A kind of aziridine-pyridone derivative and its preparation method and application

Abstract

The present invention discloses an aziridine-pyridone derivative and a preparation method and application thereof. The present invention provides a class of compounds with a new structure, which, while retaining the MAO-B inhibitory activity and iron ion chelating activity, greatly improves the selectivity for MAO-B, and also significantly improves the antioxidant activity and has extremely high blood-brain barrier permeability. The compounds are a class of lead compounds with great drug development potential.

Description

Technical Field

[0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, and specifically to a class of aziridine-pyridone derivatives that can not only target monoamine oxidase B overexpression and iron ion overload in the brain, but also have high selective inhibitory activity and antioxidant activity, thereby achieving multi-target anti-Alzheimer's disease, as well as a preparation method and the use of pharmaceutically acceptable salts thereof in drugs for preventing or treating Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease that occurs frequently in the elderly. As its pathogenic mechanism is still unclear, no effective therapeutic drugs have been developed so far. However, a large number of studies have shown that overexpression of monoamine oxidase B (MAO-B) and iron ions occurs in the brains of AD patients. This phenomenon causes significant oxidative stress in the brains of patients, thereby exacerbating the progression of AD. MAO-B, as a subtype of monoamine oxidase (MAOs) in the human body, is closely related to the pathogenesis of AD. However, its other subtype, monoamine oxidase A (MAO-A), is mostly expressed in the peripheral system and has no significant connection with AD. However, the two enzymes have 70% sequence similarity. Non-selective MAOs inhibitors can cause severe gastrointestinal reactions and even induce hypertensive crises. Therefore, the degree of selective inhibition has become one of the important criteria for measuring the success of a class of MAO-B inhibitors.

[0003] Designing small molecules that can target MAO-B overexpression and iron overload in the brain has been one of the hot topics in recent years. This group of projects also designed small molecule drugs that can target these two targets in 2020 (CN112521331B), but in subsequent studies, it was found that this type of inhibitor, like most reported inhibitors, has poor selective inhibitory activity and weak antioxidant activity. Therefore, based on this mother core, how to perform a second round of structural modification to overcome the above problems has become a technical difficulty to be faced in the future. Summary of the invention

[0004] In order to solve the above problems, the present invention compares the active cavities of MAO-A and MAO-B and carefully analyzes the specific position of the original skeleton in the cavity. It is believed that the reasonable extension of the length of the mother core may be the key to improving the selectivity. Subsequently, the characteristics of the currently marketed inhibitor (safinamide) are combined. Through a series of means such as skeleton transition and computer-aided drug design, a class of aziridine-pyridone derivatives with high selective inhibitory activity, high iron ion chelating activity and strong antioxidant activity are designed and synthesized. A preparation method of aziridine-pyridone derivatives and their usable salts is provided, and AD is prevented or treated by inhibiting MAO-B activity.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] The present invention provides an aziridine-pyridone derivative and a pharmaceutically acceptable salt thereof as shown in formula (I):

[0007]

[0008] Wherein, in formula (I),

[0009] n1 is the number of CH2, n1 is 1 or 2;

[0010] R 1 is a C1-C6 straight or branched alkyl group;

[0011] R 2 , R 3 Each is independently H, halogen, nitro, C1-C5 haloalkyl or C1-C5 straight-chain or branched-chain alkyl.

[0012] Preferably, in formula (I), R 1 CH3; R 2 or R 3 Each is independently H, F, Cl, nitro, CH3 or CF3; n1=1 or 2.

[0013] Specifically, the aziridine-pyridone derivative represented by formula (I) is one of the following compounds:

[0014]

[0015] In a second aspect, the present invention provides the use of the aziridine-pyridone derivatives represented by formula (I) or their pharmaceutically acceptable salts in the preparation of drugs for treating or preventing Alzheimer's disease.

[0016] Preferably, the aziridine-pyridone derivative represented by formula (I) is a6, a10, c4, c6, c7, and compound a10 is particularly preferred.

[0017] In a third aspect, the present invention provides a method for preparing the aziridine-pyridone derivatives represented by formula (I) or their pharmaceutically acceptable salts.

[0018] 1. When n1 is 1, the method comprises the following steps:

[0019] (1) dissolving the intermediate of formula 1 in an organic solvent A, adding alkaline substance A and compound of formula 2 in sequence, stirring and reacting at 40° C. for 4-8 hours, and subjecting the obtained reaction solution A to post-treatment A to obtain the intermediate of formula 3; the molar ratio of the intermediate of formula 1, compound of formula 2 and alkaline substance is 1:0.5-1.5:1-2 (preferably 1:0.9:1.5); the alkaline substance A is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide and triethylamine (preferably potassium carbonate);

[0020]

[0021] (2) dissolving the intermediate of formula 3 obtained in step (1) in an organic solvent B, adding a compound of formula 4 and anhydrous magnesium sulfate, stirring at 30° C. for 20-40 min, then adding a reducing agent A, and continuing the reaction at 30° C. for 4.5 h under a nitrogen atmosphere. The resulting reaction solution B is subjected to post-treatment B to obtain an intermediate of formula 5; the molar ratio of the intermediate of formula 3, the compound of formula 4, anhydrous magnesium sulfate and the reducing agent A is 1:1-1.5:1-3:1-3 (preferably 1:1.2:2:2); the reducing agent A is sodium borohydride, aluminum oxide, stannous chloride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, palladium / carbon catalyst (preferably sodium triacetoxyborohydride);

[0022]

[0023] (3) dissolving the intermediate of formula 5 obtained in step (2) in an organic solvent C, adding an alkaline substance B and a compound of formula 6, stirring and reacting at 50° C. for 4-6 hours, and subjecting the obtained reaction solution C to post-treatment C to obtain a compound of formula 7; the molar ratio of the intermediate of formula 5, the alkaline substance B and the compound of formula 6 is 1:1-2:1-2 (preferably 1:1.5:1.5); the alkaline substance B is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide and triethylamine (preferably potassium carbonate);

[0024]

[0025] (4) The compound of formula 7 described in step (3) is dissolved in an organic solvent D, and 6M hydrochloric acid is added, and the reaction is carried out at 60° C. for 1-3 hours. The obtained reaction solution D is subjected to post-treatment D to obtain the aziridine-pyridone derivative shown in formula 8.

[0026]

[0027] R in formula 6-8 2 -R 3The range of R in Formula 1, Formula 3, Formula 5, Formula 7 and Formula 8 is the same as above. 1 The scope is the same as above.

[0028] Furthermore, the organic solvent A described in step (1) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably N,N-dimethylformamide (DMF).

[0029] Furthermore, the volume of the organic solvent A in step (1) is 3 to 5 mL / mmol based on the amount of the intermediate of formula 1.

[0030] Furthermore, the post-treatment A in step (1) is as follows: adding water to the reaction solution A, extracting with dichloromethane (DCM), combining the organic phases, drying over anhydrous sodium sulfate, then distilling off the solvent under reduced pressure, performing column chromatography separation using a mixed solution of dichloromethane, methanol and triethylamine in a volume ratio of 20:1:0.1 as an eluent, collecting the eluate containing the target intermediate, and concentrating to obtain the intermediate of formula 3.

[0031] Furthermore, the organic solvent B described in step (2) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably dichloromethane (DCM).

[0032] Furthermore, the volume of the organic solvent B in step (2) is 8 to 12 mL / mmol based on the amount of the intermediate of formula 3.

[0033] Furthermore, the post-treatment B in step (2) is: adding dichloromethane to the reaction solution B, and extracting with a saturated sodium bicarbonate aqueous solution, drying the extracted organic phase with anhydrous sodium sulfate, then distilling under reduced pressure to remove the solvent, and performing column chromatography separation using a mixed solution of dichloromethane and methanol in a volume ratio of 25:1 as an eluent, collecting the eluate containing the target intermediate, and concentrating to obtain the intermediate of formula 5.

[0034] Furthermore, the organic solvent C described in step (3) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably acetonitrile.

[0035] Furthermore, the volume of the organic solvent C in step (3) is 8 to 12 mL / mmol based on the amount of the intermediate of formula 5.

[0036] Furthermore, the post-treatment C in step (3) is: the reaction solution C is distilled under reduced pressure to remove the solvent, and column chromatography is performed using a mixed solution of dichloromethane and methanol in a volume ratio of 25:1 as an eluent, and the eluate containing the target intermediate is collected and concentrated to obtain the intermediate of formula 7.

[0037] Furthermore, the organic solvent D in step (4) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably methanol.

[0038] Furthermore, the volume of the organic solvent D in step (4) is 18-22 mL / mmol based on the amount of the intermediate of formula 7.

[0039] Furthermore, in step (4), the volume of the 6M hydrochloric acid is 2 to 4 mL / mmol based on the amount of the compound represented by formula 7.

[0040] Furthermore, the post-treatment D in step (4) is: the reaction solution D is subjected to reduced pressure distillation to remove the solvent, slurried with a mixed solution of methanol and ether in a volume ratio of 10:1, filtered, and the obtained filter cake A is dried to obtain the aziridine-pyridone derivative shown in formula 8.

[0041] 2. When n1 is 2, the method comprises the following steps:

[0042] (a) dissolving the intermediate of formula 3 in an organic solvent E, adding the intermediate of formula 9 and anhydrous magnesium sulfate in sequence, stirring at 30° C. for 20-40 min, adding a reducing agent B, and continuing the reaction at 30° C. for 4.5 h under a nitrogen atmosphere. The resulting reaction solution E is subjected to post-treatment E to obtain an intermediate of formula 10; the molar ratio of the intermediate of formula 3, the intermediate of formula 9, anhydrous magnesium sulfate and the reducing agent B is 1:1-1.5:1-3:1-3 (preferably 1:1.2:2:2); the reducing agent B is sodium borohydride, aluminum oxide, stannous chloride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, palladium / carbon catalyst (preferably sodium triacetoxyborohydride);

[0043]

[0044] (b) dissolving the compound of formula 10 described in step (a) in an organic solvent F, adding a 6M aqueous hydrochloric acid solution, and reacting at 60° C. for 1-3 hours. The resulting reaction solution F is subjected to post-treatment F to obtain an aziridine-pyridone derivative represented by formula 11.

[0045]

[0046] R in formula 9-11 2 -R3 The ranges of are the same as above; R in Formula 3, Formula 10 and Formula 11 1 All the same as above.

[0047] Further, the organic solvent E in step (a) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably dichloromethane (DCM).

[0048] Furthermore, the volume of the organic solvent E in step (a) is 8-12 mL / mmol based on the amount of the intermediate of formula 3.

