Polyphenol tyrosinase inhibitor as well as preparation method and application thereof

Abstract

The invention discloses a polyphenol tyrosinase inhibitor as well as a preparation method and application thereof. The novel polyphenol tyrosinase inhibitor with potential anti-chromatosis activity is designed and synthesized on the basis of a reasonable drug design principle through a pharmacophore heterozygosis strategy. According to the compound disclosed by the invention, a diamine connecting arm which is high in structural adjustability and capable of improving drug-likeness and improving tyrosinase inhibitory activity is introduced on a design strategy. In in-vitro experiments, most inhibitory activity exceeds that of a control drug kojic acid. It is worth noting that the IC50 values of some designed compounds reach the nanomole level. The novel polyphenol tyrosinase inhibitor disclosed by the invention is expected to provide potential candidate molecules for discovery of anti-pigmentation drugs.

Description

Technical Field

[0001] The invention relates to the fields of pharmaceutical chemistry and cosmetics, and in particular to a class of polyphenol tyrosinase inhibitors and a preparation method and application thereof. Background Art

[0002] Acute or prolonged sun exposure, as well as related fluctuations in endocrine regulation, may lead to excessive skin pigmentation, which in turn may cause a series of acute or chronic skin diseases. This increased pigmentation not only increases the risk of developing inflammation, metabolic disorders, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, and Huntington's disease) and even cancer, but also directly affects the individual's external appearance, easily leading to appearance anxiety, which in turn causes tremendous psychological pressure and induces a series of social problems. In view of this, the demand for products that can effectively combat pigmentation in the medical and cosmetic fields continues to rise, and the market for skin whitening products is also booming.

[0003] Hyperpigmentation is usually caused by excessive deposition of melanin in the skin. Currently, there are two main approaches to treat hyperpigmentation. One is to regulate the production of melanin, and the other is to block the transfer of melanosomes. Among them, inhibiting melanin synthesis and reducing melanin concentration are important strategies for treating diseases related to hyperpigmentation. Tyrosinase (TYR), as a multi-subunit, binuclear copper-containing metalloenzyme, is a transmembrane protein expressed only by melanocytes. As a rate-limiting enzyme, TYR plays a vital role in melanin synthesis, and therefore, it has been widely regarded as a key target for inhibiting pigmentation. In addition, melanin is also over-secreted in melanoma cells. Studies have shown that TYR inhibitors can enhance the efficacy of anti-tumor drugs by inhibiting the activity of TYR in melanoma and inhibiting the synthesis of melanin. Therefore, TYR inhibitors can be used as auxiliary synergistic drugs for melanoma.

[0004] TYR inhibitors have shown broad application prospects in the treatment of hyperpigmentation due to their potent TYR inhibitory activity. They can effectively reduce melanin production, thereby reducing pigment deposition and achieving skin whitening effects. Existing TYR inhibitors can be divided into three categories: natural, semi-synthetic and synthetic. However, only a very small number of related TYR inhibitors can be used in clinical treatment and skin whitening products. In the prior art, the patent specification with publication number CN115353548A discloses a pearl shell tyrosinase inhibitory peptide with whitening effect and its application. The sequence of the pearl shell tyrosinase inhibitory peptide is: WLL (Trp-Leu-Leu); the patent specification with publication number CN118108601A discloses a magnolol derivative, which can be used to prepare tyrosinase inhibitors, and to prepare cosmetics that inhibit tyrosinase activity to achieve whitening.

[0005] Most of the TYR inhibitors reported so far, even some skin whitening agents used clinically, have obvious disadvantages, such as high water solubility, poor permeability, low skin absorption rate, and insufficient stability. These problems may cause adverse reactions such as skin irritation, allergies, and toxicity, thus limiting their wide application in clinical treatment and the cosmetics industry. Therefore, the development of safe, efficient, and stable new TYR inhibitors has important clinical significance and social value for the treatment of hyperpigmentation and skin whitening. Summary of the invention

[0006] The present invention hybridizes the key pharmacophores of representative TYR inhibitors reported in recent years through a pharmacophore hybridization strategy to obtain a series of novel polyphenolic TYR inhibitors. Such compounds are expected to improve the deficiencies of existing TYR inhibitors and improve their anti-pigmentation activity. In addition, the present invention also studies the preparation method and pharmacological activity thereof.

[0007] A polyphenol tyrosinase inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, wherein the general structural formula of the polyphenol tyrosinase inhibitor is shown in (I): (I); in: R 1 There are two or more hydroxyl substituents; R 2 It is a straight-chain or cyclic diamine structure containing nitrogen atoms; R 3 is a substituted or unsubstituted aromatic group or aromatic allyl group.

[0008] Furthermore, in formula (I): R 1 is a dihydroxy substituent; R 2 C 2-3 A nitrogen-containing linear diamine structure of C6 or a nitrogen-containing cyclic diamine structure of C6; R 3 It is a substituted or unsubstituted aromatic ring, or an allyl group substituted with an aromatic ring or an aromatic heterocyclic ring.

[0009] Furthermore, in formula (I): R 1 2,4-dihydroxy or 3,5-dihydroxy, preferably 2,4-dihydroxy, can further improve the inhibitory activity against tyrosinase, IC 50 Can be as low as nanomolar levels; R 2 Select from the following structures: , or ; R 3 Select from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0010] Specifically, the polyphenol tyrosinase inhibitor can be selected from the compounds A1-A shown in the following structures: 19 and B1-B 36 : ; .

[0011] The present invention also provides a method for preparing the polyphenol tyrosinase inhibitor, and the synthetic route includes: ; The preparation method comprises the steps of: Substituted or unsubstituted cinnamic acid 1 undergoes condensation reaction with Boc (tert-butyloxycarbonyl) protected diamine 2 to obtain intermediate 3; Boc-protected diamine 2 undergoes condensation reaction with aromatic or aromatic allyl carboxylic acid 5 to give intermediate 7; The intermediate 3 or 7 is deprotected by the Boc protecting group to obtain the intermediate 4 or 8; Intermediate 4 undergoes condensation reaction with aromatic or aromatic allyl carboxylic acid 5 to obtain intermediate 6; Intermediate 6 is subjected to a demethylation reaction to obtain a polyphenol tyrosinase inhibitor A as shown in formula (I). 1-19 , B 1-16 ; Intermediate 8 is subjected to condensation reaction with 3,5-dihydroxy substituted cinnamic acid 9 to obtain polyphenol tyrosinase inhibitor B as shown in formula (I)17-36 .

[0012] The present invention also provides the use of the polyphenol tyrosinase inhibitor or its pharmaceutically acceptable salt or solvate or its enantiomer or diastereomer in the preparation of anti-pigmentation, anti-melanoma drugs or cosmetics. The target of the anti-pigmentation, anti-melanoma drug is TYR.

[0013] As a general inventive concept, the present invention also provides an anti-pigmentation and anti-melanoma drug, which contains a safe and effective amount of the polyphenol tyrosinase inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof. The anti-pigmentation and anti-melanoma drug may also include at least one of a pharmacologically acceptable salt, an excipient, and a carrier.

[0014] Compared with the prior art, the present invention has the following beneficial effects: The present invention is based on the principle of rational drug design, and designs and synthesizes a novel small molecule compound with TYR inhibitory activity and potential anti-pigmentation activity.

[0015] The compounds of the present invention adopt a pharmacophore hybridization strategy in design, taking the reported phenolic compounds with high TYR inhibitory activity as the guide, introducing a diamine structure that can improve the TYR inhibitory activity as a connecting arm, fusing the advantageous structures into one molecule, improving the TYR inhibitory activity, and being able to significantly improve the pigmentation condition. DETAILED DESCRIPTION

[0016] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods in the following examples where no specific conditions are indicated are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0017] (I) Preparation of intermediates 3 and 4: .

[0018] Reaction 1: Synthesis route of intermediates 3 and 4. Reagents and conditions: (a) 1-hydroxybenzotriazole (HOBT), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N , N -Diisopropylethylamine (DIPEA), N , N -dimethylformamide (DMF), room temperature (rt), 12 h; (b) hydrochloric acid dioxane solution (HCl·Dioxane), methanol (MeOH), 0 ℃ to room temperature (rt), 4 h.

[0019] As shown in reaction formula 1, add ( E )-3-(3, 5-dimethoxyphenyl)acrylic acid (748 mg, 3.6 mmol), 1-hydroxybenzotriazole (HOBT, 486 mg, 3.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 691 mg, 3.6 mmol), DMF (8 mL), N , N -Diisopropylethylamine (DIPEA, 1161 mg, 9.0 mmol) and 1-tert-butyloxycarbonylpiperazine (558 mg, 3.0 mmol) were reacted at room temperature, and the reaction progress was monitored by thin layer chromatography (TLC) during the reaction. The developing solvent was dichloromethane:methanol (volume ratio 20:1). After the reaction was completed, an appropriate amount of ethyl acetate and water were added for dilution, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was purified by column silica gel, and the eluent was dichloromethane:methanol (volume ratio 100:1-80:1). Finally, a colorless oily liquid, namely intermediate 3a (85%), was obtained.

[0020] According to reaction formula 1 and the same method as above, the reactants were replaced to obtain intermediates 3b, 3c, 3d, 3e, and 3f.

[0021] (II) Preparation of intermediate 4: To a 50 mL round-bottom flask equipped with a magnetic stirrer, add intermediate 3a (1278 mg, 3.4 mmol) and methanol (10 mL) in sequence and stir at 0 °C. Then, use a constant pressure dropping funnel to slowly add dioxane hydrochloride solution (13 mL). After the addition is complete, continue to stir at 0 °C for 0.5 h, and then move to room temperature for reaction for 4-6 h. TLC monitors the progress of the reaction, and the developing solvent is dichloromethane:methanol (volume ratio 5:1). After the reaction is completed, the reaction solvent is removed by vacuum distillation, ethyl acetate is added to shake the mixture, filtered, washed with ethyl acetate, and dried to obtain a white solid, namely intermediate 4a (90%). According to reaction formula 1 and the same method as above, the substrate is replaced to obtain intermediates 4b, 4c, 4d, 4e, and 4f.

[0022] (III) Preparation of intermediates 6a-6s and 6a'-6s': .

