A beta-carboline compound, a preparation method thereof and an application thereof in resisting alzheimer disease

Abstract

The present application provides a kind of beta-caproline compound and its preparation method and anti-alzheimer's disease application, structural general formula is as shown in formula I;The present application can selectively inhibit GSK-3 beta and DYRK1A dual-targeting GSK-3 beta / DYRK1A inhibitor, has lower cytotoxic activity to nerve cell and normal hepatocyte, and can significantly reduce the production of NFTs in concentration-dependent manner.The way of increasing the liposolubility of drug improves the permeability of blood-brain barrier, by introducing liposoluble fluorine atom, active and brain permeability quality are better compound is obtained.Therefore, the compound has important role in the preparation of preventing or treating alzheimer's disease drug;

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis and pharmaceutical application technology, specifically relating to a β-carbomer compound, its preparation method, and its application in treating Alzheimer's disease. Background Technology

[0002] Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia and death in the elderly. Its main clinical symptoms are associated with the loss of important cognitive functions such as memory and language. Recently, with the increasing aging of society, more and more AD patients are placing a heavy emotional and economic burden on their families. Due to the complex pathogenesis of AD, various risk factors are interconnected and influence each other, forming a disease network. This has led to repeated setbacks in the development of single-target drugs. Although drugs currently approved by the FDA for the treatment of AD, such as donepezil, rivastigmine, and galantamine, can effectively alleviate AD symptoms, they have not cured it. One reason for these drug failures is that these single-target drugs may not be suitable for treating the complex pathogenesis of AD. Therefore, developing multi-target drugs (MTLDs) for AD may be a more effective way to provide treatment for the disease or slow its progression.

[0003] The main pathological features of Alzheimer's disease (AD) include cholinergic system disorders, tau hyperphosphorylation, β-amyloid (Aβ) aggregation, neuroinflammation, and oxidative stress damage. Among these, the pathological changes in tau are a crucial mechanism in AD. In particular, neurofibrillary tangles (NFTs) formed by tau protein hyperphosphorylation are a hallmark of AD; therefore, preventing tau hyperphosphorylation and clearing pathological tau are essential treatments for AD. Studies have shown that glycogen synthase-3 (GSK-3β) can promote the formation of neurofibrillary tangles by phosphorylating tau protein and is a key rate-limiting enzyme in the pathological development of tau. However, phosphorylation of specific tau residues by dual-substrate-specific tyrosine phosphorylation-regulated kinase A (DYRK1A) is a prerequisite for the subsequent effects of GSK3β. Therefore, intervening in these two key kinases in the tau hyperphosphorylation process may be an effective strategy to reduce NFTs and inhibit tau pathology.

[0004] Furthermore, the success rate of drug development for central nervous system diseases is currently very low. One of the most significant challenges is how drugs can effectively cross the blood-brain barrier (BBB). The BBB precisely controls the brain microenvironment and neural activity by regulating the transport of substances into and out of the brain, blocking almost all large molecule drugs and the vast majority of small molecule drugs. Therefore, improving the ability of drugs to cross the blood-brain barrier based on its structural characteristics is becoming increasingly important. Summary of the Invention

[0005] Purpose of the invention: This invention provides a β-carboline compound, its preparation method, and its application in treating Alzheimer's disease. The purpose is to provide a β-carboline derivative with dual GSK-3β / DYRK1A inhibitory activity, a method for preparing the novel β-carboline compound, and also to indicate the application of the β-carboline derivative in the preparation of drugs for treating Alzheimer's disease.

[0006] Technical solution:

[0007] The first aspect of this invention provides a β-carboline compound or a pharmaceutically acceptable salt thereof, the derivative having the general structural formula shown in Formula I:

[0008]

[0009] In the formula: n = 0, 1, 2, 3; R1 is a substituent on the terminal benzene ring of the side chain at position 1 of the β-carboline nucleus, and R1 is selected from: H, CH3, OCH3, F, CF3, 2,4-di-F, 3,4-di-F or 3,5-di-F; R2 is a substituent at position 6 of the β-carboline nucleus, and R2 is selected from: H, F; R3 is a substituent at position 7 of the β-carboline nucleus, and R3 is selected from: H, OCH3.

[0010] The second aspect of this invention provides for the following compounds or pharmaceutically acceptable salts thereof, selected from:

[0011]

[0012]

[0013] A third aspect of this invention provides a method for preparing the compound, the method comprising the following steps:

[0014] (1) Compound 1 and pyridine were dissolved in tetrahydrofuran, and acyl chloride was added dropwise under ice bath conditions to give compounds 2a-2c.

[0015] (2) Compound 1 was dissolved in N,N-dimethylformamide, and acid, HATU and DIPEA were added at room temperature to give compound 2d-2w.

[0016] (3) Compound 2a-2w was dissolved in anhydrous 1,4-dioxane, and boron pinacol ester, potassium acetate and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride were added. The mixture was refluxed at 90°C for 12 hours under N2 protection to obtain compound 3a-3w.

[0017] (4) Compound 3a-3w was dissolved in a solution of 1,4-dioxane / water = (5:1), cesium carbonate, nitrobenzene with different substitutions and palladium di(triphenylphosphine) chloride were added, and the mixture was refluxed at 95°C for 10 hours under N2 protection to obtain compound 4a-4y.

[0018] (5) Dissolve compound 4a-4y in o-dichlorobenzene, add triphenylphosphine, and reflux at 185°C for 6 hours under N2 protection to obtain target compounds ZLQH-1 to ZLQH-25.

[0019] Furthermore, the acyl chloride mentioned in step (1) is one of benzoyl chloride, p-fluorobenzoyl chloride, or phenylacetyl chloride.

[0020] Further, the acid mentioned in step (2) is one of 2-fluorophenylacetic acid, 3-fluorophenylacetic acid, 4-fluorophenylacetic acid, p-methylphenylacetic acid, 4-methoxyphenylacetic acid, 4-trifluoromethylphenylacetic acid, 2,4-difluoromethylphenylacetic acid, 3,4-difluoromethylphenylacetic acid, 3,5-difluoromethylphenylacetic acid, 3-phenylpropionic acid, 3-(2-fluorophenyl)propionic acid, 3-(3-fluorophenyl)propionic acid, 3-(4-fluorophenyl)propionic acid, 3-(p-tolyl)propionic acid, 3-(4-methoxyphenyl)propionic acid, 3-(4-trifluoromethylphenyl)propionic acid, 3-(2,4-difluorophenyl)propionic acid, 3-(3,4-difluorophenyl)propionic acid, 3-(3,5-difluorophenyl)propionic acid, or 4-phenylbutyric acid.

[0021] Furthermore, the different substituted nitrobenzenes mentioned in step (4) are one of 4-bromo-3-nitrobenzene, 1-bromo-2-nitrobenzene, or 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene.

[0022] A fourth aspect of the present invention provides a pharmaceutical composition comprising the said compound or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

[0023] Furthermore, the compound is used to prepare a formulation by adding one or more pharmaceutically acceptable excipients, the formulation being in the form of capsules, pills, tablets, granules or injections.

[0024] The fifth aspect of this invention proposes the use of the said compound or a pharmaceutically usable salt thereof in the preparation of a medicament for treating Alzheimer's disease.

[0025] The sixth aspect of this invention provides for the use of the said compound or a pharmaceutically usable salt thereof in the preparation of GSK-3β inhibitors, DYRK1A inhibitors or GSK-3β / DYRK1A dual inhibitors.

