Tyrosinase inhibitors, their preparation methods and applications

Abstract

The present invention discloses a tyrosinase inhibitor, a preparation method thereof, and an application thereof in the preparation of a product for inhibiting tyrosinase activity. Based on the protein structure of TYR, the present invention adopts a reasonable drug design and structure modification strategy, and discovers a TYR inhibitor with novel structure, higher efficacy and selectivity.

Description

Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and new drug research and development, and specifically relates to a class of novel small molecule tyrosinase inhibitors, their preparation methods and applications. Background Art

[0002] Melanin is a pigment naturally present in the human body and plays a crucial role in maintaining the color of the skin, hair, and eyes, as well as protecting against damage from ultraviolet rays and oxidative stress. However, excessive melanin can cause pigmentation disorders such as freckles, melasma, senile lentigines, solar lentigines, pigmented contact 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 and psychological distress, and even induce other diseases. With the improvement of people's living standards, the attention to skin pigmentation diseases is increasing day by day. Inhibiting melanin production and reducing pigmentation have become the key treatment methods for these diseases.

[0003] Research on the mechanism of melanin production has 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 the excessive deposition of melanin. TYR is a copper-containing oxidoreductase widely present in animals, plants, and microorganisms. It has dual catalytic activities for phenolic compounds, namely monophenolase activity (oxidizing monophenols to catechols) and diphenolase activity (oxidizing catechols to o-quinones), and o-quinones are further converted into melanin in vivo. In addition, research has shown that the overexpression of TYR is also closely related to the increase in neuromelanin content, enzymatic browning of fruits and vegetables, etc. Therefore, TYR inhibitors can not only be used to treat pigmentation diseases and neurodegenerative diseases but also as skin whitening agents in cosmetics and fruit and vegetable preservatives in food, which has attracted extensive attention and research in multiple fields such as biology, medicine, agronomy, and chemistry.

[0004] Currently, commonly used natural or synthetic TYR inhibitors on the market mainly include hydroquinone, kojic acid, α-arbutin, β-arbutin, L L-ascorbic acid, resveratrol, and some plant polyphenols. In addition, some prior arts have reported some tyrosinase inhibitors formed by changing the above components. For example, the patent specification with the publication number CN116478146A discloses a kojic acid-coumarin tyrosinase inhibitor, its preparation method and application, and the patent specification with the 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 a certain carcinogenic tendency, such as hydroquinone and kojic acid. Therefore, it is of great research significance to develop novel TYR inhibitors with higher efficiency, stronger inhibitory activity, and excellent physicochemical properties. Summary of the Invention

[0006] Based on the protein structure of TYR, the present invention adopted reasonable drug design and structure modification strategies, and discovered TYR inhibitors with novel structures, higher efficacy, and selectivity. The present invention also studied their preparation methods and pharmacological activities.

[0007] [1] A tyrosinase inhibitor, which is a compound having the following general formula (I) or (II) and / or a pharmaceutically acceptable salt thereof:

[0008] ;

[0009] ;

[0010] In formula (I) and (II):

[0011] R 1 、R 2 、R 3 Are each independently a substituted or unsubstituted aromatic group;

[0012] R 4 Is a nitrogen-containing heterocycle or a fatty amine;

[0013] R 5 Is hydrogen or one or more hydroxyl groups;

[0014] L 1 Is empty, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or, -CH = CHCH 2 - and the double bond end is connected to R 3 ;

[0015] L 2 Is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH = CH-;

[0016] X is -CH 2 -, -NH- or -O-;

[0017] n and m are each independently 0, 1, 2 or 3.

[0018] Furthermore, in formulas (I) and (II):

[0019] R 1 、R 2 、R 3 are each independently a substituted or unsubstituted benzene ring or heteroaromatic ring;

[0020] R 4 is a five-, six- or seven-membered nitrogen-containing heterocycle or aliphatic amine;

[0021] 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;

[0022] L 1 is empty, -CH 2 -, -CH 2 CH 2 -, or, -CH=CHCH 2 - and the double bond end is connected to R 3 ;

[0023] L 2 is -CH 2 CH 2 - or -CH=CH-;

[0024] X is -NH- or -O-;

[0025] n and m are each independently 0, 1 or 2.

[0026] Even further, in formulas (I) and (II):

[0027] R 1 is selected from the following structures: 、 、 、 ;

[0028] R 2 is selected from the following structures: 、 、 ;

[0029] R 3 is selected from the following structures: 、 、 、 、 、 、 、 、 , , , , , , ;

[0030] R 4 is selected from the following structures: , , , , ;

[0031] R 5 is hydrogen, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2,4-dihydroxy, 2,5-dihydroxy or 3,5-dihydroxy;

[0032] L 1 is empty, -CH 2 -, -CH 2 CH 2 -, or, -CH=CHCH 2 - and the double bond end is connected to R 3 ;

[0033] L 2 is -CH 2 CH 2 - or -CH=CH-;

[0034] X is -NH- or -O-;

[0035] n is 0 or 2;

[0036] m is 0 or 1.

[0037] In some preferred examples, the tyrosinase inhibitor is a compound I-VI, V-1-V-34 having the following structure and / or a pharmaceutically acceptable salt thereof:

[0038] .

[0039] [2] According to the preparation method of the tyrosinase inhibitor described in [1], the tyrosinase inhibitor is a compound having the general formula (I), and the preparation method uses synthetic route (1) or (2):

[0040] ;

[0041] The preparation method specifically includes:

[0042] R 1 substituted carboxylic acid 1 reacts with R 2 substituted amine 2 or alcohol 3 to undergo an amide condensation reaction or an esterification reaction to obtain a compound having the general formula (I); or,

[0043] R 2 Containing one or more of primary amino group and secondary amino group, R 2 The substituted alcohol 3 is first reacted with (Boc) 2 O (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).

[0044] [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):

[0045] ;

[0046] The preparation method specifically comprises:

[0047] Compound 6 undergoes an amide condensation reaction with carboxylic acid 7 to obtain a compound having the general formula (II); or,

[0048] 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,

[0049] 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).

[0050] [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.

[0051] 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

[0052] 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.

[0053] Example 1: N Preparation of (4-chlorobenzyl)quinoline-4-carboxamide (Compound I).

[0054] .

