Chalcone substituted compound, preparation method thereof and application of chalcone substituted compound in preparation of anti-inflammatory drugs

Abstract

The invention discloses a chalcone substituted compound, a preparation method thereof and application of the chalcone substituted compound in preparation of anti-inflammatory drugs, and relates to the field of medicinal chemistry. In particular relates to chalcone substituted compounds, a preparation method thereof, a pharmaceutical composition containing the compounds and medical application thereof, and particularly, the chalcone substituted compounds can remarkably inhibit generation of inflammatory mediators and have important application potential and clinical value in treatment of inflammation-related diseases. Based on the molecular hybridization principle, the chalcone substituted compound is prepared through a chemical synthesis method, and experiments show that the compound has remarkable advantages in the aspect of inhibiting generation of inflammatory mediators (such as NO) and has the application potential of developing novel anti-inflammatory drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to chalcone-substituted compounds, their preparation methods, and their use in the preparation of anti-inflammatory drugs. Background Technology

[0002] Inflammation is a complex physiological stress response of the blood vessels in the human body when exposed to harmful factors such as pathogens, physical damage, or chemical irritants. Both acute and chronic inflammation can cause varying degrees of damage to the body. If inflammation is not controlled in time, it may develop into serious diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and chronic asthma. Therefore, the development of novel anti-inflammatory drugs has always been a hot topic in the pharmaceutical field.

[0003] Existing anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), with aspirin as a representative, alleviate inflammatory symptoms by inhibiting cyclooxygenase (COX) activity and reducing prostaglandin production. However, long-term use of NSAIDs is often accompanied by gastrointestinal side effects (such as ulcers and bleeding) and kidney damage, limiting their clinical application. Chalcones are a class of flavonoids widely found in natural plants, possessing various biological activities such as anti-inflammatory, antioxidant, and immunomodulatory effects. Their anti-inflammatory effect is partly attributed to the inhibition of inflammatory mediators such as nitric oxide (NO) and cytokines. However, the bioavailability and efficacy of chalcones used alone still need improvement.

[0004] Currently, there are no reports on studies involving the anti-inflammatory activity of chalcone derivatives and anti-inflammatory molecular conjugates. Summary of the Invention

[0005] The technical problem to be solved by this invention is how to create a chalcone derivative and an anti-inflammatory molecular conjugate that, through the synergistic effect of their anti-inflammatory activities, enhances the anti-inflammatory effect and reduces side effects while ensuring biosafety.

[0006] Another technical problem to be solved by the present invention is to provide a method for preparing chalcone-substituted compounds and their application in anti-inflammatory drugs.

[0007] The present invention solves the above-mentioned technical problems through the following technical means: A first aspect of the present invention provides for the use of chalcone-substituted compound I or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention or treatment of inflammation-related diseases, wherein the general structural formula of chalcone-substituted compound I is as follows:

[0008] The benzene ring on the left can be substituted by 1 to 5 R1 atoms, and the benzene ring on the right can be substituted by 1 to 4 R2 atoms. X is located at any position on the benzene ring on the right. X is selected from hydroxyl and oxygen. n takes the value of 0, 2, 3 or 4. R1 is selected from methoxy, methyl, hydrogen, fluorine, chlorine, and dihydrobenzo[]. b One of [1,4]dioxin-6-yl, benzo[d][1,3]dioxono-5-yl, benzyloxy, morpholino, naphth-2-yl, or 6-methoxynaphth-2-yl; R2 is selected from one of hydrogen, fluorine, methoxy, and methyl. R3 is selected from hydroxyl, amino, , One of them; Indicates the connection point.

[0009] Preferably, the inflammation-related diseases are one or more of the following: inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, chronic nephritis, atherosclerosis, pancreatitis, pneumonia, and bronchitis.

[0010] Further preferably, the inflammatory bowel disease is acute colitis.

[0011] Preferred, pharmaceutically acceptable salts include acid addition salts formed by chalcone-substituted compounds I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or benzenesulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.

[0012] Preferably, the concentration of the chalcone-substituted compound I is 8-12 μM, more preferably 10 μM.

[0013] Preferably, the drug further includes a pharmaceutically acceptable carrier.

[0014] "Pharmaceutical acceptable" means non-toxic materials that do not reduce the active ingredient. Such pharmaceutically acceptable excipients and carriers are well known in the art (see Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Company (1990) and hand book of Pharmaceutical Excipients, 3rd edition, edited by A. Kibbe, Pharmaceutical Press (2000)).

[0015] Preferably, the pharmaceutically acceptable carrier includes, but is not limited to, one or more of the following: diluents, binders, wetting agents, disintegrants, absorption enhancers, surfactants, and lubricants.

[0016] Preferably, the drug is formulated into a pharmaceutically acceptable dosage form.

[0017] Preferably, the dosage form includes, but is not limited to, tablets, capsules, granules, pills, syrups, powders, granules, suppositories, drops, emulsions, injections, or suspensions.

[0018] A second aspect of the invention provides a chalcone-substituted compound II or a pharmaceutically acceptable salt thereof, said chalcone-substituted compound II having any of the following structural formulas: , , , , , , , , , , , , (That is, corresponding to compounds 1, 2, 7, 10, 14, 16, 17, 19, 23, 24, 26, 28, and 30 in the examples, respectively.) A third aspect of the present invention provides a method for preparing the above-mentioned chalcone-substituted compound I, comprising the following steps: (1) , A mixture of sodium hydroxide aqueous solution and anhydrous ethanol reacts to produce... ; (2) The result obtained from (1) halogenated compounds, potassium carbonate and N , N - After the reaction with dimethylformamide; (3) Add R3, thionyl chloride, triethylamine, and anhydrous dichloromethane, and react at room temperature to obtain the product.

[0019] Preferably, in step (1), , The ratio of sodium hydroxide aqueous solution to anhydrous ethanol is 0.9~1.4 mmol: 0.8~1.2 mmol: 8~12 mL: 15~25 mL, and more preferably 1.1 mmol: 1 mmol: 10 mL: 20 mL.

[0020] Preferably, in step (1), the reaction conditions are: room temperature, 22~26h, and more preferably 24h.

[0021] Preferably, in step (2), halogenated compounds, potassium carbonate and N ,N The ratio of dimethylformamide used is 0.8~1.2 mmol : 1.8~2.2 mmol : 2.0~3.0 mmol : 1~5 mL; more preferably 1.0 mmol : 2.0 mmol : 2.5 mmol : 3 mL.

[0022] Preferably, in step (2), the reaction conditions are: temperature 50~80 ℃, 10~14h; more preferably 65℃, 12h.

[0023] Preferably, in step (3), the ratio of R3, sulfoxide, triethylamine and anhydrous dichloromethane is 0.8~1.2 mmol: 4.6~5.2 mmol: 2.8~3.2 mmol: (5-15) mL; more preferably 1.0 mmol: 5.0 mmol: 3.0 mmol: 10 mL.

[0024] Preferably, in step (3), the heat preservation conditions are: room temperature, 3~5 h; more preferably 4 h.

[0025] The above is the general formula for chalcone-substituted compounds I, which are synthesized through Claisen-Schmidt condensation, Williamson etherification, and acyl chloride condensation to ultimately produce this series of compounds.

[0026] The beneficial effects of this invention are as follows: This invention is based on the principle of molecular hybridization and prepares chalcone-substituted compounds through chemical synthesis. Experiments show that the compounds have significant advantages in inhibiting the production of inflammatory mediators (such as NO) and have the potential to be used in the development of novel anti-inflammatory drugs.

[0027] This invention aims to combine the advantages of chalcone with anti-inflammatory molecules, thereby developing novel compounds with synergistic anti-inflammatory effects while ensuring biosafety.

[0028] Of course, implementing any product or method of the present invention does not necessarily require achieving all of the advantages described above at the same time. Attached Figure Description

[0029] Figure 1 The graph shows the inhibitory effect of compounds 1-43 obtained in Examples 1-43 of this invention on NO in an LPS-induced RAW 264.7 inflammation model, tested using the Griess reagent method.

[0030] Figure 2 The graph shows the inhibitory effects of compounds 30, 37-43 obtained in Examples 30 and 37-43 of this invention on TNF-α and IL-6 in an LPS-induced RAW 264.7 inflammation model using ELISA.