[0026] Beneficial effects:

[0027] This invention proposes β-carboline compounds by introducing an amide bond at the 1-position of the β-carboline core and adding benzene rings of various lengths and substituents. Simultaneously, it involves introducing a fluorine atom at the 6-position or a methoxy group at the 7-position of the β-carboline core, and further research on selecting advantageous substituents to develop dual-targeting GSK-3β / DYRK1A inhibitors that selectively inhibit both GSK-3β and DYRK1A. The preferred compound ZLQH-5 exhibits low cytotoxic activity and significantly reduces NFTs in a concentration-dependent manner. This invention also improves blood-brain barrier permeability by increasing the drug's lipophilicity. By introducing a lipophilic fluorine atom, compounds with improved activity and brain permeability were obtained. Therefore, these compounds play an important role in the preparation of drugs for the prevention or treatment of Alzheimer's disease. Attached Figure Description

[0028] Figure 1 This is a synthetic route diagram for the compound;

[0029] Figure 2 Evaluation of the cytotoxicity of compounds ZLQH-3, ZLQH-5, and ZLQH-25 (A: SH-SY5Y cells, incubated for 24 hours; B: HL-7702 cells, incubated for 24 hours; C: SH-SY5Y cells, incubated for 48 hours; D: HL-7702 cells, incubated for 48 hours; E: SH-SY5Y cells, incubated for 72 hours; F: HL-7702 cells, incubated for 72 hours);

[0030] Figure 3 The graph shows the inhibition of tau phosphorylation by compound ZLQH-5. Detailed Implementation

[0031] The present invention will be described below through specific embodiments, but the present invention is not limited thereto.

[0032] The structure of the compound was determined by nuclear magnetic resonance (NMR). NMR measurements were performed using a Bruker AVANCE-300 / 500 NMR spectrometer, with DMSO-d6 as the solvent and TMS as the internal standard. The preparation method is as follows: Figure 1 As shown.

[0033] Example 1 N-(4-bromopyridin-2-yl)benzamide (compound 2a)

[0034]

[0035] 4-Bromo-2-aminopyridine (compound 1) (1 equivalent) and pyridine (1.5 equivalent) were dissolved in tetrahydrofuran (10 ml), and benzoyl chloride (1.2 equivalent) was slowly added dropwise. The reaction was allowed to proceed for 4 h, and then the solvent in the mixture was removed. The mixture was filtered under ice water to give compound 2a. It was a white solid in 90% yield.

[0036] Example 2 N-(4-bromopyridin-2-yl)-4-fluorobenzamide (compound 2b)

[0037]

[0038] By replacing benzoyl chloride with p-fluorobenzoyl chloride and keeping other conditions unchanged, the experimental procedure of Example 1 was repeated to obtain compound 2b, a white solid with a yield of 85%.

[0039] Example 3 N-(4-bromopyridin-2-yl)-2-phenylacetamide (compound 2c)

[0040]

[0041] By replacing benzoyl chloride with phenylacetyl chloride and keeping other conditions unchanged, the experimental procedure of Example 1 was repeated to obtain compound 2c, a white solid with a yield of 80%.

[0042] Example 4 N-(4-bromopyridin-2-yl)-2-(2-fluorophenyl)acetamide (compound 2d)

[0043]

[0044] 2-Fluorophenylacetic acid (1.2 equivalents), the condensing agent 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.5 equivalents), and the base N,N-diisopropylethylamine (2.5 equivalents) were stirred in DMF (10 mL) for 15 min. Then, 4-bromo-2-aminopyridine (compound 1) (1 equivalent) was added, and the mixture was reacted at room temperature (20 °C) for 3 h. The mixture was then extracted three times with ethyl acetate (150 mL) and water (50 mL), and the solvent was evaporated to dryness. The product was purified by silica gel column chromatography to give compound 2d, a white solid in 81% yield.

[0045] Example 5 N-(4-bromopyridin-2-yl)-2-(3-fluorophenyl)acetamide (compound 2e)

[0046]

[0047] By replacing 2-fluorophenylacetic acid with 3-fluorophenylacetic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2e, a white solid with a yield of 80%.

[0048] Example 6 N-(4-bromopyridin-2-yl)-2-(4-fluorophenyl)acetamide (compound 2f)

[0049]

[0050] By replacing 2-fluorophenylacetic acid with 4-fluorophenylacetic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2f, a white solid with a yield of 83%.

[0051] Example 7 N-(4-bromopyridin-2-yl)-2-(p-tolyl)acetamide (compound 2g)

[0052]

[0053] By replacing 2-fluorophenylacetic acid with p-methylphenylacetic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain 2 g of the compound as a white solid with a yield of 78%.

[0054] Example 8 N-(4-bromopyridin-2-yl)-2-(4-methoxyphenyl)acetamide (compound 2h)

[0055]

[0056] Replacing 2-fluorophenylacetic acid with 4-methoxyphenylacetic acid, while keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2h, a white solid with a yield of 75%.

[0057] Example 9 N-(4-bromopyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (compound 2i)

[0058]

[0059] Replacing 2-fluorophenylacetic acid with 4-trifluoromethylphenylacetic acid, while keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2i, a white solid with a yield of 69%.

[0060] Example 10 N-(4-bromopyridin-2-yl)-2-(2,4-difluorophenyl)acetamide (compound 2j)

[0061]

[0062] Replacing 2-fluorophenylacetic acid with 2,4-difluoromethylphenylacetic acid, while keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2j, a white solid with a yield of 72%.

[0063] Example 11 N-(4-bromopyridin-2-yl)-2-(3,4-difluorophenyl)acetamide (compound 2k)

[0064]

[0065] Replacing 2-fluorophenylacetic acid with 3,4-difluoromethylphenylacetic acid, while keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2k, a white solid with a yield of 75%.

[0066] Example 12 N-(4-bromopyridin-2-yl)-2-(3,5-difluorophenyl)acetamide (compound 2l)

[0067]

[0068] Replacing 2-fluorophenylacetic acid with 3,5-difluoromethylphenylacetic acid, while keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2l, a white solid with a yield of 78%.

[0069] Example 13 N-(4-bromopyridin-2-yl)-3-phenylpropionamide (compound 2m)

[0070]

[0071] By replacing 2-fluorophenylacetic acid with 3-phenylpropionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2m, a white solid with a yield of 80%.

[0072] Example 14 N-(4-bromopyridin-2-yl)-3-(2-fluorophenyl)propionamide (compound 2n)

[0073]

[0074] By replacing 2-fluorophenylacetic acid with 3-(2-fluorophenyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2n, a white solid with a yield of 72%.

[0075] Example 15 N-(4-bromopyridin-2-yl)-3-(3-fluorophenyl)propionamide (compound 2o)

[0076]

[0077] By replacing 2-fluorophenylacetic acid with 3-(3-fluorophenyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2o, a white solid with a yield of 73%.

[0078] Example 16 N-(4-bromopyridin-2-yl)-3-(4-fluorophenyl)propionamide (compound 2p)

[0079]

[0080] By replacing 2-fluorophenylacetic acid with 3-(4-fluorophenyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2o, a white solid with a yield of 70%.

[0081] Example 17 N-(4-bromopyridin-2-yl)-3-(p-tolyl)propionamide (compound 2q)

[0082]

[0083] By replacing 2-fluorophenylacetic acid with 3-(p-tolyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2q, a white solid with a yield of 75%.

[0084] Example 18 N-(4-bromopyridin-2-yl)-3-(4-methoxyphenyl)propionamide (compound 2r)

[0085]

[0086] By replacing 2-fluorophenylacetic acid with 3-(4-methoxyphenyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2r, a white solid with a yield of 77%.

[0087] Example 19 N-(4-bromopyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)propionamide (compound 2s)

[0088]

[0089] By replacing 2-fluorophenylacetic acid with 3-(4-trifluoromethylphenyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2s, a white solid with a yield of 67%.