[0055] To a 50 mL round-bottom flask equipped with a magnetic stir bar, 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 added successively. The reaction was carried out 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 by suction, and dried to obtain Compound I (175 mg, 59%), 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 J = 6.0 Hz, 1H), 8.99 (d, J J = 4.3 Hz, 1H),8.11 (ddd, J J = 19.5, 8.5, 1.4 Hz, 2H), 7.81 (ddd, J J = 8.4, 6.8, 1.4 Hz, 1H), 7.66(ddd, J J = 8.3, 6.8, 1.3 Hz, 1H), 7.60 (d, J J = 4.3 Hz, 1H), 7.45 - 7.39 (m, 4H),4.55 (d, J 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 H14 ClN 2 O [M+H] + : 297.0789; found: 297.0790。

[0056] Example 2: Preparation of (4-(1-piperazinyl)phenyl)quinoline-3-carboxylate (Compound II).

[0057] 。

[0058] To a 50 mL round-bottom flask equipped with a magnetic stir bar were successively added 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). 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 mixture was washed with water twice and saturated brine twice. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification by thin-layer chromatography (DCM: CH 3 OH = 20:1, v / v) gave intermediate 17 (260 mg, 93%).

[0059] To a 50 mL round-bottom flask equipped with a magnetic stir bar were successively added 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). The reaction was carried out at room temperature for 12 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered, washed with water twice and saturated brine twice. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification by thin-layer chromatography (DCM: CH 3 OH = 100:1 three times, DCM: CH 3 OH = 50:1, v / v) gave intermediate 19 (84 mg, 34%).

[0060] To a 100 mL round-bottom flask equipped with a magnetic stir bar were successively added intermediate 19 (143 mg, 0.33 mmol) and methanol (3 mL). Hydrochloric acid 1,4-dioxane solution (1.5 mL) was added under ice bath, and the reaction was carried out at 0 °C for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the organic solvents and excess hydrochloric acid were removed by concentration under reduced pressure. Saturated NaHCO 3The solution was stirred until no more bubbles were produced, and then extracted twice with DCM. The organic phases were combined, washed twice with saturated brine, and the organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification by thin layer chromatography (DCM: CH 3 OH = 20:1 + ammonia water, v / v) gave compound II (70 mg, 64%), a white solid with a melting point of 176.4 - 177.2 °C. 1 1H NMR (500 MHz, DMSO- d 6 ) δ 9.43 (d, J J = 2.2 Hz, 1H), 9.20 (d, J J = 2.2 Hz, 1H), 8.27 (d, J J = 8.1 Hz, 1H), 8.15 (d, J J = 8.5 Hz, 1H), 7.96 (t, J J = 7.7Hz, 1H), 7.75 (t, J J = 7.5 Hz, 1H), 7.19 (d, J J = 8.7 Hz, 2H), 6.99 (d, J J = 9.0 Hz,2H), 3.05 (t, J J = 5.0 Hz, 4H), 2.84 (t, J J = 4.9 Hz, 4H). 13 13C 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 N 3 O 2 [M+H] + : 334.1550; found: 334.1553。

[0061] Example 3: Preparation of (4-(1-piperazinyl)phenyl) 2-hydroxyquinoline-4-carboxylate (Compound III).

[0062] 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%). Intermediate 21 (84 mg, 0.19 mmol) and methanol (2 mL) were successively added to a 100 mL round-bottom flask equipped with a magnetic stir bar. A solution of hydrochloric acid in 1,4-dioxane (0.85 mL) was added under an ice bath, and the reaction was carried out at 0 °C for 3 h while monitoring the reaction progress by TLC. After the reaction was completed, the organic solvent and excess hydrochloric acid were removed by concentration under reduced pressure. The solid was washed with EA, filtered, adjusted to the appropriate pH, filtered again, and dried to obtain Compound III (21 mg, 31%), a pale 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 N 3 O 3 [M+H] + : 350.1499; found:350.1494。

[0063] Example 4: Preparation of 3-(3-hydroxyphenyl)- N -(2-methylbenzyl)propanamide (Compound IV).

[0064] .

[0065] To a 100 mL round-bottom flask equipped with a magnetic stir bar, 3-(3-methoxyphenyl)propanoic acid 22 (356.80 mg, 1.98 mmol), (7-azabenzotriazol- 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 added successively. The mixture was stirred at 0 °C for 15 min, then 2-methylbenzylamine 23 (200 mg, 1.65 mmol) and N , N -diisopropylethylamine (DIPEA, 213.25 mg, 1.65 mmol) were added. The reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC plate. After the reaction was completed, the mixture was washed with water 2 - 3 times, the organic layer was collected, and anhydrous Na 2 SO 4 was used for drying, and then concentrated under reduced pressure. Purification by thin-layer chromatography (pure DCM) gave a yellowish-white solid, namely intermediate 24 (392 mg, 81%).

[0066] To a 100 mL round-bottom flask equipped with a magnetic stir bar, intermediate 24 (150 mg, 0.53 mmol) and DCM (5 mL) were added. The mixture was stirred at 0 °C for 5 min, and then BBr 3 (1327.7 mg, 5.3 mmol) was added dropwise to the reaction flask. The reaction was carried out at room temperature for 2 h, and the reaction progress was monitored by TLC plate. After the reaction was completed, ice water was added dropwise to the reaction solution until no gas was generated in the reaction flask, and a solid was precipitated. The solid was filtered, the filter cake was washed with water, and the filter cake was dried 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). 1313C 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 NO 2 [M+H] + :270.1489; found: 270.1487。

[0067] Example 5: Preparation of 1-(4-(4-fluorobenzyl)piperazin-1-yl)-3-(3-hydroxyphenyl)-1-propanone (Compound V).

[0068] 。

[0069] To a 50 mL round-bottom flask equipped with a magnetic stir bar were successively added 1-(4-fluorobenzyl)piperazine 26 (204 mg, 1.2 mmol), 3-hydroxyphenylpropanoic 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 N,N-diisopropylethylamine (DIPEA, 386 mg, 3.0 mmol) and DMF (5 mL). The reaction was carried out 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, and extracted with EA three times. The organic layers were combined, washed with saturated NaHCO 3 3, washed with saturated brine, the organic layer was collected, dried over anhydrous Na 2 2SO 4 4, and concentrated under reduced pressure. Purification by thin-layer chromatography (DCM: CH 3 3OH = 20:1, v / v) gave Compound V (213 mg, 62%), a white solid, with a melting point of 112.7 - 113.4 °C. 1 1H NMR (500 MHz, CDCl 3 ) δ 7.25 (dd, J 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 FN 2 O 2 [M+H] + : 343.1816; found: 343.1816。

[0070] Example 6: Preparation of (( E )-1-(4-(3-hydroxyphenyl)piperazinyl)-3-phenyl-2-propen-1-one (Compound VI).