[0049] Furthermore, the post-treatment E in step (a) is: adding dichloromethane to the reaction solution E, and extracting with a saturated sodium bicarbonate aqueous solution, drying the extracted organic phase with anhydrous sodium sulfate, then distilling under reduced pressure to remove the solvent, and performing column chromatography separation with a mixed solution of dichloromethane and methanol in a volume ratio of 30:1 as an eluent, collecting the eluate containing the target intermediate, and concentrating to obtain an intermediate of formula 10.

[0050] Further, the organic solvent F in step (b) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably methanol.

[0051] Furthermore, the volume of the organic solvent F in step (b) is 18-22 mL / mmol based on the amount of the intermediate of formula 10.

[0052] Furthermore, in step (b), the volume of the 6M hydrochloric acid is 2 to 4 mL / mmol based on the amount of the compound represented by formula 10.

[0053] Furthermore, the post-treatment F in step (b) is: the reaction solution F is distilled under reduced pressure to remove the solvent, slurried with a mixed solution of methanol and ether in a volume ratio of 10:1, filtered, and the obtained filter cake B is dried to obtain the aziridine-pyridone derivative shown in formula 11.

[0054] The present invention also provides a method for preparing the intermediate represented by Formula 1:

[0055] S1: dissolving the compound represented by formula 12 in an organic solvent G, adding the compound represented by formula 13 and an alkaline substance C, reacting at 80° C. for 4 h, and subjecting the obtained reaction solution G to post-treatment to obtain an intermediate represented by formula 14; the molar ratio of the compound represented by formula 12, the compound represented by formula 13 and the alkaline substance C is 1:1-1.5:1-2 (preferably 1:1.3:1.5); the alkaline substance C is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide and triethylamine (preferably potassium carbonate);

[0056]

[0057] S2: dissolving the compound of formula 14 obtained in step S1 in a mixed solvent H, adding alkaline substance D and ethylenediamine (EDA) in sequence, reacting at 80°C for 1h, and subjecting the obtained reaction solution H to post-treatment to obtain an intermediate of formula 1; the molar ratio of the compound of formula 14, alkaline substance D and ethylenediamine is 1:1-2:1-1.5 (preferably 1:1.5:1.2); the alkaline substance D is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide and triethylamine (preferably sodium hydroxide); R in formula 12 and formula 14 1 All the same as above.

[0058] Further, the organic solvent G described in step S1 is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably N,N-dimethylformamide (DMF).

[0059] Furthermore, the volume of the organic solvent G in step S1 is 1 to 2 mL / mmol based on the amount of the intermediate of formula 12.

[0060] Furthermore, the post-treatment G in step S1 is: adding water, extracting with dichloromethane (DCM), combining the organic phases, drying over anhydrous sodium sulfate, and then distilling off the solvent under reduced pressure to obtain an intermediate of formula 14.

[0061] Further, the mixed solvent H described in step S2 is a mixed solvent of water and an organic solvent H, and the organic solvent H is one or a mixture of two or more of N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably a mixed solvent of water and ethanol in a volume ratio of 1:1.

[0062] Furthermore, the volume of the mixed solvent H in step S2 is 1 to 5 mL / mmol based on the amount of the intermediate of formula 14.

[0063] Furthermore, the post-treatment H in step S2 is: removing the solvent by distillation under reduced pressure, performing column chromatography separation using a mixed solution of dichloromethane, methanol and triethylamine in a volume ratio of 20:1:0.1 as an eluent, collecting the eluate containing the target intermediate, and concentrating it to obtain the intermediate of formula 1.

[0064] Further, more specifically, the intermediate of formula 9 of the present invention is prepared as follows:

[0065] (i) dissolving the compound of formula 15 in an organic solvent I, then adding an alkaline substance E and a compound of formula 16, reacting at 50° C. for 5 h, and subjecting the obtained reaction solution I to post-treatment I to obtain an intermediate of formula 17; the molar ratio of the compound of formula 15, the alkaline substance E and the compound of formula 16 is 1:1-2:1-1.5 (preferably 1:1.5:1.3); the alkaline substance E is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide and triethylamine (preferably potassium carbonate);

[0066]

[0067] (ii) dissolving the compound of formula 17 obtained in step (i) in an organic solvent J, then adding Dess-Martin reagent (DMP), stirring at -10°C for 10 min under nitrogen protection, then moving to room temperature and continuing stirring for 2 h, and the obtained reaction solution J is post-treated to obtain an intermediate of formula 9; the molar ratio of the compound of formula 17 to the Dess-Martin reagent is 1:1-2 (preferably 1:1.8);

[0068] In formula 16 and 17, R 2 -R 3 The scope is the same as above.

[0069] Further, the organic solvent I in step (i) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably acetonitrile.

[0070] Furthermore, the volume of the organic solvent I in step (i) is 2 to 6 mL / mmol based on the amount of the intermediate of formula 15.

[0071] Furthermore, the post-treatment I in step (i) is: removing the solvent by distillation under reduced pressure, performing column chromatography separation using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 5:2 as an eluent, collecting the eluate containing the target intermediate, and concentrating it to obtain an intermediate of formula 17.

[0072] Furthermore, the organic solvent J in step (ii) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably dichloromethane.

[0073] Furthermore, the volume of the organic solvent J in step (ii) is 18-22 mL / mmol based on the amount of the intermediate of formula 17.

[0074] Furthermore, the post-treatment J in step (ii) is: adding dichloromethane, extracting with a mixed solution of saturated sodium thiosulfate and saturated sodium bicarbonate in a volume ratio of 1:1, drying the extracted organic layer with anhydrous sodium sulfate, and concentrating to obtain the intermediate of formula 9.

[0075] The above letters are used to distinguish different reaction stages or substances in different stages for the convenience of description and have no other special meanings.

[0076] Compared with the prior art, the beneficial effects of the present invention are as follows: the novel structural compound provided by the present invention, while retaining the MAO-B inhibitory activity and iron ion chelating activity, greatly improves the selectivity for MAO-B, and the antioxidant activity is also significantly improved, and the blood-brain barrier permeability is also extremely high, which is a class of lead compounds with great drug development potential. DETAILED DESCRIPTION

[0077] Example 1: Preparation of a1

[0078] Maltol (63.000 g, 500 mmol), DMF (750 mL), p-methoxybenzyl chloride (102.050 g, 650 mmol) and potassium carbonate (103.500 g, 750 mmol) were added to a single-necked bottle, and the mixture was reacted at 80 °C for 4 h. The reaction progress was monitored by TLC spot plate. After the reaction, water (750 mL) was added, and the mixture was extracted with 100 mL × 10 DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure to obtain 2-methyl-3-p-methoxybenzylpyran-4-one (118.080 g) with a yield of 96%.

[0079] The raw material obtained in the above reaction (93.480 g, 380 mmol) was added to a round-bottom flask and dissolved in a mixed solvent of ethanol (300 mL) and water (300 mL). Sodium hydroxide (22.800 g, 570 mmol) and ethylenediamine (27.360 g, 456 mmol) were added in sequence. The mixture was reacted at 80°C for 1 h. After the reaction, the solvent was removed by distillation under reduced pressure. The mixture was separated by column chromatography (DCM: methanol: triethylamine v / v / v = 20:1:0.1). The eluate containing the target intermediate was collected and concentrated to obtain 60.192 g of a brown oily intermediate with a yield of 55%.

[0080] In a round-bottom flask, the brown oily liquid obtained in the above reaction (57.600 g, 200 mmol), potassium carbonate (41.400 g, 300 mmol), DMF (800 mL), and 3-bromopropyne (21.420 g, 180 mmol) were added to the mixture, and the mixture was reacted at 40°C for 6 h. Water (800 mL) was added to the reaction mixture, and the mixture was extracted with 400 mL×4 DCM. The organic phases were combined and dried over anhydrous sodium sulfate. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (DCM: methanol: triethylamine v / v / v = 20:1:0.1). The eluate containing the target intermediate was collected and concentrated to obtain 35.860 g of a yellow oily intermediate with a yield of 55%.

[0081] The yellow oily liquid (17.930 g, 55 mmol), DCM (550 mL), p-hydroxybenzaldehyde (8.052 g, 66 mmol), and anhydrous magnesium sulfate (13.200 g, 110 mmol) were added to a round-bottom flask. After being stirred at 30 ° C for 30 min, sodium triacetoxyborohydride (23.320, 110 mmol) was added. The reaction was continued at 30 ° C for 4.5 h under a nitrogen atmosphere. The reaction process was detected by TLC spot plate. After the reaction was completed, dichloromethane (550 mL) was added for dilution, and extracted with 200 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The eluate containing the target intermediate was collected and concentrated to obtain 13.781 g of a colorless oily intermediate with a yield of 58%.

[0082] The colorless oily intermediate (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and benzyl bromide (0.256 g, 1.5 mmol) obtained above were added to a round-bottom flask, and the mixture was reacted at 50°C for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure, and the mixture was separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.418 g of a light yellow oily intermediate with a yield of 80%.

[0083] The above-obtained light yellow intermediate (0.418 g, 0.8 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 ° C for 2 h. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether with a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a1 (0.293 g) with a yield of 91%. 1HNMR(400MHz, CDCl3)δ7.47–7.41(m,2H),7.38(ddd,J=7.5,6.7,1.4Hz,2H), 7.35–7.29(m,1H),7.18(d,J=7.2Hz,1H),7.12–7.06(m,2H),6.91–6.85(m,2H ),6.38(d,J=7.2Hz,1H),5.05(s,2H),3.86(t,J=6.4Hz,2H),3.57(s,2H),3.3 8(d,J=2.4Hz,2H),2.81(t,J=6.4Hz,2H),2.29(t,J=2.4Hz,1H),2.23(s,3H). 13 C NMR (101MHz, CDCl3) δ169.6,158.4,146.2,137.6,137.1,130.2,129.9,128.7,12 8.0,128.0,127.6,115.0,110.9,78.2,73.9,70.1,58.5,52.3,52.1,42.8,11.8.

[0084] Example 2: Preparation of a2

[0085] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 2-chlorobenzyl bromide (0.307 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.418 g of a light yellow oily intermediate with a yield of 75%.

[0086] The above-obtained light yellow intermediate (0.418 g, 0.75 mmol), methanol (14 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a2 (0.301 g) with a yield of 92%. 1H NMR (400MHz, CDCl3) δ7.55 (dd, J=7.1, 2.3Hz, 1H), 7.39 (dd, J=7.3, 2.0Hz, 1H) ,7.32–7.26(m,2H),7.17(d,J=7.2Hz,1H),7.14–7.08(m,2H),6.94–6.84(m,2 H),6.37(d,J=7.1Hz,1H),5.15(s,2H),3.85(t,J=6.4Hz,2H),3.58(s,2H),3. 37(d,J=2.4Hz,2H),2.81(t,J=6.4Hz,2H),2.28(d,J=2.4Hz,1H),2.23(s,3H). 13 C NMR (100MHz, CDCl3) δ169.7,158.2,146.3,137.7,134.8,132.8,130.3,130.2,129.5,12 9.1,129.0,127.8,127.1,115.0,110.9,78.2,73.9,67.3,58.5,52.4,52.2,42.8,11.9.