[0090] Example 20 N-(4-bromopyridin-2-yl)-3-(2,4-difluorophenyl)propionamide (compound 2t)

[0091]

[0092] By replacing 2-fluorophenylacetic acid with 3-(2,4-difluorophenyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2t, a white solid with a yield of 69%.

[0093] Example 21 N-(4-bromopyridin-2-yl)-3-(3,4-difluorophenyl)propionamide (compound 2u)

[0094]

[0095] By replacing 2-fluorophenylacetic acid with 3-(3,4-difluorophenyl)propionic acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2u, a white solid with a yield of 68%.

[0096] Example 22 N-(4-bromopyridin-2-yl)-3-(3,5-difluorophenyl)propionamide (compound 2v)

[0097]

[0098] By replacing 2-fluorophenylacetic acid with 3-(3,5-difluorophenyl)propionic acid, and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2v, a white solid with a yield of 65%.

[0099] Example 23 N-(4-bromopyridin-2-yl)-4-phenylbutyramide (compound 2w)

[0100]

[0101] By replacing 2-fluorophenylacetic acid with 4-phenylbutyric acid and keeping other conditions unchanged, the experimental procedure of Example 4 was repeated to obtain compound 2w, a white solid with a yield of 62%.

[0102] Example 24 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)benzamide (compound 3a)

[0103]

[0104] Compound 2a (1 equivalent) and boron pinacol ester (1.5 equivalent) were dissolved in anhydrous 1,4-dioxane, followed by the addition of potassium acetate (3 equivalents) and Pd(dppf)Cl2 (0.05% mol). The reaction was carried out under nitrogen protection at 90 °C for 12 h. The solvent was then concentrated, and ice water was added to the reaction flask before filtration. The filter cake was collected to obtain compound 3a. The yield was 90%, and the solid was a grayish-white solid.

[0105] Example 25 4-Fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)benzamide (compound 3b)

[0106]

[0107] Replacing 2a with 2b, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3b, a grayish-white solid, in 82% yield.

[0108] Example 26 2-Phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3c)

[0109]

[0110] Replacing 2a with 2c, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3c, a grayish-white solid, with a yield of 84%.

[0111] Example 27 2-(2-fluorophenyl)--(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3d)

[0112]

[0113] Replacing 2a with 2d and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3d, a grayish-white solid, with a yield of 87%.

[0114] Example 28 2-(3-fluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3e)

[0115]

[0116] Replacing 2a with 2e, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3e, a grayish-white solid, in 89% yield.

[0117] Example 29 2-(4-fluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3f)

[0118]

[0119] Replacing 2a with 2f, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3f, a grayish-white solid, in 83% yield.

[0120] Example 30 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)-2-(p-tolyl)acetamide (compound 3g)

[0121]

[0122] Replacing 2a with 2g and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain 3g of compound, a grayish-white solid, with a yield of 82%.

[0123] Example 31 2-(4-methoxyphenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3h)

[0124]

[0125] Replacing 2a with 2h, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3h, a grayish-white solid, with a yield of 85%.

[0126] Example 32 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (compound 3i)

[0127]

[0128] Replacing 2a with 2i, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3i, a grayish-white solid, with a yield of 78%.

[0129] Example 33 2-(2,4-difluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3j)

[0130]

[0131] Replacing 2a with 2j and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3j, a grayish-white solid, with a yield of 82%.

[0132] Example 34 2-(3,4-difluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3k)

[0133]

[0134] Replacing 2a with 2k and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3k, a grayish-white solid, in 83% yield.

[0135] Example 35 2-(3,5-difluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)acetamide (compound 3l)

[0136]

[0137] Replacing 2a with 2l, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3l, a grayish-white solid, with a yield of 84%.

[0138] Example 36 3-Phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3m)

[0139]

[0140] Replacing 2a with 2m and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3m, a grayish-white solid, with a yield of 81%.

[0141] Example 37 3-(2-fluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3n)

[0142]

[0143] Replacing 2a with 2n and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3n, a grayish-white solid, with a yield of 82%.

[0144] Example 38 3-(3-fluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3o)

[0145]

[0146] Replacing 2a with 2o and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3o, a grayish-white solid, in 83% yield.

[0147] Example 39 3-(4-fluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3p)

[0148]

[0149] Replacing 2a with 2p, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3p, a grayish-white solid, in 84% yield.

[0150] Example 40 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)-3-(p-tolyl)propionamide (compound 3q)

[0151]

[0152] Replacing 2a with 2q, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3q, a grayish-white solid, in 87% yield.

[0153] Example 41 3-(4-methoxyphenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3r)

[0154]

[0155] Replacing 2a with 2r while keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3r, a grayish-white solid, in 82% yield.

[0156] Example 42 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)propionamide (compound 3s)

[0157]

[0158] Replacing 2a with 2s and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3s, a grayish-white solid, with a yield of 77%.

[0159] Example 43 3-(2,4-difluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3t)

[0160]

[0161] Replacing 2a with 2t and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3t, a grayish-white solid, with a yield of 81%.

[0162] Example 44 3-(3,4-difluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3u)

[0163]

[0164] Replacing 2a with 2u, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3u, a grayish-white solid, with a yield of 86%.

[0165] Example 45 3-(3,5-difluorophenyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)propionamide (compound 3v)

[0166]

[0167] Replacing 2a with 2v, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3v, a grayish-white solid, in 85% yield.

[0168] Example 46 4-Phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)butyramide (compound 3w)

[0169]

[0170] Replacing 2a with 2w, and keeping other conditions unchanged, the experimental procedure of Example 24 was repeated to obtain compound 3w, a grayish-white solid, with a yield of 78%.

[0171] Example 47 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)benzamide (compound 4a)

[0172]

[0173] Compound 3a (1.5 equivalents) was dissolved in a solution of 1,4-dioxane / water (4:1), and cesium carbonate (3 equivalents), 4-bromo-3-nitrobenzene ether (1 equivalent), and Pd(PPh3)Cl2 (0.05% mol) were added. The mixture was refluxed at 95°C for 10 hours under N2 protection, and the reaction solution was concentrated. The solution was purified by silica gel column chromatography to give compound 4a as a yellow solid in 78% yield.

[0174] Example 48 4-Fluoro-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)benzamide (Compound 4b)

[0175]

[0176] Replacing 3a with 3b, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4b, a yellow solid, with a yield of 71%.

[0177] Example 49 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-2-phenylacetamide (compound 4c)

[0178]

[0179] Replacing 3a with 3c, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4c, a white solid with a yield of 74%.

[0180] Example 50 2-(2-fluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)acetamide (compound 4d)

[0181]

[0182] Replacing 3a with 3d and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4d, a white solid with a yield of 80%.

[0183] Example 51 2-(3-fluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)acetamide (compound 4e)

[0184]

[0185] Replacing 3a with 3e, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4e, a white solid, in 78% yield.

[0186] Example 52 2-(4-fluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)acetamide (compound 4f)

[0187]

[0188] Replacing 3a with 3f, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4f, a white solid, with a yield of 75%.

[0189] Example 53 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-2-(p-tolyl)acetamide (compound 4g)

[0190]

[0191] Replacing 3a with 3g and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain 4g of compound, a white solid, with a yield of 71%.

[0192] Example 54 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-2-(4-methoxyphenyl)acetamide (compound 4h)

[0193]

[0194] Replacing 3a with 3h, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4h, a white solid, with a yield of 84%.

[0195] Example 55 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (compound 4i)

[0196]

[0197] Replacing 3a with 3i and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4i, a white solid with a yield of 67%.

