Derivatives of phthalimide-fused 3-hydroxy-pyridin-4-one and their applications

Abstract

The present invention discloses a derivative of phthalimide-conjugated 3-hydroxy-pyridin-4-one and its application, and synthesizes a class of monoamine oxidase B inhibitors with iron ion chelating activity. Innovatively, a hydroxy-pyridone derivative with iron ion chelating activity is organically combined with a phthalimide derivative with hMAO-B inhibitory activity, which has significant advantages in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease with complex pathogenesis.

Description

Technical Field

[0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, and particularly relates to derivatives of phthalimide-fused 3-hydroxy-pyridin-4-one having iron ion chelating activity and monoamine oxidase B inhibitory activity, a preparation method thereof, and an application thereof in the preparation of drugs for treating neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Background Art

[0002] Monoamine oxidases (MAOs) are a class of enzymes containing the redox cofactor flavin adenine dinucleotide (FAD) located on the outer mitochondrial membrane. Through the energy provided by ubiquitin and ATP, monoamine homeostasis and neurotransmission are regulated in neurons, glial cells, and other cells through oxidative deamination reactions. The oxidative deamination mechanism of MAOs is as follows: Substrates such as phenethylamine and benzylamine form phenylacetaldehyde, NH3, and H2O2 under the catalysis of monoamine oxidase, and phenylacetaldehyde generates phenylacetic acid under the action of aldehyde dehydrogenase. There are two subtypes of hMAOs: hMAO-A and hMAO-B. Among them, hMAO-B consists of 250 amino acids with a molecular weight of 58,800, and the main substrates for oxidative deamination are benzylamine (BA) and phenethylamine (PEA). Given that the catalytic oxidative deamination reaction of monoamine oxidase will lead to a decrease in some important neurotransmitters and the production of neurotoxic aldehydes, monoamine oxidase inhibitors (MAOIs) are widely used in the treatment of depression and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.

[0003] Phthalimide is a mother nucleus with a variety of potential drug activities, especially widely used in anti-tumor aspects. For example, pomalidomide and thalidomide, anti-multiple myeloma drugs containing the phthalimide mother nucleus. In addition, Li Xun et al. synthesized a series of phthalimide derivatives targeting ROCKⅠ (a serine / threonine protein kinase) for the treatment of diseases such as non-small cell lung cancer, liver cancer, and gastric adenocarcinoma. More importantly, studies have shown that this mother nucleus also has certain inhibitory activity against hMAO-B. For example, A. Cissola et al. synthesized a series of phthalimide derivatives targeting hMAO-B (IC 50 = 4–129 nM) and used them for the treatment and prevention of AD. However, due to the complex pathogenesis of neurodegenerative diseases, the traditional single-target drug discovery strategy of "looking for one target, developing one drug for one disease" has been difficult to achieve the best therapeutic effect. Therefore, it is crucial to design multi-target compounds for treating central neurodegenerative diseases based on the phthalimide mother nucleus with monoamine oxidase B inhibitory activity.

[0004] The overload of biological metal iron ions is also one of the important pathogenesis of central degenerative diseases. On the one hand, iron ions are related to the formation of Aβ (β-amyloid protein). Iron ions closely regulate the expression of APP through the iron-responsive element in the 5'-untranslated region of amyloid precursor protein (APP) mRNA. On the other hand, iron ions are inseparable from the generation of reactive oxygen species. One way to generate reactive oxygen species is as follows: Molecular oxygen forms superoxide anion radicals under the catalysis of enzymes such as xanthine oxidase, NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase, and cytochrome P450 enzyme system. Superoxide anion radicals generate hydrogen peroxide under the catalysis of superoxide dismutase. Hydrogen peroxide oxidizes ferrous ions to ferric ions through the Fenton reaction, and at the same time generates hydroxyl radicals. Superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals all belong to reactive oxygen species, and reactive oxygen species will damage some biological macromolecules such as proteins, nucleic acids, and lipids. In this reactive oxygen species generation pathway, since the activities of enzymes such as xanthine oxidase, NADPH oxidase, and cytochrome P450 enzyme system must rely on iron or iron derivatives, if the concentration of iron ions increases, reactive oxygen species will also increase to a certain extent. Deferiprone (DFP) is a common iron ion chelator. It is a bidentate ligand, and its iron chelating activity is mainly based on the 3-hydroxypyridin-4-one (hydroxypyridone) part in its molecular structure.

[0005] There is a close connection between the overexpression of hMAO-B and the overload of metal iron ions in the pathogenesis of neurodegenerative diseases: H2O2 is produced during the oxidative deamination of hMAO-B. H2O2 undergoes the Fenton reaction to oxidize ferrous ions to iron ions, and at the same time generates hydroxyl radicals. The overexpression of hMAO-B and the overload of metal iron ions play a synergistic role, leading to an increase in reactive oxygen species. Reactive oxygen species damage brain cells and are likely to cause the occurrence of central neurodegenerative diseases AD and PD. Therefore, choosing a suitable chemical linker to combine the phthalimide parent nucleus with hMAO-B inhibitory activity and the hydroxypyridone derivative with iron ion chelating activity into one molecule to develop a class of monoamine oxidase B inhibitors with iron ion chelating activity has great research prospects in the research and development of multi-target monoamine oxidase B inhibitors. Summary of the Invention

[0006] To solve the above problems, based on principles such as multi-target ligand strategy, computer-aided drug design, pharmacophore splicing and fusion principle, rational drug design, and drug-likeness, the present invention designed and synthesized a class of monoamine oxidase inhibitors with iron ion chelating activity, and provided a preparation method for phthalimide-fused pyridone derivatives or their pharmaceutically acceptable salts, and their applications in preventing or treating related diseases such as Alzheimer's disease and Parkinson's disease.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] In a first aspect, the present invention provides a phthalimide-fused 3-hydroxy-pyridin-4-one derivative represented by formula (I) and a pharmaceutically acceptable salt thereof:

[0009]

[0010] In formula (I):

[0011] R 1 is a C1-C6 straight-chain or branched alkyl;

[0012] R 2 is H, a C1-C6 straight-chain or branched alkyl, a halogen, a C1-C6 straight-chain or branched haloalkyl, a C1-C6 straight-chain or branched alkoxy or wherein X1 and Z1 are each independently H, a C1-C6 straight-chain or branched alkyl, a halogen, a C1-C6 straight-chain or branched haloalkyl, a C1-C6 straight-chain or branched alkoxy;

[0013] R 3 is H, a C1-C6 straight-chain or branched alkyl, Cl;

[0014] n is the number of CH2, and n is an integer between 1 and 6.

[0015] R 2 and R 3 cannot be hydroxyl. On the one hand, since there is already one hydroxyl group on the pyridone, if there is another hydroxyl group on the phthalimide, it will significantly reduce the BBB permeability of the examples and cannot achieve the purpose of treating the central neurodegenerative disease AD.

[0016] Preferably, R 1 is a C1-C4 straight-chain or branched alkyl; R 2 is H, CH3, OCH3, Cl, F or wherein X1 and Z1 are each independently H, CH3, Cl, F, CF3, Br or OCH3; R 3 is H, CH3 or Cl, and n is an integer between 1 and 3.

[0017] Preferably, R 1 is CH3; R 3 is H; R 2 is H, OBn,

[0018] n is 2.

[0019] Specifically, the phthalimide-fused 3-hydroxy-pyridin-4-one derivative represented by formula (I) is one of the following compounds:

[0020]

[0021]

[0022] Specifically, the pharmaceutically acceptable salt is the hydrochloride salt of a derivative of phthalimide-fused 3-hydroxy-4-pyridone represented by formula (I).

[0023] In a second aspect, the present invention also provides an application of the phthalimide / pyridone hybrid derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating related diseases by inhibiting monoamine oxidase (especially monoamine oxidase B), chelating metal iron ions, anti-Aβ deposition or antioxidation. More preferably, the application of the phthalimide / pyridone hybrid derivative represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating related diseases by inhibiting monoamine oxidase B or chelating metal iron ions.

[0024] Furthermore, the disease is a neurodegenerative disease, such as Alzheimer's disease or Parkinson's disease.

[0025] More preferably, the phthalimide / pyridone hybrid derivative is one of the compounds shown as a1-a25.

[0026] Preferably, the derivative of phthalimide-fused 3-hydroxy-4-pyridone represented by formula (I) is one of compounds a9, a10, a11, a13, a14, a15, a16, a17, a18, a20, a22, a23, a24. More preferably, it is compounds a10, a13, a14, a15, a16, a17, a20, a23, a24. Particularly preferably, it is compounds a16, a17, a20, a23, a24. Most preferably, it is compound a23.

[0027] In a third aspect, the present invention also provides a preparation method of a phthalimide / pyridone hybrid derivative represented by formula (I). The synthetic idea is as follows: For the preparation method of the amino-substituted hydroxy-protected pyridone shown in formula 1, please refer to patent CN112521331B; phthalic anhydrides with different substituents at different positions react with the amino-substituted hydroxy-protected pyridone to obtain formula 2, and finally deprotection is carried out to obtain the target compound a1-a7 shown in formula (I). In addition, 4-hydroxyphthalic anhydride is synthesized from 4-hydroxyphthalic acid as a raw material, then the acid anhydride reacts with the amino-substituted hydroxy-protected pyridone to obtain formula 3, and then reacts with benzyl bromides with different substituents at different positions to obtain formula 4, and finally formula 4 is deprotected to obtain the target compounds a8-a25.