[0031] Figure 3 The diagram shows the acute toxicity study of compound 43 obtained in Example 43 of this invention. In this diagram, A is an HE staining image of mouse heart, liver, spleen, lung and kidney (single oral dose of 1200 mg / kg), scale bar: 20 μm; B is a graph of mouse body weight change over time.

[0032] Figure 4 This is a graph evaluating the anti-inflammatory activity of compound 43 obtained in Example 43 of the present invention, where A is a comparison graph of mouse disease activity index; B is a graph of mouse weight change; C is a bar graph of mouse colon length; and D is a visual comparison graph of mouse colons in different groups. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, 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. Unless otherwise defined, the technical terms used below have the same meaning as understood by those skilled in the art.

[0034] Unless otherwise specified, the test materials and reagents used in the following examples are commercially available or prepared by known methods.

[0035] Unless otherwise specified, all techniques or conditions described in the embodiments can be performed in accordance with the techniques or conditions described in the literature in this field or in the product manual. Unless otherwise specified, the quantitative experiments in the following embodiments are all repeated three times or more, and the results are averaged.

[0036] The following examples illustrate the preparation method of chalcone derivatives.

[0037] The following are synthetic routes for chalcone derivatives and their conjugation with anti-inflammatory molecules:

[0038] Reaction conditions: (a) 20% (w / w) sodium hydroxide aqueous solution, anhydrous ethanol, room temperature, 24 hours; (b) Potassium carbonate, N , N - Dimethylformamide, 50-80 ℃, 12 hours; (c) Thionyl chloride, triethylamine, anhydrous dichloromethane, room temperature, 4 hours. (An intermediate was generated under condition b, and the final compound with R3 was generated under condition c.) Example 1 ( E Synthesis of 1-(3,5-dimethoxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (denoted as Compound 1) In this embodiment, there are two R1 groups, located at positions 3 and 5 of the benzene ring on the left, respectively. R1 is a methoxy group, R2 is hydrogen, and X is a hydroxyl group. The structural formula is: .

[0039] The specific steps for synthesis are as follows: 3,5-Dimethoxyacetophenone (1.1 mmol) and 4-hydroxybenzaldehyde (1.0 mmol) were added to a 100 mL round-bottom flask and then dissolved in ethanol (20 mL). While stirring in an ice bath, 10 mL of 20% (w / w) sodium hydroxide solution was added. The reaction was carried out at room temperature for 24 h. After the reaction was completed, 5% (w / w) hydrochloric acid solution was added, and a large amount of yellow solid precipitated. The obtained solid was filtered, and recrystallized from ethanol to obtain the target compound. E 1-(3,5-dimethoxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; yellow solid; yield 60.18%; 1 H NMR (600 MHz, CDCl3) δ 7.78 (dd, J = 15.6, 2.8Hz, 1H), 7.51 (dd, J = 8.5, 3.6 Hz, 2H), 7.34 (s, 1H), 7.15 – 7.12 (m, 2H), 6.93 (t, J = 8.7 Hz, 2H), 6.66 (dd, J = 2.8, 1.6 Hz, 1H), 3.83 (d, J = 6.4 Hz,6H). HRMS-EI m / z [M+H] + calcd for C 17 H 17 O4 + : 285.1121, found 285.1110. Example 2 ( E )-1-(3,5-dimethylphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (referred to as compound 2) In this embodiment, there are two R1s, located at positions 3 and 5 of the benzene ring on the left, respectively. R1 is a methyl group, R2 is hydrogen, and X is a hydroxyl group. The structural formula is: .

[0040] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3,5-dimethylacetophenone”, otherwise the same as in Example 1.

[0041] The target compound was obtained as a yellow solid; yield 54.24%. 1 H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 15.6 Hz, 1H), 7.61 (s, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 15.6 Hz,1H), 7.22 (s, 1H), 6.90 (d, J = 8.6 Hz, 2H), 2.40 (s, 6H). HRMS-EI m / z [M+H] + calcd for C 17 H 17 O2 + : 253.1223, found 253.1229. Example 3 ( E )-1-(3,4-dimethoxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (referred to as compound 3) In this embodiment, there are two R1 groups, located at positions 3 and 4 of the benzene ring on the left, respectively. R1 is a methoxy group, R2 is hydrogen, and X is a hydroxyl group. The structural formula is: .

[0042] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3,4-dimethoxyacetophenone”, otherwise the same as in Example 1.

[0043] The target compound was obtained as a yellow solid; yield 78.76%. 1 H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 15.6 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 15.5 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H), 6.89 (d, J = 8.5 Hz,2H), 5.53 (s, 1H), 3.97 (s, 6H). HRMS-EI m / z [M+H] + calcd for C 17 H 17 O4 + :285.1121, found 285.1122. Example 4 ( E )-1-(3,5-difluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (referred to as compound 4) In this embodiment, there are two R1s, located at positions 3 and 5 of the benzene ring, respectively. R1 is fluorine, R2 is hydrogen, and X is a hydroxyl group.

[0044] The structural formula is: .

[0045] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3,5-difluoroacetophenone”, otherwise the same as in Example 1.

[0046] The target compound was obtained as a yellow solid; yield 68.45%. 1 H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 15.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.53 – 7.49 (m, 2H), 7.28 (d, J =15.6 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H). HRMS-EI m / z[M+H] + calcd for C 15 H 11 F2O2 + : 261.0722, found 261.0721. Example 5 ( E )-1-(2,3-dihydrobenzo[ b [1,4]Dioxin-6-yl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (referred to as compound 5) In this embodiment, R1 is 2,3-dihydrobenzo[ b [1,4]dioxin-6-yl, R2 is hydrogen, X is hydroxyl.

[0047] The structural formula is:

[0048] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetophenone”, otherwise the same as in Example 1.

[0049] The target compound was obtained as a yellow solid; yield: 71.42%. 1 H NMR (600 MHz, CDCl3) δ7.75 (d, J = 15.6 Hz, 1H), 7.61 – 7.53 (m, 4H), 7.38 (d, J = 15.6 Hz, 1H), 6.95(d, J = 8.3 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 5.26 (s, 1H), 4.34 (dd, J = 5.6, 2.3 Hz, 2H), 4.30 (dd, J = 5.9, 2.5 Hz, 2H). HRMS-EI m / z [M+H] + calcd forC 17 H 15 O4 + : 283. 0965, found 283.0970. Example 6 ( E )-1-(benzo[ d [1,3]dioxono-5-yl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (referred to as compound 6) In this embodiment, R1 is benzo[ d [1,3]dioxono-5-yl, R2 is hydrogen, X is 4-hydroxyl The structural formula is:

[0050] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “benzo[d][1,3]dioxono-5-ylacetophenone”, and the rest is the same as in Example 1.

[0051] The target compound was obtained as a yellow solid; yield 58.97%. 1 H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 15.5 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.57 – 7.50 (m, 3H), 7.37 (d, J =15.5 Hz, 1H), 6.89 (t, J = 8.7 Hz, 3H), 6.06 (s, 2H). HRMS-EI m / z [M+H] + calcdfor C 17 H 15 O4 + : 269.0808, found 269.0810. Example 7 ( E )-1-(3,5-dichlorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (referred to as compound 7) In this embodiment, there are two R1s, located at positions 3 and 5 of the benzene ring, respectively. R1 is chlorine, R2 is hydrogen, and X is a hydroxyl group.

[0052] The structural formula is:

[0053] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3,5-dichloroacetophenone”, otherwise the same as in Example 1.

[0054] The target compound was obtained as a yellow solid; yield 23.47%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.18 (s, 1H), 8.14 (d, J = 2.0 Hz, 2H), 7.91 (t, J = 1.9 Hz, 1H), 7.83 – 7.77 (m,2H), 7.75 (d, J = 5.6 Hz, 2H), 6.87 – 6.82 (m, 2H). HRMS-EI m / z [M+H] + calcdfor C 15 H 10 Cl2O2 +: 290.9980, found 290.9984. Example 8 ( E )-3-(4-hydroxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 8) In this embodiment, R1 is hydrogen, R2 is hydrogen, and X is hydroxyl.

