Quinolinone derivatives, processes for their preparation and use thereof

Abstract

This invention discloses a quinolinone derivative, its preparation method and application. The quinolinone derivative has both iron chelating activity and MAO-B inhibition activity, and can treat neurodegenerative diseases including Alzheimer's disease and Parkinson's disease by simultaneously targeting iron overload and MAO-B overexpression.

Description

Technical Field

[0001] This invention relates to a quinolinone derivative, its preparation method, and its application. Background Technology

[0002] In neurodegenerative diseases (NDs), excess iron not only increases intracellular calcium levels but also... 2+ Levels promote mitochondrial breakdown and also through Ca 2+ The calmodulin pathway activates calmophosphatase; iron overload also activates microglia, causing metabolic changes from oxidative phosphorylation to glycolysis, polarizing them, and thus inducing neuroinflammation and neurodegenerative diseases. Elevated iron levels have been observed in the cortex and hippocampus of Alzheimer's disease (AD) patients, and the degree of iron overload is positively correlated with the severity of AD and the rate of cognitive decline. Iron overload promotes amyloid-beta (Aβ) aggregation and tau protein hyperphosphorylation, accelerating the deposition of senile plaques (SPs) and the formation of neurofibrillary tangles (NTFs). In addition, iron generates large amounts of reactive oxygen species (ROS) through the Fenton or Haber-Weiss reaction, causing lipid peroxidation and leading to neuronal damage. In Parkinson's disease (PD), iron overload is also an important pathway for cell death in dopaminergic neurons. Although iron levels increase with age, the increase in iron content in the basal ganglia is particularly pronounced, especially in the substantia nigra, where iron content is 25%–100% higher than normal. In the presence of oxygen, iron catalyzes the oxidation of dopamine (DA) to form a series of toxic species, reducing cell viability and exacerbating oxidative stress and mitochondrial dysfunction. Furthermore, excess iron can reduce reduced glutathione levels and promote the formation of oxidized glutathione, leading to impaired glutathione-dependent oxidative defense, increased lipid peroxidation, dopaminergic neuronal synaptic dysfunction, and neuronal death. Therefore, targeting iron overload with iron chelators would profoundly intervene in the potential progression of neuronal diseases (NDs), rather than merely targeting downstream sites on the surface.

[0003] Neurotransmitter regulation plays a crucial role in improving the symptoms of neurodegenerative diseases (NDs). Dopamine, known for its neuroprotective effects, is closely related to the regulation of cognitive function in the brain and is regulated by monoamine oxidase (MAO-B) metabolism. MAO-B is a flavin-containing adenine dinucleotide (FAD) enzyme that catalyzes the oxidative deamination of various exogenous amines and endogenous neurotransmitters. During this process, hydrogen peroxide is produced as a byproduct. As a major source of reactive oxygen species (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 MAO-B expression in neuronal tissue increases 3–4 times with age, directly leading to exacerbated oxidative stress and neuronal damage. This evidence suggests the potential application of MAO-B inhibitors as therapeutic agents for NDs.

[0004] In conclusion, given the complexity of neurological disorders (NDs), simultaneously targeting iron overload and MAO-B overexpression offers a novel and promising therapeutic approach. Summary of the Invention

[0005] This invention provides a quinolinone derivative, its preparation method, and its applications. The quinolinone derivative of this invention is a multi-target directed ligand containing an iron chelating agent and a monoamine oxidase B (MAO-B) inhibitor, possessing both iron chelating activity and MAO-B inhibitory activity. It can be used to prepare drugs for the prevention or treatment of neurodegenerative diseases (NDs) and psychosis 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 its pharmaceutically acceptable acid or base addition salt, stereochemical isomer, and nitride form;

[0008]

[0009] In formula Ia or formula Ib,

[0010] R 1 Selected from H, -(C1-C5) straight-chain alkyl or branched alkyl; preferably R 1 It can be 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 halogens; preferably Y is F or Cl.

[0013] Specifically, the quinolinone derivative shown in Formula Ia is one of compounds A1 to A26, and the quinolinone derivative shown in Formula Ib is one of compounds A27 to A30.

