Beta-carboboline compound, preparation method thereof and application of beta-carboboline compound in resisting Alzheimer's disease

Abstract

The invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a beta-carboline compound as well as a preparation method and application thereof in resisting Alzheimer's disease. The structural general formula of the compound is shown as a formula I or a formula II. The beta-carboline compound provided by the invention can selectively inhibit the enzyme activity of GSK-3beta and improve cognitive impairment of mouse Alzheimer's disease. Therefore, the compound plays an important role in preparation of drugs for preventing or treating Alzheimer's disease. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis and pharmaceutical application, and specifically relates to a β-carboline compound and a preparation method thereof and an application thereof in preventing Alzheimer's disease. Background Art

[0002] Glycogen synthase kinase 3β (GSK3β) is a multifunctional serine / threonine kinase that plays an important role in cell signaling. It has been extensively studied as a potential therapeutic target for a variety of diseases, including Alzheimer's disease (AD) and other neurodegenerative diseases. Its high expression in the central nervous system (CNS) makes GSK3β an important factor in regulating neuronal function. GSK3β is known to phosphorylate multiple substrates, including the microtubule-associated protein Tau and amyloid precursor protein (APP), and its abnormal activity is closely related to the pathogenesis of AD. Tau protein is expressed throughout the CNS but is mainly found in neuronal axons. In the normal adult brain, partially phosphorylated Tau contains motifs that promote its binding to tubulin, thereby stabilizing microtubules. However, pathological hyperphosphorylation of these motifs prevents microtubule binding, resulting in microtubule instability. Excessive activation of GSK3β leads to abnormal phosphorylation and misfolding of Tau protein, resulting in the formation of neurofibrillary tangles, a hallmark of AD pathology. Studies have shown that GSK3β activity is significantly increased in brain tissue of AD patients and is positively correlated with cognitive dysfunction. This evidence further emphasizes the relationship between GSK3β and AD pathology. Therefore, GSK3β plays a vital role in the pathogenesis of AD, and regulating its activity is considered a potential strategy to improve AD-related pathology.

[0003] Recent studies have shown that small molecule inhibitors targeting GSK3β (Tideglusib, LY-2090314, etc.) have the potential to improve AD-related phenotypes in animal models. These compounds work by inhibiting GSK3β activity, thereby promoting the dephosphorylation of Tau protein, thereby reducing neuronal damage and enhancing cognitive function. In addition, inhibition of GSK3β may help restore neuroplasticity, promote synaptogenesis, and improve neuronal function and connectivity. Although GSK3β inhibitors are promising in the treatment of Alzheimer's disease, their clinical application faces some challenges. In addition, insufficient target selectivity can affect multiple biological pathways and increase the risk of adverse reactions. Therefore, the development of more selective and safe GSK3β inhibitors is crucial to improve their clinical application. Looking ahead, the focus will be on developing selective GSK3β inhibitors to minimize side effects that may occur due to off-target effects while optimizing therapeutic effects. Summary of the invention

[0004] Purpose of the invention: The present invention provides a β-carboline compound, a preparation method thereof and an application in treating Alzheimer's disease. The purpose is to provide a β-carboline derivative with the ability to selectively inhibit the activity of GSK-3β, provide a preparation method of the β-carboline compound, and also point out the application of the β-carboline compound in the preparation of a drug for treating Alzheimer's disease.

[0005] Technical solution:

[0006] In a first aspect, the present invention provides a β-carboline compound or a pharmaceutically acceptable salt thereof, wherein the general structural formula of the derivative is as shown in Formula I or Formula II:

[0007]

[0008] Where: R 1 is an amide substituent at position 1 or 3 of the β-carboline pyridine ring, selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; R 2 is a substituent on the 7-position benzene ring of the β-carboline nucleus, R 2 Selected from: -OCH 3 ,

[0009] R 3 For F, OCH 3 , H or Cl.

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

[0011]

[0012]

[0013]

[0014] The third aspect of the present invention provides a method for preparing the compound, which comprises the following steps:

[0015] (1) Compound 1 is dissolved in tetrahydrofuran, pyridine is added, and the mixture is stirred under ice bath conditions, and then cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, cyclopentylcarbonyl chloride, cyclohexylcarbonyl chloride, benzoyl chloride, or acetyl chloride is slowly added dropwise to obtain compound 2a, 2b, 2c, 2d, 2e, or 2f;

[0016] (2) Compound 2a, 2b, 2c, 2d, 2e, 2f is dissolved in anhydrous dioxane, potassium acetate, 4,4,4',4',5,5,5',5'-octamethyl-2,2-bi-1,3,2-dioxaborolane and bis(triphenylphosphine)palladium chloride are added, and the mixture is heated at 95° C. under nitrogen protection to obtain compound 3a, 3b, 3c, 3d, 3e or 3f;

[0017] (3) Compound 3a, 3b, 3c, 3d, 3e, 3f is dissolved in anhydrous dioxane and water, cesium carbonate and bis(triphenylphosphine)palladium chloride are added, heated at 95° C., and reacted with compound 4a, 4b under nitrogen protection to obtain compound 5a, 5b, 5c, 5d or 5e;

[0018] (4) dissolving compound 5a, 5b, 5c, 5d, or 5e in o-dichlorobenzene, adding triphenylphosphine, and reacting to obtain compound 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22;

[0019] (5) Compounds 6a, 6b, 6c and KNO 3 Mix, add concentrated sulfuric acid dropwise under ice bath condition, and react to obtain compound 7a, 7b or 7d;

[0020] (6) Dissolve compounds 7a, 7b, 7c, 7d, and 7e in SOCl 2 , react under reflux conditions to obtain compound 8a, 8b, 8c, 8d or 8e;

[0021] (7) Compound 8a, 8b, 8c, 8d, or 8e is dissolved in dichloromethane, and triethylamine and amines with different substituents are added to react to obtain compound 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t, 9u, 9v, 9w, 9x, or 9y;

[0022] (8) Compounds 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t, 9u, 9v, 9w, and 9x were dissolved in dioxane and water, and potassium acetate, 4,4,4',4',5,5,5',5'-octamethyl-2,2-bi-1,3,2-dioxaborolane, and bis(triphenylphosphine)palladium chloride were added. , heating at 95° C. under nitrogen protection to obtain target compounds 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h, 10i, 10j, 10k, 10l, 10m, 10n, 10o, 10p, 10q, 10r, 10s, 10t, 10u, 10v, 10w, 10x, 10y, 10z, 10aa, 10ab, 10ac or 10ad;

[0023] (9) Compounds 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h, 10i, 10j, 10k, 10l, 10m, 10n, 10o, 10p, 10q, 10r, 10s, 10t, 10u, 10v, 10w, 10x, 10y, 10z, 10aa, 10ab, 10ac, and 10ad were added to o-dichlorobenzene and heated at 110°C under nitrogen. Under the protection of atmospheric pressure, the target compound 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or 75 was obtained;

[0024] (10) Compound 8c was mixed with methanol in an ice bath to form compound 9z through methylation;

[0025] (11) Compound 9z was added to dioxane and water, heated at 95 °C, and reacted under nitrogen to produce compound 10ae via Suzuki coupling reaction;

[0026] (12) Compound 10ae is added to ethanol, and then hydrazine monohydrate is added to obtain compound 11;

[0027] (13) Compound 11 reacts with 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 3-cyanobenzaldehyde, 4-cyanobenzaldehyde or 3-chlorobenzaldehyde to obtain compound 12a, 12b, 12c, 12d or 12e;

[0028] (14) Compounds 12a, 12b, 12c, 12d, or 12e were added to o-dichlorobenzene and heated at 95° C. under nitrogen protection to obtain target compounds 51, 52, 53, 54, 55, 56, 57, 58, or 59.