[0198] Example 56 2-(2,4-difluorophenyl)N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)acetamide (compound 4j)

[0199]

[0200] Replacing 3a with 3j and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4j, a white solid with a yield of 83%.

[0201] Example 57 2-(3,4-difluorophenyl)N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)acetamide (compound 4k)

[0202]

[0203] Replacing 3a with 3k and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4k, a white solid with a yield of 80%.

[0204] Example 58 2-(3,5-difluorophenyl)N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)acetamide (compound 4l)

[0205]

[0206] Replacing 3a with 3l, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4l, a white solid with a yield of 75%.

[0207] Example 59 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-3-phenylpropionamide (compound 4m)

[0208]

[0209] Replacing 3a with 3m and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4m, a white solid with a yield of 80%.

[0210] Example 60 3-(2-fluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)propionamide (compound 4n)

[0211]

[0212] Replacing 3a with 3n, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4n, a white solid with a yield of 77%.

[0213] Example 61 3-(3-fluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)propionamide (compound 4o)

[0214]

[0215] Replacing 3a with 3o and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4o, a white solid with a yield of 87%.

[0216] Example 62 3-(4-fluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)propionamide (compound 4p)

[0217]

[0218] Replacing 3a with 3p while keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4p, a white solid with a yield of 83%.

[0219] Example 63 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-3-(p-tolyl)propionamide (compound 4q)

[0220]

[0221] Replacing 3a with 3q, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4q, a white solid with a yield of 75%.

[0222] Example 64 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-3-(4-methoxyphenyl)propionamide (compound 4r)

[0223]

[0224] Replacing 3a with 3r while keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4r, a white solid with a yield of 71%.

[0225] Example 65 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)propionamide (compound 4s)

[0226]

[0227] Replacing 3a with 3s and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4s, a white solid, with a yield of 66%.

[0228] Example 66 3-(2,4-difluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)propionamide (compound 4t)

[0229]

[0230] Replacing 3a with 3t, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4t, a white solid, with a yield of 71%.

[0231] Example 67 3-(3,4-difluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)propionamide (compound 4u)

[0232]

[0233] Replacing 3a with 3u, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4u, a white solid, with a yield of 68%.

[0234] Example 68 3-(3,5-difluorophenyl)-N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)propionamide (compound 4v)

[0235]

[0236] Replacing 3a with 3v, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4v, a white solid, with a yield of 64%.

[0237] Example 69 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)-4-phenylbutyramide (compound 4w)

[0238]

[0239] Replacing 3a with 3w, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4w, a yellow solid, with a yield of 64%.

[0240] Example 70 2-(3-fluorophenyl)-N-(4-(2-nitrophenyl)pyridin-2-yl)acetamide (compound 4x)

[0241]

[0242] By replacing 3a with 3e and 4-bromo-3-nitrobenzene with 1-bromo-2-nitrobenzene, and keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4x, a yellow solid with a yield of 59%.

[0243] Example 71 N-(4-(5-fluoro-4-methoxy-2-nitrophenyl)pyridin-2-yl)-2-(3-fluorophenyl)acetamide (compound 4y)

[0244]

[0245] Replacing 3a with 3e and 4-bromo-3-nitroanisole with 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene, while keeping other conditions unchanged, the experimental procedure of Example 47 was repeated to obtain compound 4y, a yellow solid with a yield of 74%.

[0246] Example 72 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)benzamide (ZLQH-1) Compound 4a (1 equivalent) was dissolved in o-dichlorobenzene (3 ml), triphenylphosphine (2.5 equivalents) was added, and the mixture was refluxed at 185 °C for 6 hours under N2 protection. The reaction solution was concentrated and purified by silica gel column chromatography to obtain the target compound ZLQH-1 as a white solid with a yield of 11%. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),10.83(s,1H),8.16(d,J=6.9Hz,3H),8.10(d,J=8.7Hz,1H),7.95(d,J=5.3H z,1H),7.69–7.61(m,1H),7.58(t,J=7.5Hz,2H),7.13(d,J=2.3Hz,1H),6.87(dd,J=8.7,2.3Hz,1H),3.86(s,3H). 13 C NMR(101MHz,DMSO-d6)δ165.9,160.8(2C),142.5,136.9,134.3,132.4,130.7,129.9,12 8.8(2C),128.7(2C),122.9,115.0,113.0,109.7,95.4,55.8.HR-ESI-MS:318.1248[M+H] + ,(calcd forC 19 H 15N3O2, 318.1243).

[0247] Example 73 4-Fluoro-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)benzamide (ZLQH-2)

[0248] Replacing 4a with 4b and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-2, a white solid with a yield of 15%. 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),10.00(s,1H),7.40(s,2H),7.32(d,J=5.2Hz,1H),7.27(d,J=8.7Hz ,1H),7.12(d,J=5.2Hz,1H),6.59(t,J=8.6Hz,2H),6.29(d,J=2.3Hz,1H),6.08–6.01(m,1H),3.04(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.3,165.2,164.4,163.5,160.3,142.0,136.4,136.4,132.0,131.0,131 .0,129.4,125.5,122.5,115.4,115.3,114.5,112.6,109.2,94.9,55.3.HR-ESI-MS:336.1145[M+H] + ,(calcdfor C 19 H 14 FN3O2, 336.1148).

[0249] Example 74: N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)phenylacetamide (ZLQH-3) was prepared by replacing 4a with 4c, with other conditions remaining unchanged, and the experimental procedure of Example 72 was repeated to obtain compound ZLQH-3, a white solid, in 13% yield. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),10.64(s,1H),8.06(s,1H),8.05(d,J=3.4Hz,1H),7.86(d,J=5.3Hz,1H),7.43(d,J=6.9Hz ,2H),7.36(t,J=7.6Hz,2H),7.28(d,J=7.3Hz,1H),7.25(d,J=2.3Hz,1H),6.84(dd,J=8.6,2.3Hz,1H),3.87(s,2H),3.84(s,3H). 13C NMR(101MHz,DMSO-d6)δ169.9,166.3,160.3,141.6,136.5,136.3,135.7,132.0,130.6(2C),129.4(2C) ,128.3,127.3,126.6,125.4,122.2,114.5,111.8,109.4,95.2,55.3,42.3.HR-ESI-MS:332.1398[M+H] + ,(calcd for C 20 H 17 N3O2, 332.1399).

[0250] Example 75 2-(2-fluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)acetamide (ZLQH-4)

[0251] Replacing 4a with 4d and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-4, a white solid with a yield of 18%. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),10.63(s,1H),8.10–8.02(m,2H),7.86(d,J=5.2Hz,1H),7.78(d,J=6.1Hz,1H),7.49(td,J=7.6,1.7Hz ,1H),7.34(tdd,J=7.2,6.3,1.8Hz,1H),7.25(d,J=2.3Hz,1H),7.19(d,J=7.6Hz,1H),6.84(dd,J=8.7,2.3Hz,1H),3.97(s,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.3,161.6,160.3,159.6,141.6,136.4,136.4,132.2,132.2,130.6,128.9,128.8,127.3, 124.3,124.2,122.8,122.7,122.3,115.2,115.0,114.4,111.8,109.4,95.3,55.3,35.5.HR-ESI-MS:350.1303[M+H] + ,(calcd for C 20 H 16 FN3O2, 350.13O5).