[0071] .

[0072] To a 100 mL round-bottom flask equipped with a magnetic stir bar, cinnamic acid 27 (50 mg, 0.337 mmol), (7-azabenzotriazole)- N,N,N’,N’-O-(7-azabenzotriazol-1-yl)-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) were stirred at 0 °C for 15 min, then 3-(piperazin-1-yl)phenyl alcohol 28 (120.31 mg, 0.675 mmol) and N , N -Diisopropylethylamine (DIPEA, 43.6 mg, 0.34 mmol) were added, and the reaction was carried out at room temperature for 2 h. The reaction progress was monitored by TLC plate. After the reaction was completed, it was diluted with EA and water, extracted three times with EA, the organic layers were combined, washed with saturated brine, the organic layer was collected, dried over anhydrous Na 2 SO 4 4, and concentrated under reduced pressure. Purified by thin-layer chromatography (DCM: CH 3 3OH = 50:1, v / v) to obtain compound VI (120 mg, 39%), a yellowish-brown solid with a melting point of 72.1 - 73.0 °C. 1 1H NMR (500 MHz, DMSO- d 6 d6) δ 9.17 (s, 1H), 7.74 (d, J J = 7.3 Hz,2H), 7.52 (d, J J = 15.4 Hz, 1H), 7.40 (dd, J J = 10.9, 7.0 Hz, 3H), 7.31 (d, J J = 15.4Hz, 1H), 7.01 (t, J J = 5.0 Hz, 1H), 6.42 (d, J J = 5.9 Hz, 1H), 6.35 (d, J J = 2.4 Hz,1H), 6.25 (d, J J = 7.9 Hz, 1H), 3.84 (s, 2H), 3.71 (s, 2H), 3.12 (s, 4H). 13 13C 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 / z calcd for C 19 H 21 N 2 O 2 [M+H] + : 309.1598; found: 309.1598。

[0073] Example 7: Preparation of 1-(4-(2-fluorobenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-1).

[0074] 。

[0075] Referring to the synthesis method of Example 5, replace 1-(4-fluorobenzyl)piperazine 26 with 1-(2-fluorobenzyl)piperazine 29 to obtain Compound V-1 (136 mg, 40%), 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 FN 2 O 2 [M+H] + : 343.1816; found: 343.1821。

[0076] Example 8: Preparation of 1-(4-(3-fluorobenzyl)piperazin-1-yl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-2).

[0077] Referring to the synthesis method of Example 5, replace 1-(4-fluorobenzyl)piperazine 26 with 1-(3-fluorobenzyl)piperazine 30 to obtain Compound V-2 (65 mg, 23%), 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 FN 2 O 2 [M+H] + : 343.1816; found: 343.1821。

[0078] Example 9: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(2-hydroxyphenyl)-1-propanone (Compound V-3).

[0079] 。

[0080] Referring to the synthesis method of Example 5, 3-hydroxyphenylpropionic acid 25 was replaced with 2-hydroxyphenylpropionic acid 31 to obtain Compound V-3 (120 mg, 35%), 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 FN 2 O 2 [M+H] + : 343.1816; found: 343.1820。

[0081] Example 10: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(4-hydroxyphenyl)-1-propanone (Compound V-4).

[0082] Referring to the synthesis method of Example 5, replace 3-hydroxy-25 phenylpropionic acid with 4-hydroxy-32 phenylpropionic acid to obtain Compound V-4 (206 mg, 60%), a white liquid. 11H 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 13C 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 FN 2 O 2 [M+H] + : 343.1816; found: 343.1822。

[0083] Example 11: Preparation of ( E )-1-(4-(4-Fluorobenzyl)piperazinyl)-3-(3-hydroxyphenyl)-2-propen-1-one (Compound V-5).

[0084] Referring to the synthesis method of Example 5, replace 3-hydroxyphenylpropionic acid 25 with 3-hydroxyphenylacrylic acid 33 to obtain Compound V-5 (256 mg, 75%), a white solid with a melting point of 219.6 - 220.4 °C. 1 1H 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 FN 2 O 2 [M+H] + : 341.1660; found:341.1658。

[0085] Example 12: Preparation of 1-(4-(4-fluorobenzyl)-1,4-diazepanyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-6).

[0086] .

[0087] To a 50 mL round-bottom flask equipped with a magnetic stir bar, 4-fluorobenzyl chloride 34 (216.86 mg, 1.5 mmol), tert-butyl 1,4-diazepane-1-carboxylate 35 (200.28 mg, 1.0 mmol), potassium carbonate (276.42 mg, 2.0 mmol) and acetonitrile (CH 3 CN, 10 mL) were added successively. The reaction was carried out 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, and anhydrous Na 2 SO 4 dried, and concentrated under reduced pressure. Purification by column chromatography (DCM: CH 3 OH = 70:1, v / v) gave a colorless oily liquid, namely intermediate 36 (280.2 mg, 91%).

[0088] To a 100 mL round-bottom flask equipped with a magnetic stir bar, intermediate 36 (280.2 mg, 0.91 mmol) and methanol (4 mL) were added successively. Under ice bath conditions, 1,4-dioxane solution of hydrochloric acid (3 mL) was added. After 10 min, the reaction was transferred to room temperature 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. The solid was washed with EA, filtered and dried to obtain a white solid, namely intermediate 37 (98%).

[0089] To a 50 mL round-bottom flask equipped with a magnetic stir bar, intermediate 37 (200 mg, 0.71 mmol), 3-hydroxyphenylpropanoic 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 successively. The reaction was carried out at room temperature, 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 phases were combined, washed with saturated brine, the organic layer was collected, and anhydrous Na 2 SO 4 dried, and concentrated under reduced pressure. Purification by thin layer chromatography (DCM: CH 3 OH = 30:1, v / v) gave compound V-6 (89.2 mg, 35.3%), a yellow liquid. 1 1H 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 / z calcd for C 21 H 26 FN 2 O 2 [M+H] + : 357.1973; found: 357.1978。

[0090] Example 13: Preparation of 1-(5-(4-fluorobenzyl)hexahydropyrrolo[3,4- c pyrrolidin-2(1 H )-yl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-7).