[0029] Preferably, the acyl chloride with different substituents in step (1) is one of acetyl chloride, cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, cyclopentylcarbonyl chloride, cyclohexylcarbonyl chloride or phenylacetyl chloride.

[0030] Preferably, the amine with different substituents in step (7) is one of cyclopropylamine, cyclohexylamine, aniline, 4-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline, benzylamine, (S)-1-phenylethylamine, (3-fluorophenyl)methylamine, (3-chlorophenyl)methylamine, (3-fluoro-4-methoxyphenyl)methylamine, 3-(aminomethyl)benzonitrile, benzo[d][1,3]dioxol-5-ylmethylamine, (3-(trifluoromethyl)phenyl)methylamine, (R)-1-phenylethylamine, (R)-1-(3-fluorophenyl)ethylamine, (R)-1-(3-chlorophenyl)ethylamine, (R)-1-phenylpropylamine, 1-phenylcyclopropylamine, (R)-1,2,3,4-tetrahydronaphthalene-1-amine or (R)-N-methyl-1-phenylethylamine.

[0031] Preferably, the benzaldehyde with different substituents in step (13) is one of 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 3-cyanobenzaldehyde, 4-cyanobenzaldehyde or 3-chlorobenzaldehyde.

[0032] The fourth aspect of the present invention provides a pharmaceutical composition comprising the formula I according to any one of claims 1 to 3 or a pharmaceutically acceptable excipient thereof.

[0033] Furthermore, the compound of formula I according to any one of claims 1 to 3 is added with one or more pharmaceutically acceptable excipients to prepare a preparation, and the preparation is in the form of capsules, pills, tablets, granules or injections.

[0034] The fifth aspect of the present invention provides the use of the compound in the preparation of a drug for treating Alzheimer's disease.

[0035] The sixth aspect of the present invention is the use of the compound in the preparation of a GSK-3β inhibitor.

[0036] Beneficial effects:

[0037] The present invention provides a β-carboline compound and a preparation method thereof and an application in treating Alzheimer's disease. The β-carboline compounds proposed in the present invention all have high GSK-3β inhibitory activity, and the GSK3β inhibitory activity of some compounds is 191.89 times higher than that of the lead compound ZDWX-25, and the selectivity is 17337 times higher. The preferred compounds were subjected to open field behavioral experiments, new location recognition experiments, and water maze experiments, and it was concluded that the compounds proposed in the present invention support the safety and effectiveness of the drug at this dose; and the compounds proposed in the present invention play a positive role by improving cognitive function, especially spatial memory and learning ability; the compounds proposed in the present invention have a shortened incubation period, making the mouse swimming path more effective, increasing the residence time, and increasing the number of shuttle platforms.

[0038] The β-carboline compounds proposed in the present invention can selectively inhibit the enzyme activity of GSK-3β and improve the cognitive impairment of Alzheimer's disease in mice. Therefore, the compounds play an important role in the preparation of drugs for preventing or treating Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 is a synthetic route map of the compounds, in which a is a synthetic route map of compounds 13 to 22, b is a synthetic route map of compounds 23 to 50 and 60 to 75, and c is a synthetic route map of compounds 51 to 59;

[0040] Figure 2 The open field test results of the candidate compounds;

[0041] Figure 3 Identify experimental results for novel positions of candidate compounds;

[0042] Figure 4 The water maze test results for candidate compounds;

[0043] In the figures, ns means p>0.05, * means P<0.05, ** means P<0.01, *** means P<0.001, and **** means P<0.0001. DETAILED DESCRIPTION

[0044] The present invention is described below by means of specific embodiments, but the present invention is not limited thereto.

[0045] The structure of the compound was determined by nuclear magnetic resonance (NMR). NMR was measured using a Bruker AVANCE-300 / 500 NMR spectrometer and the solvent was DMSO-d 6 and CDCl 3 , the internal standard is TMS. Figure 1 shown.

[0046] Suzuki coupling preparation method: borate ester (RB(OR') 2 , 1.2eq) and halogenated aromatic hydrocarbon (Ar-X, 1.0eq) were dissolved in dioxane / water (4:1), and CS 2 CO 3 (3.0 eq) and Pd(dppf)Cl 2 (0.005eq), N 2 Under protection, the reaction was carried out at 95° C. for 12 h, and the reaction solution was concentrated, and ethyl acetate was added for extraction. The concentrated product was purified by silica gel column to obtain the corresponding intermediate (R-Ar).

[0047] Miyaura coupling preparation method: Dissolve aryl halide (Ar-X, 1.0 eq) and 4,4,4',4',5,5,5',5'-octamethyl-2,2-bi-1,3,2-dioxaborolane (1.2 eq) in dioxane / water (4:1), add KOAc (3.0 eq) and Pd(dppf)Cl 2 (0.005eq), N 2 After the reaction was carried out at 90°C for 12 h, the reaction solution was concentrated, ice water was added and allowed to stand until the solid was granular, which was then filtered and dried to obtain the corresponding intermediate (AB(OR') 2 ).

[0048] Preparation of raw materials 3a-f: Compound 1 is dissolved in tetrahydrofuran, pyridine is added, and the mixture is stirred under ice bath conditions, and then acyl chlorides with different substituents are slowly added dropwise, wherein the acyl chlorides with different substituents are one of acetyl chloride, cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, cyclopentylcarbonyl chloride, cyclohexylcarbonyl chloride or phenylacetyl chloride, and the reaction obtains compound 2a, 2b, 2c, 2d, 2e or 2f; Compound 2a, 2b, 2c, 2d, 2e, 2f is dissolved in anhydrous dioxane, potassium acetate, 4,4,4',4',5,5,5',5'-octamethyl-2,2-bi-1,3,2-dioxaborolane and bis(triphenylphosphine)palladium chloride are added, and the reaction obtains compound 3a, 3b, 3c, 3d, 3e or 3f.

[0049] Example 1 N-(4-(5-Fluoro-4-methoxy-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (5a)

[0050] Compounds 3a and 4b were used as raw materials, dissolved in anhydrous dioxane and water, and the intermediate 5a was obtained by Suzuki coupling preparation method; the intermediate 5a was obtained as a yellow solid with a yield of 93.48%.

[0051] Example 2 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)cyclobutanecarboxamide (5b)

[0052] Compounds 3b and 4a were used as raw materials, dissolved in anhydrous dioxane and water, and the Suzuki coupling preparation method was used to obtain intermediate 5b; white solid, with a yield of 84.43%.

[0053] Example 3 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)cyclopentanecarboxamide (5c)

[0054] Compounds 3c and 4a were used as raw materials, dissolved in anhydrous dioxane and water, and the Suzuki coupling preparation method was used to obtain intermediate 5c; yellow solid, with a yield of 82.25%.

[0055] Example 4 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)cyclohexanecarboxamide (5d)

[0056] Compounds 3d and 4a were used as raw materials, dissolved in anhydrous dioxane and water, and the Suzuki coupling preparation method was used to obtain intermediate 5d; yellow solid, with a yield of 90.72%.

[0057] Example 5 N-(4-(4-methoxy-2-nitrophenyl)pyridin-2-yl)benzamide (5e)

[0058] Compounds 3e and 4a were used as raw materials, dissolved in anhydrous dioxane and water, and the intermediate 5e was obtained by Suzuki coupling preparation method; the intermediate 5e was obtained as a white solid with a yield of 91.33%.

