,132.12,131.38,129.81,129.27,128.37,128.17,127.15, 125.57,123.65,116.21,115.04,114.63,107.58,104.09,101.19,97.84,68.2 2,62.42,57.47,55.95,55.64,42.29,29.39,27.31,26.12.ESI-HRMS:(m / z):C 40 H 45 NO6[M+H] + :calcd:636.3327; found:636.3304.

[0199] Example 40

[0200] (E)-3-(2,4-dimethoxy-6-((E)-4-(6-(4-hydroxypiperidinyl)hexyloxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (Compound I-40)

[0201]

[0202] The preparation method is the same as that of Example 33, except that morpholine in Example 33 is replaced by 4-hydroxypiperidine to obtain compound I-40. mp: 91.4-92.8°C. 1H NMR (600MHz, Chloroform-d), δ: 13.66 (s, 1H), 8.25 (d, J = 15.5Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 7.62 (d, J = 15.5Hz, 1H), 7.48–7.45 (m ,2H),7.33(d,J=16.0Hz,1H),6.94(d,J=16.0Hz,1H),6.90–6.88(m,2H),6.73(d,J=2.4Hz,1H),6.46–6.44(m,2H),6.35(dd,J=9.0, 2.6Hz,1H),3.98(t,J=6.5Hz,2H),3.92(s,3H),3.90(s,3H),3.83(s,3H),3.74–3.68(m,1H),2.80–2.76(m,2H),2.35(t,J=7.6Hz,2 H),2.14(s,2H),1.94–1.90(m,2H),1.82–1.78(m,2H),1.62–1.59(m,2H),1.56–1.53(m,2H),1.51–1.47(m,2H),1.40–1.35(m,2H). 13 C NMR(151MHz,Chloroform-d),δ:192.83,166.70,165.98,161.96,161.05,1 59.42,142.10,138.56,132.11,131.37,129.81,128.16,125.54,123.58,11 6.16,115.02,114.61,107.59,104.07,101.17,97.82,68.16,58.66,55.94, 55.64,55.62,51.21,34.55,29.33,27.53,27.16,26.12.ESI-HRMS:(m / z):C 37 H 45 NO7[M+H] + :calcd:616.3274; found:616.3266.

[0203] Evaluation of anti-inflammatory activity

[0204] 1. Detect the cytotoxicity of the compound using the MTT assay

[0205] The MTT method was used to detect the toxicity of the compounds, paeonol and pterostilbene on RAW264.7 cells.

[0206] During the logarithmic growth phase, RAW264.7 cells were harvested, the cell concentration was adjusted, and the cells were seeded into 96-well plates. After 24 hours of incubation, the medium was discarded, the plates were rinsed with PBS buffer, and the test compound was added at various concentrations. The plates were incubated for 24 hours at 37°C in a 5% CO2 incubator. The remaining medium was removed, and MTT solution was added. The plates were incubated for another 4 hours at 37°C in a 5% CO2 incubator. The supernatant was discarded, and DMSO solution was added to each well. The plates were shaken for 10 minutes, and the absorbance of each well was measured at 490 nm using a microplate reader.

[0207] The experimental results showed that the compound showed good safety when incubated with RAW264.7 at a concentration of 5μM for 24h. Figure 1 (I-41 is paeonol, I-42 is pterostilbene, I-43 is intermediate B, and I-44 is the methylation product of intermediate B).

[0208] 2. Griess experiment

[0209] The Griess method was used to detect the inhibitory effects of all compounds as well as paeonol and pterostilbene on LPS-induced NO production, which can reflect the anti-inflammatory activity of the compounds to a certain extent.

[0210] During the logarithmic growth phase of the cells, RAW264.7 cells were collected, the cell concentration was adjusted, and the cells were seeded into 96-well plates. After incubation for 24 hours, the culture medium was discarded, the cells were rinsed with PBS buffer, and different concentrations of the test compound were added. The cells were cultured in a 37°C, 5% CO2 incubator for 1 hour, and then LPS solution was added. The cells were cultured in a 37°C, 5% CO2 incubator for another 24 hours. The supernatant was collected according to the instructions of the NO assay kit, and the absorbance of each well was measured at 540 nm using a microplate reader.