[0014]

[0015] This invention provides a method for preparing quinolinone derivatives represented by formula Ia or formula Ib.

[0016] The preparation method of the quinolinone derivative shown in Formula Ia includes the following steps:

[0017] Step 1: Dissolve the 5-methoxyindigo shown in Formula 1 in an organic solvent and stir at 0°C. Then add an alkaline substance and stir until well mixed. Next, add the alkylating reagent R. 1 -I was stirred at 0°C for 2 hours, then moved to room temperature and stirred for another hour. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the compound shown in Formula 2 was obtained through post-processing.

[0018] The raw material 5-methoxyindigo is commercially available through regular channels;

[0019] Formula 1 shows 5-methoxyindigo, a basic substance, and alkylating reagent R. 1 The molar ratio of -I is 1:1 to 3:1 to 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, with sodium hydride being preferred;

[0021] Alkylating agent R 1 In -I, R 1 The definition is the same as in equation 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 5-methoxyindigo shown in Formula 1 is 1 to 3:1, mL / mmol;

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

[0024] Step 2: The compound shown in Formula 2 was suspended in hydrobromic acid and refluxed under a nitrogen atmosphere for 3 hours. After post-treatment, the compound shown in Formula 3 was obtained.

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

[0026] Step 3: Dissolve the compound shown in Formula 3 in an organic solvent, add an alkaline substance, stir and mix at 0-60°C, then add the bromine compound shown in Formula 4 dropwise, continue stirring for 0.25-1 h, and then after post-treatment, obtain the compound shown in Formula 5.

[0027] The molar ratio of the compound shown in Formula 3, the basic substance, and the brominated compound shown in Formula 4 is 1:1 to 2:0.5 to 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, with sodium tert-butoxide being preferred;

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

[0030] The specific post-processing method is as follows: After the reaction is completed, the reaction solution is diluted with saturated saline solution, then extracted with EA, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain the compound shown in Formula 5.

[0031] Step 4: Dissolve the compound shown in Formula 5 in a mixed solvent, and add DUB (1,8-diazabicyclo[5,4,0]-7-7-undecene) and trimethylsilyl diazomethane in sequence. Stir at room temperature in the dark under a nitrogen atmosphere for 8-12 hours. After post-treatment, the quinolinone derivative shown in Formula Ia is obtained.

[0032] The molar ratio of the compound shown in Formula 5, DUB, and trimethylsilyldiazomethane is 1:0.1 to 0.3:1 to 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-processing method is as follows: after the reaction is completed, the reaction is quenched with 1M hydrochloric acid, then diluted with saturated saline solution, then extracted with EA, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the quinolinone derivative shown in formula Ia.

[0035]

[0036] In equations 2-5, R1 The definition of X is the same as in equation Ia;

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

[0038] The preparation method of the quinolinone derivative shown in Formula Ib includes the following steps:

[0039] Step 1: Dissolve 6-methoxyindigo (Formula 6) in an organic solvent and stir at 0°C. Then add an alkaline substance and stir until well mixed. Next, add the alkylating agent R. 1 -I was stirred at 0°C for 2 hours, then moved to room temperature and stirred for another hour. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the compound shown in Formula 7 was obtained by post-processing.

[0040] The raw material 6-methoxyindigo is commercially available through regular channels;

[0041] Formula 6 shows 6-methoxyindigo, a basic substance, and alkylating reagent R. 1 The molar ratio of -I is 1:1 to 3:1 to 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, with sodium hydride being preferred;

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

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

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

[0046] Step 2: LiI was added in batches to an organic solvent, followed by the addition of an acidic substance and the compound shown in Formula 7. The mixture was refluxed for 8 hours and then post-treated to obtain the compound shown in Formula 8.

[0047] The molar ratio of the compound shown in Formula 7, LiI, and the acidic substance is 1:1 to 10:0.1 to 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, with phosphoric acid being preferred;

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

[0050] The specific post-processing method is as follows: After the reaction is completed, the reaction solution is quenched with hydrochloric acid, diluted with saturated saline, extracted with EA, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the compound shown in Formula 8.