[0087] Example 3: Preparation of a3

[0088] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 3-chlorobenzyl bromide (0.307 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.423 g of a light yellow oily intermediate with a yield of 76%.

[0089] The above-obtained light yellow intermediate (0.423 g, 0.76 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.3 mL) were added to a round-bottom flask and reacted at 60 ° C for 2 h. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether with a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid a3 (0.319 g) with a yield of 96%. 1H NMR (400MHz, CDCl3) δ7.44(d,J=1.9Hz,1H),7.30(qd,J=4.5,1.4Hz,3H),7.15(d,J=7.2Hz,1H),7.12–7.06(m,2H),6.88–6.83(m,2H),6.35(d,J =7.1Hz,1H),5.02(s,2H),3.85(t,J=6.4Hz,2H),3.57(s,2H),3.38(d,J=2.4Hz,2H),2.80(t,J=6.4Hz,2H),2.29(t,J=2.4Hz,1H),2.22(s,3H). 13 C NMR (100MHz, CDCl3) δ169.8,158.2,146.4,139.3,137.6,134.6,130.3,130.3,130.0,12 8.2,127.8,127.6,125.5,115.0,110.9,78.2,73.9,69.3,58.5,52.3,52.2,42.8,11.9.

[0090] Example 4: Preparation of a4

[0091] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 4-chlorobenzyl bromide (0.307 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.446 g of a light yellow oily intermediate with a yield of 80%.

[0092] The above-obtained light yellow intermediate (0.446 g, 0.8 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 ° C for 2 h. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether with a volume ratio of 10:1. The mixture was filtered with suction and the filter cake was collected and dried to obtain a white solid a4 (0.332 g) with a yield of 95%. 1HNMR (400MHz, CDCl3) δ7.39–7.31(m,4H),7.15(d,J=7.2Hz,1H),7.10–7.04(m,2H),6.86–6.81(m,2H),6.35(d,J=7.0Hz,1H),5. 00(s,2H),3.84(t,J=6.4Hz,2H),3.56(s,2H),3.38(d,J=2.4Hz,2H),2.79(t,J=6.4Hz,2H),2.28(t,J=2.4Hz,1H),2.20(s,3H). 13 CNMR (100MHz, CDCl3) δ169.7,158.2,146.3,137.7,135.7,133.8,130.3,130.1,1 28.9,128.8,128.0,114.9,110.9,78.2,73.9,69.4,58.5,52.2,52.1,42.8,11.8.

[0093] Example 5: Preparation of a5

[0094] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 2-fluorobenzyl bromide (0.283 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.411 g of a light yellow oily intermediate with a yield of 76%.

[0095] The above-obtained light yellow intermediate (0.411 g, 0.76 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.3 mL) were added to a round-bottom flask and reacted at 60 ° C for 2 h. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction and the filter cake was collected and dried to obtain a white solid a5 (0.287 g) with a yield of 90%. 1H NMR(400MHz, CDCl3)δ7.50(td,J=7.5,1.8Hz,1H),7.31(tdd,J=7.4,5.3,1.8Hz,1H),7.21–7.13(m,2H),7.13–7.04(m,3H),6.92–6.86(m,2H),6.39 (d,J=6.9Hz,1H),5.12(s,2H),3.87(t,J=6.4Hz,2H),3.58(s,2H),3.37(d ,J=2.4Hz,2H),2.81(t,J=6.4Hz,2H),2.29(t,J=2.4Hz,1H),2.23(s,3H). 13 C NMR (100MHz, CDCl3) δ169.6,160.6(d, 1 J C-F =246Hz),158.2,146.2,137.6,130.3,130.1,129.9,129.8(d, 3 J C-F =12Hz),128.0,124.4(d, 3 J C-F =4Hz),124.2(d, 2 J C-F =14Hz),115.4(d, 2 J C-F =21Hz),114.9,110.9,78.1,73.9,63.9(d, 3 J C-F =4Hz),58.5,52.4,52.2,42.8,11.9.

[0096] Example 6: Preparation of a6

[0097] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 3-fluorobenzyl bromide (0.283 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.444 g of a light yellow oily intermediate with a yield of 82%.

[0098] The light yellow intermediate (0.444 g, 0.82 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.5 mL) obtained above were added to a round-bottom flask and reacted at 60 ° C for 2 h. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether with a volume ratio of 10:1. The mixture was filtered with suction and the filter cake was collected and dried to obtain a white solid a6 (0.320 g) with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ7.36(td,J=7.9,5.8Hz,1H),7.25–7.15(m,3H),7.11(d,J=8.2Hz,2H),7.02(td,J=8.4,2.5Hz,1H),6.88(d,J=8.3Hz,2H),6.40 (d,J=6.7Hz,1H),5.07(s,2H),3.88(t,J=6.4Hz,2H),3.59(s,2H),3.41(d ,J=2.4Hz,2H),2.83(t,J=6.4Hz,2H),2.31(d,J=2.4Hz,1H),2.24(s,3H). 13 C NMR(101MHz,CDCl3)δ169.5,163.1(d, 1 J C-F =245Hz),158.2,146.2,139.8(d, 3 J C-F =7Hz),137.7,130.3,130.2,130.2,128.1,122.8(d, 4 J C-F =2Hz),115.0,114.8,114.3(d, 2 J C-F =21Hz),110.9,78.2,73.9,69.3,69.3,58.5,52.2,42.8,11.9.

[0099] Example 7: Preparation of a7

[0100] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 4-fluorobenzyl bromide (0.283 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.438 g of a light yellow oily intermediate with a yield of 81%.

[0101] The above-obtained light yellow intermediate (0.438 g, 0.81 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a7 (0.320 g) with a yield of 94%. 1 H NMR(400MHz,Chloroform-d)δ7.44–7.37(m,2H),7.18(d,J=6.9Hz,1H),7.06(t,J=8.7Hz,4H),6.88–6.82(m,2H),6.39(d,J=6.7Hz,1 H),5.00(s,2H),3.87(t,J=6.4Hz,2H),3.57(s,2H),3.39(d,J=2.4Hz,2H),2.80(t,J=6.4Hz,2H),2.29(t,J=2.4Hz,1H),2.22(s,3H). 13 C NMR(101MHz,CDCl3)δ169.6,162.6(d, 1 J C-F =245Hz),158.2,146.2,137.7,132.9(d, 4 J C-F =3Hz),130.3,130.1,129.5(d, 3 J C-F =8Hz),128.1,115.6(d, 2 J C-F =21Hz),114.9,110.9,78.2,73.9,69.5,60.5,58.5,52.2,42.8,11.9.

[0102] Example 8: Preparation of a8

[0103] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 2-methylbenzyl bromide (0.277 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.403 g of a light yellow oily intermediate with a yield of 75%.

[0104] The above-obtained light yellow intermediate (0.403 g, 0.75 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.2 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a8 (0.287 g) with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ7.44–7.37(m,1H),7.29–7.15(m,4H),7.11(d,J=8.2Hz,2H),6.90(d,J=8.2Hz,2H),6.38(d,J=5.9Hz,1H),5. 02(s,2H),3.86(s,2H),3.58(s,2H),3.38(d,J=2.0Hz,2H),2.82(d,J=5.2Hz,2H),2.38(s,3H),2.29(d,J=2.0Hz,1H),2.23(s,3H). 13 C NMR (100MHz, CDCl3) δ169.7,158.6,146.4,137.6,136.9,134.9,130.5,130.3,129.9,128. 8,128.4,128.1,126.1,114.9,110.9,78.2,73.9,68.8,58.5,52.4,52.2,42.8,19.0,11.9.

[0105] Example 9: Preparation of a9

[0106] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 3-methylbenzyl bromide (0.277 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.413 g of a light yellow oily intermediate with a yield of 77%.

[0107] The above-obtained light yellow intermediate (0.413 g, 0.77 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.3 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a9 (0.291 g) with a yield of 91%. 1H NMR (400MHz, CDCl3) δ7.28(d,J=7.4Hz,1H),7.26–7.07(m,6H),6.92–6.85(m,2H),6.38(d,J=6.6Hz,1H),5.01(s,2H),3.85( t,J=6.4Hz,2H),3.57(s,2H),3.37(d,J=2.4Hz,2H),2.81(t,J=6.4Hz,2H),2.37(s,3H),2.29(d,J=2.4Hz,1H),2.23(s,3H). 13 CNMR (100MHz, CDCl3) δ169.6,158.6,146.3,138.4,137.7,137.0,130.3,129.9,128.9,128. 6,128.4,128.0,124.7,115.0,110.9,78.2,73.9,70.3,58.5,52.4,52.2,42.8,21.5,11.9.

[0108] Example 10: Preparation of a10

[0109] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 4-methylbenzyl bromide (0.277 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.419 g of a light yellow oily intermediate with a yield of 78%.

[0110] The above-obtained light yellow intermediate (0.419 g, 0.78 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a10 (0.302 g) with a yield of 93%. 1H NMR (400MHz, CDCl3) δ7.32(d,J=7.9Hz,2H),7.22–7.15(m,3H),7.12–7.06(m,2H),6.90–6.84(m,2H),6.39(d,J=7.0Hz,1H),5.00(s,2 H),3.86(t,J=6.4Hz,2H),3.57(s,2H),3.37(d,J=2.4Hz,2H),2.81(t,J=6.4Hz,2H),2.35(s,3H),2.28(t,J=2.4Hz,1H),2.23(s,3H). 13 C NMR (100MHz, CDCl3) δ169.4,158.6,146.2,137.9,137.7,134.1,130.3,129.8,129. 4,128.4,127.7,115.0,111.0,78.2,73.9,70.1,58.5,52.4,52.3,42.8,21.3,11.9.

[0111] Example 11: Preparation of a11

[0112] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 2-nitrobenzyl bromide (0.324 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.449 g of a light yellow oily intermediate with a yield of 79%.