[0059] Example 6 4-Bromo-N-cyclopropyl-3-nitrobenzamide (9a)

[0060] Preparation of compounds 8a-e: Compounds 6a, 6b, 6c and KNO 3 Mix, add concentrated sulfuric acid dropwise under ice bath condition, and react to obtain compound 7a, 7b or 7d; dissolve compound 7a, 7b, 7c, 7d, 7e in SOCl 2 , and react under reflux conditions to obtain compound 8a, 8b, 8c, 8d or 8e.

[0061] Cyclopropylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9a, which was a yellow solid with a yield of 82.29%.

[0062] Example 7 4-Bromo-N-cyclohexyl-3-nitrobenzamide (9b)

[0063] Cyclohexylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-bath conditions, and stirred to react to obtain compound 9b, a white solid, with a yield of 87.78%.

[0064] Example 8 4-Bromo-3-nitro-N-phenylbenzamide (9c)

[0065] Aniline (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9c, a white solid, with a yield of 88.73%.

[0066] Example 9 4-Bromo-3-nitro-N-(4-(trifluoromethyl)phenyl)benzamide (9d)

[0067] 4-(Trifluoromethyl)aniline (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9d, which was a yellow solid with a yield of 86.54%.

[0068] Example 10 4-Bromo-N-(4-chloro-3-(trifluoromethyl)phenyl)-3-nitrobenzamide (9e)

[0069] 4-Chloro-3-(trifluoromethyl)aniline (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and stirred to react to obtain compound 9e, a white solid, with a yield of 96.03%.

[0070] Example 11 N-Benzyl-4-bromo-3-nitrobenzamide (9f)

[0071] Benzylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-bath conditions, and stirred to react to obtain compound 9f, which was a yellow solid with a yield of 94.47%.

[0072] Example 12 (S)-4-Bromo-3-nitro-N-(1-phenylethyl)benzamide (9 g)

[0073] (S)-alpha-methylbenzylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice bath conditions, and stirred to react to obtain compound 9g, a yellow solid, with a yield of 58.53%.

[0074] Example 13 (R)-4-Bromo-3-nitro-N-(1-phenylethyl)benzamide (9h)

[0075] (R)-alpha-methylbenzylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice bath conditions, and stirred to react to obtain compound 9h, a yellow solid, with a yield of 67.96%.

[0076] Example 14 4-Bromo-N-(3-fluorobenzyl)-3-nitrobenzamide (9i)

[0077] (3-Fluorophenyl)methylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and stirred to react to obtain compound 9i as a white solid with a yield of 90.12%.

[0078] Example 15 4-Bromo-N-(3-chlorobenzyl)-3-nitrobenzamide (9j)

[0079] (3-Chlorophenyl)methylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9j, which was a yellow solid with a yield of 94.72%.

[0080] Example 16 4-Bromo-N-(3-fluoro-4-methoxybenzyl)-3-nitrobenzamide (9k)

[0081] (3-Fluoro-4-methoxyphenyl)methylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9k, which was a yellow solid with a yield of 92.47%.

[0082] Example 17 4-Bromo-N-(3-cyanobenzyl)-3-nitrobenzamide (91)

[0083] 3-(Aminomethyl)benzonitrile (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 91, which was a yellow solid with a yield of 86.76%.

[0084] Example 18 4-Bromo-3-nitro-N-(3-(trifluoromethyl)benzyl)benzamide (9m)

[0085] (3-(Trifluoromethyl)phenyl)methanamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9m, which was a yellow solid with a yield of 90.72%.

[0086] Example 19 N-(Benzo[d][1,3]dioxolane-5-methyl)-4-bromo-3-nitrobenzamide (9n)

[0087] Benzo[d][1,3]dioxolan-5-ylmethylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice bath conditions, and stirred to react to obtain compound 9n, a yellow solid, with a yield of 80.57%.

[0088] Example 20 (R)-4-Chloro-2-fluoro-5-nitro-N-(1-phenylethyl)benzamide (9o)

[0089] (R)-alpha-methylbenzylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8e (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9o, which was a yellow solid with a yield of 85.99%.

[0090] Example 21 (R)-4-Bromo-2-chloro-5-nitro-N-(1-phenylethyl)benzamide (9p)

[0091] (R)-alpha-methylbenzylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8a (1.0 eq) was added under ice bath conditions, and stirred to react to obtain compound 9p, a yellow solid, with a yield of 76.41%.

[0092] Example 22 (R)-4-Chloro-2-(1-(3-fluorophenyl)ethyl)-5-nitrobenzamide (9q)

[0093] (3-Fluorophenyl)methylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8e (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9q, which was a white solid with a yield of 75.21%.

[0094] Example 23 (R)-4-bromo-2-(1-(3-fluorophenyl)ethyl)-5-nitrobenzamide (9r)

[0095] (3-Fluorophenyl)methylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8d (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9r, which was a yellow solid with a yield of 69.80%.

[0096] Example 24 (R)-4-Chloro-N-(1-(3-chlorophenyl)ethyl)-2-fluoro-5-nitrobenzamide (9s)

[0097] (3-Chlorophenyl)methylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8e (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9s, which was a yellow solid with a yield of 62.62%.

[0098] Example 25 (R)-4-Bromo-N-(1-(3-chlorophenyl)ethyl)-2-fluoro-5-nitrobenzamide (9t)

[0099] (3-Chlorophenyl)methylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8d (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9t, which was a yellow solid with a yield of 84.11%.

[0100] Example 26 (R)-4-Bromo-2-methoxy-5-nitro-N-(1-phenylethyl)benzamide (9u)

[0101] (R)-alpha-methylbenzylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8b (1.0 eq) was added under ice bath conditions, and stirred to react to obtain compound 9u, a yellow solid, with a yield of 70.05%.

[0102] Example 27 (R)-4-Bromo-3-nitro-N-(1-phenylpropyl)benzamide (9v)

[0103] (R)-alpha-ethylbenzylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-cooling conditions, and the mixture was stirred to react to obtain compound 9v, which was a white solid with a yield of 84.01%.

[0104] Example 28 4-Bromo-3-nitro-N-(1-phenylcyclopropyl)benzamide (9w)

[0105] 1-Phenylcyclopropylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-bath conditions, and stirred to react to obtain compound 9w, which was a white solid with a yield of 85.93%.

[0106] Example 29 (R)-4-Bromo-3-nitro-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (9x)

[0107] (R)-1,2,3,4-tetrahydro-1-naphthylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice bath conditions, and the mixture was stirred to react to obtain compound 9x, which was a light yellow solid with a yield of 93.33%.

[0108] Example 30 (R)-4-Bromo-N-methyl-3-nitro-N-(1-phenylethyl)benzamide (9y)

[0109] (R)-N-methyl-1-phenylethylamine (1.0 eq) and triethylamine (3.0 eq) were dissolved in dichloromethane, and compound 8c (1.0 eq) was added under ice-bath conditions, and stirred to react to obtain compound 9y, a brown-yellow oily liquid, with a yield of 86.99%.

[0110] Example 31 Methyl 4-bromo-3-nitrobenzoate (9z)

[0111] 4-Bromo-3-nitrobenzoyl chloride (1.0 eq) (8c) was dissolved in anhydrous THF (20 ml), and slowly added dropwise to anhydrous methanol under ice bath. After 2 h of reaction, the methanol was concentrated and the residue was recrystallized from ethanol to obtain compound 9z as white flaky crystals with a yield of 95.00%.

[0112] Example 32 4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-N-cyclopropyl-3-nitrobenzamide (10a)

[0113] Compound 9a (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10a, which was a white solid with a yield of 96.26%.