[0051] Step 3: Dissolve the compound shown in Formula 8 in an organic solvent, add an alkaline substance, stir and mix at 80°C, then add the substituted benzyl bromide compound shown in Formula 9 dropwise, continue stirring for 6 hours, and then after post-treatment, obtain the compound shown in Formula 10.

[0052] The molar ratio of the compound shown in Formula 8, the basic substance, and the substituted benzyl bromide compound shown in Formula 9 is 1:1 to 2:0.5 to 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, with sodium tert-butoxide being preferred;

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

[0055] The specific post-processing method is as follows: After the reaction is completed, the reaction solution is diluted with saturated saline solution, then extracted with EA, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the compound shown in Formula 10.

[0056] Step 4: Dissolve the compound shown in Formula 10 in a mixed solvent, add DUB and trimethylsilyl diazomethane in sequence, stir at room temperature in the dark for 8-12 hours under a nitrogen atmosphere, and then perform post-treatment to obtain the quinolinone derivative shown in Formula Ib.

[0057] The molar ratio of the compound shown in Formula 10, DUB, and trimethylsilyldiazomethane is 1:0.1 to 0.3:1 to 2, preferably 1:0.15:1.4;

[0058] 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 5:4.

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

[0060]

[0061] In equations 7-10, R 1 The definitions of Y and Y are the same as in equation Ib.

[0062] The quinolinone derivatives of Formula Ia or Formula Ib of this invention are multi-target guided ligands with iron chelating and MAO-B inhibitory activities, which can protect neurons and improve disease states through iron chelating and MAO-B inhibition pathways.

[0063] Therefore, the quinolinone derivatives of Formula Ia or Ib of the present invention, and their pharmaceutically acceptable acid or base addition salts, stereochemical isomers, and nitride forms, can be used to prepare medicaments for the prevention or treatment of neurodegenerative diseases (NDs) and psychosis associated with iron overload and MAO-B overexpression.

[0064] Neurodegenerative diseases (NDs) and mental illnesses 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 beneficial effects of the present invention are as follows:

[0066] The quinolinone derivatives provided by this invention represent a novel class of compounds and are the first type of multi-target guided ligands capable of simultaneously targeting iron overload and MAO-B. These quinolinone derivatives not only chelate iron ions but also inhibit MAO-B, thereby protecting neurons and improving disease states. Therefore, these quinolinone derivatives can be used to treat or prevent the effects of neuromodulation associated with iron overload and MAO-B overexpression, or the risk of various neurological and psychiatric disorders, especially Alzheimer's disease or Parkinson's disease. Attached Figure Description

[0067] Figure 1 Metal ion selectivity of compounds A3, A4, A6, and A27-30. Detailed Implementation

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

[0069] Example 1

[0070] Preparation method of (A1)

[0071] 5-Methoxyindigo (0.886 g, 5 mmol) was placed in a 100 mL round-bottom flask and dissolved in DMF (15 mL). The mixture was stirred at 0 °C for 5 min, then NaH (0.180 g, 7.5 mmol) was added and stirred for 30 min. CH3I (1.064 g, 7.5 mmol) was then added, and the mixture was stirred in an ice bath for 2 h. After that, the reaction mixture 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 by column chromatography (DCM) to obtain 0.822 g of 5-methoxy-1-methylindole-2,3-dione, with a yield of 86%.

