Tyrosinase inhibitor as well as preparation method and application thereof

Abstract

The invention discloses a tyrosinase inhibitor, a preparation method thereof and application of the tyrosinase inhibitor in preparation of a product for inhibiting tyrosinase activity. Based on the protein structure of the TYR, the TYR inhibitor which is novel in structure and higher in curative effect and selectivity is found by adopting reasonable drug design and structural modification strategies.

Description

Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and new drug research and development, and in particular to a novel small molecule tyrosinase inhibitor and a preparation method and application thereof. Background Art

[0002] Melanin is a naturally occurring pigment in the human body that plays a vital role in maintaining the color of the skin, hair, and eyes, and protecting against damage from ultraviolet rays and oxidative stress. However, excessive melanin can cause pigmentation diseases such as freckles, chloasma, age spots, sun spots, pigmented dermatitis, and even malignant melanoma. These diseases not only affect appearance, but also increase the risk of skin damage, accelerate skin aging, cause negative emotions, psychological distress, and even induce other diseases. As people's living standards improve, the attention paid to skin pigmentation diseases is increasing day by day, and inhibiting melanin production and reducing pigmentation have become key treatments for these diseases.

[0003] Studies on the mechanism of melanin production have found that tyrosinase (TYR, EC 1.14.18.1) is the key rate-limiting enzyme that catalyzes melanin production, and its abnormal expression is closely related to excessive melanin deposition. TYR is a copper-containing oxidoreductase that is widely present in animals, plants and microorganisms. It has dual catalytic activity for phenolic compounds, namely monophenolase activity (oxidizing monophenols to catechol) and diphenolase activity (oxidizing catechols to o-quinone), which is further converted into melanin in the body. In addition, studies have shown that overexpression of TYR is also closely related to increased neuromelanin content and enzymatic browning of fruits and vegetables. Therefore, TYR inhibitors can not only be used to treat pigmentation diseases and neurodegenerative diseases, but also can be used as skin whitening agents in cosmetics and fruit and vegetable preservatives in food, etc., and have attracted widespread attention and research in many fields such as biology, medicine, agronomy, and chemistry.

[0004] At present, the commonly used natural or synthetic TYR inhibitors on the market mainly include hydroquinone, kojic acid, α-arbutin, β-arbutin, L -ascorbic acid, resveratrol and some plant polyphenols, etc. In addition, some prior arts have reported some tyrosinase inhibitors formed based on the changes of the above components, such as the patent specification with publication number CN116478146A discloses a kojic acid-coumarin tyrosinase inhibitor and its preparation method and application, and the patent specification with publication number CN116023260A discloses a preparation method of a resorcinol ester derivative with tyrosinase inhibitory activity, etc.

[0005] Existing TYR inhibitors generally have poor inhibitory activity and strong hydrophilicity. Some TYR inhibitors even have high cytotoxicity and certain carcinogenic tendencies, such as hydroquinone and kojic acid. Therefore, it is of great research significance to develop new TYR inhibitors with higher efficiency, stronger inhibitory activity and excellent physical and chemical properties. Summary of the invention

[0006] Based on the protein structure of TYR, the present invention adopts a reasonable drug design and structural modification strategy to discover a TYR inhibitor with novel structure, higher efficacy and selectivity. The present invention also studies its preparation method and pharmacological activity.

[0007] [1] A tyrosinase inhibitor, which is a compound having the following general formula (I) or (II) and / or a pharmaceutically acceptable salt thereof: ; ; In formula (I) and (II): R 1 , R 2 , R 3 are independently substituted or unsubstituted aromatic groups; R 4 It is a nitrogen-containing heterocycle or aliphatic amine; R 5 is hydrogen or one or more hydroxyl groups; L1 is empty, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH=CHCH2- and the double bond end is connected to R 3 ; L2 is -CH2CH2-, -CH2CH2CH2- or -CH=CH-; X is -CH2-, -NH- or -O-; n and m are independently 0, 1, 2 or 3.

[0008] Furthermore, in formula (I) and (II): R 1 , R 2 , R 3 are independently substituted or unsubstituted benzene ring or aromatic heterocycle; R 4 is a five-, six- or seven-membered nitrogen-containing heterocyclic ring or an aliphatic amine; R 5 is hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2,3-dihydroxy, 2,4-dihydroxy, 2,5-dihydroxy, 2,6-dihydroxy, 3,4-dihydroxy or 3,5-dihydroxy; L1 is empty, -CH2-, -CH2CH2-, or -CH=CHCH2- and the double bond end is connected to R 3 ; L2 is -CH2CH2- or -CH=CH-; X is -NH- or -O-; n and m are independently 0, 1 or 2.

[0009] Furthermore, in formula (I) and (II): R 1 Select from the following structures: , , , ; R 2 Select from the following structures: , , ; R 3 Select from the following structures: , , , , , , , , , , , , , , ; R 4 Select from the following structures: , , , , ; R 5 is hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2,4-dihydroxy, 2,5-dihydroxy or 3,5-dihydroxy; L1 is empty, -CH2-, -CH2CH2-, or -CH=CHCH2- and the double bond end is connected to R 3 ; L2 is -CH2CH2- or -CH=CH-; X is -NH- or -O-; n is 0 or 2; m is 0 or 1.

[0010] In some preferred embodiments, the tyrosinase inhibitor is a compound I to VI, V-1 to V-34 and / or a pharmaceutically acceptable salt thereof having the following structure: .

[0011] [2] The method for preparing a tyrosinase inhibitor according to [1], wherein the tyrosinase inhibitor is a compound having the general formula (I), and the preparation method adopts the synthetic route (1) or (2): ; The preparation method specifically comprises: R 1 Substituted carboxylic acid 1 with R 2 The substituted amine 2 or alcohol 3 undergoes an amide condensation reaction or an esterification reaction to obtain a compound having the general formula (I); or, R 2 Containing one or more of primary amino group and secondary amino group, R 2 The substituted alcohol 3 first reacts with (Boc)2O (Boc is tert-butyloxycarbonyl) to obtain Boc-protected alcohol intermediate 4, which is then reacted with R 1 The substituted carboxylic acid 1 undergoes an esterification reaction, and finally the Boc protecting group is removed to obtain a compound having the general formula (I).

[0012] [3] The method for preparing a tyrosinase inhibitor according to [1], wherein the tyrosinase inhibitor is a compound having the general formula (II), and the preparation method adopts the synthetic route (1), (2) or (3): ; The preparation method specifically comprises: Compound 6 undergoes an amide condensation reaction with carboxylic acid 7 to obtain a compound having the general formula (II); or, Boc-protected amine 8 undergoes amide condensation reaction with carboxylic acid 7 to obtain intermediate 9, intermediate 9 is deprotected from Boc protecting group to obtain intermediate 10, intermediate 10 undergoes substitution reaction or reductive amination reaction with raw material 11 or 12 to obtain a compound having general formula (II); or, The Boc protected amine 8 undergoes a substitution reaction or a reductive amination reaction with the raw material 11 or 12 to obtain the intermediate 13. The intermediate 13 removes the Boc protecting group to obtain the compound 6. The compound 6 undergoes an amide condensation reaction with the carboxylic acid 7 to obtain a compound having the general formula (II).

[0013] [4] Use of the tyrosinase inhibitor according to [1] in the preparation of a product for inhibiting tyrosinase activity. Furthermore, the tyrosinase inhibitor can be used to prepare medicines, cosmetics or fruit and vegetable preservatives.

[0014] Compared with the prior art, the present invention has the following beneficial effects: Based on the protein structure of TYR, the present invention adopts reasonable drug design and structural modification strategies to discover TYR inhibitors with novel structure, higher efficacy and selectivity. DETAILED DESCRIPTION

[0015] 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.

[0016] Embodiment 1: N Preparation of -(4-chlorobenzyl)quinoline-4-carboxamide (Compound I).

[0017] .

[0018] In a 50 mL round-bottom flask equipped with a magnetic stirrer, 4-chlorobenzylamine 14 (141 mg, 1.0 mmol), 4-quinolinecarboxylic acid 15 (208 mg, 1.2 mmol), 1-hydroxybenzotriazole (HOBT, 176 mg, 1.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 250 mg, 1.3 mmol), N , N -Diisopropylethylamine (DIPEA, 387 mg, 3.0 mmol) and DMF (5 mL) were reacted at room temperature for 4 h, and the reaction progress was monitored by TLC. After the reaction was completed, water was added to precipitate the solid, which was washed with EA, filtered and dried to obtain compound I (175 mg, 59%) as a white solid with a melting point of 151.9-152.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.35 (t, J = 6.0 Hz, 1H), 8.99 (d, J = 4.3 Hz, 1H),8.11 (ddd, J = 19.5, 8.5, 1.4 Hz, 2H), 7.81 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.66(ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.60 (d, J = 4.3 Hz, 1H), 7.45-7.39 (m, 4H), 4.55 (d, J= 6.0 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 167.2, 150.8, 148.4,142.2, 138.6, 132.0, 130.3, 129.9, 129.7, 128.9, 127.9, 125.8, 124.6, 119.6,42.4. ESI-HRMS: m / z calcd for C 17 H 14 ClN2O [M+H] + : 297.0789; found: 297.0790.

[0019] Example 2: Preparation of (4-(1-piperazinyl)phenyl)quinoline-3-carboxylate (Compound II).

[0020] .

[0021] 4-(1-piperazinyl)phenol 16 (179 mg, 1.0 mmol), di-tert-butyl dicarbonate (328 mg, 1.5 mmol), triethylamine (205 mg, 2.0 mmol) and DCM (6 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stirrer. The reaction was carried out in an ice bath for 2 h, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was washed with water twice and saturated brine twice. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Thin layer chromatography purification (DCM: CH3OH = 20:1, v / v) gave intermediate 17 (260 mg, 93%).

[0022] To a 50 mL round-bottom flask equipped with a magnetic stirrer, intermediate 17 (150 mg, 0.54 mmol), quinoline-3-carboxylic acid 18 (218 mg, 1.15 mmol), dicyclohexylcarbodiimide (DCC, 167 mg, 0.81 mmol), 4-dimethylaminopyridine (6.6 mg, 0.054 mmol) and DCM (8 mL) were added in sequence and reacted at room temperature for 12 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered, washed with water twice, washed with saturated brine twice, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. It was purified by thin layer chromatography (DCM:CH3OH = 100:1 three times, DCM:CH3OH = 50:1, v / v) to obtain intermediate 19 (84 mg, 34%).