[0028] Specifically, the phthalimide / pyridone hybrid derivative represented by formula (I) of the present invention is prepared according to the following method:

[0029] I. When R 2 is not , the method includes the following steps:

[0030] (1) React the compound shown in formula 2 and the intermediate of formula 1 in organic solvent A at 120 °C with stirring for 2 h. The obtained reaction solution A is post-treated by post-treatment A to obtain the intermediate shown in formula 3; the molar ratio of the compound shown in formula 2 to the intermediate of formula 1 is 1:1.2 to 2.0 (preferably 1:1.5);

[0031] (2) Dissolve the intermediate of formula 3 obtained in step (1) in organic solvent B. Under nitrogen protection, dropwise add a dichloromethane solution of the compound shown in formula 4 at -48 °C. After dropping, stir and react at room temperature for 12 h, then add methanol to quench the reaction. After adding, continue to stir and react for 1 h. The obtained reaction solution B is post-treated by post-treatment B to obtain the phthalimide / pyridone derivative shown in formula (I); the molar ratio of the intermediate of formula 3 to the compound shown in formula 4 contained in the dichloromethane solution of the compound shown in formula 4 is 1:2.0 to 4.0 (preferably 1:3.0);

[0032]

[0033] The ranges of each substituent and n are the same as above.

[0034] Furthermore, the organic solvent A in step (1) is acetic acid.

[0035] Furthermore, the volume of the organic solvent A in step (1) is 3 to 6 mL / mmol (preferably 4 mL / mmol) based on the amount of substance of the intermediate of formula 1.

[0036] Furthermore, the post-treatment A in step (1) is: pour the reaction solution A into ice water, a solid precipitates, filter by suction, wash the obtained filter cake with water, and dry it to obtain the intermediate shown in formula 3.

[0037] In an embodiment of the present invention, the concentration of the dichloromethane solution of the compound shown in formula 4 in step (2) is 0.3 mol / L.

[0038] Furthermore, the organic solvent B in step (2) is dichloromethane (DCM), and the volume of the organic solvent B is 10 to 20 mL / mmol (preferably 14 mL / mmol) based on the amount of substance of the intermediate of formula 3.

[0039] Further, the volume of methanol in step (2) is 4 - 8 mL / mmol (preferably 5 mL / mmol) based on the amount of substance of the intermediate of formula 3.

[0040] Further, the post-treatment B in step (2) is as follows: The reaction solution B is distilled under reduced pressure to remove the solvent, recrystallized with methanol, filtered by suction, and the obtained filter cake is dried to obtain the phthalimide / pyridone hybrid derivative shown in formula (I).

[0041] II. When R 2 is the method comprises the following steps:

[0042] 1) Dissolve the compound shown in formula 6 in acetic anhydride, stir at 120 °C for 30 min, and evaporate the solvent from the obtained reaction solution to obtain the compound shown in formula 7;

[0043] 2) Dissolve the compound of formula 7 in step 1) in organic solvent C, add the intermediate of formula 1, stir at 120 °C for 2 h, and the obtained reaction solution C is subjected to post-treatment C to obtain the intermediate of formula 8; the molar ratio of the compound of formula 7 to the intermediate of formula 1 is 1:1.0 - 2.0 (preferably 1:1.5);

[0044] 3) Dissolve the intermediate of formula 8 and a basic substance in organic solvent D, stir and react at 65 °C for 10 min, dropwise add the compound shown in formula 9, and after completion of the dropwise addition, continue to react for 8 h. The obtained reaction solution D is subjected to post-treatment D to obtain the intermediate of formula 10. The molar ratio of the intermediate of formula 8, the basic substance to the compound shown in formula 9 is 1:1.0 - 1.3:1.5 - 2.5 (preferably 1:1.1:2.0);

[0045] 4) Dissolve the intermediate of formula 10 obtained in step 3) in organic solvent E, dropwise add a dichloromethane solution of the compound shown in formula 4 under nitrogen protection at -48 °C, and after completion of the dropwise addition, transfer to room temperature and continue to stir and react for 12 h. Then add methanol to quench the reaction, and after completion of the addition, continue to stir and react for 1 h. The obtained reaction solution E is subjected to post-treatment E to obtain the phthalimide / pyridone hybrid derivative shown in formula (I); the molar ratio of the intermediate of formula 10 to the compound shown in formula 4 is 1:1.1 - 1.7 (preferably 1:1.3);

[0046]

[0047]

[0048] The ranges of each substituent and n are the same as above.

[0049] Further, the volume of acetic anhydride described in step 1) is 1.3 - 1.6 mL / mmol (preferably 1.5 mL / mmol) based on the amount of substance of the compound of formula 6.

[0050] Further, the organic solvent C in step 2) is acetic acid, and the volume of the organic solvent C is 3 - 6 mL / mmol (preferably 4 mL / mmol) based on the amount of substance of the intermediate of formula 1.

[0051] Further, the post-treatment C in step 2) is as follows: Pour the reaction solution C into ice water, a solid precipitates, filter by suction, wash the obtained filter cake with water, and dry it to obtain the intermediate shown in formula 8.

[0052] Further, the basic substance in step 3) is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, and sodium hydroxide (preferably potassium carbonate).

[0053] Further, the organic solvent D in step 3) is methanol; the volume of the organic solvent D is 4 - 8 mL / mmol (preferably 6 mL / mmol) based on the amount of substance of the intermediate of formula 8.

[0054] Further, the post-treatment D in step 3) is as follows: After the reaction is completed, distill off the solvent methanol in the reaction solution under reduced pressure, add water for dilution, extract with dichloromethane (DCM), combine the organic phases, dry with anhydrous sodium sulfate, then distill off the solvent under reduced pressure, and perform column chromatography separation using a dichloromethane / methanol mixed solution with a volume ratio of 60:1, 40:1, 20:1 as the eluent, collect the eluate containing the target intermediate, and concentrate it to obtain the intermediate of formula 10.

[0055] In one embodiment of the present invention, the concentration of the dichloromethane solution of the compound shown in formula 4 in step 4) is 0.2 mol / L.

[0056] Further, the organic solvent E in step 4) is dichloromethane, and the volume of the organic solvent E is 10 - 20 mL / mmol (preferably 14 mL / mmol) based on the amount of substance of the intermediate of formula 3.

[0057] Further, the volume of methanol in step 4) is 4 - 8 mL / mmol (preferably 5 mL / mmol) based on the amount of substance of the intermediate of formula 10.

[0058] Further, the post-treatment E in step 4) is as follows: Distill off the solvent from the reaction solution E under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain the phthalimide / pyridone hybrid derivative shown in formula (I).

[0059] The letters A, B, C, D, E, etc. in the above steps are only used to distinguish substances in different stages, different reaction solutions and different post-treatment methods, and have no other special meanings.

[0060] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention synthesizes a class of monoamine oxidase B inhibitors with iron ion chelating activity, and innovatively combines a hydroxypyridone derivative with iron ion chelating activity and a phthalimide derivative with hMAO-B inhibitory activity, and has significant advantages in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease with complex pathogenesis. Detailed implementation manners

[0061] The present invention will be further described below in conjunction with specific examples, but the present invention is not limited to these examples.

[0062] The synthesis method of compound 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one refers to patent CN112521331B. Phthalic anhydrides substituted with different substituents (such as 3-methylphthalic anhydride, 3-chlorophthalic anhydride, etc., except 4-hydroxypthalic anhydride) and benzyl bromides (such as 4-fluorobenzyl bromide and 4-chlorobenzyl bromide) required in the experimental process are all purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd. and Bide Pharmatech. Solvents required in the experiment such as acetic acid, acetic anhydride, methanol, ethanol, dichloromethane (including analytical grade dichloromethane and anhydrous dichloromethane), etc. are all purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai Experiment). Other reagents required in the experiment such as boron trichloride, sodium hydroxide, potassium carbonate, etc. are all purchased from Sigma-Aldrich Chemical Technology (Shanghai) Co., Ltd.

[0063] The synthesis route of the key intermediate 4-hydroxypthalic anhydride in the following Examples 8-25 is as follows: 4-Hydroxyphthalic acid and acetic anhydride are stirred at 120 °C for 30 min, and the obtained reaction solution is distilled under reduced pressure to obtain white solid 4-hydroxypthalic anhydride; the volume of the acetic anhydride is 1.5 mL / mmol based on the amount of substance of the 4-hydroxyphthalic acid.

[0064] Taking Example 8 as an example: 4-Hydroxyphthalic acid (1.82 g, 10 mmol) and acetic anhydride (15 mL) are added to a single-necked flask, stirred at 120 °C for 30 min, and after the reaction is completed, the solvent acetic anhydride is removed by distillation under reduced pressure to obtain white solid 4-hydroxypthalic anhydride (1.48 g), with a yield of 90.2%.

[0065] Example 1

[0066] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-3-methylphthalimide (a1)

[0067] Add 3-methylphthalic anhydride (0.81 g, 5 mmol), 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (1.9 g, 7.5 mmol) and acetic acid (30 mL) as the solvent into a single-necked flask. Stir at 120 °C for 2 h until the reaction is completed. Then pour the reaction solution into 50 mL of ice water. A large amount of solid precipitates. Filter by suction, wash the filter cake with 10 mL of water, and dry to obtain a yellow solid (1.36 g) with a yield of 67.7%.

[0068] Add the above yellow solid (1.20 g, 2.98 mmol) and anhydrous dichloromethane (41.72 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 8.94 mL) with anhydrous dichloromethane solution (29.8 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After dropping, transfer to room temperature and continue to stir and react for 12 h. After the raw materials are completely converted, add 14.9 mL of methanol to quench. After reacting for 1 h, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a1 (0.88 g) with a yield of 94.6% and a purity of 99.38%.

[0069] m.p. 281.4 - 282.7 °C; ESI-HRMS: m / z calcd for C 17 H 16 N2O4[M + H] + : 313.1110; found: 313.1183; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.15 (d, J = 6.8 Hz, 1H), 7.73–7.61 (m, 3H), 7.22 (d, J = 6.8 Hz, 1H), 4.59 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 2.61 (s, 3H), 2.59 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 168.1, 167.3, 159.3, 143.1, 141.4, 138.6, 137.3, 136.7, 134.1, 131.7, 128.1, 120.9, 110.6, 54.4, 36.6, 17.0, 12.6.

