Quinolinone derivative as well as preparation method and application thereof

Abstract

The invention discloses a quinolinone derivative and a preparation method and application thereof, the quinolinone derivative has iron chelating activity and MAO-B inhibition activity at the same time, and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease can be treated by targeting iron overload and MAO-B overexpression at the same time; # imgabs0 #

Description

Technical Field

[0001] The invention relates to a quinolinone derivative and a preparation method and application thereof. Background Art

[0002] In neurodegenerative diseases (NDs), excess iron not only increases intracellular Ca 2+ levels promote mitochondrial rupture and also through Ca 2+ / calmodulin pathway activates calcineurin; iron overload also activates microglia, causing metabolic changes from oxidative phosphorylation to glycolysis, polarizing them, and inducing neuroinflammation and neurodegeneration. Increased iron levels have been observed in the cortex and hippocampus of patients with Alzheimer's disease (AD), and the degree of iron overload is positively correlated with the severity of AD and the rate of cognitive decline. Iron overload promotes amyloid protein (Aβ) aggregation and Tau protein hyperphosphorylation, accelerating the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs). In addition, iron produces a large amount of reactive oxygen species (ROS) through the Fenton or Haber-Weiss reaction, causing lipid peroxidation, leading to neuronal damage. In Parkinson's disease (PD), iron overload is also an important cell death pathway for dopaminergic neurons. Although iron levels increase with age, the increase in iron content is particularly evident in the basal ganglia, especially the substantia nigra, where iron content is 25% to 100% higher than normal levels. In the presence of oxygen, iron catalyzes the oxidation of dopamine (DA) to form a series of toxic species, which reduces cell viability and exacerbates oxidative stress and mitochondrial dysfunction; in addition, excess iron can also reduce the level of reduced glutathione and promote the formation of oxidized glutathione, thereby leading to impaired glutathione-dependent oxidative defense function, increased lipid peroxidation levels, dopaminergic neuron synaptic dysfunction and neuronal death. Therefore, targeting iron overload with iron chelators will profoundly intervene in the potential progression of NDs, rather than just targeting superficial downstream targets.

[0003] Neurotransmitter regulation plays a vital role in improving NDs symptoms. Dopamine is well known for its neuroprotective effects, is closely related to the regulation of brain cognitive functions, and is regulated by monoamine oxidase (MAO-B) metabolism. MAO-B is a flavin adenine dinucleotide (FAD)-containing enzyme that catalyzes the oxidative deamination of a variety of exogenous amines and endogenous neurotransmitters. In this process, hydrogen peroxide is produced as a byproduct. As the main source of ROS, hydrogen peroxide promotes oxidative stress through the iron-catalyzed Fenton reaction, ultimately leading to neuronal damage. Conversely, upregulation of MAO-B can cause abnormal iron regulation in the brain. Studies have shown that with age, the expression of MAO-B in neuronal tissue increases 3 to 4 times, directly leading to increased oxidative stress and neuronal damage. These evidences suggest the potential application of MAO-B inhibitors as therapeutic drugs for NDs.

[0004] In summary, given the complexity of NDs, simultaneous targeting of iron overload and MAO-B overexpression provides a new and promising therapeutic avenue for the treatment of neurological diseases. Summary of the invention

[0005] The present invention provides a quinolinone derivative and a preparation method and application thereof. The quinolinone derivative of the present invention is a multi-target ligand comprising an iron chelator and a monoamine oxidase B (MAO-B) inhibitor, and has both iron chelating activity and MAO-B inhibition activity, and can be used to prepare drugs for preventing or treating neurodegenerative diseases (NDs) and mental illnesses associated with iron overload and MAO-B overexpression.

[0006] The technical solution of the present invention is as follows:

[0007] A quinolinone derivative of Formula Ia or Ib, and a pharmaceutically acceptable acid or base addition salt, stereochemical isomeric form, and nitrogen oxide form thereof;

[0008]

[0009] In Formula Ia or Formula Ib,

[0010] R 1 Selected from H, -(C1-C5) straight chain alkyl or branched chain alkyl; preferably R 1 is H, methyl or ethyl;

[0011] X is selected from H, OH, -(C1-C5) straight chain or branched alkyl, -(C1-C5)-substituted aryl or -(C1-C5)-substituted heteroaryl; preferably X is H, CH3,

[0012] Y is selected from H or halogen; preferably Y is F or Cl.

[0013] Specifically, the quinolinone derivative represented by Formula Ia is one of Compounds A1 to A26, and the quinolinone derivative represented by Formula Ib is one of Compounds A27 to A30:

[0014]

[0015] The present invention provides a method for preparing a quinolinone derivative represented by Formula Ia or Formula Ib.

[0016] The preparation method of the quinolinone derivative represented by formula Ia comprises the following steps:

[0017] Step 1: Dissolve 5-methoxy isatin shown in formula 1 in an organic solvent, stir at 0°C, then add an alkaline substance and stir to mix, then add an alkylating agent R 1 -I, stirred at 0°C for 2h, then moved to room temperature and continued stirring for 1h, the reaction progress was monitored by thin layer chromatography (TLC), and after the reaction was completed, post-treatment was performed to obtain the compound shown in formula 2;

[0018] The raw material 5-methoxyisatin is commercially available;

[0019] 5-methoxy isatin, alkaline substance, alkylating agent R shown in formula 1 1 -I's molar ratio is 1:1-3:1-3, preferably 1:1.5:1.5;

[0020] The alkaline substance is selected from one or more of potassium carbonate, sodium hydride, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, and potassium carbonate, preferably sodium hydride;

[0021] Alkylating agent R 1 -I, R 1 The definition is the same as in Formula Ia;

[0022] The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and N,N-dimethylformamide (DMF), preferably DMF; the volume molar ratio of the organic solvent to the 5-methoxyisatin shown in Formula 1 is 1 to 3:1, mL / mmol;

[0023] The specific post-treatment method is: after the reaction is completed, saturated sodium bicarbonate aqueous solution is added to the reaction solution to quench, extracted with ethyl acetate (EA), the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain a compound shown in Formula 2;

[0024] Step 2: suspend the compound represented by formula 2 in hydrobromic acid, reflux for 3 hours under a nitrogen atmosphere, and then post-treat to obtain the compound represented by formula 3;

[0025] The specific post-treatment method is as follows: after the reaction is completed, the reaction solution is diluted with saturated brine, then extracted with EA, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain a compound shown in Formula 3;

[0026] Step 3: dissolving the compound represented by Formula 3 in an organic solvent, adding an alkaline substance, stirring and mixing at 0 to 60° C., then dropping the brominated compound represented by Formula 4, continuing to stir for 0.25 to 1 hour, and then post-treating to obtain the compound represented by Formula 5;

[0027] The molar ratio of the compound represented by formula 3, the alkaline substance, and the brominated compound represented by formula 4 is 1:1-2:0.5-1.5, preferably 1:1.1:1;

[0028] The alkaline substance is selected from one or more of sodium cyanide, potassium carbonate, sodium tert-butoxide, sodium hydroxide, and potassium hydroxide, preferably sodium tert-butoxide;

[0029] The organic solvent is selected from one or more of acetonitrile, dichloromethane (DCM), methanol, ethanol, and DMF, preferably DMF; the volume molar ratio of the organic solvent to the compound represented by Formula 3 is 3 to 6:1, mL / mmol;

[0030] The specific post-treatment method is as follows: after the reaction is completed, the reaction solution is diluted with saturated brine, then extracted with EA, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo to obtain a compound shown in Formula 5;

[0031] Step 4: dissolving the compound represented by Formula 5 in a mixed solvent, adding DUB (1,8-diazabicyclo[5,4,0]-7-7 undecene) and trimethylsilylated diazomethane in sequence, stirring at room temperature in the dark for 8 to 12 hours under a nitrogen atmosphere, and then post-treating to obtain a quinolinone derivative represented by Formula Ia;

[0032] The molar ratio of the compound represented by formula 5, DUB, and trimethylsilylated diazomethane is 1:0.1-0.3:1-2, preferably 1:0.15:1.4;

[0033] The mixed solvent is selected from any two or more of ethanol, methanol, DMF, DCM and acetonitrile, preferably a mixed solvent with a volume ratio of ethanol to DMF of 5:1;

[0034] The specific post-treatment method is: after the reaction is completed, the reaction is quenched with 1M hydrochloric acid, then diluted with saturated brine, and then extracted with EA, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the quinolinone derivative represented by formula Ia;

[0035]

[0036] In formula 2 to formula 5, R1 , X is defined as in Formula Ia;

[0037] It should be noted that, during the synthesis process, due to the different substituents of the actual target compound, those skilled in the art can select the simplest route from the above synthesis route according to the actual situation; Examples 1-27 of the present invention all use Formula 1 as the starting material, wherein: Examples 1-11, 16-22 implement steps 1 to 4; Examples 12-15 implement steps 2 to 4; Example 23 implements step 4; Examples 24 and 25 implement steps 1 and 4; Example 26 implements steps 1, 2 and 4.