[0211] At a concentration of 4 μM, compounds I-2, I-4, I-6, I-11, I-13, I-14, and I-15 had a strong inhibitory effect on NO release in RAW264.7 cells. The results are shown in Tables 1 and Figure 2 (I-41 is paeonol, I-42 is pterostilbene, I-43 is intermediate B, I-44 is intermediate B′ (methylated product of B), and indomethacin is a positive control drug).

[0212]

[0213] The anti-NO secretion activity of the compounds was further tested, with indomethacin as the control, and the results are shown in Table 1. Among them, compound I-6 has the strongest activity, which is significantly better than indomethacin, IC 50 =2.24±0.65μM.

[0214] Table 1

[0215] Group <![CDATA[IC 50 ]]> I-2 5.02±0.85μM I-4 2.81±0.53μM I-6 2.24±0.65μM I-11 3.60±0.93μM I-13 4.80±0.76μM I-14 2.69±0.63μM I-15 3.68±0.56μM Indomethacin 10.66±0.81μM

[0216] 3. Western blot experiment

[0217] The compound with the best activity was evaluated by Griess test, and then a protein blotting experiment was performed: using β-actin as the internal reference and Bay11-7082 as the control drug, the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IκB and p65 proteins in the NF-κB inflammatory signaling pathway, and ERK, JNK, and P38 proteins in the MAPKs signaling pathway in the LPS cell model were detected to further analyze the anti-inflammatory activity of the optimal compound.

[0218] The experimental steps are as follows: cell treatment - extraction of cell protein - BCA protein quantification - SDS-PAGE gel electrophoresis (electrophoresis, transfer, sealing, incubation, protein development). First, cells in the logarithmic growth phase are inoculated into culture dishes and placed in a carbon dioxide constant temperature incubator overnight. Four groups of experiments need to be set up, namely the model group, the experimental group, the blank control group and the positive control group. After the cells are cultured overnight, the culture medium of the blank group and the model group is replaced with fresh culture medium. The positive control drug Bay11-7082 is added to the culture medium at a specific concentration. Similarly, the test compound I-6 is added to the experimental group culture medium at different concentrations (4μM, 2μM, 1μM). After 1 hour, 1μg / mL LPS is added for stimulation. After 24 hours, the cells are concentrated, and then RIPA lysis buffer, protease inhibitor PMSF and phosphatase inhibitor are added in sequence for lysis for 1 hour. Place in a refrigerated centrifuge for centrifugation, and the supernatant is taken for protein separation by SDS-PAGE gel electrophoresis. After removing the gel, cut the target protein blot and transfer it to a PVDF membrane. Block it with 5% skim milk powder for 2 hours. Wash it three times with TBST for 15 minutes. Then, incubate it with primary and secondary antibodies. Finally, apply LumiGLO solution to the PVDF membrane for protein visualization.

[0219] like Figure 3 As shown, the LPS group and the blank group had completely different protein expression levels, indicating that the model was successfully established. After treating LPS-induced cells with compound I-6, protein expression was significantly reduced, and the higher the compound concentration used, the lower the protein expression level, indicating that the inhibitory effect of compound I-6 on the above two proteins was concentration-dependent within this concentration range. This experiment shows that compound I-6 can exert an anti-inflammatory effect by inhibiting the expression of iNOS and COX-2 proteins.

[0220] like Figure 4As shown, the protein expression levels of p-P65 and p-IκB in the LPS group and the blank group were significantly different, indicating successful model establishment. After treatment with compound I-6, the phosphorylated IκB and P65 protein blot bands were significantly lighter than those in the LPS group. Higher compound concentrations resulted in lighter phosphorylated protein blots and stabilized IκB and P65 protein expression. This suggests that compound I-6 can inhibit the phosphorylation of IκB and P65, inhibiting the transduction of the NF-κB signaling pathway and exerting its anti-inflammatory effects.