[0023] To a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 19 (143 mg, 0.33 mmol) and methanol (3 mL) were added in sequence, and a hydrochloric acid 1,4-dioxane solution (1.5 mL) was added under an ice bath. The reaction was allowed to react for 3 h at 0 °C, and the reaction progress was monitored by TLC. After the reaction was completed, the organic solvent and excess hydrochloric acid were removed by vacuum concentration, and a saturated NaHCO3 solution was added until no bubbles were generated. The product was extracted twice with DCM, and the organic phases were combined and washed twice with saturated brine. The organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Thin layer chromatography purification (DCM: CH3OH = 20:1 + ammonia water, v / v) gave compound II (70 mg, 64%) as a white solid with a melting point of 176.4-177.2 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.43 (d, J = 2.2 Hz, 1H), 9.20 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.96 (t, J = 7.7Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 9.0 Hz,2H), 3.05 (t, J = 5.0 Hz, 4H), 2.84 (t, J = 4.9 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 )) δ 164.1, 149.7, 149.4, 148.7, 139.5, 132.7, 129.9, 128.9, 127.9, 126.6,122.4, 118.5, 116.8, 115.7, 47.9, 46.8, 43.4, 33.4. ESI-HRMS: m / z calcd forC 20 H 20 N3O2[M+H] + : 334.1550; found: 334.1553.

[0024] Example 3: Preparation of (4-(1-piperazinyl)phenyl)2-hydroxyquinoline-4-carboxylate (Compound III).

[0025] Referring to the synthesis method of Example 2, quinoline-3-carboxylic acid 18 was replaced with 2-hydroxyquinoline-4-carboxylic acid 20 to obtain intermediate 21 (84 mg, 34%). To a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 21 (84 mg, 0.19 mmol) and methanol (2 mL) were added in sequence, and a hydrochloric acid 1,4-dioxane solution (0.85 mL) was added under an ice bath, and the reaction was carried out at 0 ° C for 3 h, and the reaction progress was monitored by TLC. After the reaction was completed, the organic solvent and excess hydrochloric acid were removed by concentration under reduced pressure, and the solid was washed with EA, filtered, adjusted to pH, filtered, and dried to obtain compound III (21 mg, 31%), a light yellow solid with a melting point of 249.8-250.6 ° C. 1 HNMR (500 MHz, DMSO- d 6 ) δ 8.14 (dd, J = 8.2, 1.4 Hz, 1H), 7.60 (ddd, J = 8.5, 7.2,1.4 Hz, 1H), 7.42 (dd, J = 8.4, 1.2 Hz, 1H), 7.28 (ddd, J = 8.3, 7.1, 1.3 Hz,1H), 7.25 – 7.21 (m, 2H), 7.19 (s, 1H), 7.02 – 6.98 (m, 2H), 3.05 (t, J = 5.0Hz, 4H), 2.84 (t, J = 5.0 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 164.1, 160.8,150.0, 142.4, 139.5, 139.3, 131.2, 125.9, 124.8, 122.5, 122.0, 117.8, 116.0,115.4, 49.5, 45.5. ESI-HRMS: m / z calcd for C 20 H 20 N3O3[M+H] + : 350.1499; found:350.1494.

[0026] Example 4: 3-(3-Hydroxyphenyl)-N Preparation of -(2-methylbenzyl)propionamide (Compound IV).

[0027] .

[0028] In a 100 mL round-bottom flask equipped with a magnetic stirrer, 3-(3-methoxyphenyl)propionic acid 22 (356.80 mg, 1.98 mmol), (7-azobenzotriazole)- N,N,N’,N’ -Tetramethyluronium hexafluorophosphate (HATU, 627.40 mg, 1.65 mmol), N , N -diisopropylethylamine (DIPEA, 213.25 mg, 1.65 mmol) and DCM (5.0 mL) were stirred at 0 °C for 15 min, and then 2-methylbenzylamine 23 (200 mg, 1.65 mmol) and N , N -Diisopropylethylamine (DIPEA, 213.25 mg, 1.65 mmol), react at room temperature for 2 h, and monitor the reaction progress with a TLC plate. After the reaction is completed, wash with water 2-3 times, collect the organic layer, dry it over anhydrous Na2SO4, and concentrate it under reduced pressure. Purify it with thin layer chromatography (pure DCM) to obtain a yellow-white solid, namely intermediate 24 (392 mg, 81%).

[0029] Add intermediate 24 (150 mg, 0.53 mmol) and DCM (5 mL) to a 100 mL round-bottom flask equipped with a magnetic stirrer, stir at 0 °C for 5 min, then drop BBr3 (1327.7 mg, 5.3 mmol) into the reaction flask, react at room temperature for 2 h, and monitor the reaction progress with a TLC plate. After the reaction, drop ice water into the reaction solution until no gas is generated in the reaction flask, precipitate solid, filter, wash the filter cake with water, and dry the filter cake to obtain compound IV (130 mg, 91%), a white solid with a melting point of 115.8-116.5 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.23 (s, 1H), 8.16 (t, J = 5.7 Hz, 1H),7.14 – 7.03 (m, 5H), 6.63 – 6.57 (m, 3H), 4.22 (d, J = 5.6 Hz, 2H), 2.75 (t, J =7.7 Hz, 2H), 2.44 – 2.40 (m, 2H), 2.22 (s, 3H). 13C NMR (125 MHz, DMSO- d 6 ) δ171.2, 157.3, 142.7, 137.0, 135.6, 129.8, 129.2, 127.6, 126.8, 125.8, 118.9,115.3, 112.9, 40.2, 36.9, 31.2, 18.6. ESI-HRMS: m / z calcd for C 17 H 20 NO2[M+H] + :270.1489; found: 270.1487.

[0030] Example 5: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V).

[0031] .

[0032] In a 50 mL round-bottom flask equipped with a magnetic stirrer, 1-(4-fluorobenzyl)piperazine 26 (204 mg, 1.2 mmol), 3-hydroxyphenylpropionic acid 25 (195 mg, 1.0 mmol), 1-hydroxybenzotriazole (HOBT, 177 mg, 1.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 245 mg, 1.3 mmol), N,N -Diisopropylethylamine (DIPEA, 386 mg, 3.0 mmol) and DMF (5 mL) were reacted at room temperature for 4 h, and the reaction progress was monitored by TLC. After the reaction was completed, it was diluted with EA and water, extracted with EA three times, the organic layers were combined, washed with saturated NaHCO3 and saturated brine, the organic layers were collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Thin layer chromatography purification (DCM: CH3OH = 20:1, v / v) gave compound V (213 mg, 62%) as a white solid with a melting point of 112.7-113.4 °C. 1 H NMR (500 MHz, CDCl3) δ 7.25 (dd, J =8.5, 5.5 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 7.02 – 6.96 (m, 2H), 6.74 – 6.67(m, 3H), 3.62 (t, J = 5.0 Hz, 2H), 3.44 (s, 2H), 3.37 (t, J= 5.0 Hz, 2H), 2.90(t, J = 10.0 Hz, 2H), 2.61 (t, J = 5.0 Hz, 2H), 2.38 (t, J = 5.0 Hz, 2H), 2.25 (t, J = 5.0 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 169.8, 162.3 (d, 1 J = 241.3 Hz),157.3, 142.7, 134.1 (d, 4 J = 2.5 Hz), 130.7 (d, 3 J = 7.5 Hz), 129.1, 119.0,115.3, 114.9 (d, 2 J = 20.0 Hz), 112.8, 60.9, 52.6, 52.2, 44.9, 41.0, 33.9,30.8. ESI-HRMS: m / z calcd for C 20 H 24 FN2O2[M+H] + : 343.1816; found: 343.1816.

[0033] Example 6: E Preparation of )-1-(4-(3-hydroxyphenyl)piperazinyl)-3-phenyl-2-propen-1-one (Compound VI).

[0034] .

[0035] In a 100 mL round-bottom flask equipped with a magnetic stirrer, cinnamic acid 27 (50 mg, 0.337 mmol), (7-azobenzotriazole)- N,N,N’,N’ -Tetramethyluronium hexafluorophosphate (HATU, 128.14 mg, 0.337 mmol), N, N -diisopropylethylamine (DIPEA, 43.6 mg, 0.34 mmol) and N,N-dimethylformamide (DMF, 5.0 mL), stirred at 0 °C for 15 min, then added m-hydroxyphenylpiperazine 28 (120.31 mg, 0.675 mmol) and N , N -Diisopropylethylamine (DIPEA, 43.6 mg, 0.34 mmol), react at room temperature for 2 h, and monitor the reaction progress with a TLC plate. After the reaction is completed, dilute with EA and water, extract with EA three times, combine the organic layers, wash with saturated brine, collect the organic layers, dry over anhydrous Na2SO4, and concentrate under reduced pressure. Purify with thin layer chromatography (DCM: CH3OH = 50:1, v / v) to obtain compound VI (120 mg, 39%) as a yellow-brown solid with a melting point of 72.1-73.0 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.17 (s, 1H), 7.74 (d, J = 7.3 Hz,2H), 7.52 (d, J = 15.4 Hz, 1H), 7.40 (dd, J = 10.9, 7.0 Hz, 3H), 7.31 (d, J = 15.4Hz, 1H), 7.01 (t, J = 5.0 Hz, 1H), 6.42 (d, J = 5.9 Hz, 1H), 6.35 (d, J = 2.4 Hz,1H), 6.25 (d, J = 7.9 Hz, 1H), 3.84 (s, 2H), 3.71 (s, 2H), 3.12 (s, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 164.4, 158.1, 152.2, 141.6, 135.1, 129.6, 129.6, 128.8,128.1, 118.1, 107.0, 106.6, 102.9, 49.0, 48.4, 44.9, 41.5. ESI-HRMS: m / zcalcd for C 19 H 21 N2O2[M+H] + : 309.1598; found: 309.1598.

[0036] Example 7: Preparation of 1-(4-(2-fluorobenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-1).

[0037] .

[0038] Referring to the synthesis method of Example 5, 1-(4-fluorobenzyl)piperazine 26 was replaced by 1-(2-fluorobenzyl)piperazine 29 to obtain compound V-1 (136 mg, 40%) as a white solid with a melting point of 90.9-91.6 °C. 1 H NMR (500 MHz, DMSO- d 6 )δ 9.21 (s, 1H), 7.40 (td, J = 7.7, 1.9 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.20 –7.13 (m, 2H), 7.03 (t, J = 7.7 Hz, 1H), 6.64 – 6.60 (m, 2H), 6.56 (ddd, J = 8.1,2.5, 1.0 Hz, 1H), 3.52 (d, J = 1.3 Hz, 2H), 3.44 (t, J = 5.1 Hz, 2H), 3.38 (t, J =5.0 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.54 (dd, J = 8.7, 6.8 Hz, 2H), 2.30 (dt, J = 6.8, 4.7 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 169.9, 161.8 (d, 1 J = 243.75Hz), 157.3, 142.8, 131.6 (d, 4 J = 3.75 Hz), 129.2 (d, 3 J = 7.5 Hz), 129.1, 124.3(d, 2 J = 13.8 Hz), 124.2 (d, 4 J= 3.8 Hz), 119.0, 115.4, 115.3 (d, 2 J = 21.3 Hz),112.9, 54.4, 52.5, 52.2, 44.9, 41.1, 33.9, 30.9. ESI-HRMS: m / z calcd forC 20 H 24 FN2O2[M+H] + : 343.1816; found: 343.1821.