[0114] Example 33 N-cyclohexyl-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-nitrobenzamide (10b)

[0115] Compound 9b (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10b, which was a white solid with a yield of 91.12%.

[0116] Example 34 4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-3-nitro-N-phenylbenzamide (10c)

[0117] Compound 9c (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10c, which was a white solid with a yield of 81.76%.

[0118] Example 35 4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-3-nitro-N-(4-(trifluoromethyl)phenyl)benzamide (10d)

[0119] Compound 9d (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10d, which was a white solid with a yield of 86.55%.

[0120] Example 36 N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-nitrobenzamide (10e)

[0121] Compound 9e (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10e, which was a white solid with a yield of 82.36%.

[0122] Example 37 N-Benzyl-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-nitrobenzamide (10f)

[0123] Compound 9f (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10f, which was a white solid with a yield of 80.08%.

[0124] Example 38 (R)-4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-3-nitro-N-(1-phenylethyl)benzamide (10 g)

[0125] Compound 9g (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10g, which was a white solid with a yield of 73.22%.

[0126] Example 39 (S)-4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-3-nitro-N-(1-phenylethyl)benzamide (10h)

[0127] Compound 9h (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10h as a white solid with a yield of 68.31%.

[0128] Example 40 4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-N-(3-fluorobenzyl)-3-nitrobenzamide (10i)

[0129] Compound 9i (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10i as a white solid with a yield of 70.87%.

[0130] Example 41 N-(3-chlorobenzyl)-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-nitrobenzamide (10j)

[0131] Compound 9j (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10j, which was a white solid with a yield of 74.95%.

[0132] Example 42 4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-N-(3-fluoro-4-methoxybenzyl)-3-nitrobenzamide (10k)

[0133] Compound 9k (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10k, which was a white solid with a yield of 77.73%.

[0134] Example 43 N-(3-cyanobenzyl)-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-nitrobenzamide (101)

[0135] Compound 91 (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 101, which was a white solid with a yield of 88.78%.

[0136] Example 44 4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-3-nitro-N-(3-(trifluoromethyl)benzyl)benzamide (10m)

[0137] Compound 9m (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10m, which was a white solid with a yield of 86.57%.

[0138] Example 45 N-(Benzo[d][1,3]dioxolan-5-ylmethyl)-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-nitrobenzamide (10n)

[0139] Compound 9n (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10n, which was a yellow solid with a yield of 82.11%.

[0140] Example 46 (R)-4-(2-acetamidopyridin-4-yl)-3-nitro-N-(1-phenylethyl)benzamide (10o)

[0141] Compound 9g (1.0 eq) and compound 3f (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10o, which was a yellow solid with a yield of 46.66%.

[0142] Example 47 (R)-4-(2-(Cyclobutanecarboxamido)pyridin-4-yl)-3-nitro-N-(1-phenylethyl)benzamide (10p)

[0143] Compound 9g (1.0 eq) and compound 3b (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10p, which was a yellow solid with a yield of 90.01%.

[0144] Example 48 (R)-4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-3-nitro-N-(1-phenylethyl)benzamide (10q)

[0145] Compound 9g (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10q, which was a yellow solid with a yield of 72.44%.

[0146] Example 49 (R)-4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-2-fluoro-5-nitro-N-(1-phenylethyl)benzamide (10r)

[0147] Compound 9o (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10r, which was a yellow solid with a yield of 49.89%.

[0148] Example 50 (R)-2-Chloro-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-5-nitro-N-(1-phenylethyl)benzamide (10S)

[0149] Compound 9p (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10s as a pale yellow solid with a yield of 73.65%.

[0150] Example 51 (R)-4-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-2-fluoro-N-(1-(3-fluorophenyl)ethyl)-5-nitrobenzamide (10t)

[0151] Compound 9r (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10t as a light yellow solid with a yield of 48.64%.

[0152] Example 52 (R)-N-(1-(3-chlorophenyl)ethyl)-4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-2-fluoro-5-nitrobenzamide (10u)

[0153] Compound 9s (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10u as a yellow solid with a yield of 34.79%.

[0154] Example 53 (R)-4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-2-methoxy-5-nitro-N-(1-phenylethyl)benzamide (10v)

[0155] Compound 9u (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10v, which was a yellow solid with a yield of 66.55%.

[0156] Example 54 (R)-4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-2-fluoro-5-nitro-N-(1-phenylethyl)benzamide (10w)

[0157] Compound 9o (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10w as a light yellow solid with a yield of 40.65%.

[0158] Example 55 (R)-2-Chloro-4-(2-(cyclopentanecarboxamido)pyridin-4-yl)-5-nitro-N-(1-phenylethyl)benzamide (10x)

[0159] Compound 9p (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10x, which was a yellow solid with a yield of 63.42%.

[0160] Example 56 (R)-4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-2-fluoro-N-(1-(3-fluorophenyl)ethyl)-5-nitrobenzamide (10y)

[0161] Compound 9q (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10y as a yellow solid with a yield of 46.85%.

[0162] Example 57 (R)-N-(1-(3-chlorophenyl)ethyl)-4-(2-(cyclopentanecarboxamido)pyridin-4-yl)-2-fluoro-5-nitrobenzamide (10z)

[0163] Compound 9t (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10z, which was a yellow solid with a yield of 49.73%.

[0164] Example 58 (R)-4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-3-nitro-N-(1-phenylpropyl)benzamide (10aa)

[0165] Compound 9v (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10aa as a white solid with a yield of 90.77%.

[0166] Example 59 4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-3-nitro-N-(1-phenylcyclopropyl)benzamide (10ab)

[0167] Compound 9w (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized by Suzuki coupling method to obtain intermediate 10ab as a white solid with a yield of 93.05%.

[0168] Example 60 (S)-4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-3-nitro-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (10ac)

[0169] Compound 9x (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10ac, which was a white solid with a yield of 97.67%.

[0170] Example 61 (R)-4-(2-(Cyclopentanecarboxamido)pyridin-4-yl)-N-methyl-3-nitro-N-(1-phenylethyl)benzamide (10ad)

[0171] Compound 9y (1.0 eq) and compound 3c (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10ad as a white solid with a yield of 83.77%.

[0172] Example 62 Methyl 4-(2-(cyclopropanecarboxamido)pyridin-4-yl)-3-nitrobenzoate (10ae)

[0173] Compound 9z (1.0 eq) and compound 3a (1.5 eq) were mixed and synthesized using Suzuki coupling method to obtain intermediate 10ae, which was a yellow solid with a yield of 80.02%.

[0174] Example 63 N-(4-(4-(hydrazinecarbonyl)-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (11)

[0175] To the ethanol solution of 10ae was added hydrazine monohydrate (1.5 eq), and the reaction mixture was reacted under reflux for 2 h. Afterwards, the mixture was filtered to obtain compound 11. Yield 90.00%, white solid.

[0176] Example 64 (E)-N-(4-(4-(3-methoxybenzyl)hydrazine-1-carbonyl)-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (12a)

[0177] A mixture of intermediate 11 and 3-methoxybenzaldehyde (1.2 eq) in ethanol was refluxed for 1 h. The resulting precipitate was collected by filtration to obtain compound 12a as a white solid with a yield of 95.24%.

[0178] Example 65 (E)-N-(4-(4-(2-(4-methoxybenzyl)hydrazine-1-carbonyl)-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (12b)

[0179] A mixture of intermediate 11 and 4-methoxybenzaldehyde (1.2 eq) in ethanol was refluxed for 1 h. The resulting precipitate was collected by filtration to obtain compound 12b as a white solid with a yield of 88.42%.