[0038] The preparation method of the quinolinone derivative represented by formula Ib comprises the following steps:

[0039] Step 1: Dissolve 6-methoxy isatin shown in formula 6 in an organic solvent, stir at 0°C, then add an alkaline substance and stir to mix, then add an alkylating agent R 1 -I, stirred at 0°C for 2h, then moved to room temperature and continued stirring for 1h, the reaction progress was monitored by thin layer chromatography (TLC), and after the reaction was completed, post-treatment was performed to obtain the compound shown in formula 7;

[0040] The raw material 6-methoxyisatin is commercially available;

[0041] 6-methoxy isatin, alkaline substance, alkylating agent R shown in formula 6 1 -I's molar ratio is 1:1-3:1-3, preferably 1:1.5:1.5;

[0042] The alkaline substance is selected from one or more of potassium carbonate, sodium hydride, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, and potassium carbonate, preferably sodium hydride;

[0043] Alkylating agent R 1 -I, R 1 The definition is the same as in Formula Ib;

[0044] The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and DMF, preferably DMF; the volume molar ratio of the organic solvent to the 6-methoxyisatin shown in Formula 6 is 1 to 3:1, mL / mmol;

[0045] The specific post-treatment method is: after the reaction is completed, saturated sodium bicarbonate aqueous solution is added to the reaction solution to quench, extracted with ethyl acetate (EA), the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain a compound shown in Formula 7;

[0046] Step 2: Add LiI to an organic solvent in batches, then add an acidic substance and a compound shown in Formula 7 in sequence, reflux for 8 hours, and then post-treat to obtain a compound shown in Formula 8;

[0047] The molar ratio of the compound represented by formula 7, LiI, and the acidic substance is 1:1-10:0.1-0.5, preferably 1:6.6:0.28;

[0048] The acidic substance is selected from one or more of hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, and nitric acid, preferably phosphoric acid;

[0049] The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and DMF, preferably DMF; the volume molar ratio of the organic solvent to the compound represented by Formula 7 is 2 to 6:1, mL / mmol;

[0050] The specific post-treatment method is as follows: after the reaction is completed, the reaction solution is quenched with hydrochloric acid, diluted with saturated brine and extracted with EA, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the compound shown in Formula 8;

[0051] Step 3: dissolving the compound represented by Formula 8 in an organic solvent, adding an alkaline substance, stirring and mixing at 80° C., then dropwise adding the substituted benzyl bromide compound represented by Formula 9, continuing stirring for 6 hours, and then post-treating to obtain the compound represented by Formula 10;

[0052] The molar ratio of the compound represented by Formula 8, the alkaline substance, and the substituted benzyl bromide compound represented by Formula 9 is 1:1-2:0.5-1.5, preferably 1:1.1:1;

[0053] The alkaline substance is selected from one or more of sodium cyanide, potassium carbonate, sodium tert-butoxide, sodium hydroxide, and potassium hydroxide, preferably sodium tert-butoxide;

[0054] The organic solvent is selected from one or more of acetonitrile, DCM, methanol, ethanol, and DMF, preferably DMF; the volume molar ratio of the organic solvent to the compound represented by Formula 8 is 3 to 6:1, mL / mmol;

[0055] The specific post-treatment method is as follows: after the reaction is completed, the reaction solution is diluted with saturated brine, then extracted with EA, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain a compound represented by formula 10;

[0056] Step 4: dissolving the compound represented by formula 10 in a mixed solvent, adding DUB and trimethylsilylated diazomethane in sequence, stirring at room temperature in the dark for 8 to 12 hours under a nitrogen atmosphere, and then post-treating to obtain a quinolinone derivative represented by formula Ib;

[0057] The molar ratio of the compound represented by formula 10, DUB, and trimethylsilylated diazomethane is 1:0.1-0.3:1-2, preferably 1:0.15:1.4;

[0058] The mixed solvent is selected from a mixture of any two or more of ethanol, methanol, DMF, DCM, and acetonitrile, preferably a mixed solvent of ethanol and DMF in a volume ratio of 5:4;

[0059] The specific post-treatment method is: after the reaction is completed, the reaction is quenched with 1M hydrochloric acid, then diluted with saturated brine, and then extracted with EA, the organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the quinolinone derivative shown in Formula Ib;

[0060]

[0061] In formula 7-10, R 1 , and Y are defined the same as in Formula Ib.

[0062] The quinolinone derivatives represented by Formula Ia or Ib of the present invention are multi-target ligands with iron chelation and MAO-B inhibition activities, and can protect neurons and improve disease states through iron chelation pathways and inhibition of MAO-B pathways.

[0063] Therefore, the quinolinone derivatives represented by Formula Ia or Formula Ib of the present invention, and pharmaceutically acceptable acid or base addition salts, stereochemical isomer forms and nitrogen oxide forms thereof, can be used to prepare drugs for preventing or treating neurodegenerative diseases (NDs) and mental illnesses associated with iron overload and MAO-B overexpression.

[0064] Neurodegenerative diseases (NDs) and psychiatric disorders associated with iron overload and MAO-B overexpression such as stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, retinal disorders, cerebral ischemia, depression, etc.; especially Alzheimer's disease or Parkinson's disease.

[0065] Compared with the prior art, the present invention has the following beneficial effects:

[0066] The quinolinone derivatives provided by the present invention are a new class of compounds and are the first class of multi-target ligands that can simultaneously target iron overload and MAO-B. The quinolinone derivatives of the present invention can not only chelate iron ions, but also inhibit MAO-B, thereby protecting neurons and improving disease states. Therefore, the quinolinone derivatives of the present invention can be used to treat or prevent the effects of neuromodulatory effects associated with iron overload and MAO-B overexpression or the risks of various neurological and psychiatric disorders, especially Alzheimer's disease or Parkinson's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 : Metal ion selectivity of compounds A3, A4, A6, A27-30. DETAILED DESCRIPTION

[0068] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.

[0069] Example 1

[0070] Preparation method of (A1)

[0071] 5-Methoxyisatin (0.886 g, 5 mmol) was placed in a 100 mL round-bottom flask, and solvent DMF (15 mL) was added to dissolve it. The mixture was stirred at 0°C for 5 min, and then NaH (0.180 g, 7.5 mmol) was added and stirred for 30 min. CH3I (1.064 g, 7.5 mmol) was added and continued to stir under an ice bath. After 2 h, the reaction solution was moved to room temperature and stirred for 1 h. After the reaction was completed, the reaction was quenched with a saturated NaHCO3 solution (80 mL), and extracted with saturated brine and EA (40 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified and separated by column chromatography (DCM) to obtain 0.822 g of 5-methoxy-1-methylindole-2,3-dione with a yield of 86%.

[0072] 5-Methoxy-1-methylindole-2,3-dione (0.765 g, 4 mmol) and hydrobromic acid (40 wt.%, 20 mL) were added to a 100 mL round-bottom flask and refluxed for 3 h under nitrogen protection; after the reaction, it was diluted with brine (30 mL) and then extracted with EA (30 mL×3); the collected organic layer was dried over anhydrous Na2SO4, concentrated, and separated and purified by column chromatography (DCM:MeOH=30:1, v / v) to obtain 0.546 g of 5-hydroxy-1-methylindole-2,3-dione with a yield of 77%.

[0073] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solution, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Benzyl bromide (0.342 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and the mixture was stirred for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.422 g of 5-(benzyloxy)-1-methylindole-2,3-dione with a yield of 79%.

[0074] 5-(Benzyloxy)-1-methylindole-2,3-dione (0.401 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), and DBU (0.034 g, 0.225 mmol) was added. The atmosphere was replaced with nitrogen three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added. The mixture was stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.198 g of off-white solid A1 with a yield of 47%.