[0113] The above-obtained light yellow intermediate (0.449 g, 0.79 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a11 (0.332 g) with a yield of 94%. 1H NMR (400MHz, CDCl3) δ8.15(d,J=7.9Hz,1H),7.88(d,J=7.4Hz,1H),7.68(t,J=7.3Hz,1H),7.49(t,J=7.6Hz,1H),7.25–7.15(m,1H),7.11(d,J =7.8Hz,2H),6.89(d,J=7.8Hz,2H),6.38(s,1H),5.47(s,2H),3.88(s, 2H),3.58(s,2H),3.38(s,2H),2.81(s,2H),2.29(s,1H),2.23(s,3H). 1 13 C NMR (100MHz, CDCl3) δ169.4,158.0,157.9,147.2,146.2,137.7,134.1,133.9,130.6,130.4 ,128.9,128.5,128.3,125.1,115.1,111.0,78.1,74.0,67.1,58.5,52.3,42.8,29.8,11.9.

[0114] Example 12: Preparation of a12

[0115] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 3-nitrobenzyl bromide (0.324 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.426 g of a light yellow oily intermediate with a yield of 75%.

[0116] The light yellow intermediate (0.426 g, 0.75 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.2 mL) obtained above were added to a round-bottom flask and reacted at 60 ° C for 2 h. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether with a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid a12 (0.318 g) with a yield of 95%. 1H NMR (400MHz, CDCl3) δ8.29 (d, J=2.1Hz, 1H), 8.16 (dd, J=8.0, 2.2Hz, 1H), 7.78 (d,J=7.2Hz,1H),7.55(t,J=7.7Hz,1H),7.16(s,1H),7.06(d,J=7.9Hz,2H),6 .85(d,J=8.0Hz,2H),6.35(d,J=5.4Hz,1H),5.13(s,2H),3.86(s,2H),3.56(s ,2H),3.49(d,J=2.0Hz,2H),2.79(t,J=4.6Hz,2H),2.29(s,1H),2.19(s,3H). 13 C NMR (100MHz, CDCl3) δ169.6,157.8,148.6,146.2,139.4,137.7,133.3,130.6,130.4,12 9.7,128.3,122.9,122.2,114.9,110.9,78.2,73.9,68.8,58.5,52.2,52.0,42.8,11.8.

[0117] Example 13: Preparation of a13

[0118] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 4-nitrobenzyl bromide (0.324 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.454 g of a light yellow oily intermediate with a yield of 80%.

[0119] The above-obtained light yellow intermediate (0.454 g, 0.80 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 ° C for 2 h. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether with a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid a13 (0.329 g) with a yield of 92%. 1H NMR (400MHz, CDCl3) δ8.22(d,J=7.9Hz,2H),7.61(d,J=8.1Hz,2H),7.15(d,J=6.3Hz,1H),7.05(d,J=7.9Hz,2H),6.83(d,J=8.1Hz,2H),6.38–6 .31(m,1H),5.15(s,2H),3.86(t,J=5.6Hz,2H),3.56(s,2H),3.40(d,J=2.0Hz,2H),2.79(t,J=4.8Hz,2H),2.29(d,J=2.0Hz,1H),2.19(s,3H). 13 C NMR (100MHz, CDCl3) δ169.8,157.8,147.7,146.3,144.7,137.8,130.6,130.4,12 8.1,127.8,123.9,114.9,110.9,78.2,73.9,68.8,58.5,52.1,52.0,42.8,11.8.

[0120] Example 14: Preparation of a14

[0121] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 2,5-difluorobenzyl bromide (0.310 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.453 g of a light yellow oily intermediate with a yield of 81%.

[0122] The above-obtained light yellow intermediate (0.453 g, 0.81 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid a14 (0.330 g) with a yield of 93%. 1H NMR (400MHz, CDCl3) δ7.25–7.16(m,2H),7.10(d,J=7.9Hz,2H),7.03(td,J=8.9,4.2Hz,1H),6.97(dq,J=8.7,4.6,4.0Hz,1H),6 .87(d,J=7.9Hz,2H),6.38(s,1H),5.08(s,2H),3.87(s,2H),3.57(s,2H),3.37(s,2H),2.81(s,2H),2.28(s,1H),2.22(s,3H). 13 C NMR(100MHz,CDCl3)δ169.4,158.9(dd, 1 J C-F =241Hz, 4 J C-F =2Hz),157.9,156.2(dd, 1 J C-F =241Hz, 4 J C-F =2Hz),155.8,146.2,137.7,130.4,130.3,128.4,126.1(dd, 2 J C-F =17Hz, 3 J C-F =8Hz),116.4(dd, 2 J C-F =23Hz, 3 J C-F =9Hz),115.9(d, 2 J C-F =25Hz),115.9(dd, 2 J C-F =25Hz, 3 J C-F =4Hz),111.0,78.1,74.0,63.4,63.4,58.5,52.3,42.8,29.8,11.9.

[0123] Example 15: Preparation of a15

[0124] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 3,5-difluorobenzyl bromide (0.310 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.447 g of a light yellow oily intermediate with a yield of 80%.

[0125] The above-obtained light yellow intermediate (0.447 g, 0.80 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid a15 (0.336 g) with a yield of 96%. 1 H NMR(400MHz,Chloroform-d)δ7.16(s,1H),7.07(d,J=7.9Hz,2H),6.96(h,J=4.7Hz,2H),6.83(d,J=8.0Hz,2H),6.73(tt,J=8.9 ,2.1Hz,1H),6.35(d,J=4.8Hz,1H),5.02(s,2H),3.86(s,2H),3.56(s,2H),3.39(s,2H),2.80(s,2H),2.29(s,1H),2.21(s,3H). 13 C NMR(100MHz,CDCl3)δ169.7,163.3(dd, 1 J C-F =247Hz, 3 J C-F =13Hz),157.8,146.3,141.3(t, 3 J C-F =9Hz),137.7,130.5,130.3,127.9,114.9,110.9,109.9(t, 2 J C-F =26Hz),103.2(t, 2 J C-F =25Hz),78.1,73.9,68.8,58.5,52.1,42.8,29.8,11.8.

[0126] Example 16: Preparation of a16

[0127] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 2-trifluoromethylbenzyl bromide (0.358 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.485 g of a light yellow oily intermediate with a yield of 82%.

[0128] The above-obtained light yellow intermediate (0.485 g, 0.82 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a16 (0.347 g) with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.77-7.65(m,2H),7.56(t,J=7.7Hz,1H),7.41(t,J=7.7Hz,1H),7.17(d,J=7.1Hz,1H),7.11(d,J=8.1Hz,2H),6.87(d,J=7 .9Hz,2H),6.36(d,J=6.4Hz,1H),5.25(s,2H),3.85(t,J=6.4Hz,2H),3. 57(s,2H),3.36(s,2H),2.79(d,J=6.0Hz,2H),2.28(s,1H),2.22(s,3H). 13 C NMR (100MHz, CDCl3) δ169.7,158.0,146.3,137.6,135.7,132.3,130.3,130.3,128.8,128.0,127.9,127.5(q, 2 J C-F =30Hz),126.1(q, 3 J C-F =5Hz),124.5(q, 1 J C-F =272Hz),115.0,111.0,78.1,74.0,66.3(q, 4 J C-F =3Hz)58.4,52.3,52.2,42.7,11.8.

[0129] Example 17: Preparation of a17

[0130] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 3-trifluoromethylbenzyl bromide (0.358 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.473 g of a light yellow oily intermediate with a yield of 80%.

[0131] The above-obtained light yellow intermediate (0.473 g, 0.80 mmol), methanol (17 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a17 (0.342 g) with a yield of 91%. 1 H NMR (400MHz, CDCl3) δ7.70(s,1H),7.66–7.54(m,2H),7.50(t,J=7.6Hz,1H),7.15(d,J=6.7Hz,1H),7.08(d,J=8.0Hz,3H),6.86(d ,J=7.8Hz,3H),6.35(d,J=6.0Hz,1H),5.09(s,2H),3.85(s,2H),3.57(s,2H),3.38(s,2H),2.80(s,2H),2.29(s,1H),2.20(s,3H). 13 C NMR (100MHz, CDCl3) δ169.7,158.0,146.3,138.2,137.7,131.1(q, 2 J C-F =32Hz),130.8,130.3,129.2,128.1,124.8(q, 3 J C-F =3Hz),124.2(q, 3 J C-F =4Hz),124.2(q, 1 J C-F =271Hz),114.9,110.9,78.1,74.0,69.3,58.5,52.1,52.1,42.7,11.8

[0132] Example 18: Preparation of a18

[0133] The colorless oily intermediate prepared in Example 1 (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and 4-trifluoromethylbenzyl bromide (0.358 g, 1.5 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.473 g of a light yellow oily intermediate with a yield of 80%.

[0134] The above-obtained light yellow intermediate (0.473 g, 0.80 mmol), methanol (17 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid a18 (0.338 g) with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.63(d,J=7.9Hz,2H),7.55(d,J=7.9Hz,2H),7.15(d,J=7.3Hz,1H),7.07(d,J=8.0Hz,2H),6.84(d,J=8.1Hz,2H),6.3 5(d,J=6.7Hz,1H),5.10(s,2H),3.86(d,J=6.4Hz,2H),3.56(s,2H),3.38(s,2H),2.80(d,J=6.4Hz,2H),2.28(t,J=2.4Hz,1H),2.19(s,3H). 13 C NMR (100MHz, CDCl3) δ169.7,158.0,146.3,141.3,137.7,130.8,130.3,130.1(q, 2 J C-F =33Hz),126.8(q, 1 J C-F =263.5Hz),125.6(q, 3 J C-F =4Hz),122.9,114.9,111.0,78.1,77.5,77.2,76.8,74.0,69.2,58.5,52.1,52.0,42.7,11.8.

[0135] Example 19: Preparation of b1

[0136] In a round-bottom flask, the yellow oily liquid prepared in Example 1 (3.586 g, 11 mmol), DCM (110 mL), m-hydroxybenzaldehyde (1.610 g, 13.2 mmol), and anhydrous magnesium sulfate (2.640 g, 22 mmol) were added. After being stirred at 30° C. for 30 min, sodium triacetoxyborohydride (4.664 g, 22 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. The reaction process was monitored by TLC spot plate. After the reaction was completed, dichloromethane (110 mL) was added for dilution, and the mixture was extracted with 40 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=25:1), and the eluent containing the target intermediate was collected and concentrated to obtain 2.756 g of a colorless oily intermediate of the formula (yield 58%).

[0137] The colorless oily intermediate (0.432 g, 1 mmol), acetonitrile (10 mL), potassium carbonate (0.207 g, 1.5 mmol) and benzyl bromide (0.256 g, 1.5 mmol) obtained above were added to a round-bottom flask, and the mixture was reacted at 50°C for 5 h. The reaction progress was monitored by TLC spot plate. After the reaction was completed, the solvent was distilled off under reduced pressure, and the mixture was separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.418 g of a light yellow oily intermediate with a yield of 80%.