[0070] Example 2

[0071] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-3-chlorophthalimide (a2)

[0072] Add 3-chlorophthalic anhydride (0.91 g, 5 mmol), 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (1.9 g, 7.5 mmol) and acetic acid (30 mL) as the solvent into a single-necked flask. Stir at 120 °C for 2 h until the reaction is completed. Then pour the reaction solution into 50 mL of ice water. A large amount of solid precipitates. Filter by suction, wash the filter cake with 10 mL of water, and dry to obtain a yellow solid (1.48 g) with a yield of 70.1%.

[0073] Add the above yellow solid (1.30 g, 3.07 mmol) and anhydrous dichloromethane (42.98 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 9.21 mL) with anhydrous dichloromethane solution (30.7 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After dropping, transfer to room temperature and continue to stir the reaction for 12 h. After the raw materials are completely converted, add 15.35 mL of methanol to quench the reaction. After reacting for 1 h, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a2 (0.97 g) with a yield of 95.1% and a purity of 98.99%.

[0074] m.p. 280.3 - 281.2 °C; ESI-HRMS: m / z calcd for C 16 H 13 ClN2O4[M + H] + : 333.0564; found: 333.0638; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.19 (d, J = 6.8 Hz, 1H), 7.88–7.81 (m, 3H), 7.22 (d, J = 6.8 Hz, 1H), 4.59 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.6 Hz, 2H), 2.62 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 166.2, 165.2, 159.3, 143.2, 141.4, 138.7, 136.1, 135.8, 133.7, 129.6, 127.3, 122.2, 110.6, 54.3, 37.0, 12.6.

[0075] Example 3

[0076] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-chlorophthalimide (a3)

[0077] Add 4-chlorophthalic anhydride (0.91 g, 5 mmol), 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (1.9 g, 7.5 mmol) and acetic acid (30 mL) as the solvent into a single-necked flask. Stir at 120 °C for 2 h until the reaction is completed. Then pour the reaction solution into 50 mL of ice water. A large amount of solid precipitates. Filter by suction, wash the filter cake with 10 mL of water, and dry to obtain a yellow solid (1.52 g) with a yield of 72.0%.

[0078] Add the above yellow solid (1.33 g, 3.15 mmol) and anhydrous dichloromethane (44.1 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 9.45 mL) with anhydrous dichloromethane solution (31.5 mL) and place it in a constant-pressure dropping funnel. Under the protection of N2, slowly drop the diluted boron trichloride anhydrous dichloromethane solution at -48 °C. After dropping, transfer to room temperature and continue to stir the reaction for 12 h. After the raw materials are completely converted, add 15.75 mL of methanol to quench the reaction. After reacting for 1 h, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a3 (0.97 g) with a yield of 92.4% and a purity of 100.00%.

[0079] m.p. 290.8 - 292.5 °C; ESI-HRMS: m / z calcd for C 16 H 13 ClN2O4 [M + H] + : 333.0564; found: 333.0637; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.16 (d, J = 6.8 Hz, 1H), 7.98 (dd, J = 1.6, 0.8 Hz, 1H), 7.92–7.87 (m, 2H), 7.21 (d, J = 6.8 Hz, 1H), 4.59 (t, J = 5.6 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 2.61 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 166.6, 166.3, 159.3, 143.1, 141.3, 139.5, 138.7, 134.4, 133.4, 130.0, 125.0, 123.4, 110.6, 54.4, 37.0, 12.6.

[0080] Example 4

[0081] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-fluorophthalimide (a4)

[0082] Add 4-fluorophthalic anhydride (0.83 g, 5 mmol), 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (1.9 g, 7.5 mmol) and acetic acid (30 mL) as the solvent into a single-necked flask. Stir at 120 °C for 2 h until the reaction is completed. Then pour the reaction solution into 50 mL of ice water. A large amount of solid precipitates. Filter by suction, wash the filter cake with 10 mL of water, and dry to obtain a yellow solid (1.57 g) with a yield of 77.3%.

[0083] Add the above yellow solid (1.30 g, 3.20 mmol) and anhydrous dichloromethane (44.8 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 9.60 mL) with anhydrous dichloromethane solution (32 mL) and place it in a constant-pressure dropping funnel. Under N2 protection, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise at -48 °C. After dropping, transfer to room temperature and continue to stir and react for 12 h. After the raw materials are completely converted, add 16 mL of methanol to quench the reaction. After reacting for 1 h, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a4 (0.90 g) with a yield of 89.1% and a purity of 99.22%.

[0084] m.p. 273.6 - 275.1 °C; ESI-HRMS: m / z calcd for C 16 H 13 FN2O4[M + H] + : 317.0859; found: 317.0933; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.94 (dd, J = 8.4, 4.4 Hz, 1H), 7.78 (dd, J = 7.2, 2.0 Hz, 1H), 7.71–7.63 (m, 2H), 6.39 (d, J = 6.8 Hz, 1H), 4.34 (t, J = 5.6 Hz, 2H), 3.91 (t, J = 5.6 Hz, 2H), 2.42 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 167.1 (d, 1 J C-F = 252.2 Hz), 166.5, 166.2, 166.2, 165.5, 144.7, 138.2, 134.4 (d, 3 J C-F = 9.7 Hz), 133.2, 127.6 (d, 4 J C-F = 2.6 Hz), 126.1 (d, 3 J C-F = 9.6 Hz), 121.5 (d,2 J C-F = 23.5 Hz), 111.3 (d, 2 J C-F = 25.2 Hz), 110.7, 52.2, 37.4, 11.8.

[0085] Example 5

[0086] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridin-1-yl)ethyl)-4-methylphthalimide (a5)

[0087] Add 4-methylphthalic anhydride (0.81 g, 5 mmol), 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (1.9 g, 7.5 mmol) and solvent acetic acid (30 mL) into a single-necked flask. Stir at 120 °C for 2 h until the reaction is completed. Then pour the reaction solution into 50 mL of ice water. A large amount of solid precipitates. Filter by suction, wash the filter cake with 10 mL of water, and dry to obtain a yellow solid (1.40 g) with a yield of 69.7%.

[0088] Add the above yellow solid (1.15 g, 2.86 mmol) and anhydrous dichloromethane (40.04 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 8.58 mL) with anhydrous dichloromethane solution (28.6 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After dropping, transfer to room temperature and continue to stir and react for 12 h. After the raw materials are completely converted, add 14.3 mL of methanol to quench. After reacting for 1 h, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a5 (0.84 g) with a yield of 94.4% and a purity of 99.18%.

[0089] m.p. 296.6 - 298.6 °C; ESI-HRMS: m / z calcd for C 17 H 16 N2O4 [M + H] + : 313.1110; found: 313.1184; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.13 (d, J = 6.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.70–7.68 (m, 1H), 7.65 (dt, J = 7.6, 0.8 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 4.59 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H), 2.47 (s, 3H);13 13C NMR(100MHz, DMSO-d6): δ 167.6, 167.5, 159.3, 145.7, 143.2, 141.3, 138.7, 135.0, 131.7, 128.7, 123.7, 123.2, 110.6, 54.5, 36.8, 21.3, 12.6.

[0090] Example 6

[0091] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-methoxyphthalimide (a6)

[0092] Add 4-methoxyphthalic anhydride (0.89 g, 5 mmol), 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (1.9 g, 7.5 mmol) and solvent acetic acid (30 mL) into a single-necked flask, stir at 120 °C for 2 h until the reaction is completed. Then pour the reaction solution into 50 mL of ice water, a large amount of solid precipitates. Filter by suction, wash the filter cake with 10 mL of water, dry to obtain a yellow solid (1.38 g), and the yield is 66.0%.

[0093] Add the above yellow solid (1.10 g, 2.63 mmol) and anhydrous dichloromethane (36.82 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 7.89 mL) with anhydrous dichloromethane solution (26.3 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After dropping, transfer to room temperature and continue to stir and react for 12 h. After the raw materials are completely converted, add 13.15 mL of methanol to quench. After reacting for 1 h, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a6 (0.79 g), with a yield of 91.9% and a purity of 99.70%.

[0094] m.p. 290.2 - 291.9 °C; ESI-HRMS: m / z calcd for C 17 H 16 N2O5[M + H] + : 329.1059; found: 329.1133; 11H NMR (400 MHz, DMSO-d6) δ (ppm) 8.14 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 4.58 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.59 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.2, 167.1, 164.6, 159.3, 143.1, 141.3, 138.7, 134.0, 125.2, 123.1, 120.0, 110.6, 108.5, 56.4, 54.5, 36.8, 12.6.

[0095] Example 7

[0096] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)phthalimide (a7)

[0097] Add phthalic anhydride (0.74 g, 5 mmol), 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (1.9 g, 7.5 mmol) and solvent acetic acid (30 mL) into a single-necked flask, stir at 120 °C for 2 h until the reaction is completed, then pour the reaction solution into 50 mL of ice water, a large amount of solid precipitates, filter by suction, wash the filter cake with 10 mL of water, dry to obtain a yellow solid (1.38 g), and the yield is 71.1%.

[0098] Add the above yellow solid (1.10 g, 2.83 mmol) and anhydrous dichloromethane (39.62 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 8.49 mL) with anhydrous dichloromethane solution (28.3 mL) and place it in a constant-pressure dropping funnel. Slowly drop the diluted boron trichloride anhydrous dichloromethane solution under N2 protection at -48 °C. After dropping, transfer to room temperature and continue to stir and react for 12 h. After the raw materials are completely converted, add 14.15 mL of methanol to quench. After reacting for 1 h, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake to obtain white solid a7 (0.78 g), the yield is 92.9%, and the purity is 99.31%.

[0099] m.p. 290.2 - 291.4 °C; ESI-HRMS: m / z calcd for C 16 H 14 N2O4[M + H] +: 299.0954; found: 299.1027; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.16 (d, J = 7.2 Hz, 1H), 7.90–7.82 (m, 4H), 7.20 (d, J = 6.8 Hz, 1H), 4.60 (t, J = 5.2 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 2.60 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.5, 159.3, 143.2, 141.3, 138.7, 134.7, 131.4, 123.3, 110.6, 54.5, 36.8, 12.6.