[0252] Example 76 2-(3-fluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)acetamide (ZLQH-5)

[0253] Replacing 4a with 4e and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-5, a white solid with a yield of 16%. 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),10.64(s,1H),8.07(s,1H),8.05(d,J=3.8Hz,1H),7.87(d,J=5.2Hz,1H),7.40(td,J=8.1,6 .3Hz,1H),7.26(d,J=6.9Hz,2H),7.24(d,J=2.3Hz,1H),7.15–7.06(m,1H),6.84(dd,J=8.7,2.3Hz,1H),3.90(s,2H),3.84(s,3H). 13 C NMR (151MHz, DMSO-d6) δ169.4,162.9,161.3,160.4,141.7,138.4,138.4,136.4,130.7,130.2,130.1,127.4,125 .7,125.6,122.3,116.4,116.2,114.4,113.5,113.4,112.0,109.5,95.2,55.3,41.8.HR-ESI-MS:350.1309[M+H] + ,(calcd forC 20 H 16 FN3O2, 350.13O5).

[0254] Example 76 2-(4-fluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)acetamide (ZLQH-6)

[0255] Replacing 4a with 4f, and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-6, a white solid, with a yield of 17%. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),10.64(s,1H),8.07(d,J=0.8Hz,1H),8.05(d,J=4.3Hz,1H),7.86(d,J=5.3Hz,1H),7.4 6(dd,J=8.5,5.7Hz,2H),7.24(d,J=2.3Hz,1H),7.18(t,J=8.9Hz,2H),6.84(dd,J=8.7,2.3Hz,1H),3.87(s,2H),3.85(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.9,162.4,160.4,160.0,141.6,136.3,131.9,131.9,131.3(2C),131.3(2C),130 .6,127.4,122.3,115.1(2C),114.9(2C),114.5,111.9,109.4,95.2,55.3,41.3.HR-ESI-MS:350.1307[M+H] + ,(calcd for C 20 H 16 FN3O2, 350.13O5).

[0256] Example 77 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-2-(p-tolyl)acetamide (ZLQH-7)

[0257] Replacing 4a with 4g and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-7, a white solid with a yield of 19%. 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),9.78(s,1H),7.21(s,1H),7.19(d,J=3.5Hz,1H),7.00(d,J=5.2Hz,1H),6.46(d,J=7. 7Hz,2H),6.39(d,J=2.2Hz,1H),6.30(d,J=7.8Hz,2H),5.98(dd,J=8.7,2.3Hz,1H),2.99(s,3H),2.96(s,2H),1.43(s,3H). 13CNMR(101MHz,DMSO-d6)δ170.2,160.4,141.6,136.5,136.3,135.6,132.7,130.6,129.3(2C),12 8.9(2C),127.3,122.3,114.5,111.8,109.4,95.3,55.3,41.9,20.7.HR-ESI-MS:346.1557[M+H] + ,(calcd for C 21 H 19 N3O2, 346.1556).

[0258] Example 78 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-2-(4-methoxyphenyl)acetamide (ZLQH-8)

[0259] Replacing 4a with 4h and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-8, a white solid with a yield of 22%. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),10.65(s,1H),8.06(dd,J=7.0,1.7Hz,2H),7.86(d,J=5.3Hz,1H),7.35(d,J=8.6H z,2H),7.25(d,J=2.3Hz,1H),6.92(d,J=8.6Hz,2H),6.84(dd,J=8.6,2.3Hz,1H),3.85(s,3H),3.80(s,2H),3.74(s,3H). 13 C NMR(101MHz,DMSO-d6)δ170.3,160.3,158.1,141.6,136.5,136.3,130.6,130.4(2C),127.6,12 7.2,122.2,114.4,113.7(2C),111.8,109.4,95.2,55.3,55.0,41.4.HR-ESI-MS:362.1503[M+H] + ,(calcd for C 21 H 19 N3O3, 362.1505).

[0260] Example 79 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-2-(4-(trifluoromethyl)phenyl)acetamide (ZLQH-9)

[0261] Replacing 4a with 4i and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-9, a white solid with a yield of 14%. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.63(s,1H),8.07(d,J=1.4Hz,1H),8.05(d,J=4.8Hz,1H),7.87(d,J=5.3Hz,1H),7 .73(d,J=8.1Hz,2H),7.65(d,J=8.0Hz,2H),7.23(d,J=2.3Hz,1H),6.84(dd,J=8.6,2.3Hz,1H),4.00(s,2H),3.84(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.2,160.3,141.6,140.6,136.3,136.3,130.6,130.3(2C),127.4,12 5.1(2C),125.1(2C),122.3,114.4,111.9,109.4,95.2,55.3,41.9.HR-ESI-MS:400.1276[M+H] + ,(calcd for C 21 H 16 F3N3O2, 400.1273).

[0262] Example 80 2-(2,4-difluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)acetamide (ZLQH-10)

[0263] Replacing 4a with 4j and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-10, a white solid with a yield of 23%. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),10.62(s,1H),8.08(d,J=3.2Hz,1H),8.06(d,J=6.6Hz,1H),7.87(d,J=5.2Hz,1H),7.54(t d,J=8.6,6.6Hz,1H),7.25(t,J=2.0Hz,2H),7.10(td,J=8.6,2.7Hz,1H),6.84(dd,J=8.7,2.3Hz,1H),3.95(s,2H),3.84(s,3H). 13C NMR(101MHz,DMSO-d6)δ169.1,164.6,160.3,141.6,137.6,136.3,133.2,133.2,133.1,130.6,127.3,122.3,119.2, 119.0,114.4,111.9,111.3,111.1,109.4,104.5,103.8,103.6,103.3,95.2,55.3,34.9.HR-ESI-MS:368.1214[M+H] + ,(calcd forC 20 H 12 F2N3O2, 368.1211).

[0264] Example 81 2-(3,4-difluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)acetamide (ZLQH-11)

[0265] Replacing 4a with 4k and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-11, a white solid with a yield of 24%. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),10.63(s,1H),8.07(s,1H),8.05(d,J=4.0Hz,1H),7.87(d,J=5.2Hz,1H),7.49(ddd,J=12.0, 7.9, 2.1Hz, 1H), 7.41 (dt, J = 10.9, 8.5Hz, 1H), 7.25 (dd, J = 14.8, 3.5Hz, 2H), 6.84 (dd, J = 8.7, 2.3Hz, 1H), 3.89 (s, 2H), 3.85 (s, 3H). 13 C NMR(101MHz,DMSO-d6)δ169.2,160.3,150.4,150.2,149.7,149.6,147.9,147.8,147.3,147.2,141.6,136.3,136.3,133.3,133.3,130.6, 127.4,126.4,126.4,126.3,126.3,122.3,118.6,118.4,117.2,117.1,114.4,111.9,109.4,95.2,55.3,41.1.HR-ESI-MS:368.1211[M+H] + ,(calcd for C 20 H 12 F2N3O2, 368.1211).

[0266] Example 82 2-(3,5-difluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)acetamide (ZLQH-12)

[0267] Replacing 4a with 4l and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-12, a white solid with a yield of 26%. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),10.61(s,1H),8.07(d,J=3.4Hz,1H),8.05(d,J=6.8Hz,1H),7.86(d,J=5.2Hz,1H),7.53(t d,J=8.6,6.6Hz,1H),7.23(d,J=2.1Hz,2H),7.09(dd,J=2.7,1.0Hz,1H),6.83(dd,J=8.6,2.3Hz,1H),3.94(s,2H),3.83(s,3H). 13 C NMR(101MHz,DMSO-d6)δ168.8,162.7,162.6,162.0,161.9,160.2,160.1 ,159.6,159.5,141.7,136.4,133.3,133.2,133.2,133.1,130.6,127.3, 122.3,119.2,119.1,114.4,111.9,111.3,111.3,111.1,111.1,109.5,1 04.5,103.9,103.6,103.4,95.2,55.3,34.9.HR-ESI-MS:368.1213[M+H] + ,(calcd for C 20 H 12 F2N3O2, 368.1211).