[0138] The above-obtained light yellow intermediate (0.418 g, 0.8 mmol), methanol (16 mL) and 6 M aqueous hydrochloric acid solution (2.4 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid b1 (0.293 g) with a yield of 91%. 1 HNMR (400MHz, CDCl3) δ7.43(d,J=7.4Hz,2H),7.37(t,J=7.2Hz,2H),7.31(d,J=6.9Hz,1H),7.19(t,J=7.8Hz,2H),6.87(d,J=5.9Hz,2 H),6.80(d,J=7.3Hz,1H),6.36(s,1H),5.04(s,2H),3.85(br,2H),3.61(s,2H),3.36(s,2H),2.81(s,2H),2.28(s,1H),2.26(s,3H). 13C NMR (100MHz, CDCl3) δ169.6,159.1,146.2,139.4,137.5,137.1,134.2,129.7,128.7,1 28.0,127.6,121.5,115.6,114.1,111.0,78.1,74.0,70.0,59.1,52.8,52.2,43.0,11.9

[0139] Example 20: Preparation of b2

[0140] The colorless oily intermediate (0.216 g, 0.5 mmol) obtained in Example 19, acetonitrile (10 mL), potassium carbonate (0.103 g, 0.75 mmol) and 2-methylbenzyl bromide (0.139 g, 0.75 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.215 g of a light yellow oily intermediate with a yield of 80%.

[0141] The above-obtained light yellow intermediate (0.215 g, 0.4 mmol), methanol (8 mL) and 6 M aqueous hydrochloric acid solution (1.2 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid b2 (0.155 g) with a yield of 93%. 1 HNMR(400MHz, CDCl3)δ7.26(s,2H),7.25–7.11(m,4H),6.89(d,J=6.7Hz,2H),6.81(d,J=7.4Hz,1H),6.37(d,J=5.8Hz,1H), 5.01(s,2H),3.86(d,J=6.5Hz,2H),3.62(s,2H),3.37(s,2H),2.83(d,J=6.0Hz,2H),2.37(s,3H),2.29(s,1H),2.21(s,3H). 13 C NMR (100MHz, CDCl3) δ169.6,159.1,146.2,139.3,138.4,137.5,136.9,129.8,128.9,128.6,128. 4,128.0,124.7,121.5,115.6,114.0,111.1,78.1,74.0,70.1,59.0,52.8,52.2,43.0,21.5,11.9.

[0142] Example 21: Preparation of b3

[0143] The colorless oily intermediate (0.216 g, 0.5 mmol) obtained in Example 19, acetonitrile (10 mL), potassium carbonate (0.103 g, 0.75 mmol) and 3-methylbenzyl bromide (0.139 g, 0.75 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.217 g of a light yellow oily intermediate with a yield of 81%.

[0144] The above-obtained light yellow intermediate (0.217 g, 0.4 mmol), methanol (8 mL) and 6 M aqueous hydrochloric acid solution (1.2 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid b3 (0.158 g) with a yield of 95%. 1 HNMR (400MHz, CDCl3) δ7.40(d,J=7.1Hz,1H),7.23(q,J=7.3,6.4Hz,5H),6.89(d,J=5.9Hz,2H),6.82(d,J=7.4Hz,1H),6.36(d,J=6.4 Hz,1H),5.02(s,2H),3.85(d,J=6.4Hz,2H),3.63(s,2H),3.37(s,2H),2.82(d,J=6.4Hz,2H),2.38(s,3H),2.29(s,1H),2.26(s,3H). 13 C NMR (100MHz, CDCl3) δ169.6,159.2,146.2,139.4,137.5,136.8,134.8,130.5,129.8,128.8,128. 4,128.0,126.1,121.5,115.6,113.8,111.0,78.0,74.0,68.6,59.0,52.8,52.2,43.0,19.0,11.9.

[0145] Example 22: Preparation of b4

[0146] The colorless oily intermediate (0.216 g, 0.5 mmol) obtained in Example 19, acetonitrile (10 mL), potassium carbonate (0.103 g, 0.75 mmol) and 4-methylbenzyl bromide (0.139 g, 0.75 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.217 g of a light yellow oily intermediate with a yield of 81%.

[0147] The above-obtained light yellow intermediate (0.217 g, 0.4 mmol), methanol (8 mL) and 6 M aqueous hydrochloric acid solution (1.2 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid b4 (0.160 g) with a yield of 96%. 1 HNMR (400MHz, CDCl3) δ7.32(d,J=7.8Hz,2H),7.19(t,J=8.3Hz,4H),6.87(d,J=6.4Hz,2H),6.79(d,J=7.4Hz,1H),6.36(d,J=6.3Hz,1H),5.0 0(s,2H),3.85(t,J=6.4Hz,2H),3.61(s,2H),3.36(d,J=2.2Hz,2H),2.82(d,J=6.0Hz,2H),2.34(s,3H),2.28(t,J=2.4Hz,1H),2.25(s,3H). 13 C NMR (100MHz,CDCl3)δ 13 C NMR (100MHz, CDCl3) δ169.6,159.2,146.3,139.3,137.9,137.5,134.0,129.7,129.4,128. 1,127.7,121.5,115.7,114.1,111.1,78.1,73.9,70.0,59.1,52.9,52.2,43.1,21.3,11.9.

[0148] Example 23: Preparation of b5

[0149] The colorless oily intermediate (0.216 g, 0.5 mmol) obtained in Example 19, acetonitrile (10 mL), potassium carbonate (0.103 g, 0.75 mmol) and 2-fluorobenzyl bromide (0.142 g, 0.75 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.219 g of a light yellow oily intermediate with a yield of 81%.

[0150] The above-obtained light yellow intermediate (0.219 g, 0.4 mmol), methanol (8 mL) and 6 M aqueous hydrochloric acid solution (1.2 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid b5 (0.156 g) with a yield of 93%. 1 HNMR(400MHz, CDCl3)δ7.50(t,J=7.1Hz,1H),7.36–7.28(m,1H),7.25–7.12(m,3H),7.07(t,J=9.0Hz,1H),6.89(d,J=6.6Hz,2H), 6.81(d,J=7.0Hz,1H),6.38(s,1H),5.11(s,2H),3.88(br,2H),3.62(s,2H),3.37(s,2H),2.83(br,2H),2.28(s,1H),2.27(s,3H). 13 C NMR(100MHz,CDCl3)δ167.7,160.6(d, 1 J C-F =246Hz),158.9,146.2,139.4,137.5,129.9,129.9,129.8,128.2,124.4(d, 3 J C-F =3Hz),124.2(d, 2 J C-F =14Hz),121.7,115.6,115.4(d, 2 J C-F =21Hz),114.0,111.0,78.1,74.0,63.8(d, 3 J C-F =3Hz),59.1,52.8,52.3,43.1,11.9.

[0151] Example 24: Preparation of b6

[0152] The colorless oily intermediate (0.216 g, 0.5 mmol) obtained in Example 19, acetonitrile (10 mL), potassium carbonate (0.103 g, 0.75 mmol) and 3-fluorobenzyl bromide (0.142 g, 0.75 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.222 g of a light yellow oily intermediate with a yield of 82%.

[0153] The above-obtained light yellow intermediate (0.222 g, 0.41 mmol), methanol (9 mL) and 6 M aqueous hydrochloric acid solution (1.3 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid b6 (0.162 g) with a yield of 94%. 1 HNMR (400MHz, CDCl3) δ7.38–7.29(m,1H),7.18(dd,J=17.3,9.3Hz,4H),6.99(t,J=8.3Hz,1H),6.85(d,J=6.5Hz,2H),6.80( d,J=7.3Hz,1H),6.38(s,1H),5.03(s,2H),3.br(s,2H),3.61(s,2H),3.37(s,2H),2.83(br,2H),2.29(s,1H),2.26(s,3H). 13 C NMR(100MHz,CDCl3)δ169.3,163.1(d, 1 J C-F =245Hz),158.8 146.2,139.7(d, 3 J C-F =7Hz),139.4,137.5,130.2(d, 3 J C-F =8Hz),128.4,128.3,122.9(d, 4 J C-F =2Hz),121.8,115.6,114.9(d, 2 J C-F =21Hz),114.3(d, 2 J C-F =22Hz),114.0,111.1,78.1,74.0,69.2,59.1,52.8,52.2,43.0,11.9.

[0154] Example 25: Preparation of b7

[0155] The colorless oily intermediate (0.216 g, 0.5 mmol) obtained in Example 19, acetonitrile (10 mL), potassium carbonate (0.103 g, 0.75 mmol) and 4-fluorobenzyl bromide (0.142 g, 0.75 mmol) were added to a round-bottom flask and reacted at 50° C. for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure and separated by column chromatography (DCM: methanol v / v = 25:1). The eluate containing the target intermediate was collected and concentrated to obtain 0.203 g of a light yellow oily intermediate in a yield of 75%.

[0156] The above-obtained light yellow intermediate (0.203 g, 0.37 mmol), methanol (9 mL) and 6 M aqueous hydrochloric acid solution (1.3 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered with suction, and the filter cake was collected and dried to obtain a white solid b7 (0.148 g) with a yield of 95%. 1 HNMR (400MHz, CDCl3) δ7.41(t,J=6.8Hz,2H),7.19(t,J=7.5Hz,2H),7.06(t,J=8.5Hz,2H),6.85(d,J=10.3Hz,2H),6.79(d,J=7.4H z,1H),6.39(s,1H),4.99(s,2H),3.88(d,J=7.2Hz,2H),3.61(s,2H),3.37(s,2H),2.83(d,J=6.0Hz,2H),2.29(s,1H),2.26(s,3H). 13 CNMR(101MHz,CDCl3)δ171.7,162.6(d, 1 J C-F =245Hz),158.9,146.2,139.4,137.6,132.8(d, 4 J C-F =3Hz),129.8,129.5(d, 3 J C-F =8Hz),127.8,121.7,115.6(d, 2 J C-F =22Hz),115.6,113.9,111.1,78.0,74.1,69.4,59.0,52.7,52.2,42.9,12.0.

[0157] Example 26: Preparation of c1

[0158] p-Hydroxyphenylethanol (0.690 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.035 g, 7.5 mmol) and benzyl bromide (1.111 g, 6.5 mmol) were added to a round-bottom flask and reacted at 50°C for 5 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (petroleum ether:ethyl acetate v / v=5:2). The eluate containing the target intermediate was collected and concentrated to obtain 0.855 g of a colorless oily intermediate with a yield of 75%.

