Amine-alkylated paeonol chalcone derivatives, their preparation methods and pharmaceutical uses

Abstract

This invention belongs to the field of pharmaceutical synthesis technology, specifically disclosing an aminoalkylated paeonol chalcone derivative, its preparation method, and its pharmaceutical uses. The aminoalkylated paeonol chalcone derivative of this invention is shown in general formula (I). It is obtained by using paeonol as a raw material, linking the phenolic hydroxyl groups on paeonol to organic amine fragments using different linking arms, and then performing Claisen-Schmidt condensation with various benzaldehydes. In vitro antitumor experiments have demonstrated that the derivative of this invention exhibits good antitumor activity against human colon cancer cells (HCT116), human liver cancer cells (HepG2), human lung cancer cells (A549), and human osteosarcoma cells (U2OS), and has significantly better water solubility than paeonol chalcone. It holds promise for development as a therapeutic drug for various cancers such as colon cancer, osteosarcoma, lung cancer, and liver cancer, with broad clinical application prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and specifically discloses an amine-alkylated paeonol chalcone derivative, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Conventional clinical treatments for cancer include radiotherapy, chemotherapy, immunotherapy, and targeted therapy. However, these treatments have inherent limitations, such as multidrug resistance and the induction of short-term and long-term multi-organ damage, ultimately leading to a significant decline in the quality of life and life expectancy of cancer survivors. Therefore, developing highly selective anticancer drugs with fewer side effects to improve cancer treatment outcomes remains one of the most important problems that urgently need to be solved.

[0003] Chalcones are a class of flavonoids widely found in nature, including fruits, vegetables, spices, and tea. They exhibit clinical potential for treating various diseases, such as cancer, inflammation, diabetes, bacteria, and oxidation. Paeonol chalcone is a chalcone compound obtained by structural modification of paeonol (the main active ingredient in peony bark), a traditional Chinese medicine. It possesses enhanced antitumor activity; however, its poor water solubility affects its drug-like properties, and its antitumor efficacy still needs further improvement. Summary of the Invention

[0004] To address the aforementioned problems with the antitumor effects of paeonol chalcone compounds, this invention provides an amine-alkylated paeonol chalcone derivative, its preparation method, and its pharmaceutical applications. Using paeonol as a raw material, this invention connects the phenolic hydroxyl groups on paeonol to organic amine fragments via different linking arms, and then performs Claisen-Schmidt condensation with various benzaldehydes to obtain the target compound with good water solubility and significant antitumor effects.

[0005] In a first aspect, the present invention provides an aminoalkylated paeonol chalcone derivative of general formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Where: n is an integer from 1 to 10; R1 is a six-membered saturated heterocyclic group containing only N heteroatoms or containing O heteroatoms in addition to N heteroatoms, and the six-membered saturated heterocyclic group is unsubstituted or substituted by substituents selected from C1-C6 alkyl or C1-C6 hydroxyalkyl groups; R2 is a halogen atom.

[0008] In some implementations, n is an integer from 2 to 7.

[0009] In some implementations, there are 1 to 3 N heteroatoms, preferably 1 to 2.

[0010] In some implementations, there are 1 to 3 O heteroatoms, preferably 1 to 2.

[0011] In some embodiments, the six-membered saturated heterocyclic group is unsubstituted or substituted by a substituent selected from C1-C3 alkyl or C1-C3 hydroxyalkyl groups.

[0012] In some implementations, R1 is morpholino, piperidino, N -Methylpiperazinyl, N -Ethylpiperazinyl or 4-hydroxyethylpiperazinyl.

[0013] In some implementations, R2 is an ortho substitution and / or para substitution.

[0014] In some implementations, R2 is F or Cl.

[0015] In some embodiments, the amine-alkylated paeonol chalcone derivatives represented by general formula (I) are selected from the following (I1) to (I2) 26 Any of the following compounds: 3-(4-chlorophenyl)-1-(4-methoxy-2-(2-(morpholin-4-yl)ethoxy)phenyl)prop-2-en-1-one (Ⅰ1); 3-(4-chlorophenyl)-1-(4-methoxy-2-(3-(morpholin-4-yl)propoxy)phenyl)prop-2-en-1-one (Ⅰ2); 3-(4-chlorophenyl)-1-(4-methoxy-2-(4-(morpholin-4-yl)butoxy)phenyl)prop-2-en-1-one (Ⅰ3); 3-(2-chlorophenyl)-1-(4-methoxy-2-(4-(morpholin-4-yl)butoxy)phenyl)prop-2-en-1-one (Ⅰ4); 3-(2,4-dichlorophenyl)-1-(4-methoxy-2-(4-(morpholin-4-yl)butoxy)phenyl)prop-2-en-1-one - Ketone (Ⅰ5); 3-(4-chlorophenyl)-1-(4-methoxy-2-(5-(morpholin-4-yl)pentoxy)phenyl)prop-2-en-1-one (Ⅰ6); 3-(4-chlorophenyl)-1-(4-methoxy-2-(6-(morpholin-4-yl)hexyl)phenyl)prop-2-en-1-one (Ⅰ7); 3-(4-chlorophenyl)-1-(4-methoxy-2-(7-(morpholin-4-yl)heptoxy)phenyl)prop-2-en-1-one (Ⅰ8); 3-(4-chlorophenyl)-1-(4-methoxy-2-(4-(piperidin-1-yl)butoxy)phenyl)prop-2-en-1-one (Ⅰ9); 3-(2-chlorophenyl)-1-(4-methoxy-2-(4-(piperidin-1-yl)butoxy)phenyl)prop-2-en-1-one (Ⅰ5) 10 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)butoxy)phenyl)prop-2-en-1-one (I) 11); 3-(2-chlorophenyl)-1-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)butoxy)phenyl)prop-2-en-1-one (I) 12 );

[0016] 3-(4-chlorophenyl)-1-(2-(4-(4-ethylpiperazin-1-yl)butoxy)-4-methoxyphenyl)prop-2-en-1-one (I) 13 );

[0017] 3-(2-chlorophenyl)-1-(2-(4-(4-ethylpiperazin-1-yl)butoxy)-4-methoxyphenyl)prop-2-en-1-one (I) 14 ); 3-(4-chlorophenyl)-1-(2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)butoxy)-4-methoxyphenyl)prop-2-en-1-one (I) 15 ); 3-(2-chlorophenyl)-1-(2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)butoxy)-4-methoxyphenyl)prop-2-en-1-one (I) 16 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)prop-2-en-1-one (I) 17 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)prop-2-en-1-one (I) 18 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (I) 19 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (I) 20 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(5-(4-methylpiperazin-1-yl)pentoxy)phenyl)prop-2-en-1-one (I) 21 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(5-(4-methylpiperazin-1-yl)pentoxy)phenyl)prop-2-en-1-one (I) 22 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(6-(4-methylpiperazin-1-yl)hexyloxy)phenyl)prop-2-en-1-one (I) 23 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(6-(4-methylpiperazin-1-yl)hexyloxy)phenyl)prop-2-en-1-one (I) 24); 3-(4-chlorophenyl)-1-(4-methoxy-2-(7-(4-methylpiperazin-1-yl)heptoxy)phenyl)prop-2-en-1-one (I) 25 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(7-(4-methylpiperazin-1-yl)heptoxy)phenyl)prop-2-en-1-one (I) 26 ).

[0018] In a second aspect, the present invention provides a method for preparing the amine-alkylated paeonol chalcone derivative represented by formula (I) above, comprising:

[0019] Step 1: The compound shown in formula (1) is reacted with a dihaloalkane by the Williamson reaction to obtain the compound shown in formula (2);

[0020]

[0021] The molar ratio of the compound shown in formula (1) to the dihaloalkane is 1:2~4; the reaction is carried out in the presence of organic solvent and alkali, the reaction temperature is 40~50℃, and the reaction time is 6~8 h.

[0022] Step 2: React the compound shown in formula (2) with different organic amines to obtain the compound shown in formula (3);

[0023]

[0024] The molar ratio of the compound shown in formula (2) to the organic amine is 1:2~4; the reaction is carried out in the presence of an organic solvent, the reaction temperature is 50~60℃, and the reaction time is 7~9 h.

[0025] Step 3: The compound shown in formula (3) and the compound shown in formula (4) are subjected to a Claisen-Schmidt condensation reaction to obtain the compound shown in formula (Ⅰ);

[0026]

[0027] The molar ratio of the compound shown in formula (3) to the compound shown in formula (4) is 1:1~2; the reaction is carried out in the presence of an organic solvent, the reaction temperature is 40~50℃, and the reaction time is 0.5~1.5h.