[0023] Scheme 2: Synthesis route of intermediates 6a-s and 6a'-6s'. Reagents and conditions: (a) HOBT, EDCI, DIPEA, DMF, rt, 12 h.

[0024] As shown in reaction formula 2, intermediate 4a (3.6 mmol), HOBT (486 mg, 3.6 mmol), EDCI (691 mg, 3.6 mmol), DMF (8 mL), DIPEA (1161 mg, 9.0 mmol) and 1-tert-butyloxycarbonylpiperazine (558 mg, 3.0 mmol) were added to a 100 mL round-bottom flask equipped with a magnetic stirrer in sequence, and the reaction was carried out at room temperature. During the reaction, the progress of the reaction was monitored by TLC, and the developing solvent was dichloromethane: methanol (volume ratio 20:1). After the reaction was completed, an appropriate amount of ethyl acetate and water were added for dilution, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Purification was performed on a silica gel column, and the eluent was dichloromethane: methanol (volume ratio 100:1-80:1), and finally a colorless oily liquid, namely intermediate 6a (65%), was obtained.

[0025] According to Reaction Scheme 2 and the same method as above, the reactants were replaced to prepare intermediates 6b-s and 6a'-6s'.

[0026] (IV) TYR inhibitor end product A 1-19 and B 1-16 Preparation: .

[0027] Reaction 3: TYR inhibitor final product A 1-19 and B 1-16 Reagents and conditions: (c) BBr3, dichloromethane (DCM), 0 °C to rt, 24 h.

[0028] Add intermediate 6a (440 mg, 1.0 mmol) to a 100 mL round-bottom flask equipped with a magnetic stirrer and dissolve it in 5 mL of dichloromethane. Cool the solution to 0 °C. Under nitrogen protection, slowly drop a dichloromethane solution of boron tribromide (0.4 mL, 6.0 mmol) into the reaction solution. After the addition is complete, stir the reaction mixture at room temperature for 24 h. Monitor the progress of the reaction by TLC, and the developing solvent is dichloromethane:methanol (5:1). After the reaction is completed, cool the reaction to 0 °C and add ice water to quench (slowly dropwise). Solids will precipitate during the quenching process. Filter the solids, wash the solids with water and dichloromethane, and finally obtain a white solid, i.e., the TYR inhibitor final product A1 (12%). According to reaction formula 3 and the same method as above, replace the substrate to obtain the TYR inhibitor final product A. 2-19 and B 1-16 .

[0029] (V) Preparation of intermediates 7 and 8: .

[0030] Scheme 4: Synthesis route of intermediates 7 and 8. Reagents and conditions: (a) HOBT, EDCI, DIPEA, DMF, rt, 12 h; (b) HCl·Dioxane, MeOH, 0 °C to rt, 4 h.

[0031] As shown in reaction formula 4, 3-methylbenzoic acid (490 mg, 3.6 mmol), HOBT (486 mg, 3.6 mmol), EDCI (691 mg, 3.6 mmol), DMF (8 mL), DIPEA (1161 mg, 9.0 mmol) and 1-tert-butyloxycarbonylpiperazine (558 mg, 3.0 mmol) were added to a 100 mL round-bottom flask equipped with a magnetic stirrer in sequence, and the reaction was carried out at room temperature. During the reaction, the reaction progress was monitored by TLC, and the developing solvent was dichloromethane:methanol (volume ratio 20:1). After the reaction was completed, an appropriate amount of ethyl acetate and water were added for dilution, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Purification was performed on a silica gel column, and the eluent was dichloromethane:methanol (volume ratio 100:1-80:1), and finally a colorless oily liquid, namely intermediate 7a (62%), was obtained.

[0032] According to reaction formula 4 and the same method as above, the reactants were replaced to obtain intermediate 7b-s.

[0033] (VI) Preparation of Intermediate 8: To a 50 mL round-bottom flask equipped with a magnetic stirrer, add intermediate 7a (1035 mg, 3.4 mmol) and methanol (10 mL) in sequence and stir at 0 °C. Then, use a constant pressure dropping funnel to slowly add dioxane hydrochloride solution (13 mL). After the addition is complete, continue to stir at 0 °C for 0.5 h, and then move to room temperature for reaction for 4-6 h. TLC monitors the progress of the reaction, and the developing solvent is dichloromethane: methanol (volume ratio 5:1). After the reaction is completed, the reaction solvent is removed by vacuum distillation, ethyl acetate is added to shake the mixture, filtered, washed with ethyl acetate, and dried to obtain a white solid, namely intermediate 8a (92%). According to reaction formula 4 and the same method as above, the substrate is replaced to obtain intermediate 8b-s.

[0034] (VII) TYR inhibitor end product B 17-36 Preparation: .

[0035] Reaction 5: TYR inhibitor final product B17-36 Synthesis route of . Reagents and conditions: (a) HOBT, EDCI, DIPEA, DMF, rt, 12 h.

[0036] As shown in reaction formula 5, add ( E )-3-(2, 4-dihydroxyphenyl)acrylic acid 9 (216 mg, 1.2 mmol), HOBT (162 mg, 1.2 mmol), EDCI (230 mg, 1.2mmol), DMF (5 mL), DIPEA (258 mg, 1.2 mmol) and 8a (241 mg, 1.0 mmol) were reacted at room temperature. The reaction progress was monitored by TLC during the reaction. The developing solvent was dichloromethane: methanol (volume ratio 20:1). After the reaction was completed, an appropriate amount of ethyl acetate and water were added for dilution, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was purified by column silica gel. The eluent was dichloromethane: methanol (volume ratio 100:1-80:1). Finally, a white solid was obtained, i.e., the final product B. 17 (16%).

[0037] According to reaction formula 5 and the same method as above, the reactants are replaced to obtain the final product B 18-36 .

[0038] All intermediates and final products used can be prepared according to the above (i) to (vii), which will not be described in detail here.

[0039] Example 1: E Preparation of 3-(3,5-dihydroxyphenyl)-1-[4-(2-hydroxybenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound A1): According to the synthetic methods in (i) to (iv) above, compound A1 (44 mg, 12%) was obtained as a white solid with a melting point of 168.0-168.9 °C. H NMR spectrum data 1 H NMR (500 MHz, DMSO- d 6 ) d 9.85 (s, 1H),9.35 (s, 2H), 7.29 – 7.21 (m, 2H), 7.15 (dd, J = 7.5, 1.5 Hz, 1H), 6.94 – 6.80(m, 3H), 6.51 (s, 2H), 6.27 (s, 1H), 3.63 (s, 8H); NMR carbon data13 C NMR (125MHz, DMSO- d 6 ) d 167.3, 164.7, 158.6, 153.3, 142.3, 136.8, 130.3, 128.3, 123.6,119.2, 117.6, 115.7, 106.1, 104.1, 45.0, 45.0, 41.7, 41.7; LCMS (ESI) m / z:367.1 [MH] – .

[0040] Example 2: E Preparation of 3-(3,5-dihydroxyphenyl)-1-[4-(3-hydroxybenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound A2): The preparation method is basically the same as that of Example 1. In this example, compound A2 (52 mg, 14%) is obtained as a white solid with a melting point of 248.9-249.8 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.70 (s, 1H), 9.35 (s, 2H), 7.34 –7.19 (m, 2H), 7.05 (s, 1H), 6.89 – 6.74 (m, 3H), 6.51 (s, 2H), 6.27 (s, 1H), 3.62 (s, 8H); 13 C NMR (125 MHz, DMSO- d 6 ) d 169.1, 164.7, 158.6, 157.3, 142.4,137.0, 136.8, 129.6, 117.6, 117.4, 116.6, 113.8, 106.1, 104.1, 50.2, 50.1,50.0, 49.9; LCMS (ESI) m / z: 367.1 [MH] – .

[0041] Example 3: E Preparation of 3-(3,5-dihydroxyphenyl)-1-[4-(3-hydroxybenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound A3): The preparation method is basically the same as that of Example 1. In this example, compound A3 (77 mg, 21%) is obtained as a white solid with a melting point of 268.3-269.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.89 (s, 1H), 9.37 (s, 2H), 7.30(dd, J = 11.7, 3.2 Hz, 3H), 7.05 (d, J = 15.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H),6.52 (d, J = 1.5 Hz, 2H), 6.28 (s, 1H), 3.71 (s, 2H), 3.56 (d, J = 37.6 Hz, 6H); 13 C NMR (125 MHz, DMSO- d 6 ) d 169.6, 164.8, 159.0, 158.7, 142.5, 136.9, 129.5,125.9, 117.7, 115.0, 106.2, 104.2, 45.1, 45.1, 41.8, 41.7;LCMS (ESI) m / z:367.1 [MH] – .

[0042] Example 4: E Preparation of 3-(3,5-dihydroxyphenyl)-1-[4-[4-(dimethylamino)benzoyl]piperazin-1-yl]prop-2-en-1-one (Compound A4): The preparation method is basically the same as that of Example 1. In this example, compound A4 (95 mg, 24%) is obtained as a white solid with a melting point of 279.5-280.6°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.35 (s, 2H), 7.33 – 7.27 (m, 3H), 7.05 (d, J = 15.3 Hz, 1H), 6.72 (d, J = 8.9 Hz, 2H), 6.52 (d, J = 2.0 Hz, 2H), 6.27(t,J = 2.1 Hz, 1H), 3.73 – 3.51 (m, 8H), 2.95 (s, 6H); 13 C NMR (125 MHz, DMSO- d 6 ) d 169.9, 164.7, 158.6, 151.3, 142.3, 136.8, 129.2, 121.7, 117.6, 111.0,106.1, 104.1, 45.1, 45.1, 41.7, 41.7, 39.8; (ESI) m / z: 394.2 [MH] – .

[0043] Example 5: E Preparation of 1-[4-(4-acetylbenzoyl)piperazin-1-yl]-3-(3,5-dihydroxyphenyl)prop-2-en-1-one (Compound A5): The preparation method is basically the same as that of Example 1. In this example, compound A5 (71 mg, 18%) is obtained as a white solid with a melting point of 282.9-284.1°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.35 (s, 2H), 8.03 (d, J = 8.3 Hz,2H), 7.58 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 15.3 Hz, 1H), 7.04 (d, J = 37.7 Hz,1H), 6.52 (s, 2H), 6.27 (s, 1H), 3.68 (t, J = 54.9 Hz, 8H), 2.62 (s, 3H); 13 C NMR (125 MHz, DMSO- d 6 ) d 197.6, 168.4, 164.7, 158.6, 142.4, 140.0, 137.4, 136.8,128.4, 127.3, 117.6, 106.2, 104.1, 45.0, 45.0, 41.3, 41.3, 26.9; LCMS (ESI)m / z: 393.2 [MH]– .