[0159] The above-prepared product (0.684 g, 3 mmol), DCM (60 mL), and Dess-Martin reagent (2.290 g, 5.4 mmol) were added to a round-bottom flask, and stirred at -10 ° C for 10 min under nitrogen protection, then moved to room temperature and continued to stir for 2 h. After the reaction, DCM dilution system (60 mL) was added, and extracted with 50 mL×4 saturated sodium thiosulfate and saturated sodium bicarbonate mixed solution (v / v=1:1). The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0.380 g of a yellow-brown oily liquid with a yield of 56%.

[0160] The yellow oily intermediate (0.326 g, 1 mmol) obtained in Example 1, DCM (10 mL), the yellow-brown oily liquid (0.271 g, 1.2 mmol) obtained above and anhydrous magnesium sulfate (0.240 g, 2 mmol) were added to a round-bottom flask, and stirred at 30° C. for 30 min. Then, sodium triacetoxyborohydride (0.424 g, 2 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. After the reaction, dichloromethane (10 mL) was added, and the mixture was extracted with 20 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=30:1), and the eluent containing the target intermediate was collected and concentrated to obtain 0.403 g of a light yellow oily liquid with a yield of 75%.

[0161] The above-obtained light yellow intermediate (0.403 g, 0.75 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.2 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a methanol-ether mixed solution with a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid c1 (0.284 g) with a yield of 91%. 1H NMR(400MHz, CDCl3)δ7.43(d,J=7.0Hz,2H),7.37(t,J=7.2Hz,2H),7.34–7.28(m,1H) ,7.06(d,J=8.2Hz,2H),7.03–6.98(m,1H),6.91(d,J=8.2Hz,2H),6.34(d,J=6.8Hz,1H ),5.05(s,2H),3.84(t,J=6.2Hz,2H),3.39(d,J=2.2Hz,2H),2.81(t,J=5.9Hz,2H),2 .75(dd,J=8.2,6.3Hz,2H),2.63(t,J=7.2Hz,2H),2.36(s,3H),2.23(d,J=2.2Hz,1H). 13 C NMR (100MHz, CDCl3) δ168.9,157.5,146.1,137.7,137.2,131.9,129.7,128.7,128. 6,128.1,127.6,115.1,111.0,78.1,73.7,70.2,56.1,54.2,52.4,42.8,33.4,12.2.

[0162] Example 27: Preparation of c2

[0163] p-Hydroxyphenylethanol (0.690 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.035 g, 7.5 mmol) and 2-methylbenzyl bromide (1.202 g, 6.5 mmol) were added to a round-bottom flask and reacted at 50°C for 5 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (petroleum ether:ethyl acetate v / v=5:2). The eluate containing the target intermediate was collected and concentrated to obtain 0.895 g of a colorless oily intermediate in a yield of 74%.

[0164] The above-prepared product (0.726 g, 3 mmol), DCM (60 mL), and Dess-Martin reagent (2.290 g, 5.4 mmol) were added to a round-bottom flask, and stirred at -10 ° C for 10 min under nitrogen protection, then moved to room temperature and continued to stir for 2 h. After the reaction, DCM dilution system (60 mL) was added, and extracted with 50 mL×4 saturated sodium thiosulfate and saturated sodium bicarbonate mixed solution (v / v=1:1). The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0.389 g of a yellow-brown oily liquid with a yield of 54%.

[0165] The yellow oily intermediate (0.326 g, 1 mmol) obtained in Example 1, DCM (10 mL), the yellow-brown oily liquid (0.288 g, 1.2 mmol) obtained above and anhydrous magnesium sulfate (0.240 g, 2 mmol) were added to a round-bottom flask, and stirred at 30° C. for 30 min. Then, sodium triacetoxyborohydride (0.424 g, 2 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. After the reaction, dichloromethane (10 mL) was added, and the mixture was extracted with 20 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=30:1), and the eluent containing the target intermediate was collected and concentrated to obtain 0.402 g of a light yellow oily liquid with a yield of 73%.

[0166] The above-obtained light yellow intermediate (0.402 g, 0.73 mmol), methanol (14 mL) and 6 M aqueous hydrochloric acid solution (2.1 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid c2 (0.289 g) with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ7.40(d,J=7.0Hz,1H),7.21(h,J=5.4,4.7Hz,3H),7.07(d,J=7.7Hz,3H),6.92(d,J=7.7Hz,2H),6.31(s,1 H),5.01(s,2H),3.84(s,2H),3.40(s,2H),2.86–2.71(m,4H),2.64(t,J=7.0Hz,2H),2.37(s,3H),2.35(s,3H),2.23(s,1H).13C NMR (100MHz, CDCl3) δ169.7,157.6,146.4,137.6,136.8,135.0,132.0,130.5,129.7,128.7,1 28.4,127.8,126.1,115.0,110.9,78.2,73.6,68.8,56.2,54.3,52.3,42.8,33.4,19.0,12.1.

[0167] Example 28: Preparation of c3

[0168] p-Hydroxyphenylethanol (0.690 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.035 g, 7.5 mmol) and 3-methylbenzyl bromide (1.202 g, 6.5 mmol) were added to a round-bottom flask and reacted at 50°C for 5 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (petroleum ether:ethyl acetate v / v=5:2). The eluate containing the target intermediate was collected and concentrated to obtain 0.895 g of a colorless oily intermediate with a yield of 74%.

[0169] The above-prepared product (0.726 g, 3 mmol), DCM (60 mL), and Dess-Martin reagent (2.290 g, 5.4 mmol) were added to a round-bottom flask, and stirred at -10 ° C for 10 min under nitrogen protection, then moved to room temperature and continued to stir for 2 h. After the reaction, DCM dilution system (60 mL) was added, and extracted with 50 mL×4 saturated sodium thiosulfate and saturated sodium bicarbonate mixed solution (v / v=1:1). The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0.403 g of a yellow-brown oily liquid with a yield of 56%.

[0170] The yellow oily intermediate (0.326 g, 1 mmol) obtained in Example 1, DCM (10 mL), the yellow-brown oily liquid (0.288 g, 1.2 mmol) obtained above and anhydrous magnesium sulfate (0.240 g, 2 mmol) were added to a round-bottom flask, and stirred at 30° C. for 30 min. Then, sodium triacetoxyborohydride (0.424 g, 2 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. After the reaction, dichloromethane (10 mL) was added, and the mixture was extracted with 20 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=30:1), and the eluent containing the target intermediate was collected and concentrated to obtain 0.386 g of a light yellow oily liquid with a yield of 70%.

[0171] The above-obtained light yellow intermediate (0.386 g, 0.70 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.1 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid c3 (0.280 g) with a yield of 93%. 1H NMR (400MHz, CDCl3) δ7.24(p,J=7.3Hz,4H),7.12(d,J=7.2Hz,1H),7.06(d,J=7.9Hz,2H),7.00(s,1H),6.91(d,J=7.8Hz,2H),6.30(d, J=4.6Hz,1H),5.00(s,2H),3.82(s,2H),3.39(s,2H),2.83–2.72(m,4H),2.63(t,J=7.1Hz,2H),2.36(s,3H),2.35(s,3H),2.22(s,1H). 13 C NMR (100MHz, CDCl3) δ169.7,157.6,146.4,138.4,137.6,137.1,131.9,129.7,128.8,128.6,1 28.3,127.7,124.7,115.0,110.9,78.2,73.6,70.3,56.1,54.3,52.2,42.8,33.4,21.5,12.0.

[0172] Example 29: Preparation of c4

[0173] p-Hydroxyphenylethanol (0.690 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.035 g, 7.5 mmol) and 4-methylbenzyl bromide (1.202 g, 6.5 mmol) were added to a round-bottom flask and reacted at 50°C for 5 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (petroleum ether:ethyl acetate v / v=5:2). The eluate containing the target intermediate was collected and concentrated to obtain 0.895 g of a colorless oily intermediate in a yield of 74%.

[0174] The above-prepared product (0.726 g, 3 mmol), DCM (60 mL), and Dess-Martin reagent (2.290 g, 5.4 mmol) were added to a round-bottom flask, and stirred at -10 ° C for 10 min under nitrogen protection, then moved to room temperature and continued to stir for 2 h. After the reaction, DCM dilution system (60 mL) was added, and extracted with 50 mL×4 saturated sodium thiosulfate and saturated sodium bicarbonate mixed solution (v / v=1:1). The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0.403 g of a yellow-brown oily liquid with a yield of 56%.

[0175] The yellow oily intermediate (0.326 g, 1 mmol) obtained in Example 1, DCM (10 mL), the yellow-brown oily liquid (0.288 g, 1.2 mmol) obtained above and anhydrous magnesium sulfate (0.240 g, 2 mmol) were added to a round-bottom flask, and stirred at 30° C. for 30 min. Then, sodium triacetoxyborohydride (0.424 g, 2 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. After the reaction, dichloromethane (10 mL) was added, and the mixture was extracted with 20 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=30:1), and the eluent containing the target intermediate was collected and concentrated to obtain 0.413 g of a light yellow oily liquid with a yield of 75%.

[0176] The above-obtained light yellow intermediate (0.413 g, 0.75 mmol), methanol (15 mL) and 6 M aqueous hydrochloric acid solution (2.1 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid c4 (0.310 g) with a yield of 96%. 1 H NMR (400MHz, CDCl3) δ7.31(d,J=7.6Hz,2H),7.18(d,J=7.6Hz,2H),7.05(d,J=7.9Hz,2H),7.02(s,1H),6.90(d,J=7.9Hz,2H),6.33(s,1H ),5.00(s,2H),3.81(d,J=9.8Hz,2H),3.39(s,2H),2.80(s,2H),2.75(t,J=7.2Hz,2H),2.62(t,J=7.2Hz,2H),2.35(s,6H),2.22(s,1H). 13 C NMR (100MHz, CDCl3) δ169.7,157.6,146.3,137.8,137.7,134.2,131.9,129.7,129.4,1 27.9,127.7,115.1,111.0,78.2,73.6,70.2,56.2,54.3,52.3,42.9,33.4,21.3,12.1.

[0177] Example 30: Preparation of c5

[0178] p-Hydroxyphenylethanol (0.690 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.035 g, 7.5 mmol) and 2-fluorobenzyl bromide (1.228 g, 6.5 mmol) were added to a round-bottom flask and reacted at 50°C for 5 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (petroleum ether:ethyl acetate v / v=5:2). The eluate containing the target intermediate was collected and concentrated to obtain 0.910 g of a colorless oily intermediate with a yield of 74%.