[0075] mp=146.4-147.6℃; 1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),7.50–7.44(m,2H),

[0076] 7.43–7.36(m,3H),7.36–7.29(m,1H),7.22(s,1H),7.14–7.07(m,1H),7.07–7.03(m,1H),5.13(s,2H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.7,153.7,145.8,137.1,129.2,128.4,127.8,127.7,122.0,115.6,115.3,111.3,110.2,69.5,29.8.HRMS(ESI):m / zcalcd.for C 17 H 16 NO3[M+H] + :282.1125, found 282.1147; HPLC purity:99.0%.

[0077] Example 2

[0078] Preparation method of (A2)

[0079] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Then, 2-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.485 g of 5-((2-fluorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 85%.

[0080] 5-((2-Fluorobenzyl)oxy)-1-methylindole-2,3-dione (0.428 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), and DBU (0.034 g, 0.225 mmol) was added. The atmosphere was replaced with nitrogen three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added. The mixture was stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.184 g of off-white solid A2 with a yield of 41%.

[0081] mp=149.9-151.4℃; 1 H NMR (400MHz, DMSO-d6) δ9.49 (s, 1H), 7.58 (t, J = 8.0Hz,

[0082] 1H),7.47–7.36(m,2H),7.29–7.19(m,3H),7.11(d,J=9.2Hz,1H),7.07(s,1H),5.17(s,2H),3.67(s,3H). 13 C NMR(100MHz,DMSO-d6)δ160.4(d, 1 J=244.6Hz),157.7,153.5,145.8,130.7(d, 3 J=4.0Hz),130.4(d, 3 J=8.2Hz),129.4,124.5(d, 4 J=3.5Hz),123.8(d, 2J=14.4Hz),122.0,115.7,115.4(d, 2 J=19.5Hz),115.3,111.3,110.2,63.9(d, 3 J=3.7Hz),29.9.HRMS(ESI):m / z calcd.for C 17 H 15 FNO3[M+H] + :300.1030, found300.1046; HPLC purity:99.2%.

[0083] Example 3

[0084] Preparation method of (A3)

[0085] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 3-Fluorobenzyl bromide (0.378 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.480 g of 5-((3-fluorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 84%.

[0086] 5-((3-Fluorobenzyl)oxy)-1-methylindole-2,3-dione (0.428 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.189 g of off-white solid A3 with a yield of 42%.

[0087] mp=298.2-300.7℃; 1 H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.47–7.36(m,2H),

[0088] 7.33–7.26(m,2H),7.22(d,J=3.2Hz,1H),7.18–7.08(m,2H),7.06(s,1H),5.16(s,2H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ162.2(d, 1 J C-F =242.2Hz),157.7,153.4,145.8,140.0(d, 3 J C-F =7.4Hz),130.4(d, 3 J C-F =8.4Hz),129.3,123.5(d, 4 J C-F =2.8Hz),122.0,115.6,115.3,114.5(d, 2 J C-F =20.8Hz),114.2(d, 2 J C-F =21.8Hz),111.2,110.3,68.7(d, 4 J C-F =1.9Hz),29.8.HRMS(ESI):m / z calcd.for C 17 H 15 FNO3[M+H] + :300.1030, found300.1057; HPLC purity:99.8%.

[0089] Example 4

[0090] Preparation method of (A4)

[0091] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 4-Fluorobenzyl bromide (0.378 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.502 g of 5-((4-fluorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 88%.

[0092] 5-((4-Fluorobenzyl)oxy)-1-methylindole-2,3-dione (0.428 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.157 g of off-white solid A4 with a yield of 35%.

[0093] mp=188.0-188.5℃; 1 H NMR(400MHz,DMSO-d6)δ9.45(s,1H),7.59–7.47(m,2H),

[0094] 7.39(d,J=9.2Hz,1H),7.29–7.15(m,3H),7.10(dd,J=9.2,2.8Hz,1H),7.05(s,1H),5.11(s,2H),3.67(s,3H). 13 C NMR(100MHz,DMSO-d6)δ161.7(d, 1 J C-F =242.1Hz),157.7,153.6,145.7,133.2(d, 4 J C-F =3.0Hz),129.9(d, 3 J C-F =8.2Hz),129.3,122.0,115.5,115.3,115.2(d, 2 J C-F =21.2Hz),111.2,110.3,68.8,29.8.HRMS(ESI):m / z calcd.forC 17 H 15 FNO3[M+H] + :300.1030, found 300.1040; HPLC purity:98.6%.

[0095] Example 5

[0096] Preparation method of (A5)

[0097] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and stirred at 0°C for 15 min. 2-Chlorobenzyl bromide (0.411 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.467 g of 5-((2-chlorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 82%.

[0098] 5-((2-chlorobenzyl)oxy)-1-methylindole-2,3-dione (0.453 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.204 g of off-white solid A5 with a yield of 43%.

[0099] mp=167.7-169.1℃; 1 H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.66–7.59(m,1H),

[0100] 7.55–7.49(m,1H),7.44–7.35(m,3H),7.26(d,J=2.8Hz,1H),7.12(dd,J=9.2,2.8Hz,1H),7.08(s,1H),5.19(s,2H),3.67(s,3H). 13 C NMR (100MHz, DMSO-d6) δ157.7,153.5,145.8,134.3,132.6,130.1,129.9,129. 4,129.4,127.4,122.1,115.7,115.3,111.3,110.2,67.2,29.9.HRMS(ESI):m / z calcd.for C 17 H 15ClNO3[M+H] + :316.0735, found316.0749; HPLC purity:99.9%.

[0101] Example 6

[0102] Preparation method of (A6)

[0103] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and stirred at 0°C for 15 min. 3-chlorobenzyl bromide (0.411 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.483 g of 5-((3-chlorobenzyl)oxy)-1-methylindole-2,3-dione, with a yield of 80%.

[0104] 5-((3-chlorobenzyl)oxy)-1-methylindole-2,3-dione (0.453 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.208 g of off-white solid A6 with a yield of 44%.

[0105] mp=169.2-170.8℃; 1 H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.53(s,1H),7.46–

[0106] 7.36(m,4H),7.25–7.19(m,1H),7.15–7.08(m,1H),7.06(s,1H),5.16(s,2H),3.66(s,3H). 13C NMR(100MHz,DMSO-d6)δ157.7,153.4,145.8,139.7,133.1,130.4,129.4,127.7,127 .3,126.2,122.0,115.7,115.3,111.2,110.3,68.6,29.9.HRMS(ESI):m / zcalcd.for C 17 H 15 ClNO3[M+H] + :316.0735, found 316.0752; HPLC purity:99.9%.

[0107] Example 7

[0108] Preparation method of (A7)

[0109] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 4-chlorobenzyl bromide (0.411 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.489 g of 5-((4-chlorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 81%.

[0110] 5-((4-chlorobenzyl)oxy)-1-methylindole-2,3-dione (0.453 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.189 g of white solid A7 with a yield of 40%.

[0111] mp=188.6-190.0℃; 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.52–7.42(m,4H),

[0112] 7.39(d,J=9.2Hz,1H),7.21(s,1H),7.09(d,J=9.2Hz,1H),7.05(s,1H),5.13(s,2H),3.66(s,3H). 13 C NMR (100MHz, DMSO-d6) δ157.7,153.5,145.8,136.1,132.4,129.5,129.3,128.4,122.0,115.7,115.3,111.2,110.3,68.7,29.9.HRMS(ESI):m / z calcd.forC 17 H 15 ClNO3[M+H] + :316.0735, found 316.0747; HPLC purity:99.4%.

[0113] Example 8

[0114] Preparation method of (A8)

[0115] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Then, 2-methylbenzyl bromide (0.370 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.444 g of 1-methyl-5-((2-methylbenzyl)oxy)indole-2,3-dione, with a yield of 79%.

[0116] 1-Methyl-5-((2-methylbenzyl)oxy)indole-2,3-dione (0.422 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.173 g of white solid A8 with a yield of 39%.

[0117] mp=167.9-169.8℃; 1 H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.45–7.36(m,2H),

[0118] 7.29–7.16(m,4H),7.15–7.09(m,1H),7.08(s,1H),5.11(s,2H),3.67(s,3H),2.34(s,3H). 13 CNMR(100MHz,DMSO-d6)δ157.7,153.8,145.8,136.6,135.0,130.1,129.3,128.5,128.1 ,125.8,122.0,115.7,115.4,111.3,110.1,68.3,29.9,18.5.HRMS(ESI):m / zcalcd.for C 18 H 18 NO3[M+H] + :296.1281, found 296.1289; HPLC purity:99.8%.