[0028] In the above reaction equations, X is a halogen atom, and the definitions of n, R1, and R2 are the same as before.

[0029] All of the above intermediates or target compounds can be purified using conventional separation techniques and, if necessary, converted into addition salts with pharmaceutically acceptable acids.

[0030] Thirdly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned amine-alkylated paeonol chalcone derivative of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0031] Fourthly, the present invention provides the use of the amine-alkylated paeonol chalcone derivative of the aforementioned general formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in the preparation of a medicament for treating cancer, specifically, the cancer being selected from colon cancer, osteosarcoma, lung cancer or liver cancer.

[0032] The beneficial effects of this invention are as follows:

[0033] This invention provides a series of novel structural compounds, particularly those with enhanced antitumor activity through the introduction of different amine alkyl groups at the 2-position of paeonol, via hydrogen or ionic bonds with receptors. The hydrophilicity of the amine fragments also improves the water solubility of the compounds. In vitro antitumor experiments have demonstrated good antitumor activity against human colon cancer cells (HCT116), human liver cancer cells (HepG2), human lung cancer cells (A549), and human osteosarcoma cells (U2OS). Water solubility tests show that the synthesized compounds are more water-soluble than paeonol chalcone. The compounds involved in this invention hold promise for the treatment of various cancers, including colon cancer, osteosarcoma, lung cancer, and liver cancer, and have broad clinical application prospects. Detailed Implementation

[0034] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0035] Terminology Definition

[0036] Unless otherwise stated, the technical terms used in this invention have the meanings commonly understood by those skilled in the art. The laboratory procedures involved are standard procedures widely used by those skilled in the art. To better understand this invention, definitions and explanations of relevant terms are provided below.

[0037] The term “six-membered saturated heterocyclic group” as used in this article refers to a group in a saturated ring system with a total of 6 cyclic carbon atoms and cyclic heteroatoms.

[0038] As used in this article, the term "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0039] As used in this article, the term "C1-C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms.

[0040] As used herein, the term “C1-C6 hydroxyalkyl” refers to a straight-chain or branched alkyl group with 1 to 6 carbon atoms that is replaced by 1 to 5 hydroxyl groups.

[0041] As used in this article, the term "C1-C3 hydroxyalkyl" refers to a straight-chain or branched alkyl group with 1 to 3 carbon atoms that is replaced by 1 to 2 hydroxyl groups.

[0042] As used in this article, the term "halogen atom" refers to a fluorine, chlorine, bromine, or iodine atom.

[0043] This invention uses paeonol (1) as the starting material, and synthesizes compounds (2a~2f) via Williamson reaction and corresponding dibromoalkane, and then links them with different organic amine fragments to synthesize compounds (3a~3o); compounds (3a~3o) are then synthesized by Claisen-Schmidt condensation with various benzaldehyde compounds to synthesize the target compound. The synthetic route is as follows:

[0044]

[0045] Reaction conditions and reagents: I: DMF, NaOH, Br(CH2) n Br, 45℃; II: CH3CN, morpholine, piperidine N -Methylpiperazine, N -Ethylpiperazine, hydroxyethylpiperazine, 55℃; III: 50% NaOH, 95% EtOH, 45℃.

[0046] Example 1

[0047] Synthesis of intermediate 2a

[0048] 1 mmol (166 mg) of paeonol and 3 mmol (120 mg) of sodium hydroxide were added to a reaction flask, followed by 5 mL of DMF. The mixture was refluxed and stirred at 45 °C. After 20 min, 3 mmol (0.26 mL) of 1,2-dibromoethane was added. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The mixture was filtered, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was separated by column chromatography [V(ethyl acetate):V(petroleum ether) = 1:20] to give 133 mg of white solid, with a yield of 49.0%.

[0049] Synthesis of intermediate 3a

[0050] 1 mmol (272 mg) of compound 2a, 3 mmol (0.26 mL) of morpholine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 134.8 mg of a pale yellow solid, with a yield of 48.2%.

[0051] Synthesis of target compound I1

[0052] 1 mmol (279 mg) of 3a and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I1, 205 mg, yield 51.3%, mp: 101.2–101.9 °C. 1 H NMR (600 MHz, Chloroform-d) δ 7.76 (d, J = 8.6 Hz, 1H, Ar-H), 7.60 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.52 (d, J = 7.5 Hz, 2H, Ar-H), 7.36 (d,J = 8.0 Hz, 2H, Ar-H), 7.31 (d, J = 8.3 Hz, 1H, -CH=CH-), 6.58 (d, J = 8.7Hz, 1H, Ar-H), 6.48 (s, 1H, Ar-H), 4.18 (t, J = 5.5 Hz, 2H, -OCH2-), 3.86 (s,3H, -CH3), 3.66 – 3.60 (m, 4H, -OCH2-), 2.80 (t, J = 5.5 Hz, 2H, -NCH2-), 2.48 (d, J = 5.7 Hz, 4H, -NCH2-). 13C NMR (151 MHz, CDCl3) δ 190.20, 164.29, 159.59,140.24, 135.83, 133.99, 133.03, 129.39, 129.14, 127.92, 122.30, 105.73,99.60, 66.81, 66.71, 57.61, 55.61, 54.05.ESI-MS, C 22 H 24 ClNO4, measured (calculated), m / z: 402.1464 (402.1472) [M+H] + .

[0053] Example 2

[0054] Synthesis of intermediate 2b

[0055] 1 mmol (166 mg) of paeonol and 3 mmol (120 mg) of sodium hydroxide were added to a reaction flask, followed by 5 mL of DMF. The mixture was refluxed and stirred at 45 °C. After 20 min, 3 mmol (0.3 mL) of 1,3-dibromopropane was added. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The mixture was filtered, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was separated by column chromatography [V(ethyl acetate):V(petroleum ether) = 1:20] to give 171.6 mg of a white solid, with a yield of 60.0%.

[0056] Synthesis of intermediate 3b

[0057] 1 mmol (286 mg) of compound 2b, 3 mmol (0.26 mL) of morpholine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC. After 7 h, the reaction mixture was stopped, evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 162.3 mg of a pale yellow solid, with a yield of 55.4%.

[0058] Synthesis of target compound I2

[0059] 1 mmol (293 mg) of 3b and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I2, 190 mg, yield 45.8%, mp: 69.4–70.3 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.76 (d, J = 8.5 Hz, 1H, Ar-H), 7.59 (d, J =15.7 Hz, 1H, -CH=CH-), 7.50 (d, J = 8.3 Hz, 2H, Ar-H), 7.36 (d, J = 8.1 Hz, 1H, -CH=CH-), 7.31 (d, J = 9.6 Hz, 2H, Ar-H), 6.56 (d, J = 8.6 Hz, 1H, Ar-H), 6.48 (s,1H, Ar-H), 4.10 (t, 2H, -OCH2-), 3.86 (s, 3H, -CH3), 3.62 (t, J = 7.9, 6.4 Hz,4H, -OCH2-), 2.45 (s, 2H, -NCH2-), 2.28 (s, 4H, -NCH2-), 1.98 (s, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 190.29, 164.36, 159.85, 139.93, 135.78, 134.04,132.99, 129.36, 129.16, 128.26, 128.05, 105.42, 99.36, 66.87, 66.84, 55.60,55.56, 53.58, 26.44.ESI-MS, C 23 H 26 ClNO4, measured (calculated), m / z: 416.1629 (416.1618) [M+H]+ .

[0060] Example 3

[0061] Synthesis of intermediate 2c

[0062] 1 mmol (166 mg) of paeonol and 3 mmol (120 mg) of sodium hydroxide were added to a reaction flask, followed by 5 mL of DMF. The mixture was refluxed and stirred at 45 °C. After 20 min, 3 mmol (0.3 mL) of 1,4-dibromobutane was added. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The mixture was filtered, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was separated by column chromatography [V(ethyl acetate):V(petroleum ether) = 1:20] to give 174 mg of white solid, with a yield of 58.0%.

[0063] Synthesis of intermediate 3c

[0064] 1 mmol (300 mg) of compound 2c, 3 mmol (0.26 mL) of morpholine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 162.3 mg of a pale yellow oil, with a yield of 52.3%.