[0039] Example 8: Preparation of 1-(4-(3-fluorobenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-2).

[0040] Referring to the synthesis method of Example 5, 1-(4-fluorobenzyl)piperazine 26 was replaced by 1-(3-fluorobenzyl)piperazine 30 to obtain compound V-2 (65 mg, 23%) as a white solid with a melting point of 244.7-245.5 °C. 1 H NMR (500 MHz, DMSO- d 6 )δ 9.21 (s, 1H), 7.39 – 7.33 (m, 1H), 7.16 – 7.11 (m, 2H), 7.10 – 7.02 (m,2H), 6.64 – 6.60 (m, 2H), 6.56 (dd, J = 9.2, 2.4 Hz, 1H), 3.48 (s, 2H), 3.44(d, J = 5.0 Hz, 2H), 3.40 (t, J = 5.0 Hz, 2H), 2.70 (t, J = 7.7 Hz, 2H), 2.58 –2.52 (m, 2H), 2.32 – 2.25 (m, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 169.8, 163.2(d, 1 J = 241.3 Hz), 157.3, 142.7, 141.1 (d, 3 J = 7.5 Hz), 130.1 (d, 3 J= 8.8 Hz),129.1, 124.7 (d, 4 J = 2.5 Hz), 119.0, 115.3, 115.3 (d, 2 J = 21.3 Hz), 113.8 (d, 2 J = 20.0 Hz), 112.8, 61.1, 52.7, 52.3, 44.9, 41.0, 33.9, 30.8. ESI-HRMS: m / zcalcd for C 20 H 24 FN2O2[M+H] + : 343.1816; found: 343.1821.

[0041] Example 9: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(2-hydroxyphenyl)-1-propanone (Compound V-3).

[0042] .

[0043] Referring to the synthesis method of Example 5, 3-hydroxyphenylpropionic acid 25 was replaced by 2-hydroxyphenylpropionic acid 31 to obtain compound V-3 (120 mg, 35%) as a white solid with a melting point of 123.8-124.6 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.35(s, 1H), 7.32 (dd, J = 8.5, 5.8 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 7.05 (dd, J =7.5, 1.7 Hz, 1H), 6.99 (td, J = 7.7, 1.8 Hz, 1H), 6.76 (dd, J = 8.0, 1.2 Hz, 1H),6.69 (td, J = 7.4, 1.2 Hz, 1H), 3.44 (d, J = 4.1 Hz, 4H), 3.40 (t, J = 5.1 Hz, 2H),2.75 – 2.68 (m, 2H), 2.53 (d, J = 8.3 Hz, 2H), 2.26 (q,J = 5.7 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.3, 162.3 (d, 1 J = 240.0 Hz), 155.2, 134.0 (d, 4 J = 2.5Hz), 130.7 (d, 3 J = 7.5 Hz), 130.0, 127.3 (d, 2 J = 33.8 Hz), 118.9, 115.0,115.0, 114.8, 60.9, 52.6, 52.2, 44.9, 41.0, 32.7, 25.9. ESI-HRMS: m / z calcdfor C 20 H 24 FN2O2[M+H] + : 343.1816; found: 343.1820.

[0044] Example 10: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(4-hydroxyphenyl)-1-propanone (Compound V-4).

[0045] Referring to the synthesis method of Example 5, 3-hydroxyphenylpropionic acid 25 was replaced by 4-hydroxyphenylpropionic acid 32 to obtain compound V-4 (206 mg, 60%) as a white liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.12 (s, 1H), 7.35 – 7.29(m, 2H), 7.17 – 7.11 (m, 2H), 7.02 – 6.98 (m, 2H), 6.67 – 6.62 (m, 2H), 3.43(s, 4H), 3.37 (t, J = 5.0 Hz, 2H), 2.67 (dd, J = 8.9, 6.5 Hz, 2H), 2.54 – 2.50(m, 2H), 2.26 (dd, J = 9.9, 5.0 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 170.0,162.3 (d, 1 J = 241.3 Hz), 155.5, 134.1 (d, 4 J = 3.8 Hz), 131.3, 130.7 (d, 3 J = 7.5Hz), 129.25, 115.00, 114.83, 60.92, 52.63, 52.22, 44.90, 41.01, 34.39, 30.07.ESI-HRMS: m / z calcd for C 20 H 24 FN2O2[M+H] + : 343.1816; found: 343.1822.

[0046] Example 11: E Preparation of )-1-(4-(4-fluorobenzyl)piperazinyl)-3-(3-hydroxyphenyl)-2-propen-1-one (Compound V-5).

[0047] Referring to the synthesis method of Example 5, 3-hydroxyphenylpropionic acid 25 was replaced by 3-hydroxyphenylacrylic acid 33 to obtain compound V-5 (256 mg, 75%) as a white solid with a melting point of 219.6-220.4 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ9.54 (s, 1H), 7.38 (d, J = 15.4 Hz, 1H), 7.36 – 7.32 (m, 2H), 7.18 (t, J = 7.8Hz, 1H), 7.16 – 7.13 (m, 2H), 7.13 – 7.10 (m, 2H), 7.05 (t, J = 2.0 Hz, 1H),6.79 (dd, J = 8.0, 1.5 Hz, 1H), 3.67 (s, 2H), 3.56 (s, 2H), 3.48 (s, 2H), 2.36(dt, J = 18.1, 4.8 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 164.4, 162.3 (d,1 J =240.0 Hz), 157.6, 141.7, 136.4, 134.0 (d, 4 J = 3.8 Hz), 130.8 (d, 3 J = 7.5 Hz),129.7, 118.9, 118.0, 116.6, 115.0 (d, 2 J = 21.3 Hz), 114.5, 60.9, 53.1, 52.2,45.1, 41.7. ESI-HRMS: m / z calcd for C 20 H 22 FN2O2[M+H] + : 341.1660; found:341.1658.

[0048] Example 12: Preparation of 1-(4-(4-fluorobenzyl)-1,4-diazepinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-6).

[0049] .

[0050] 4-Fluorobenzyl chloride 34 (216.86 mg, 1.5 mmol), tert-butyl 1,4-diazacycloheptane-1-carboxylate 35 (200.28 mg, 1.0 mmol), potassium carbonate (276.42 mg, 2.0 mmol) and acetonitrile (CH3CN, 10 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stirrer. The reaction was allowed to proceed at room temperature and the reaction progress was monitored by TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, the product was diluted with EA and water, and EA was extracted three times. The organic phases were combined and washed with saturated brine. The organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography purification (DCM: CH3OH = 70:1, v / v) gave a colorless oily liquid, namely intermediate 36 (280.2 mg, 91%).

[0051] To a 100 mL round-bottom flask equipped with a magnetic stirrer, add intermediate 36 (280.2 mg, 0.91 mmol) and methanol (4 mL) in sequence, add hydrochloric acid 1,4-dioxane solution (3 mL) under ice bath conditions, move to room temperature for reaction after 10 min, and monitor the reaction progress by TLC. After the reaction is completed, the organic solvent and excess hydrochloric acid are removed by vacuum concentration, and the solid is washed with EA, filtered, and dried to obtain a white solid, namely intermediate 37 (98%).

[0052] In a 50 mL round-bottom flask equipped with a magnetic stirrer, intermediate 37 (200 mg, 0.71 mmol), 3-hydroxyphenylpropionic acid 25 (142.3 mg, 0.86 mmol), 1-hydroxybenzotriazole (HOBT, 124.6 mg, 0.92 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 176.6 mg, 0.92 mmol), DIPEA (247.8 mg, 2.13 mmol) and DMF (4 mL) were added in sequence and reacted at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, it was diluted with EA and water, extracted with EA three times, the organic phases were combined, washed with saturated brine, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Thin layer chromatography purification (DCM: CH3OH = 30:1, v / v) gave compound V-6 (89.2 mg, 35.3%) as a yellow liquid. 1 H NMR (500MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 7.32 (dd, J = 8.6, 5.9 Hz, 2H), 7.12 (td, J = 8.9,2.8 Hz, 2H), 7.04 (t, J = 7.7 Hz, 1H), 6.63 (ddd, J = 8.5, 5.1, 1.8 Hz, 2H), 6.56(dq, J = 8.1, 1.9 Hz, 1H), 3.55 (d, J = 2.6 Hz, 2H), 3.51 – 3.43 (m, 4H), 2.72(td, J = 7.6, 2.0 Hz, 2H), 2.58 – 2.51 (m, 4H), 2.49 – 2.44 (m, 2H), 1.79 –1.64 (m, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.9, 162.2 (d, 1 J = 241.3 Hz),157.3, 142.9 (d, 4 J = 3.8 Hz), 135.3, 130.3 (t, 3 J= 8.8 Hz), 129.1, 119.0,115.4, 114.8 (dd, 2 J = 20.0 Hz), 112.8, 60.2, 60.0, 55.4, 54.9, 54.0, 53.5,47.0, 46.0, 44.4, 44.0, 34.2, 34.1, 30.9, 30.8, 27.8, 26.9. ESI-HRMS: m / zcalcd for C 21 H 26 FN2O2[M+H] + : 357.1973; found: 357.1978.

[0053] Example 13: 1-(5-(4-fluorobenzyl)hexahydropyrrolo[3,4- c ]Pyrrolidine-2(1 H Preparation of 3-(3-hydroxyphenyl)-1-propanone (compound V-7).

[0054] Referring to the synthesis method of Example 12, 1,4-diazepane-1-carboxylic acid tert-butyl ester 35 was replaced by hexahydropyrrolo[3,4- c ]pyrrole-2(1 H )-tert-butyl formate 38 to give intermediates 39 (55%) and 40 (95%), which were then reacted with 3-hydroxyphenylpropionic acid 25 to give compound V-7 (116 mg, 81%) as a white solid with a melting point of 140.5-141.0 °C. 1 H NMR (500MHz, DMSO- d 6 ) δ 9.23 (s, 1H), 7.34 – 7.28 (m, 2H), 7.15 – 7.09 (m, 2H), 7.04(t, J = 7.7 Hz, 1H), 6.65 – 6.61 (m, 2H), 6.59 – 6.55 (m, 1H), 3.58 – 3.48 (m,4H), 3.21 (dt, J = 12.1, 4.2 Hz, 2H), 2.83 – 2.65 (m, 5H), 2.49 – 2.42 (m, 3H), 2.33 (ddd, J = 9.3, 3.8, 2.1 Hz, 2H). 13 C NMR (125 MHz, DMSO- d6 ) δ 169.4, 162.1(d, 1 J = 240.0 Hz), 157.3, 142.9, 135.3 (d, 4 J = 2.5 Hz), 130.1 (d, 3 J = 8.8 Hz),129.2, 118.9, 115.3, 114.9 (d, 2 J = 21.3 Hz), 112.8, 59.7, 59.4, 57.8, 51.8,50.9, 41.8, 40.0, 35.6, 30.5. ESI-HRMS: m / z calcd for C 22 H 26 FN2O2[M+H] + :369.1973; found: 369.1977.