[0044] Example 6: E )-3-(3-chlorophenyl)- N -[2-[[( E Preparation of 3-(3,5-dihydroxyphenyl)acrylamide]ethyl]acrylamide (Compound A6): The preparation method is basically the same as that of Example 1. In this example, compound A6 (46 mg, 12%) is obtained as a white solid with a melting point of 251.6-252.4°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.40 (s, 2H), 8.23 ​​(d, J = 7.4 Hz,2H), 7.64 (s, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.46 – 7.40 (m, 3H), 7.21 (d, J =15.7 Hz, 1H), 6.68 (d, J = 15.8 Hz, 1H), 6.45 – 6.38 (m, 3H), 6.23 (s, 1H), 3.29 (s, 4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.3, 164.9, 158.7, 139.2, 137.2,137.2, 136.5, 133.7, 130.8, 129.1, 127.2, 126.0, 123.9, 121.6, 105.6, 103.9,38.7, 38.6; LCMS (ESI) m / z: 385.1 [MH] – .

[0045] Example 7: E )-3-(3,5-dihydroxyphenyl)- N -[2-[[( E Preparation of 3-[3-(trifluoromethyl)phenyl]acrylamide]ethyl]acrylamide (Compound A7): The preparation method is basically the same as that of Example 1. In this example, compound A7 (76 mg, 18%) is obtained as a white solid with a melting point of 231.6-232.3 °C. 1H NMR (500 MHz, DMSO- d 6 ) d 9.39 (s, 2H), 8.32 – 8.18 (m, 2H),7.92 (s, 1H), 7.87 (t, J = 9.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.69 – 7.60 (m,1H), 7.53 (dd, J = 15.8, 4.4 Hz, 1H), 7.21 (d, J = 15.7 Hz, 1H), 6.77 (d, J = 15.9Hz, 1H), 6.47 – 6.35 (m, 3H), 6.23 (t, J = 2.1 Hz, 1H), 3.30 (d, J = 6.1 Hz, 4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.3, 164.8, 158.7, 139.2, 137.0, 136.5, 136.1,131.3, 130.1, 129.9, 125.7, 124.3, 123.9, 123.9, 121.6, 105.6, 103.9, 38.7,38.5; LCMS (ESI) m / z: 419.1 [MH] – .

[0046] Example 8: E )-3-(3,5-dihydroxyphenyl)- N -[3-[[( E Preparation of 3-(4-fluorophenyl)acrylamide]propyl]acrylamide (Compound A8): The preparation method is basically the same as that of Example 1. In this example, compound A8 (48 mg, 13%) is obtained as a white solid with a melting point of 279.7-280.4°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.42 (s, 2H), 8.24 (s, 2H), 7.63(dd, J= 8.7, 5.6 Hz, 2H), 7.43 (d, J = 15.8 Hz, 1H), 7.29 – 7.15 (m, 3H), 6.56(d, J = 15.8 Hz, 1H), 6.48 – 6.36 (m, 3H), 6.23 (d, J = 1.9 Hz, 1H), 3.28 (s,4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.3 (d, 2 J = 25.0 Hz), 163.7, 161.7, 158.7,139.2 (d, 1 J = 212.5 Hz), 136.5, 131.5, 129.7 (d, 3 J = 12.5 Hz), 122.1, 121.7,121.6, 116.0 (d, 2 J = 25.0 Hz), 105.6, 103.9, 38.6, 38.6; LCMS (ESI) m / z: 369.1[MH] – .

[0047] Example 9: 2E,2'E )- N,N Preparation of '-(ethane-1,2-diyl)bis(3-(3,5-dihydroxyphenyl)acrylamide) (Compound A9): The preparation method is basically the same as that of Example 1. In this example, compound A9 (61 mg, 16%) is obtained as a white solid with a melting point of 338.4-339.4 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.40 (s, 4H), 8.22 (s, 2H), 7.21(d, J = 15.7 Hz, 2H), 6.43 (d, J = 15.7 Hz, 2H), 6.38 (d, J = 1.9 Hz, 4H), 6.23 (s, 2H), 3.27 (s, 4H); 13C NMR (125 MHz, DMSO- d 6 ) d 165.2, 158.7, 139.2, 136.5,121.7, 105.6, 103.9, 48.6, 38.6; LCMS (ESI) m / z: 383.1 [MH] – .

[0048] Embodiment 10: E )-3-(3,5-dihydroxyphenyl)- N -(2-(( E )-3-(pyridin-2-yl)acrylamide)ethyl)acrylamide (Compound A 10 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 10 (95 mg, 27%), white solid, melting point 203.7-204.5 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.43 (s, 2H), 8.74 (d, J = 5.0 Hz,1H), 8.52 (d, J = 5.1 Hz, 1H), 8.29 – 8.11 (m, 2H), 7.91 (d, J = 7.9 Hz, 1H),7.72 – 7.59 (m, 1H), 7.51 (d, J = 15.6 Hz, 1H), 7.15 (dd, J = 39.8, 15.7 Hz, 2H),6.42 (d, J = 15.7 Hz, 1H), 6.36 (d, J = 2.1 Hz, 2H), 6.22 (t, J = 2.0 Hz, 1H), 3.29(d, J = 6.4 Hz, 4H); 13 C NMR (125 MHz, DMSO- d 6 ) d165.4, 165.0, 158.9, 153.1,149.9, 139.3, 138.2, 137.2, 136.5, 125.8, 124.2, 124.1, 121.6, 105.6, 104.1,38.7, 38.6; LCMS (ESI) m / z: 352.1 [MH] – .

[0049] Example 11: E )-3-(3,5-dihydroxyphenyl)- N -(2-(( E )-3-(furan-2-yl)acrylamide)ethyl)acrylamide (Compound A 11 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 11 (99 mg, 29%), white solid, melting point 238.9-239.9 ℃. 1 H NMR (500 MHz, DMSO- d6 ) d 9.39 (s, 2H), 8.23 ​​(d, J = 27.9 Hz,2H), 7.76 (s, 1H), 7.22 (t, J = 16.2 Hz, 2H), 6.76 (d, J = 3.3 Hz, 1H), 6.58(dd, J = 3.3, 1.8 Hz, 1H), 6.47 – 6.35 (m, 4H), 6.23 (t, J = 1.9 Hz, 1H), 3.27(s, 4H); 13 C NMR (125 MHz, DMSO- d6 ) d LCMS(ESI) m / z: 341.1 [MH] – .

[0050] Example 12: E )-3-(3,5-dihydroxyphenyl)- N -(2-(( E)-3-(thiophen-2-yl)acrylamide)ethyl)acrylamide (Compound A 12 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 12 (93 mg, 26%), white solid, melting point 257.6-258.7 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.42 (s, 2H), 8.23 ​​(d, J = 5.3 Hz,2H), 7.64 – 7.52 (m, 2H), 7.37 (d, J = 3.5 Hz, 1H), 7.21 (d, J = 15.7 Hz, 1H),7.10 (dd, J = 5.0, 3.6 Hz, 1H), 6.48 – 6.32 (m, 4H), 6.23 (s, 1H), 3.26 (s, 4H); 13 C NMR (125 MHz, DMSO- d 6 ) d LCMS(ESI) m / z: 357.1 [MH] – .

[0051] Example 13: E )-3-(3-chlorophenyl)- N -(3-(( E )-3-(3,5-dihydroxyphenyl)acrylamide)propyl)acrylamide (Compound A 13 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 13 (116 mg, 29%), white solid, melting point 138.1-138.7 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.34 (s, 2H), 8.13 (dt, J= 11.0, 5.5Hz, 2H), 7.64 (s, 1H), 7.56 – 7.50 (m, 1H), 7.47 – 7.37 (m, 3H), 7.20 (d, J =15.7 Hz, 1H), 6.69 (d, J = 15.8 Hz, 1H), 6.50 – 6.35 (m, 3H), 6.23 (t, J = 2.0Hz, 1H), 3.21 (p, J = 6.2 Hz, 4H), 1.65 (p, J = 6.9 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.1, 164.6, 158.7, 139.1, 137.3, 137.0, 136.6, 133.7, 130.8,129.0, 127.2, 126.0, 124.0, 121.7, 105.6, 103.9, 36.7, 36.6, 29.3; LCMS (ESI)m / z: 399.1 [MH] – .

[0052] Example 14: E )-3-(3,5-dihydroxyphenyl)- N -(3-(( E )-3-(3-(trifluoromethyl)phenyl)acrylamide)propyl)acrylamide (Compound A 14 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 14 (91 mg, 21%), white solid, melting point 196.1-196.7 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.40 (s, 2H), 8.15 (dt, J = 21.1, 5.6Hz, 2H), 7.95 – 7.82 (m, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 – 7.59 (m, 1H), 7.51 (dd, J= 15.8, 4.0 Hz, 1H), 7.21 (d, J = 15.7 Hz, 1H), 6.77 (d, J = 15.8 Hz,1H), 6.46 (d, J = 15.7 Hz, 1H), 6.39 (d, J = 2.0 Hz, 2H), 6.24 (t, J = 2.1 Hz, 1H),3.23 (p, J = 6.6 Hz, 4H), 1.66 (p, J = 7.0 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.1, 164.6, 158.7, 139.1, 136.9, 136.6, 136.2, 131.3, 130.1, 125.7, 125.2,124.4, 123.9, 123.0, 121.7, 105.6, 103.9, 36.7, 36.6, 29.3; LCMS (ESI) m / z:433.1 [MH] – .