[0065] Synthesis of target compound I3

[0066] 1 mmol (307 mg) of 3c and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I3, 179.3 mg, yield 41.8%, mp: 54.2–55.2 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.76 (d, J = 8.6 Hz, 1H, Ar-H), 7.59 (d,J =15.8 Hz, 1H, -CH=CH-), 7.53 (d, J = 15.5 Hz, 1H, -CH=CH-), 7.51 (d, J = 8.2 Hz, 2H, Ar-H), 7.36 (d, J = 8.4 Hz, 2H, Ar-H), 6.56 (d, J = 8.6 Hz, 1H, Ar-H), 6.48(d, J = 2.3 Hz, 1H, Ar-H), 4.10 (t, J = 6.1 Hz, 2H, -OCH2), 3.86 (s, 3H, -CH3), 3.62 (q, J = 4.5 Hz, 4H, -OCH2), 2.44 (t, J = 7.3 Hz, 2H, -NCH2-), 2.27 (d, J = 7.0Hz, 4H, -NCH2-), 2.00 – 1.94 (m, 2H, -CH2-), 1.79 – 1.65 (m, 2H, -CH2-). 13 C NMR(151 MHz, CDCl3) δ 190.24, 164.35, 159.86, 139.89, 135.77, 134.06, 132.99,129.36, 129.16, 128.07, 122.19, 105.41, 99.37, 68.49, 66.88, 58.46, 55.60,53.61, 27.28, 26.48.ESI-MS, C 24 H 28 ClNO4, measured (calculated), m / z: 430.1776 (430.1785) [M+H] + .

[0067] Example 4

[0068] Synthesis of target compound I4

[0069] 1 mmol (307 mg) of 3c and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I4, 165.1 mg, yield 38.5%, mp: 80.4–81.2 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 8.02 (d, J = 15.8 Hz, 1H, -CH=CH-),7.77 (d, J = 8.6 Hz, 1H, Ar-H), 7.68 (d, J = 9.3 Hz, 1H, Ar-H), 7.53 (d, J = 15.8Hz, 1H, -CH=CH-), 7.42 (d, J = 7.5 Hz, 1H, Ar-H), 7.30 (dd, J = 7.5, 2.1 Hz, 1H,Ar-H), 7.27 (dd, J = 7.5, 1.9 Hz, 1H, Ar-H), 6.56 (dd, J = 8.6, 2.2 Hz, 1H, Ar-H), 6.46 (d, J = 2.1 Hz, 1H, Ar-H), 4.06 (t, J = 6.2 Hz, 2H, -OCH2), 3.86 (s, 3H,-CH3), 3.62 (t, J = 4.5 Hz, 4H, -OCH2), 2.26 (d, J = 7.8 Hz, 4H, -NCH2-), 2.24 (d, J = 7.5 Hz, 2H, -NCH2-), 1.85 – 1.79 (m, 2H, -CH2-), 1.59 (p, J = 7.5 Hz, 2H, -CH2-). 13C NMR (151 MHz, CDCl3) δ 190.48, 164.45, 160.03, 137.25, 135.52,133.88, 133.16, 130.76, 130.42, 130.03, 127.57, 127.07, 122.24, 105.46,99.40, 68.60, 67.02, 58.57, 55.70, 53.65, 27.38, 23.28.ESI-MS, C 24 H 28 ClNO4, measured (calculated), m / z: 430.1776 (430.1785) [M+H] + .

[0070] Example 5

[0071] Synthesis of target compound I5

[0072] 1 mmol (307 mg) of 3c and 1.75 mmol (306 mg) of 2,4-dichlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 50 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I5, 120 mg, yield 26%, mp: 75.3–76.1 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.94 (d, J = 15.9 Hz, 1H, -CH=CH-),7.77 (d, J = 8.7 Hz, 1H, Ar-H), 7.61 (d, J = 8.5 Hz, 1H, Ar-H), 7.52 (d, J = 15.8Hz, 1H, -CH=CH-), 7.45 (d, J = 2.1 Hz, 1H, Ar-H), 7.28 – 7.25 (m, 1H, Ar-H), 6.56 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.46 (d, J= 2.3 Hz, 1H, Ar-H), 4.06 (t, J =6.1 Hz, 2H, -OCH2), 3.86 (s, 3H, -CH3), 3.64 (t, J = 4.6 Hz, 4H, -OCH2), 2.30(s, 4H, -NCH2-), 2.25 (t, J = 7.5 Hz, 2H, -NCH2-), 1.83 – 1.78 (m, 2H, -CH2-), 1.59 (p, J = 7.6 Hz, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 190.28, 164.81,160.30, 136.24, 136.14, 136.08, 133.44, 132.76, 130.62, 130.41, 128.49,127.76, 122.26, 105.75, 99.62, 68.81, 67.22, 58.77, 55.93, 53.91, 27.58,23.46.ESI-MS, C 24 H 28 Cl₂NO₄, measured (calculated) value, m / z: 464.1386 (464.1395) [M+H] + .

[0073] Example 6

[0074] Synthesis of intermediate 2d

[0075] 1 mmol (166 mg) of paeonol and 3 mmol (120 mg) of sodium hydroxide were added to a reaction flask, followed by 5 mL of DMF. The mixture was refluxed and stirred at 45 °C. After 20 min, 3 mmol (0.41 mL) of 1,5-dibromopentane was added. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The mixture was filtered, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was separated by column chromatography [V(ethyl acetate):V(petroleum ether) = 1:20] to give 183 mg of white solid, with a yield of 58.3%.

[0076] Synthesis of intermediate 3D

[0077] 1 mmol (314 mg) of compound 2d, 3 mmol (0.26 mL) of morpholine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 9 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 145.1 mg of a pale yellow solid, with a yield of 45.2%.

[0078] Synthesis of target compound I6

[0079] 1 mmol (321 mg) of 3d and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I6, 187.3 mg, yield 42.3%, mp: 64.1–65.1 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.78 (d, J = 8.6 Hz, 1H, Ar-H), 7.60(d, J = 15.8 Hz, 1H, -CH=CH-), 7.55 (d, J = 13.4 Hz, 1H, -CH=CH-), 7.51 (d, J = 8.5Hz, 2H, Ar-H), 7.36 (d, J = 8.5 Hz, 2H, Ar-H), 6.56 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.45 (d, J = 2.3 Hz, 1H, Ar-H), 4.04 (t, J = 6.1 Hz, 2H, -OCH2), 3.86 (s, 3H,-CH3), 3.67 (t, J= 4.7 Hz, 4H, -OCH2), 2.32 (s, 4H, -NCH2-), 2.18 – 2.11 (m,2H, -NCH2-), 1.86 – 1.78 (m, 2H -CH2-), 1.46 – 1.42 (m, 4H, -CH2-). 13 C NMR (151MHz, CDCl3) δ 190.24, 164.52, 160.15, 139.77, 135.80, 134.24, 133.17, 129.44,129.26, 128.21, 122.23, 105.50, 99.30, 68.62, 67.05, 58.89, 55.70, 53.83,29.46, 26.49, 24.37..ESI-MS, C 25 H 30 ClNO4, measured (calculated), m / z: 444.1931 (444.1942) [M+H] + .

[0080] Example 7

[0081] Synthesis of intermediate 2e

[0082] 1 mmol (166 mg) of paeonol and 3 mmol (120 mg) of sodium hydroxide were added to a reaction flask, followed by 5 mL of DMF. The mixture was refluxed and stirred at 45 °C. After 20 min, 3 mmol (0.48 mL) of 1,6-dibromohexane was added. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The mixture was filtered, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was separated by column chromatography [V(ethyl acetate):V(petroleum ether) = 1:20] to give 181 mg of white solid, with a yield of 55.2%.

[0083] Synthesis of intermediate 3e

[0084] 1 mmol (328 mg) of compound 2e, 3 mmol (0.26 mL) of morpholine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 8 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 145.1 mg of a pale yellow solid, with a yield of 56.5%.

[0085] Synthesis of target compound I7

[0086] 1 mmol (335 mg) of 3e and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I7, 170 mg, yield 37.2%, mp: 48.2–49.1 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.78 (d, J = 8.6 Hz, 1H, Ar-H), 7.59 (d, J =15.6 Hz, 1H, -CH=CH-), 7.58 (d, J = 15.4 Hz, 1H, -CH=CH-), 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.35 (d, J = 8.5 Hz, 2H, Ar-H), 6.55 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),6.45 (d, J = 2.3 Hz, 1H, Ar-H), 4.03 (t, J = 6.2 Hz, 2H, -OCH2), 3.86 (s, 3H, -CH3), 3.69 (t, J = 4.7 Hz, 4H, -OCH2), 2.36 (s, 4H, -NCH2-), 2.22 (t, 2H, -NCH2-), 1.82 – 1.78 (m, 2H, -CH2-), 1.47 – 1.42 (m, 2H, -CH2-), 1.38 – 1.33(m, 2H, -CH2-), 1.29 – 1.24 (m, 2H, -CH2-). 13C NMR (151 MHz, CDCl3) δ 190.24,164.53, 160.21, 139.83, 135.75, 134.24, 133.20, 129.46, 129.22, 128.18,122.20, 105.48, 99.33, 68.72, 67.05, 59.09, 55.69, 53.84, 29.48, 27.45,26.50, 26.42.ESI-MS, C 26 H 32 ClNO4, measured (calculated), m / z: 458.2089 (458.2098) [M+H] + .