[0055] Embodiment 14: N Preparation of -(2-((4-fluorobenzyl)amino)propyl)-3-(3-hydroxyphenyl)propionamide (Compound V-8).

[0056] .

[0057] In a 50 mL round-bottom flask equipped with a magnetic stirrer, 3-hydroxyphenylpropionic acid 25 (365.33 mg, 2.2 mmol), N -tert-Butyloxycarbonyl-1,2-ethylenediamine 44 (320.44 mg, 2.0 mmol), 1-hydroxybenzotriazole (HOBT, 351 mg, 2.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 499.2 mg, 2.6 mmol), DIPEA (516 mg, 4.0 mmol) and DMF (4 mL) were reacted at room temperature and the reaction progress was monitored by TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, diluted with EA and water, extracted with EA three times, the organic phases were combined, washed with saturated brine, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by thin layer chromatography (DCM: CH3OH = 20:1, v / v) gave a colorless oily liquid, namely intermediate 45 (456 mg, 74%).

[0058] To a 100 mL round-bottom flask equipped with a magnetic stirrer, add intermediate 45 (456 mg, 1.48 mmol) and methanol (6 mL) in sequence, add hydrochloric acid 1,4-dioxane solution (5 mL) under ice bath conditions, move to room temperature for reaction after 10 min, and monitor the reaction progress by TLC. After the reaction is completed, the organic solvent and excess hydrochloric acid are removed by vacuum concentration, and the solid is washed with EA, filtered, and dried to obtain a colorless oily liquid, namely intermediate 46, with a yield of 96%.

[0059] In a 50 mL round-bottom flask equipped with a magnetic stirrer, intermediate 46 (183 mg, 0.5 mmol), 4-fluorobenzyl chloride 34 (48 mg, 0.33 mmol), triethylamine (TEA, 101.2 mg, 1.0 mmol) and acetonitrile (CH3CN, 5 mL) were added in sequence and reacted at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, the pH was adjusted to 6 with dilute hydrochloric acid solution, and then adjusted to 8 with saturated NaHCO3 solution, and EA was extracted three times. The organic phases were combined and washed with saturated brine. The organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Thin layer chromatography purification (DCM: CH3OH = 20:1, v / v) gave compound V-8 (30 mg, 19%) as an orange liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.23 (s, 1H), 7.76 (t, J = 5.7 Hz,1H), 7.38 – 7.30 (m, 2H), 7.16 – 7.08 (m, 2H), 7.05 – 7.00 (m, 1H), 6.60 –6.57 (m, 2H), 6.55 (ddd, J = 8.0, 2.5, 1.1 Hz, 1H), 3.64 (s, 2H), 3.12 (q, J =6.3 Hz, 2H), 2.69 (dd, J = 8.7, 6.8 Hz, 2H), 2.50 – 2.47 (m, 2H), 2.31 (dd, J =8.7, 6.9 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 171.4, 162.0 (d, 1 J= 240.0 Hz),157.3, 142.8, 136.8 (d, 4 J = 2.5 Hz), 129.8 (d, 3 J = 7.5 Hz), 129.1, 118.8,115.1, 114.8 (d, 2 J = 20.0 Hz), 112.8, 51.8, 48.0, 38.6, 37.0, 31.1. ESI-HRMS:m / z calcd for C 18 H 22 FN2O2[M+H] + : 317.1660; found: 317.1663.

[0060] Embodiment 15: N Preparation of -(3-((4-fluorobenzyl)amino)propyl)-3-(3-hydroxyphenyl)propionamide (Compound V-9).

[0061] Referring to the synthesis method of Example 12, 1,4-diazepane-1-carboxylic acid tert-butyl ester 35 was replaced by N -tert-Butyloxycarbonyl-1,3-propanediamine 41 to give intermediates 42 (53%) and 43 (95%), which were subsequently reacted with 3-hydroxyphenylpropionic acid 25 to give compound V-9 (30 mg, 18%) as a red liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.85 (t, J = 5.7 Hz,1H), 7.42 – 7.35 (m, 2H), 7.16 – 7.11 (m, 2H), 7.04 (t, J = 7.9 Hz, 1H), 6.61 –6.52 (m, 3H), 3.70 (s, 2H), 3.08 (q, J = 6.5 Hz, 2H), 2.69 (dd, J = 8.7, 6.8 Hz,2H), 2.50 – 2.46 (m, 2H), 2.30 (dd, J = 8.8, 6.8 Hz, 2H), 1.55 (p, J = 6.9 Hz,2H). 13 C NMR (125 MHz, DMSO- d6 ) δ 171.4, 162.2 (d, 1 J = 240.0 Hz), 157.3, 142.8,135.8, 130.3 (d, 3 J = 7.5 Hz), 129.2, 118.8, 115.2, 115.0 (d, 2 J = 21.3 Hz),112.9, 51.7, 45.8, 37.1, 36.5, 31.2, 28.9. ESI-HRMS: m / z calcd for C 19 H 24 FN2O2[M+H] + : 331.1816; found: 331.1812.

[0062] Example 16: Preparation of 1-(4-(3-chlorobenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-10).

[0063] .

[0064] 3-Chlorobenzyl chloride 48 (744.6 mg, 4 mmol), tert-butylpiperazine-1-carboxylate 47 (722.9 mg, 4.8 mmol), potassium carbonate (829 mg, 6 mmol), potassium iodide (41.5 mg, 0.25 mmol) and acetonitrile (CH3CN, 6 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stirrer. The mixture was reacted at room temperature and the reaction progress was monitored by TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, the mixture was diluted with EA and water, and EA was extracted three times. The organic phases were combined, washed with saturated brine, the organic layers were collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography purification (DCM: CH3OH = 50:1, v / v) gave a colorless oily liquid, namely intermediate 49 (843 mg, 68%).

[0065] To a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 49 (843 mg, 2.7 mmol) and methanol (10 mL) were added in sequence, and a hydrochloric acid 1,4-dioxane solution (8 mL) was added under an ice bath. After 10 min, the mixture was moved to room temperature for reaction, and the reaction progress was monitored by TLC. After the reaction was completed, the organic solvent and excess hydrochloric acid were removed by concentration under reduced pressure, and the solid was washed with EA, filtered, and dried to obtain a white solid, namely intermediate 50 (98%).

[0066] In a 50 mL round-bottom flask equipped with a magnetic stirrer, intermediate 50 (153.87 mg, 0.66 mmol), 3-hydroxyphenylpropionic acid 25 (142.57 mg, 0.86 mmol), 1-hydroxybenzotriazole (HOBT, 178.2 mg, 1.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 253.44 mg, 1.32 mmol), DIPEA (255.42 mg, 1.98 mmol) and DMF (4 mL) were added in sequence and reacted at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, diluted with EA and water, extracted with EA three times, the organic phases were combined, washed with saturated brine, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by thin layer chromatography (DCM: CH3OH = 15:1, v / v) gave compound V-10 (83 mg, 35%) as a colorless transparent liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (d, J = 1.6 Hz, 1H), 7.35(d, J = 7.5 Hz, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.04 (t, J =7.7 Hz, 1H), 6.65 – 6.60 (m, 2H), 6.59 – 6.55 (m, 1H), 3.44 (d, J = 5.0 Hz,2H), 3.39 (t, J = 4.9 Hz, 2H), 3.35 (d, J = 2.8 Hz, 2H), 2.70 (t, J = 7.7 Hz, 2H),2.57 – 2.52 (m, 2H), 2.28 (h, J = 4.7 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ169.9, 157.3, 142.8, 140.7, 133.0, 130.1, 129.1, 128.5, 127.5, 127.0, 119.0,115.3, 112.8, 61.0, 52.7, 52.3, 44.9, 41.1, 33.9, 30.8. ESI-HRMS: m / z calcdfor C 20 H 24 ClN2O2[M+H] + : 359.1521; found: 359.1522.

[0067] Example 17: Preparation of 1-(4-(4-methylbenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-11).

[0068] .

[0069] 3-Hydroxyphenylpropionic acid 25 (558.78 mg, 3.0 mmol), tert-butylpiperazine-1-carboxylate 47 (598.25 mg, 3.6 mmol), 1-hydroxybenzotriazole (HOBT, 526.5 mg, 3.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 748.8 mg, 3.9 mmol), DIPEA (774 mg, 6.0 mmol) and DMF (6 mL) 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. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and the mixture was diluted with EA and water, extracted with EA three times, and the organic phases were combined and washed with saturated brine. The organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (DCM:CH3OH = 50:1, v / v) gave a brown liquid, intermediate 54 (926 mg, 92%).

[0070] To a 100 mL round-bottom flask equipped with a magnetic stirrer, add intermediate 54 (926 mg, 2.8 mmol) and methanol (12 mL) in sequence, add hydrochloric acid 1,4-dioxane solution (10 mL) under ice bath conditions, move to room temperature for reaction after 10 min, and monitor the reaction progress by TLC. After the reaction is completed, the organic solvent and excess hydrochloric acid are removed by vacuum concentration, and the solid is washed with EA, filtered, and dried to obtain a colorless oily liquid, namely intermediate 55 (98%).

[0071] In a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 55 (150 mg, 0.64 mmol), 4-methylbenzyl chloride 56 (108 mg, 0.77 mmol), potassium carbonate (132.7 mg, 0.96 mmol) and acetonitrile (CH3CN, 5 mL) were added in sequence and reacted at room temperature. The reaction progress was monitored by TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, diluted with EA and water, extracted with EA three times, the organic phases were combined, washed with saturated brine, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Thin layer chromatography purification (DCM: CH3OH = 20:1, v / v) gave compound V-11 (157 mg, 73%) as a gray solid with a melting point of 84.5-85.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 7.18 – 7.15 (m, 2H), 7.12(d, J = 7.9 Hz, 2H), 7.03 (t, J = 7.7 Hz, 1H), 6.64 – 6.59 (m, 2H), 6.57 (d, J =7.9 Hz, 1H), 3.43 (t, J = 5.0 Hz, 2H), 3.37 (t, J = 5.0 Hz, 2H), 3.33 (d, J = 2.2Hz, 4H), 2.70 (t, J = 7.7 Hz, 2H), 2.56 – 2.51 (m, 2H), 2.27 (s, 3H), 2.25 –2.23 (m, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 169.9, 157.3, 142.8, 136.1, 134.8,129.2, 128.9, 128.8, 119.0, 115.4, 112.8, 61.6, 52.7, 52.3, 44.9, 41.1, 33.9,30.8, 20.7. ESI-HRMS: m / z calcd for C 21 H 27 N2O2[M+H] + : 339.2067; found:339.2067.