[0100] Example 8

[0101] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(2,4-difluorobenzyloxy)phthalimide (a8): In a single-necked flask, add 4-hydroxyphthalic anhydride (1.40 g, 8.53 mmol), then add 1-(2-aminoethyl)-2-methyl-3-benzyloxypyridin-4-one (3.3 g, 12.80 mmol) and solvent acetic acid (51.2 mL). React at 120 °C for 2 h. After the reaction is completed, pour the reaction solution into 50 mL of ice water. A large amount of solid precipitates. Filter by suction, wash the filter cake with 10 mL of water, and dry to obtain 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinyl)ethyl)-5-hydroxyisoindole-1,3-dione (2.68 g) as a yellow solid, with a yield of 77.7%.

[0102] Add the above yellow solid (2.50 g, 6.18 mmol) to a single-necked flask, add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 2,4-difluorobenzyl bromide (2.56 g, 12.36 mmol) dropwise to the reaction solution through a constant-pressure dropping funnel. After the addition is completed, continue to stir and react for 8 h. After the reaction is completed, distill off methanol from the reaction solution under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, and concentrate under reduced pressure to obtain a pale yellow solid of the compound (1.97 g), with a yield of 60.1%.

[0103] Add the above-mentioned pale yellow solid (1.70 g, 3.20 mmol) and anhydrous dichloromethane (44.8 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.16 mL) with anhydrous dichloromethane solution (20.8 mL) and place it in a constant-pressure dropping funnel. Under N2 protection and at -48 °C, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise. After the addition, transfer it to room temperature and continue stirring the reaction for 12 h. Then add 16 mL of methanol to quench the reaction. After continuing to stir for 1 h, the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a8 (1.32 g) with a yield of 93.6% and a purity of 97.07%.

[0104] m.p. 258.2 - 259.3 °C; ESI-HRMS: m / z calcd for C 23 H 18 F2N2O5[M + H] + : 441.1184; found: 441.1261; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.16 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.67 (td, J = 8.4, 6.4 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.4, 2.4 Hz, 1H), 7.36–7.29 (m, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.19–7.13 (m, 1H), 5.30 (s, 2H), 4.59 (t, J = 5.2 Hz, 2H), 3.98 (t, J = 5.2 Hz, 2H), 2.60 (s, 3H); 13 C NMR (100 MHz, DMSO-d6): δ 167.1, 167.1, 163.8 (d, 1 J C-F = 246.1 Hz), 163.7 (d, 1 J C-F = 246.8 Hz), 163.3, 162.1 (d, 3 J C-F = 12.2 Hz), 159.6 (d, 3 J C-F = 12.6 Hz), 159.2, 143.1, 141.4, 138.7, 134.0, 132.6 (d, 3 J C-F = 10.0 Hz), 132.5 (d, 3 J C-F= 9.9 Hz), 120.7, 119.5 (d, 4 J C-F = 3.6 Hz), 119.3 (d, 4 J C-F = 3.7 Hz), 111.8 (d, 2 J C-F = 21.2 Hz), 111.8 (d, 2 J C-F = 21.1 Hz), 110.6, 109.2, 104.4 (t, 2 J C-F = 25.6 Hz), 103.9, 64.3, 54.5, 36.8, 12.6.

[0105] Example 9

[0106] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(2-(trifluoromethyl)benzyloxy)phthalimide (a9)

[0107] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 2-(trifluoromethyl)benzyl bromide (2.95 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol from the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction, and combine the organic layers. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, and obtain a pale yellow solid (2.04 g) of the compound after concentration under reduced pressure, with a yield of 58.6%.

[0108] Add the above-mentioned pale yellow solid (1.70 g, 3.02 mmol) and anhydrous dichloromethane (42.28 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 3.93 mL) with anhydrous dichloromethane solution (19.65 mL) and place it in a constant-pressure dropping funnel. Under N2 protection and at -48 °C, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise. After the addition is complete, transfer it to room temperature and continue stirring for reaction for 12 h. Subsequently, add 15.10 mL of methanol to quench the reaction, continue stirring for 1 h, and then the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake, and obtain white solid a9 (1.29 g) with a yield of 90.2% and a purity of 98.01%.

[0109] m.p. 272.5 - 274.2 °C; ESI-HRMS: m / z calcd for C 24 H 19 F3N2O5[M + H] + : 473.1246; found: 473.1322; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.15 (d, J = 7.2 Hz, 1H), 7.84–7.78 (m, 3H), 7.75 (td, J = 7.2, 1.2 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.4, 2.4 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 5.41 (s, 2H), 4.59 (t, J = 6.0 Hz, 2H), 3.98 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H); 13 C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.1, 159.3, 143.1, 141.3, 138.7, 134.1, 133.7, 132.9, 131.1, 129.2, 127.4 (d, 2 J C-F = 25.4 Hz), 126.3 (t, 4 J C-F = 5.5 Hz), 125.6 (d, 1 J C-F = 272.4 Hz), 125.3, 123.7, 120.6, 110.6, 109.2, 67.4, 54.5, 36.8, 12.6.

[0110] Example 10

[0111] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(2-chlorobenzyloxy)phthalimide (a10)

[0112] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g (6.18 mmol) and place it in a single-necked flask. Add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min. Then slowly add 2-chlorobenzyl bromide (2.54 g, 12.36 mmol) dropwise to the reaction solution through a constant-pressure dropping funnel. After the addition is complete, continue stirring and reacting for 8 h. After the reaction is completed, remove methanol in the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate. Concentrate under reduced pressure and perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound. After concentration under reduced pressure, a pale yellow solid (1.86 g) of the compound is obtained, and the yield is 56.9%.

[0113] Add the above pale yellow solid (1.50 g, 2.84 mmol) and anhydrous dichloromethane (39.76 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 3.69 mL) with anhydrous dichloromethane solution (18.45 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue stirring and reacting for 12 h. Then add 14.2 mL of methanol to quench the reaction and continue stirring for 1 h. After the reaction is completed. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake, and obtain white solid a10 (1.19 g) with a yield of 95.2% and a purity of 98.74%.

[0114] m.p. 270.1 - 271.1 °C; ESI-HRMS: m / z calcd for C 23 H 19 ClN2O5[M + H] + : 439.0982; found: 439.1059; 11H NMR (400 MHz, DMSO-d6) δ (ppm) 8.15 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.65–7.61 (m, 1H), 7.55–7.50 (m, 2H), 7.44–7.39 (m, 3H), 7.18 (d, J = 6.8 Hz, 1H), 5.34 (s, 2H), 4.59 (t, J = 6.0 Hz, 2H), 3.98 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.1, 167.1, 163.4, 159.3, 143.1, 141.3, 138.7, 134.0, 133.3, 133.0, 130.6, 130.3, 129.5, 127.5, 125.3, 123.6, 120.7, 110.6, 109.2, 68.0, 54.5, 36.9, 12.6.

[0115] Example 11

[0116] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(2-fluorobenzyloxy)phthalimide (a11)

[0117] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 2-fluorobenzyl bromide (2.34 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol from the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction, and combine the organic layers. Dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, and concentrate under reduced pressure to obtain a pale yellow solid (1.97 g) of the compound, with a yield of 62.1%.

[0118] Add the above-mentioned pale yellow solid (1.70 g, 3.32 mmol) and anhydrous dichloromethane (46.48 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.32 mL) with anhydrous dichloromethane solution (21.6 mL) and place it in a constant-pressure dropping funnel. Under N2 protection and at -48 °C, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise. After the addition is complete, transfer it to room temperature and continue stirring the reaction for 12 h. Subsequently, add 16.6 mL of methanol to quench the reaction. After continuing to stir for 1 h, the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a11 (1.27 g) with a yield of 90.7% and a purity of 98.10%.

[0119] m.p. 264.1 - 265.6 °C; ESI-HRMS: m / z calcd for C 23 H 19 FN2O5[M + H] + : 423.1278; found: 423.1356; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.13 (d, J = 6.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.59 (td, J = 7.6, 1.6 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.49–7.38 (m, 2H), 7.31–7.23 (m, 2H), 7.16 (d, J = 6.8 Hz, 1H), 5.33 (s, 2H), 4.58 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H); 13 C NMR (100 MHz, DMSO-d6): δ 167.1, 167.1, 163.3, 161.7 (d, 1 J C-F = 243.7 Hz), 159.3, 143.2, 141.2, 138.7, 134.0, 131.0, 130.9, 130.9 (d, 3 J C-F = 8.4 Hz), 125.3, 124.6 (d, 4 J C-F = 3.4 Hz), 123.5, 122.9, 122.8, 120.7, 115.6 (d, 2 J C-F = 20.8 Hz), 110.6, 109.2, 64.7, 54.5, 36.8, 12.6.

[0120] Example 12

[0121] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(3,4-difluorobenzyloxy)phthalimide (a12)

[0122] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g (6.18 mmol) and place it in a single-necked flask. Add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min. Then slowly add 3,4-difluorobenzyl bromide (2.56 g, 12.36 mmol) dropwise to the reaction solution through a constant-pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol in the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction, and combine the organic layers. Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure to obtain a pale yellow solid of the compound (1.99 g), and the yield is 60.7%.

[0123] Add the above pale yellow solid (1.74 g, 3.28 mmol) and anhydrous dichloromethane (45.92 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.26 mL) with anhydrous dichloromethane solution (21.3 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue to stir and react for 12 h. Then add 16.4 mL of methanol to quench the reaction, continue to stir for 1 h, and the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake to obtain white solid a12 (1.25 g), the yield is 86.8%, and the purity is 99.27%.