[0087] Example 8

[0088] Synthesis of intermediate 2f

[0089] 1 mmol (166 mg) of paeonol and 3 mmol (120 mg) of sodium hydroxide were added to a reaction flask, followed by 5 mL of DMF. The mixture was refluxed and stirred at 45 °C. After 20 min, 3 mmol (0.51 mL) of 1,7-dibromoheptane was added. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The mixture was filtered, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The solution was separated by column chromatography [V(ethyl acetate):V(petroleum ether) = 1:20] to give 202.4 mg of white solid, with a yield of 59.2%.

[0090] Synthesis of intermediate 3f

[0091] 1 mmol (342 mg) of compound 2f, 3 mmol (0.26 mL) of morpholine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC. After 7 h, the reaction mixture was stopped, evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 199.6 mg of a pale yellow solid, with a yield of 57.2%.

[0092] Synthesis of target compound I8

[0093] 1 mmol (349 mg) of 3f and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I8, 185.5 mg, yield 39.4%, mp: 62.7–63.7 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.79 (d, J = 8.7 Hz, 1H, Ar-H), 7.59(d, J = 15.9 Hz, 1H, -CH=CH-), 7.59 (d, J = 15.3 Hz, 1H, -CH=CH-), 7.50 (d, J = 8.5Hz, 2H, Ar-H), 7.35 (d, J = 8.5 Hz, 2H, Ar-H), 6.55 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.45 (d, J = 2.3 Hz, 1H, Ar-H), 4.03 (t, J = 6.2 Hz, 2H, -OCH2), 3.86 (s, 3H,-CH3), 3.71 (t, J = 4.7 Hz, 4H, -OCH2), 2.41 (s, 4H, -NCH2-), 2.27 – 2.20 (m,2H, -CH2-), 1.83 – 1.75 (m, 2H, -CH2-), 1.47 – 1.35 (m, 4H, -CH2-), 1.30 –1.22 (m, 2H, -CH2-), 1.18 – 1.12 (m, 2H, -CH2-). 13C NMR (151 MHz, CDCl3) δ190.18, 164.53, 160.24, 139.79, 135.70, 134.27, 133.22, 129.46, 129.20,128.21, 122.20, 105.46, 99.31, 68.77, 67.08, 59.19, 55.69, 53.88, 29.52,29.47, 27.48, 26.59, 26.47.ESI-MS, C 27 H 34 ClNO4, measured (calculated), m / z: 472.2247 (472.2255) [M+H] + .

[0094] Example 9

[0095] Synthesis of intermediate 3g

[0096] 1 mmol (300 mg) of compound 2c, 3 mmol (0.3 mL) of piperidine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC. After 7 h, the reaction mixture was stopped, evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 215.9 mg of a pale yellow solid, with a yield of 70.8%.

[0097] Synthesis of target compound I9

[0098] 1 mmol (305 mg) of 3 g and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 0.75 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow solid I9, 223.3 mg, yield 52.3%, mp: 67.6–68.4 °C. 1 H NMR (600 MHz, Chloroform- d ) δ 7.77 (d, J = 8.6 Hz, 1H, Ar-H), 7.59(d,J = 15.8 Hz, 1H, -CH=CH-), 7.55 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.53 – 7.48(m, 2H, Ar-H), 7.38 – 7.32 (m, 2H, Ar-H), 6.55 (dd, J = 8.6, 2.3 Hz, 1H, Ar-H),6.46 (d, J = 2.3 Hz, 1H, Ar-H), 4.05 (t, J = 6.3 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 2.34 – 2.19 (m, 6H, -NCH2-), 1.85 – 1.76 (m, 2H, -CH2-), 1.67 – 1.59 (m,2H, -CH2-), 1.56 – 1.49 (m, 4H, -CH2-), 1.43 – 1.35 (m, 2H, -CH2-). 13 C NMR (151MHz, CDCl3) δ 190.32, 164.48, 160.11, 139.96, 135.80, 134.20, 133.11, 129.45,129.25, 128.12, 122.21, 105.55, 99.34, 68.68, 58.92, 55.69, 54.48, 27.60,25.85, 24.41, 23.48.ESI-MS, C 25 H 30 ClNO3, measured (calculated), m / z: 428.1967 (428.1992) [M+H] + .

[0099] Example 10

[0100] Target compound I 10 Synthesis

[0101] 1 mmol (305 mg) of 3 g and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 0.75 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:20] yielded a pale yellow oily substance I. 10 240.4 mg, yield 56.3%, mp: 68.3~69.1 ℃; 1 H NMR (600 MHz, Chloroform- d ) δ 8.03 (d, J = 15.8 Hz, 1H, -CH=CH-),7.78 (d, J = 8.7 Hz, 1H, Ar-H), 7.69 (dd, J = 7.1, 2.4 Hz, 1H, Ar-H), 7.55 (d, J =15.8 Hz, 1H, -CH=CH-), 7.41 (dd, J = 7.4, 1.9 Hz, 1H, Ar-H), 7.28 (d, J = 2.2 Hz, 1H, Ar-H), 7.27 (d, J = 3.1 Hz, 1H, Ar-H), 6.56 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),6.46 (d, J = 2.3 Hz, 1H, Ar-H), 4.05 (t, J = 6.3 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 2.32 – 2.18 (m, 6H, -NCH2-), 1.83 – 1.76 (m, 2H, -CH2-), 1.66 – 1.57 (m,2H, -CH2-), 1.54 – 1.49 (m, 4H, -CH2-), 1.41 – 1.34 (m, 2H, -CH2-). 13C NMR (151MHz, CDCl3) δ 190.32, 164.48, 160.11, 139.96, 135.80, 134.20, 133.11, 129.45,129.25, 128.12, 122.21, 105.55, 99.34, 68.68, 58.92, 55.69, 54.48, 27.60,25.85, 24.41, 23.48.ESI-MS, C 25 H 30 ClNO3, measured (calculated), m / z: 428.1965 (428.1992) [M+H] + .

[0102] Example 11

[0103] Synthesis of intermediate 3h

[0104] 1 mmol (300 mg) of compound 2c, 3 mmol (0.33 mL) of methylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 218.9 mg of a yellow solid, with a yield of 68.4%.

[0105] Target compound I 11 Synthesis

[0106] 1 mmol (320 mg) of chlorobenzaldehyde and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol were added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 11 232.9 mg, yield 52.7%, mp: 54.1~54.9℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.76 (d, J= 8.6 Hz, 1H, Ar-H), 7.59 (d, J =15.8 Hz, 1H, -CH=CH-), 7.53 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.35 (d, J = 8.5 Hz, 2H, Ar-H), 6.55 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H),6.46 (d, J = 2.3 Hz, 1H, Ar-H), 4.05 (t, J = 6.3 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 2.58 – 2.30 (m, 8H, -NCH2-), 2.30 – 2.26 (m, 2H, -NCH2-), 2.25 (s, 3H, -CH3), 1.85 – 1.78 (m, 2H, -CH2-), 1.65 – 1.57 (m, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 190.37, 164.44, 160.06, 139.96, 135.80, 134.16, 133.08, 129.44,129.27, 128.07, 122.30, 105.49, 99.39, 68.67, 58.11, 55.68, 55.10, 53.09,46.06, 27.47, 23.64.ESI-MS, C 25 H 31 ClN2O3, measured (calculated), m / z: 443.2073 (443.2101) [M+H] + .

[0107] Example 12

[0108] Target compound I 12 Synthesis

[0109] 1 mmol (320 mg) of o-chlorobenzaldehyde was added to a round-bottom flask over 3 hours, followed by 5 mL of anhydrous ethanol. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 hour. After the reaction was complete, the reaction solution was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow oil, I. 12 215.7 mg, yield 48.8%. 1 H NMR (600MHz, Chloroform- d ) δ 8.02 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.77 (d, J = 8.6 Hz, 1H,Ar-H), 7.68 (dd, J = 7.2, 2.3 Hz, 1H, Ar-H), 7.53 (d, J = 15.8 Hz, 1H, -CH=CH-),7.41 (dd, J = 7.1, 2.3 Hz, 1H, Ar-H), 7.30 – 7.26 (m, 2H, Ar-H), 6.56 (dd, J =8.7, 2.3 Hz, 1H, Ar-H), 6.46 (d, J = 2.3 Hz, 1H, Ar-H), 4.05 (t, J = 6.2 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 2.76 – 2.29 (m, 8H, -NCH2-), 2.28 – 2.25 (m, 2H, -NCH2-), 2.25 (s, 3H, -CH3), 1.83 – 1.77 (m, 2H, -CH2-), 1.63 – 1.55 (m, 2H, -CH2-). 13C NMR (151 MHz, CDCl3) δ 190.46, 164.45, 160.07, 137.26, 135.48,133.86, 133.15, 130.74, 130.39, 129.99, 127.55, 127.07, 122.18, 105.49,99.37, 68.64, 58.09, 55.68, 55.06, 53.02, 46.04, 27.44, 23.62.ESI-MS, C 25 H 31 ClN2O3, measured (calculated), m / z: 443.2073 (443.2101) [M+H] + .