[0053] Example 15: E )-3-(3,5-dihydroxyphenyl)- N -[3-[[( E )-3-(4-fluorophenyl)acrylamide]amino]propyl]acrylamide (Compound A 15 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 15 (61 mg, 16%), white solid, melting point 127.0-128.0 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.42 (s, 2H), 8.14 (t, J = 5.2 Hz,2H), 7.62 (dd, J = 8.6, 5.6 Hz, 2H), 7.42 (d, J = 15.8 Hz, 1H), 7.31 – 7.14 (m,3H), 6.57 (d, J= 15.8 Hz, 1H), 6.50 – 6.34 (m, 3H), 6.23 (s, 1H), 3.21 (s,4H), 1.66 (q, J = 6.9 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.0, 163.6, 161.7,158.7, 139.1 (d, 1 J = 312 .5Hz), 137.4, 131.6, 129.7 (d, 3 J = 12.5 Hz), 122.2 (d, 3 J = 12.5 Hz), 121.7, 116.0 (d, 2 J = 25.0 Hz), 105.6, 103.9, 36.7, 36.6, 29.3; LCMS (ESI) m / z: 383.1 [MH] – .

[0054] Example 16: 2E,2'E )- N,N' -(propane-1,3-diyl)bis(3-(3,5-dihydroxyphenyl)acrylamide) (Compound A 16 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 16 (88 mg, 22%), white solid, melting point 162.8-163.3 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.38 (s, 4H), 8.11 (t, J = 5.5 Hz,2H), 7.19 (d, J = 15.7 Hz, 2H), 6.44 (d, J = 15.7 Hz, 2H), 6.38 (d, J = 2.0 Hz,4H), 6.23 (t, J = 2.0 Hz, 2H), 3.20 (dd, J= 12.8, 6.6 Hz, 4H), 1.68 – 1.60 (m,2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.1, 158.7, 139.1, 136.6, 121.7, 105.6,103.9, 36.7, 29.4; LCMS (ESI) m / z: 397.1 [MH] – .

[0055] Example 17: E )-3-(3,5-dihydroxyphenyl)- N -[3-[[( E )-3-(pyridin-2-yl)acrylamido]propyl]]acrylamide (Compound A 17 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 17 (92 mg, 25%), white solid, melting point 272.5-273.4 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 8.75 (d, J = 4.5 Hz, 1H), 8.47 (t, J =5.4 Hz, 1H), 8.28 – 8.12 (m, 2H), 7.91 (d, J = 7.9 Hz, 1H), 7.66 (q, J = 6.6 Hz,1H), 7.51 (d, J = 15.6 Hz, 1H), 7.17 (dd, J = 23.0, 15.6 Hz, 2H), 6.51 – 6.33 (m,3H), 6.24 (t, J = 2.0 Hz, 1H), 3.23 (dq, J = 11.6, 6.4 Hz, 4H), 1.67 (p, J = 6.9Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d165.1, 163.7, 158.7, 150.1, 145.6, 142.4,139.1, 136.6, 133.0, 129.8, 125.5, 124.5, 121.7, 105.6, 103.9, 36.9, 36.6,29.1; LCMS (ESI) m / z: 366.2 [MH] – .

[0056] Example 18: E )-3-(3,5-dihydroxyphenyl)- N -[3-[[( E )-3-(furan-2-yl)acrylamido]propyl]]acrylamide (Compound A 18 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 18 (39 mg, 11%), gray-green solid, melting point 152.5-153.5 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.38 (s, 2H), 8.14 (dt, J = 23.8,5.6 Hz, 2H), 7.76 (d, J = 1.4 Hz, 1H), 7.29 – 7.15 (m, 2H), 6.76 (d, J = 3.3 Hz,1H), 6.58 (dd, J = 3.3, 1.8 Hz, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 6.41 – 6.36(m, 2H), 6.23 (t, J = 2.0 Hz, 1H), 3.27 – 3.11 (m, 4H), 1.64 (p, J = 7.0 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d165.0, 164.8, 158.7, 151.0, 144.7, 139.1, 136.6,126.0, 121.7, 119.5, 113.7, 112.4, 105.6, 103.9, 36.7, 36.6, 29.3; LCMS (ESI)m / z: 355.1 [MH] – .

[0057] Example 19: E )-3-(3,5-dihydroxyphenyl)- N -[3-[[( E )-3-(thiophen-2-yl)acrylamido]propyl]]acrylamide (Compound A 19 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound A is obtained. 19 (93 mg, 25%), yellow solid, melting point 158.9-159.6 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.41 (s, 2H), 8.27 – 7.99 (m, 2H), 7.62 – 7.52 (m, 2H), 7.36 (d, J = 3.1 Hz, 1H), 7.19 (d, J = 15.7 Hz, 1H), 7.10(dd, J = 5.0, 3.6 Hz, 1H), 6.44 (d, J = 15.7 Hz, 1H), 6.41 – 6.32 (m, 3H), 6.23 (s, 1H), 3.27 – 3.11 (m, 4H), 1.63 (p, J = 6.9 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.0, 164.7, 158.7, 139.9, 139.1, 136.6, 131.6, 130.5, 128.3, 127.8,121.7, 121.0, 105.6, 103.9, 36.7, 36.6, 29.3; LCMS (ESI) m / z: 371.1 [MH] – .

[0058] Example 20: E Preparation of 3-(2,4-dihydroxyphenyl)-1-[4-(4-dimethylaminobenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound B1): The preparation method is basically the same as that of Example 1. In this example, compound B1 (67 mg, 17%) is obtained as a white solid with a melting point of 224.0-224.9 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.82 (d, J = 95.1 Hz, 2H), 7.73 (d, J =15.4 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 15.4Hz, 1H), 6.72 (d, J = 8.9 Hz, 2H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3Hz, 1H), 3.64 (d, J = 30.7 Hz, 4H), 3.53 (s, 4H), 2.95 (s, 6H); 13 C NMR (125 MHz, DMSO- d 6 ) d 169.9, 165.6, 160.1, 157.8, 151.3, 137.7, 129.4, 129.2, 121.8,113.5, 112.6, 111.0, 107.4, 102.5, 41.8, 41.8, 41.7, 41.7, 39.8; LCMS (ESI)m / z: 394.2 [MH] – .

[0059] Example 21: E Preparation of 3-(2,4-dihydroxyphenyl)-1-[4-(2-hydroxybenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound B2): The preparation method is basically the same as that of Example 1. In this example, compound B2 (48 mg, 13%) is obtained as a white solid with a melting point of 169.6-170.5°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.98 (s, 3H), 7.73 (d, J = 15.4 Hz,1H), 7.48 (s, 1H), 7.27 – 7.20 (m, 1H), 7.15 (dd, J = 7.5, 1.6 Hz, 1H), 7.00 –6.82 (m, 3H), 6.34 (d, J = 2.2 Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 3.96 – 3.33 (m,8H); 13 C NMR (125 MHz, DMSO- d 6 ) d 167.3, 165.6, 160.2, 157.8, 153.3, 137.7,130.3, 129.4, 128.3, 123.7, 119.1, 115.7, 113.5, 112.6, 107.5, 102.5, 48.6,48.6, 48.7, 48.7; LCMS (ESI) m / z: 367.1 [MH] – .

[0060] Example 22: E Preparation of 3-(2,4-dihydroxyphenyl)-1-[4-(3-hydroxybenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound B3): The preparation method is basically the same as that of Example 1. In this example, compound B3 (52 mg, 14%) is obtained as a white solid with a melting point of 245.4-246.2°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.84 (d, J = 69.1 Hz, 3H), 7.73 (d, J =15.4 Hz, 1H), 7.48 (s, 1H), 7.24 (t, J= 7.8 Hz, 1H), 6.94 (s, 1H), 6.87 – 6.77(m, 3H), 6.34 (d, J = 2.2 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 3.62 (s, 6H), 3.36 (s, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 169.1, 165.6, 160.2, 157.8, 157.3, 137.8,137.0, 129.6, 129.4, 117.4, 116.6, 113.8, 113.5, 112.6, 107.5, 102.5, 48.6,48.6, 44.9, 44.9; LCMS (ESI) m / z: 367.1 [MH] – .

[0061] Example 23: E Preparation of 3-(2,4-dihydroxyphenyl)-1-[4-(4-hydroxybenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound B4): The preparation method is basically the same as that of Example 1. In this example, compound B4 (74 mg, 20%) is obtained as a white solid with a melting point of 252.2-252.9°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.83 (d, J = 89.3 Hz, 3H), 7.73 (d, J =15.4 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 15.4Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.35 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.2Hz, 1H), 3.72 – 3.47 (m, 8H); 13 C NMR (125 MHz, DMSO-d 6 ) d 169.5, 165.6, 160.1,158.9, 157.8, 137.8, 129.5, 129.4, 125.9, 114.9, 113.6, 112.6, 107.5, 102.5,48.6, 48.6, 48.7, 48.7; LCMS (ESI) m / z: 367.1 [MH] – .

[0062] Example 24: E Preparation of )-1-[4-(4-acetylbenzoyl)piperazin-1-yl]-3-(2,4-dihydroxyphenyl)prop-2-en-1-one (Compound B5): The preparation method is basically the same as that of Example 1. In this example, compound B5 (87 mg, 22%) is obtained as a white solid with a melting point of 217.2-218.1°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.92 (s, 2H), 8.14 (s, 1H), 8.03(d, J = 8.2 Hz, 2H), 7.73 (d, J = 15.4 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 6.96 (s,1H), 6.34 (d, J = 1.9 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 3.67 (s, 8H), 2.62 (s, 3H); 13 C NMR (125 MHz, DMSO- d 6 ) d 197.5, 168.3, 165.6, 160.1, 157.8, 140.1,137.8, 137.4, 129.5, 128.4, 127.3, 113.5, 112.5, 107.5, 102.5, 49.4, 49.4,48.9, 48.9, 26.9; LCMS (ESI) m / z: 393.2 [MH] – .

[0063] Example 25: E)-3-(3-chlorophenyl)- N -[2-(( E Preparation of [(2,4-dihydroxyphenyl)acrylamide)ethyl]acrylamide (Compound B6): The preparation method is basically the same as that of Example 1. In this example, compound B6 (96 mg, 25%) is obtained as a yellow solid with a melting point of 123.1-123.8°C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.81 (d, J = 107.2 Hz, 2H), 8.26 –8.18 (m, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.64 (s, 1H), 7.56 – 7.51 (m, 2H), 7.44– 7.39 (m, 3H), 7.22 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 15.8 Hz, 1H), 6.45 (d, J =15.8 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3 Hz, 1H), 3.28 (s,4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.4, 164.8, 159.8, 157.8, 137.2, 137.1,135.0, 133.7, 130.8, 129.6, 129.1, 127.2, 126.0, 123.9, 117.8, 113.3, 107.5,102.6, 38.8, 38.5; LCMS (ESI) m / z: 385.1 [MH] – .