[0072] Example 18: Preparation of 1-(4-(4-ethylbenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-12).

[0073] Referring to the synthesis method of Example 17, intermediate 55 (150 mg, 0.64 mmol), 4-ethylbenzaldehyde 57 (128.8 mg, 0.96 mmol), glacial acetic acid (57.6 mg, 1.5 mmol) and 1,2-dichloroethane (DCE, 6 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stirrer in sequence, and reacted at room temperature. After two hours, sodium triacetoxyborohydride (135.64 mg, 0.64 mmol) was added, and sodium triacetoxyborohydride (135.64 mg, 0.64 mmol) was added again after two hours. The reaction was reacted at room temperature and the reaction progress was monitored by TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, neutralized with saturated NaHCO3 solution, extracted with EA 3-4 times, and the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by thin layer chromatography (DCM: CH3OH = 20:1, v / v) gave compound V-12 (63 mg, 28%) as a colorless transparent oily liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.21 (s,1H), 7.19 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.03 (t, J = 7.7 Hz, 1H), 6.64 – 6.59 (m, 2H), 6.56 (ddd, J = 8.0, 2.5, 1.0 Hz, 1H), 3.46 – 3.41 (m, 2H), 3.41 (s, 2H), 3.39 – 3.35 (m, 2H), 2.70 (t, J = 7.7 Hz, 2H), 2.60 – 2.52 (m,4H), 2.28 – 2.21 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H). 13 C NMR (125 MHz, DMSO- d 6) δ170.3, 157.4, 142.9, 142.7, 135.1, 129.4, 129.2, 127.8, 119.3, 115.5, 113.1,61.8, 52.8, 52.4, 45.1, 41.3, 34.1, 31.0, 28.0, 15.8. ESI-HRMS: m / z calcd forC 22 H 29 N2O2[M+H] + : 353.2224; found: 353.2224.

[0074] Example 19: Preparation of 1-(4-(4-methoxybenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-13).

[0075] Referring to the synthesis method of Example 18, 4-ethylbenzaldehyde 57 was replaced by 4-methoxybenzaldehyde 58 to obtain compound V-13 (163.9 mg, 72%) as a brown oily liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.23 (s, 1H),7.19 (d, J = 8.6 Hz, 2H), 7.04 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.64– 6.60 (m, 2H), 6.57 (dd, J = 8.1, 1.1 Hz, 1H), 3.73 (s, 3H), 3.42 (d, J = 5.3Hz, 2H), 3.38 (s, 4H), 2.70 (t, J = 7.7 Hz, 2H), 2.56 – 2.51 (m, 2H), 2.25 (d, J = 6.4 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 169.8, 158.3, 157.3, 142.8, 130.1,129.6, 129.1, 119.0, 115.3, 113.6, 112.8, 61.3, 55.0, 52.6, 52.2, 44.9, 41.1,33.9, 30.8. ESI-HRMS: m / z calcd for C 21 H 27 N2O3[M+H] + : 355.2016; found:355.2013.

[0076] Example 20: Preparation of 4-((4-(3-(3-hydroxyphenyl)propionyl)piperazin-1-yl)methyl)benzonitrile (Compound V-14).

[0077] Referring to the synthesis method of Example 16, 3-chlorobenzyl chloride 48 was replaced by 4-cyanobenzyl bromide 51 to obtain intermediates 52 (90%) and 53 (96%), which were then reacted with 3-hydroxyphenylpropionic acid 25 to obtain compound V-14 (103 mg, 34%) as a white solid with a melting point of 150.8-151.4 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 7.82 – 7.77 (m, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.03 (t, J = 7.7 Hz, 1H), 6.65 – 6.53 (m, 3H), 3.55 (s, 2H), 3.45 (t, J = 5.0 Hz, 2H), 3.40 (q, J = 4.4 Hz, 2H), 2.70 (t, J = 7.7Hz, 2H), 2.55 (dd, J = 8.6, 6.8 Hz, 2H), 2.28 (q, J = 5.6 Hz, 4H). 13 C NMR (125MHz, DMSO- d 6) δ 169.9, 157.3, 144.1, 142.7, 132.2, 129.6, 129.1, 119.0,118.9, 115.4, 112.8, 109.8, 61.1, 52.7, 52.3, 44.9, 41.0, 33.9, 30.8. ESI-HRMS: m / z calcd for C 21 H 24 N3O2[M+H] + : 350.1863; found: 350.1866.

[0078] Example 21: E )-1-(4-(3-(4-fluorobenzyl)allyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-15).

[0079] Referring to the synthesis method of Example 18, 4-ethylbenzaldehyde 57 was replaced by 4-fluorocinnamaldehyde 59 to obtain compound V-15 (64.6 mg, 27%) as a white solid with a melting point of 148.9-149.6 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ9.22 (s, 1H), 7.53 – 7.45 (m, 2H), 7.18 – 7.10 (m, 2H), 7.06 – 7.01 (m, 1H), 6.65 – 6.60 (m, 2H), 6.58 – 6.49 (m, 2H), 6.29 – 6.20 (m, 1H), 3.49 – 3.43 (m, 2H), 3.42 – 3.38 (m, 2H), 3.08 (d, J = 6.3 Hz, 2H), 2.71 (t, J = 7.7 Hz, 2H),2.59 – 2.53 (m, 2H), 2.32 (q, J = 5.2 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ169.9, 162.5 (d, 1 J = 242.5 Hz), 157.3, 142.8, 133.2 (d, 4 J= 2.5 Hz), 131.1,129.2, 128.1 (d, 3 J = 7.5 Hz), 126.7, 119.0, 115.5 (d, 2 J = 21.3 Hz), 115.4,112.8, 59.9, 52.8, 52.3, 44.9, 41.1, 33.9, 30.8. HRMS: m / z calcd forC 22 H 26 FN2O2[M+H] + : 369.1973; found: 369.1973.

[0080] Example 22: Preparation of 3-(3-hydroxyphenyl)-1-(4-phenethylpiperazinyl)-1-propanone (Compound V-16).

[0081] .

[0082] Referring to the synthesis method of Example 5, 1-(4-fluorobenzyl)piperazine 26 was replaced by 1-(1-phenylethyl)piperazine 62 to obtain compound V-16 (220 mg, 65%) as an orange liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (s, 1H),7.29 – 7.25 (m, 2H), 7.21 (d, J = 6.6 Hz, 2H), 7.19 – 7.15 (m, 1H), 7.04 (t, J =7.7 Hz, 1H), 6.66 – 6.60 (m, 2H), 6.57 (dd, J = 7.6, 2.2 Hz, 1H), 3.47 – 3.42(m, 2H), 3.38 (t, J = 5.0 Hz, 2H), 2.71 (td, J = 7.8, 4.0 Hz, 4H), 2.56 (t, J = 7.7Hz, 2H), 2.51 (d, J = 4.7 Hz, 1H), 2.50 – 2.48 (m, 1H), 2.39 – 2.32 (m, 4H). 13 CNMR (125 MHz, DMSO- d6 ) δ 169.9, 157.3, 142.8, 140.4, 129.2, 128.7, 128.3,125.9, 119.1, 115.4, 112.9, 59.6, 52.9, 52.4, 45.0, 41.1, 33.9, 32.6, 30.9.HRMS: m / z calcd for C 21 H 27 N2O2[M+H] + : 339.2067; found: 339.2067.

[0083] Example 23: Preparation of 3-(3-hydroxyphenyl)-1-(4-(2-furanylmethyl)piperazinyl)-1-propanone (Compound V-17).

[0084] .

[0085] To a 50 mL round-bottom flask equipped with a magnetic stirrer, furan-2-carboxaldehyde 63 (288.2 mg, 3.0 mmol), tert-butylpiperazine-1-carboxylate 47 (372.5 mg, 2.0 mmol), glacial acetic acid (180 mg, 3.0 mmol) and 1,2-dichloroethane (DCE, 6 mL) were added in sequence and reacted at room temperature. After two hours, sodium triacetoxyborohydride (423.9 mg, 2.0 mmol) was added, and after two hours, sodium triacetoxyborohydride (423.9 mg, 2.0 mmol) was added again. The reaction was reacted at room temperature and the reaction progress was monitored by TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, neutralized with saturated NaHCO3 solution, extracted with DCM 3-4 times, the organic layer was collected, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (DCM: CH3OH = 100:1, v / v) to obtain an orange liquid, namely intermediate 64 (216 mg, 41%).

[0086] To a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 64 (216 mg, 0.8 mmol) and methanol (4 mL) were added in sequence, and a hydrochloric acid 1,4-dioxane solution (2.5 mL) was added under ice bath conditions. After 10 min, the mixture was moved to room temperature for reaction, and the reaction progress was monitored by TLC. After the reaction was completed, the organic solvent and excess hydrochloric acid were removed by concentration under reduced pressure, and the solid was washed with EA, filtered, and dried to obtain a black solid, namely intermediate 65 (98%).

[0087] In a 50 mL round-bottom flask equipped with a magnetic stirrer, intermediate 65 (286 mg, 0.8 mmol), 3-hydroxyphenylpropionic acid 25 (161.2 mg, 0.96 mmol), 1-hydroxybenzotriazole (HOBT, 142.2 mg, 1.04 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 201.6 mg, 1.04 mmol), DIPEA (309.6 mg, 2.4 mmol) and DMF (4 mL) were added in sequence and reacted at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and the mixture was diluted with EA and water, extracted with EA three times, the organic phases were combined, washed with saturated brine, the organic layers were collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Thin layer chromatography purification (DCM: CH3OH = 20:1, v / v) gave compound V-17 (61.2 mg, 24%) as a yellow liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.21 (s, 1H), 7.58 (dd, J = 1.8, 0.9 Hz, 1H),7.03 (t, J = 7.7 Hz, 1H), 6.61 (dd, J = 8.0, 5.2 Hz, 2H), 6.56 (ddd, J = 8.0, 2.5,1.0 Hz, 1H), 6.39 (dd, J = 3.1, 1.8 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 3.49 (s,2H), 3.43 (t, J = 5.1 Hz, 2H), 3.39 – 3.36 (m, 2H), 2.71 – 2.67 (m, 2H), 2.56 –2.51 (m, 2H), 2.29 (q, J = 4.6 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 170.3,157.4, 151.5, 142.9, 142.6, 129.4, 119.3, 115.5, 113.1, 110.6, 109.1, 53.9,52.4, 52.0, 45.0, 41.2, 34.0, 31.0. HRMS: m / z calcd for C 18 H 23 N2O3[M+H] + :315.1703; found: 315.1701.