[0055] The structural formula is:

[0056] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, otherwise the same as in Example 1.

[0057] The target compound was obtained as a yellow solid; yield 23.78%. 1 H NMR (600 MHz, Methanol- d 4) δ8.07 – 8.03 (m, 2H), 7.75 (d, J = 15.6 Hz, 1H), 7.65 – 7.60 (m, 3H), 7.59 –7.51 (m, 3H), 6.87 – 6.83 (m, 2H). HRMS-EI m / z [M+H] + calcd for C 15 H 13 O2 + :225.091, found 225.0910. Example 9 ( E )-3-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (referred to as compound 9) In this embodiment, there are 3 R1s, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group, R2 is hydrogen, and X is a hydroxyl group.

[0058] The structural formula is:

[0059] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3,4,5-trimethoxyacetophenone”, otherwise the same as in Example 1.

[0060] The target compound was obtained as a yellow solid; yield 41.23%. 1 H NMR (600 MHz, CDCl3) δ 7.78 (d, J= 15.6 Hz, 1H), 7.58 – 7.56 (m, 2H), 7.36 (d, J = 15.6 Hz, 1H), 7.27 (s, 2H), 6.91 – 6.88 (m, 2H), 3.95 (s, 6H), 3.94 (d, J = 1.0 Hz, 3H). HRMS-EI m / z [M+H] + calcd for C 18 H 19 O5 + 315.1227, found 315.1227 Example 10 ( E )-1-(3,5-bis(benzyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one; (denoted as compound 10) In this embodiment, there are two R1s, located at the 3rd and 5th positions of the benzene ring, respectively. R1 is a benzyloxy group, R2 is hydrogen, and X is a hydroxyl group.

[0061] The structural formula is:

[0062] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3,5-di(benzyloxy)acetophenone”, otherwise the same as in Example 1.

[0063] The target compound was obtained as a yellow solid; yield 31.57%. 1 H NMR (600 MHz, Methanol- d 4) δ7.71 (d, J = 15.5 Hz, 1H), 7.62 – 7.59 (m, 2H), 7.48 – 7.43 (m, 5H), 7.38 (dd, J = 8.4, 6.8 Hz, 4H), 7.34 – 7.31 (m, 2H), 7.25 (d, J = 2.3 Hz, 2H), 6.89 (t, J = 2.3 Hz, 1H), 6.86 – 6.83 (m, 2H), 5.15 (s, 4H). HRMS-EI m / z [M+H] + calcd forC 29 H 25 O4 +: 437.1747, found 437.1732. Example 11 ( E )-3-(4-hydroxyphenyl)-1-(4-morpholinophenyl)prop-2-en-1-one; (referred to as compound 11) In this embodiment, there is one R1 located at the 4th position of the benzene ring. R1 is a morpholino group, R2 is hydrogen, and X is a hydroxyl group.

[0064] The structural formula is:

[0065] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “4-morpholinoacetophenone”, otherwise the same as in Example 1.

[0066] The target compound was obtained as a yellow solid; yield 39.47%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.01 (s, 1H), 8.04 (d, J = 8.9 Hz, 2H), 7.71 (dd, J = 12.0, 3.4 Hz, 3H), 7.60 (d, J =15.4 Hz, 1H), 7.01 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.75 – 3.73(m, 4H), 3.34 (s, 4H). HRMS-EI m / z [M+H] + calcd for C 19 H 20 NO3 + : 310.1438, found310.1438. Example 12 ( E )-3-(4-hydroxyphenyl)-1-(3-methoxyphenyl)prop-2-en-1-one; (referred to as compound 12) In this embodiment, there is one R1 located at the 3 position of the benzene ring. R1 is a methoxy group, R2 is hydrogen, and X is a hydroxyl group.

[0067] The structural formula is:

[0068] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3-methoxyacetophenone”, otherwise the same as in Example 1.

[0069] The target compound was obtained as a yellow solid; yield 68.85%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.10(s, 1H), 7.76 – 7.72 (m, 3H), 7.69 (d, J = 3.0 Hz, 2H), 7.58 (t, J = 2.1 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.22 (dd, J = 8.2, 2.6 Hz, 1H), 6.84 (d, J = 8.5Hz, 2H), 3.85 (s, 3H). HRMS-EI m / z [M+H] + calcd for C 16 H 15 O3 + : 255.1016, found255.1015. Example 13 ( E )-3-(4-hydroxyphenyl)-1-(naphth-2-yl)prop-2-en-1-one; (referred to as compound 13) In this embodiment, R1 is naphth-2-yl, R2 is hydrogen, and X is hydroxyl.

[0070] The structure is as follows:

[0071] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “1-naphth-2-ylacetophenone”, otherwise the same as in Example 1.

[0072] The target compound was obtained as a yellow solid; yield 66.92%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.11(s, 1H), 8.90 (s, 1H), 8.18 – 8.10 (m, 2H), 8.04 (dd, J = 20.0, 8.3 Hz, 2H), 7.93 (d, J= 15.5 Hz, 1H), 7.84 – 7.72 (m, 3H), 7.71 – 7.63 (m, 2H), 6.87 (d, J = 8.6 Hz, 2H). HRMS-EI m / z [M+H] + calcd for C 16 H 15 O3 + :275.1067, found 275.1063. Example 14 ( E )-3-(4-hydroxyphenyl)-1-(6-methoxynaphth-2-yl)prop-2-en-1-one; (referred to as compound 14) In this embodiment, R1 is 6-methoxynaphth-2-yl, R2 is hydrogen, and X is hydroxyl.

[0073] The structural formula is:

[0074] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “6-methoxynaphthalene-2-ylacetophenone”, otherwise the same as in Example 1.

[0075] The target compound was obtained as a yellow solid; yield 66.92%. 1 H NMR (600 MHz, Methanol- d 4) δ8.63 (d, J = 1.8 Hz, 1H), 8.06 (dd, J = 8.6, 1.8 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.82 – 7.73 (m, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 2.5 Hz, 1H), 7.23 (dd, J = 9.0, 2.6 Hz, 1H), 6.87 (d, J = 8.3 Hz,2H), 3.96 (s, 3H). HRMS-EI m / z [M+H] + calcd for C 20 H 17 O3 +: 305.1172, found305.1168. Example 15 ( E )-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one; (referred to as compound 15) In this embodiment, there is one R1 located at the 4th position of the benzene ring. R1 is a methoxy group, R2 is hydrogen, and X is a hydroxyl group.

[0076] The structural formula is:

[0077] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “4-methoxyacetophenone”, otherwise the same as in Example 1.

[0078] The target compound was obtained as a yellow solid; yield 66.92%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.05 (s, 1H), 8.13 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 11.5 Hz, 3H), 7.63 (d, J = 15.5Hz, 1H), 7.08 – 7.06 (m, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.86 (s, 3H). HRMS-EIm / z [M+H] + calcd for C 16 H 15 O3 + : 255.1, found 255.1. Example 16 ( E )-3-(3,5-difluoro-4-hydroxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 16) In this embodiment, R1 is hydrogen, there are two R2s located at positions 3 and 5 of the benzene ring, respectively, R2 is fluorine, and X is a hydroxyl group.

[0079] The structural formula is:

[0080] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone” and “4-hydroxybenzaldehyde” with “3,5-difluoro-4-hydroxybenzaldehyde”, the rest is the same as in Example 1.

[0081] The target compound was obtained as a yellow solid; yield 66.92%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.87(s, 1H), 8.17 – 8.14 (m, 2H), 7.89 (d, J = 15.5 Hz, 1H), 7.71 (dd, J = 8.0, 1.7Hz, 2H), 7.67 – 7.63 (m, 2H), 7.57 (t, J = 7.7 Hz, 2H). HRMS-EI m / z [M+H] + calcd for C 15 H 11 F2O2 + : 261.0722, found 261.0722. Example 17 ( E )-3-(2,6-difluoro-4-hydroxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 17) In this embodiment, R1 is hydrogen, there are two R2s located at positions 2 and 6 of the benzene ring, respectively, R2 is fluorine, and X is a hydroxyl group.