[0119] Example 9

[0120] Preparation method of (A9)

[0121] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 3-methylbenzyl bromide (0.370 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.467 g of 1-methyl-5-((3-methylbenzyl)oxy)indole-2,3-dione, with a yield of 83%.

[0122] 1-Methyl-5-((3-methylbenzyl)oxy)indole-2,3-dione (0.422 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.190 g of off-white solid A9 with a yield of 43%.

[0123] mp=127.0-128.3℃; 1 H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 7.38 (d, J = 9.2Hz,

[0124] 1H),7.31–7.23(m,3H),7.22(d,J=3.2Hz,1H),7.16–7.12(m,1H),7.09(d d,J=9.2,2.8Hz,1H),7.06(s,1H),5.08(s,2H),3.66(s,3H),2.31(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.7,153.7,145.8,137.6,137.0,129.2,128.5,128.3,1 28.3,124.8,122.0,115.6,115.3,111.3,110.2,69.5,29.8,21.0.HRMS(ESI):m / z calcd.for C18 H 18 NO3[M+H] + :296.1281, found 296.1308; HPLC purity:98.6%.

[0125] Example 10

[0126] Preparation method of (A10)

[0127] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Then, 4-methylbenzyl bromide (0.370 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.461 g of 1-methyl-5-((4-methylbenzyl)oxy)indole-2,3-dione, with a yield of 82%.

[0128] 1-Methyl-5-((4-methylbenzyl)oxy)indole-2,3-dione (0.422 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.159 g of white solid A10 with a yield of 36%.

[0129] mp=183.0-183.9℃; 1 H NMR (400MHz, DMSO-d6) δ9.46 (s, 1H), 7.38 (d, J = 9.2Hz,

[0130] 1H),7.36–7.33(m,2H),7.23–7.16(m,3H),7.08(dd,J=9.2,2.8Hz,1H),7.05(s,1H),5.08(s,2H),3.66(s,3H),2.30(s,3H).13 C NMR (100MHz, DMSO) δ157.7,153.7,145.8,137.1,134.0,129.2,129.0,127.8,122.0,115.6,115.4,111.3,110.3,69.4,29.8,20.8.HRMS(ESI):m / z calcd.for C 18 H 18 NO3[M+H] + :296.1281,found 296.1294;HPLCpurity:99.8%.

[0131] Embodiment 11

[0132] Preparation method of (A11)

[0133] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 3-methoxybenzyl bromide (0.402 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.464 g of 5-((4-methoxybenzyl)oxy)-1-methylindole-2,3-dione with a yield of 78%.

[0134] 5-((4-methoxybenzyl)oxy)-1-methylindole-2,3-dione (0.446 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.154 g of white solid A11 with a yield of 33%.

[0135] mp=133.4-134.5℃; 1H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 7.39 (d, J = 9.2Hz,

[0136] 1H),7.33–7.27(m,1H),7.22(d,J=2.8Hz,1H),7.10(dd,J=9.2,2.8Hz,1H),7.05(s ,1H),7.04–7.00(m,2H),6.91–6.86(m,1H),5.11(s,2H),3.76(s,3H),3.66(s,3H). 13 CNMR(100MHz,DMSO-d6)δ159.3,157.7,153.6,145.7,138.6,129.5,129.2,122.0, 119.7,115.6,115.3,113.2,113.1,111.2,110.3,69.4,55.0,29.8.HRMS(ESI):m / z calcd.forC 18 H 18 NO4[M+H] + :312.1230, found 312.1246; HPLC purity:98.6%.

[0137] Example 12

[0138] Preparation method of (A12)

[0139] 5-Methoxyisatin (0.708 g, 4 mmol) and hydrobromic acid (40 wt.%, 20 mL) were added to a 100 mL round-bottom flask and refluxed for 3 h under nitrogen protection; after the reaction, it was diluted with brine (30 mL) and then extracted with EA (30 mL×3); the collected organic layer was dried over anhydrous Na2SO4, concentrated, and separated and purified by column chromatography (DCM:MeOH=30:1, v / v) to obtain 0.431 g of 5-hydroxyindole-2,3-dione with a yield of 66%.

[0140] 5-Hydroxyindole-2,3-dione (0.326 g, 2 mmol) was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the mixture, followed by NaOtBu (0.211 g, 2.2 mmol), which was stirred at 0°C for 15 min. 3-Fluorobenzyl bromide (0.378 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.396 g of 5-((3-fluorobenzyl)oxy)indole-2,3-dione with a yield of 73%.

[0141] 5-((3-Fluorobenzyl)oxy)indole-2,3-dione (0.407 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), and DBU (0.034 g, 0.225 mmol) was added. The atmosphere was replaced with nitrogen three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added. The mixture was stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.171 g of brown solid A12 with a yield of 40%.

[0142] mp=197.0-198.1℃; 1 H NMR(400MHz,DMSO-d6)δ8.18(s,2H),7.39-7.27(m,1H),

[0143] 7.15(d,J=8.8Hz,1H),7.09(s,1H),7.08-6.95(m,3H),6.92(d,J=2.8Hz,1H),6.80(dd,J=8.8,2.4Hz,1H),5.53(s,2H). 13 C NMR(100MHz,DMSO-d6)δ162.3(d, 1 J=242.4Hz),158.0,152.8,145.4,139.9(d, 3 J=7.3Hz),130.6(d, 3 J=8.3Hz),127.1,122.5(d, 4 J=2.6Hz),122.5,115.8,115.6,113.9(d, 2 J=20.8Hz),113.5(d, 2 J=22.0Hz),112.1,111.1,45.0.HRMS(ESI):m / z calcd.for C 16 H 13 FNO3[M+H] + :286.0874, found 286.0882; HPLC purity: 98.6%.

[0144] Example 13

[0145] Preparation method of (A13)

[0146] The 5-hydroxyindole-2,3-dione (0.326 g, 2 mmol) prepared according to Example 12 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Then, 4-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.369 g of 5-((4-fluorobenzyl)oxy)indole-2,3-dione with a yield of 68%.

[0147] 5-((4-Fluorobenzyl)oxy)indole-2,3-dione (0.407 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added. The mixture was stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.158 g of off-white solid A13 with a yield of 37%.

[0148] mp=217.0-218.6℃; 1 H NMR(400MHz,DMSO-d6)δ9.34(s,2H),7.29-7.20(m,2H),

[0149] 7.20-7.10(m,3H),7.07(s,1H),6.90(d,J=2.8Hz,1H),6.78(dd,J=8.8,2.8Hz,1H),5.50(s,2H). 13 C NMR(100MHz,DMSO-d6)δ161.2(d, 1 J C-F =241.3Hz),157.9,152.7,145.4,133.0(d, 4 J C-F =3.0Hz),128.7(d, 3 J C-F=8.2Hz),127.1,122.5,115.8,115.5,115.4(d, 2 J C-F =21.3Hz),112.0,111.1,44.7.HRMS(ESI):m / z calcd.for C 16 H 13 FNO3[M+H] + :286.0874, found 286.0877; HPLC purity: 98.7%.

[0150] Embodiment 14

[0151] Preparation method of (A14)

[0152] The 5-hydroxyindole-2,3-dione (0.326 g, 2 mmol) prepared according to Example 12 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 3-chlorobenzyl bromide (0.411 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.391 g of 5-((3-chlorobenzyl)oxy)indole-2,3-dione with a yield of 68%.

[0153] 5-((3-chlorobenzyl)oxy)indole-2,3-dione (0.432 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.172 g of off-white solid A14 with a yield of 38%.

[0154] mp=176.6-178.2℃; 1 H NMR(400MHz,DMSO-d6)δ9.38(s,2H),7.38–7.28(m,2H),

[0155] 7.27–7.24(m,1H),7.17(d,J=9.2Hz,1H),7.16–7.09(m,2H),7.09(s,1H),6.92(d,J=2.8Hz,1H),6.80(dd,J=9.2,2.8Hz,1H),5.53(s,2H). 13 C NMR(100MHz,DMSO-d6)δ158.5,153.3,145.9,140.0,133.7,131.0,127.6,12 7.6,127.0,125.8,123.0,116.3,116.1,112.7,111.7,45.4.HRMS(ESI):m / z calcd.for C 16 H 13 ClNO3[M+H] + :302.0578, found302.0583; HPLC purity:99.6%.