[0268] Example 82 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-3-phenylpropionamide (ZLQH-13)

[0269] Replacing 4a with 4m and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-13, a white solid with a yield of 12%. 1H NMR (400MHz, DMSO-d6) δ10.65(s,2H),8.09–8.03(m,2H),7.86(d,J=5.2Hz,1H),7.32(d,J=4.4Hz,4H),7.25(d,J=2.3Hz,1 H),7.26–7.17(m,1H),6.86(dd,J=8.7,2.3Hz,1H),3.87(s,3H),3.03(dd,J=9.0,6.6Hz,2H),2.86(dd,J=9.1,6.5Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ171.2,160.4,141.6,141.1,136.5,136.2,130.5,128.4(2C),128.3(2C ),127.4,126.0,122.3,114.5,111.7,109.4,95.2,55.3,37.2,30.8.HR-ESI-MS:346.1555[M+H] + ,(calcd for C 21 H 19 N3O2, 346.1556).

[0270] Example 83 3-(2-fluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)propionamide (ZLQH-14)

[0271] Replacing 4a with 4n and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-14, a white solid with a yield of 15%. 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),10.67(s,1H),8.09–8.01(m,2H),7.85(d,J=5.2Hz,1H),7.35(q,J=7.5Hz,1H),7.23(d,J=2.3Hz,1H),7.16(d ,J=7.4Hz,2H),7.03(td,J=7.9,7.3,2.2Hz,1H),6.85(dd,J=8.7,2.3Hz,1 H), 3.86 (s, 3H), 3.04 (dd, J=8.9, 6.5Hz, 2H), 2.87 (dd, J=8.8, 6.7Hz, 2H). 13C NMR(101MHz,DMSO-d6)δ170.9,163.4,161.0,160.3,144.2,144.1,141.6,136.5,136.3,130.4,130.2,130.1,127.4,124.5 ,124.4,122.3,115.1,114.9,114.5,112.8,112.6,111.7,109.4,95.1,55.3,36.8,30.4,30.4.HR-ESI-MS:364.1461[M+H] + ,(calcd for C 21 H 18 FN3O2, 364.1461).

[0272] Example 84 3-(3-fluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)propionamide (ZLQH-15)

[0273] Replacing 4a with 4o and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-15, a white solid with a yield of 18%. 1 H NMR (400MHz, DMSO-d6) δ9.81(s,1H),9.79(s,1H),7.23(d,J=6.2Hz,1H),7.21(d,J=2.8 Hz,1H),7.02(d,J=5.3Hz,1H),6.57(td,J=7.7,1.9Hz,1H),6.44(ddt,J=7.9,3.3,1.9H z,1H),6.41(d,J=2.4Hz,1H),6.35(d,J=9.9Hz,1H),6.31(d,J=7.2Hz,1H),6.02(dd,J= 8.7,2.3Hz,1H),3.03(s,3H),2.22(dd,J=9.1,6.5Hz,2H),2.02(dd,J=9.0,6.7Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ170.8,166.3,161.8,160.3,159.3,141.6,136.5,136.3,132.0,130.7,130.7,130.5,128.2,128.1,127.7,12 7.6,127.5,125.4,124.4,124.4,122.3,115.2,115.0,114.5,111.8,109.4,95.2,55.3,35.6,24.0,24.0.HR-ESI-MS:364.1463[M+H] +,(calcd for C 21 H 18 FN3O2, 364.1461).

[0274] Example 85 3-(4-fluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)propionamide (ZLQH-16)

[0275] Replacing 4a with 4p and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-16, a white solid with a yield of 19%. 1 H NMR (400MHz, DMSO-d6) δ9.76 (s, 2H), 7.25–7.17 (m, 2H), 7.01 (d, J = 5.2Hz, 1H), 6.50 (dd, J = 8.5, 5.7Hz, 2H), 6.40 (d, J = 2.3Hz, 1H), 6.29 (t, J=8.9Hz, 2H), 6.01 (dd, J=8.7, 2.3Hz, 1H), 3.02 (s, 3H), 2.17 (dd, J=8.9, 6.6Hz, 2H), 1.99 (dd, J=8.7, 6.8Hz, 2H). 13 C NMR(151MHz,DMSO-d6)δ171.1,161.6,160.3,160.0,141.6,137.3,137.3,136.5,136.3,130.5,130.1(2C),13 0.1,127.5,122.3,115.1,115.0(2C),114.5,111.8,109.4,95.2,55.3,37.3,30.0.HR-ESI-MS:364.1458[M+H] + ,(calcd for C 21 H 18 FN3O2, 364.1461).

[0276] Example 86 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-3-(p-tolyl)propionamide (ZLQH-17)

[0277] Replacing 4a with 4q and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-17, a white solid with a yield of 23%. 1H NMR (400MHz, DMSO-d6) δ10.59(s,2H),8.08–7.99(m,2H),7.84(d,J=5.3Hz,1H),7.23(d,J=2.3Hz,1H),7.18(d,J=7.8Hz,2H),7.10 (d,J=7.9Hz,2H),6.84(dd,J=8.6,2.3Hz,1H),3.85(s,3H),2.96(dd,J=9.0,6.5Hz,2H),2.80(dd,J=8.9,6.6Hz,2H),2.25(s,3H). 13 C NMR(101MHz,DMSO-d6)δ171.2,160.3,141.6,138.0,136.6,136.3,134.9,130.5,128.9(2C),128.2 (2C),127.5,122.3,114.5,111.7,109.4,95.2,55.3,37.3,30.4,20.6.HR-ESI-MS:360.1709[M+H] + ,(calcd for C 22 H 21 N3O2, 360.1712).

[0278] Example 87 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-3-(4-methoxyphenyl)propionamide (ZLQH-18)

[0279] Replacing 4a with 4r and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-18, a white solid with a yield of 25%. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,2H),8.06(d,J=8.6Hz,1H),8.04(d,J=5.3Hz,1H),7.86(d,J=5.3Hz,1H),7.24(d,J=2.3Hz,1H),7.22(d,J= 8.6Hz,2H),6.87(d,J=8.4Hz,2H),6.84(d,J=2.3Hz,1H),3.87(s,3H),3.72(s,3H),2.96(dd,J=9.0,6.4Hz,2H),2.81(dd,J=8.9,6.6Hz,2H). 13C NMR(101MHz,DMSO-d6)δ171.3,160.4,157.6,141.6,136.5,136.1,133.0,130.5,129.2(2C),127. 3,122.3,114.5,113.8(2C),111.7,109.4,95.2,55.3,55.0,37.5,30.HR-ESI-MS:376.1660[M+H] + ,(calcd for C 22 H 19 N3O3, 376.1661).

[0280] Example 88 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-3-(4-(trifluoromethyl)phenyl)propionamide (ZLQH-19)

[0281] Replacing 4a with 4s and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-19, a white solid with a yield of 16%. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),10.61(s,1H),8.06(d,J=7.5Hz,1H),8.04(d,J=4.0Hz,1H),7.85(d,J=5.2Hz,1H),7.67(d,J=8.0Hz ,2H),7.54(d,J=8.0Hz,2H),7.24(d,J=2.3Hz,1H),6.85(dd,J=8.6,2.3Hz,1H),3.86(s,3H),3.12(t,J=7.7Hz,2H),2.89(t,J=7.7Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ170.8,160.3,146.2,141.6,136.5,136.3,130.5,129.2(2C),127.5,127.0,126.7,125.8,12 5.3,125.2,125.2(2C),125.1,123.1,122.3,114.5,111.8,109.4,95.2,55.3,36.6,30.5.HR-ESI-MS:414.1428[M+H] + ,(calcd for C 22 H 18 F3N3O2, 414.1429).