[0082] The structural formula is:

[0083] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone” and “4-hydroxybenzaldehyde” with “2,6-difluoro-4-hydroxybenzaldehyde”, the rest is the same as in Example 1.

[0084] The target compound was obtained as a yellow solid; yield 66.92%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.14 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.66 (s, 3H), 7.58 (d, J = 15.4 Hz, 2H), 6.62 (d, J = 11.0 Hz, 2H). HRMS-EI m / z [M+H] + calcd for C 15 H 11 F2O2 +: 261.0722, found 261.0724. Example 18 ( E )-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 18) In this embodiment, R1 is hydrogen, there are two R2s located at the 3 and 5 positions of the benzene ring, respectively, R2 is methoxy, and X is hydroxyl.

[0085] The structural formula is:

[0086] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “4-hydroxy-3,5-dimethoxybenzaldehyde”, the rest is the same as in Example 1.

[0087] The target compound was obtained as a yellow solid; yield 66.92%. 1 H NMR (600 MHz, DMSO- d 6) δ 9.05(s, 1H), 8.15 – 8.10 (m, 2H), 7.77 (d, J = 15.4 Hz, 1H), 7.68 – 7.62 (m, 2H), 7.55 (dd, J = 8.3, 7.1 Hz, 2H), 7.18 (s, 2H), 3.83 (s, 6H). HRMS-EI m / z [M+H] + calcd for C 17 H 17 O4 + : 285.1121, found 285.1123. Example 19 ( E )-3-(4-hydroxy-2,6-dimethoxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 19) In this embodiment, R1 is hydrogen, and there are two R2s located at positions 2 and 6 of the benzene ring, respectively. R2 is methoxy and X is hydroxyl.

[0088] The structural formula is:

[0089] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “4-hydroxy-2,6-dimethoxybenzaldehyde”, the rest is the same as in Example 1.

[0090] The target compound was obtained as a yellow solid; yield 66.92%. 1 H NMR (600 MHz, Methanol- d 4) δ8.27 (d, J = 15.8 Hz, 1H), 7.98 – 7.95 (m, 2H), 7.87 (d, J = 15.8 Hz, 1H), 7.61– 7.58 (m, 1H), 7.52 (t, J = 7.7 Hz, 2H), 6.16 (s, 2H), 3.91 (s, 6H). HRMS-EIm / z [M+H] + calcd for C 17 H 17 O4 + : 285.1121, found 285.1121. Example 20 ( E )-3-(3-hydroxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 20) In this embodiment, R1 is hydrogen, R2 is hydrogen, and X is hydroxyl.

[0091] The structural formula is: .

[0092] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “5-hydroxybenzaldehyde”, otherwise the same as in Example 1.

[0093] The target compound was obtained as a yellow solid; yield 56.70%. 1 H NMR (600 MHz, DMSO- d 6) δ 9.62 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 15.6 Hz, 1H), 7.66 – 7.62 (m,2H), 7.56 (t, J = 7.7 Hz, 2H), 7.30 (d, J= 7.7 Hz, 1H), 7.26 – 7.20 (m, 2H), 6.87 (s, 1H). HRMS-EI m / z [M+H] + calcd for C 15 H 13 O3 + : 225.0910, found 225.0910. Example 21 ( E )-3-(2-hydroxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 21) In this embodiment, R1 is hydrogen, R2 is hydrogen, and X is hydroxyl.

[0094] The structural formula is:

[0095] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “2-hydroxybenzaldehyde”, otherwise the same as in Example 1.

[0096] The target compound was obtained as a yellow solid; yield 46.86%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.28(s, 1H), 8.12 – 7.99 (m, 3H), 7.89 – 7.81 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 8.5 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H). HRMS-EI m / z [M+H] + calcd for C 15 H 13 O2 + : 225.0910, found225.0909. Example 22 ( E )-3-(4-hydroxy-3,5-dimethylphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 22) In this embodiment, R1 is hydrogen, there are two R2s located at the 3rd and 5th positions of the benzene ring, respectively, R2 is methyl, and X is hydroxyl.

[0097] The structural formula is:

[0098] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone” and “4-hydroxybenzaldehyde” with “4-hydroxy-3,5-dimethylbenzaldehyde”, the rest is the same as in Example 1.

[0099] The target compound was obtained as a yellow solid; yield 55.98%. 1 H NMR (600 MHz, CDCl3) δ 8.03 –8.00 (m, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.59 – 7.55 (m, 1H), 7.52 – 7.48 (m,2H), 7.39 (d, J = 15.6 Hz, 1H), 2.29 (s, 6H). HRMS-EI m / z [M+H] + calcd forC 17 H 17 O2 + : 253.1223, found 253.1221. Example 23 ( E )-3-(4-hydroxy-2,6-dimethylphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 23) In this embodiment, R1 is hydrogen, there are two R2s, located at positions 2 and 6 of the benzene ring respectively, R2 is methyl, and X is hydroxyl.

[0100] The structural formula is:

[0101] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone” and “4-hydroxybenzaldehyde” with “4-hydroxy-2,6-dimethylbenzaldehyde”, the rest is the same as in Example 1.

[0102] The target compound was obtained as a yellow solid; yield 54.98%. 1 H NMR (600 MHz, Methanol- d4) δ8.03 – 8.00 (m, 3H), 7.64 – 7.60 (m, 1H), 7.55 – 7.52 (m, 2H), 7.24 (d, J =16.0 Hz, 1H), 6.57 (s, 2H), 2.40 (s, 6H). HRMS-EI m / z [M+H] + calcd for C 17 H 17 O2 + : 253.1223, found 253.1226. Example 24 ( E )-3-(4-hydroxy-2-methoxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 24) In this embodiment, R1 is hydrogen, there is one R2 located at position 2 of the benzene ring, R2 is methoxy, and X is hydroxyl.

[0103] The structural formula is: .

[0104] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “4-hydroxy-2-methoxybenzaldehyde”, otherwise the same as in Example 1.

[0105] The target compound was obtained as a yellow solid; yield 56.77%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.21 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 15.6 Hz, 1H), 7.80 (d, J = 8.5Hz, 1H), 7.68 (d, J = 15.6 Hz, 1H), 7.64 (t, J = 6.8 Hz, 1H), 7.55 (t, J = 7.6Hz, 2H), 6.49 – 6.44 (m, 2H). HRMS-EI m / z [M+H] + calcd for C 16 H 15 O3 + :255.1016,found 255.1015. Example 25 ( E )-3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 25) In this embodiment, R1 is hydrogen, there is one R2 located at the 3 position of the benzene ring, R2 is methoxy, and X is hydroxyl.

[0106] The structural formula is: .

[0107] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “4-hydroxy-3-methoxybenzaldehyde”, the rest is the same as in Example 1.

[0108] The target compound was obtained as a yellow solid; yield 67.55%. 1 H NMR (600 MHz, DMSO-d6) δ 9.71(s, 1H), 8.14 – 8.11 (m, 2H), 7.75 (d, J = 15.4 Hz, 1H), 7.69 – 7.63 (m, 2H), 7.56 (dd, J HRMS-EI m / z [M+H] + calcdfor C 16 H 15 O3 + :255.1016, found 255.1016. Example 26 ( E )-3-(4-hydroxy-2-methylphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 26) In this embodiment, R1 is hydrogen, there is one R2 located at position 2 of the benzene ring, R2 is methyl, and X is hydroxyl.

[0109] The structural formula is: .

[0110] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “4-hydroxy-2-methylbenzaldehyde”, otherwise the same as in Example 1.

[0111] The target compound was obtained as a yellow solid; yield 78.98%. 1 H NMR (600 MHz, DMSO- d 6) δ 8.31 –8.08 (m, 2H), 7.98 – 7.89 (m, 2H), 7.68 – 7.63 (m, 2H), 7.56 (t, J = 7.7 Hz, 2H), 6.69 (d, J = 7.7 Hz, 2H), 2.37 (s, 3H). HRMS-EI m / z [M+H] + calcd forC 16 H 15 O2 + : 239.1067, found 239.1073. Example 27 ( E )-3-(4-hydroxy-3-methylphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 27) In this embodiment, R1 is hydrogen, there is one R2 located at position 3 of the benzene ring, R2 is methyl, and X is hydroxyl.