[0091] Referring to the synthesis method of Example 12, replace tert-butyl 1,4-diazepane-1-carboxylate 35 with tert-butyl hexahydropyrrolo[3,4] c pyrrole-2(1 H )-carboxylate 38 to obtain intermediates 39 (55%) and 40 (95%). Subsequently, react with 3-hydroxyphenylpropionic acid 25 to obtain compound V-7 (116 mg, 81%), 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- d 6 ) 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 FN 2 O 2 [M+H] +: 369.1973; found: 369.1977。

[0092] Example 14: N Preparation of -(2-((4-fluorobenzyl)amino)propyl)-3-(3-hydroxyphenyl)propanamide (Compound V-8).

[0093] 。

[0094] To a 50 mL round-bottom flask equipped with a magnetic stir bar, add 3-hydroxyphenylpropionic acid 25 (365.33 mg, 2.2 mmol), N -tert-Butoxycarbonyl-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) in sequence. React at room temperature and monitor the reaction progress with a TLC plate. After the reaction is completed, concentrate under reduced pressure to remove the organic solvent, dilute with EA and water, extract with EA three times, combine the organic phases, wash with saturated brine, collect the organic layer, and dry with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. Purify by thin-layer chromatography (DCM: CH 3 OH = 20:1, v / v) to obtain a colorless oily liquid, i.e., intermediate 45 (456 mg, 74%).

[0095] To a 100 mL round-bottom flask equipped with a magnetic stir bar, add intermediate 45 (456 mg, 1.48 mmol) and methanol (6 mL) in sequence. Add 1,4-dioxane solution of hydrochloric acid (5 mL) under ice bath conditions, transfer to room temperature for reaction after 10 min, and monitor the reaction progress with TLC. After the reaction is completed, concentrate under reduced pressure to remove the organic solvent and excess hydrochloric acid. Wash the solid with EA, filter, and dry to obtain a colorless oily liquid, i.e., intermediate 46, with a yield of 96%.

[0096] To a 50 mL round-bottom flask equipped with a magnetic stir bar, add 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 (CH 3 CN, 5 mL) in sequence. React at room temperature and monitor the reaction progress with TLC. After the reaction is completed, concentrate under reduced pressure to remove the organic solvent, adjust the pH to 6 with dilute hydrochloric acid solution, and then use saturated NaHCO 3The solution was adjusted to pH 8, extracted three times with EA, the organic phases were combined, washed with saturated brine, the organic layer was collected, and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification by thin-layer chromatography (DCM: CH 3 OH = 20:1, v / v) gave compound V-8 (30 mg, 19%), an orange liquid. 1 1H NMR (500 MHz, DMSO- d 6 ) δ 9.23 (s, 1H), 7.76 (t, J 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 J = 8.0, 2.5, 1.1 Hz, 1H), 3.64 (s, 2H), 3.12 (q, J J=6.3 Hz, 2H), 2.69 (dd, J J = 8.7, 6.8 Hz, 2H), 2.50 – 2.47 (m, 2H), 2.31 (dd, J J=8.7, 6.9 Hz, 2H). 13 13C NMR (125 MHz, DMSO- d 6 ) δ 171.4, 162.0 (d, 1 J J = 240.0 Hz),157.3, 142.8, 136.8 (d, 4 J J = 2.5 Hz), 129.8 (d, 3 J J = 7.5 Hz), 129.1, 118.8,115.1, 114.8 (d, 2 J 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 FN 2 O 2 [M+H] + : 317.1660; found: 317.1663。

[0097] Example 15: N Preparation of -(3-((4-fluorobenzyl)amino)propyl)-3-(3-hydroxyphenyl)propanamide (Compound V-9).

[0098] Referring to the synthesis method of Example 12, replace tert-butyl 1,4-diazepane-1-carboxylate 35 with N -tert-butoxycarbonyl-1,3-propanediamine 41 to obtain intermediates 42 (53%) and 43 (95%), which were then reacted with 3-hydroxyphenylpropanoic acid 25 to obtain Compound V-9 (30 mg, 18%), a red liquid. 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.85 (t, J J = 5.7 Hz,1H), 7.42 – 7.35 (m, 2H), 7.16 – 7.11 (m, 2H), 7.04 (t, J J = 7.9 Hz, 1H), 6.61 –6.52 (m, 3H), 3.70 (s, 2H), 3.08 (q, J J = 6.5 Hz, 2H), 2.69 (dd, J J = 8.7, 6.8 Hz,2H), 2.50 – 2.46 (m, 2H), 2.30 (dd, J J = 8.8, 6.8 Hz, 2H), 1.55 (p, J J = 6.9 Hz,2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 171.4, 162.2 (d, 1 J J = 240.0 Hz), 157.3, 142.8,135.8, 130.3 (d, 3 J J = 7.5 Hz), 129.2, 118.8, 115.2, 115.0 (d, 2 J 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 FN 2 O 2[M+H] + : 331.1816; found: 331.1812。

[0099] Example 16: Preparation of 1-(4-(3-chlorobenzyl)piperazin-1-yl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-10).

[0100] 。

[0101] To a 50 mL round-bottom flask equipped with a magnetic stir bar, 3-chlorobenzyl chloride 48 (744.6 mg, 4 mmol), tert-butyl piperazine-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 (CH 3 CN, 6 mL) were added successively, and the reaction was carried out 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, and anhydrous Na 2 SO 4 was dried, and concentrated under reduced pressure. Purification by column chromatography (DCM: CH 3 OH = 50:1, v / v) gave a colorless oily liquid, namely intermediate 49 (843 mg, 68%).

[0102] To a 100 mL round-bottom flask equipped with a magnetic stir bar, intermediate 49 (843 mg, 2.7 mmol) and methanol (10 mL) were added successively, and a 1,4-dioxane solution of hydrochloric acid (8 mL) was added under ice bath. After 10 min, the reaction was transferred to room temperature, 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 give a white solid, namely intermediate 50 (98%).