[0088] Example 24: Preparation of 3-(3-hydroxyphenyl)-1-(4-(2-thienylmethyl)piperazinyl)-1-propanone (Compound V-18).

[0089] Referring to the synthesis method of Example 18, 4-ethylbenzaldehyde 57 was replaced by 2-thiophenecarboxaldehyde 60 to obtain compound V-18 (50 mg, 24%) as a brown oily liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 7.43 (dd, J = 4.7, 1.6 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.98 – 6.94 (m, 2H), 6.64 –6.59 (m, 2H), 6.56 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 3.67 (s, 2H), 3.46 – 3.37(m, 4H), 2.70 (t, J = 7.6 Hz, 2H), 2.54 (dd, J = 8.6, 6.8 Hz, 2H), 2.31 (dt, J =8.0, 5.0 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 169.9, 157.3, 142.8, 141.3,129.1, 126.6, 126.3, 125.6, 119.0, 115.3, 112.8, 56.1, 52.4, 52.0, 44.8,41.0, 33.9, 30.8. HRMS: m / z calcd for C 18 H23 N2O2S [M+H] + : 331.1475; found:331.1475.

[0090] Example 25: Preparation of 3-(3-hydroxyphenyl)-1-(4-(2-pyridylmethyl)piperazinyl)-1-propanone (Compound V-19).

[0091] Referring to the synthesis method of Example 17, 4-methylbenzyl chloride 56 was replaced by 2-chloromethylpyridine hydrochloride 61 to obtain compound V-19 (56 mg, 27%) as a yellow liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 8.48 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.43 (d, J = 7.8Hz, 1H), 7.30 – 7.23 (m, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.65 – 6.59 (m, 2H), 6.58 – 6.54 (m, 1H), 3.59 (s, 2H), 3.46 (t, J = 5.0 Hz, 2H), 3.40 (t, J = 5.0 Hz,2H), 2.70 (t, J = 7.7 Hz, 2H), 2.55 (dd, J = 8.6, 6.8 Hz, 2H), 2.34 (q, J = 4.5 Hz,4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.1, 158.1, 157.4, 148.9, 142.8, 136.7,129.3, 123.0, 122.4, 119.1, 115.4, 113.0, 63.6, 53.0, 52.6, 45.0, 41.2, 34.0,30.9. HRMS: m / z calcd for C 19 H 24 N3O2[M+H] +: 326.1863; found: 326.1867.

[0092] Example 26: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(3,5-dihydroxyphenyl)-1-propanone (Compound V-20).

[0093] .

[0094] 1-(4-Fluorobenzyl)piperazine 26 (194.2 mg, 1.0 mmol), 3,5-dimethoxyphenylpropionic acid 66 (252.3 mg, 1.2 mmol), 1-hydroxybenzotriazole (HOBT, 175.5 mg, 1.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 249.6 mg, 1.3 mmol), DIPEA (387 mg, 3.0 mmol) and DMF (4 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stirrer in sequence, and the reaction was carried out at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was diluted with EA and water, extracted with EA three times, the organic phases were combined, washed with saturated brine, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by thin layer chromatography (DCM:CH3OH = 20:1, v / v) gave an orange solid, Intermediate 68 (185.6 mg, 48%).

[0095] In a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 68 (193.24 mg, 0.5 mmol) and DCM (4 mL) were added. Under N2 protection, the mixture was stirred at -78 °C for 30 min, and then boron tribromide (0.94 ml, 10 mmol) was added. The mixture was then moved to room temperature for reaction and the reaction progress was monitored by TLC. Under ice bath conditions, the mixture was quenched with water, the pH was adjusted to 7 with saturated NaHCO3 solution, and EA was extracted three times. The organic phases were combined, washed with saturated brine, and the organic layers were collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Column chromatography purification (DCM: CH3OH = 20:1, v / v) gave compound V-20 (62 mg, 35%) as an orange solid with a melting point of 90.4-91.3 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.04 (s, 2H), 7.35 – 7.30 (m, 2H), 7.17 –7.11 (m, 2H), 6.04 (dd, J = 12.1, 2.2 Hz, 3H), 3.44 (s, 4H), 3.38 (t, J= 5.0 Hz,2H), 2.59 (dd, J = 8.8, 6.5 Hz, 2H), 2.50 – 2.47 (m, 2H), 2.30 – 2.23 (m, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.0, 162.3 (d, 1 J = 241.3 Hz), 158.3, 143.3,134.1 (d, 4 J = 3.8 Hz), 130.8 (d, 3 J = 7.5 Hz), 115.0 (d, 2 J = 20.0 Hz), 106.5,100.3, 61.0, 52.6, 52.2, 44.9, 41.1, 33.9, 31.0. HRMS: m / z calcd forC 20 H 24 FN2O3[M+H] + : 359.1765; found: 359.1764.

[0096] Example 27: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(2,5-dihydroxyphenyl)-1-propanone (Compound V-21).

[0097] Referring to the synthesis method of Example 26, 3,5-dimethoxyphenylpropionic acid 66 was replaced by 2,5-dimethoxyphenylpropionic acid 67 to obtain intermediate 69 (18%), and then the methyl group was removed to obtain compound V-21 (46 mg, 26%), an orange oily liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.62 (s, 1H), 8.54 (s, 1H), 7.33 (dd, J = 8.3, 5.6Hz, 2H), 7.14 (t, J = 8.7 Hz, 2H), 6.55 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 2.9 Hz,1H), 6.40 (dd, J= 8.5, 3.0 Hz, 1H), 3.48 – 3.36 (m, 6H), 2.63 (t, J = 7.6 Hz,2H), 2.49 (d, J = 2.0 Hz, 2H), 2.27 (s, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.4,162.3 (d, 1 J = 241.3 Hz), 149.8, 147.5, 134.0, 130.8 (d, 3 J = 8.8 Hz), 128.1,116.6, 115.6, 115.0 (d, 2 J = 21.3 Hz), 113.2, 60.9, 52.6, 52.2, 44.9, 41.0,32.8, 26.1. HRMS: m / z calcd for C 20 H 24 FN2O3[M+H] + : 359.1765; found: 359.1765.

[0098] Example 28: E Preparation of )-1-(4-(4-fluorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-22).

[0099] Referring to the synthesis method of Example 26, 3,5-dimethoxyphenylpropionic acid 66 was replaced by ( E )-2,4-dimethoxycinnamic acid 70 to obtain intermediate 71 (94%), which was then demethylated to obtain compound V-22 (20 mg, 11%) as a light green solid with a melting point of 108.2-108.6 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.88 (s, 1H), 9.68 (s, 1H),7.68 (d, J = 15.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.35 (dd, J= 8.6, 5.7 Hz,2H), 7.18 – 7.12 (m, 2H), 6.93 (d, J = 15.4 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H),6.24 (dd, J = 8.5, 2.4 Hz, 1H), 3.58 (d, J = 29.1 Hz, 4H), 3.48 (s, 2H), 2.35 (s, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.4, 162.3 (d, 1 J = 241.3 Hz), 160.0, 157.7,137.5, 134.1 (d, 4 J = 3.8 Hz), 130.8 (d, 3 J = 7.5 Hz), 129.5, 115.0 (d, 2 J = 20.0Hz), 113.6, 112.8, 107.4, 102.5, 60.9, 53.1, 52.3, 48.6, 41.7. HRMS: m / zcalcd for C 20 H 22 FN2O3[M+H] + : 357.1609; found: 357.1609.

[0100] Example 29: Preparation of 1-(4-(4-methylbenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-23).

[0101] .

[0102] Referring to the synthesis method of Example 16, 3-chlorobenzyl chloride 48 was replaced by 4-methylbenzyl chloride 56 to obtain intermediates 74 (82%) and 78 (98%), which were then reacted with 3-(2,4-dihydroxyphenyl)propionic acid 82 to obtain compound V-23 (22 mg, 23%), a yellow solid with a melting point of 86.7-87.5 °C. 1 H NMR (500 MHz, DMSO- d 6) δ 9.18 (s, 1H), 8.95 (s, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.79 (d, J = 8.1 Hz, 1H),6.24 (d, J = 2.4 Hz, 1H), 6.11 (dd, J = 8.1, 2.4 Hz, 1H), 3.44 – 3.41 (m, 2H), 3.40 (s, 2H), 3.38 (d, J = 5.3 Hz, 2H), 2.59 (dd, J = 9.1, 6.2 Hz, 2H), 2.44 (dd, J = 8.8, 6.6 Hz, 2H), 2.27 (s, 3H), 2.25 (q, J = 5.7 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.5, 156.6, 155.8, 136.0, 134.7, 130.3, 128.9, 128.8, 117.8,106.0, 102.5, 61.6, 52.7, 52.3, 44.9, 41.0, 33.2, 25.4, 20.7. HRMS: m / z calcdfor C 21 H 27 N2O3[M+H] + : 355.2016; found: 355.2016.

[0103] Example 30: E Preparation of )-1-(4-(4-methylbenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-24).

[0104] Referring to the synthesis method of Example 29, 3-(2,4-dihydroxyphenyl)propionic acid 82 was replaced by 2,4-dihydroxycinnamic acid 83 to obtain compound V-24 (44 mg, 45%) as a yellow solid with a melting point of 119.7-120.5 °C. 1 H NMR (500 MHz, DMSO- d 6) δ 9.86 (s, 1H), 9.66 (s, 1H), 7.68 (dd, J = 15.4, 1.6 Hz, 1H), 7.46(d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.7 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.92 (d, J =15.4 Hz, 1H), 6.33 (dd, J = 2.4, 1.4 Hz, 1H), 6.24 (dd, J = 8.5, 2.4 Hz, 1H),3.57 (d, J = 27.9 Hz, 4H), 3.44 (s, 2H), 2.34 (s, 4H), 2.28 (s, 3H). 13 C NMR (125MHz, DMSO- d 6 ) δ 165.3, 160.0, 157.7, 137.4, 136.0, 134.7, 129.4, 128.9,128.8, 113.6, 112.8, 107.4, 102.5, 61.6, 53.1, 52.4, 44.9, 41.6, 20.7. HRMS: m / z calcd for C 21 H 25 N2O3[M+H] + : 353.1860; found: 353.1860.

[0105] Example 31: Preparation of 1-(4-(4-methoxybenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-25).