[0072] 0.765 g (4 mmol) of 5-methoxy-1-methylindole-2,3-dione and 20 mL of hydrobromic acid (40 wt.%) were added to a 100 mL round-bottom flask and refluxed for 3 h under nitrogen protection. After the reaction was completed, the mixture 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 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] 0.354 g (2 mmol) of 5-hydroxy-1-methylindole-2,3-dione was placed in a 50 mL round-bottom flask, dissolved in 10 mL of DMF solvent, and then 0.211 g (2.2 mmol) of NaOtBu was added. The mixture was stirred at 0 °C for 15 min, and then benzyl bromide (0.342 g (2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, 80 mL of saturated brine was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried over anhydrous Na2SO4, concentrated, and then dried under vacuum 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). DBU (0.034 g, 0.225 mmol) was added, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain 0.198 g of off-white solid Al, 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 2-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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). DBU (0.034 g, 0.225 mmol) was added, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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 = 4.0 Hz), 130.4 (d, 3 J = 8.2 Hz), 129.4, 124.5 (d, 4 J = 3.5 Hz), 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 3-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a white solid A3 of 0.189 g, 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 4-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a white solid A4 of 0.157 g, 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 2-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a white solid A5 of 0.204 g, 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 3-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 4-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to give 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 2-methylbenzyl bromide (0.370 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to give 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 3-methylbenzyl bromide (0.370 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a white solid A9 of 0.190 g, 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] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 4-methylbenzyl bromide (0.370 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 11

[0132] Preparation method of (A11)

[0133] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 3-methoxybenzyl bromide (0.402 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, 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 then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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-Methoxyindigo (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 was completed, the mixture 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 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] 0.326 g (2 mmol) of 5-hydroxyindole-2,3-dione was placed in a 50 mL round-bottom flask, dissolved in 10 mL of DMF solvent, and then 0.211 g (2.2 mmol) of NaOtBu was added. The mixture was stirred at 0 °C for 15 min, and then 0.378 g (2 mmol) of 3-fluorobenzyl bromide was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, 80 mL of saturated brine was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried over anhydrous Na2SO4, concentrated, and then vacuum dried 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). DBU (0.034 g, 0.225 mmol) was added, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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 = 7.3 Hz), 130.6 (d, 3 J = 8.3 Hz), 127.1, 122.5 (d, 4 J=2.6Hz),122.5,115.8,115.6,113.9(d, 2 J = 20.8 Hz), 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 4-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 3-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 4-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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). DBU (0.034 g, 0.225 mmol) was added, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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-Methoxyindigo (0.886 g, 5 mmol) was placed in a 100 mL round-bottom flask and dissolved in DMF (15 mL). The mixture was stirred at 0 °C for 5 min, then NaH (0.180 g, 7.5 mmol) was added and stirred for 30 min. CH3CH2I (1.064 g, 7.5 mmol) was then added, and the mixture was stirred in an ice bath for 2 h. After that, the reaction mixture 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 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, the mixture 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 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] 0.382 g (2 mmol) of 1-ethyl-5-hydroxyindole-2,3-dione was placed in a 50 mL round-bottom flask, dissolved in 10 mL of DMF solvent, and then 0.211 g (2.2 mmol) of NaOtBu was added. The mixture was stirred at 0 °C for 15 min, and then 0.378 g (2 mmol) of 3-fluorobenzyl bromide was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, 80 mL of saturated brine was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried over anhydrous Na2SO4, concentrated, and then vacuum dried 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 60:1, v / v) 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] Example 17

[0171] Preparation method of (A17)

[0172] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 4-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 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 with anhydrous Na2SO4, concentrated, and then vacuum dried 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 60:1, v / v) to give 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] Example 18

[0177] Preparation method of (A18)

[0178] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 3-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 60:1, v / v) 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] Example 19

[0183] Preparation method of (A19)

[0184] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 0 °C for 15 min, and then 4-chlorobenzyl bromide (0.411 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 0.5 h. After the reaction was complete, saturated brine (80 mL) was added, and the mixture was extracted with EA (60 mL × 3). The organic layer was dried with anhydrous Na2SO4, concentrated, and then vacuum dried 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 60:1, v / v) 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] Example 20

[0189] Preparation method of (A20)

[0190] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 60 °C for 15 min, and then 2-(bromomethyl)pyridine hydrobromide (0.506 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for another 1 h. After the reaction was complete, 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 vacuum dried 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)indol-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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 21

[0195] Preparation method of (A21)

[0196] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 60 °C for 15 min, and then 3-(bromomethyl)pyridine hydrobromide (0.506 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred 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 with anhydrous Na2SO4, concentrated, and vacuum dried 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)indol-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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 22

[0201] Preparation method of (A22)