[0180] Example 66 (E)-N-(4-(4-(2-(3-cyanobenzyl)hydrazine-1-carbonyl)-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (12c)

[0181] A mixture of intermediate 11 and 3-cyanobenzaldehyde (1.2 eq) in ethanol was refluxed for 1 h. The resulting precipitate was collected by filtration to afford compound 12c as a white solid with a yield of 88.12%.

[0182] Example 67 (E)-N-(4-(4-cyanobenzyl)hydrazine-1-carboxylate)-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (12d)

[0183] A mixture of intermediate 11 and 4-cyanobenzaldehyde (1.2 eq) in ethanol was refluxed for 1 h. The resulting precipitate was collected by filtration to afford compound 12d as a white solid with a yield of 86.66%.

[0184] Example 68 (E)-N-(4-(4-(2-chlorobenzyl)hydrazine-1-carbonyl)-2-nitrophenyl)pyridin-2-yl)cyclopropanecarboxamide (12e)

[0185] A mixture of intermediate 11 and 3-chlorobenzaldehyde (1.2 eq) in ethanol was refluxed for 1 h. The resulting precipitate was collected by filtration to obtain compound 12e as a white solid with a yield of 84.59%.

[0186] Example 69 N-(6-Fluoro-7-methoxy-9H-pyrido[3,4-b]indol-3-yl)cyclopropanecarboxamide (13)

[0187] Compound 5a (1 eq) and triphenylphosphine (2.5 eq) were dissolved in o-dichlorobenzene (3 mL). 2 After 6 h of reaction at 185°C under protection, the reaction solution was concentrated and purified by silica gel column to obtain compound 13. White solid, yield 12%. HPLC analysis: retention time, 3.251 min; peak area, 98.81%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.34(s,1H),10.58(s,1H),8.69–8.40(m,2H),7.99(d,J=11.3Hz,1H),7.19(d ,J=7.3Hz,1H),3.95(s,3H),2.02(ddd,J=7.9,5.4,3.1Hz,1H),0.88–0.74(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.99,149.39,146.47,143.93,139.07,134.14,131.26,130.37,112.78,108.19,103.95,96.15,56.57,14.52,7.60(2C).HRMS(ESI,m / z)for C 16 H 14 FN 3 O 2 [M+Na] + :calcd,322.0967; found,322.0950.

[0188] Example 70 N-(6-Fluoro-7-methoxy-9H-pyrido[3,4-b]indol-1-yl)cyclopropanecarboxamide (14)

[0189] Compound 5a was used as the raw material, and the synthesis method was the same as compound 13. Yield 13%, white solid. HPLC analysis: retention time, 3.768min; peak area, 97.96%. 1 H NMR (400 MHz, DMSO-d6 )δ10.96(s,1H),10.67(s,1H),8.09–8.01(m,2H),7.85(d,J=5.3Hz,1H), 7.48(d,J=7.4Hz,1H),3.93(s,3H),2.20–2.06(m,1H),1.05–0.80(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.12,149.20,146.71,137.48,137.41,136.54,130.98,127.85,112.76,112.29,107.57,96.99,56.46,14.37,8.25(2C).HRMS(ESI,m / z)for C 16 H 14 FN 3 O 2 [M+Na] + :calcd,322.0968; found,322.0962.

[0190] Example 71 N-(7-methoxy-9H-pyrido[3,4-b]indol-3-yl)cyclobutanecarboxamide (15)

[0191] 5a was replaced by 5b. The synthesis method was the same as compound 13. Yield: 28%, yellow solid. HPLC analysis: retention time, 3.826min; peak area, 99.35%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.27(s,1H),10.09(s,1H),8.64(s,1H),8.50(d,J=1.0Hz,1H),8.02(d,J=8.7Hz,1H),7.00(d,J=2.2Hz,1H),6.82(dd,J=8.7,2. 2Hz,1H),3.87(s,3H),3.39(p,J=8.4Hz,1H),2.27(pd,J=9.1,2.4Hz,2H),2.17–2.05(m,2H),2.02–1.90(m,1H),1.89–1.75(m,1H); 13 C NMR (101 MHz, DMSO-d 6)δ173.24,160.94,144.09,143.75,133.96,130.79,130.42,123.02,114.99 ,109.47,103.74,95.10,55.82,39.69,25.05(2C),18.27.HRMS(ESI,m / z)for C 17 H 17 N 3 O 2 [M+Na] + :calcd,318.1219; found,318.1213.

[0192] Example 72 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)cyclobutanecarboxamide (16)

[0193] 5a was replaced by 5b. The synthesis method was the same as compound 13. Yield: 13%, white solid. HPLC analysis: retention time, 4.630min; peak area, 96.99%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.63(s,1H),10.42(s,1H),8.09–8.02(m,2H),7.84(d,J=5.3Hz,1H),7.28(d,J=2.3Hz,1H),6.85(dd,J=8.7,2.3Hz ,1H),3.86(s,3H),3.51(p,J=8.4Hz,1H),2.45–2.30(m,2H),2.26–2.12(m,2H),2.05–1.93(m,1H),1.92–1.79(m,1H); 13 C NMR (101 MHz, DMSO-d 6 )δ174.12,160.79,142.14,137.17,136.78,130.97,127.96,122.72,114.99 ,112.14,109.86,95.74,55.76,39.31,25.17(2C),18.19.HRMS(ESI,m / z)for C 17 H 17 N 3 O 2 [M+Na] + :calcd,318.1219; found,318.1214.

[0194] Example 73 N-(7-methoxy-9H-pyrido[3,4-b]indol-3-yl)cyclopentanecarboxamide (17)

[0195] 5a was replaced by 5c. The synthesis method was the same as compound 13. Yield: 23%, yellow solid. HPLC analysis: retention time, 6.119 min; peak area, 99.46%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.25(s,1H),10.20(s,1H),8.62(s,1H),8.50(s,1H),8.01(d,J=8.7Hz,1H),7.00(d,J=2.3Hz,1H),6 .81(dd,J=8.7,2.3Hz,1H),3.04–2.88(m,1H),1.97–1.82(m,2H),1.81–1.63(m,4H),1.62–1.45(m,2H); 13 CNMR (101MHz, DMSO-d 6 )δ174.86,160.94,144.20,143.75,133.97,130.76,130.43,123.00,115.04,1 09.43,103.76,95.13,55.83,45.21,30.63(2C),26.28(2C).HRMS(ESI,m / z)for C 18 H 19 N 3 O 2 [M+Na] + :calcd,332.1375; found,332.1369.

[0196] Example 74 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)cyclopentanecarboxamide (18)

[0197] 5a was replaced by 5c. The synthesis method was the same as compound 13. Yield: 14%, white solid. HPLC analysis: retention time, 7.337min; peak area, 100%. 1 H NMR (400 MHz, DMSO-d 6)δ10.55(s,1H),10.54(s,1H),8.06(d,J=2.8Hz,1H),8.04(brs,1H),7.85(d,J=5.2Hz,1H),7.29(d,J=2.3Hz,1H),6 .85(dd,J=8.7,2.3Hz,1H),3.86(s,3H),3.17–2.95(m,1H),2.02–1.81(m,4H),1.80–1.67(m,2H),1.65–1.50(m,2H); 13 C NMR (101 MHz, DMSO-d 6 )δ175.76,160.78,142.12,137.29,136.79,131.04,127.86,122.69,114.99,1 12.10,109.89,95.79,55.76,44.80,30.64(2C),26.36(2C).HRMS(ESI,m / z)for C 18 H 19 N 3 O 2 [M+Na] + :calcd,332.1375; found,332.1368.