[0156] Embodiment 15

[0157] Preparation method of (A15)

[0158] The 5-hydroxyindole-2,3-dione (0.326 g, 2 mmol) prepared according to Example 12 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Then, 4-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.374 g of 5-((4-chlorobenzyl)oxy)indole-2,3-dione with a yield of 65%.

[0159] 5-((4-chlorobenzyl)oxy)indole-2,3-dione (0.432 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), and DBU (0.034 g, 0.225 mmol) was added. The atmosphere was replaced with nitrogen three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added. The mixture was stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.185 g of off-white solid A15 with a yield of 41%.

[0160] mp=231.8-233.5℃; 1 H NMR(400MHz,DMSO-d6)δ9.36(s,2H),7.41–7.33(m,2H),

[0161] 7.24–7.16(m,2H),7.14(d,J=9.2Hz,1H),7.08(s,1H),6.91(d,J=2.8Hz,1H),6.78(dd,J=8.8,2.8Hz,1H),5.51(s,2H). 13 C NMR (100MHz, DMSO-d6) δ157.9,152.8,145.4,135.9,131.6,128.6,128.5,127.0,122.5,115.8,115.6,112.1,111.1,44.8.HRMS(ESI):m / z calcd.for C 16 H 13 ClNO3[M+H] + :302.0578, found 302.0580; HPLC purity:99.3%.

[0162] Example 16

[0163] Preparation method of (A16)

[0164] 5-Methoxyisatin (0.886 g, 5 mmol) was placed in a 100 mL round-bottom flask, and solvent DMF (15 mL) was added to dissolve it. The mixture was stirred at 0°C for 5 min, and then NaH (0.180 g, 7.5 mmol) was added and stirred for 30 min. Then CH3CH2I (1.064 g, 7.5 mmol) was added and continued to stir in an ice bath. After 2 h, the reaction solution was moved to room temperature and stirred for 1 h. After the reaction was completed, the reaction was quenched with a saturated NaHCO3 solution (80 mL), and extracted with saturated brine and EA (40 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified and separated by column chromatography (DCM) to obtain 0.831 g of 1-ethyl-5-methoxyindole-2,3-dione with a yield of 81%.

[0165] 1-Ethyl-5-methoxyindole-2,3-dione (0.821 g, 4 mmol) and hydrobromic acid (40 wt.%, 20 mL) were added to a 100 mL round-bottom flask and refluxed for 3 h under nitrogen protection; after the reaction was completed, it was diluted with brine (30 mL) and then extracted with EA (30 mL×3); the collected organic layer was dried over anhydrous Na2SO4, concentrated, and separated and purified by column chromatography (DCM: petroleum ether (PE) = 1:1, v / v) to obtain 0.566 g of 1-ethyl-5-hydroxyindole-2,3-dione with a yield of 74%.

[0166] 1-Ethyl-5-hydroxyindole-2,3-dione (0.382 g, 2 mmol) was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solution, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Then, 3-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and the stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.497 g of 1-ethyl-5-((3-fluorobenzyl)oxy)indole-2,3-dione, with a yield of 83%.

[0167] 1-Ethyl-5-((3-fluorobenzyl)oxy)indole-2,3-dione (0.449 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added. Stir overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=60:1, v / v) and purified to obtain 0.207 g of off-white solid A16 with a yield of 44%.

[0168] mp=145.6-147.2℃; 1 H NMR(400MHz,DMSO-d6)δ7.49–7.40(m,2H),7.34–7.26(m,

[0169] 2H),7.23(d,J=2.9Hz,1H),7.19–7.13(m,1H),7.11(dd,J=9.2,2.9Hz,1H ),7.06(s,1H),5.16(s,2H),4.30(q,J=7.0Hz,2H),1.21(t,J=7.0Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ162.2(d, 1 J C-F =242.2Hz),157.2,153.3,145.7,141.1(d, 3 J C-F =7.3Hz),130.5(d, 3 J C-F =8.2Hz),128.1,123.6(d, 4 J C-F =2.8Hz),122.4,115.5,115.5,114.6(d, 2 J C-F =20.8Hz),114.3(d, 2 J C-F =21.6Hz),111.4,110.5,68.7(d, 4 J C-F =2.0Hz),37.3,12.8.HRMS(ESI):m / zcalcd.for C 18 H 17FNO3[M+H] + :314.1187, found 314.1207; HPLC purity:98.5%.

[0170] Embodiment 17

[0171] Preparation method of (A17)

[0172] 1-Ethyl-5-hydroxyindole-2,3-dione (0.382 g, 2 mmol) prepared according to Example 16 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. Then, 4-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.491 g of 1-ethyl-5-((4-methylbenzyl)oxy)indole-2,3-dione with a yield of 82%.

[0173] 1-Ethyl-5-((4-methylbenzyl)oxy)indole-2,3-dione (0.449 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added. Stir overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=60:1, v / v) and purified to obtain 0.183 g of white solid A17 with a yield of 39%.

[0174] mp=188.8-190.8℃; 1 H NMR(400MHz,DMSO-d6)δ9.46(s,1H),7.55–7.49(m,2H),

[0175] 7.45(d,J=9.2Hz,1H),7.26–7.18(m,3H),7.09(dd,J=9.2,2.8Hz,1H),7.06(s,1H),5.11(s,2H),4.31(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H). 13C NMR(100MHz,DMSO-d6)δ161.8(d, 1 J C-F =242.2Hz),157.2,153.5,145.7,133.3(d, 4 J C-F =3.1Hz),130.0(d, 3 J C-F =8.2Hz),128.0,122.4,115.6,115.4,115.3(d, 2 J C-F =21.3Hz),111.4,110.5,68.8,37.3,12.8.HRMS(ESI):m / zcalcd.for C 18 H 17 FNO3[M+H] + :314.1187,found 314.1202;HPLCpurity:99.9%.

[0176] Embodiment 18

[0177] Preparation method of (A18)

[0178] 1-Ethyl-5-hydroxyindole-2,3-dione (0.382 g, 2 mmol) prepared according to Example 16 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 3-chlorobenzyl bromide (0.411 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.530 g of 5-((3-chlorobenzyl)oxy)-1-ethylindole-2,3-dione with a yield of 84%.

[0179] 5-((3-chlorobenzyl)oxy)-1-ethylindole-2,3-dione (0.474 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=60:1, v / v) and purified to obtain 0.208 g of off-white solid A18 with a yield of 42%.

[0180] mp=136.2-138.4℃; 1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),7.55–7.51(m,1H),

[0181] 7.47–7.37(m,4H),7.23(d,J=3.2Hz,1H),7.11(dd,J=9.2,2.8Hz,1H),7.06(s,1H),5.15(s,2H),4.31(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ157.2,153.3,145.7,139.7,133.1,130.4,128.1,127.8,1 27.3,126.2,122.4,115.5,115.8,111.4,110.5,68.6,37.3,12.8.HRMS(ESI):m / z calcd.for C 18 H 17 ClNO3[M+H] + :330.0891, found 330.0905; HPLC purity:99.9%.

[0182] Embodiment 19

[0183] Preparation method of (A19)

[0184] 1-Ethyl-5-hydroxyindole-2,3-dione (0.382 g, 2 mmol) prepared according to Example 16 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 0°C for 15 min. 4-chlorobenzyl bromide (0.411 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 0.5 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.575 g of 5-((4-chlorobenzyl)oxy)-1-ethylindole-2,3-dione with a yield of 91%.

[0185] 5-((4-chlorobenzyl)oxy)-1-ethylindole-2,3-dione (0.474 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=60:1, v / v) and purified to obtain 0.173 g of off-white solid A19 with a yield of 35%.

[0186] mp=190.9-192.0℃; 1 H NMR(400MHz,DMSO-d6)δ9.47(s,1H),7.53–7.42(m,5H),

[0187] 7.22(d,J=3.2Hz,1H),7.09(dd,J=9.2,3.2Hz,1H),7.05(s,1H),5.13(s,2H),4.31(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ157.2,153.4,145.7,136.2,132.4,129.5,128.4,128.0 ,122.4,115.5,115.4,111.4,110.5,68.6,37.3,12.8.HRMS(ESI):m / zcalcd.for C 18 H 17 ClNO3[M+H]+ :330.0891, found330.0898; HPLCpurity:99.5%.

[0188] Embodiment 20

[0189] Preparation method of (A20)

[0190] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 60° C. for 15 min. Then, 2-(bromomethyl)pyridine hydrobromide (0.506 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 1 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.263 g of 1-methyl-5-(pyridin-2-ylmethoxy)indole-2,3-dione with a yield of 49%.