[0103] To a 50 mL round-bottom flask equipped with a magnetic stir bar, intermediate 50 (153.87 mg, 0.66 mmol), 3-hydroxyphenylpropanoic 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 successively, and the reaction was carried out at room temperature, and 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, and anhydrous Na2 SO 4 Dry under reduced pressure and concentrate. Purify by thin layer chromatography (DCM: CH 3 OH = 15:1, v / v) to obtain compound V-10 (83 mg, 35%), a colorless transparent liquid. 1 1H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (d, J J = 1.6 Hz, 1H), 7.35(d, J J = 7.5 Hz, 2H), 7.31 (d, J J = 8.1 Hz, 1H), 7.26 (d, J J = 7.2 Hz, 1H), 7.04 (t, J J =7.7 Hz, 1H), 6.65 – 6.60 (m, 2H), 6.59 – 6.55 (m, 1H), 3.44 (d, J J = 5.0 Hz,2H), 3.39 (t, J J = 4.9 Hz, 2H), 3.35 (d, J J = 2.8 Hz, 2H), 2.70 (t, J J = 7.7 Hz, 2H),2.57 – 2.52 (m, 2H), 2.28 (h, J J = 4.7 Hz, 4H). 13 13C 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 ClN 2 O 2 [M+H] + : 359.1521; found: 359.1522。

[0104] Example 17: Preparation of 1-(4-(4-methylbenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-11).

[0105] .

[0106] To a 100 mL round-bottom flask equipped with a magnetic stir bar, 3-hydroxybenzenepropanoic acid 25 (558.78 mg, 3.0 mmol), tert-butyl piperazine-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 successively. The reaction was carried out at room temperature, and 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, and anhydrous Na 2 SO 4 dried and concentrated under reduced pressure. Purification by column chromatography (DCM: CH 3 OH = 50:1, v / v) gave a pale yellow liquid, namely intermediate 54 (926 mg, 92%).

[0107] To a 100 mL round-bottom flask equipped with a magnetic stir bar, intermediate 54 (926 mg, 2.8 mmol) and methanol (12 mL) were added successively. Under ice bath conditions, 1,4-dioxane solution of hydrochloric acid (10 mL) was added. After 10 min, the reaction was transferred to room temperature 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. The solid was washed with EA, filtered and dried to give a colorless oily liquid, namely intermediate 55 (98%).

[0108] To a 100 mL round-bottom flask equipped with a magnetic stir bar, 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 (CH 3 CN, 5 mL) were added successively. The reaction was carried out 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, and anhydrous Na 2 SO 4 dried and concentrated under reduced pressure. Purification by thin layer chromatography (DCM: CH 3 OH = 20:1, v / v) gave compound V-11 (157 mg, 73%), a gray solid with a melting point of 84.5 - 85.3 °C. 1 1H 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 N 2 O 2 [M+H] + : 339.2067; found:339.2067。

[0109] Example 18: Preparation of 1-(4-(4-ethylbenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-12).

[0110] Referring to the synthesis method of Example 17, into a 50 mL round-bottom flask equipped with a magnetic stir bar were successively added 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). The reaction was carried out at room temperature. After two hours, sodium triacetoxyborohydride (135.64 mg, 0.64 mmol) was added. After another two hours, sodium triacetoxyborohydride (135.64 mg, 0.64 mmol) was added again. The reaction was carried out at room temperature, and the reaction progress was monitored with a TLC plate. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, neutralized with saturated NaHCO 3 solution, extracted 3 - 4 times with EA, the organic layer was collected, and anhydrous Na 2 SO 4 was used for drying, and then concentrated under reduced pressure. Purification by thin-layer chromatography (DCM: CH 3 OH = 20:1, v / v) gave compound V-12 (63 mg, 28%), a colorless transparent oily liquid. 1 1H NMR (500 MHz, DMSO- d 6 ) δ 9.21 (s,1H), 7.19 (d, J J = 8.1 Hz, 2H), 7.15 (d, J J = 8.1 Hz, 2H), 7.03 (t, J J = 7.7 Hz, 1H),6.64 – 6.59 (m, 2H), 6.56 (ddd, J 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 J = 7.7 Hz, 2H), 2.60 – 2.52 (m,4H), 2.28 – 2.21 (m, 4H), 1.16 (t, J J = 7.6 Hz, 3H). 13 13C 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 N 2 O 2 [M+H] + : 353.2224; found: 353.2224。

[0111] Example 19: Preparation of 1-(4-(4-methoxybenzyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-13).

[0112] Referring to the synthesis method of Example 18, 4-ethylbenzaldehyde 57 was replaced with 4-methoxybenzaldehyde 58 to obtain Compound V-13 (163.9 mg, 72%), 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 N 2 O 3 [M+H] + : 355.2016; found: 355.2013。

[0113] Example 20: Preparation of 4-((4-(3-(3-hydroxyphenyl)propanoyl)piperazin-1-yl)methyl)benzonitrile (Compound V-14).

[0114] Referring to the synthesis method of Example 16, replacing 3-chlorobenzyl chloride 48 with 4-cyanobenzyl bromide 51, intermediates 52 (90%) and 53 (96%) were obtained, and then reacted with 3-hydroxyphenylpropionic acid 25 to obtain Compound V-14 (103 mg, 34%), 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 = 7.7 Hz, 2H), 2.55 (dd, J = 8.6, 6.8 Hz, 2H), 2.28 (q, J = 5.6 Hz, 4H). 13 C NMR (125 MHz, 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 N 3 O 2 [M+H] + : 350.1863; found: 350.1866。

[0115] Example 21:( E ) Preparation of -1-(4-(3-(4-fluorobenzyl)allyl)piperazinyl)-3-(3-hydroxyphenyl)-1-propanone (Compound V-15).

[0116] Referring to the synthesis method of Example 18, replace 4-ethylbenzaldehyde 57 with 4-fluorocinnamaldehyde 59 to obtain Compound V-15 (64.6 mg, 27%), 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 for C 22 H 26 FN 2 O 2 [M + H] + : 369.1973; found: 369.1973。

[0117] Example 22: Preparation of 3-(3-hydroxyphenyl)-1-(4-phenethylpiperazinyl)-1-propanone (Compound V-16).

[0118] 。

[0119] Referring to the synthesis method of Example 5, replace 1-(4-fluorobenzyl)piperazine 26 with 1-(1-phenylethyl)piperazine 62 to obtain Compound V-16 (220 mg, 65%), 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 = 7.7 Hz, 2H), 2.51 (d, J = 4.7 Hz, 1H), 2.50 – 2.48 (m, 1H), 2.39 – 2.32 (m, 4H). 13CNMR (125 MHz, DMSO- d 6 ) 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 N 2 O 2 [M+H] + : 339.2067; found: 339.2067。

[0120] Example 23: Preparation of 3-(3-hydroxyphenyl)-1-(4-(furan-2-ylmethyl)piperazin-1-yl)propan-1-one (Compound V-17).