[0110] Example 13

[0111] Synthesis of intermediate 3i

[0112] 1 mmol (300 mg) of compound 2c, 3 mmol (0.38 mL) of ethylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC. After 7 h, the reaction mixture was stopped, evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 241.4 mg of a yellow solid, with a yield of 72.3%.

[0113] Target compound I 13 Synthesis

[0114] 1 mmol (334 mg) of 3i and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. The reaction solution was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 13 243 mg, yield 53.3%, mp: 49.5~50.3 ℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.75 (d, J= 8.6 Hz, 1H, Ar-H), 7.59 (d, J = 15.8 Hz,1H, -CH=CH-), 7.53 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.50 (d, J = 8.5 Hz, 2H, Ar-H), 7.35 (d, J = 8.5 Hz, 2H, Ar-H), 6.55 (dd, J = 8.6, 2.3 Hz, 1H, Ar-H), 6.46 (d, J =2.3 Hz, 1H, Ar-H), 4.05 (t, J = 6.3 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 2.39 (q, J = 7.2 Hz, 10H, -NCH2-), 2.30 – 2.27 (m, 2H, -NCH2), 1.86 – 1.78 (m, 2H, -CH2-), 1.61 (p, J = 7.6 Hz, 2H, -CH2-), 1.07 (t, J = 7.2 Hz, 3H, -CH3). 13 C NMR (151MHz, CDCl3) δ 190.42, 164.43, 160.05, 140.00, 135.81, 134.14, 133.06, 129.45,129.27, 128.05, 122.31, 105.50, 99.40, 68.68, 58.17, 55.69, 53.07, 52.74,52.37, 27.49, 23.63, 11.97.ESI-MS, C 26 H 33 ClN2O3, measured (calculated), m / z: 457.2231 (457.2258) [M+H] + .

[0115] Example 14

[0116] Target compound I 14 Synthesis

[0117] 1 mmol (334 mg) of 3i and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. The reaction solution was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a yellow oily solution. 14 206.6 mg, yield 45.3%. 1 H NMR (600 MHz, Chloroform- d ) δ 8.03 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.78 (d, J = 8.6 Hz, 1H, Ar-H), 7.69 (dd, J = 7.0, 2.4 Hz, 1H, Ar-H), 7.55 (d, J = 15.8 Hz, 1H, -CH=CH-),7.42 (dd, J = 7.5, 1.8 Hz, 1H, Ar-H), 7.30 – 7.28 (m, 1H, Ar-H), 7.28 – 7.26(m, 1H, Ar-H), 6.56 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H), 6.47 (d, J = 2.2 Hz, 1H, Ar-H), 4.06 (t, J = 6.2 Hz, 2H, -OCH2), 3.86 (s, 3H, -CH3), 2.58 – 2.31 (m, 10H, -NCH2-), 2.30 – 2.26 (m, 2H, -NCH2), 1.85 – 1.77 (m, 2H, -CH2-), 1.64 – 1.55(m, 2H, -CH2-), 1.07 (t, J = 7.2 Hz, 3H, -CH3). 13C NMR (151 MHz, CDCl3) δ 190.41,164.43, 160.05, 137.23, 135.46, 133.83, 133.12, 130.72, 130.36, 129.95,127.53, 127.06, 122.16, 105.48, 99.34, 68.63, 58.10, 55.66, 52.98, 52.73,52.70, 52.34, 27.43, 23.57, 11.93.ESI-MS, C 26 H 33 ClN2O3, measured (calculated), m / z: 457.2229 (457.2258) [M+H] + .

[0118] Example 15

[0119] Synthesis of intermediate 3j

[0120] 1 mmol (300 mg) of compound 2c, 3 mmol (0.38 mL) of hydroxyethylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 8 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 244.3 mg of a yellow solid, with a yield of 69.8%.

[0121] Target compound I 15 Synthesis

[0122] 1 mmol (350 mg) of 3j and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 15 125.3 mg, yield 26.5%, mp: 65.8~66.6 ℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.75 (d,J = 8.6 Hz, 1H, Ar-H), 7.58(d, J = 15.8 Hz, 1H, -CH=CH-), 7.53 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.50 (d, J = 8.5Hz, 2H, Ar-H), 7.35 (d, J = 8.5 Hz, 2H, Ar-H), 6.55 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.45 (d, J = 2.3 Hz, 1H, Ar-H), 4.05 (t, J = 6.2 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 3.62 – 3.58 (m, 2H, -CH2-), 2.75 (s, 4H, -NCH2), 2.54 – 2.51 (m, 2H, -CH2-), 2.50 – 2.39 (m, 4H, -NCH2), 2.30 – 2.26 (m, 2H, -NCH2), 1.85 – 1.77 (m,2H, -CH2-), 1.64 – 1.56 (m, 2H, -CH2-). 13 C NMR (151 MHz, CDCl3) δ 190.37,164.44, 160.02, 139.94, 135.80, 134.16, 133.06, 129.45, 129.27, 128.07,122.27, 105.48, 99.39, 68.60, 59.34, 58.05, 57.73, 55.68, 52.95, 52.77,27.44, 23.55.ESI-MS, C 26 H 33 ClN₂O₄, measured (calculated), m / z: 473.2176 (473.2207) [M+H] + .

[0123] Example 16

[0124] Target compound I 16 Synthesis

[0125] 1 mmol (350 mg) of 3-methyl chlorobenzaldehyde and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow oily substance I. 16 97.2 mg, yield 20.6%. 1 H NMR (600MHz, Chloroform- d ) δ 8.02 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.76 (d, J = 8.6 Hz, 1H,Ar-H), 7.68 (dd, J = 7.3, 2.2 Hz, 1H, Ar-H), 7.53 (d, J = 15.8 Hz, 1H, -CH=CH-),7.41 (dd, J = 7.7, 1.6 Hz, 1H, Ar-H), 7.29 (dd, J = 7.4, 2.0 Hz, 1H, Ar-H), 7.29– 7.25 (m, 1H, Ar-H), 6.55 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.45 (d, J = 2.3 Hz, 1H, Ar-H), 4.05 (t, J = 6.2 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 3.61 – 3.57 (m,2H, -CH2-), 2.70 (s, 4H, -NCH2), 2.52 – 2.49 (m, 2H, -NCH2), 2.49 – 2.38 (m,4H, -NCH2), 2.28 – 2.23 (m, 2H, -NCH2), 1.84 – 1.76 (m, 2H, -CH2-) 1.63 – 1.54(m, 2H, -CH2-). 13C NMR (151 MHz, CDCl3) δ 190.41, 164.44, 160.03, 137.21,135.48, 133.85, 133.13, 130.74, 130.38, 129.97, 127.56, 127.07, 122.16,105.47, 99.35, 68.57, 59.31, 58.03, 57.74, 55.67, 52.97, 52.79, 27.39,23.51.ESI-MS, C 26 H 33 ClN₂O₄, measured (calculated), m / z: 473.2207 (473.2179) [M+H] + .

[0126] Example 17

[0127] Synthesis of intermediate 3k

[0128] 1 mmol (272 mg) of compound 2a, 3 mmol (0.33 mL) of methylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 196.2 mg of a yellow solid, with a yield of 67.2%.