[0179] The above-prepared product (0.738 g, 3 mmol), DCM (60 mL), and Dess-Martin reagent (2.290 g, 5.4 mmol) were added to a round-bottom flask, and stirred at -10 ° C for 10 min under nitrogen protection, then moved to room temperature and continued to stir for 2 h. After the reaction, DCM dilution system (60 mL) was added, and extracted with 50 mL×4 saturated sodium thiosulfate and saturated sodium bicarbonate mixed solution (v / v=1:1). The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0.403 g of a yellow-brown oily liquid with a yield of 55%.

[0180] The yellow oily intermediate (0.326 g, 1 mmol) obtained in Example 1, DCM (10 mL), the yellow-brown oily liquid (0.293 g, 1.2 mmol) obtained above and anhydrous magnesium sulfate (0.240 g, 2 mmol) were added to a round-bottom flask, and stirred at 30° C. for 35 min. Then, sodium triacetoxyborohydride (0.424 g, 2 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. After the reaction, dichloromethane (10 mL) was added, and the mixture was extracted with 20 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=30:1), and the eluent containing the target intermediate was collected and concentrated to obtain 0.388 g of a light yellow oily liquid with a yield of 70%.

[0181] The above-obtained light yellow intermediate (0.388 g, 0.70 mmol), methanol (14 mL) and 6 M aqueous hydrochloric acid solution (2.1 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a methanol and ether mixed solution with a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid c5 (0.289 g) with a yield of 95%. 1H NMR (400MHz, CDCl3) δ7.50(t,J=7.4Hz,1H),7.34–7.28(m,1H),7.15(t,J=7.4Hz,1H),7.07(dd,J=8.9,6.3Hz,3H),7.00(s,1H),6.92(d,J=7.9Hz,2 H),6.34–6.27(m,1H),5.11(s,2H),3.82(s,2H),3.39(s,2H),2.80(s,2H ),2.75(t,J=7.1Hz,2H),2.63(t,J=7.1Hz,2H),2.34(s,3H),2.22(s,1H). 13 C NMR (100MHz, CDCl3) δ169.6,160.6(d, 1 J C-F =245Hz),157.3,146.2,137.7,132.2,129.9,129.8,129.7,127.7(d, 4 J C-F =1Hz),124.4(d, 3 J C-F =4Hz),124.2,115.4(d, 2 J C-F =21Hz),115.0,111.0,78.1,73.6,63.9(d, 3 J C-F =4Hz),56.1,54.3,52.2,42.8,33.4,12.1.

[0182] Example 31: Preparation of c6

[0183] p-Hydroxyphenylethanol (0.690 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.035 g, 7.5 mmol) and 3-fluorobenzyl bromide (1.228 g, 6.5 mmol) were added to a round-bottom flask and reacted at 50°C for 5 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (petroleum ether:ethyl acetate v / v=5:2). The eluate containing the target intermediate was collected and concentrated to obtain 0.959 g of a colorless oily intermediate with a yield of 78%.

[0184] The above-prepared product (0.738 g, 3 mmol), DCM (60 mL), and Dess-Martin reagent (2.290 g, 5.4 mmol) were added to a round-bottom flask, and stirred at -10 ° C for 10 min under nitrogen protection, then moved to room temperature and continued to stir for 2 h. After the reaction, DCM dilution system (60 mL) was added, and extracted with 50 mL×4 saturated sodium thiosulfate and saturated sodium bicarbonate mixed solution (v / v=1:1). The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0.381 g of a yellow-brown oily liquid with a yield of 52%.

[0185] The yellow oily intermediate (0.326 g, 1 mmol) obtained in Example 1, DCM (10 mL), the yellow-brown oily liquid (0.293 g, 1.2 mmol) obtained above and anhydrous magnesium sulfate (0.240 g, 2 mmol) were added to a round-bottom flask, and stirred at 30° C. for 40 min. Then, sodium triacetoxyborohydride (0.424 g, 2 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. After the reaction, dichloromethane (10 mL) was added, and the mixture was extracted with 20 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=30:1), and the eluent containing the target intermediate was collected and concentrated to obtain 0.400 g of a light yellow oily liquid with a yield of 72%.

[0186] The above-obtained light yellow intermediate (0.400 g, 0.72 mmol), methanol (14 mL) and 6 M aqueous hydrochloric acid solution (2.2 mL) were added to a round-bottom flask and reacted at 60°C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid c6 (0.294 g) with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ7.33(td,J=7.8,5.6Hz,1H),7.23–7.11(m,2H),7.06(d,J=7.8Hz,2H),6.99(td,J=8.4,2.6Hz,2H),6.88(d,J=7.9Hz,2H),6 .29(d,J=5.1Hz,1H),5.04(s,2H),3.82(s,2H),3.39(s,2H),2.80(s,2H) ,2.74(t,J=7.2Hz,2H),2.62(t,J=7.2Hz,2H),2.34(s,3H),2.22(s,1H). 13 C NMR(100MHz,CDCl3)δ169.7,163.1(d, 1 J C-F=245Hz),157.2,146.3,139.9(d, 3 J C-F =7Hz),137.7,132.2,130.7(d, 3 J C-F =8Hz),129.7,127.7,122.8,115.0,114.8(d, 2 J C-F =21Hz),114.3(d, 2 J C-F =22Hz),110.9,78.1,73.6,69.3,56.1,54.2,52.2,42.8,33.4,12.1.

[0187] Example 32: Preparation of c7

[0188] p-Hydroxyphenylethanol (0.690 g, 5 mmol), acetonitrile (20 mL), potassium carbonate (1.035 g, 7.5 mmol) and 4-fluorobenzyl bromide (1.228 g, 6.5 mmol) were added to a round-bottom flask and reacted at 50°C for 5 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (petroleum ether:ethyl acetate v / v=5:2). The eluate containing the target intermediate was collected and concentrated to obtain 0.984 g of a colorless oily intermediate with a yield of 80%.

[0189] The above-prepared product (0.738 g, 3 mmol), DCM (60 mL), and Dess-Martin reagent (2.290 g, 5.4 mmol) were added to a round-bottom flask, and stirred at -10 ° C for 10 min under nitrogen protection, then moved to room temperature and continued to stir for 2 h. After the reaction, DCM dilution system (60 mL) was added, and extracted with 50 mL×4 saturated sodium thiosulfate and saturated sodium bicarbonate mixed solution (v / v=1:1). The extracted organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 0.366 g of a yellow-brown oily liquid with a yield of 50%.

[0190] The yellow oily intermediate (0.326 g, 1 mmol) obtained in Example 1, DCM (10 mL), the yellow-brown oily liquid (0.293 g, 1.2 mmol) obtained above and anhydrous magnesium sulfate (0.240 g, 2 mmol) were added to a round-bottom flask, and stirred at 30° C. for 30 min. Then, sodium triacetoxyborohydride (0.424 g, 2 mmol) was added. The reaction was continued at 30° C. for 4.5 h under a nitrogen atmosphere. After the reaction, dichloromethane (10 mL) was added, and the mixture was extracted with 20 mL×4 saturated sodium bicarbonate aqueous solution. The organic phase after extraction was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The mixture was separated by column chromatography (DCM: methanol v / v=30:1), and the eluent containing the target intermediate was collected and concentrated to obtain 0.400 g of a light yellow oily liquid with a yield of 72%.

[0191] The above-obtained light yellow intermediate (0.400 g, 0.72 mmol), methanol (14 mL) and 6 M aqueous hydrochloric acid solution (2.2 mL) were added to a round-bottom flask and reacted at 60 °C for 2 h. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was slurried with a mixed solution of methanol and ether in a volume ratio of 10:1. The mixture was filtered and the filter cake was collected and dried to obtain a white solid c7 (0.287 g) with a yield of 92%.

[0192] Example 33: MAO-B Inhibitory Activity Test

[0193] All the examples in this case were tested for MAO-B inhibitory activity. The MAO-B inhibitor screening kit (MAK296) used was purchased from Sigma. Some compounds showed good inhibition rates at 10 μM. The results are shown in Table 1. IC 50 The results are shown in Table 2. Example a10 has the best activity, IC 50 It reached 97nM, which is 6 times stronger than the positive drug paroxysmal. The MAO-B inhibitory activity of the b series compounds is generally poor, so selective testing is not considered. For the convenience of comparison, we also retested the best embodiment b2 in patent CN112521331B. The activities of embodiments a10 and c4 are better than those of embodiment b2 before the modification, and the rest are at the same activity level.

[0194] Table 1 Inhibition rate of all examples at 1 μM

[0195]

[0196]

[0197] Note: aThis b2 is an embodiment of patent CN112521331B, and its structure is The same below.

[0198] Table 2 IC of some compounds 50

[0199]

[0200] Example 34: MAO-A Inhibitory Activity and Selectivity Test

[0201] The compounds of this case were subsequently tested for MAO-A inhibitory activity, and the test results are shown in Table 3. Among them, Example a10 has the strongest selectivity for MAO-B, with a selectivity index exceeding 5.15, which is significantly improved compared to the best example before the transformation, an order of magnitude (5.15 vs. 73.5). In addition, the selectivity of Examples a6 and c7 also exceeds the best example before the transformation. The selectivity of Examples c4 and c6 is equivalent to that of the best example before the transformation. The data in Patent CN112521331B are shown in Table 4.

[0202] Table 3 Some examples of MAO-A IC 50 Value and selectivity

[0203]

[0204] a The inhibition rate measured in the embodiment at the concentration of 50 μM of maximum solubility is b This b2 is an embodiment of patent CN112521331B, and its structure is

[0205] Table 4 Best embodiment before transformation MAO-A IC 50 Value and selectivity

[0206]

[0207]

[0208] Note: Since the enzyme batches used in this patent are different from those used in CN112521331B, and the enzyme activity is different, the test results are different. However, comparing the selectivity indexes of the two times, the results are within the error range.

[0209] Example 35: Iron ion chelation ability test

[0210] In this case, the iron ion chelation ability of all examples was tested by gradient titration spectrophotometry. All examples inherited the excellent iron chelation ability of the positive drug deferiprone, among which example c5 had the best iron chelation activity (pFe 3+=19.88), as shown in Table 5.

[0211] Table 5. pFe of all examples 3+ value

[0212]

[0213] Example 36: Antioxidant capacity test

[0214] In this case, the DCFH-DA fluorescent probe was used to detect the intracellular reactive oxygen content, and finally the intracellular reactive oxygen was detected by flow cytometry (Ex = 488nm; Em = 530nm). The specific situation is shown in Table 6. By comparison, it can be found that the antioxidant activity of the embodiment before the modification is extremely weak, and the antioxidant activity has been greatly improved through the modification, such as compound a10 (33.79 ± 0.38 vs. 41.21 ± 0.40). In addition, the antioxidant activities of a6, c4, c6, and c7 are better than those of the compounds before the modification, as shown in Table 7.