[0191] 1-Methyl-5-(pyridin-2-ylmethoxy)indole-2,3-dione (0.402 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:4, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.174 g of gray solid A20 with a yield of 41%.

[0192] mp=245.7-247.6℃; 1 H NMR(400MHz,DMSO-d6)δ8.87–8.80(m,1H),8.40(td,J=

[0193] 8.0,1.6Hz,1H),7.98(d,J=8.0Hz,1H),7.88–7.80(m,1H),7.43(d,J=9.2Hz,1H),7.29 (d,J=2.8Hz,1H),7.18(dd,J=8.8,2.8Hz,1H),7.09(s,1H),5.49(s,2H),3.67(s,3H).13 C NMR(100MHz,DMSO-d6)δ157.8,152.9,152.8,146.0,144.0,143.7,129.8,1 25.5,124.6,122.1,115.9,115.3,111.2,110.5,67.0,29.9.HRMS(ESI):m / z calcd.forC 16 H 15 N2O3[M+H] + :283.1077, found 283.1108; HPLC purity:98.7%.

[0194] Embodiment 21

[0195] Preparation method of (A21)

[0196] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 60° C. for 15 min. 3-(bromomethyl)pyridine hydrobromide (0.506 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 1 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.193 g of 1-methyl-5-(pyridin-3-ylmethoxy)indole-2,3-dione with a yield of 36%.

[0197] 1-Methyl-5-(pyridin-3-ylmethoxy)indole-2,3-dione (0.402 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:4, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.174 g of gray solid A21 with a yield of 41%.

[0198] mp=269.9-271.6℃; 1H NMR(400MHz,DMSO-d6)δ8.99(d,J=2.0Hz,1H),8.88–

[0199] 8.82(m,1H),8.57–8.50(m,1H),8.02–7.95(m,1H),7.43(d,J=9.2Hz,1H),7.27(d, J=2.8Hz,1H),7.16(dd,J=9.2,2.8Hz,1H),7.08(s,1H),5.35(s,2H),3.67(s,3H). 13 CNMR(100MHz,DMSO-d6)δ157.8,153.0,146.0,143.1,142.8,142.1,136.4,1 29.6,126.5,122.1,115.8,115.3,111.2,110.4,66.1,29.9.HRMS(ESI):m / z calcd.for C 16 H 15 N2O3[M+H] + :283.1077, found 283.1133; HPLC purity:98.5%.

[0200] Embodiment 22

[0201] Preparation method of (A22)

[0202] 5-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 1 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 60° C. for 15 min. Then, 4-(bromomethyl)pyridine hydrobromide (0.506 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 1 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and dried in vacuo to obtain 0.231 g of 1-methyl-5-(pyridin-4-ylmethoxy)indole-2,3-dione with a yield of 43%.

[0203] 1-Methyl-5-(pyridin-4-ylmethoxy)indole-2,3-dione (0.402 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:4, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.157 g of gray solid A22 with a yield of 37%.

[0204] mp=259.8-261.4℃; 1 H NMR(400MHz,DMSO-d6)δ8.93–8.85(m,2H),8.07–7.97

[0205] (m,2H),7.44(d,J=9.2Hz,1H),7.25(d,J=2.8Hz,1H),7.17(dd,J=9.2,2.8Hz,1H),7.09(s,1H),5.50(s,2H),3.67(s,3H). 13 C NMR (100MHz, DMSO-d6) δ157.7,156.3,152.8,146.0,142.4,129.7,124.0,122.1,115.9,115.2,111.3,110.4,67.5,29.9.HRMS(ESI):m / z calcd.for C 16 H 15 N2O3[M+H] + :283.1077, found 283.1125; HPLC purity:98.6%.

[0206] Embodiment 23

[0207] Preparation method of (A23)

[0208] 5-Methoxyindole-2,3-dione (0.266 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain an off-white solid A230.161 g with a yield of 56%.

[0209] mp=239.0-240.9℃; 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H),9.44(s,1H),7.18(d,

[0210] J=8.8Hz,1H),7.07–7.01(m,2H),6.92(dd,J=8.8,2.8Hz,1H),3.75(s,3H). 13 CNMR(100MHz,DMSO-d6)δ158.0,154.5,146.7,127.9,121.6,115.9,115.1,112.2,107.8,55.3.HRMS(ESI):m / z calcd.for C 10 H 10 NO3[M+H] + :192.0655, found192.0651; HPLCpurity:99.1%.

[0211] Embodiment 24

[0212] Preparation method of (A24)

[0213] 5-Methoxy-1-methylindole-2,3-dione (0.288 g, 1.5 mmol) prepared in Example 1 was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and the mixture was stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.148 g of off-white solid A24 with a yield of 48%.

[0214] mp=176.7-178.3℃; 1 H NMR (400MHz, DMSO-d6) δ7.38 (d, J=9.2Hz, 1H), 7.11 (d, J=

[0215] 2.8Hz,1H),7.07(s,1H),7.02(dd,J=9.2,2.8Hz,1H),3.78(s,3H),3.67(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.7,154.7,145.8,129.1,122.0,115.6,114.8,111.4,108.9,55.4,29.9.HRMS(ESI):m / z calcd.for C 11 H 12 NO3[M+H] + :206.0812, found206.0819; HPLC purity:98.7%.

[0216] Embodiment 25

[0217] Preparation method of (A25)

[0218] In a 50 mL double-necked flask, 1-ethyl-5-methoxyindole-2,3-dione (0.308 g, 1.5 mmol) prepared in Example 16 was added and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and the mixture was stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.161 g of off-white solid A25 with a yield of 49%.

[0219] mp=153.4-155.3℃; 1 H NMR (400MHz, DMSO-d6) δ9.44 (s, 1H), 7.43 (d, J = 9.2Hz,

[0220] 1H),7.13(d,J=2.8Hz,1H),7.07(s,1H),7.02(dd,J=9.2,2.8Hz,1H),4.31(q,J=7.0Hz,2H),3.78(s,3H),1.21(t,J=7.0Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ157.2,154.5,145.6,127.8,122.4,115.4,115.0,111.5,109.2,55.4,37.3,12.8.HRMS(ESI):m / zcalcd.for C 12 H 14 NO3[M+H] + :220.0968, found220.0966; HPLC purity:99.5%.

[0221] Embodiment 26

[0222] Preparation method of (A26)

[0223] 5-Hydroxy-1-methylindole-2,3-dione (0.266 g, 1.5 mmol) prepared in Example 1 was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:1, v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and the mixture was stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.161 g of off-white solid A26 with a yield of 56%.

[0224] mp=223.5-224.9℃; 1 H NMR(400MHz,DMSO-d6)δ7.30-7.26(m,1H),6.99(s,1H),

[0225] 6.92-6.88 (m, 2H), 3.64 (s, 3H). 13 C NMR(100MHz,DMSO-d6)δ157.6,152.8,145.5,128.1,122.2,115.6,115.5,111.2,110.9,29.8.HRMS(ESI):m / z calcd.for C 10 H 10 NO3[M+H] + :192.0655, found192.0653; HPLC purity:99.7%.

[0226] Embodiment 27

[0227] Preparation method of (A27)

[0228] 6-Methoxyisatin (0.886 g, 5 mmol) was placed in a 100 mL round-bottom flask, and solvent DMF (15 mL) was added to dissolve it. The mixture was stirred at 0°C for 5 min, and then NaH (0.180 g, 7.5 mmol) was added and stirred for 30 min. CH3I (1.064 g, 7.5 mmol) was added and continued to stir under an ice bath. After 2 h, the reaction solution was moved to room temperature and stirred for 1 h. After the reaction was completed, the reaction was quenched with a saturated NaHCO3 solution (80 mL), and extracted with saturated brine and EA (40 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified and separated by column chromatography (DCM) to obtain 0.784 g of 6-methoxy-1-methylindole-2,3-dione with a yield of 82%.

[0229] In a 50mL round-bottom flask, solvent DMF (10mL) was added, followed by LiI (1.641g, 12.26mmol), H3PO4 (85wt.%, 33.2μL, 0.28mmol) and 6-methoxy-1-methylindole-2,3-dione (0.382g, 2mmol) in batches, and the mixture was refluxed for 8h. After the reaction was completed, 1M HCl (2mL) was added to quench the reaction, and then the mixture was extracted with saturated brine and EA (80mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (DCM) to obtain 0.315g of 6-hydroxy-1-methylindole-2,3-dione with a yield of 89%.