[0282] Example 89 3-(2,4-difluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)propionamide (ZLQH-20)

[0283] Replacing 4a with 4t and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-20, a white solid with a yield of 23%. 1 H NMR (400MHz, DMSO-d6) δ10.61(s,2H),8.10–8.02(m,2H),7.85(d,J=5.2Hz,1H),7.44(td,J=8.8,6.7Hz,1H),7.23(d,J=2.4Hz,1H),7.20(dd, J=9.9,2.3Hz,1H),7.04(td,J=8.5,2.8Hz,1H),6.85(dd,J=8.6,2.3Hz,1H),3.87(s,3H),3.02(t,J=7.7Hz,2H),2.83(dd,J=8.8,6.7Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ171.1,160.8,159.5,142.1,136.9,136.8,132.1,132.0,131.0,128.0,122.8,11 5.0,112.3,111.9,111.7,109.8,104.4,104.1,103.9,95.7,55.8,36.0,24.0.HR-ESI-MS:382.1370[M+H] + ,(calcdfor C 21 H 17 F2N3O2, 382.1367).

[0284] Example 90 3-(3,4-difluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)propionamide (ZLQH-21)

[0285] Replacing 4a with 4u and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-21, a white solid with a yield of 25%. 1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),10.60(s,1H),8.10–8.02(m,2H),7.8 6(d,J=5.3Hz,1H),7.44(td,J=8.7,6.6Hz,1H),7.23(d,J=2.3Hz,1H),7.20 (dd,J=9.9,2.1Hz,1H),7.04(tdd,J=8.6,2.9,1.0Hz,1H),6.85(dd,J=8.7, 2.3Hz, 1H), 3.87 (s, 3H), 3.02 (t, J = 7.7Hz, 2H), 2.83 (dd, J = 8.8, 6.7Hz, 2H). 13 C NMR(101MHz,DMSO-d6)δ160.3,141.6,136.4,136.3,131.7,131.6,131.5,130.4,127.5,122.2,114.4,111.7,111 .4,111.4,111.2,111.2,109.3,103.9,103.6,103.3,95.1,55.3,35.5,23.5.HR-ESI-MS:382.1369[M+H]+,(calcd for C 21 H 17 F2N3O2, 382.1367).

[0286] Example 91 3-(3,5-difluorophenyl)-N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)propionamide (ZLQH-22)

[0287] Replacing 4a with 4v, and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-22, a white solid, with a yield of 26%. 1 H NMR (400MHz, DMSO-d6) δ10.60(s,2H),8.06(d,J=7.6Hz,1H),8.04(d,J=4.0Hz,1H),7.85(d,J=5.2Hz,1H),7.23(d,J=2.3Hz,1H),7.07 (d,J=2.6Hz,1H),7.05(d,J=2.1Hz,2H),6.85(dd,J=8.6,2.3Hz,1H),3.86(s,3H),3.05(t,J=7.6Hz,2H),2.87(dd,J=8.5,6.9Hz,2H). 13C NMR(101MHz,DMSO-d6)δ170.7,163.6,163.5,161.2,161.0,160.3,145.8,141.6,136.4,136.3,130.5,127.4,122.2,11 4.5,111.7,111.6,111.5,111.4,111.3,109.3,101.7,101.5,101.2,95.2,55.3,36.3,30.3.HR-ESI-MS:382.1367[M+H] + ,(calcd for C 21 H 17 F2N3O2, 382.1367).

[0288] Example 92 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-4-phenylbutyramide (ZLQH-23) was prepared by replacing 4a with 4w and keeping other conditions unchanged. The experimental procedure of Example 72 was repeated to obtain compound ZLQH-23, a white solid, in 14% yield. 1 H NMR (400MHz, DMSO-d6) δ10.60 (s, 1H), 10.56 (s, 1H), 8.06 (d, J = 3.5Hz, 1H), 8. 04(s,1H),7.85(d,J=5.2Hz,1H),7.31(t,J=7.5Hz,2H),7.25(d,J=6.8Hz,2H) ,7.23(d,J=2.3Hz,1H),7.19(t,J=7.1Hz,1H),6.84(dd,J=8.7,2.3Hz,1H),3. 85(s,3H),2.70(t,J=7.7Hz,2H),2.56(t,J=7.4Hz,2H),2.00(p,J=7.6Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ171.7,160.3,141.7,141.6,136.6,136.3,130.4,128.3,128.3,127. 6,125.8,122.2,114.5,111.7,109.3,95.2,55.3,35.0,34.7,26.8.HR-ESI-MS:360.1714[M+H] + ,(calcdfor C 22 H 21 N3O2, 360.1712).

[0289] Example 93 2-(3-fluorophenyl)-N-(9H-pyrido[3,4-b]indol-1-yl)acetamide (ZLQH-24) was prepared by replacing 4a with 4x, with other conditions unchanged, and the experimental procedure of Example 72 was repeated to obtain compound ZLQH-24, a white solid, in 26% yield. 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),10.81(s,1H),8.20(d,J=7.9Hz,1H),8 .12(d,J=5.2Hz,1H),7.99(d,J=5.2Hz,1H),7.73(d,J=8.2Hz,1H),7.53(ddd ,J=8.3,7.0,1.2Hz,1H),7.40(td,J=8.0,6.2Hz,1H),7.28(dd,J=10.1,4.4H z,2H),7.27–7.19(m,1H),7.11(td,J=8.4,2.4Hz,1H),3.92(d,J=2.1Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ169.4,163.3,160.9,140.0,138.4,138.3,136.9,136.1,130.2,130.2,130.1,128.2,127. 7,125.6,125.6,121.4,120.7,119.4,116.4,116.2,113.5,113.3,112.7,112.5,41.8.HR-ESI-MS:320.1201[M+H] + ,(calcd for C 19 H 14 FN3O, 320.1199).

[0290] Example 94 N-(6-fluoro-7-methoxy-9H-pyrido[3,4-b]indol-1-yl)-2-(3-fluorophenyl)acetamide (ZLQH-25)

[0291] Replacing 4a with 4y and keeping other conditions unchanged, the experimental procedure of Example 72 was repeated to obtain compound ZLQH-25, a yellow solid, with a yield of 22%. 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),9.90(s,1H),7.25(d,J=2.4Hz,1H),7.23(d,J=8.4Hz,1H),7.06(d,J=5.3Hz,1H),6.65(d,J=7.4H z,1H),6.59(td,J=8.0,6.2Hz,1H),6.47(d,J=2.2Hz,1H),6.45(d,J=6.7Hz,1H),6.30(td,J=8.1,2.2Hz,1H),3.11(s,3H),3.10(s,2H). 13 C NMR(101MHz,DMSO-d6)δ169.4,163.3,160.9,148.9,148.8,148.6,146.2,138.4,138.3,137.0,136.7,136.1,130.5,130.5,130.2,130 .1,127.5,125.6,125.6,116.4,116.2,113.5,113.3,112.3,112.2,112.1,107.3,107.1,96.5,56.0,41.8.HR-ESI-MS:368.1203[M+H] + ,(calcd for C 20 H 15 F2N3O2, 368.1211).