[0215] Table 6. Antioxidant activity of the best embodiment a10

[0216]

[0217] Table 7. Antioxidant activity of the best example before modification

[0218]

[0219] Example 37: Blood-brain barrier (BBB) ​​permeability experiment

[0220] We still chose the SwissADME prediction platform (http: / / www.swissadme.ch.) to predict several key physicochemical parameters related to ADMET and BBB permeability of all examples. BBB permeability is crucial for drugs for central nervous system diseases. P-gP is a transmembrane glycoprotein with a molecular weight of 170KD, which has an energy-dependent "drug pump" function. P-gP will bind to the drug, pump the intracellular drug out of the cell, reduce the intracellular drug concentration, and cause the cell to develop drug resistance or off-target effects. As shown in Table 8, all compounds have moderate topological polar surface area (TPSA) (TPSA≤50) and iLog P value (iLog P≤5), and all compounds have good drug-like activity and can pass through the BBB.

[0221] Table 8 Drug-like data and blood-brain barrier permeability of all compounds

[0222]

[0223]

[0224] Example 38: Parallel Artificial Membrane (PAMPA) Experiment

[0225] The test compound was dissolved in DMSO at a concentration of 5 mg / mL, and then diluted to 25 μg / mL with PBS buffer solution (pH = 7.4) for testing. Then, an appropriate amount of polar brain extract (PBL) was directly dissolved in dodecane to a concentration of 20 mg / mL. The PBL used in this experiment was purchased from Avanti Polar Lipids, Inc. 2 ) pretreatment, the prepared PBL solution was added to the filter membrane surface of the donor plate (4 μL per well), followed by the test compound solution (V d ) was added to the donor plate (150 μL), and 300 μL PBS buffer (V a ). After the solution is added, carefully place the donor plate on the receptor plate so that the membrane is in contact with the upper and lower liquid surfaces. Afterwards, cover the lid and let it stand in the dark at a constant temperature of 25°C for 6 hours. The concentration of the drug in the receptor wells is measured with an ELISA reader. According to the Pe equation, the concentration and permeability of the compound in the well are calculated (the concentration of the compound is calculated by substituting the UV absorbance into the standard curve, 8 times in parallel). The results are shown in Table 9. Example a10 shows high permeability, while b2 in Chinese patent CN112521331B shows uncertain BBB permeability, as shown in Table 10. In contrast, there is a significant improvement.

[0226]

[0227] Table 9 BBB values ​​of some examples

[0228]

[0229] Table 10. Anti-BBB value of the best embodiment before modification

[0230]

[0231] Pe≥4, BBB high permeability; Pe≤2, BBB low permeability; 2

Claims

1. An aziridine-pyridone derivative as shown in formula a10, formula c4, formula c6 or formula c7 and a pharmaceutically acceptable salt thereof: 。 2. Use of the aziridine-pyridone derivatives represented by formula a10, formula c4, formula c6 or formula c7 as claimed in claim 1 or their pharmaceutically acceptable salts in the preparation of drugs for treating or preventing Alzheimer's disease.

3. The use according to claim 2, characterized in that: The aziridine-pyridone derivative is compound a10.

4. The method for preparing the aziridine-pyridone derivatives or pharmaceutically acceptable salts thereof represented by formula a10, formula c4, formula c6 or formula c7 according to claim 1, characterized in that: When n1 is 1, the method is: (1) dissolving the intermediate of formula 1 in an organic solvent A, adding alkaline substance A and compound of formula 2 in sequence, stirring and reacting at 40° C. for 4-8 h, and subjecting the obtained reaction solution A to post-treatment A to obtain the intermediate of formula 3; the molar ratio of the intermediate of formula 1, compound of formula 2 and alkaline substance is 1:0.5-1.5:1-2; the alkaline substance A is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide and triethylamine; （2） The intermediate of formula 3 obtained in step (1) is dissolved in an organic solvent B, and a compound of formula 4 and anhydrous magnesium sulfate are added, and the mixture is stirred at 30° C. for 20-40 min, and then a reducing agent A is added, and the reaction is continued at 30° C. for 4.5 h under a nitrogen atmosphere. The obtained reaction solution B is subjected to post-treatment B to obtain an intermediate of formula 5; the molar ratio of the intermediate of formula 3, the compound of formula 4, anhydrous magnesium sulfate and the reducing agent A is 1:1-1.5:1-3:1-3; the reducing agent A is sodium borohydride, aluminum oxide, stannous chloride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, and a palladium / carbon catalyst; （3） The intermediate of formula 5 obtained in step (2) is dissolved in an organic solvent C, and an alkaline substance B and a compound of formula 6 are added, and the mixture is stirred at 50° C. for 4-6 h. The reaction solution C is subjected to post-treatment C to obtain a compound of formula 7; the molar ratio of the intermediate of formula 5, the alkaline substance B and the compound of formula 6 is 1:1-2:1-2; the alkaline substance B is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide and triethylamine; （4） The compound of formula 7 described in step (3) is dissolved in an organic solvent D, and 6M hydrochloric acid is added, and the reaction is carried out at 60° C. for 1-3 h. The obtained reaction solution D is subjected to post-treatment D to obtain the aziridine-pyridone derivative shown in formula 8; Among the compounds described in Formula 1, Formula 3, Formula 3, Formula 5, Formula 6, Formula 7 or Formula 8, R 1 For CH3, R 2 For H, R 3 is F or CH3.

5. The method for preparing the aziridine-pyridone derivatives represented by formula a10, formula c4, formula c6 or formula c7 or their pharmaceutically acceptable salts as claimed in claim 1, characterized in that: The organic solvent A in step (1) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide, methanol, ethanol, acetonitrile, and dichloromethane, preferably N,N-dimethylformamide; The volume of the organic solvent A in step (1) is 3-5 mL / mmol based on the amount of the intermediate of formula 1; The post-treatment A in step (1) is as follows: adding water to the reaction solution A, extracting with dichloromethane (DCM), combining the organic phases, drying over anhydrous sodium sulfate, then distilling under reduced pressure to remove the solvent, performing column chromatography separation using a mixed solution of dichloromethane, methanol and triethylamine in a volume ratio of 20:1:0.1 as an eluent, collecting the eluate containing the target intermediate, and concentrating to obtain the intermediate of formula 3; The organic solvent B in step (2) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM); The volume of the organic solvent B in step (2) is 8-12 mL / mmol based on the amount of the intermediate of formula 3; The post-treatment B in step (2) is: adding dichloromethane to the reaction solution B, and extracting with a saturated sodium bicarbonate aqueous solution, drying the extracted organic phase with anhydrous sodium sulfate, then distilling under reduced pressure to remove the solvent, performing column chromatography separation using a mixed solution of dichloromethane and methanol in a volume ratio of 25:1 as an eluent, collecting the eluate containing the target intermediate, and concentrating to obtain the intermediate of formula 5; The organic solvent C in step (3) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM); The volume of the organic solvent C in step (3) is 8-12 mL / mmol based on the amount of the intermediate of formula 5; The post-treatment C in step (3) is: the reaction solution C is distilled under reduced pressure to remove the solvent, and column chromatography is performed using a mixed solution of dichloromethane and methanol in a volume ratio of 25:1 as an eluent, and the eluate containing the target intermediate is collected and concentrated to obtain the intermediate of formula 7; The organic solvent D in step (4) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide, methanol, ethanol, acetonitrile and dichloromethane; The volume of the organic solvent D in step (4) is 18-22 mL / mmol based on the amount of the intermediate of formula 7; In step (4), the volume of the 6M hydrochloric acid is 2-4 mL / mmol based on the amount of the compound represented by formula 7; The post-treatment D in step (4) is: the reaction solution D is subjected to reduced pressure distillation to remove the solvent, slurried with a mixed solution of methanol and ether in a volume ratio of 10:1, filtered, and the obtained filter cake A is dried to obtain the aziridine-pyridone derivative shown in formula 8.

6. The method for preparing the aziridine-pyridone derivatives represented by formula a10, formula c4, formula c6 or formula c7 or their pharmaceutically acceptable salts as claimed in claim 1, characterized in that: When n1 is 2, the method is: (a) dissolving the intermediate of formula 3 in an organic solvent E, adding the intermediate of formula 9 and anhydrous magnesium sulfate in sequence, stirring at 30° C. for 20-40 min, adding a reducing agent B, and continuing the reaction at 30° C. for 4.5 h under a nitrogen atmosphere. The resulting reaction solution E is subjected to post-treatment E to obtain an intermediate of formula 10; the molar ratio of the intermediate of formula 3, the intermediate of formula 9, anhydrous magnesium sulfate and the reducing agent B is 1:1-1.5:1-3:1-3; the reducing agent B is sodium borohydride, aluminum oxide, stannous chloride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride, and a palladium / carbon catalyst; （b） The compound of formula 10 described in step (a) is dissolved in an organic solvent F, and a 6M hydrochloric acid aqueous solution is added, and the reaction is carried out at 60° C. for 1-3 hours. The obtained reaction solution F is subjected to post-treatment F to obtain an aziridine-pyridone derivative represented by formula 11; Among the compounds described in Formula 3, Formula 9, Formula 10, and Formula 11, R 1 For CH3, R 2 For H, R 3 is F or CH3.

7. The method for preparing the aziridine-pyridone derivatives represented by formula a10, formula c4, formula c6 or formula c7 or their pharmaceutically acceptable salts as claimed in claim 6, characterized in that: The organic solvent E in step (a) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide, methanol, ethanol, acetonitrile and dichloromethane; The volume of the organic solvent E in step (a) is 8-12 mL / mmol based on the amount of the intermediate of formula 3; The post-treatment E in step (a) is: adding dichloromethane to the reaction solution E, and extracting with a saturated sodium bicarbonate aqueous solution, drying the extracted organic phase with anhydrous sodium sulfate, then distilling under reduced pressure to remove the solvent, and performing column chromatography separation using a mixed solution of dichloromethane and methanol in a volume ratio of 30:1 as an eluent, collecting the eluate containing the target intermediate, and concentrating to obtain the intermediate of formula 10; The organic solvent F in step (b) is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide, methanol, ethanol, acetonitrile and dichloromethane; The volume of the organic solvent F in step (b) is 18-22 mL / mmol based on the amount of the intermediate of formula 10; In step (b), the volume of the 6M hydrochloric acid is 2-4 mL / mmol based on the amount of the compound represented by formula 10; The post-treatment F in step (b) is: the reaction solution F is distilled under reduced pressure to remove the solvent, slurried with a methanol and ether mixed solution with a volume ratio of 10:1, filtered, and the obtained filter cake B is dried to obtain the aziridine-pyridone derivative shown in formula 11.

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