[0202] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 60 °C for 15 min, and then 4-(bromomethyl)pyridine hydrobromide (0.506 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred 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 with anhydrous Na2SO4, concentrated, and vacuum dried 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)indol-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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a 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] Example 24

[0212] Preparation method of (A24)

[0213] 5-Methoxy-1-methylindole-2,3-dione (0.288 g, 1.5 mmol) prepared according to 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a white solid A24 of 0.148 g, 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] Example 25

[0217] Preparation method of (A25)

[0218] 1-Ethyl-5-methoxyindole-2,3-dione (0.308 g, 1.5 mmol) prepared according to Example 16 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a white solid A25 of 0.161 g, 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] Example 26

[0222] Preparation method of (A26)

[0223] 5-Hydroxy-1-methylindole-2,3-dione (0.266 g, 1.5 mmol) prepared according to 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 27

[0227] Preparation method of (A27)

[0228] 6-Methoxyindigo (0.886 g, 5 mmol) was placed in a 100 mL round-bottom flask and dissolved in DMF (15 mL). The mixture was stirred at 0 °C for 5 min, then NaH (0.180 g, 7.5 mmol) was added and stirred for 30 min. CH3I (1.064 g, 7.5 mmol) was then added, and the mixture was stirred in an ice bath for 2 h. After that, the reaction mixture 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 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 50 mL round-bottom flask, DMF (10 mL) was added sequentially, followed by LiI (1.641 g, 12.26 mmol), H3PO4 (85 wt.%, 33.2 μL, 0.28 mmol), and 6-methoxy-1-methylindole-2,3-dione (0.382 g, 2 mmol). The mixture was refluxed for 8 h. After the reaction was complete, 1 M HCl (2 mL) was added to quench the reaction, followed by extraction with saturated brine and EA (80 mL × 3). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (DCM) to obtain 0.315 g of 6-hydroxy-1-methylindole-2,3-dione, with a yield of 89%.

[0230] 0.354 g (2 mmol) of 6-hydroxy-1-methylindole-2,3-dione was placed in a 50 mL round-bottom flask, dissolved in 10 mL of DMF solvent, and then 0.211 g (2.2 mmol) of NaOtBu was added. The mixture was stirred at 80 °C for 15 min, and then 0.378 g (2 mmol) of 3-fluorobenzyl bromide was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred for 6 h. After the reaction was completed, 80 mL of saturated brine 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 28

[0235] Preparation method of (A28)

[0236] The 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, dissolved in DMF (10 mL), and then NaOtBu (0.211 g, 2.2 mmol) was added. The mixture was stirred at 80 °C for 15 min, and then 4-fluorobenzyl bromide (0.378 g, 2 mmol) was slowly added dropwise using a constant pressure dropping funnel. The mixture was stirred 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 0.337 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 the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 29

[0241] Preparation method of (A29)

[0242] The 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, dissolved in DMF (10 mL), 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. The mixture was stirred 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, with 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) to obtain a white solid A29 of 0.190 g, 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] Example 30

[0247] Preparation method of (A30)

[0248] 0.354 g (2 mmol) of 6-hydroxy-1-methylindole-2,3-dione was placed in a 50 mL round-bottom flask according to Example. DMF (10 mL) was added to dissolve the flask, followed by the addition of NaOtBu (0.211 g, 2.2 mmol). The mixture was stirred at 80 °C for 15 min. Then, 0.411 g (2 mmol) of 3-chlorobenzyl bromide was slowly added dropwise using a constant-pressure dropping funnel, and stirring was continued for 6 h. After the reaction was complete, 80 mL of saturated brine 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 0.350 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, and the mixture was purged with nitrogen three times. Finally, trimethylsilyldiazomethane (2 M 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 purified by silica gel plate separation (DCM:MeOH = 50:1, v / v) 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] Example 31

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

[0254] 1. Inhibitory activity of monoamine oxidase

[0255] Both the MAO-B inhibitor screening kit (MAK296) and the MAO-A inhibitor screening kit (MAK295) were purchased from Sigma. The experimental procedures were strictly followed 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 rate in Examples 1-30