[0121] 。

[0122] To a 50 mL round-bottom flask equipped with a magnetic stir bar, add furan-2-carbaldehyde 63 (288.2 mg, 3.0 mmol), tert-butyl piperazine-1-carboxylate 47 (372.5 mg, 2.0 mmol), glacial acetic acid (180 mg, 3.0 mmol) and 1,2-dichloroethane (DCE, 6 mL) in sequence, react at room temperature, add sodium triacetoxyborohydride (423.9 mg, 2.0 mmol) after two hours, add sodium triacetoxyborohydride (423.9 mg, 2.0 mmol) again after two hours, react at room temperature, and monitor the reaction progress with a TLC plate. After the reaction is completed, concentrate the organic solvent under reduced pressure, neutralize with saturated NaHCO 3 solution, extract with DCM 3-4 times, collect the organic layer, dry over anhydrous Na 2 SO 4 , concentrate under reduced pressure, and purify by column chromatography (DCM: CH 3 OH = 100:1, v / v) to obtain an orange liquid, which is intermediate 64 (216 mg, 41%).

[0123] To a 100 mL round-bottom flask equipped with a magnetic stir bar, intermediate 64 (216 mg, 0.8 mmol) and methanol (4 mL) were successively added. Under ice bath conditions, 1,4-dioxane solution of hydrochloric acid (2.5 mL) was added. After 10 min, the reaction was transferred to room temperature and monitored by TLC. After the reaction was completed, the organic solvents and excess hydrochloric acid were removed by concentration under reduced pressure. The solid was washed with EA, filtered, and dried to obtain a black solid, namely intermediate 65 (98%).

[0124] To a 50 mL round-bottom flask equipped with a magnetic stir bar, intermediate 65 (286 mg, 0.8 mmol), 3-hydroxybenzenepropanoic 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 successively added. The reaction was carried out at room temperature and monitored by TLC. After the reaction was completed, the organic solvents were 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, and anhydrous Na 2 SO 4 was dried and concentrated under reduced pressure. Purification by thin layer chromatography (DCM: CH 3 OH = 20:1, v / v) gave compound V-17 (61.2 mg, 24%), 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 N 2 O 3 [M+H] + :315.1703; found: 315.1701。

[0125] Example 24: Preparation of 3-(3-hydroxyphenyl)-1-(4-(2-thienylmethyl)piperazinyl)-1-propanone (Compound V-18).

[0126] Referring to the synthesis method of Example 18, replacing 4-ethylbenzaldehyde 57 with 2-thiophenecarboxaldehyde 60 gave Compound V-18 (50 mg, 24%), 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). 1313C 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 H 23 N 2 O 2 S [M+H] + : 331.1475; found:331.1475。

[0127] Example 25: Preparation of 3-(3-hydroxyphenyl)-1-(4-(2-pyridylmethyl)piperazinyl)-1-propanone (Compound V-19).

[0128] Referring to the synthesis method of Example 17, replacing 4-methylbenzyl chloride 56 with 2-chloromethylpyridine hydrochloride 61 gave Compound V-19 (56 mg, 27%), a yellow liquid. 1 1H NMR (500 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 8.48(ddd, J J = 4.9, 1.8, 0.9 Hz, 1H), 7.76 (td, J J = 7.7, 1.8 Hz, 1H), 7.43 (d, J J = 7.8Hz, 1H), 7.30 – 7.23 (m, 1H), 7.04 (t, J 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 J = 5.0 Hz, 2H), 3.40 (t, J J = 5.0 Hz,2H), 2.70 (t, J J = 7.7 Hz, 2H), 2.55 (dd, J J = 8.6, 6.8 Hz, 2H), 2.34 (q, J J = 4.5 Hz,4H). 13 13C 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 N 3 O 2 [M+H] + : 326.1863; found: 326.1867。

[0129] Example 26: Preparation of 1-(4-(4-fluorobenzyl)piperazinyl)-3-(3,5-dihydroxyphenyl)-1-propanone (Compound V-20).

[0130] 。

[0131] To a 50 mL round-bottom flask equipped with a magnetic stir bar were successively added 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). The reaction was carried out at room temperature and monitored by TLC. After completion of the reaction, 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, and anhydrous Na 2 SO 4 dried and concentrated under reduced pressure. Purification by thin-layer chromatography (DCM: CH 3 OH = 20:1, v / v) gave an orange solid, namely intermediate 68 (185.6 mg, 48%).

[0132] To a 100 mL round-bottom flask equipped with a magnetic stir bar was added intermediate 68 (193.24 mg, 0.5 mmol) and DCM (4 mL). Under N 2 protection, it was stirred at -78 °C for 30 min, then boron tribromide (0.94 ml, 10 mmol) was added, and then the reaction was transferred to room temperature and monitored by TLC. Under ice bath conditions, water was added to quench the reaction, and saturated NaHCO 3The solution was adjusted to pH 7, extracted three times with EA, the organic phases were combined, washed with saturated brine, the organic layer was collected, and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Purification by column chromatography (DCM: CH 3 OH = 20:1, v / v) afforded compound V-20 (62 mg, 35%), an orange solid, mp 90.4-91.3 °C. 1 1H 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 J = 12.1, 2.2 Hz, 3H), 3.44 (s, 4H), 3.38 (t, J J = 5.0 Hz,2H), 2.59 (dd, J J = 8.8, 6.5 Hz, 2H), 2.50 – 2.47 (m, 2H), 2.30 – 2.23 (m, 4H). 13 13C NMR (125 MHz, DMSO- d 6 ) δ 170.0, 162.3 (d, 1 J J = 241.3 Hz), 158.3, 143.3,134.1 (d, 4 J J = 3.8 Hz), 130.8 (d, 3 J J = 7.5 Hz), 115.0 (d, 2 J 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 FN 2 O 3 [M+H] + : 359.1765; found: 359.1764。

[0133] Example 27: Preparation of 1-(4-(4-fluorobenzyl)piperazin-1-yl)-3-(2,5-dihydroxyphenyl)propan-1-one (Compound V-21).