[0198] Example 75 N-(7-methoxy-9H-pyrido[3,4-b]indol-3-yl)cyclohexanecarboxamide (19)

[0199] 5a was replaced by 5d. The synthesis method was the same as compound 13. Yield: 25%, yellow solid. HPLC analysis: retention time, 5.406min; peak area, 99.29%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.26(s,1H),10.12(s,1H),8.61(s,1H),8.50(d,J=1.1Hz,1H),8.01(d,J=8.7Hz,1H),7.00(d,J=2.2Hz,1H),6.81(dd,J=8.7,2.3Hz ,1H),3.87(s,3H),2.57–2.50(m,1H),1.90–1.69(m,4H),1.65(dd,J=10.7,4.8Hz,1H),1.45(qd,J=12.1,2.9Hz,2H),1.35–1.13(m,3H); 13 CNMR (101MHz, DMSO-d 6)δ174.76,160.93,144.16,143.74,133.96,130.77,130.40,123.01,115.03,109. 43,103.79,95.11,55.82,44.70,29.69(2C),25.94,25.73(2C).HRMS(ESI,m / z)for C 19 H 21 N 3 O 2 [M+Na] + :calcd,346.1532; found,346.1531.

[0200] Example 76 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)cyclohexanecarboxamide (20)

[0201] 5a was replaced by 5d. The synthesis method was the same as compound 13. Yield: 16%, white solid. HPLC analysis: retention time, 7.244min; peak area, 100.00%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),10.52(s,1H),8.18–7.94(m,2H),7.88(d,J=5.4Hz,1H),7.29(d,J=2.3Hz,1H),6.86(dd,J=8.7,2.3Hz,1H),3.87(s,3H), 2.63(s,1H),1.95(q,J=9.5,6.6Hz,2H),1.81(d,J=11.7Hz,2H),1.70(d,J=11.9Hz,1H),1.54(td,J=13.5,10.3Hz,2H),1.39–1.15(m,3H). 13 CNMR (101MHz, DMSO-d 6 )δ175.6,160.8,142.1,137.3,136.8,131.0,127.9,122.7,115.0,112.1,109.9,95.8,55.8,44.4,29.7(2C),26.0,25.7(2C).HRMS(ESI,m / z)for C 19 H 21 N 3 O 2 [M+Na] + :calcd,346.1532; found,346.1529.

[0202] Example 77 N-(7-methoxy-9H-pyrido[3,4-b]indol-3-yl)benzamide (21)

[0203] 5e was used to replace 5a. The synthesis method was the same as compound 13. Yield: 30%, yellow solid. HPLC analysis: retention time, 4.193min; peak area, 98.65%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.36(s,1H),10.60(s,1H),8.70(d,J=2.4Hz,1H),8.60(d,J=1.0Hz,1H),8.22–8.00(m,3H),7.64–7. 56(m,1H),7.53(dd,J=8.2,6.5Hz,2H),7.04(d,J=2.2Hz,1H),6.85(dd,J=8.7,2.2Hz,1H),3.88(s,3H); 13 CNMR (101MHz, DMSO-d 6 )δ165.63,161.03,143.81,143.67,135.08,134.41,132.02,130.86,130.45,128.82 (2C),128.25(2C),123.17,115.02,109.62,105.57,95.17,55.86.HRMS(ESI,m / z)for C 19 H 15 N 3 O 2 [M+Na] + :calcd,340.1062; found,340.1043.

[0204] Example 78 N-(7-methoxy-9H-pyrido[3,4-b]indol-1-yl)benzamide (22)

[0205] 5e was used to replace 5a. The synthesis method was the same as compound 13. Yield: 11%, white solid. HPLC analysis: retention time, 4.480min; peak area, 96.70%. 1 H NMR (400 MHz, DMSO-d 6)δ10.94(s,1H),10.83(s,1H),8.16(d,J=7.5Hz,3H),8.10(d,J=8.7Hz,1H),7.95(d,J=5.2Hz,1H),7.65(dd ,J=9.4,5.3Hz,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 (101 MHz, DMSO-d 6 )δ165.94,160.79(2C),142.51,136.86,134.31,132.41,130.74,129.88,128.84(2 C),128.74(2C),122.92,114.99,112.99,109.73,95.45,55.76.HRMS(ESI,m / z)for C 19 H 15 N 3 O 2 [M+Na] + :calcd,340.1062; found,340.1060.

[0206] Example 79 3-(Cyclopropanecarboxamido)-N-cyclopropyl-9H-pyrido[3,4-b]indole-7-carboxamide (23)

[0207] 10a replaced 5a, the synthesis method was the same as compound 13. Yield 27%, yellow solid. HPLC analysis: retention time, 2.853min; peak area, 99.86%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.62(s,1H),10.69(s,1H),8.75(s,1H),8.67(s,1H),8.56(d,J=4.3Hz,1H),8.20(d,J=8.3Hz,1H ),8.00(s,1H),7.65(dd,J=8.3,1.5Hz,1H),2.98–2.81(m,1H),2.07–2.00(m,1H),0.97–0.54(m,8H); 13 C NMR (101 MHz, DMSO-d 6)δ172.17,168.27,144.19,141.53,134.83,134.61,132.07,129.51,123.21,121. 77,118.43,111.73,104.63,23.68,14.55,7.68(2C),6.24(2C).HRMS(ESI,m / z)for C 19 H 18 N 4 O 2 [M+Na] + :calcd,357.1328; found,357.1329.

[0208] Example 80 1-(Cyclopropanecarboxamido)-N-cyclopropyl-9H-pyrido[3,4-b]indole-7-carboxamide (24)

[0209] 10a replaced 5a, the synthesis method was the same as compound 13. Yield 11%, white solid. HPLC analysis: retention time, 2.904min; peak area, 97.44%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.97(s,1H),10.88(s,1H),8.50(d,J=1.5Hz,1H),8.25(d,J=8.3Hz,1H),8.18(brs,1H),8.14(d,J=5.3Hz,1H),8.01( d,J=5.3Hz,1H),7.67(dd,J=8.3,1.5Hz,1H),3.00–2.85(m,1H),2.25–2.05(m,1H),1.05–0.85(m,4H),0.80–0.52(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.16,168.44,139.88,138.03,136.82,134.78,130.00,129.05,123.14,121. 51,118.60,113.18,112.54,23.67,14.40,8.29(2C),6.26(2C).HRMS(ESI,m / z)for C 19 H 18 N 4 O 2 [M+Na] + :calcd,357.1328; found,357.1322.

[0210] Example 81 N-cyclohexyl-3-cyclopropanecarboxamido-9H-pyrido[3,4-b]indole-7-carboxamide (25)

[0211] 10b was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18%, yellow solid. HPLC analysis: retention time, 3.798min; peak area, 99.28%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.60(s,1H),10.70(s,1H),8.75(s,1H),8.67(d,J=1.1Hz,1H),8.34(d,J=7.9 Hz,1H),8.20(d,J=8.2Hz,1H),8.02(d,J=1.4Hz,1H),7.68(dd,J=8.3,1.5Hz,1H) ,3.90–3.70(m,1H),2.10–2.00(m,1H),1.86(dt,J=7.6,3.5Hz,2H),1.79–1.70(m ,2H),1.68–1.56(m,1H),1.44–1.25(m,4H),1.23–1.06(m,1H),0.89–0.76(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.17,166.14,144.17,141.53,135.31,134.57,132.05,129.52,123.08,121.72,118.57 ,111.85,104.61,48.96,32.93(2C),25.77,25.46(2C),14.55,7.70(2C).HRMS(ESI,m / z)for C 22 H 24 N 4 O 2 [M+Na] + :calcd,399.1797; found,399.1796.