[0064] Example 26: E )-3-(2,4-dihydroxyphenyl)- N -[2-(( E Preparation of 3-[3-(trifluoromethyl)phenyl]acrylamide)ethyl]acrylamide (Compound B7): The preparation method is basically the same as that of Example 1. In this example, compound B7 (67 mg, 16%) is obtained as a yellow solid with a melting point of 175.4-176.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.77 (d, J = 119.8 Hz, 2H), 8.36 –8.19 (m, 1H), 8.02 (s, 1H), 7.97 – 7.80 (m, 2H), 7.68 – 7.48 (m, 4H), 7.22(d, J = 8.5 Hz, 1H), 6.82 – 6.70 (m, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.34 (d, J =2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.2 Hz, 1H), 3.28 (s, 4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.4, 164.8, 159.8, 157.8, 147.2, 137.3, 137.0, 136.1, 135.1,135.0, 130.1, 129.6, 129.3, 124.4, 123.9, 117.8, 113.3, 107.5, 102.6, 38.8,38.5; LCMS (ESI) m / z: 419.1 [MH] – .

[0065] Example 27: E )- N -Hydroxy-3-(3-((5-(2-(naphthalen-1-yl)ethyl)octahydropyrrolyl[3,4-c]pyrrole-2(1 H Preparation of (4-(4-(4-yl)methyl)phenyl)acrylate (Compound B8): The preparation method is basically the same as that of Example 1. In this example, compound B8 (48 mg, 13%) is obtained as a white solid with a melting point of 279.7-280.4°C. 1 H NMR (500 MHz, DMSO- d 6 ) d9.42 (s, 2H), 8.24 (s, 2H), 7.63(dd, J = 8.7, 5.6 Hz, 2H), 7.43 (d, J = 15.8 Hz, 1H), 7.29 – 7.15 (m, 3H), 6.56(d, J = 15.8 Hz, 1H), 6.48 – 6.36 (m, 3H), 6.23 (d, J = 1.9 Hz, 1H), 3.28 (s,4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 165.3 (d, 2 J = 25.0 Hz), 163.7, 161.7, 158.7,139.2 (d, 1 J = 212.5 Hz), 136.5, 131.5, 129.7 (d, 3 J = 12.5 Hz), 122.1, 121.7,121.6, 116.0 (d, 2 J = 25.0 Hz),, 105.6, 103.9, 38.6, 38.6; LCMS (ESI) m / z:369.1 [MH] – .

[0066] Example 28: E )-3-(2,4-dihydroxyphenyl)- N -[2-[( E Preparation of 3-(pyridin-2-yl)acrylamido]ethyl]acrylamide (Compound B9): The preparation method is basically the same as that of Example 1. In this example, compound B9 (81 mg, 23%) is obtained as a light green solid with a melting point of 190.5-191.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.80 (d, J = 113.1 Hz, 2H), 8.60(d, J = 3.9 Hz, 1H), 8.39 (d, J= 5.2 Hz, 1H), 8.02 (t, J = 5.1 Hz, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.60 – 7.51 (m, 2H), 7.45 (d, J = 15.4 Hz, 1H), 7.35 (ddd, J = 7.6, 4.8, 0.9 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 15.4 Hz, 1H),6.44 (d, J = 15.8 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3 Hz,1H), 3.28 (s, 4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.4, 164.9, 159.8, 157.8,153.1, 149.8, 138.0, 137.2, 135.0, 129.5, 125.8, 124.2, 124.0, 117.8, 113.3,107.4, 102.6, 38.8, 38.5; LCMS (ESI) m / z: 352.1 [MH] – .

[0067] Example 29: E )-3-(2,4-dihydroxyphenyl)- N -[2-[( E )-3-(furan-2-yl)acrylamido]ethyl]acrylamide (Compound B 10 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound B is obtained. 10 (68 mg, 20%), light green solid, melting point 167.4-167.9 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) d9.90 (s, 1H), 9.66 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.55 (s, 1H), 7.28 – 7.18 (m,2H), 6.76 (d, J = 3.3 Hz, 1H), 6.58 (dd, J = 3.3, 1.8 Hz, 1H), 6.42 (dd, J = 20.2,15.7 Hz, 2H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3 Hz, 1H), 3.25 (s,4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.4, 165.0, 159.8, 157.8, 151.0, 144.7,135.0, 129.6, 126.1, 119.5, 117.8, 113.7, 113.3, 112.4, 107.5, 102.6, 38.8,38.6; LCMS (ESI) m / z: 341.1 [MH] – .

[0068] Example 30: E )-3-(2,4-dihydroxyphenyl)- N -[2-[( E )-3-(thiophen-2-yl)acrylamide]ethyl]acrylamide (Compound B 11 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound B is obtained. 11 (107 mg, 30%), light yellow solid, melting point 158.0-159.0 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.92 (s, 2H), 8.21 (d, J = 3.3 Hz,1H), 8.01 (s, 1H), 7.61 – 7.52 (m, 3H), 7.36 (d, J= 3.3 Hz, 1H), 7.23 (d, J =8.5 Hz, 1H), 7.09 (dd, J = 5.0, 3.6 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.40 –6.34 (m, 2H), 6.26 (dd, J = 8.5, 2.3 Hz, 1H), 3.26 (s, 4H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.4, 164.9, 159.8, 157.8, 139.9, 135.0, 131.7, 130.6, 129.6,128.4, 127.9, 120.9, 117.9, 113.4, 107.5, 102.6, 38.8, 38.6; LCMS (ESI) m / z:357.1 [MH] – .

[0069] Example 31: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-[3-(trifluoromethyl)phenyl]acrylamide]propyl]acrylamide (Compound B 12 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound B is obtained. 12 (82 mg, 19%), yellow solid, melting point 185.6-186.4 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.88 (s, 1H), 9.64 (s, 1H), 8.15(t, J = 5.6 Hz, 1H), 7.93 (d, J = 6.1 Hz, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.72 (d, J =7.7 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.52 (dd, J = 15.8, 7.2 Hz, 2H), 7.22 (d,J = 8.5 Hz, 1H), 6.77 (d, J = 15.8 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.34 (d, J =2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3 Hz, 1H), 3.21 (dq, J = 12.6, 6.7 Hz, 4H),1.64 (p, J = 7.0 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.2, 164.5, 159.7, 157.8,136.8, 136.2, 134.8, 131.3, 130.1, 129.6, 129.5, 124.5, 117.9, 113.4, 107.5,102.6, 36.7, 36.5, 29.4; LCMS (ESI) m / z: 433.1 [MH] – .

[0070] Example 32: E )-3-(3-chlorophenyl)- N -[3-[( E )-3-(2,4-dihydroxyphenyl)acrylamide]propyl]acrylamide (Compound B 13 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound B is obtained. 13 (44 mg, 11%), white solid, melting point 134.1-135.1 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.89 (s, 1H), 9.65 (s, 1H), 8.13(t, J = 5.6 Hz, 1H), 7.92 (t, J = 5.6 Hz, 1H), 7.64 (s, 1H), 7.57 – 7.49 (m, 2H), 7.47 – 7.37 (m, 3H), 7.22 (d, J = 8.5 Hz, 1H), 6.69 (d,J = 15.8 Hz, 1H), 6.44(d, J = 15.8 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3 Hz, 1H), 3.25 – 3.15 (m, 4H), 1.63 (p, J = 6.9 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.2,164.6, 159.7, 157.8, 137.3, 137.0, 134.8, 133.7, 130.8, 129.5, 129.0, 127.2,126.0, 124.0, 117.9, 113.4, 107.5, 102.6, 36.7, 36.5, 29.4; LCMS (ESI) m / z:399.1 [MH] – .

[0071] Example 33: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-(4-fluorophenyl)acrylamide]propyl]acrylamide (Compound B 14 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound B is obtained. 14 (54 mg, 14%), white solid, melting point 193.4-194.1 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.90 (s, 1H), 8.12 (t, J = 5.6 Hz,1H), 7.97 – 7.90 (m, 2H), 7.65 – 7.59 (m, 2H), 7.53 (d, J = 15.8 Hz, 1H), 7.42(d, J = 15.8 Hz, 1H), 7.23 (t, J = 8.9 Hz, 3H), 6.57 (d, J = 15.8 Hz, 1H), 6.45 (d,J = 15.8 Hz, 1H), 6.35 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3 Hz, 1H), 2.88(s, 2H), 2.73 (s, 2H), 1.64 (p, J = 6.9 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.2(d, 1 J = 162.5 Hz), 159.7, 157.8, 137.4, 134.8, 131.6 (d, 3 J = 12.5 Hz), 129.7 (d, 3 J = 12.5 Hz), 129.6, 122.2, 117.9, 116.0 (d, 2 J = 25.0 Hz), 113.4, 107.5,102.6, 36.7, 36.6, 29.5; LCMS (ESI) m / z: 383.1 [MH] – .

[0072] Example 34: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-(pyridin-2-yl)acrylamido]propyl]acrylamide (Compound B 15 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound B is obtained. 15 (103 mg, 28%), light yellow solid, melting point 167.2-167.8 °C. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.88 (s, 1H), 9.64 (s, 1H), 8.60(d, J = 3.9 Hz, 1H), 8.30 (t, J = 5.6 Hz, 1H), 7.93 (t, J = 5.6 Hz, 1H), 7.82 (td,J = 7.7, 1.8 Hz, 1H), 7.59 – 7.50 (m, 2H), 7.43 (d, J = 15.4 Hz, 1H), 7.37 – 7.32(m, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 15.4 Hz, 1H), 6.45 (d, J = 15.8 Hz,1H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.3 Hz, 1H), 3.20 (dq, J = 12.5,6.7 Hz, 4H), 1.64 (p, J = 7.0 Hz, 2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.2, 164.7,159.7, 157.7, 153.1, 149.8, 137.9, 137.2, 134.8, 129.5, 125.9, 124.1, 124.0,117.9, 113.4, 107.4, 102.6, 36.7, 36.5, 29.4; LCMS (ESI) m / z: 366.2 [MH] – .