[0292] Example 95: Evaluation of GSK-3β / DYRK1A inhibitory activity

[0293] Kinase Glo assays were performed using a white 96-well plate in assay buffer. 1 μL (500 nM) of the test compound (ZLQH-1–25) (dissolved in DMSO and then diluted to the desired concentration with kinase buffer) and 2 μL (5 ng) of enzyme were added to each well. Then, 2 μL of a mixture containing 0.2 μg of substrate and 25 μM ATP was added. After incubation at room temperature for 60 minutes, the enzymatic reaction was stopped with 5 μL of kinase Glo reagent, and the remaining ATP was removed. After incubation at room temperature for another 40 minutes, the ADP generated in the reaction was converted to ATP using a kinase assay reagent. The luminescence value was recorded using a multi-mode microplate reader after 30 minutes. The method for measuring DYRKIA enzyme activity was similar. Conclusion: Experiments demonstrate that some of the compounds prepared in this invention can effectively inhibit the activity of GSK-3β / DYRK1A (Table 1).

[0294]

[0295]

[0296] [a]ND=Not determined.[b]%inhibition at 500nM.

[0297] Example 96: In vitro blood-brain barrier penetration test

[0298] To test the ability of the compounds to penetrate the blood-brain barrier, we used the PAMPA-BBB method to detect the in vitro BBB penetration ability of ZLQH-3, ZLQH-5, and ZLQH-25. e >4.0×10 -6 cm / s -1 Compounds can cross the BBB. P e <2.0×10 -6 cm / s -1 Compounds cannot cross the BBB. P e >2.0×10 -6 cm / s -1 To P e >4.0×10 -6 cm / s -1 The compounds could not be definitively identified as crossing the BBB. The results of the compound detection are shown in Table 2. Satisfactorily, the results demonstrate that ZLQH-3, ZLQH-5, and ZLQH-25 can cross the BBB (P0). e >4.0×10 -6 Furthermore, based on the chemical structural formula and principles, other compounds in this application can also cross the BBB.

[0299]

[0300] [a]Data are mean±SD of at least three independent experiments intriplicate.

[0301] Example 97: Cytotoxicity evaluation of compounds ZLQH-3, ZLQH-5 and ZLQH-25

[0302] Human normal hepatocytes HL-7702 and neuroblastoma-producing cells SH-SY5Y were used for cytotoxicity evaluation. Cells in the logarithmic growth phase were selected, and 100 μL of cell suspension (0.8 × 10⁶ cells per well) was added to each well of a 96-well cell culture plate. 4Cells were cultured for 24 hours. DMEM medium containing different concentrations of the test compound was added to each well; a blank control group (DMEM medium only) was also included. After culturing for 24, 48, or 72 hours, 20 μL of MTT solution (5 mg / mL) was added to each well, and the cells were incubated for another 4 hours. The culture medium was discarded, and 150 μL of DMSO was added to each well to dissolve the crystals. The mixture was shaken for 5 minutes to completely dissolve the crystals. The OD value was read at 490 nm using a multi-mode microplate reader, and the cell viability was calculated. (See [link to microplate reader]). Figure 2 The experimental results show the viability of compounds ZLQH-3, ZLQH-5, and ZLQH-25 against SH-SY5Y and HL-7702 cells at 24, 48, and 72 hours. When SHSY5Y and HL-7702 cells were treated with 15 μM for 24, 48, and 72 hours, ZLQH-3 and ZLQH-5 did not show cytotoxicity. However, ZLQH-25 showed significant cytotoxicity against both cell lines at 10 μM.

[0303] Example 98: Inhibition of protein tau phosphorylation

[0304] Tau protein hyperphosphorylation can be mediated by GSK-3β and DYRK1A, and the accumulation of hyperphosphorylated tau leads to neurofibrillary tangles (NFTs). To detect NFT formation, inhibition of tau protein hyperphosphorylation was evaluated at the cellular level using a HEK-293T cell model with a P301L point mutation. Figure 3 As shown, NFT production was significantly increased in the m-model group compared to normal HEK-293T cells, but NFT production was reduced by pretreatment with AR-A014418 (a GSK-3β inhibitor) or Harmine (a DYRK1A inhibitor). Importantly, ZLQH-5 significantly reduced NFT production in a concentration-dependent manner.

Claims

1. A kind β -Carboline compounds or pharmaceutically acceptable salts thereof, characterized in that... The compound is selected from: 。 2. A method for preparing the compound as described in claim 1, characterized in that, The method for preparing the compound includes the following steps: ； ； (1) Compound 1 and pyridine were dissolved in tetrahydrofuran, and acyl chloride was added dropwise under ice bath conditions to react and give compounds 2a-2c; (2) Compound 1 was dissolved in N,N-dimethylformamide, and acid, HATU and DIPEA were added at room temperature to give compound 2d-2w. (3) Compound 2a-2w was dissolved in anhydrous 1,4-dioxane, and boron pinacol ester, potassium acetate and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride were added. The mixture was refluxed at 90°C for 12 hours under N2 protection to obtain compound 3a-3w. (4) Compound 3a-3w was dissolved in a solution of 1,4-dioxane / water = 5:1, cesium carbonate, nitrobenzene with different substitutions and palladium di(triphenylphosphine) chloride were added, and the mixture was refluxed at 95°C for 10 hours under N2 protection to obtain compound 4a-4y. (5) Dissolve compound 4a-4y in o-dichlorobenzene, add triphenylphosphine, and reflux at 185°C for 6 hours under N2 protection to obtain target compounds ZLQH-1, ZLQH-2, ZLQH-3, ZLQH-4, ZLQH-5, ZLQH-6, ZLQH-7, ZLQH-8, ZLQH-9, ZLQH-10, ZLQH-11, ZLQH-12, ZLQH-13, ZLQH-14, ZLQH-15, ZLQH-16, ZLQH-17, ZLQH-18, ZLQH-19, ZLQH-20, ZLQH-21, ZLQH-22, ZLQH-23, ZLQH-24, and ZLQH-25.

3. The method for preparing the compound according to claim 2, characterized in that, The acyl chloride mentioned in step (1) is one of benzoyl chloride, p-fluorobenzoyl chloride, or phenylacetyl chloride.

4. The method for preparing the compound according to claim 2, characterized in that, The acid mentioned in step (2) is one of 2-fluorophenylacetic acid, 3-fluorophenylacetic acid, 4-fluorophenylacetic acid, p-methylphenylacetic acid, 4-methoxyphenylacetic acid, 4-trifluoromethylphenylacetic acid, 2,4-difluoromethylphenylacetic acid, 3,4-difluoromethylphenylacetic acid, 3,5-difluoromethylphenylacetic acid, 3-phenylpropionic acid, 3-(2-fluorophenyl)propionic acid, 3-(3-fluorophenyl)propionic acid, 3-(4-fluorophenyl)propionic acid, 3-(p-tolyl)propionic acid, 3-(4-methoxyphenyl)propionic acid, 3-(4-trifluoromethylphenyl)propionic acid, 3-(2,4-difluorophenyl)propionic acid, 3-(3,4-difluorophenyl)propionic acid, 3-(3,5-difluorophenyl)propionic acid, or 4-phenylbutyric acid.

5. The method for preparing the compound according to claim 2, characterized in that, The different substituted nitrobenzenes mentioned in step (4) are one of 4-bromo-3-nitrobenzene, 1-bromo-2-nitrobenzene, or 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene.

6. A pharmaceutical composition, characterized in that, The compound comprising claim 1 and pharmaceutically acceptable excipients.

7. The pharmaceutical composition of claim 6, characterized in that, A formulation is prepared by adding one or more pharmaceutically acceptable excipients to the compound of claim 1, wherein the dosage form of the formulation is a capsule, pill, tablet, granule or injection.

8. Use of the compound of claim 1 or a pharmaceutically usable salt thereof in the preparation of a medicament for treating Alzheimer's disease.

9. Use of the compound of claim 1 or a pharmaceutically usable salt thereof in the preparation of a GSK-3β inhibitor, a DYRK1A inhibitor, or a GSK-3β / DYRK1A dual inhibitor.

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