[0124] m.p. 256.5 - 257.6 °C; ESI-HRMS: m / z calcd for C 23 H 18 F2N2O5[M + H] + : 441.1184; found: 441.1260; 11H NMR (400 MHz, DMSO-d6) δ (ppm) 8.15 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.57 (ddd, J = 11.6, 7.6, 2.0 Hz, 1H), 7.52–7.43 (m, 2H), 7.39 (dd, J = 8.4, 2.4 Hz, 1H), 7.37–7.31 (m, 1H), 7.24 (d, J = 7.2 Hz, 1H), 5.29 (s, 2H), 4.59 (t, J = 6.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 2.59 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.2, 159.3, 150.6 (d, 1 J C-F = 244.4 Hz), 150.5 (d, 1 J C-F = 244.0 Hz), 150.4 (d, 3 J C-F = 12.3 Hz), 148.0 (d, 3 J C-F = 12.2 Hz), 143.1, 141.3, 138.6, 134.0, 133.9 (d, 3 J C-F = 9.4 Hz), 133.8 (d, 4 J C-F = 2.2 Hz), 125.2, 124.8 (d, 3 J C-F = 10.1 Hz), 124.8 (d, 4 J C-F = 3.4 Hz), 123.5, 120.8, 117.7 (d, 2 J C-F = 17 Hz), 117.1 (d, 2 J C-F = 17.5 Hz), 110.6, 109.3, 68.8, 54.5, 36.8, 12.6.

[0125] Example 13

[0126] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridin-1-yl)ethyl)-4-(3,4-dichlorobenzyloxy)phthalimide (a13)

[0127] 2-(2-(2-Methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione was prepared according to the method of Example 8. Take 2.50 g (6.18 mmol) and place it in a single-necked flask. Add potassium carbonate (0.94 g, 6.80 mmol) and the solvent methanol (37 mL). Stir at 65 °C for 10 min. Then, slowly add 3,4-dichlorobenzyl bromide (2.97 g, 12.36 mmol) dropwise to the reaction solution through a constant-pressure dropping funnel. After the addition is complete, continue stirring and reacting for 8 h. After the reaction is completed, remove methanol from the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction, and combine the organic layers. Dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure, and obtain a pale yellow solid of the compound (2.39 g) with a yield of 68.7%.

[0128] Add the above pale yellow solid (2.10 g, 3.73 mmol) and anhydrous dichloromethane (52.22 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.85 mL) with anhydrous dichloromethane solution (24.25 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue stirring and reacting for 12 h. Then, add 18.65 mL of methanol to quench the reaction, and continue stirring for 1 h. After the reaction is completed, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake, and obtain white solid a13 (1.50 g) with a yield of 84.7% and a purity of 99.21%.

[0129] m.p. 263.2 - 264.5 °C; ESI-HRMS: m / z calcd for C 23 H 18 C l2 N2O5[M + H] + : 473.0593; found: 473.0669; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.13 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 7.6, 2.4 Hz, 2H), 7.40 (dd, J = 8.4, 2.4 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 5.32 (s, 2H), 4.58 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H);13 13C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.1, 159.4, 143.1, 141.1, 138.6, 137.3, 134.0, 131.2, 130.8, 130.7, 129.6, 127.9, 125.2, 123.6, 120.8, 110.6, 109.3, 68.6, 54.4, 36.8, 12.6.

[0130] Example 14

[0131] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(3,5-difluorobenzyloxy)phthalimide (a14)

[0132] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 3,5-difluorobenzyl bromide (2.56 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol in the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure to obtain a pale yellow solid (2.30 g) of the compound, and the yield is 70.1%.

[0133] Add the above pale yellow solid (2.00 g, 3.77 mmol) and anhydrous dichloromethane (52.78 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.90 mL) with anhydrous dichloromethane solution (24.5 mL) and place it in a constant pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue to stir and react for 12 h. Then add 18.85 mL of methanol to quench the reaction, continue to stir for 1 h, and the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake to obtain white solid a14 (1.51 g) with a yield of 91.0% and a purity of 99.25%.

[0134] m.p. 257.9 - 259.3 °C; ESI-HRMS: m / z calcd for C 23 H 18F2N2O5[M+H] + : 441.1184; found: 441.1257; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.15 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.4, 2.4 Hz, 1H), 7.25–7.18 (m, 4H), 5.34 (s, 2H), 4.59 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.7 (d, 1 J C-F = 245.0 Hz), 163.6 (d, 1 J C-F = 245.0 Hz), 163.0, 159.2, 143.1, 141.3, 140.8 (t, 3 J C-F = 9.5 Hz), 138.7, 134.0, 125.3, 123.6, 120.8, 110.7 (d, 2 J C-F = 25.7 Hz), 110.6 (d, 3 J C-F = 11.8 Hz), 110.6, 109.3, 103.7 (t, 2 J C-F = 25.5 Hz), 68.7, 54.5, 36.8, 12.6.

[0135] Example 15

[0136] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridin-1-yl)ethyl)-4-(3,5-dichlorobenzyloxy)phthalimide (a15)

[0137] 2-(2-(2-Methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione was prepared according to the method of Example 8. Take 2.50 g (6.18 mmol) and place it in a single-necked flask. Then add potassium carbonate (0.94 g, 6.80 mmol) and the solvent methanol (37 mL). Stir at 65 °C for 10 min. Then slowly add 3,5-dichlorobenzyl bromide (2.97 g, 12.36 mmol) dropwise to the reaction solution through a constant-pressure dropping funnel. After the addition is complete, continue stirring and reacting for 8 h. After the reaction is completed, remove methanol in the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound and concentrate under reduced pressure to obtain a pale yellow solid of the compound (2.53 g), with a yield of 72.7%.

[0138] Add the above pale yellow solid (2.30 g, 4.08 mmol) and anhydrous dichloromethane (57.12 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 5.30 mL) with anhydrous dichloromethane solution (26.5 mL) and place it in a constant-pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue stirring and reacting for 12 h. Then add 20.4 mL of methanol to quench the reaction and continue stirring for 1 h. After the reaction is completed, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake to obtain white solid a15 (1.72 g), with a yield of 89.1% and a purity of 99.71%.

[0139] m.p. 268.1 - 268.7 °C; ESI-HRMS: m / z calcd for C 23 H 18 Cl2N2O5[M + H] + : 473.0593; found: 473.0670; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.15 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 2H), 7.49 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.0, 2.4 Hz, 1H), 7.22 (d, J = 6.8 Hz, 1H), 5.33 (s, 2H), 4.59 (t, J = 6.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H); 1313C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.0, 159.2, 143.1, 141.3, 140.4, 138.6, 134.2, 134.0, 127.7, 126.2, 125.3, 123.6, 120.8, 110.6, 109.3, 68.4, 54.5, 36.8, 12.6.

[0140] Example 16

[0141] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(3-bromobenzyloxy)phthalimide (a16)

[0142] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 3-bromobenzyl bromide (3.09 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition, continue to stir and react for 8 h. After the reaction is completed, distill off methanol in the reaction solution under reduced pressure. Add dichloromethane (20 mL × 5) for extraction, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure to obtain a pale yellow solid of the compound (2.71 g), and the yield is 76.6%.

[0143] Add the above pale yellow solid (2.35 g, 4.10 mmol) and anhydrous dichloromethane (57.4 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 5.33 mL) with anhydrous dichloromethane solution (26.65 mL) and place it in a constant pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition, transfer to room temperature and continue to stir and react for 12 h. Then add 20.5 mL of methanol to quench the reaction, continue to stir for 1 h, and the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a16 (1.83 g), with a yield of 92.4% and a purity of 99.04%.

[0144] m.p. 263.1 - 264.0 °C; ESI-HRMS: m / z calcd for C 23 H 19 BrN2O5 [M + H] +: 483.0477; found: 483.0554; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.14 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.57–7.54 (m, 1H), 7.50–7.47 (m, 2H), 7.42–7.35 (m, 2H), 7.18 (d, J = 7.2 Hz, 1H), 5.32 (s, 2H), 4.58 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.2, 159.3, 143.1, 141.2, 138.9, 138.6, 134.0, 130.9, 130.7, 130.3, 126.7, 125.2, 123.5, 121.7, 120.8, 110.6, 109.2, 69.1, 54.4, 36.8, 12.6.

[0145] Example 17

[0146] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(3-(trifluoromethyl)benzyloxy)phthalimide (a17)

[0147] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 3-(trifluoromethyl)benzyl bromide (2.95 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol from the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction, and combine the organic layers. Dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, and concentrate under reduced pressure to obtain a pale yellow solid of the compound (2.44 g), with a yield of 70.1%.

[0148] Add the above-mentioned pale yellow solid (2.10 g, 3.73 mmol), anhydrous dichloromethane (52.22 mL) into a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.85 mL) with anhydrous dichloromethane solution (24.25 mL), place it in a constant-pressure dropping funnel. Under N2 protection and at -48 °C, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise. After the addition, transfer it to room temperature and continue to stir the reaction for 12 h. Then add 18.65 mL of methanol to quench the reaction, continue to stir for 1 h, and the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake to obtain white solid a17 (1.66 g) with a yield of 94.3% and a purity of 99.58%.

[0149] m.p. 254.6 - 256.5 °C; ESI-HRMS: m / z calcd for C 24 H 19 F3N2O5[M + H] + : 473.1246; found: 473.1322; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.16 (d, J = 6.8 Hz, 1H), 7.86 (s, 1H), 7.80 (t, J = 7.6 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 8.4, 2.4 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H), 5.41 (s, 2H), 4.59 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.60 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.6, 167.5, 163.8, 159.7, 143.6, 141.9, 139.2, 138.1, 134.5, 132.3, 130.2, 129.9 (d, 2 J C-F = 31.4 Hz), 129.6, 126.0 (d, 1 J C-F = 270.6 Hz), 125.8, 125.4 (t, 4 J C-F = 3.4 Hz), 124.8 (t, 4 J C-F = 3.8 Hz), 124.0, 121.3, 111.1, 109.7, 69.8, 55.0, 37.3, 13.1.

[0150] Example 18

[0151] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(3-methylbenzyloxy)phthalimide (a18)

[0152] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g (6.18 mmol) and place it in a single-necked flask. Add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min. Then slowly add 3-methylbenzyl bromide (2.29 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, distill off methanol in the reaction solution under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure to obtain a pale yellow solid (2.14 g) of the compound, and the yield is 68.2%.