[0212] Example 82 N-cyclohexyl-1-cyclopropanecarboxamido-9H-pyrido[3,4-b]indole-7-carboxamide (26)

[0213] 10b was used to replace 5a. The synthesis method was the same as compound 13. Yield: 11%, white solid. HPLC analysis: retention time, 5.334min; peak area, 100%. 1 H NMR (400 MHz, DMSO-d6 )δ10.99(s,1H),10.89(s,1H),8.26(d,J=8.2Hz,2H),8.19(d,J=1.4Hz,1H),8.14(d,J =5.3Hz,1H),8.02(d,J=5.3Hz,1H),7.70(dd,J=8.2,1.5Hz,1H),3.82(d,J=10.5Hz,1H ),2.14(dq,J=7.9,4.0,3.5Hz,1H),1.87(d,J=8.6Hz,2H),1.76(dd,J=9.2,3.9Hz,2H) ,1.63(d,J=12.7Hz,1H),1.46–1.27(m,4H),1.16(d,J=11.0Hz,1H),1.05–0.82(m,4H); 13 C NMR (151 MHz, DMSO-d 6 )δ173.16,166.32,139.92,137.95,136.67,135.31,130.07,128.98,122.99,121.49,118.78 ,113.20,112.66,48.92,32.93(2C),25.77,25.43(2C),14.40,8.31(2C).HRMS(ESI,m / z)for C 22 H 24 N 4 O 2 [M+Na] + :calcd,399.1797; found,399.1775.

[0214] Example 83 3-(Cyclopropanecarboxamido)-N-phenyl-9H-pyrido[3,4-b]indole-7-carboxamide (27)

[0215] 10c was used to replace 5a. The synthesis method was the same as compound 13. Yield: 31%, yellow solid. HPLC analysis: retention time, 3.330min; peak area, 99.04%. 1 H NMR (400 MHz, DMSO-d 6)δ11.72(s,1H),10.72(s,1H),10.40(s,1H),8.79(s,1H),8.71(d,J=1.1Hz,1H),8.30(d,J=8.2Hz,1H),8.14(d,J=1.4H z,1H),7.82(ddd,J=13.8,8.5,1.5Hz,3H),7.42–7.34(m,2H),7.16–7.08(m,1H),2.10–2.00(m,1H),0.91–0.77(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.20,166.36,144.27,141.47,139.80,135.21,134.69,132.24,129.44,129.10(2C),124. 12,123.56,122.04,120.87(2C),118.81,112.25,104.68,14.56,7.72(2C).HRMS(ESI,m / z)forC 22 H 18 N 4 O 2 [M+Na] + :calcd,393.1328; found,393.1330.

[0216] Example 84 1-(Cyclopropanecarboxamido)-N-phenyl-9H-pyrido[3,4-b]indole-7-carboxamide (28)

[0217] 10c was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18%, white solid. HPLC analysis: retention time, 3.581min; peak area, 99.56%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.00(d,J=9.1Hz,2H),10.35(s,1H),8.35(d,J=8.2Hz,1H),8.31(d,J=1.5Hz,1H),8.17(d,J=5.3Hz,1H),8.06(d,J=5.3Hz ,1H),7.82(ddd,J=8.3,6.0,1.5Hz,3H),7.46–7.29(m,2H),7.19–7.02(m,1H),2.15(tt,J=7.9,4.5Hz,1H),1.05–0.88(m,4H); 13 C NMR (101 MHz, DMSO-d 6)δ173.22,166.54,139.86,138.10,136.82,135.23,130.02,129.11(2C),124.09,123.49, 121.77,120.80(2C),120.70,119.06,113.26,113.04,14.42,8.32(2C).HRMS(ESI,m / z)for C 22 H 18 N 4 O 2 [M+Na] + :calcd,393.1328; found,393.1328.

[0218] Example 85 3-Cyclopropanecarboxamido-N-(4-trifluoromethyl)phenyl-9H-pyrido[3,4-b]indole-7-carboxamide (29)

[0219] 10d was used to replace 5a. The synthesis method was the same as compound 13. Yield: 30%, yellow solid. HPLC analysis: retention time, 4.594min; peak area, 98.77%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.75(s,1H),10.73(d,J=2.8Hz,2H),8.80(s,1H),8.72(s,1H),8.33(d,J=8.3Hz,1H),8.17(s,1H),8 .08(d,J=8.4Hz,2H),7.82(d,J=8.3Hz,1H),7.75(d,J=8.4Hz,2H),2.10–2.00(m,1H),0.95–0.75(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.23,166.86,144.29,143.46,141.42,134.73,134.62,132.31,129.40,126.44,126.40 ,123.84,122.16,120.62(4C),118.88,112.45,104.72,14.56,7.73(2C).HRMS(ESI,m / z)for C 23 H 17 F 3 N 4 O 2 [M+Na] + :calcd,461.1202; found,461.1205.

[0220] Example 86 1-Cyclopropanecarboxamido-N-(4-trifluoromethyl)phenyl-9H-pyrido[3,4-b]indole-7-carboxamide (30)

[0221] 10d was used to replace 5a. The synthesis method was the same as compound 13. Yield: 13%, white solid. HPLC analysis: retention time, 4.860min; peak area, 98.98%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.03(d,J=7.7Hz,2H),10.72(s,1H),8.38(d,J=8.3Hz,1H),8.34(d,J=1.5Hz,1H),8.18(d,J=5.3Hz,1H), 8.10–8.02(m,3H),7.83(dd,J=8.3,1.6Hz,1H),7.76(d,J=8.6Hz,2H),2.20–2.10(m,1H),1.05–0.87(m,4H); 13 C NMR (151 MHz, DMSO-d 6 )δ173.20,167.06,143.49,139.81,138.12,134.61,129.93,129.20,126.47(2C),125.81,123.92,1 23.75,121.90,120.53(2C),120.44,119.10,113.33,113.27,14.42,8.34(2C).HRMS(ESI,m / z)forC 23 H 17 F 3 N 4 O 2 [M+Na] + :calcd,461.1202; found,461.1203.

[0222] Example 87 N-(4-chloro-3-trifluoromethylphenyl)-3-cyclopropanecarboxamido-9H-pyrido[3,4-b]indole-7-carboxamide (31)

[0223] 10e was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18%, yellow solid. HPLC analysis: retention time, 6.235min; peak area, 98.94%. 1 H NMR (400 MHz, DMSO-d 6)δ11.76(s,1H),10.79(s,1H),10.73(s,1H),8.80(s,1H),8.72(d,J=1.1Hz,1H),8.44(d,J=2.6Hz,1H),8.34(d,J=8. 3Hz,1H),8.22–8.07(m,2H),7.82(dd,J=8.3,1.5Hz,1H),7.75(d,J=8.9Hz,1H),2.11–1.99(m,1H),0.90–0.77(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.23,166.77,144.31,141.42,139.32,134.74,134.27,132.52,132.33,129.37,127.27,126.97, 125.46,124.71,123.95,122.22,119.42,118.76,112.41,104.73,14.55,7.73(2C).HRMS(ESI,m / z)for C 23 H 16 CIF 3 N 4 O 2 [M+Na] + :calcd,495.0812; found,495.0816.