[0073] Example 35: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-(thiophen-2-yl)acrylamido]propyl]acrylamide (Compound B 16 ) Preparation: The preparation method is basically the same as that in Example 1. In this example, compound B is obtained. 16 (63 mg, 17%), light yellow solid, melting point 139.9-140.6 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) d 9.88 (s, 1H), 9.65 (s, 1H), 8.17– 8.07 (m, 1H), 7.91 (t, J= 5.6 Hz, 1H), 7.61 – 7.57 (m, 1H), 7.54 (d, J = 7.9Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 3.4 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.10(dd, J = 5.0, 3.6 Hz, 1H), 6.41 (dd, J = 32.2, 15.6 Hz, 2H), 6.34 (d, J = 2.3 Hz,1H), 6.25 (dd, J = 8.5, 2.3 Hz, 1H), 3.21 – 3.15 (m, 4H), 1.62 (p, J = 7.0 Hz,2H); 13 C NMR (125 MHz, DMSO- d 6 ) d 166.2, 164.7, 159.7, 157.8, 139.9, 134.8,131.6, 130.6, 129.6, 128.3, 127.8, 121.0, 117.9, 113.4, 107.5, 102.6, 36.7,36.5, 29.4; LCMS (ESI) m / z: 371.1 [MH] – .

[0074] Example 36: E )-1-(4-(3-methylbenzoyl)piperazin-1-yl)-3-(2,4-dihydroxyphenyl)prop-2-en-1-one (Compound B 17 ) Preparation: According to the synthesis method in (V) to (VII) above, compound B is obtained. 17 (58 mg, 16%), white solid, melting point 216.1-216.8 ℃. 1 H NMR (500 MHz, DMSO- d 6) δ 9.81 (d, J = 96.6 Hz, 2H),7.74 (d, J = 15.3 Hz, 1H), 7.48 (s, 1H), 7.33 (t, J= 7.6 Hz, 1H), 7.27 (d, J = 7.9Hz, 1H), 7.25 – 7.19 (m, 2H), 6.96 (s, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 10.8 Hz, 1H), 3.64 (s, 8H), 2.34 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6) δ 169.3,165.6, 160.2, 157.8, 137.9, 137.8, 135.7, 130.2, 129.5, 128.3, 127.5, 124.0,113.6, 112.6, 107.5, 102.5, 48.6, 47.0, 44.9, 41.6, 20.9. LCMS (ESI) m / z:367.1649 [M+H] + .

[0075] Example 37: E )-3-(2,4-dihydroxyphenyl)-1-[4-(4-methylbenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound B 18 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 18 (70 mg, 38%), yellow solid, melting point 221.2-221.4 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.91 (s, 1H), 9.71 (s, 1H), 7.73(d, J = 15.4 Hz, 1H), 7.48 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.9 Hz,2H), 6.96 (s, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 8.5 Hz, 1H), 3.63 (s, 8H), 2.35 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6) d 169.3, 165.6, 160.1, 157.8,139.4, 137.8, 132.8, 129.4, 128.9, 127.2, 113.5, 112.6, 107.5, 102.5, 48.6,47.3, 44.9, 41.5, 20.9. LCMS (ESI) m / z : 389.1 [M+Na] + .

[0076] Example 38: E )-3-(2,4-dihydroxyphenyl)-1-[4-(4-trifluoromethylbenzoyl)piperazin-1-yl]prop-2-en-1-one (Compound B 19 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 19 (84 mg, 40%), white solid, melting point 218.4-218.9 ℃. 1 H NMR (500 MHz, DMSO- d 6) δ 9.92 (s, 1H), 9.72 (s, 1H), 7.84(d, J = 8.0 Hz, 2H), 7.72 (d, J = 15.3 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.47 (s,1H), 6.95 (s, 1H), 6.34 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 8.5 Hz, 1H), 3.67 (s,8H). 13 C NMR (125 MHz, DMSO- d 6) δ 167.9, 165.7, 160.2, 157.9, 139.9, 137.9,129.9, 129.7, 129.5, 127.9, 125.6, 125.5, 125.5, 125.8, 125.0, 122.9, 113.5,112.6, 107.5, 102.5, 54.9, 46.9, 44.7, 41.8. LCMS (ESI) m / z: 421.1 [M+H] + .

[0077] Example 39: E)-3-(2,4-dihydroxyphenyl)-1-[4-(( E )-3-(o-tolyl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 20 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 20 (50 mg, 25%), yellow solid, melting point 239.7-240.2 ℃. 1 H NMR (500 MHz, DMSO- d 6) d 9.91 (s, 1H), 9.70 (s, 1H), 7.91 –7.69 (m, 3H), 7.50 (d, J = 8.4 Hz, 1H), 7.25 (s, 3H), 7.16 (d, J = 15.2 Hz, 1H),6.98 (d, J = 15.4 Hz, 1H), 6.38 – 6.33 (m, 1H), 6.29 – 6.24 (m, 1H), 3.68 (d, J =60.7 Hz, 8H), 2.38 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6) d 165.6, 164.6, 160.1,157.8, 139.0, 137.8, 136.8, 133.8, 130.6, 129.4, 126.5, 126.2, 119.5, 113.6,112.6, 109.9, 107.5, 102.5, 52.6, 45.7, 19.3. LCMS (ESI) m / z: 393.2 [M+H] + .

[0078] Example 40: E )-3-(2,4-dihydroxyphenyl)-1-[4-(( E )-3-(2-methoxyphenyl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 21 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 21 (43 mg, 21%), light yellow solid, melting point 216.8-217.7 °C. 1H NMR (500 MHz, DMSO- d 6) d 9.92 (s, 1H), 9.70 (s, 1H), 7.85– 7.77 (m, 2H), 7.74 (d, J = 15.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.40 – 7.35(m, 1H), 7.22 (d, J = 15.4 Hz, 1H), 7.07 (d, J = 9.5 Hz, 1H), 7.01 – 6.95 (m,2H), 6.35 (d, J = 2.3 Hz, 1H), 6.27 (dd, J = 8.5, 2.3 Hz, 1H), 3.86 (s, 3H), 3.66(d, J = 55.2 Hz, 8H). 13 C NMR (125 MHz, DMSO- d 6) d 165.6, 164.9, 160.1, 157.8,157.5, 137.8, 136.4, 131.1, 129.6, 127.9, 123.4, 120.6, 117.9, 113.6, 112.7,111.6, 107.5, 102.5, 55.6, 48.6, 44.8. LCMS (ESI) m / z: 409.2 [M+H] + .

[0079] Example 41: E )-3-(2,4-dihydroxyphenyl)-1-[4-((E)-3-(m-tolyl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 22 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 22 (36 mg, 18%), light yellow solid, melting point 262.4-263.0 ℃. 1 H NMR (500 MHz, DMSO- d 6) d 9.92 (s, 1H), 9.70 (s, 1H), 7.74(d, J= 15.4 Hz, 1H), 7.57 (s, 1H), 7.52 – 7.46 (m, 3H), 7.32 – 7.24 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 15.4 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.27(dd, J = 8.5, 2.3 Hz, 1H), 3.68 (d, J = 64.9 Hz, 8H), 2.34 (s, 3H). 13 C NMR (125MHz, DMSO- d 6) d 165.6, 164.7, 160.1, 157.8, 141.9, 138.0, 137.8, 135.0, 130.3,129.6, 128.7, 128.4, 125.5, 117.9, 113.6, 112.7, 107.5, 102.5, 45.2, 41.9,20.9. LCMS (ESI) m / z: 393.2 [M+H] + .

[0080] Example 42: E )-3-(2,4-dihydroxyphenyl)-1-[4-(( E )-3-(3-methoxyphenyl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 23 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 23 (50 mg, 25%), yellow solid, melting point 212.4-213.0 ℃. 1 H NMR (500 MHz, DMSO- d 6) d 9.91 (s, 1H), 9.70 (s, 1H), 7.73(d, J = 15.4 Hz, 1H), 7.52 – 7.47 (m, 2H), 7.31 (dq, J = 9.5, 8.0 Hz, 4H), 7.01 –6.93 (m, 2H), 6.35 (d, J = 2.4 Hz, 1H), 6.26 (dd,J = 8.5, 2.3 Hz, 1H), 3.80 (s,3H), 3.78 – 3.57 (m, 8H). 13 C NMR (125 MHz, DMSO- d 6) d 165.6, 164.9, 160.1,157.8, 157.5, 137.8, 136.4, 131.1, 129.6, 127.9, 123.4, 120.6, 117.9, 113.6,112.7, 111.6, 107.5, 102.5, 55.6, 48.6, 44.8. LCMS (ESI) m / z: 409.2 [M+H] + .

[0081] Example 43: E )-3-(2,4-dihydroxyphenyl)-1-[4-(( E )-3-(3-fluorophenyl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 24 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 24 (48 mg, 12%), yellow solid, melting point 240.1-240.6 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.89 (d, J = 20.0 Hz, 1H), 9.68 (d, J =21.4 Hz, 1H), 7.77 – 7.66 (m, 2H), 7.57 – 7.48 (m, 3H), 7.48 – 7.42 (m, 1H),7.37 (d, J = 15.4 Hz, 1H), 7.21 (td, J = 8.5, 2.6 Hz, 1H), 6.95 (dd, J = 37.8, 15.4Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.26 (dd, J = 8.5, 2.4 Hz, 1H), 3.68 (d, J =71.6 Hz, 8H). 13 C NMR (125 MHz, DMSO-d 6) d 165.6, 164.4, 163.5, 161.5, 160.1,157.8, 140.4 (d, 4 J =2.5 Hz), 137.8 (d, 3 J = 7.5 Hz), 130.7 (d, 3 J = 8.75 Hz),129.6, 124.8 (d, 4 J =2.5 Hz), 119.8, 116.4 (d, 2 J = 21.25 Hz) 114.1 (d, 2 J = 22.5Hz), 113.6, 112.6, 107.5, 102.5, 45.1, 42.0. LCMS (ESI) m / z: 397.2 [M+H] + .