[0153] Add the above pale yellow solid (1.80 g, 3.54 mmol) and anhydrous dichloromethane (49.56 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.60 mL) with anhydrous dichloromethane solution (23 mL) and place it in a constant pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue to stir and react for 12 h. Then add 17.7 mL of methanol to quench the reaction, continue to stir for 1 h, and the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a18 (1.34 g) with a yield of 90.5% and a purity of 98.88%.

[0154] m.p. 257.9 - 258.9 °C; ESI-HRMS: m / z calcd for C 24 H 22 N2O5[M + H] + : 419.1529; found: 419.1604; 11H NMR (600 MHz, DMSO-d6) δ (ppm) 8.13 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.4 Hz, 1H), 7.31–7.27 (m, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.2, 2.4 Hz, 2H), 5.25 (s, 2H), 4.58 (t, J = 6.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 2.59 (s, 3H), 2.32 (s, 3H); 13 13C NMR (150 MHz, DMSO-d6): δ 167.2, 167.1, 163.6, 159.2, 143.1, 141.4, 138.7, 137.8, 136.0, 134.0, 128.8, 128.5, 128.4, 125.3, 125.0, 123.3, 120.8, 110.6, 109.2, 70.3, 54.6, 36.8, 21.0, 12.6.

[0155] Example 19

[0156] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(3-chlorobenzyloxy)phthalimide (a19)

[0157] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 3-chlorobenzyl bromide (2.54 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol in the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, and obtain a pale yellow solid (1.98 g) of the compound after concentration under reduced pressure, with a yield of 60.6%.

[0158] Add the above-mentioned pale yellow solid (1.70 g, 3.21 mmol) and anhydrous dichloromethane (44.94 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.17 mL) with anhydrous dichloromethane solution (20.85 mL) and place it in a constant-pressure dropping funnel. Under N2 protection and at -48 °C, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise. After the addition is complete, transfer it to room temperature and continue to stir the reaction for 12 h. Subsequently, add 16.05 mL of methanol to quench the reaction, and continue to stir for 1 h. Then the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake to obtain white solid a19 (1.29 g) with a yield of 91.5% and a purity of 99.24%.

[0159] m.p. 265.5 - 267.1 °C; ESI-HRMS: m / z calcd for C 23 H 19 ClN2O5 [M + H] + : 439.0982; found: 439.1054; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.14 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.46–7.39 (m, 4H), 7.17 (d, J = 7.2 Hz, 1H), 5.32 (s, 2H), 4.58 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.1, 167.1, 163.3, 159.3, 143.2, 141.2, 138.7, 138.6, 134.0, 133.2, 130.5, 128.1, 127.5, 126.3, 125.3, 123.5, 120.8, 110.6, 109.3, 69.2, 54.5, 36.8, 12.6.

[0160] Example 20

[0161] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(3-fluorobenzyloxy)phthalimide (a20)

[0162] 2-(2-(2-Methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindoline-1,3-dione was prepared according to the method of Example 8. Take 2.50 g (6.18 mmol) and place it in a single-neck flask. Then add potassium carbonate (0.94 g, 6.80 mmol) and the solvent methanol (37 mL). Stir at 65 °C for 10 min. Then slowly add 3-fluorobenzyl bromide (2.34 g, 12.36 mmol) dropwise to the reaction solution through a constant-pressure dropping funnel. After the addition is complete, continue stirring and reacting for 8 h. After the reaction is completed, remove methanol in the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound and concentrate under reduced pressure to obtain a pale yellow solid of the compound (2.00 g) with a yield of 63.1%.

[0163] Add the above pale yellow solid (1.65 g, 3.22 mmol) and anhydrous dichloromethane (45.08 mL) to a single-neck flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.19 mL) with anhydrous dichloromethane solution (20.95 mL) and place it in a constant-pressure dropping funnel. Under N2 protection, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise at -48 °C. After the addition is complete, transfer to room temperature and continue stirring and reacting for 12 h. Then add 16.10 mL of methanol to quench the reaction and continue stirring for 1 h. After the reaction is completed, concentrate the reaction solution under reduced pressure. Recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a20 (1.26 g) with a yield of 92.6% and a purity of 98.76%.

[0164] m.p. 267.1 - 268.0 °C; ESI-HRMS: m / z calcd for C 23 H 19 FN2O5[M + H] + : 423.1278; found: 423.1355; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.13 (d, J = 6.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.51–7.41 (m, 2H), 7.40 (dd, J = 8.4, 2.4 Hz, 1H), 7.36–7.28 (m, 2H), 7.23–7.13 (m, 2H), 5.33 (s, 2H), 4.58 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H); 1313C NMR (100 MHz, DMSO-d6): δ 167.1, 167.1, 163.4 (d, 1 J C-F = 242.2 Hz), 163.3, 159.3, 143.1, 141.3, 139.0 (d, 3 J C-F = 7.7 Hz), 138.7, 134.0, 130.6 (d, 3 J C-F = 8.3 Hz), 125.3, 123.7 (d, 4 J C-F = 3.2 Hz), 123.5, 120.8, 115.0 (d, 2 J C-F = 20.7 Hz), 114.5 (d, 2 J C-F = 21.7 Hz), 110.6, 109.3, 69.3, 54.5, 36.8, 12.6.

[0165] Example 21

[0166] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-benzyloxyphthalimide (a21)

[0167] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 3-fluorobenzyl bromide (2.11 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol from the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure to obtain a pale yellow solid of the compound (1.71 g), and the yield is 55.9%.

[0168] Add the above-mentioned pale yellow solid (1.45 g, 2.93 mmol) and anhydrous dichloromethane (41.02 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 3.81 mL) with anhydrous dichloromethane solution (19.05 mL) and place it in a constant-pressure dropping funnel. Under N2 protection and at -48 °C, slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise. After the addition is complete, transfer it to room temperature and continue stirring the reaction for 12 h. Then add 14.65 mL of methanol to quench the reaction, and continue stirring for 1 h. After the reaction is completed, concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a21 (1.10 g) with a yield of 93.2% and a purity of 98.79%.

[0169] m.p. 272.3 - 274.3 °C; ESI-HRMS: m / z calcd for C 23 H 20 N2O5[M + H] + : 405.1372; found: 405.1449; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.14 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.49–7.46 (m, 3H), 7.43–7.40 (m, 2H), 7.40–7.35 (m, 2H), 7.20 (d, J = 6.8 Hz, 1H), 5.30 (s, 2H), 4.58 (t, J = 6.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 2.59 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.2, 167.1, 163.5, 159.2, 143.1, 141.3, 138.7, 136.0, 134.0, 128.5, 128.1, 127.8, 125.2, 123.3, 120.8, 110.6, 109.2, 70.2, 54.5, 36.8, 12.6.

[0170] Example 22

[0171] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridin-1-yl)ethyl)-4-(3-methoxybenzyloxy)phthalimide (a22)

[0172] 2-(2-(2-Methyl)-(3-benzyloxy)-4-oxopyridin-1-yl)ethyl)-5-hydroxyisoindoline-1,3-dione was prepared according to the method of Example 8. 2.50 g (6.18 mmol) was taken in a single-necked flask, and potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL) were added. The mixture was stirred at 65 °C for 10 min, and then 3-methoxybenzyl bromide (2.49 g, 12.36 mmol) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel. After the addition was completed, the reaction was continued with stirring for 8 h. After the reaction was completed, methanol in the reaction solution was removed by distillation under reduced pressure. Dichloromethane (20 mL × 5) was added for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. The reaction solution containing the target compound was collected, concentrated under reduced pressure, and a pale yellow solid (1.91 g) of the compound was obtained, with a yield of 59.0%.

[0173] The above pale yellow solid (1.55 g, 2.95 mmol) and anhydrous dichloromethane (41.30 mL) were added to a single-necked flask. Boron trichloride (1.0 mol / L in DCM, 3.84 mL) was diluted with anhydrous dichloromethane solution (19.2 mL) and placed in a constant pressure dropping funnel. Under N2 protection and at -48 °C, the diluted boron trichloride anhydrous dichloromethane solution was slowly added dropwise. After the addition was completed, the reaction mixture was transferred to room temperature and stirred for 12 h. Subsequently, 14.75 mL of methanol was added to quench the reaction, and the reaction was continued with stirring for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, recrystallized with methanol, filtered by suction, and the obtained filter cake was dried to obtain a white solid a22 (1.20 g) with a yield of 93.8% and a purity of 95.73%.

[0174] m.p. 250.8 - 252.6 °C; ESI-HRMS: m / z calcd for C 24 H 22 N2O6[M + H] + : 435.1478; found: 435.1554; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.13 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 5.28 (s, 2H), 4.57 (t, J = 5.6 Hz, 2H), 3.96 (t, J = 5.6 Hz, 2H), 3.76 (s, 3H), 2.59 (s, 3H);13 13C NMR(100MHz, DMSO-d6): δ 167.2, 167.1, 163.5, 159.4, 159.2, 143.1, 141.4, 138.7, 137.6, 134.0, 129.7, 125.3, 123.3, 120.8, 119.9, 113.5, 113.4, 110.6, 109.3, 70.0, 55.1, 54.6, 36.9, 12.6.

[0175] Example 23

[0176] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(4-(trifluoromethyl)benzyloxy)phthalimide (a23)

[0177] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 4-(trifluoromethyl)benzyl bromide (2.95 g, 12.36 mmol) to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, distill off methanol in the reaction solution under reduced pressure. Add dichloromethane (20 mL × 5) for extraction and combine the organic layers. Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure to obtain a pale yellow solid of the compound (2.07 g), with a yield of 59.5%.