[0129] Target compound I 17 Synthesis

[0130] 1 mmol (292 mg) of 3kJ and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 17 242.2 mg, yield 58.5%, mp: 57.6~58.6℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.76 (d, J= 8.6 Hz, 1H, Ar-H), 7.59 (d, J =15.8 Hz, 1H, -CH=CH-), 7.54 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.51 (d, J = 8.5 Hz, 2H, Ar-H), 7.34 (d, J = 8.5 Hz, 2H, Ar-H), 6.56 (dd, J = 8.6, 2.3 Hz, 1H, Ar-H),6.46 (d, J = 2.3 Hz, 1H, Ar-H), 4.16 (t, J = 5.8 Hz, 2H, -OCH2), 3.84 (s, 3H, -CH3), 2.81 (t, J = 5.8 Hz, 2H, -NCH2), 2.60 – 2.30 (m, 8H, -NCH2), 2.23 (s, 3H, -CH3). 13 C NMR (151 MHz, CDCl3) δ 190.26, 164.40, 159.78, 140.25, 135.83,134.14, 133.10, 129.51, 129.21, 128.03, 122.35, 105.86, 99.58, 66.91, 57.20,55.68, 55.02, 53.64, 46.05.ESI-MS, C 23 H 27 ClN2O3, measured (calculated) value, m / z: 415.1778 (415.1781) [M+H] + .

[0131] Example 18

[0132] Target compound I 18 Synthesis

[0133] 1 mmol (292 mg) of 3kJ and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a yellow oily substance I. 18 199.5 mg, yield 48.2%. 1 H NMR (600MHz, Chloroform- d ) δ 8.01 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.76 (d, J = 8.6 Hz, 1H,Ar-H), 7.70 (dd, J = 7.3, 2.1 Hz, 1H, Ar-H), 7.52 (d, J = 15.8 Hz, 1H, -CH=CH-),7.41 (dd, J = 7.8, 1.6 Hz, 1H, Ar-H), 7.29 (dd, J = 7.4, 2.0 Hz, 1H, Ar-H), 7.26(dd, J = 6.2, 2.0 Hz, 1H, Ar-H), 6.57 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.47 (d, J =2.3 Hz, 1H, Ar-H), 4.16 (t, J = 5.8 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 2.79 (t, J = 5.8 Hz, 2H, -NCH2), 2.67 – 2.31 (m, 8H, -NCH2), 2.23 (s, 3H, -CH3). 13C NMR(151 MHz, CDCl3) δ 190.45, 164.40, 159.78, 137.62, 135.43, 133.90, 133.15,130.75, 130.33, 130.01, 127.73, 127.05, 122.26, 105.85, 99.59, 66.87, 57.12,55.69, 54.95, 53.54, 45.96.ESI-MS, C 23 H 27 ClN2O3, measured (calculated) value, m / z: 415.1782 (415.1781) [M+H] + .

[0134] Example 19

[0135] Synthesis of intermediate 3l

[0136] 1 mmol (286 mg) of compound 2b, 3 mmol (0.33 mL) of methylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 210.5 mg of a yellow solid, with a yield of 68.8%.

[0137] Target compound I 19 Synthesis

[0138] 1 mmol (306 mg) of 3 L and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 19 219.5 mg, yield 51.3%, mp: 62.1~63.1℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.75 (d, J= 8.6 Hz, 1H, Ar-H), 7.58 (d, J =15.8 Hz, 1H, -CH=CH-), 7.51 (d, J = 12.8 Hz, 1H, -CH=CH-), 7.49 (d, J = 5.6 Hz, 2H, Ar-H), 7.34 (d, J = 8.5 Hz, 2H, Ar-H), 6.55 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H),6.46 (d, J = 2.2 Hz, 1H, Ar-H), 4.08 (t, J = 6.2 Hz, 2H, -OCH2), 3.84 (s, 3H, -CH3), 2.45 – 2.43 (m, 2H, -NCH2), 2.42 – 2.25 (m, 8H, -NCH2), 2.24 (s, 3H, -CH3), 1.96 (dt, J = 13.4, 6.3 Hz, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 190.27,164.44, 159.99, 139.96, 135.79, 134.14, 133.08, 129.46, 129.24, 128.11,122.25, 105.53, 99.41, 67.12, 55.67, 55.18, 55.08, 53.12, 46.05, 26.86.ESI-MS, C 24 H 29 ClN2O3, measured (calculated), m / z: 429.1940 (429.1945) [M+H] +

[0139] Example 20

[0140] Target compound I 20 Synthesis

[0141] 1 mmol (306 mg) of 3 L and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a yellow oily substance I. 20 237.9 mg, yield 55.6%. 1 H NMR (600MHz, Chloroform- d ) δ 8.02 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.77 (d, J = 8.5 Hz, 1H,Ar-H), 7.69 (d, J = 6.7 Hz, 1H, Ar-H), 7.51 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.41(d, J = 6.9 Hz, 1H, Ar-H), 7.28 (d, J = 2.7 Hz, 2H, Ar-H), 6.57 (d, J = 8.8 Hz, 1H, Ar-H), 6.48 (s, 1H, Ar-H), 4.09 (t, J = 6.3 Hz, 2H, -OCH2), 3.86 (d, J = 2.2 Hz,3H, -CH3), 2.52 – 2.30 (m, 10H, -NCH2), 2.25 (s, 3H, -CH3), 2.00 – 1.94 (m,2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 190.49, 164.41, 159.94, 137.38, 135.40,133.83, 133.08, 130.70, 130.31, 129.97, 127.63, 127.09, 122.16, 105.53,99.40, 67.09, 55.66, 55.12, 55.01, 53.00, 45.99, 26.76.ESI-MS, C24 H 29 ClN2O3, measured (calculated), m / z: 429.1942 (429.1945) [M+H] + .

[0142] Example 21

[0143] Synthesis of intermediate 3m

[0144] 1 mmol (314 mg) of compound 2d, 3 mmol (0.33 mL) of methylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 7 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 199.7 mg of a yellow solid, with a yield of 62.4%.

[0145] Target compound I 21 Synthesis

[0146] 1 mmol (320 mg) of 3M and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 21 260.3 mg, yield 57.1%, mp: 52.2~53.2℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.76 (d, J = 8.6 Hz, 1H, Ar-H), 7.58 (d, J =15.8 Hz, 1H, -CH=CH-), 7.54 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.49 (d, J = 8.5 Hz, 2H, Ar-H), 7.34 (d, J = 8.5 Hz, 2H, Ar-H), 6.54 (dd,J = 8.7, 2.3 Hz, 1H, Ar-H),6.44 (d, J = 2.2 Hz, 1H, Ar-H), 4.02 (t, J = 6.2 Hz, 2H, -OCH2), 3.84 (s, 3H, -CH3), 2.56 – 2.29 (m, 8H, -NCH2), 2.26 (s, 3H, -CH3)), 2.15 (t, J = 7.3 Hz, 2H,-NCH2), 1.83 – 1.75 (m, 2H, -CH2), 1.45 – 1.38 (m, 4H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 190.24, 164.49, 160.13, 139.77, 135.76, 134.18, 133.13, 129.41,129.23, 128.15, 122.17, 105.50, 99.23, 68.59, 58.41, 55.66, 55.09, 53.18,46.05, 29.41, 26.76, 24.39.ESI-MS, C 26 H 33 ClN2O3, measured (calculated), m / z: 457.2247 (457.2258) [M+H] + .

[0147] Example 22

[0148] Target compound I 22 Synthesis

[0149] 1 mmol (320 mg) of 3M and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a yellow oily substance I. 22 243.5 mg, yield 53.4%. 1 H NMR (600MHz, Chloroform- d ) δ 8.03 (d,J = 15.8 Hz, 1H, -CH=CH-), 7.78 (d, J = 8.6 Hz, 1H,Ar-H), 7.68 (d, J = 6.9 Hz, 1H, Ar-H), 7.55 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.42(d, J = 7.1 Hz, 1H, Ar-H), 7.28 (d, J = 5.6 Hz, 2H, Ar-H), 6.56 (d, J = 8.6 Hz, 1H, Ar-H), 6.45 (s, 1H, Ar-H), 4.03 (t, J = 5.9 Hz, 2H, -OCH2), 3.86 (s, 3H, -CH3), 2.75 – 2.36 (m, 8H, -NCH2), 2.28 (s, 3H, -CH3), 2.18 (t, J = 6.8 Hz, 2H, -NCH2), 1.85 – 1.77 (m, 2H, -CH2), 1.48 – 1.36 (m, 4H, -CH2). 13 C NMR (151 MHz, CDCl3) δ190.33, 164.45, 160.11, 137.09, 135.43, 133.87, 133.14, 130.68, 130.35,130.03, 127.49, 127.01, 122.09, 105.48, 99.22, 68.60, 58.32, 55.64, 55.04,53.11, 46.02, 29.32, 26.67, 24.34.ESI-MS, C 26 H 33 ClN2O3, measured (calculated) value, m / z: 457.2248 (457.2258) [M+H] + .

[0150] Example 23

[0151] Synthesis of intermediate 3n

[0152] 1 mmol (328 mg) of compound 2e, 3 mmol (0.33 mL) of methylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 8 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 274.5 mg of a yellow solid, with a yield of 78.9%.