[0082] Example 44: E )-3-(2,4-dihydroxyphenyl)-1-[4-(( E )-3-(3-trifluoromethylphenyl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 25 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 25 (66 mg, 15%), yellow solid, melting point 214.1-214.6 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.95 (s, 1H), 9.73 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.76 – 7.71 (m, 2H), 7.66 – 7.61 (m, 1H), 7.59 (s, 1H), 7.52 – 7.45 (m, 2H), 6.99 (d, J = 15.4 Hz, 1H), 6.37 (d, J = 2.3Hz, 1H), 6.27 (dd, J= 8.5, 2.4 Hz, 1H), 3.78 (s, 4H), 3.62 (s, 4H). 13 C NMR (125MHz, DMSO- d 6) d 165.7, 164.3, 160.1, 157.8, 140.1, 137.8, 136.3, 132.2, 129.8,129.6, 125.8, 125.2, 124.3, 123.1, 120.4, 113.6, 112.7, 107.5, 102.5, 45.1,42.0. LCMS (ESI) m / z: 447.1 [M+H] + .

[0083] Example 45: E )-3-(2,4-dihydroxyphenyl)-1-[4-(( E )-3-(pyridin-2-yl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 26 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 26 (36 mg, 19%), yellow solid, melting point 251.0-251.3 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.91 (s, 1H), 9.70 (s, 1H), 8.63(d, J = 4.3 Hz, 1H), 7.85 (td, J = 7.7, 1.8 Hz, 1H), 7.77 – 7.71 (m, 2H), 7.59 –7.53 (m, 2H), 7.50 (d, J = 11.1 Hz, 1H), 7.37 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H),6.97 (d, J = 15.4 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.26 (dd, J = 8.5, 2.3 Hz,1H), 3.77 – 3.58 (m, 8H). 13 C NMR (125 MHz, DMSO- d 6) d165.6, 164.3, 160.1,157.8, 153.2, 149.8, 141.1, 137.8, 137.1, 129.5, 124.1, 124.0, 121.5, 113.5,112.6, 107.5, 102.5, 45.2, 41.5. LCMS (ESI) m / z: 380.2 [M+H] + .

[0084] Example 46: E )-3-(2,4-dihydroxyphenyl)-1-[4-(( E )-3-(thiophen-2-yl)acryloyl)piperazin-1-yl]prop-2-en-1-one (Compound B 27 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 27 (31 mg, 8%), light yellow solid, melting point 223.5-223.8 ℃. 1 H NMR (500 MHz, DMSO- d 6) d 9.91 (s, 1H), 9.70 (s, 1H), 7.78– 7.63 (m, 3H), 7.53 – 7.47 (m, 2H), 7.12 (dd, J = 5.0, 3.6 Hz, 1H), 6.96 (dd, J = 15.3, 13.5 Hz, 2H), 6.35 (d, J = 2.3 Hz, 1H), 6.26 (dd, J = 8.5, 2.4 Hz, 1H),3.64 (d, J = 38.3 Hz, 8H). 13 C NMR (125 MHz, DMSO- d 6) d 165.6, 164.3, 160.1, 157.8,139.9, 137.8, 136.7, 134.7, 131.8, 129.6, 127.7, 117.6, 116., 112.6, 107.5,102.5, 54.0, 45.0. LCMS (ESI) m / z : 385.1 [M+H] + .

[0085] Example 47: E )-N -[3-(3-(2,4-dihydroxyphenyl)acrylamide)propyl]benzamide (Compound B 28 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 28 (155 mg, 46%), yellow solid, melting point 143.4-143.6 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.89 (s, 1H), 9.65 (s, 1H), 8.48(t, J = 5.7 Hz, 1H), 7.95 (t, J = 5.8 Hz, 1H), 7.87 – 7.82 (m, 2H), 7.54 (d, J =6.7 Hz, 1H), 7.51 (dd, J = 5.6, 1.7 Hz, 1H), 7.48 – 7.47 (m, 1H), 7.47 – 7.44(m, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.34 (d, J = 2.3 Hz,1H), 6.25 (dd, J = 8.5, 2.4 Hz, 1H), 3.29 (q, J = 6.6 Hz, 2H), 3.24 – 3.15 (m,2H), 1.73 – 1.64 (m, 2H). 13 C NMR (125 MHz, DMSO- d 6) d 166.3, 165.0, 159.8,159.6, 157.8, 138.5, 136.4, 134.9, 130.0, 129.6, 122.6, 119.9, 117.9, 115.3,113.4, 112.6, 107.5, 102.7, 55.1, 36.7, 36.6, 29.5. LCMS (ESI) m / z: 341.1 [M+H] + .

[0086] Example 48: E )- N-[3-(3-(2,4-dihydroxyphenyl)acrylamide)propyl]-2-methoxybenzamide (Compound B 29 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 29 (62 mg, 17%), yellow solid, melting point 257.5-258.1 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.89 (s, 1H), 9.65 (s, 1H), 8.33(t, J = 5.9 Hz, 1H), 7.96 (t, J = 5.9 Hz, 1H), 7.74 (dd, J = 7.6, 1.9 Hz, 1H), 7.54(d, J = 15.8 Hz, 1H), 7.45 (ddd, J = 8.3, 7.3, 1.9 Hz, 1H), 7.23 (d, J = 8.5 Hz,1H), 7.12 (dd, J = 8.4, 1.0 Hz, 1H), 7.02 (td, J = 7.5, 1.0 Hz, 1H), 6.46 (d, J =15.8 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.26 (dd, J = 8.5, 2.4 Hz, 1H), 3.91 (s,3H), 3.29 (q, J = 6.5 Hz, 2H), 3.23 (q, J = 6.5 Hz, 2H), 1.65 (p, J = 6.7 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6) d166.4, 164.9, 159.7, 157.8, 157.0, 134.9, 132.1,130.4, 129.6, 123.2, 120.4, 117.9, 113.4, 112.0, 107.5, 102.6, 55.8, 36.6,36.2, 29.6. LCMS (ESI) m / z : 371.2 [M+H] + .

[0087] Example 49: E )- N -(3-(3-(2,4-dihydroxyphenyl)acrylamide)propyl)-4-methoxybenzamide (Compound B 30 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 30 (60 mg, 32%), light yellow solid, melting point 109.7-110.3 ℃. 1 H NMR (500 MHz, DMSO- d 6) d 9.70 (s, 2H), 8.33 (t, J = 5.7 Hz,1H), 7.95 (t, J = 5.8 Hz, 1H), 7.86 – 7.78 (m, 2H), 7.53 (d, J = 15.8 Hz, 1H),7.22 (d, J = 8.5 Hz, 1H), 7.02 – 6.95 (m, 2H), 6.45 (d, J = 15.8 Hz, 1H), 6.34(d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.5, 2.4 Hz, 1H), 3.80 (s, 3H), 3.27 (d, J = 6.3Hz, 2H), 3.20 (d, J = 6.3 Hz, 2H), 1.71 – 1.64 (m, 2H). 13 C NMR (125 MHz, DMSO- d 6) d166.3, 165.6, 161.4, 159.7, 157.8, 134.8, 129.5, 128.9, 126.8, 117.9,113.5, 113.4, 107.4, 102.6, 55.3, 36.9, 36.5, 29.5. LCMS (ESI) m / z: 371.2 [M+H] + .

[0088] Example 50: E )-3-chloro- N -[3-[3-(2,4-dihydroxyphenyl)acrylamide]propyl]benzamide (Compound B 31 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 31 (82 mg, 44%), white solid, melting point 142.1-142.9 ℃. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.89 (s, 1H), 9.65 (s, 1H), 8.60(t, J = 5.6 Hz, 1H), 7.95 (t, J = 5.8 Hz, 1H), 7.88 (t, J = 1.9 Hz, 1H), 7.80 (dt, J = 7.8, 1.3 Hz, 1H), 7.59 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 7.55 – 7.48 (m, 2H),7.23 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.26(dd, J = 8.5, 2.4 Hz, 1H), 3.29 (q, J = 6.6 Hz, 2H), 3.21 (q, J = 6.6 Hz, 2H), 1.70(p, J = 7.0 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6) δ 166.3, 164.7, 159.7, 157.8,136.6, 134.9, 133.2, 130.9, 130.3, 129.5, 127.0, 125.9, 117.9, 113.4, 107.5,102.6, 37.2, 36.5, 29.3. LCMS (ESI) m / z: 375.1 [M+H] + .

[0089] Example 51: E )- N -[3-(Cinnamylamido)propyl]-3-(2,4-dihydroxyphenyl)acrylamide (Compound B 32 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 32 (173 mg, 47%), yellow liquid. 1 HNMR (500 MHz, DMSO- d 6) d 9.88 (s, 1H), 9.68 (s, 1H), 8.14 (t, J = 5.7 Hz, 1H),7.94 (t, J = 5.7 Hz, 1H), 7.59 – 7.51 (m, 3H), 7.45 – 7.34 (m, 4H), 7.23 (d, J =8.5 Hz, 1H), 6.63 (d, J = 15.8 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 6.35 (d, J = 2.4Hz, 1H), 6.26 (dd, J = 8.5, 2.4 Hz, 1H), 3.26 – 3.15 (m, 4H), 1.64 (p, J = 7.0Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6) d166.2, 164.9, 159.7, 157.8, 138.5, 135.0,134.8, 129.5, 129.4, 128.9, 127.5, 122.3, 117.9, 113.4, 107.5, 102.6, 36.7,36.5, 29.5. LCMS (ESI) m / z : 367.2 [M+H] + .

[0090] Example 52: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-(3-methoxyphenyl)acrylamide]propyl]acrylamide (Compound B 33 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 33 (196 mg, 49%), white solid, melting point 166.6-167.1 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.91 (s, 1H), 9.67 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.55 (d, J = 15.8 Hz, 1H), 7.40 (d, J = 15.7 Hz, 1H), 7.31(s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 12.9 Hz, 2H), 6.93 (dd, J = 8.1,2.5 Hz, 1H), 6.64 (d, J = 15.8 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 6.36 (d, J = 2.4Hz, 1H), 6.26 (dd, J = 8.4, 2.3 Hz, 1H), 3.77 (s, 3H), 3.42 (s, 2H), 3.19 (d, J =13.7 Hz, 2H), 1.74 – 1.56 (m, 2H). 13 C NMR (125 MHz, DMSO- d 6) d 166.3, 165.0,159.8, 159.6, 157.8, 138.5, 136.4, 134.9, 130.0, 129.6, 122.6, 119.9, 117.9,115.3, 113.4, 112.6, 107.5, 102.7, 55.1, 36.7, 36.6, 29.5. LCMS (ESI) m / z:397.2 [M+H] + .