[0178] Add the above pale yellow solid (1.75 g, 3.11 mmol) and anhydrous dichloromethane (43.54 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.04 mL) with anhydrous dichloromethane solution (20.2 mL) and place it in a constant pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue to stir and react for 12 h. Then add 15.55 mL of methanol to quench the reaction, continue to stir for 1 h, and the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, and dry the obtained filter cake to obtain white solid a23 (1.36 g), with a yield of 92.5% and a purity of 99.72%.

[0179] m.p. 270.4 - 271.8 °C; ESI-HRMS: m / z calcd for C 24 H19 F3N2O5[M+H] + : 473.1323; found: 473.1246; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.14 (d, J = 6.8 Hz, 1H), 7.80 (dd, J = 10.0, 8.4 Hz, 3H), 7.70 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.0, 2.0 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 5.43 (s, 2H), 4.58 (t, J = 6.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 2.59 (s, 3H); 13 C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.2, 159.3, 143.2, 141.3, 141.0, 138.7, 134.0, 128.7 (d, 2 J C-F = 31.7 Hz), 128.2, 125.5 (d, 1 J C-F = 270.6 Hz), 125.4 (t, 4 J C-F = 3.8 Hz), 125.3, 123.6, 120.9, 110.6, 109.3, 69.2, 54.5, 36.9, 12.6.

[0180] Example 24

[0181] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(4-chlorobenzyloxy)phthalimide (a24)

[0182] 2-(2-(2-Methyl)-(3-benzyloxy)-4-oxopyridineethyl)-5-hydroxyisoindole-1,3-dione was prepared according to the method of Example 8. 2.50 g (6.18 mmol) was taken in a single-necked flask, and potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL) were added. It was stirred at 65 °C for 10 min, and then 4-chlorobenzyl bromide (2.54 g, 12.36 mmol) was slowly added dropwise to the reaction solution through a constant pressure dropping funnel. After the addition was completed, the reaction was continued with stirring for 8 h. After the reaction was completed, methanol in the reaction solution was removed by distillation under reduced pressure. Dichloromethane (20 mL × 5) was added for extraction, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography was carried out using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. The reaction solution containing the target compound was collected, concentrated under reduced pressure, and a pale yellow solid (2.09 g) of the compound was obtained, with a yield of 63.9%.

[0183] The above pale yellow solid (1.70 g, 3.21 mmol) and anhydrous dichloromethane (44.94 mL) were added to a single-necked flask. Boron trichloride (1.0 mol / L in DCM, 4.17 mL) was diluted with anhydrous dichloromethane solution (20.85 mL) and placed in a constant pressure dropping funnel. Under N2 protection, the diluted anhydrous dichloromethane solution of boron trichloride was slowly added dropwise at -48 °C. After the addition was completed, it was transferred to room temperature and the reaction was continued with stirring for 12 h. Subsequently, 16.05 mL of methanol was added to quench the reaction, and after continuing to stir for 1 h, the reaction was completed. The reaction solution was concentrated under reduced pressure, recrystallized with methanol, filtered by suction, and the obtained filter cake was dried to obtain white solid a24 (1.26 g) with a yield of 89.4% and a purity of 96.80%.

[0184] m.p. 256.7 - 257.5 °C; ESI-HRMS: m / z calcd for C 23 H 19 ClN2O5[M + H] + : 439.0982; found: 439.1059; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.15 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.52–7.45 (m, 5H), 7.38 (dd, J = 8.0, 2.4 Hz, 1H), 7.22 (d, J = 6.8 Hz, 1H), 5.30 (s, 2H), 4.58 (t, J = 5.2 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H); 1313C NMR (100 MHz, DMSO-d6): δ 167.1, 167.0, 163.3, 159.2, 143.1, 141.3, 138.6, 135.1, 134.0, 132.7, 129.6, 128.5, 125.2, 123.4, 120.8, 110.6, 109.2, 69.3, 54.5, 36.8, 12.6.

[0185] Example 25

[0186] Preparation method of N-(2-(3-hydroxy-2-methyl-4-oxopyridinyl)ethyl)-4-(4-fluorobenzyloxy)phthalimide (a25)

[0187] Prepare 2-(2-(2-methyl)-(3-benzyloxy)-4-oxopyridinylethyl)-5-hydroxyisoindole-1,3-dione according to the method of Example 8. Take 2.50 g, 6.18 mmol in a single-necked flask, and add potassium carbonate (0.94 g, 6.80 mmol) and solvent methanol (37 mL). Stir at 65 °C for 10 min, and then slowly add 4-fluorobenzyl bromide (2.34 g, 12.36 mmol) dropwise to the reaction solution through a constant pressure dropping funnel. After the addition is complete, continue to stir and react for 8 h. After the reaction is completed, remove methanol in the reaction solution by distillation under reduced pressure. Add dichloromethane (20 mL × 5) for extraction, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Perform silica gel column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, 40:1, and 20:1 as the eluent. Collect the reaction solution containing the target compound, concentrate under reduced pressure to obtain a pale yellow solid of the compound (2.02 g), and the yield is 63.7%.

[0188] Add the above pale yellow solid (1.70 g, 3.32 mmol) and anhydrous dichloromethane (46.48 mL) to a single-necked flask. Dilute boron trichloride (1.0 mol / L in DCM, 4.32 mL) with anhydrous dichloromethane solution (21.6 mL) and place it in a constant pressure dropping funnel. Slowly add the diluted boron trichloride anhydrous dichloromethane solution dropwise under N2 protection at -48 °C. After the addition is complete, transfer to room temperature and continue to stir and react for 12 h. Then add 16.6 mL of methanol to quench the reaction, continue to stir for 1 h, and the reaction ends. Concentrate the reaction solution under reduced pressure, recrystallize with methanol, filter by suction, dry the obtained filter cake to obtain white solid a25 (1.32 g), with a yield of 94.3% and a purity of 98.21%.

[0189] m.p. 263.7 - 264.9 °C; ESI-HRMS: m / z calcd for C 23 H 19 FN2O5 [M + H] +: 423.1278; found: 423.1355; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.13 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.56–7.50 (m, 2H), 7.47 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.4, 2.4 Hz, 1H), 7.27–7.21 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 5.28 (s, 2H), 4.58 (t, J = 6.0 Hz, 2H), 3.97 (t, J = 6.0 Hz, 2H), 2.59 (s, 3H); 13 13C NMR (100 MHz, DMSO-d6): δ 167.2, 167.1, 163.4, 163.1 (d, 1 J C-F = 242.5 Hz), 159.3, 143.1, 141.2, 138.7, 134.0, 132.3 (d, 4 J C-F = 3.1 Hz), 130.2 (d, 3 J C-F = 8.4 Hz), 125.2, 123.3, 120.8, 115.5 (d, 2 J C-F = 21.4 Hz), 110.6, 109.2, 69.5, 54.5, 36.8, 12.6.

[0190] The following are the pharmacological experimental data of some compounds of the present invention:

[0191] 1. Determination of the iron ion chelating ability of compounds a1 - a25

[0192] According to the principle of spectrophotometry, an automatic titration system was used to measure the pK a and Logβ of the examples. All the data measured in the whole process were recorded and backed up by an internal Visual Basic program. According to the above method, the pK a1 , pK a2 , Logβ1, Logβ2 and Logβ3 values of each example were obtained, and then the pFe 3+ value was calculated by fitting with HYSS software.

[0193] The results showed that the pFe 3+The values are all greater than 17, such as Examples a7, a10, a16, a23, etc. The iron chelating activities of the examples are equivalent to or stronger than those of Deferiprone (DFP), indicating that this series of compounds has excellent iron ion chelating ability.

[0194] Table 1. pFe of Examples a1 - a25 3+ value a

[0195]

[0196]

[0197] a: pK a Measurement system: 0.1M KCl solution

[0198] b: Measurement systems for Logβ1, Logβ2 and Logβ3: DMSO:KCl(0.1M) = 2:3 (V / V)

[0199] c: Measurement systems for Logβ2 and Logβ3: DMSO:KCl(0.1M) = 1:1 (V / V)

[0200] d: Reference values (0.1M KCl) of CP20 (deferiprone) reported in the literature (Xie YY, Lu ZD, Kong XL, Zhou T, Bansal S, Hider R. Systematic comparison of the mono-, dimethyl- and trimethyl 3-hydroxy-4(1H)-pyridones - Attempted optimization of the orally active iron chelator, deferiprone. Eur J Med Chem 2016;115:132 - 140.)

[0201] From the determination of the iron ion chelating constant, we can know that Example a7 (pFe 3+ = 19.32) and Example a23 (pFe 3+ = 19.52) perform the best among the 25 compounds in this case.

[0202] 2. Determination of the inhibitory activity of the compound against hMAO - B

[0203] Experimental method:

[0204] Purchase the hMAO B kit from Sigma and store it at -80 °C for later use. Prepare the enzyme solution and substrate solution in advance according to the kit instructions. Take 5 μL of test compounds at different concentrations (1 nM, 10 nM, 500 nM, 1 μM, 10 μM, 20 μM) and mix them with 25 μL of the enzyme solution, then add the mixture to a Corning bottom-reading 96-well microtiter plate and incubate it with shaking at 37 °C for 10 minutes. Then add 20 μL of the substrate solution, and quantify the results based on the fluorescence generated (excitation, 535 nm; emission, 587 nm) in a multi-detection microplate fluorescence reader. The hMAO-A test method is similar to that of hMAO-B, but the test temperature should be set at 25 °C.

[0205] The results show that the compounds prepared in some embodiments of the present invention have strong inhibitory effects on hMAO-B. When the concentration of the embodiment is 1 μM, the inhibition rate of hMAO-B is generally good, up to 95.89% ± 3.03%. The IC 50 value of the best active embodiment a16 reaches 0.064 ± 0.08 μM, which is better than the IC 50 value of the positive control drug Pargyline (0.341 ± 0.01 μM). In addition, the inhibition rate of the compounds prepared in some embodiments on hMAO-A is about 10% at 20 μM, which is much lower than the inhibition rate of the positive drug Pargyline (60.69% ± 2.03%). Therefore, the selectivity of these compounds for hMAO-B is also better than that of Pargyline.