[0153] Target compound I 23 Synthesis

[0154] 1 mmol (348 mg) of 3n and 1.5 mmol (210 mg) of p-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 1 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 23 216.6 mg, yield 46.1%, mp: 62.1~63.1℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.77 (d, J = 8.7 Hz, 1H, Ar-H), 7.59 (d, J =15.6 Hz, 1H, -CH=CH-), 7.56 (d, J = 15.4 Hz, 1H, -CH=CH-), 7.49 (d, J = 8.5 Hz, 2H, Ar-H), 7.34 (d, J = 8.5 Hz, 2H, Ar-H), 6.54 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),6.44 (d, J = 2.3 Hz, 1H, Ar-H), 4.01 (t, J= 6.2 Hz, 2H, -OCH2), 3.84 (s, 3H, -CH3), 2.61 – 2.29 (m, 8H, -NCH2), 2.26 (s, 3H, -CH3), 2.24 – 2.18 (m, 2H, -NCH2), 1.83 – 1.75 (m, 2H, -CH2), 1.47 – 1.39 (m, 2H, -CH2), 1.38 – 1.31 (m,2H, -CH2), 1.26 – 1.19 (m, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 190.16, 164.50,160.20, 139.79, 135.71, 134.20, 133.16, 129.41, 129.18, 128.14, 122.13,105.47, 99.26, 68.70, 58.60, 55.65, 55.14, 53.23, 46.09, 29.43, 27.49, 26.84,26.39.ESI-MS, C 27 H 35 ClN2O3, measured (calculated), m / z: 471.2404 (471.2414) [M+H] + .

[0155] Example 24

[0156] Target compound I 24 Synthesis

[0157] 1 mmol (348 mg) of 3n and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was stopped after 0.5 h by TLC monitoring. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a yellow oily substance I. 24 244.8 mg, yield 52.1%. 1 H NMR (600MHz, Chloroform- d ) δ 8.04 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.80 (d, J= 8.7 Hz, 1H,Ar-H), 7.69 (dd, J = 7.1, 2.3 Hz, 1H, Ar-H), 7.58 (d, J = 15.8 Hz, 1H, -CH=CH-),7.42 (dd, J = 7.4, 1.9 Hz, 1H, Ar-H), 7.28 (d, J = 4.3 Hz, 1H, Ar-H), 7.27 (d, J =3.7 Hz, 1H, Ar-H), 6.56 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.46 (d, J = 2.3 Hz, 1H,Ar-H), 4.03 (t, J = 6.2 Hz, 2H, -OCH2), 3.86 (s, 3H, -CH3), 2.56 – 2.31 (m, 8H, -NCH2), 2.28 (s, 3H, -CH3), 2.25 – 2.20 (m, 2H, -NCH2), 1.82 – 1.76 (m, 2H, -CH2), 1.46 – 1.39 (m, 2H, -CH2), 1.39 – 1.33 (m, 2H, -CH2), 1.27 – 1.21 (m,2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 190.15, 164.39, 160.10, 136.96, 135.35,133.82, 133.11, 130.53, 130.24, 129.97, 127.42, 126.89, 121.98, 105.36,99.16, 68.61, 58.48, 55.55, 55.01, 53.09, 45.97, 29.28, 27.33, 26.67,26.24.ESI-MS, C 27 H 35 ClN2O3, measured (calculated), m / z: 471.2405 (471.2414) [M+H] + .

[0158] Example 25

[0159] Synthesis of intermediate 3o

[0160] 1 mmol (342 mg) of compound 2f, 3 mmol (0.33 mL) of methylpiperazine, and 5 mL of acetonitrile were added to a 50 mL round-bottom flask and heated and stirred at 55 °C. The reaction was monitored by TLC, and the reaction was stopped after 9 h. The reaction mixture was evaporated to dryness, and extracted three times with 100 mL of water and 50 mL of dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:25] yielded 255.2 mg of a yellow solid, with a yield of 70.5%.

[0161] Target compound I 25 Synthesis

[0162] 1 mmol (362 mg) of chlorobenzaldehyde and 1.5 mmol (210 mg) of dichlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 25 227.9 mg, yield 47.1%, mp: 50.1~51.1℃; 1 H NMR (600 MHz, Chloroform- d ) δ 7.78 (d, J = 8.7 Hz, 1H, Ar-H), 7.59 (d, J =15.8 Hz, 1H, -CH=CH-), 7.56 (d, J = 15.6 Hz, 1H, -CH=CH-), 7.49 (d, J = 8.5 Hz, 2H, Ar-H), 7.33 (d, J = 8.5 Hz, 2H, Ar-H), 6.54 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H),6.44 (d, J = 2.3 Hz, 1H, Ar-H), 4.01 (t, J= 6.2 Hz, 2H, -OCH2), 3.85 (s, 3H, -CH3), 2.74 – 2.28 (m, 8H, -NCH2), 2.27 (s, 3H, -CH3), 2.25 – 2.23 (m, 2H, -NCH2), 1.81 – 1.75 (m, 2H, -CH2), 1.45 – 1.35 (m, 4H, -CH2), 1.28 – 1.21 (m,2H, -CH2), 1.16 – 1.10 (m, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 190.19, 164.51,160.23, 139.80, 135.69, 134.22, 133.18, 129.43, 129.17, 128.17, 122.14,105.46, 99.26, 68.75, 58.73, 55.66, 55.14, 53.24, 46.09, 29.49, 29.43, 27.55,26.92, 26.42.ESI-MS, C 28 H 37 ClN2O3, measured (calculated) value, m / z: 485.2563 (485.2571) [M+H] + .

[0163] Example 26

[0164] Target compound I 26 Synthesis

[0165] 1 mmol (362 mg) of o-chlorobenzaldehyde and 1.5 mmol (0.17 mL) of o-chlorobenzaldehyde were placed in a round-bottom flask, and 5 mL of anhydrous ethanol was added. The mixture was stirred at 45 °C until completely dissolved. Then, 0.2 mL of 50% sodium hydroxide was added to the reaction solution to continue the reaction. The reaction was monitored by TLC, and stopped after 1 h. After the reaction was complete, the reaction solution was evaporated to dryness, and 100 mL of water and 50 mL of ethyl acetate were added for extraction three times. The organic layer was washed with saturated sodium chloride solution, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Thin-layer chromatography [V(methanol):V(dichloromethane) = 1:18] yielded a pale yellow solid I. 26 207.6 mg, yield 42.9%. 1 H NMR (600MHz, Chloroform- d ) δ 8.04 (d, J = 15.8 Hz, 1H, -CH=CH-), 7.80 (d,J = 8.6 Hz, 1H,Ar-H), 7.68 (dd, J = 7.4, 2.1 Hz, 1H, Ar-H), 7.58 (d, J = 15.8 Hz, 1H, -CH=CH-),7.41 (dd, J = 7.7, 1.6 Hz, 1H, Ar-H), 7.29 (dd, J = 7.4, 1.9 Hz, 1H, Ar-H), 7.26(dd, J = 7.2, 1.9 Hz, 1H, Ar-H), 6.56 (dd, J = 8.7, 2.3 Hz, 1H, Ar-H), 6.46 (d, J =2.3 Hz, 1H, Ar-H), 4.03 (t, J = 6.2 Hz, 2H, -OCH2), 3.86 (s, 3H, -CH3), 2.46 (s,8H, -NCH2), 2.29 (s, 3H, -CH3), 2.27 – 2.23 (m, 2H, -NCH2), 1.81 – 1.75 (m,2H, -CH2), 1.45 – 1.36 (m, 4H, -CH2), 1.27 – 1.22 (m, 2H, -CH2), 1.19 – 1.11 (m, 2H, -CH2). 13 C NMR (151 MHz, CDCl3) δ 190.20, 164.49, 160.23, 137.05,135.45, 133.95, 133.23, 130.62, 130.31, 130.09, 127.53, 126.96, 122.08,105.44, 99.24, 68.76, 58.77, 55.65, 55.19, 53.30, 46.13, 29.43, 29.38, 27.51,26.91, 26.38.ESI-MS, C 28 H 37 ClN2O3, measured value (calculated value), m / z: 485.2571 (485.2571) [M+H] + .

[0166] Example 27 Pharmacological experiments to test the anti-proliferative activity of the compounds of the present invention against cancer cells.

[0167] The test drug compound I was tested using the MTT assay. 1-26 In vitro anti-cell proliferation activity against human colon cancer cells (HCT116), human liver cancer cells (HepG2), human lung cancer cells (A549), and human osteosarcoma cells (U2OS).