[0230] 6-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solution, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 80 °C for 15 min. Then, 3-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 6 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (PE:EA=1:3, v / v) to obtain 0.308 g of 6-((3-fluorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 54%.

[0231] 6-((3-Fluorobenzyl)oxy)-1-methylindole-2,3-dione (0.428 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:4 v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.171 g of pink solid A27 with a yield of 38%.

[0232] mp=140.1-142.6℃; 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.52-7.40(m,2H),

[0233] 7.37-7.28(m,2H),7.21-7.12(m,1H),7.07(s,1H),7.04(d,J=2.0Hz,1H),6.95(dd,J=8.4,2.0Hz,1H),5.24(s,2H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ162.2(d, 1 J C-F =242.3Hz),158.6,157.4,143.2,139.9(d, 3 J C-F =7.3Hz),135.9,130.5(d, 3 J C-F =8.2Hz),127.8,123.6(d, 4 J C-F =2.7Hz),115.0,114.6(d, 2 J C-F =20.8Hz),114.3(d, 2 J C-F =21.7Hz),111.9,110.7,100.2,68.7(d, 4 J C-F =1.9Hz),29.8.HRMS(ESI):m / z calcd.forC 17 H 15 FNO3[M+H] +:300.1030, found300.1046; HPLC purity:99.8%.

[0234] Embodiment 28

[0235] Preparation method of (A28)

[0236] 6-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 28 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 80° C. for 15 min. 4-Fluorobenzyl bromide (0.378 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 6 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified and separated by column chromatography (PE:EA=1:3, v / v) to obtain 0.337 g of 6-((4-fluorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 59%.

[0237] 6-((4-Fluorobenzyl)oxy)-1-methylindole-2,3-dione (0.428 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:4 v / v), DBU (0.034 g, 0.225 mmol) was added, and nitrogen was replaced three times. Finally, trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark. After the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.179 g of off-white solid A28 with a yield of 40%.

[0238] mp=155.7-156.6℃; 1 H NMR (400MHz, DMSO-d6) δ7.57-7.50 (m, 2H), 7.48 (d, J = 8.8

[0239] Hz,1H),7.28-7.17(m,2H),7.07(s,1H),7.03(d,J=2.4Hz,1H),6.94(dd,J=8.8,2.4Hz,1H),5.19(s,2H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ161.8(d,1 J C-F =242.3Hz),158.6,157.5,143.2,136.0,133.1(d, 4 J C-F =3.1Hz),130.1(d, 3 J C-F =8.2Hz),127.8,115.4(d, 2 J C-F =21.3Hz),114.9,112.0,110.8,100.1,68.9,29.9.HRMS(ESI):m / zcalcd.for C 17 H 15 FNO3[M+H] + :300.1030, found 300.1040; HPLC purity:99.9%.

[0240] Embodiment 29

[0241] Preparation method of (A29)

[0242] 6-Hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) prepared according to Example 28 was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, followed by NaOtBu (0.211 g, 2.2 mmol), and the mixture was stirred at 80° C. for 15 min. 3-chlorobenzyl bromide (0.411 g, 2 mmol) was then slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 6 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (PE:EA=1:3, v / v) to obtain 0.302 g of 6-((3-chlorobenzyl)oxy)-1-methylindole-2,3-dione in a yield of 50%.

[0243] 6-((3-chlorobenzyl)oxy)-1-methylindole-2,3-dione (0.453 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:4 v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.190 g of off-white solid A29 with a yield of 42%.

[0244] mp=164.7-166.6℃; 1 H NMR(400MHz,DMSO-d6)δ9.49(s,1H),7.66-7.58(m,1H),

[0245] 7.55-7.48(m,1H),7.43-7.35(m,3H),7.26(d,J=2.8Hz,1H),7.12(dd,J=9.1,2.8Hz,1H),7.08(s,1H),5.18(s,2H),3.67(s,3H). 13 C NMR (150MHz, DMSO-d6) δ158.5,157.3,143.2,139.5,135.9,133.1,130.3,127. 8,127.3,126.2,115.0,111.9,111.8,110.6,100.2,68.6,29.8.HRMS(ESI):m / z calcd.for C 17 H 15 ClNO3[M+H] + :316.0735, found316.0750; HPLC purity:99.9%.

[0246] Embodiment 30

[0247] Preparation method of (A30)

[0248] According to the example, 6-hydroxy-1-methylindole-2,3-dione (0.354 g, 2 mmol) was placed in a 50 mL round-bottom flask, and DMF (10 mL) was added to dissolve the solvent, and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 80° C. for 15 min, and then 3-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel, and stirring was continued for 6 h. After the reaction was completed, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL×3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified and separated by column chromatography (PE:EA=1:3, v / v) to obtain 0.350 g of 6-((4-chlorobenzyl)oxy)-1-methylindole-2,3-dione with a yield of 58%.

[0249] 6-((4-chlorobenzyl)oxy)-1-methylindole-2,3-dione (0.453 g, 1.5 mmol) was added to a 50 mL double-necked flask and dissolved in a mixed solvent (12 mL, EtOH:DMF=5:4 v / v), DBU (0.034 g, 0.225 mmol) was added, nitrogen was replaced three times, and finally trimethylsilylated diazomethane (2M in Hexane) (1.05 mL, 2.1 mmol) was added, and stirred overnight in the dark; after the reaction was completed, the reaction was quenched with 1 M hydrochloric acid (2 mL), diluted with brine (80 mL), and then extracted with EA (50 mL×3); the organic layer was dried over anhydrous Na2SO4 and concentrated; the concentrate was separated on a silica gel plate (DCM:MeOH=50:1, v / v) and purified to obtain 0.185 g of gray solid A30 with a yield of 39%.

[0250] mp=206.2-208.2℃; 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),7.54-7.45(m,5H),

[0251] 7.07(s,1H),7.04(d,J=2.4Hz,1H),6.94(dd,J=8.8,2.4Hz,1H),5.21(s,2H). 13 CNMR(150MHz,DMSO-d6)δ158.6,157.4,143.2,136.0,132.5,129.7,129.6,128.5,127.8,114.9,111.9,110.8,100.2,68.7,29.9.HRMS(ESI):m / z calcd.for C 17 H 15 ClNO3[M+H] +:316.0735, found316.0735; HPLC purity:99.7%.

[0252] Embodiment 31

[0253] The following are the pharmacological experimental data of some compounds of the present invention:

[0254] 1. Monoamine oxidase inhibitory activity

[0255] MAO-B inhibitor screening kit (MAK296) and MAO-A inhibitor screening kit (MAK295) were purchased from Sigma, and the experimental operation procedures were strictly carried out according to the instructions. The results are shown in Table 1. It can be observed that at a test concentration of 10 μM, compounds A1-11, A20-21 and A27-30 showed potential inhibitory activity against MAO-B (inhibition rate>50%); among them, compounds A3, A4, A6, and A27-30 still showed excellent inhibitory activity at a test concentration of 1 μM (inhibition rate>60%).

[0256] Table 1. MAO-B inhibition rates of Examples 1 to 30

[0257]

[0258] IC analysis of the compounds with excellent activity (A3, A4, A6, A27-30) 50 The IC values ​​of all compounds for MAO-B were determined by the selective assay of MAO-B and MAO-B isoforms. The results are shown in Table 2. 50 The values ​​were better than those of pargyline; among them, compound A4 (IC 50 =61.48nM, SI>325), A28 (IC 50 =74.78 nM, SI>267) and A30 (IC 50 =87.47nM, SI>229) 50 The value was below 100 nM, which was comparable to that of safinamide and showed high selectivity.

[0259] Table 2. IC of some compounds 50 Value, selectivity and iron chelating capacity

[0260]

[0261]

[0262] a SI:hMAO-Bselectivityindex=IC 50 (hMAO-A) / IC 50 (hMAO-B).b Valuesobtainedunder the assumption that the corresponding IC 50 against hMAO-A is the highest concentration tested (20μM). c ThebindingaffinityofligandswithFe 3+ .