[0221] like Figure 5 As shown in the figure, there are significant differences in the protein blots of phosphorylated JNK, P38, and ERK between the LPS group and the blank group, indicating that the model was successfully established. After treatment with compound I-6, the bands of p-JNK and p-P38 became significantly lighter, indicating that compound I-6 has a significant inhibitory effect on the phosphorylation of JNK and P38, but has no significant inhibitory effect on the phosphorylation of ERK. This result shows that compound I-6 can exert an anti-inflammatory effect by inhibiting the phosphorylation of JNK and P38 in the MAPK pathway.

[0222] The basic principles, main features and advantages of the present invention are shown and described above. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention, and such changes and modifications fall within the scope of the invention as claimed.

Claims

1. A pterostilbene chalcone compound or a pharmaceutically acceptable salt thereof, characterized in that: The pterostilbene chalcone compound is selected from one of the following compounds: 、 、 、 、 、 、 。 2. A method for preparing the pterostilbene chalcone compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The preparation method comprises: S1. In the presence of an acidic chloride, pterostilbene is reacted with a formylating agent to obtain intermediate A. The reaction formula is as follows: ； S2. In the presence of an alkaline reagent, intermediate A is reacted with paeonol in a solvent to obtain intermediate B. The reaction formula is as follows: ； S3. In the presence of an alkaline reagent, reacting intermediate B with a dihaloalkane in a solvent to obtain intermediate C, wherein the dihaloalkane is 1,2-dibromoethane or 1,3-dibromopropane; S4. In the presence of an alkaline reagent, the intermediate C is reacted with a nitrogen-containing compound in a solvent to obtain the pterostilbene chalcone compound; the nitrogen-containing compound is piperidine, methylpiperazine, hydroxyethylpiperazine, pyrrolidine, ethylpiperazine, hydroxyethylpiperazine or N -One of the methylbenzylamines.

3. The preparation method according to claim 2, characterized in that In step S1, the mass volume ratio of pterostilbene to the formylating agent is 10 g:10-30 mL.

4. The preparation method according to claim 3, characterized in that In step S1, the formylating agent is N,N -dimethylformamide.

5. The preparation method according to claim 3, characterized in that In step S1, the reaction temperature is 35-45° C., and the reaction time is 5-7 h.

6. The preparation method according to claim 2, characterized in that In step S2, the molar ratio of intermediate A to paeonol is 1:1-3.

7. The preparation method according to claim 6, characterized in that In step S2, the alkaline reagent is pyrrolidine, and the solvent is anhydrous ethanol.

8. The preparation method according to claim 6, characterized in that In step S2, the reaction temperature is 35-45° C., and the reaction time is 30-40 h.

9. The preparation method according to claim 2, characterized in that In step S3, the molar ratio of intermediate B to dihalogenated alkane is 1:4-6; and / or, in step S4, the molar ratio of intermediate C to nitrogen-containing compound is 1:2-4.

10. The preparation method according to claim 9, characterized in that In step S3, the alkaline reagent is potassium carbonate, and the solvent is N,N -dimethylformamide.

11. The preparation method according to claim 9, characterized in that In step S3, the reaction temperature is room temperature, and the reaction time is 7 to 9 hours.

12. The preparation method according to claim 9, characterized in that In step S4, the alkaline reagent is potassium carbonate, and the solvent is anhydrous acetonitrile.

13. The preparation method according to claim 9, characterized in that In step S4, the reaction temperature is 45-55° C., and the reaction time is 5-7 h.

14. A pharmaceutical composition, characterized in that: The pharmaceutical composition is composed of a therapeutically effective amount of the pterostilbene chalcone compound or a pharmaceutically acceptable salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.

15. Use of the pterostilbene chalcone compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an anti-inflammatory drug.

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