[0168] Experimental Methods: Cells were cultured routinely in an incubator at 37 ℃ and 5% CO2 saturated humidity. Cancer cells in good logarithmic growth phase were digested with 0.25% trypsin to detach adherent cells, and the cell count was (2~3) × 10⁻⁶. 4 Cells were seeded at a density of approximately 5000 cells / mL into 96-well plates and incubated for 24 hours. The culture medium was then replaced, and the test drug (0.1–25.0 μmol / L, 5 concentrations) was added at 100 μL per well. The plates were then incubated at 37 °C with 5% CO2 and saturated humidity for another 72 hours. MTT reagent was added to each well at 20 μL, and the plates were incubated for 4 hours. The supernatant was removed, and 120 μL of DMSO was added to each well. The plates were shaken on a shaker for 10 min, and the absorbance at 495 nm was measured using an ELISA reader. All experiments were repeated three times under the same conditions, and the cell inhibition rate was calculated.

[0169] Cell inhibition rate = [(OD value of negative control group – OD value of test group) / (OD value of negative control group – OD value of blank group)] × 100%

[0170] Experimental data were analyzed using GraphPad Prism 8.0 and IC was calculated through nonlinear regression analysis. 50 Some of the experimental results are shown in Table 1.

[0171] Table 1

[0172]

[0173] IC 50 a It refers to the half-maximal inhibitory concentration (MCIC) required to inhibit cell growth.

[0174] As can be seen from the above results, compound I of the present invention 1-26 In vitro anti-cell proliferation activity IC50 against human colon cancer cells (HCT116), human liver cancer cells (HepG2), human lung cancer cells (A549), and human osteosarcoma cells (U2OS) 50 The effective concentrations were 4.74–38.62 μM, 1.28–11.44 μM, 4.00–18.95 μM, and 1.31–16.74 μM, respectively. The antitumor activity was mostly superior to that of the positive control drug 5-Fu, and the antitumor effect was significant.

[0175] Example 28: Solubility evaluation experiment of the compound of the present invention

[0176] Accurately weigh 1 mg of the test compound (compounds I2, I3, I9, I...). 10 I 11 I 12 I 13 and I 17 The compound was placed in a 10 mL volumetric flask, 10 mL of methanol was added, and the mixture was shaken on a shaker for 4 h until completely dissolved. The maximum UV absorption wavelength was then measured. The solution was then divided and diluted to prepare five solutions of different concentrations. The absorbance was measured at the maximum absorption wavelength, and a standard concentration-absorption curve was plotted. An excess amount of the compound was weighed, 5 mL of water was added, and the mixture was stirred at room temperature for 24 h. The solution was then filtered through a microporous membrane to obtain the corresponding saturated solutions. The absorbance was measured at the maximum absorption wavelength for each solution, and the solubility of each compound was determined using the standard curve. The results of the water solubility test are shown in Table 2.

[0177] Table 2

[0178]

[0179] As shown in Table 2, the water solubility of the compounds of this invention is 1.5 to 3.5 times higher than that of paeonol chalcone, and the water solubility can be further improved by forming salts with acids. The results indicate that the introduction of organic amine fragments not only enhances the antitumor efficacy of the compounds but also effectively improves their water solubility.

[0180] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. An amine alkylated paeonol chalcone derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof: wherein n is an integer from 1 to 10; R 1 is a six-membered saturated heterocyclic group containing only N heteroatoms or containing O heteroatoms in addition to N heteroatoms, the six-membered saturated heterocyclic group being unsubstituted or substituted with a substituent selected from C 1-C 6 alkyl, C 1-C 6 hydroxyalkyl; R 2 is a halogen atom. wherein: The N heteroatoms are 1 to 3, and the O heteroatoms are 1 to 3. The six-membered saturated heterocyclic group is unsubstituted or substituted with a substituent selected from C 1-C 3 alkyl, C 1-C 3 hydroxyalkyl. The R 2 is ortho-substitution and / or para-substitution.

2. The amine alkylated paeonol chalcone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized by: The R 2 is F or Cl.

3. The amine alkylated paeonol chalcone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized by: 3-(4-chlorophenyl)-1-(4-methoxy-2-(2-(morpholin-4-yl)ethoxy)phenyl)prop-2-en-1-one (I1); 4. The amine alkylated paeonol chalcone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized by: said R1 is morpholinyl, piperidinyl, N - methylpiperazinyl, N - ethylpiperazinyl or 4-hydroxyethylpiperazinyl.

5. The amine alkylated paeonol chalcone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: ###0002### 3-(4-chlorophenyl)-1-(4-methoxy-2-(3-(morpholin-4-yl)propoxy)phenyl)prop-2-en-1-one (I2); 6. The amine alkylated paeonol chalcone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: 3-(4-chlorophenyl)-1-(4-methoxy-2-(4-(morpholin-4-yl)butoxy)phenyl)prop-2-en-1-one (I3); 7. The amine alkylated paeonol chalcone derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized by: The amine alkylated paeonol chalcone derivatives represented by the general formula (I) are selected from any one of the following (I1)~(I 26 ) compounds: 3-(2-chlorophenyl)-1-(4-methoxy-2-(4-(morpholin-4-yl)butoxy)phenyl)prop-2-en-1-one (I4); 3-(2,4-dichlorophenyl)-1-(4-methoxy-2-(4-(morpholin-4-yl)butoxy)phenyl)prop-2-en-1-one (I5); 3-(4-chlorophenyl)-1-(4-methoxy-2-(5-(morpholin-4-yl)pentoxy)phenyl)prop-2-en-1-one (I6); 3-(4-chlorophenyl)-1-(4-methoxy-2-(6-(morpholin-4-yl)hexyloxy)phenyl)prop-2-en-1-one (I7); 3-(4-chlorophenyl)-1-(4-methoxy-2-(7-(morpholin-4-yl)heptyloxy)phenyl)prop-2-en-1-one (I8); 3-(4-chlorophenyl)-1-(4-methoxy-2-(4-(piperidin-1-yl)butoxy)phenyl)prop-2-en-1-one (I9); The preparation method comprises: Claisen-Schmidt condensation of a compound represented by formula (3) and a compound represented by formula (4) to obtain the amine alkylated paeonol chalcone derivative represented by formula (I). The definitions of n, R 1 and R 2 are the same as those in claim 1. The pharmaceutical composition comprises a therapeutically effective amount of the amine alkylated paeonol chalcone derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. 3-(2-chlorophenyl)-1-(4-methoxy-2-(4-(piperidin-1-yl)butoxy)phenyl)prop-2-en-1-one (I 10 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)butoxy)phenyl)prop-2-en-1-one (I 11 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)butoxy)phenyl)prop-2-en-1-one (I 12 ); 3-(4-chlorophenyl)-1-(2-(4-(4-ethylpiperazin-1-yl)butyloxy)-4- methoxyphenyl)prop-2-en-1-one (I 13 ); 3-(2-chlorophenyl)-1-(2-(4-(4-ethylpiperazin-1-yl)butyloxy)-4- methoxyphenyl)prop-2-en-1-one (I) 14 ); 3-(4-chlorophenyl)-1-(2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)butoxy)-4- methoxyphenyl)prop-2-en-1-one (I 15 ); 3-(2-chlorophenyl)-1-(2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)butoxy)-4- methoxyphenyl)prop-2-en-1-one (I 16 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)prop-2-en-1-one (I 17 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)prop-2-en-1-one (I 18 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (I 19 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)prop-2-en-1-one (I 20 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(5-(4-methylpiperazin-1-yl) pentyloxy) phenyl)prop-2-en-1-one (I 21 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(5-(4-methylpiperazin-1-yl) pentyloxy) phenyl)prop-2-en-1-one (I 22 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(6-(4-methylpiperazin-1-yl)hexyloxy)phenyl)prop-2-en-1-one (I 23 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(6-(4-methylpiperazin-1-yl)hexyloxy)phenyl)prop-2-en-1-one (I 24 ); 3-(4-chlorophenyl)-1-(4-methoxy-2-(7-(4-methylpiperazin-1-yl)heptyloxy)phenyl)prop-2-en-1-one (I 25 ); 3-(2-chlorophenyl)-1-(4-methoxy-2-(7-(4-methylpiperazin-1-yl)heptyloxy)phenyl)prop-2-en-1-one (I) 26 ).

8. A method for preparing the amine alkylated paeonol chalcone derivative of formula (I) according to any one of claims 1 to 7, characterized in that, 10.Use of the amine alkylated paeonol chalcone derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating cancer, the cancer being selected from colon cancer, osteosarcoma, lung cancer or liver cancer. ； ​ 9. A pharmaceutical composition, characterized by: ​ ​

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