[0263] 2. Iron ion chelating activity

[0264] Weigh an appropriate amount of calcein solid into a 100mL brown volumetric flask, dissolve it with 0.1M sodium hydroxide solution, then add PBS buffer (phosphate, pH=7.4, 10mM) to make up the volume. At this time, the concentration of calcein solution is 0.5μM, and store it in the dark at 4°C for later use; pipette an appropriate amount of FeCl3 aqueous solution (45% FeCl3 basis in H2O) and prepare it into an 8μM solution for later use; weigh 2-3mg of the test compound or positive control drug, and prepare it into solutions with different concentration gradients with methanol for later use. Take an appropriate amount of 0.5μM calcein solution, 8μM FeCl3 solution and PBS buffer into a centrifuge tube, shake in the dark, then add an appropriate amount of the test compound, and shake in the dark for 2h. After the end, take 200μL / well of the mixed solution into a 96-well black board, measure the fluorescence value of compounds containing different concentrations (Ex=460nm, Em=518nm), and use Graphpad 8.0 software to fit the IC 50 Curve, and calculate its K according to the following formula b value.

[0265]

[0266] Where probe is the test concentration of the probe (0.1 μM), K probe(calcein) is the binding constant of calcein and iron ion; K probe(calcein) is the dissociation constant of iron ion embedding into calcein, which is 1 / 10 24 M.

[0267] The results are shown in Table 2. The selected compounds (A3, A4, A6, A27-30) all showed excellent iron chelating ability, and the binding constant (K b ) range is 2.55×10 22 ~5.72×10 22 M -1 , both exceeded the positive control drug deferiprone (DFP, K b =2.25×10 22 M-1 ).

[0268] 3. Metal ion selectivity

[0269] Weigh 2-3 mg of compound and prepare it into 10 mM stock solution with DMSO for later use; weigh appropriate amount of FeCl3, FeSO4·7H2O, CuCl2·2H2O, AlCl3, MgCl2, CaCl2, ZnCl2, KCl, NaCl solid and prepare it into 10 mM solution with ultrapure water for later use. Set up and prepare experimental group and background group, shake at room temperature for 30 minutes, measure with UV spectrophotometer, and plot it with Graphpad software ( Figure 1 The results showed that compounds A3, A4, A6, and A27-30 had a significant effect on Fe 2+ / Fe 3+ After chelation, a new chelate peak was formed, showing high selectivity.

Claims

1. A quinolinone derivative represented by formula Ia or formula Ib: In Formula Ia or Formula Ib, R 1 Selected from H, -(C1-C5) straight chain alkyl or branched chain alkyl; X is selected from H, OH, -(C1-C5) linear or branched alkyl, -(C1-C5)-substituted aryl or -(C1-C5)-substituted heteroaryl; Y is selected from H or halogen.

2. The quinolinone derivative of formula Ia or Ib according to claim 1, characterized in that: R 1 is H, methyl or ethyl.

3. The quinolinone derivative of formula Ia or Ib according to claim 1, characterized in that: X is H, CH3, 4. The quinolinone derivative of formula Ia or Ib according to claim 1, characterized in that: Y is F or Cl.

5. The quinolinone derivative of formula Ia or Ib according to claim 1, characterized in that: The quinolinone derivative represented by formula Ia is one of compounds A1 to A26, and the quinolinone derivative represented by formula Ib is one of compounds A27 to A30:

6. The quinolinone derivative of formula Ia or Ib according to claim 1, characterized in that: The quinolinone derivatives include pharmaceutically acceptable acid or base addition salts, stereochemical isomeric forms and nitrogen oxide forms thereof.

7. The method for preparing the quinolinone derivative of formula Ia or Ib as claimed in claim 1, characterized in that: The preparation method of the quinolinone derivative represented by formula Ia comprises the following steps: Step 1: Dissolve 5-methoxy isatin shown in formula 1 in an organic solvent, stir at 0°C, then add an alkaline substance and stir to mix, then add an alkylating agent R 1 -I, stirring at 0°C for 2h, then moving to room temperature and continuing stirring for 1h, monitoring the reaction progress by thin layer chromatography, and after the reaction is completed, post-treatment to obtain a compound of formula 2; 5-methoxy isatin, alkaline substance, alkylating agent R shown in formula 1 1 -I has a molar ratio of 1:1 to 3:1 to 3; The alkaline substance is selected from one or more of potassium carbonate, sodium hydride, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, and potassium carbonate; Alkylating agent R 1 -I, R 1 The definition is the same as in Formula Ia; The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and N,N-dimethylformamide; Step 2: suspend the compound represented by formula 2 in hydrobromic acid, reflux for 3 hours under a nitrogen atmosphere, and then post-treat to obtain the compound represented by formula 3; Step 3: dissolving the compound represented by Formula 3 in an organic solvent, adding an alkaline substance, stirring and mixing at 0 to 60° C., then dropping the brominated compound represented by Formula 4, continuing to stir for 0.25 to 1 hour, and then post-treating to obtain the compound represented by Formula 5; The molar ratio of the compound represented by formula 3, the alkaline substance, and the brominated compound represented by formula 4 is 1:1-2:0.5-1.5; The alkaline substance is selected from one or more of sodium cyanide, potassium carbonate, sodium tert-butoxide, sodium hydroxide and potassium hydroxide; The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol and DMF; Step 4: dissolving the compound represented by Formula 5 in a mixed solvent, adding DUB and trimethylsilylated diazomethane in sequence, stirring at room temperature in the dark for 8 to 12 hours under a nitrogen atmosphere, and then post-treating to obtain a quinolinone derivative represented by Formula Ia; The molar ratio of the compound represented by formula 5, DUB, and trimethylsilylated diazomethane is 1:0.1-0.3:1-2; The mixed solvent is selected from any two or more of ethanol, methanol, DMF, DCM and acetonitrile; In formula 2 to formula 5, R 1 , X is defined as in Formula Ia; The preparation method of the quinolinone derivative represented by formula Ib comprises the following steps: Step 1: Dissolve 6-methoxy isatin shown in formula 6 in an organic solvent, stir at 0°C, then add an alkaline substance and stir to mix, then add an alkylating agent R 1 -I, stirred at 0°C for 2h, then moved to room temperature and continued stirring for 1h, the reaction progress was monitored by thin layer chromatography, and after the reaction was completed, post-treatment was performed to obtain a compound of formula 7; 6-methoxy isatin, alkaline substance, alkylating agent R shown in formula 6 1 -I has a molar ratio of 1:1 to 3:1 to 3; The alkaline substance is selected from one or more of potassium carbonate, sodium hydride, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, and potassium carbonate; Alkylating agent R 1 -I, R 1 The definition is the same as in Formula Ib; The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol and DMF; Step 2: Add LiI to an organic solvent in batches, then add an acidic substance and a compound shown in Formula 7 in sequence, reflux for 8 hours, and then post-treat to obtain a compound shown in Formula 8; The molar ratio of the compound represented by formula 7, LiI, and the acidic substance is 1:1-10:0.1-0.5; The acidic substance is selected from one or more of hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, and nitric acid; The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol and DMF; Step 3: dissolving the compound represented by Formula 8 in an organic solvent, adding an alkaline substance, stirring and mixing at 80° C., then dropwise adding the substituted benzyl bromide compound represented by Formula 9, continuing stirring for 6 hours, and then post-treating to obtain the compound represented by Formula 10; The molar ratio of the compound represented by Formula 8, the alkaline substance, and the substituted benzyl bromide compound represented by Formula 9 is 1:1-2:0.5-1.5; The alkaline substance is selected from one or more of sodium cyanide, potassium carbonate, sodium tert-butoxide, sodium hydroxide and potassium hydroxide; The organic solvent is selected from one or more of acetonitrile, DCM, methanol, ethanol and DMF; Step 4: dissolving the compound represented by formula 10 in a mixed solvent, adding DUB and trimethylsilylated diazomethane in sequence, stirring at room temperature in the dark for 8 to 12 hours under a nitrogen atmosphere, and then post-treating to obtain a quinolinone derivative represented by formula Ib; The molar ratio of the compound represented by formula 10, DUB, and trimethylsilylated diazomethane is 1:0.1-0.3:1-2; The mixed solvent is selected from any two or more of ethanol, methanol, DMF, DCM and acetonitrile; In formula 7-10, R 1 , and Y are defined the same as in Formula Ib.

8. Use of the quinolinone derivative of formula Ia or Ib according to any one of claims 1 to 6 in the preparation of a drug for preventing or treating neurodegenerative diseases and psychoses associated with iron overload and MAO-B overexpression.

9. The use according to claim 8, characterized in that Neurodegenerative and psychiatric diseases associated with iron overload and MAO-B overexpression include: stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, retinal disorders, cerebral ischemia, and depression.

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