[0091] Example 53: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-(m-tolyl)acrylamido]propyl]acrylamide (Compound B 34 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 34 (220 mg, 58%), yellow liquid. 1 HNMR (500 MHz, DMSO- d 6) d 9.88 (s, 1H), 9.64 (s, 1H), 8.10 (t, J = 5.5 Hz, 1H),7.93 (d, J = 6.4 Hz, 1H), 7.55 – 7.48 (m, 1H), 7.41 – 7.33 (m, 3H), 7.29 (t, J =7.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6.61 (d, J = 15.8Hz, 1H), 6.48 – 6.42 (m, 1H), 6.35 (d, J = 2.6 Hz, 1H), 6.25 (dt, J = 8.5, 1.7Hz, 1H), 3.19 (dq, J = 11.3, 5.8 Hz, 4H), 2.32 (s, 3H), 1.63 (p, J = 7.1 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6) d 166.2, 165.0, 159.7, 157.7, 138.6, 138.1, 134.9,134.8, 130.1, 129.5, 128.8, 128.0, 124.7, 122.1, 117.9, 113.4, 107.4, 102.6,36.7, 36.5, 29.5, 20.9. LCMS (ESI) m / z: 381.2 [M+H] + .

[0092] Example 54: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-(p-methylphenyl)acrylamide]propyl]acrylamide (Compound B 35 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 35 (120 mg, 32%), yellow solid, melting point 195.0-195.3 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.88 (s, 1H), 9.64 (s, 1H), 8.08(dt, J = 6.5, 3.1 Hz, 1H), 7.93 (t, J = 3.9 Hz, 1H), 7.53 (dd, J = 15.7, 2.9 Hz,1H), 7.48 – 7.43 (m, 2H), 7.38 (d, J = 15.7 Hz, 1H), 7.24 – 7.19 (m, 3H), 6.56(dd, J = 15.7, 1.3 Hz, 1H), 6.49 – 6.42 (m, 1H), 6.34 (t, J = 2.4 Hz, 1H), 6.25(dt, J = 8.5, 1.9 Hz, 1H), 3.24 – 3.15 (m, 4H), 2.31 (s, 3H), 1.63 (tt, J = 7.0,4.3 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6) d166.2, 165.1, 159.7, 157.7, 139.1,138.5, 134.8, 132.2, 129.5, 127.5, 121.2, 117.9, 113.4, 107.4, 102.6, 36.6,36.5, 29.5, 20.9. LCMS (ESI) m / z: 381.2 [M+H] + .

[0093] Example 55: E )-3-(2,4-dihydroxyphenyl)- N -[3-[( E )-3-(2-(trifluoromethyl)phenyl)acrylamide]propyl]acrylamide (Compound B 36 ) Preparation: The preparation method is basically the same as that of Example 36. In this example, compound B is obtained. 36 (72 mg, 33%), yellow solid, melting point 196.3-197.2 °C. 1 H NMR (500 MHz, DMSO- d 6) d 9.88 (s, 1H), 9.64 (s, 1H), 8.27(t, J = 5.7 Hz, 1H), 7.93 (t, J = 5.7 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.81 –7.77 (m, 1H), 7.76 – 7.67 (m, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 15.8Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 15.5 Hz, 1H), 6.45 (d, J = 15.8 Hz,1H), 6.34 (d, J = 2.3 Hz, 1H), 6.25 (dd, J = 8.4, 2.4 Hz, 1H), 3.21 (dq, J = 13.0,6.6 Hz, 4H), 1.65 (t, J = 7.0 Hz, 2H). 13C NMR (125 MHz, DMSO- d 6) d 166.2, 164.1,159.7, 157.7, 134.8, 133.5, 133.4, 133.1, 129.5, 129., 127.8, 126.9, 126.8,126.1, 126.1, 117.9, 113.4, 107.4, 102.6, 36.8, 36.5, 29.4. LCMS (ESI) m / z:435.2 [M+H] + .

[0094] Pharmacodynamics experiments: 1. Determination of the inhibitory activity of compounds on TYR.

[0095] 1.1 Experimental methods

[0096] Dissolve the test compound in an appropriate amount of dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, and then dilute it to the desired concentration (8-10 concentrations for each compound) with a pH 6.8 phosphate buffer (PBS). L -Tyrosine and L -DOPA) were dissolved in PBS to obtain 300 U / mL (substrate is L -DOPA), 600 U / mL (substrate is L -tyrosine) mTYR solution, 1 mM L -Tyrosine solution and 0.85 mM L -DOPA solution. Add 160 μL of PBS solution of the test compound to a 96-well plate, then add 20 μL of enzyme solution, and perform the first pre-incubation at 25 °C (10 min). Finally, add 20 μL of substrate solution, followed by a second pre-incubation at 25 °C (20 min). The total reaction volume is 200 μL. After the incubation is completed, the absorbance of the reaction system at 475 nm is immediately measured using an enzyme reader. The PBS solvent is used as a blank control and the measurement is repeated three times. By measuring the numerical changes in the absorbance of the experimental group along the concentration gradient, the corresponding IC is calculated using GraphPad Prism software. 50 value.

[0097] .

[0098] 1.2 Experimental results

[0099] Table 1 shows Example A 1-19 and B1-16 Results of the inhibitory activity of compounds against TYR.

[0100] Table 1

[0101] From the experimental results (Table 1), most of the compounds in the 35 examples showed significant inhibitory activity against TYR. 10-17 , B2, B3, B 6-16 A total of 24 examples showed significantly better inhibitory activity against TYR than the positive control drugs kojic acid, α-arbutin and β-arbutin, among which the compound with the best activity was B 15 , its IC 50 reached 1.49 nM (substrate is L -tyrosine) and 2.55 nM (substrate is L -Dopa).

[0102] 2. Determination of the TYR inhibitory activity of the preferred compounds.

[0103] After obtaining the optimal compound B 15 Afterwards, a series of compounds were designed based on its structure. Finally, 20 preferred compounds (B 17-36 ). Their inhibitory activities against TYR are summarized in Table 2. In the second round of inhibitory activity testing, a total of 19 compounds (B 17-24 and B 26-36 ) showed high inhibitory activity against TYR, and the IC 50 The value reached the nanomolar level. In general, the compounds with propylene diamine as the linker group (B 28-36 ) compared to the compound with piperazine as the linker (B 17-22 ) showed better results. Among them, two compounds (B 28 and B 31 ) is more active than B 15 , and another 5 compounds (B 29-30 , B 35 and B 36 ) and B 15 resemblance.

[0104] Table 2

[0105] Note: Since tyrosinase is purchased from different batches, its activity may have slight differences. Therefore, there are slight differences in the inhibitory activities of kojic acid and designed compounds in Table 1 and Table 2, but it does not affect the comparison of the activity strength between the compounds; Table 1 is tested from the same batch; Table 2 is tested from the same batch.

[0106] In general, most of the compounds designed in the present invention showed excellent inhibitory activity against TYR. Among them, a total of 43 compounds showed strong TYR inhibitory activity, which was better than the positive control drug kojic acid. Among them, compound B 15 , B 16 , B 28 and B 31 The inhibitory activity against TYR even reached more than 10,000 times that of the positive control drug kojic acid. The novel small molecule compounds designed and synthesized by the present invention showed excellent inhibitory activity in the TYR inhibitory activity test. These compounds are expected to provide highly potential lead compounds or candidate drugs for the treatment of hyperpigmentation, skin whitening, and melanoma.

[0107] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A polyphenol tyrosinase inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, characterized in that: The general structural formula of the polyphenol tyrosinase inhibitor is shown as (I): （I）； in: R 1 There are two or more hydroxyl substituents; R 2 It is a straight-chain or cyclic diamine structure containing nitrogen atoms; R 3 is a substituted or unsubstituted aromatic group or aromatic allyl group.

2. The polyphenol tyrosinase inhibitor according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, characterized in that: In formula (I): R 1 is a dihydroxy substituent; R 2 C 2-3 A nitrogen-containing linear diamine structure of C6 or a nitrogen-containing cyclic diamine structure of C6; R 3 It is a substituted or unsubstituted aromatic ring, or an allyl group substituted with an aromatic ring or an aromatic heterocyclic ring.

3. The polyphenol tyrosinase inhibitor according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, characterized in that: In formula (I): R 1 2,4-dihydroxy or 3,5-dihydroxy; R 2 Select from the following structures: , or ; R 3 Select from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , or .

4. The polyphenol tyrosinase inhibitor according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, characterized in that: The polyphenol tyrosinase inhibitor is selected from the following compounds A1-A 19 and B1-B 36 : ； 。 5. The method for preparing a polyphenol tyrosinase inhibitor according to any one of claims 1 to 4, characterized in that: The synthetic routes include: ； The preparation method comprises the steps of: Substituted or unsubstituted cinnamic acid 1 undergoes condensation reaction with Boc-protected diamine 2 to obtain intermediate 3; Boc-protected diamine 2 undergoes condensation reaction with aromatic or aromatic allyl carboxylic acid 5 to give intermediate 7; The intermediate 3 or 7 is deprotected by removing the Boc protecting group to obtain the intermediate 4 or 8; Intermediate 4 undergoes condensation reaction with aromatic or aromatic allyl carboxylic acid 5 to obtain intermediate 6; Intermediate 6 is subjected to a demethylation reaction to obtain a polyphenol tyrosinase inhibitor A as shown in formula (I). 1-19 , B 1-16 ; Intermediate 8 is subjected to condensation reaction with 3,5-dihydroxy substituted cinnamic acid 9 to obtain polyphenol tyrosinase inhibitor B as shown in formula (I) 17-36 .

6. Use of the polyphenol tyrosinase inhibitor according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, in the preparation of an anti-pigmentation or anti-melanoma drug or cosmetic.

7. The use according to claim 6, characterized in that: The target of the anti-pigmentation and anti-melanoma drug is TYR.

8. An anti-pigmentation and anti-melanoma drug, characterized in that: A composition comprising a safe and effective amount of the polyphenol tyrosinase inhibitor according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof.

9. The anti-pigmentation and anti-melanoma drug according to claim 8, characterized in that: The anti-pigmentation and anti-melanoma drugs also include at least one of pharmacologically acceptable salts, excipients, and carriers.

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