[0206] Table 2. Inhibition rates of some embodiments on MAO-B

[0207]

[0208] Table 3. IC 50 values of enzyme inhibitory activities of some embodiments

[0209]

[0210] Table 4. Inhibition rates of some embodiments on hMAO-A

[0211]

[0212] From the determination of the IC 50 values of the compounds prepared in some embodiments on hMAO-B inhibition, we can know that for embodiment a16 (IC 50 = 0.064 ± 0.08 μM), a20 (IC 50 = 0.074 ± 0.01 μM) and a23 (IC 50(= 0.071 ± 0.07 μM) showed excellent performance among the 25 compounds in this case. At the same time, it can be seen from the hMAO-A activity test that the selectivity of these compounds for hMAO-B is higher than that of the positive drug pargyline.

[0213] 3. Prediction of BBB permeability of compounds a14 - a17, a20, a23 - a24

[0214] For drugs treating neurodegenerative diseases, crossing the blood - brain barrier (BBB) is an important prerequisite for their efficacy. In this invention, the website https: / / admet.scbdd.com was used to predict the BBB permeability of the examples and compound X, and the structure of compound X is as follows:

[0215]

[0216] Table 5. Prediction results of BBB permeability of compound X and examples a1 - a25

[0217]

[0218]

[0219] a: CNS(+) indicates that the compound has BBB permeability

[0220] In this invention, the phthalimide nucleus with monoamine oxidase B inhibitory activity was connected to the iron chelator active skeleton through an alkyl chain, and the obtained examples all have multi - target anti - AD and anti - PD activities. Among them, examples a16 - a17 and a23 - a24 are multi - target anti - AD / PD lead compounds with great application prospects.

Claims

1. A derivative of phthalimide-fused 3-hydroxy-pyridine-4-one of formula (I) and its pharmaceutically acceptable salts: In formula (I): R 1 is a C1-C6 straight-chain or branched-chain alkyl group; R 2 is H, a C1-C6 straight-chain or branched alkyl group, a halogen, a C1-C6 straight-chain or branched haloalkyl group, a C1-C6 straight-chain or branched alkoxy group or wherein X1 and Z1 are each independently H, a C1-C6 straight-chain or branched-chain alkyl group, a halogen, a C1-C6 straight-chain or branched-chain haloalkyl group, or a C1-C6 straight-chain or branched-chain alkoxy group; R 3 is H, a C1-C6 linear or branched alkyl group, Cl; n is the number of CH2, and n is 2.

2. The phthalimide-fused 3-hydroxy-pyridine-4-one derivative of formula (I) as claimed in claim 1 and its pharmaceutically acceptable salts, characterized in that The derivative of phthalimide-fused 3-hydroxy-pyridine-4-one of formula (I) is one of the following compounds:

3. The derivative of phthalimide-fused 3-hydroxy-4-pyridone represented by formula (I) as claimed in claim 1 and its pharmaceutically acceptable salts, characterized in that: The pharmaceutically acceptable salt is the hydrochloride salt of the derivative of phthalimide-fused 3-hydroxy-pyridine-4-one of formula (I).

4. The phthalimide-fused 3-hydroxy-pyridine-4-one derivative of formula (I) as claimed in claim 2 and its pharmaceutically acceptable salts, characterized in that: The derivative of phthalimide-fused 3-hydroxy-pyridine-4-one of formula (I) is one of compounds a9, a10, a11, a13, a14, a15, a16, a17, a18, a20, a22, a23, a24.

5. Use of the derivative of phthalimide-fused 3-hydroxy-pyridine-4-one of formula (I) and its pharmaceutically acceptable salts according to any one of claims 1-4 in the preparation of a drug for preventing or treating related diseases by inhibiting monoamine oxidase, chelating metal iron ions, anti-Aβ deposition or antioxidant.

6. The application according to claim 5, wherein: The disease is a neurodegenerative disease.

7. A method for preparing the derivative of phthalimide-fused 3-hydroxy-pyridine-4-one of formula (I) according to claim 1, characterized in that: R 2 not When it is not, the method includes the following steps: (1) React the compound of formula 2 and the intermediate of formula 1 in organic solvent A at 120 °C with stirring for 2 h. The resulting reaction solution A is subjected to post-treatment A to obtain the intermediate of formula 3; the molar ratio of the compound of formula 2 to the intermediate of formula 1 is 1:1.2-2.0; (2) Dissolve the intermediate of formula 3 obtained in step (1) in organic solvent B. Under nitrogen protection, dropwise add a dichloromethane solution of the compound of formula 4 at -48 °C. After dropping, stir and react at room temperature for 12 h, then add methanol to quench the reaction. After adding, continue to stir and react for 1 h. The resulting reaction solution B is subjected to post-treatment B to obtain the derivative of phthalimide-fused 3-hydroxy-pyridine-4-one of formula (I); the molar ratio of the intermediate of formula 3 to the compound of formula 4 contained in the dichloromethane solution of the compound of formula 4 is 1:2.0-4.0; 8. The preparation method of the phthalimide-fused 3-hydroxy-pyridine-4-one derivative represented by formula (I) according to claim 7, characterized in that: The organic solvent A in step (1) is acetic acid; The volume of the organic solvent A in step (1) is 3-6 mL / mmol based on the amount of substance of the intermediate of formula 1; The post-treatment A in step (1) is: pour the reaction solution A into ice water, a solid precipitates, filter by suction, wash the obtained filter cake with water, and dry to obtain the intermediate of formula 3; The concentration of the dichloromethane solution of the compound of formula 4 in step (2) is 0.3 mol / L; The organic solvent B in step (2) is dichloromethane, and the volume of the organic solvent B is 10-20 mL / mmol based on the amount of substance of the intermediate of formula 3; The volume of the methanol in step (2) is 4-8 mL / mmol based on the amount of substance of the intermediate of formula 3; The post-treatment B in step (2) is as follows: The reaction solution B is subjected to vacuum distillation to remove the solvent, recrystallized with methanol, filtered by suction, and the obtained filter cake is dried to obtain the phthalimido-fused 3-hydroxypyridine-4-one derivative represented by formula (I) and its pharmaceutically acceptable salts.

9. The preparation method of the phthalimide-fused 3-hydroxy-pyridine-4-one derivative of formula (I) as claimed in claim 1 and its pharmaceutically acceptable salts, characterized in that: R 2 When the method includes the following steps: 1) Dissolve the compound shown in formula 6 in acetic anhydride, stir at 120 °C for 30 min, and evaporate the solvent from the obtained reaction solution to obtain the compound shown in formula 7; 2) Dissolve the compound shown in formula 7 in step 1) in organic solvent C, add the intermediate shown in formula 1, stir at 120 °C for 2 h, and the obtained reaction solution C is subjected to post-treatment C to obtain the intermediate shown in formula 8; the molar ratio of the compound shown in formula 7 to the intermediate shown in formula 1 is 1:1.0 - 2.0; 3) Dissolve the intermediate shown in formula 8 and a basic substance in organic solvent D, stir and react at 65 °C for 10 min, dropwise add the compound shown in formula 9, and after the addition is complete, continue the reaction for 8 h. The obtained reaction solution D is subjected to post-treatment D to obtain the intermediate shown in formula 10; the molar ratio of the intermediate shown in formula 8, the basic substance to the compound shown in formula 9 is 1:1.0 - 1.3:1.5 - 2.5; 4) Dissolve the intermediate shown in formula 10 obtained in step 3) in organic solvent E, under nitrogen protection, dropwise add a dichloromethane solution of the compound shown in formula 4 at -48 °C, and after the addition is complete, transfer to room temperature and continue to stir and react for 12 h. Subsequently, add methanol to quench the reaction, and after the addition is complete, continue to stir and react for 1 h. The obtained reaction solution E is subjected to post-treatment E to obtain the phthalimido-fused 3-hydroxypyridine-4-one derivative represented by formula (I) and its pharmaceutically acceptable salts; the molar ratio of the intermediate shown in formula 10 to the compound shown in formula 4 is 1:1.1 - 1.7; 10. The preparation method of the phthalimide-fused 3-hydroxy-pyridine-4-one derivative represented by formula (I) as described in claim 9, characterized in that: The volume of acetic anhydride in step 1) is 1.3 - 1.6 mL / mmol based on the amount of substance of the compound shown in formula 6; The organic solvent C in step 2) is acetic acid, and the volume of the organic solvent C is 3 - 6 mL / mmol based on the amount of substance of the intermediate shown in formula 1; The post-treatment C in step 2) is as follows: Pour the reaction solution C into ice water, a solid precipitates, filter by suction, wash the obtained filter cake with water, and dry to obtain the intermediate shown in formula 8; The basic substance in step 3) is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, and sodium hydroxide; The organic solvent D in step 3) is methanol; the volume of the organic solvent D is 4 - 8 mL / mmol based on the amount of substance of the intermediate shown in formula 8; The post-treatment D in step 3) is as follows: After the reaction is completed, vacuum distill to remove the solvent methanol in the reaction solution, add water for dilution, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and then vacuum distill to remove the solvent. Column chromatography separation is carried out using a dichloromethane / methanol mixed solution with a volume ratio of 60:1, 40:1, 20:1 as the eluent, collect the eluate containing the target intermediate, and concentrate to obtain the intermediate shown in formula 10; The concentration of the dichloromethane solution of the compound shown in formula 4 in step 4) is 0.2 mol / L; The organic solvent E described in step 4) is dichloromethane, and the volume of the organic solvent E is 10 - 20 mL / mmol based on the amount of substance of the intermediate of formula 3; The volume of the methanol described in step 4) is 4 - 8 mL / mmol based on the amount of substance of the intermediate of formula 10; The post-treatment E in step 4) is as follows: the reaction solution E is distilled under reduced pressure to remove the solvent, recrystallized with methanol, filtered by suction, and the obtained filter cake is dried to obtain the derivative of phthalimido-fused 3-hydroxypyridin-4-one shown in formula (I).

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