[0257]

[0258] IC50 assay was performed on compounds with excellent activity (A3, A4, A6, A27-30). 50 The selectivity for MAO-B subtypes was determined, and the results are shown in Table 2. The IC50 values ​​for all compounds to MAO-B are also presented. 50 The values ​​were all superior to those of phenoxybenzamine; among them, compound A4 (IC) 50 =61.48nM, SI>325), A28(IC) 50 =74.78nM, SI>267) and A30(IC 50 IC = 87.47nM, SI>229) 50 Its value is below 100 nM, comparable to safenamide, and it exhibits high selectivity.

[0259] Table 2. IC50 of some compounds 50 Value, selectivity and iron chelating ability

[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 chelation activity

[0264] Weigh an appropriate amount of calcein solid into a 100 mL brown volumetric flask, dissolve it first with 0.1 M sodium hydroxide solution, then add PBS buffer (phosphate, pH = 7.4, 10 mM) to make up to volume. The calcein solution concentration is now 0.5 μM. Store at 4 °C protected from light until use. Transfer an appropriate amount of FeCl3 aqueous solution (45% FeCl3 basis in H2O) and prepare an 8 μM solution for later use. Weigh 2–3 mg of the test compound or positive control and prepare solutions with different concentration gradients using methanol for later use. Transfer an appropriate amount of 0.5 μM calcein solution, 8 μM 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 2 h. After completion, transfer 200 μL / well of the mixed solution to a 96-well black plate and measure the fluorescence values ​​(Ex = 460 nm, Em = 518 nm) containing different concentrations of the compound. Use Graphpad 8.0 software to fit the IC50 values. 50 The 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) K is the binding constant between calcein and iron ions; probe(calcein) It is the dissociation constant of iron ions intercalating with calcein, which is 1 / 10. 24 M.

[0267] The results are shown in Table 2. The selected compounds (A3, A4, A6, A27-30) all exhibited excellent iron chelating ability and low binding constants (K2). b The range is 2.55 × 10 22 ~5.72×10 22 M -1 All exceeded the positive control drug deferoxone (DFP, K). b =2.25×10 22 M-1 ).

[0268] 3. Metal ion selectivity

[0269] Weigh 2–3 mg of the compound and prepare a 10 mM stock solution with DMSO; weigh appropriate amounts of FeCl3, FeSO4·7H2O, CuCl2·2H2O, AlCl3, MgCl2, CaCl2, ZnCl2, KCl, and NaCl solids and prepare 10 mM solutions with ultrapure water; set up and prepare experimental and background groups, and after shaking at room temperature for 30 min, measure the results using a UV spectrophotometer and plot them using Graphpad software. Figure 1 The results showed that compounds A3, A4, A6, and A27-30 affected Fe. 2+ / Fe 3+ After chelation, a new chelate peak is formed, exhibiting high selectivity.

Claims

1. A quinolinone derivative of formula Ia or formula Ib: In formula Ia or formula Ib, R 1 Selected from H, -(C1-C5) straight-chain alkyl or branched alkyl; X is selected from Y is selected from halogens.

2. The quinoline ketone derivative of formula Ia or Ib as described in claim 1, characterized in that, R 1 It can be H, methyl, or ethyl.

3. The quinolinone derivative of formula Ia or formula Ib as described in claim 1, characterized in that, Y is either F or Cl.

4. The quinoline ketone derivative of formula Ia or Ib as described in claim 1, characterized in that, The quinolinone derivative shown in Formula Ia is one of compounds A1 to A22, and the quinolinone derivative shown in Formula Ib is one of compounds A27 to A30.

5. The quinolinone derivative of formula Ia or formula Ib as described in claim 1, characterized in that, The quinolinone derivatives include pharmaceutically acceptable acid or base addition salts.