[0112] The structural formula is: .

[0113] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “4-hydroxy-3-methylbenzaldehyde”, the rest is the same as in Example 1.

[0114] The target compound was obtained as a yellow solid; yield 56.50%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.02(s, 1H), 8.13 – 8.10 (m, 2H), 7.72 – 7.68 (m, 2H), 7.66 – 7.63 (m, 2H), 7.56(t, J = 7.7 Hz, 2H), 7.52 (dd, J = 8.3, 2.3 Hz, 1H), 6.84 (d, J= 8.2 Hz, 1H),2.17 (s, 3H). HRMS-EI m / z [M+H] + calcd for C 16 H 15 O2 + : 239.1067, found 239.1062. Example 28 ( E )-3-(2-fluoro-4-hydroxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 28) In this embodiment, R1 is hydrogen, there is one R2 located at position 2 of the benzene ring, R2 is fluorine, and X is a hydroxyl group.

[0115] The structural formula is: .

[0116] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “2-fluoro-4-hydroxybenzaldehyde”, otherwise the same as in Example 1.

[0117] The target compound was obtained as a yellow solid; yield 54.20%. 1 H NMR (600 MHz, DMSO- d 6) δ 8.12 –8.08 (m, 2H), 7.96 (d, J = 8.8 Hz, 1H), 7.77 (s, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.7 Hz, 2H), 6.72 (dd, J = 8.6, 2.4 Hz, 1H), 6.67 (dd, J = 12.7,2.4 Hz, 1H). HRMS-EI m / z [M+H] + calcd for C 15 H 12 FO2 + : 243.0816, found 243.0817. Example 29 ( E )-3-(3-fluoro-4-hydroxyphenyl)-1-phenylprop-2-en-1-one; (referred to as compound 29) In this embodiment, R1 is hydrogen, there is one R2 located at position 3 of the benzene ring, R2 is fluorine, and X is a hydroxyl group.

[0118] The structural formula is: .

[0119] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “acetophenone”, and “4-hydroxybenzaldehyde” with “3-fluoro-4-hydroxybenzaldehyde”, otherwise the same as in Example 1.

[0120] The target compound was obtained as a yellow solid; yield 48.50%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.54(s, 1H), 8.16 – 8.11 (m, 2H), 7.86 (dd, J = 12.6, 2.1 Hz, 1H), 7.80 (d, J =15.5 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.51 (dd, J = 8.4, 2.0 Hz, 1H), 7.00 (t, J = 8.7 Hz, 1H). HRMS-EI m / z [M+H] + calcd for C 15 H 12 FO2 + :243.0816, found 243.0821. Example 30 ( E )-3-(3,5-difluoro-4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (referred to as compound 30) In this embodiment, there are 3 R1s located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are 2 R2s located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine and X is a hydroxyl group.

[0121] The structural formula is:

[0122] The specific synthesis steps differ from those in Example 1 in the following ways: Replace “3,5-dimethoxyacetophenone” with “3,4,5-trimethoxyacetophenone”, and “4-hydroxybenzaldehyde” with “3,5-difluoro-4-hydroxybenzaldehyde”, the rest is the same as in Example 1.

[0123] The target compound was obtained as a yellow solid; yield 78.65%. 1 H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 15.4 Hz, 1H), 7.28 (d, J = 21.0 Hz, 3H), 7.17 (dd, J = 7.2, 2.0 Hz, 2H), 3.95(s, 6H), 3.94 (s, 3H).HRMS-EI m / z [M+H] + calcd for C 18 H 17 F2O5 + : 351.1039, found351.1039. Example 31 ( E )-3-(3,5-difluoro-4-(2-hydroxyethoxy)phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (denoted as compound 31) In this embodiment, there are 3 R1s located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are 2 R2s located at positions 3 and 5 of the benzene ring. R2 is fluorine, R3 is a hydroxyl group, X is oxygen, and n is 2.

[0124] The structural formula is:

[0125] The specific steps for synthesis are as follows: Compound 30 (1.0 mmol) was added to a 50 mL round-bottom flask, followed by 3 mL of DMF, anhydrous potassium carbonate (2.5 mmol), and bromoethanol (2.0 mmol). The mixture was heated to 80 °C for 12 h. After the reaction was complete, a large amount of water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, collected, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography at a PE:EA ratio of 3:1 (v:v) to obtain the target compound. E )-3-(3,5-difluoro-4-(2-hydroxyethoxy)phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; yellow solid; yield 55.55%; 1 H NMR (600 MHz, CDCl3) δ7.65 (d, J = 15.5 Hz, 1H), 7.37 (d, J = 15.5 Hz, 1H), 7.26 (s, 2H), 7.22 (d, J=8.4 Hz, 2H), 4.34 – 4.31 (m, 2H), 3.96 (s, 6H), 3.94 (d, J = 9.7 Hz, 5H).HRMS-EI m / z [M+H] + calcd for C 20 H 21 F2O6 + : 395.1301, found 395.1289. Example 32 ( E )-3-(3,5-difluoro-4-(3-hydroxypropoxy)phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (denoted as compound 32) In this embodiment, there are 3 R1s located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are 2 R2s located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, R3 is hydroxyl, X is oxygen, and n is 3.

[0126] The structural formula is:

[0127] The specific synthesis steps differ from those in Example 31 in the following ways: Replace “bromoethanol” with “bromopropanol”, otherwise the same as in Example 31.

[0128] The target compound was obtained as a yellow solid; yield 60.85%. 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 15.5 Hz, 1H), 7.36 (d, J = 15.5 Hz, 1H), 7.26 (s, 2H), 7.20 (d, J = 8.7 Hz, 2H), 4.38 (t, J = 5.9 Hz, 2H), 3.96 (s, 6H), 3.95 (s, 3H), 3.92 (t, J = 5.9 Hz, 2H), 2.06 (q, J = 5.9 Hz, 2H). HRMS-EI m / z [M+H] + calcd for C 21 H 23 F2O6 + : 409.1457, found 409.1447. Example 33 ( E )-3-(3,5-difluoro-4-(4-hydroxybutoxy)phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (referred to as compound 33) In this embodiment, there are 3 R1s located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are 2 R2s located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, R3 is hydroxyl, X is oxygen, and n is 4.

[0129] The structural formula is: .

[0130] The specific synthesis steps differ from those in Example 31 in the following ways: Replace “bromoethanol” with “bromobutanol”, otherwise the same as in Example 31.

[0131] The target compound was obtained as a yellow solid; yield 58.79%. 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 15.5 Hz, 1H), 7.36 (d, J = 15.5 Hz, 1H), 7.26 (s, 2H), 7.19 (s, 2H), 4.26(t, J = 6.2 Hz, 2H), 3.96 (s, 6H), 3.94 (s, 3H), 3.74 (t, J = 6.3 Hz, 2H), 1.89(p, J = 6.5 Hz, 2H), 1.79 (p, J = 6.6 Hz, 2H). HRMS-EI m / z [M+H] + calcd forC 22 H 25 F2O6 + : 423.1619, found 423.1619. Example 34 ( E )-3-(4-(2-aminoethoxy)-3,5-difluorophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (referred to as compound 34) In this embodiment, there are 3 R1 groups located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are 2 R2 groups located at positions 3 and 5 of the benzene ring, respectively. R2 is a fluorine group, R3 is an amino group, X is oxygen, and n is 2.

[0132] The structural formula is: .

[0133] The specific synthesis steps differ from those in Example 31 in the following ways: Replace “bromoethanol” with “bromoethylamine”, otherwise the same as in Example 31.

[0134] The target compound is a yellow solid; yield 95.10%. 1 H NMR (600 MHz, Methanol- d 4) δ 7.81(d, J = 15.5 Hz, 1H), 7.67 (d, J = 15.5 Hz, 1H), 7.59 (d, J = 9.1 Hz, 2H), 7.43(s, 2H), 4.42 (t, J = 4.9 Hz, 2H), 3.94 (s, 6H), 3.86 (s, 3H), 3.40 – 3.37 (m,2H), 3.36 – 3.31 (m, 2H). HRMS-EI m / z [M+H] + calcd for C 21 H 23 F2O6 + : 394.1461, found 394.1469. Example 35 ( E )-3-(4-(3-aminopropoxy)-3,5-difluorophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (referred to as compound 35) In this embodiment, there are 3 R1 groups, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are 2 R2 groups, located at positions 3 and 5 of the benzene ring, respectively. R2 is a fluorine group, R3 is an amino group, X is oxygen, and n is 3.