[0134] Referring to the synthesis method of Example 26, 3,5-dimethoxyphenylpropionic acid 66 was replaced with 2,5-dimethoxyphenylpropionic acid 67 to obtain intermediate 69 (18%). Subsequently, the methyl group was removed to obtain compound V-21 (46 mg, 26%), which is 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 FN 2 O 3 [M+H] + : 359.1765; found: 359.1765。

[0135] Example 28: ( E) Preparation of -1-(4-(4-fluorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-22).

[0136] Referring to the synthesis method of Example 26, replace 3,5-dimethoxyphenylpropionic acid 66 with ( E )-2,4-dimethoxycinnamic acid 70 to obtain intermediate 71 (94%). Subsequently, the methyl group was removed to obtain Compound V-22 (20 mg, 11%), a pale 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 = 20.0 Hz), 113.6, 112.8, 107.4, 102.5, 60.9, 53.1, 52.3, 48.6, 41.7. HRMS: m / z calcd for C 20 H 22 FN2 O 3 [M+H] + : 357.1609; found: 357.1609。

[0137] Example 29: Preparation of 1-(4-(4-methylbenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-23).

[0138] 。

[0139] Referring to the synthesis method of Example 16, replacing 3-chlorobenzyl chloride 48 with 4-methylbenzyl chloride 56 gave intermediates 74 (82%) and 78 (98%), which were then reacted with 3-(2,4-dihydroxyphenyl)propanoic 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 N 2 O 3 [M+H] + : 355.2016; found: 355.2016。

[0140] Example 30:( E ) Preparation of -1-(4-(4-methylbenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-24).

[0141] Referring to the synthesis method of Example 29, replace 3-(2,4-dihydroxyphenyl)propionic acid 82 with 2,4-dihydroxycinnamic acid 83 to obtain Compound V-24 (44 mg, 45%), 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 N 2 O 3 [M+H] + : 353.1860; found: 353.1860。

[0142] Example 31: Preparation of 1-(4-(4-Methoxybenzyl)piperazin-1-yl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-25).

[0143] To a 50 mL round-bottom flask equipped with a magnetic stir bar, 4-methoxybenzaldehyde 58 (612.7 mg, 4.5 mmol), tert-butyl piperazine-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 successively. The reaction was carried out at room temperature. After two hours, sodium triacetoxyborohydride (635.8 mg, 3.0 mmol) was added. After another two hours, sodium triacetoxyborohydride (635.8 mg, 3.0 mmol) was added again. The reaction was carried out 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 NaHCO 3 solution, extracted with DCM 3-4 times, the organic layer was collected, and anhydrous Na 2 SO 4 dried, concentrated under reduced pressure, and purified by column chromatography (DCM:CH 3 OH = 60:1, v / v) to obtain a white solid, namely Intermediate 75 (890 mg, 97%).

[0144] To a 50 mL round-bottom flask equipped with a magnetic stir bar, Intermediate 75 (890 mg, 2.9 mmol) and methanol (11 mL) were added successively. Under ice bath conditions, 1,4-dioxane solution of hydrochloric acid (9 mL) was added. After 10 min, the reaction was transferred to room temperature 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. The solid was washed with EA, filtered and dried to obtain a white solid, namely Intermediate 79, with a yield of 95%.

[0145] To a 50 mL round-bottom flask equipped with a magnetic stir bar, intermediate 79 (86.6 mg, 0.36 mmol), 3-(2,4-dihydroxyphenyl)propanoic 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 successively. The reaction was carried out at room temperature and monitored by TLC. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, diluted with EA and water, and extracted with EA three times. The organic phases were combined, washed with saturated brine, and the organic layer was collected. Anhydrous Na 2 SO 4 was dried and concentrated under reduced pressure. Purification by thin-layer chromatography (DCM: CH 3 OH = 15:1, v / v) gave compound V-25 (36.5 mg, 36%), a pale yellow solid, with a melting point of 96.7 - 97.4 °C. 1 1H NMR (500 MHz, DMSO- d 6 ) δ 9.19 (s, 1H), 8.96 (s, 1H), 7.19 (d, J J = 8.7 Hz, 2H), 6.87 (d, J J = 8.7 Hz, 2H), 6.79 (d, J J = 8.2 Hz, 1H), 6.24 (d, J J = 2.4 Hz, 1H), 6.11 (dd, J 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 J = 8.9, 6.5 Hz, 2H), 2.47 – 2.42 (m, 2H), 2.25 (q, J J = 4.4 Hz, 4H). 13 13C 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 N 2 O 4 [M+H] + : 371.1965; found: 371.1963。

[0146] Example 32: ( E ) Preparation of -1-(4-(4-methoxybenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-26).

[0147] Referring to the synthesis method of Example 31, replace 3-(2,4-dihydroxyphenyl)propionic acid 82 with 2,4-dihydroxycinnamic acid 83 to obtain Compound V-26 (68 mg, 67%), 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 for C 21 H 25 N 2 O 4 [M + H] + : 369.1809; found: 369.1807。

[0148] Example 33: Preparation of 1-(4-(4-Ethoxybenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-27).

[0149] Referring to the synthetic method of Example 31, 4-Methoxybenzaldehyde 58 was replaced with 4-Ethoxybenzaldehyde 73 to obtain intermediates 76 (94%) and 80 (85%), which were then reacted with 3-(2,4-Dihydroxyphenyl)propanoic 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 = 7.7 Hz, 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 N 2 O 4 [M+H] + : 385.2122; found: 385.2126。

[0150] Example 34:( E ) Preparation of -1-(4-(4-ethoxybenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-28).

[0151] Referring to the synthetic method of Example 33, replace 3-(2,4-dihydroxyphenyl)propionic acid 82 with 2,4-dihydroxycinnamic acid 83 to obtain Compound V-28 (71 mg, 67%), 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 N 2 O 4 [M+H] + : 383.1965; found: 383.1969。

[0152] Example 35: Preparation of 1-(4-(3-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-29).

[0153] Referring to the synthesis method of Example 16, replacing 3-hydroxyphenylpropionic acid 25 with 3-(2,4-dihydroxyphenyl)propionic acid 82 gave Compound V-29 (52 mg, 42%), 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 ClN 2 O 3 [M+H] + : 375.1470; found: 375.1471。

[0154] Example 36: ( E ) -1-(4-(3-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-30) preparation.