6. The method for preparing the quinolinone derivative of formula Ia or Ib as described in claim 1, characterized in that: The preparation method of the quinolinone derivative shown in Formula Ia includes the following steps: Step 1: Dissolve the 5-methoxyindigo shown in Formula 1 in an organic solvent and stir at 0°C. Then add an alkaline substance and stir until well mixed. Next, add the alkylating reagent R. 1 -I was stirred at 0°C for 2 hours, then moved to room temperature and stirred for another hour. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the compound shown in Formula 2 was obtained by post-processing. Formula 1 shows 5-methoxyindigo, a basic substance, and alkylating reagent R. 1 The molar ratio of -I is 1:1~3:1~3; 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 In -I, R 1 The definition is the same as in equation Ia; The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and N,N-dimethylformamide; Step 2: The compound shown in Formula 2 was suspended in hydrobromic acid and refluxed under a nitrogen atmosphere for 3 hours. After post-treatment, the compound shown in Formula 3 was obtained. Step 3: Dissolve the compound shown in Formula 3 in an organic solvent, add an alkaline substance, stir and mix at 0-60°C, then add the bromine compound shown in Formula 4 dropwise, continue stirring for 0.25-1 h, and then after post-treatment, obtain the compound shown in Formula 5. The molar ratio of the compound shown in Formula 3, the basic substance, and the brominated compound shown in Formula 4 is 1:1 to 2:0.5 to 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: Dissolve the compound shown in Formula 5 in a mixed solvent, add DBU and trimethylsilyldiazomethane in sequence, stir at room temperature in the dark for 8-12 h under a nitrogen atmosphere, and then perform post-treatment to obtain the quinolinone derivative shown in Formula Ia. The molar ratio of the compound shown in Formula 5, DBU, and trimethylsilyldiazomethane is 1:0.1-0.3:1-2; The mixed solvent is selected from any two or more of the following: ethanol, methanol, DMF, DCM, and acetonitrile. In equations 2-5, R 1 The definition of X is the same as in equation Ia; The preparation method of the quinolinone derivative shown in Formula Ib includes the following steps: Step 1: Dissolve 6-methoxyindigo (Formula 6) in an organic solvent and stir at 0°C. Then add an alkaline substance and stir until well mixed. Next, add the alkylating agent R. 1 -I was stirred at 0°C for 2 hours, then moved to room temperature and stirred for another hour. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the compound shown in Formula 7 was obtained by post-processing. Formula 6 shows 6-methoxyindigo, a basic substance, and alkylating reagent R. 1 The molar ratio of -I is 1:1~3:1~3; 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 In -I, R 1 The definition is the same as in equation Ib; The organic solvent is selected from one or more of acetonitrile, dichloromethane, methanol, ethanol, and DMF; Step 2: LiI was added in batches to an organic solvent, followed by the addition of an acidic substance and the compound shown in Formula 7. The mixture was refluxed for 8 hours and then post-treated to obtain the compound shown in Formula 8. The molar ratio of the compound shown in Formula 7, LiI, and the acidic substance is 1:1 to 10:0.1 to 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: Dissolve the compound shown in Formula 8 in an organic solvent, add an alkaline substance, stir and mix at 80°C, then add the substituted benzyl bromide compound shown in Formula 9 dropwise, continue stirring for 6 hours, and then after post-treatment, obtain the compound shown in Formula 10. The molar ratio of the compound shown in Formula 8, the basic substance, and the substituted benzyl bromide compound shown in Formula 9 is 1:1 to 2:0.5 to 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: Dissolve the compound shown in Formula 10 in a mixed solvent, add DBU and trimethylsilyldiazomethane in sequence, stir at room temperature in the dark for 8-12 h under a nitrogen atmosphere, and then perform post-treatment to obtain the quinolinone derivative shown in Formula Ib. The molar ratio of the compound shown in Formula 10, DBU, and trimethylsilyldiazomethane 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 equations 7-10, R 1 The definitions of Y and Y are the same as in equation Ib.

7. The use of the quinolinone derivative of formula Ia or formula Ib as described in any one of claims 1 to 5 in the preparation of a medicament for the prevention or treatment of neurodegenerative diseases and psychosis associated with iron overload and MAO-B overexpression.

8. The application as described in claim 7, characterized in that, Neurodegenerative diseases and mental illnesses 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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