[0135] The structural formula is: .

[0136] The specific synthesis steps differ from those in Example 31 in the following ways: Replace “bromoethanol” with “bromopropylamine”, otherwise the same as in Example 31.

[0137] The target compound was obtained as a yellow solid; yield 95.48%. 1 H NMR (600 MHz, Methanol- d 4) δ7.79 (d, J = 15.5 Hz, 1H), 7.66 (d, J= 15.5 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H),7.42 (s, 2H), 4.35 (t, J = 5.7 Hz, 2H), 3.95 (s, 6H), 3.87 (s, 3H), 3.25 –3.20 (m, 2H), 2.19 – 2.13 (m, 2H). HRMS-EI m / z [M+H] + calcd for C 21 H 24 F2NO5 + :408.1617, found 408.1619. Example 36 ( E )-3-(4-aminobutoxy)-3,5-difluorophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one; (referred to as compound 36) In this embodiment, there are 3 R1 groups, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are 2 R2 groups, located at positions 3 and 5 of the benzene ring, respectively. R2 is a fluorine group, R3 is an amino group, X is oxygen, and n is 4.

[0138] The structural formula is: .

[0139] The specific synthesis steps differ from those in Example 31 in the following ways: Replace “bromoethanol” with “bromobutylamine”, otherwise the same as in Example 31.

[0140] The target compound was obtained as a yellow solid; yield 89.67%. 1 H NMR (600 MHz, Methanol- d 4) δ7.79 (d, J = 15.5 Hz, 1H), 7.66 (d, J = 15.5 Hz, 1H), 7.53 (d, J = 9.1 Hz, 2H),7.43 (s, 2H), 3.95 (s, 6H), 3.87 (s, 3H), 3.05 (dd, J = 8.1, 6.6 Hz, 2H), 1.95– 1.88 (m, 4H). HRMS-EI m / z [M+H] + calcd for C 22 H 26 F2NO5 +: 422.1779, found422.1811. Example 37 ( E )-2-(2,6-difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy)ethyl-2-acetoxybenzoate; (referred to as compound 37) In this embodiment, there are three R1 atoms, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are two R2 atoms, located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, and R3 is... , The connection point is indicated by X, where X represents oxygen and n is 2.

[0141] The structural formula is: .

[0142] The specific steps for synthesis are as follows: Acetylsalicylic acid (1 mmol) was dissolved in DCM (5 mL), and thionyl chloride (5 mmol) was added under ice bath conditions, followed by stirring at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated to obtain acetylsalicylic acid chloride. Compound 31 (1 mmol) was then dissolved in anhydrous DCM (3 mL), triethylamine (3 mmol) was added, and the reaction mixture was cooled to 0 °C. Acetylsalicylic acid chloride (1.2 mmol) dissolved in anhydrous DCM (7 mL) was then slowly added to the above mixture and stirred for 4 h. After the reaction was completed, the reaction solution was concentrated, and the crude product was dissolved in anhydrous ethanol and recrystallized to collect the target product. E 2-(2,6-difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy)ethyl 2-acetoxybenzoate; yellow solid; yield 76.45%. 1 H NMR (600 MHz, DMSO- d 6) δ 7.94 (d, J = 15.5 Hz, 1H), 7.83 (d, J = 9.6Hz, 3H), 7.66 (d, J = 15.5 Hz, 2H), 7.43 (s, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.52 (s, 4H), 3.90 (s, 6H), 3.77 (s, 3H), 2.27 (s,3H). HRMS-EI m / z [M+H] +calcd for C 29 H 27 F2O9 + : 557.1618, found 557.1628. Example 38 ( E )-3-(2,6-difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy)propyl 2-acetoxybenzoate; (denoted as compound 38) In this embodiment, there are three R1 atoms, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are two R2 atoms, located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, and R3 is... , The connection point is indicated by X, which stands for oxygen, and n is 3.

[0143] The structural formula is: .

[0144] The specific synthesis steps differ from those in Example 37 in the following ways: Replace “Compound 31” with “Compound 32”, otherwise the same as in Example 37.

[0145] The target product was obtained as a yellow solid; the yield was 69.50%. 1 H NMR (600 MHz, CDCl3) δ 8.01 (dd, J = 7.8, 1.7 Hz, 1H), 7.64 (d, J = 15.5 Hz, 1H), 7.57 (ddd, J = 8.1, 7.4, 1.7 Hz,1H), 7.38 – 7.30 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.11 (dd, J = 8.1, 1.2 Hz, 1H), 4.53 (t, J = 6.3 Hz, 2H), 4.36 (t, J = 6.1 Hz, 2H), 3.95 (d, J = 7.3 Hz,9H), 2.35 (s, 3H), 2.22 (q, J = 6.2 Hz, 2H). HRMS-EI m / z [M+H] + calcd forC 30 H 29 F2O9 +: 571.1774, found 571.1798. Example 39 ( E )-4-(2,6-difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy)butyl-2-acetoxybenzoate; (denoted as compound 39) In this embodiment, there are three R1 atoms, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are two R2 atoms, located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, and R3 is... , The connection point is indicated by X, which stands for oxygen, and n is 4.

[0146] The structural formula is: .

[0147] The specific synthesis steps differ from those in Example 37 in the following ways: Replace “Compound 31” with “Compound 33”, otherwise the same as in Example 37.

[0148] The target product was obtained as a yellow solid; the yield was 67.58%. 1 H NMR (600 MHz, Chloroform- d ) δ8.01 (dd, J = 7.9, 1.7 Hz, 1H), 7.64 (d, J = 15.5 Hz, 1H), 7.56 (td, J = 7.8,1.7 Hz, 1H), 7.38 – 7.26 (m, 4H), 7.19 (d, J = 8.3 Hz, 2H), 7.10 (dd, J = 8.1, 1.2 Hz, 1H), 4.36 (t, J = 6.4 Hz, 2H), 4.27 (t, J = 6.0 Hz, 2H), 3.96 (s, 6H), 3.94 (s, 3H), 2.36 (s, 3H), 2.00 – 1.90 (m, 4H). HRMS-EI m / z [M+H] + calcd forC 31 H 31 F2O9 + : 585.1936, found 589.1914. Example 40 ( E)-2-((2-(2,6-difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy)ethyl)carbamoyl)phenylacetate; (denoted as compound 40) In this embodiment, there are three R1 atoms, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are two R2 atoms, located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, and R3 is... , The connection point is indicated by X, where X represents oxygen and n is 2.

[0149] The structural formula is: .

[0150] The specific synthesis steps differ from those in Example 37 in the following ways: Replace “Compound 31” with “Compound 34”, otherwise the same as in Example 37.

[0151] The target product was obtained as a yellow solid; the yield was 78.32%. 1 H NMR (600 MHz, CDCl3) δ 7.87 (dd, J = 7.8, 1.7 Hz, 1H), 7.64 (d, J = 15.5 Hz, 1H), 7.51 – 7.48 (m, 1H), 7.38 –7.32 (m, 2H), 7.26 (s, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 8.1, 1.1Hz, 1H), 7.02 (s, 1H), 4.37 (t, J = 4.9 Hz, 2H), 3.96 (s, 6H), 3.95 (s, 3H), 3.83 – 3.80 (m, 2H), 2.35 (s, 3H). HRMS-EI m / z [M+H] + calcd for C 29 H 28 F2NO8 + :556.1777, found 556.1775. Example 41 ( E )-2-((3-(2,6-difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy)propyl)carbamoyl)phenylacetate; (referred to as compound 41) In this embodiment, there are three R1 atoms, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are two R2 atoms, located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, and R3 is... , The connection point is indicated by X, which stands for oxygen, and n is 3.

[0152] The structural formula is:

[0153] The specific synthesis steps differ from those in Example 37 in the following ways: Replace “Compound 31” with “Compound 35”, otherwise the same as in Example 37.