[0155] Referring to the synthesis method of Example 16, replacing 3-hydroxycinnamic acid 25 with 2,4-dihydroxycinnamic acid 83, Compound V-30 (49 mg, 26%) was obtained, 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 ClN 2 O 3 [M+H] + : 373.1313; found:373.1313。

[0156] Example 37: Preparation of 1-(4-(4-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-31).

[0157] Referring to the synthetic method of Example 16, replacing 3-chlorobenzyl chloride 48 with 4-chlorobenzyl bromide 72 gave intermediates 77 (76%) and 81 (93%), which were then reacted with 3-(2,4-dihydroxyphenyl)propanoic acid 82 to give 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- d6 ) 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 ClN 2 O 3 [M+H] + : 375.1470; found: 375.1474。

[0158] Example 38: ( E ) Preparation of -1-(4-(4-chlorobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-32).

[0159] Referring to the synthesis method of Example 37, replace 3-(2,4-dihydroxyphenyl)propionic acid 82 with 2,4-dihydroxycinnamic acid 83 to obtain Compound V-32 (92 mg, 49%), 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 ClN 2 O 3 [M+H] + : 373.1313; found: 373.1312.

[0160] Example 39: Preparation of 1-(4-(4-cyanobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-1-propanone (Compound V-33).

[0161] Referring to the synthesis method of Example 20, replacing 3-hydroxybenzenepropanoic acid 25 with 3-(2,4-dihydroxyphenyl)propanoic acid 82 gave Compound V-33 (46 mg, 46%), a pale 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 for C 21 H 24 N 3 O 3 [M + H] + : 366.1812; found: 366.1813。

[0162] Example 40: ( E ) Preparation of -1-(4-(4-cyanobenzyl)piperazinyl)-3-(2,4-dihydroxyphenyl)-2-propen-1-one (Compound V-34).

[0163] Referring to the synthesis method of Example 20, replacing 3-hydroxyphenylpropionic acid 25 with 2,4-dihydroxycinnamic acid 83, Compound V-34 (54 mg, 53%) was obtained, 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 N 3 O 3 [M + H] + : 364.1656; found: 364.1656。

[0164] Pharmacological experiment data:

[0165] 1. Mushroom tyrosinase inhibition experiment:

[0166] The mushroom tyrosinase (EC 1.14.18.1) (T3824) provided by Sigma - Aldrich was used for testing, with kojic acid, α - arbutin, and β - arbutin as positive drugs. The stock solutions (10 or 100 mM DMSO solutions) of the compound and positive drugs were diluted with PBS (pH = 6.8) to obtain the required test concentrations (8 to 10 concentration gradients). The tyrosinase powder was dissolved in PBS to prepare solutions of 100 U / mL ( L - dopa as substrate) and 300 U / mL ( L - tyrosine as substrate). The substrates ( L - dopa and L - tyrosine) were prepared with PBS into 0.85 mM L - dopa solution and 1 mM L - tyrosine solution. 160 μL of the compound and 20 μL of the tyrosinase solution were added to a 96 - well plate and incubated at 25 °C for 10 minutes. Then 20 μL of the substrate solution was added and incubated at 25 °C for 20 minutes. Finally, the absorbance (OD) was immediately measured at a wavelength of 475 nm. PBS was used as the blank, and the mixture of tyrosinase and substrate was used as the control. The inhibition rate was calculated using the following formula, and the IC 50 value was calculated using GraphPad Prism: 。

[0167] Table 1 shows the IC 50 values of Compounds I - VI, and Table 2 shows the IC 50 values of Compounds V - 1 to V - 34 modified based on the structure of the preferred compound V. As can be seen from 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 arbutin ( L - Dopa: IC 50 >800 μM, L - Tyrosine: IC 50 = 136.0 ± 12.2 μM), among which Compound V showed the strongest inhibitory activity, and its inhibitory activity ( L - Dopa: IC 50 = 18.5 ± 2.4 μM, L - Tyrosine: IC 50 = 9.6 ± 1.1 μM) even exceeded the inhibitory activity of the positive control drug kojic acid ( L - Dopa: IC 50 = 36.5 ± 5.5 μM, L - Tyrosine: IC 50 = 18.8 ± 0.9 μM).

[0168] Therefore, based on the structure of this compound, further structural modifications were made to the R 3 , R 4 , R 5 , L 1 and L 2 parts in its general structural formula (II) to obtain the modified Compounds V-1 to V-34, and the enzyme inhibitory activities of these compounds were further tested. As can be seen from Table 2, most of the compounds showed better inhibitory activity than Compound V, and the activity was significantly stronger than that of the positive control drugs arbutin and kojic acid. Among them, 13 compounds (V-22 to V-34) even showed nanomolar IC 50 values. Compound V-24 showed the strongest inhibitory activity, and its IC 50 value ( L - Dopa: IC 50 = 0.018 ± 0.0007 μM, L - Tyrosine: IC 50 = 0.020 ±0.001 μM) was increased by more than 600 - 2300 times compared with Compound V ( L - Dopa: IC 50 = 41.8 ± 3.0 μM, L - Tyrosine: IC 50 = 11.9 ± 0.5μM). Therefore, the compounds obtained in the present invention generally have excellent tyrosinase inhibitory activity, which is significantly stronger than that of the positive control drugs.

[0169] Table 1

[0170]

[0171] Table 2

[0172]

[0173] Note: Due to 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 strengths between compounds; Table 1 is for tests of the same batch; Table 2 is for tests of the same batch.

[0174] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A tyrosinase inhibitor, characterized in that A compound having the following general formula (II) and / or a pharmaceutically acceptable salt thereof: (II); In formula (II): R 3 Select from the following structures: , , , , , , , , , , , ; R 4 for ; R 5 It is 2,4-dihydroxy; 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-.

2. The tyrosinase inhibitor according to claim 1, characterized in that The tyrosinase inhibitor is a compound V-22 to V-34 having the following structure and / or a pharmaceutically acceptable salt thereof: 。 3. The method for preparing a tyrosinase inhibitor according to claim 1 or 2, 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).

4. Use of the tyrosinase inhibitor according to claim 1 or 2 in the preparation of a product for inhibiting tyrosinase activity.

5. The use according to claim 4, characterized in that: The tyrosinase inhibitor is used for preparing medicines, cosmetics or fruit and vegetable preservatives.

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