[0106] 4-Methoxybenzaldehyde 58 (612.7 mg, 4.5 mmol), tert-butylpiperazine-1-carboxylate 47 (558.4 mg, 3.0 mmol), glacial acetic acid (270 mg, 4.5 mmol) and 1,2-dichloroethane (DCE, 6 mL) were added to a 50 mL round-bottom flask equipped with a magnetic stirrer in sequence, and reacted at room temperature. After two hours, sodium triacetoxyborohydride (635.8 mg, 3.0 mmol) was added, and sodium triacetoxyborohydride (635.8 mg, 3.0 mmol) was added again two hours later, and reacted at room temperature. The reaction progress was monitored by TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, neutralized with saturated NaHCO3 solution, extracted with DCM 3-4 times, and the organic layer was collected, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (DCM: CH3OH = 60:1, v / v) to obtain a white solid, namely intermediate 75 (890 mg, 97%).

[0107] To a 50 mL round-bottom flask equipped with a magnetic stirrer, intermediate 75 (890 mg, 2.9 mmol) and methanol (11 mL) were added in sequence, and hydrochloric acid 1,4-dioxane solution (9 mL) was added under ice bath conditions. After 10 min, the mixture was moved to room temperature for reaction, and the reaction progress was monitored by TLC. After the reaction was completed, the organic solvent and excess hydrochloric acid were removed by vacuum concentration, and the solid was washed with EA, filtered, and dried to obtain a white solid, namely intermediate 79, with a yield of 95%.

[0108] In a 50 mL round-bottom flask equipped with a magnetic stirrer, intermediate 79 (86.6 mg, 0.36 mmol), 3-(2,4-dihydroxyphenyl)propionic acid 82 (50 mg, 0.27 mmol), 1-hydroxybenzotriazole (HOBT, 73 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 105.6 mg, 0.54 mmol), DIPEA (143.5 mg, 1.1 mmol) and DMF (4 mL) were added in sequence and reacted at room temperature. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, diluted with EA and water, extracted with EA three times, the organic phases were combined, washed with saturated brine, the organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by thin layer chromatography (DCM:CH3OH =15:1, v / v) gave compound V-25 (36.5 mg, 36%) as a light yellow solid with a melting point of 96.7-97.4 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.19 (s, 1H),8.96 (s, 1H), 7.19 (d,J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.2Hz, 1H), 6.24 (d, J = 2.4 Hz, 1H), 6.11 (dd, J = 8.1, 2.4 Hz, 1H), 3.73 (s, 3H), 3.42 (s, 2H), 3.39 – 3.36 (m, 4H), 2.59 (dd, J = 8.9, 6.5 Hz, 2H), 2.47 – 2.42(m, 2H), 2.25 (q, J = 4.4 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.6, 158.3,156.6, 155.8, 130.3, 130.2, 129.6, 117.8, 113.6, 106.0, 102.5, 61.3, 55.0,52.6, 52.2, 44.9, 41.0, 33.2, 25.4. HRMS: m / z calcd for C 21 H 27 N2O4[M+H] + :371.1965; found: 371.1963.

[0109] Example 32: E Preparation of )-1-(4-(4-methoxybenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-26).

[0110] Referring to the synthesis method of Example 31, 3-(2,4-dihydroxyphenyl)propionic acid 82 was replaced by 2,4-dihydroxycinnamic acid 83 to obtain compound V-26 (68 mg, 67%) as a yellow solid with a melting point of 125.9-126.5 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.87 (s, 1H), 9.68 (s, 1H), 7.68 (d, J = 15.4 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.23 – 7.18 (m, 2H), 6.92 (d, J = 15.4 Hz, 1H), 6.88 (d, J = 8.6Hz, 2H), 6.33 (d, J = 2.4 Hz, 1H), 6.24 (dd, J = 8.5, 2.4 Hz, 1H), 3.73 (s, 3H), 3.56 (d, J = 22.7 Hz, 4H), 3.42 (s, 2H), 2.33 (s, 4H). 13 C NMR (125 MHz, DMSO- d 6 )δ 165.4, 160.0, 158.4, 157.8, 137.5, 130.2, 129.6, 129.5, 113.6, 113.6,112.8, 107.5, 102.5, 61.3, 55.0, 53.2, 52.3, 45.0, 41.6. HRMS: m / z calcd forC 21 H 25 N2O4[M+H] + : 369.1809; found: 369.1807.

[0111] Example 33: Preparation of 1-(4-(4-ethoxybenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-27).

[0112] Referring to the synthesis method of Example 31, 4-methoxybenzaldehyde 58 was replaced by 4-ethoxybenzaldehyde 73 to obtain intermediates 76 (94%) and 80 (85%), which were then reacted with 3-(2,4-dihydroxyphenyl)propionic acid 82 to obtain compound V-27 (35 mg, 34%), a yellow solid with a melting point of 124.5-125.2 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.18 (s,1H), 8.95 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.79 (d, J =8.2 Hz, 1H), 6.24 (d, J= 2.4 Hz, 1H), 6.11 (dd, J = 8.1, 2.4 Hz, 1H), 3.99 (q, J =7.0 Hz, 2H), 3.42 (s, 2H), 3.37 (s, 4H), 2.61 – 2.56 (m, 2H), 2.44 (t, J = 7.7Hz, 2H), 2.28 – 2.21 (m, 4H), 1.31 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.6, 157.7, 156.6, 155.8, 130.3, 130.2, 129.5, 117.8, 114.1, 106.1,102.5, 63.0, 61.3, 52.6, 52.3, 45.0, 41.0, 33.2, 25.4, 14.7. HRMS: m / z calcdfor C 22 H 29 N2O4[M+H] + : 385.2122; found: 385.2126.

[0113] Example 34: E Preparation of )-1-(4-(4-ethoxybenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-28).

[0114] Referring to the synthesis method of Example 33, 3-(2,4-dihydroxyphenyl)propionic acid 82 was replaced by 2,4-dihydroxycinnamic acid 83 to obtain compound V-28 (71 mg, 67%) as a yellow solid with a melting point of 118.7-119.2 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.77 (s, 2H), 7.68 (d, J = 15.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H),7.19 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 15.4 Hz, 1H), 6.86 (d, J= 8.5 Hz, 2H), 6.33(d, J = 2.4 Hz, 1H), 6.24 (dd, J = 8.5, 2.4 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.56(d, J = 26.4 Hz, 4H), 3.41 (s, 2H), 2.33 (s, 4H), 1.31 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.3, 160.0, 157.7, 157.6, 137.4, 130.2, 129.5, 129.4,114.0, 113.6, 112.8, 107.4, 102.5, 62.9, 61.3, 53.1, 52.3, 45.0, 33.6, 14.7.HRMS: m / z calcd for C 22 H 27 N2O4[M+H] + : 383.1965; found: 383.1969.

[0115] Example 35: Preparation of 1-(4-(3-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-29).

[0116] Referring to the synthesis method of Example 16, 3-hydroxyphenylpropionic acid 25 was replaced by 3-(2,4-dihydroxyphenyl)propionic acid 82 to obtain compound V-29 (52 mg, 42%) as a brown liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.19 (s,1H), 8.96 (s, 1H), 7.38 – 7.34 (m, 2H), 7.31 (dt, J = 8.2, 1.6 Hz, 1H), 7.27(dt, J = 7.4, 1.5 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 6.12(dd, J= 8.1, 2.4 Hz, 1H), 3.47 (s, 2H), 3.42 (dt, J = 19.9, 5.3 Hz, 4H), 2.60(dd, J = 9.1, 6.3 Hz, 2H), 2.45 (dd, J = 8.9, 6.6 Hz, 2H), 2.28 (q, J = 5.4 Hz,4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.6, 156.6, 155.8, 140.7, 133.0, 130.3,130.1, 128.5, 127.5, 127.0, 117.8, 106.0, 102.5, 61.0, 52.7, 52.3, 44.9,41.0, 33.2, 25.4. HRMS: m / z calcd for C 20 H 24 ClN2O3[M+H] + : 375.1470; found:375.1471.

[0117] Example 36: E Preparation of )-1-(4-(3-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-30).

[0118] Referring to the synthesis method of Example 16, 3-hydroxyphenylpropionic acid 25 was replaced by 2,4-dihydroxycinnamic acid 83 to obtain compound V-30 (49 mg, 26%) as a yellow solid with a melting point of 124.4-124.7 °C. 1 H NMR (500 MHz, DMSO- d 6 )δ 9.77 (d, J = 85.7 Hz, 2H), 7.68 (d, J = 15.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H),7.39 – 7.34 (m, 2H), 7.34 – 7.27 (m, 2H), 6.93 (d, J = 15.4 Hz, 1H), 6.34 (s,1H), 6.24 (d, J= 8.5 Hz, 1H), 3.59 (d, J = 27.9 Hz, 4H), 3.51 (s, 2H), 2.36 (s, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 165.8, 160.5, 158.2, 141.1, 138.0, 133.4,130.6, 129.9, 129.0, 128.0, 127.5, 114.1, 113.2, 107.9, 102.9, 61.5, 53.6,52.9, 49.1, 45.4. HRMS: m / z calcd for C 20 H 22 ClN2O3[M+H] + : 373.1313; found:373.1313.

[0119] Example 37: Preparation of 1-(4-(4-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-31).

[0120] Referring to the synthesis method of Example 16, 3-chlorobenzyl chloride 48 was replaced by 4-chlorobenzyl bromide 72 to obtain intermediates 77 (76%) and 81 (93%), which were then reacted with 3-(2,4-dihydroxyphenyl)propionic acid 82 to obtain compound V-31 (42 mg, 33%), a yellow liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.18 (d, J = 1.1 Hz, 1H), 8.96 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.2 Hz, 1H), 6.24 (d, J = 2.3Hz, 1H), 6.11 (dd, J = 8.1, 2.4 Hz, 1H), 3.44 (d, J = 9.6 Hz, 4H), 3.39 (d, J = 5.0Hz, 2H), 2.59 (dd, J= 9.0, 6.4 Hz, 2H), 2.45 (dd, J = 8.9, 6.6 Hz, 2H), 2.26 (q, J = 5.4 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 170.6, 156.6, 155.8, 137.0, 131.6,130.7, 130.3, 128.2, 117.8, 106.0, 102.5, 60.9, 52.7, 52.3, 44.9, 41.0, 33.2,25.4. HRMS: m / z calcd for C 20 H 24 ClN2O3[M+H] + : 375.1470; found: 375.1474.

[0121] Example 38: E Preparation of )-1-(4-(4-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-32).