[0154] The target product was obtained as a yellow solid; the yield was 75.67%. 1 H NMR (600 MHz, CDCl3) δ 7.74 (dd, J = 7.7, 1.6 Hz, 1H), 7.64 (d, J = 15.5 Hz, 1H), 7.49 – 7.44 (m, 1H), 7.37 (d, J = 15.5 Hz, 1H), 7.30 (td, J = 7.5, 1.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.11(dd, J = 8.1, 1.1 Hz, 1H), 6.64 (t, J = 5.8 Hz, 1H), 4.33 (t, J = 5.7 Hz, 2H), 3.96 (s, 6H), 3.95 (s, 3H), 3.69 (q, J = 6.2 Hz, 2H), 2.33 (s, 3H), 2.11 (p, J = 6.1 Hz, 2H). HRMS-EI m / z [M+H] + calcd for C 30 H 30 F2NO8 + : 570.1934, found570.1938. Example 42 ( E )-2-((4-(2,6-difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenoxy)butyl)carbamoyl)phenylacetate; (referred to as compound 42) In this embodiment, there are three R1 atoms, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are two R2 atoms, located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, and R3 is... , The connection point is indicated by X, which stands for oxygen, and n is 4.

[0155] The structural formula is:

[0156] The specific synthesis steps differ from those in Example 37 in the following ways: Replace “Compound 31” with “Compound 36”, otherwise the same as in Example 37.

[0157] The target product was obtained as a yellow solid; the yield was 77.89%. 1 H NMR (600 MHz, CDCl3) δ 7.72 (dd, J = 7.7, 1.7 Hz, 1H), 7.63 (d, J = 15.5 Hz, 1H), 7.46 (td, J = 7.3, 6.8, 1.3 Hz,1H), 7.36 (d, J = 15.5 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.32 (d, J = 6.2 Hz, 1H), 4.26 (t, J = 5.8 Hz, 2H), 3.95 (d, J = 6.3 Hz, 9H), 3.51 (q, J = 6.5 Hz, 2H), 2.34 (s, 3H), 1.85(dd, J = 12.6, 5.5 Hz, 2H), 1.61 – 1.55 (m, 2H). HRMS-EI m / z [M+H] + calcd forC 31 H 32 F2NO8 + : 584.2090, found 584.2088. Example 43 ( E2,6-Difluoro-4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl-2-acetoxybenzoate; (referred to as compound 43) In this embodiment, there are three R1 atoms, located at positions 3, 4, and 5 of the benzene ring, respectively. R1 is a methoxy group. There are two R2 atoms, located at positions 3 and 5 of the benzene ring, respectively. R2 is fluorine, and R3 is... , The connection point is indicated by X, where X represents oxygen and n is 0.

[0158] The structural formula is: .

[0159] The specific synthesis steps differ from those in Example 37 in the following ways: Replace “Compound 31” with “Compound 30”, otherwise the same as in Example 37.

[0160] The target product was obtained as a yellow solid; the yield was 68.97%. 1 H NMR (600 MHz, CDCl3) δ 8.27 (dd, J = 7.9, 1.5 Hz, 1H), 7.70 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.44(d, J = 6.1 Hz, 1H), 7.42 (d, J = 5.5 Hz, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 7.27(s, 2H), 7.22 (d, J = 8.1 Hz, 1H), 3.97 (s, 6H), 3.95 (s, 3H), 2.33 (s, 3H).HRMS-EI m / z [M+H] + calcd for C 27 H 23 F2O6 + : 513.1356, found 513.1341. The chalcone-substituted compounds prepared by this invention have a purity of over 95%.

[0161] Pharmacological experiments: in vitro and in vivo anti-inflammatory activity studies Experimental materials Experimental animals: SPF grade C57BL / 6 mice, male, weighing 20-25 g, 6-8 weeks old, all provided by Nanjing Jicui Pharmaceutical Co., Ltd., and fed standard feed.

[0162] Medicines and reagents: Lipopolysaccharide (LPS), Beyotime Corporation; DMEM culture medium, fetal bovine serum (FBS), Vicente Biotechnology Co., Ltd.; Griess reagents, Beyotime Corporation; TNF-α and IL-6 ELISA kit, Shanghai Enzyme-Linked Biotechnology Co., Ltd. The test drug was prepared by the Pharmaceutical Chemistry Laboratory of the School of Pharmaceutical Sciences, Anhui Medical University.

[0163] Cell line: RAW 264.7 mouse macrophages, derived from the cell bank of the School of Pharmaceutical Sciences, Anhui Medical University.

[0164] Experimental methods and results Experiment 1: Effects of chalcone-substituted compounds on LPS-induced NO production in RAW 264.7 cells Experimental Background Nitric oxide (NO) is a key inflammatory mediator generated by inducible nitric oxide synthase (iNOS) during inflammation and is closely related to inflammatory damage. This experiment aims to evaluate the inhibitory effect of chalcone-substituted compounds on NO production.

[0165] Experimental methods Cell culture: RAW 264.7 cells were cultured in DMEM medium containing 10% fetal bovine serum and incubated in an incubator at 37°C, 5% CO2, and saturated humidity.

[0166] Experimental grouping: Cells were grouped at a rate of 2 × 10⁻⁶. 4 Cells were seeded at a density of cells / well in 96-well plates and divided into the following groups after cell adhesion: Untreated control group (blank group); LPS stimulation group (1 μg / mL LPS, inducing an inflammation model); test compound 1-43 (10 μM test compound pretreated for 4 hours, then 1 μg / mL LPS added); positive control group (10 μM aspirin pretreated for 4 hours, then LPS added); NO determination: After 24 hours of culture, 100 μL of cell supernatant from each group was collected, mixed with an equal volume of Griess reagent, incubated at room temperature in the dark for 15 minutes, and the absorbance was measured at 540 nm using a microplate reader.

[0167] Experimental results The experimental results are shown in Figure 1 As shown, the synthesized chalcone-substituted compounds all inhibited NO release at a concentration of 10 μM, and most of the compounds showed stronger NO-inhibiting ability than aspirin.

[0168] Experiment 2: Effects of chalcone-substituted compounds on LPS-induced expression of pro-inflammatory cytokines in RAW 264.7 cells (ELISA method) Experimental Background Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are important pro-inflammatory cytokines in the inflammatory process, and their overexpression can exacerbate the inflammatory response and tissue damage. This study used ELISA to evaluate the inhibitory effect of chalcone-substituted compounds on the secretion of these cytokines.

[0169] Experimental methods Cell culture and grouping: Same as Experiment 1, cells were cultured at 2 × 10⁶ cells / year. 4 The cells were seeded at a density of cells / well in 96-well plates. Experimental groups included: blank group, LPS stimulation group (1 μg / mL), test compound treatment group (compounds 30 and 37-43, pretreated with 10 μM for 4 hours and then treated with LPS), and positive control group (10 μM).

[0170] ELISA assay: After 24 hours of culture, cell supernatant was collected and centrifuged at 2000 rpm for 10 minutes at 4°C. Cytokine levels in the supernatant were measured using a commercial TNF-α and IL-6 ELISA kit (R&D Systems). The specific procedure was performed according to the kit instructions: 100 μL of supernatant was added to a pre-coated 96-well plate and incubated at 37°C for 2 hours; after washing, biotin-labeled detection antibody was added and incubated at 37°C for 1 hour; after washing again, streptavidin-HRP working solution was added and incubated at 37°C for 30 minutes; after washing, TMB substrate was added for color development, and the absorbance was measured at 450 nm (reference wavelength 570 nm) after terminating the reaction. The concentrations of TNF-α and IL-6 (pg / mL) were calculated based on the standard curve.

[0171] Experimental results The experimental results are shown in Figure 2 As shown, chalcone-substituted compounds inhibited TNF-α expression by approximately 50% at 10 μM, while other chalcone-substituted compounds showed no significant inhibitory effect. Chalcone-substituted compounds all significantly inhibited IL-6 at a concentration of 10 μM, and were superior to chalcone derivatives alone.