[0122] Referring to the synthesis method of Example 37, 3-(2,4-dihydroxyphenyl)propionic acid 82 was replaced by 2,4-dihydroxycinnamic acid 83 to obtain compound V-32 (92 mg, 49%) as a yellow solid with a melting point of 156.8-157.0 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.87 (s, 1H), 9.67 (s, 1H), 7.68 (d, J = 15.4 Hz, 1H), 7.46 (d, J =8.6 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 15.4Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 6.24 (dd, J = 8.5, 2.4 Hz, 1H), 3.58 (d, J =28.6 Hz, 4H), 3.49 (s, 2H), 2.36 (d,J = 8.9 Hz, 4H). 13 C NMR (125 MHz, DMSO- d 6 )δ 165.4, 160.0, 157.8, 137.5, 137.0, 131.6, 130.7, 129.5, 128.2, 113.6,112.8, 107.5, 102.5, 60.9, 53.10, 52.4, 48.6, 45.0. HRMS: m / z calcd forC 20 H 22 ClN2O3[M+H] + : 373.1313; found: 373.1312. Example 39: Preparation of 1-(4-(4-cyanobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-33).

[0123] Referring to the synthesis method of Example 20, 3-hydroxybenzenepropionic acid 25 was replaced by 3-(2,4-dihydroxyphenyl)propionic acid 82 to obtain compound V-33 (46 mg, 46%) as a light yellow solid with a melting point of 98.0-98.6 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 9.19 (s, 1H), 8.96 (s, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.9Hz, 2H), 6.79 (d, J = 8.1 Hz, 1H), 6.24 (d, J = 2.4 Hz, 1H), 6.11 (dd, J = 8.1, 2.4Hz, 1H), 3.56 (s, 2H), 3.41 (dd, J = 14.3, 9.4 Hz, 4H), 2.59 (dd, J = 9.1, 6.3Hz, 2H), 2.45 (dd, J = 8.8, 6.6 Hz, 2H), 2.29 (s, 4H). 13 C NMR (125 MHz, DMSO- d 6)δ 170.6, 156.6, 155.8, 132.2, 130.3, 129.6, 118.9, 117.7, 109.8, 106.0,102.5, 93.2, 61.1, 52.7, 52.3, 44.9, 41.0, 33.2, 25.4. HRMS: m / z calcd forC 21 H 24 N3O3[M+H] + : 366.1812; found: 366.1813.

[0124] Example 40: E Preparation of )-1-(4-(4-cyanobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-34).

[0125] Referring to the synthesis method of Example 20, 3-hydroxyphenylpropionic acid 25 was replaced by 2,4-dihydroxycinnamic acid 83 to obtain compound V-34 (54 mg, 53%) as a yellow solid with a melting point of 129.9-130.3 °C. 1 H NMR (500 MHz, DMSO- d 6 )δ 9.88 (s, 1H), 9.68 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 15.4 Hz,1H), 7.54 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 15.5 Hz, 1H),6.33 (t, J = 1.9 Hz, 1H), 6.24 (dd, J = 8.8, 2.3 Hz, 1H), 3.62 (s, 2H), 3.59 (s,2H), 3.56 (s, 2H), 2.37 (s, 4H). 13 C NMR (125 MHz, DMSO- d 6) δ 165.4, 160.1,157.8, 144.2, 137.6, 132.2, 129.6, 129.5, 118.9, 113.6, 112.8, 109.8, 107.5,102.5, 61.2, 53.2, 52.5, 45.0, 41.6. HRMS: m / z calcd for C 21 H 22 N3O3[M+H] + :364.1656; found: 364.1656.

[0126] Pharmacological experimental data: 1. Mushroom tyrosinase inhibition experiment: Mushroom tyrosinase (EC 1.14.18.1) (T3824) from Sigma-Aldrich was used for the test, with kojic acid, α-arbutin, and β-arbutin as positive drugs. Stock solutions of the compounds and positive drugs (10 or 100 mM DMSO solution) were diluted with PBS (pH = 6.8) to obtain the desired concentrations to be tested (8 to 10 concentration gradients). Tyrosinase powder was dissolved in PBS to prepare 100 U / mL ( L -DOPA as substrate) and 300 U / mL ( L -tyrosine as substrate) solution. L -Dopa and L -Tyrosine) was prepared with PBS to 0.85 mM L -DOPA solution and 1 mM L -Tyrosine solution. Add 160 μL of compound and 20 μL of tyrosinase solution to a 96-well plate and incubate at 25 °C for 10 minutes. Then add 20 μL of substrate solution and incubate at 25 °C for 20 minutes. Finally, immediately measure the absorbance (OD) at a wavelength of 475 nm. PBS was used as a blank (Blank), and the mixture of tyrosinase and substrate was used as a control (Control). The inhibition rate was calculated using the following formula, IC 50 Values ​​were calculated using GraphPad Prism: .

[0127] Table 1 shows the IC values ​​of compounds I~VI 50 Table 2 shows the IC values ​​of compounds V-1~V-34 after structural modification based on the preferred compound V. 50 As shown in Table 1, the enzyme inhibition activity of most compounds exceeded that of the positive control drug α-arbutin ( L -DOPA: no inhibitory activity, L -Tyrosine: IC 50= 332.7 ± 26.2 μM) and β-arbutin ( L -Doba:IC 50 >800 μM, L -Tyrosine: IC 50 = 136.0 ± 12.2 μM), among which compound V showed the strongest inhibitory activity. L -Doba:IC 50 = 18.5 ± 2.4 μM, L -Tyrosine: IC 50 = 9.6 ± 1.1 μM) and even exceeded the inhibitory activity of the control drug kojic acid ( L -Doba:IC 50 = 36.5 ± 5.5 μM, L -Tyrosine: IC 50 = 18.8 ± 0.9 μM).

[0128] Therefore, based on the structure of the compound, R in the general formula (II) is further analyzed. 3 , R 4 , R 5 , L1 and L2 were structurally modified to obtain the modified compounds V-1~V-34, and the enzyme inhibitory activities of these compounds were further tested. As shown in Table 2, most compounds showed inhibitory activity superior to that of compound V, and their activity was significantly stronger than that of the positive control drugs arbutin and kojic acid. Among them, 13 compounds (V-22~V-34) even showed nanomolar IC 50 Compound V-24 showed the strongest inhibitory activity, with an IC 50 value( L -Doba:IC 50 = 0.018 ± 0.0007 μM, L -Tyrosine: IC 50 = 0.020 ± 0.001 μM) compared to compound V ( L -Doba:IC 50 = 41.8 ± 3.0 μM, L -Tyrosine: IC 50 = 11.9 ± 0.5 μM) was increased by more than 600-2300 times. Therefore, the compounds obtained in the present invention have excellent tyrosinase inhibitory activity as a whole, which is significantly stronger than the positive control drug.

[0129] Table 1

[0130] Table 2

[0131] Note: Due to the different purchase batches of tyrosinase, there may be slight differences in its activity. Therefore, there are slight differences in the inhibitory activities of kojic acid and compound V 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.

[0132] 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 tyrosinase inhibitor, characterized in that A compound having the following general formula (I) or (II) and / or a pharmaceutically acceptable salt thereof: （I）； (II); In formula (I) and (II): R 1 , R 2 , R 3 are independently substituted or unsubstituted aromatic groups; R 4 It is a nitrogen-containing heterocyclic ring or aliphatic amine; R 5 is hydrogen or one or more hydroxyl groups; L1 is empty, -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH=CHCH2- and the double bond end is connected to R 3 ; L2 is -CH2CH2-, -CH2CH2CH2- or -CH=CH-; X is -CH2-, -NH- or -O-; n and m are independently 0, 1, 2 or 3.

2. The tyrosinase inhibitor according to claim 1, characterized in that In formula (I) and (II): R 1 , R 2 , R 3 are independently substituted or unsubstituted benzene ring or aromatic heterocycle; R 4 is a five-, six- or seven-membered nitrogen-containing heterocyclic ring or an aliphatic amine; R 5 is hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2,3-dihydroxy, 2,4-dihydroxy, 2,5-dihydroxy, 2,6-dihydroxy, 3,4-dihydroxy or 3,5-dihydroxy; L1 is empty, -CH2-, -CH2CH2-, or -CH=CHCH2- and the double bond end is connected to R 3 ; L2 is -CH2CH2- or -CH=CH-; X is -NH- or -O-; n and m are independently 0, 1 or 2.

3. The tyrosinase inhibitor according to claim 1, characterized in that In formula (I) and (II): R 1 Select from the following structures: , , , ; R 2 Select from the following structures: , , ; R 3 Select from the following structures: , , , , , , , , , , , , , , ; R 4 Select from the following structures: , , , , ; R 5 is hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2,4-dihydroxy, 2,5-dihydroxy or 3,5-dihydroxy; L1 is empty, -CH2-, -CH2CH2-, or -CH=CHCH2- and the double bond end is connected to R 3 ; L2 is -CH2CH2- or -CH=CH-; X is -NH- or -O-; n is 0 or 2; m is 0 or 1.

4. The tyrosinase inhibitor according to claim 1, characterized in that The tyrosinase inhibitor is a compound I to VI, V-1 to V-34 and / or a pharmaceutically acceptable salt thereof having the following structure: 。 5. The method for preparing a tyrosinase inhibitor according to any one of claims 1 to 4, characterized in that: The tyrosinase inhibitor is a compound having the general formula (I), and the preparation method adopts the synthetic route (1) or (2): ； The preparation method specifically comprises: R 1 Substituted carboxylic acid 1 with R 2 The substituted amine 2 or alcohol 3 undergoes an amide condensation reaction or an esterification reaction to obtain a compound having the general formula (I); or, R 2 Containing one or more of primary amino group and secondary amino group, R 2 The substituted alcohol 3 was first reacted with (Boc)2O to obtain the Boc-protected alcohol intermediate 4, which was then reacted with R 1 The substituted carboxylic acid 1 undergoes an esterification reaction, and finally the Boc protecting group is removed to obtain a compound having the general formula (I).

6. The method for preparing a tyrosinase inhibitor according to any one of claims 1 to 4, characterized in that: The tyrosinase inhibitor is a compound having the general formula (II), and the preparation method adopts the synthetic route (1), (2) or (3): ； The preparation method specifically comprises: Compound 6 undergoes an amide condensation reaction with carboxylic acid 7 to obtain a compound having the general formula (II); or, Boc-protected amine 8 undergoes amide condensation reaction with carboxylic acid 7 to obtain intermediate 9, intermediate 9 is deprotected from Boc protecting group to obtain intermediate 10, intermediate 10 undergoes substitution reaction or reductive amination reaction with raw material 11 or 12 to obtain a compound having general formula (II); or, The Boc protected amine 8 undergoes a substitution reaction or a reductive amination reaction with the raw material 11 or 12 to obtain the intermediate 13. The intermediate 13 removes the Boc protecting group to obtain the compound 6. The compound 6 undergoes an amide condensation reaction with the carboxylic acid 7 to obtain a compound having the general formula (II).

7. Use of the tyrosinase inhibitor according to any one of claims 1 to 4 in the preparation of a product for inhibiting tyrosinase activity.

8. The use according to claim 7, characterized in that: The tyrosinase inhibitor is used for preparing medicines, cosmetics or fruit and vegetable preservatives.

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