[0172] Experiment 3: Acute toxicity study of chalcone-substituted compounds Experimental Background Acute toxicity testing is an important indicator for evaluating drug safety. It is used to determine the potential toxic reactions and toxic dose range after a single dose, providing a safe dosage reference for subsequent pharmacodynamic studies and clinical trials. This experiment evaluates the acute toxicity of compound 43 after a single high-dose administration.

[0173] Experimental methods Laboratory animals and their grouping: Female C57BL / 6 mice (7 weeks old, weighing 19-21 g) were selected and administered the drug (1200 mg / kg, single oral gavage) after 7 days of acclimatization. Administration and observation: Mice in each group were fasted for 12 hours but allowed free access to water. On the first day of the experiment, between 9 and 10 AM, a single dose was administered via gavage. The dose volume was 20 mL / kg body weight. Normal food and water intake were resumed immediately after administration.

[0174] Closely observe the general condition of mice after administration, and record symptoms of poisoning and mortality. Observational indicators include: activity level, coat condition, respiratory rate, food and water intake, fecal characteristics, neurological symptoms (such as tremors, spasms, ataxia, etc.) and other abnormal manifestations. Observations should be conducted at 0.5, 1, 2, 4, and 6 hours after administration, and thereafter twice daily (once in the morning and once in the afternoon) for 14 consecutive days. Weight should be measured and recorded before and daily after administration.

[0175] Experimental results The experimental results are shown in Figure 3 As shown in the figure. During the 14-day observation period, no mice in the treatment group (1200 mg / kg) died, and the mortality rate was 0%. No obvious symptoms of poisoning were observed at any time point after administration. The mice's activity, diet, water intake, fur condition, respiration and fecal characteristics were normal. No abnormal manifestations such as tremors, spasms, salivation, or diarrhea were observed, and their weight remained stable and steadily increased.

[0176] Experiment 4: DSS-induced acute colitis model in mice and evaluation of the anti-inflammatory activity of compound 43 Experimental Background Dextran sulfate sodium (DSS)-induced colitis is a classic animal model for studying inflammatory bowel disease (IBD), mimicking the clinicopathological features of human colitis, including colonic shortening, mucosal ulceration, and extensive inflammatory cell infiltration. This study aimed to evaluate the preventive and therapeutic effects of compound 43 on DSS-induced colitis in mice.

[0177] Experimental methods Laboratory animals and their grouping: Female C57BL / 6 mice (7 weeks old, weighing 19–21 g) were selected and randomly divided into 5 groups (n = 5) after 7 days of acclimatization: Normal control group (drinking distilled water); DSS model group (2.5% DSS aqueous solution for free drinking); Low-dose group of compound 43 (DSS + 43, 25 mg / kg, daily by gavage); The medium-dose group of compound 43 (DSS + 43, 50 mg / kg, daily by gavage); High-dose group of compound 43 (DSS + 43, 100 mg / kg, daily by gavage); Model establishment and drug administration: From day 1 to day 7 of the experiment, except for the normal control group, mice in the other groups had free access to 2.5% DSS (w / v, MW 36–50 kDa) solution. Compound 43 was administered by gavage starting on the day of modeling (Day 0), once daily for 7 consecutive days; the normal control and DSS model groups were given an equal volume of 0.5% CMC-Na suspension.

[0178] Observation and testing: Record weight, stool characteristics, and rectal bleeding daily, and calculate the Disease Activity Index (DAI). Mice were sacrificed on day 8, and colon length was measured.

[0179] Experimental results The experimental results are shown in Figure 4 As shown, mice in the DSS model group experienced a continuous decrease in body weight from day 4 onwards, exhibiting loose stools and visible bloody stools, and a significantly elevated DAI score. The high-dose compound 43 group showed a significantly reduced rate of body weight loss, with a DAI score approximately 50% lower than the model group. Furthermore, the colon in the DSS group was significantly shortened, and the colon length in the treated groups showed varying degrees of relief compared to the DSS group.

[0180] Compounds 1-42 prepared using the methods described in Examples 1-42 were also subjected to acute toxicity studies and anti-inflammatory activity evaluations. The results showed that compounds 1-42 had similar effects to compound 43.

[0181] in conclusion The above experiments show that: Significant in vitro anti-inflammatory activity: Chalcone-substituted compounds significantly inhibited LPS-induced NO production in RAW 264.7 cells (inhibition rate 60%); Effective inhibition of inflammatory mediators: Chalcone-substituted compounds effectively reduced the expression of pro-inflammatory cytokines TNF-α and IL-6; High biocompatibility: A single oral administration of 1200 mg / kg to the treatment group did not produce significant acute toxicity in mice, indicating good safety. In vivo anti-inflammatory activity: Chalcone-substituted compound 43 could alleviate inflammatory symptoms in colitis mice, effectively reduce the disease index, reduce weight loss, and alleviate colonic shortening caused by DSS. In summary, chalcone-substituted compounds have high biocompatibility and can exert anti-inflammatory effects by inhibiting various inflammatory mediators (e.g., NO, TNF-α, IL-6). Furthermore, they also exhibited anti-inflammatory effects in in vivo experiments on colitis mice, providing experimental evidence for the development of novel anti-inflammatory drugs.

[0182] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The use of chalcone-substituted compounds I or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention or treatment of inflammation-related diseases, characterized in that, The general structural formula of the chalcone-substituted compound I is as follows: The benzene ring on the left can be substituted by 1 to 5 R1 atoms, and the benzene ring on the right can be substituted by 1 to 4 R2 atoms. X is located at any position on the benzene ring on the right. X is selected from hydroxyl and oxygen. n takes the value of 0, 2, 3 or 4. R1 is selected from methoxy, methyl, hydrogen, fluorine, chlorine, and dihydrobenzo[]. b One of [1,4]dioxin-6-yl, benzo[d][1,3]dioxono-5-yl, benzyloxy, morpholino, naphth-2-yl, or 6-methoxynaphth-2-yl; R2 is selected from one of hydrogen, fluorine, methoxy, and methyl. R3 is selected from hydroxyl, amino, , One of them; Indicates the connection point.

2. The use according to claim 1, characterized in that, Pharmaceutically acceptable salts include acid addition salts formed by chalcone-substituted compounds I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or benzenesulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid; the inflammation-related diseases are one or more of inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, chronic nephritis, atherosclerosis, pancreatitis, pneumonia, and bronchitis.

3. The use according to claim 1, characterized in that, The concentration of the chalcone-substituted compound I is 8-12 μM.

4. The use according to claim 1, characterized in that, The drug also includes a pharmaceutically acceptable carrier.

5. The use according to claim 1, characterized in that, The drug is formulated into a pharmaceutically acceptable dosage form.

6. A chalcone-substituted compound II or a pharmaceutically acceptable salt thereof, characterized in that, The chalcone-substituted compound II has any of the following structural formulas: 、 、 、 、 、 、 、 、 、 、 、 、 。 7. A method for preparing chalcone-substituted compound I, characterized in that, Includes the following steps: (1) , A mixture of sodium hydroxide aqueous solution and anhydrous ethanol reacts to produce... ; (2) The result obtained from (1) halogenated compounds, potassium carbonate and N , N - After the reaction with dimethylformamide; (3) Add R3, thionyl chloride, triethylamine, and anhydrous dichloromethane, and react at room temperature to obtain the product; The chalcone-substituted compound I has the general structural formula as described in claim 1.

8. The preparation method according to claim 7, characterized in that, In step (1), , The ratio of sodium hydroxide aqueous solution to anhydrous ethanol is 0.9~1.4 mmol: 0.8~1.2 mmol: 8~12 mL: 15~25 mL; the reaction conditions are: room temperature, 22~26 h.

9. The preparation method according to claim 7, characterized in that, In step (2), halogenated compounds, potassium carbonate and N , N The ratio of dimethylformamide used is 0.8~1.2 mmol : 1.8~2.2 mmol : 2.0~3.0 mmol : 1~5 mL; the reaction conditions are: temperature 50~80 ℃, 10~14 h.

10. The preparation method according to claim 7, characterized in that, In step (3), the ratio of R3, sulfoxide, triethylamine and anhydrous dichloromethane is 0.8~1.2 mmol: 4.6~5.2 mmol: 2.8~3.2 mmol: (5-15) mL; the incubation conditions are: room temperature, 3~5 h.

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