[0224] Example 88 N-(4-chloro-1-trifluoromethylphenyl)-3-cyclopropanecarboxamido-9H-pyrido[3,4-b]indole-7-carboxamide (32)

[0225] 10e was used to replace 5a. The synthesis method was the same as compound 13. Yield: 14%, white solid. HPLC analysis: retention time, 6.467min; peak area, 97.19%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.11(brs,2H),10.79(s,1H),8.46–8.37(m,2H),8.35(d,J=1.5Hz,1H),8.21–8.13(m,2H),8.09(d, J=5.4Hz,1H),7.85(dd,J=8.2,1.6Hz,1H),7.75(d,J=8.8Hz,1H),2.20–2.10(m,1H),1.10–0.80(m,4H); 13 C NMR (101 MHz, DMSO-d 6)δ173.33,166.92,139.89,139.34,138.03,134.37,133.74,132.72,132.53,132.01,131.92,129.30, 129.18,125.39,124.71,123.81,122.01,119.41,119.08,113.27,14.48,8.43(2C).HRMS(ESI,m / z)for C 23 H 15 CIF 3 N 4 O 2 [MH] - :calcd,471.0841; found,471.0851.

[0226] Example 89 N-Benzyl-3-cyclopropanecarboxamido-9H-pyrido[3,4-b]indole-7-carboxamide (33)

[0227] 10f was used to replace 5a. The synthesis method was the same as compound 13. Yield: 23%, yellow solid. HPLC analysis: retention time, 3.367min; peak area, 95.85%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.66(s,1H),10.70(s,1H),9.18(t,J=6.0Hz,1H),8.77(s,1H),8.69(s,1H),8.24(d,J=8.3Hz,1H),8.10(s,1H),7.75( d,J=8.2Hz,1H),7.35(d,J=7.1Hz,4H),7.24(d,J=6.9Hz,1H),4.54(d,J=5.9Hz,2H),2.07–2.03(m,1H),0.88–0.78(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.18,167.03,144.23,141.58,140.26,134.69,134.63,132.14,129.48,128.77(2C),127.71( 2C),127.20,123.34,121.94,118.44,111.87,104.64,43.24,14.56,7.70(2C).HRMS(ESI,m / z)for C 23 H 20 N 4 O 2 [M+Na]+ :calcd,407.1484; found,407.1512.

[0228] Example 90 N-Benzyl-1-cyclopropanecarboxamido-9H-pyrido[3,4-b]indole-7-carboxamide (34)

[0229] 10f was used to replace 5a. The synthesis method was the same as compound 13. Yield: 21%, white solid. HPLC analysis: retention time, 3.407min; peak area, 99.52%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.98(s,1H),10.92(s,1H),9.12(t,J=6.0Hz,1H),8.29(d,J=8.3Hz,1H),8.26(d,J=1.4Hz,1H),8.15(d,J=5.3Hz,1H),8.03(d,J=5.3 Hz,1H),7.76(dd,J=8.3,1.5Hz,1H),7.44–7.29(m,4H),7.29–7.21(m,1H),4.54(d,J=5.8Hz,2H),2.19–2.08(m,1H),1.05–0.85(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.15,167.23,140.26,139.95,138.04,136.82,134.73,129.99,129.10,128.77(2C),127.72( 2C),127.21,123.25,121.67,118.61,113.21,112.70,43.23,14.40,8.28(2C).HRMS(ESI,m / z)for C 23 H 20 N 4 O 2 [M+Na] + :calcd,407.1484; found,407.1488.

[0230] Example 91 (R)-3-(Cyclopropanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (35)

[0231] 10 g of 5a was used to replace 5a. The synthesis method was the same as compound 13. Yield 30%, yellow solid. HPLC analysis: retention time, 3.485 min; peak area, 96.79%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.63(s,1H),10.70(s,1H),8.95(d,J=8.0Hz,1H),8.77(s,1H),8.68(d,J =1.1Hz,1H),8.24(d,J=8.2Hz,1H),8.07(d,J=1.4Hz,1H),7.75(dd,J=8.3,1. 5Hz,1H),7.47–7.41(m,2H),7.34(t,J=7.5Hz,2H),7.27–7.19(m,1H),5.24( p,J=7.2Hz,1H),2.11–2.00(m,1H),1.52(d,J=7.1Hz,3H),0.90–0.76(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.18,166.37,145.52,144.21,141.54,134.95,134.61,132.11,129.51,128.72(2C),127.06,126 .58(2C),123.27,121.82,118.62,111.99,104.64,49.08,22.77,14.56,7.70(2C).HRMS(ESI,m / z)for C 24 H 22 N 4 O 2 [M+Na] + :calcd,421.1641; found,421.1648.

[0232] Example 92 (R)-1-(Cyclopropanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (36)

[0233] 10 g of 5a was used to replace 5a. The synthesis method was the same as compound 13. Yield: 16%, white solid. HPLC analysis: retention time, 3.575 min; peak area, 96.40%. 1 H NMR (400 MHz, DMSO-d 6)δ10.99(s,1H),10.91(s,1H),8.90(d,J=8.0Hz,1H),8.31–8.22(m,2H),8.03(d,J=4.8Hz,1H),7.75(dd,J=8.2,1.5Hz,1H),7.45(d,J=7.2Hz ,2H),7.34(t,J=7.5Hz,2H),7.24(td,J=7.1,1.4Hz,1H),5.23(p,J=7.2Hz,1H),2.16–2.12(m,1H),1.52(d,J=7.0Hz,3H),1.06–0.88(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.13,166.57,145.52,139.87,138.07,136.80,134.95,130.00,128.73(2C),127.07(2C),126. 58(2C),123.17,121.55,118.84,113.24,112.76,49.07,31.15,22.84,8.28(2C).HRMS(ESI,m / z)for C 24 H 22 N 4 O 2 [M+Na] + :calcd,421.1641; found,421.1663.

[0234] Example 93 (S)-3-(Cyclopropanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (37)

[0235] 10h was used to replace 5a. The synthesis method was the same as compound 13. Yield: 31%, yellow solid. HPLC analysis: retention time, 3.524min; peak area, 99.60%. 1 H NMR (400 MHz, DMSO-d 6)δ11.62(s,1H),10.70(s,1H),8.95(d,J=8.1Hz,1H),8.77(s,1H),8.24(d,J=8.3Hz,1H),8.06(d,J=1.4Hz,1H),7.75(dd,J=8.3,1.5Hz,1H),7.4 4(d,J=7.2Hz,2H),7.34(t,J=7.6Hz,2H),7.27–7.19(m,1H),5.23(p,J= 7.2Hz,1H),2.20–2.10(m,1H),1.52(d,J=7.1Hz,3H),0.90–0.76(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.18,166.37,145.52,144.22,141.54,134.95,134.61,132.11,129.50,128.72(2C),127.06,126 .58(2C),123.27,121.82,118.62,111.98,104.64,49.08,22.77,14.55,7.70(2C).HRMS(ESI,m / z)for C 24 H 22 N 4 O 2 [M+Na] + :calcd,421.1641; found,421.1642.

[0236] Example 94 (S)-1-(Cyclopropanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (38)

[0237] 10h was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18%, white solid. HPLC analysis: retention time, 3.593min; peak area, 98.93%. 1 H NMR (400 MHz, DMSO-d 6)δ10.98(s,1H),10.91(s,1H),8.88(d,J=8.1Hz,1H),8.28(d,J=8.3Hz,1H) ,8.24(d,J=1.5Hz,1H),8.15(d,J=5.3Hz,1H),8.03(d,J=5.3Hz,1H),7.75( dd,J=8.2,1.5Hz,1H),7.52–7.42(m,2H),7.35(dd,J=8.4,6.8Hz,2H),7.28 –7.18(m,1H),2.20–2.10(m,1H),1.52(d,J=7.1Hz,3H),1.07–0.82(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.17,166.57,145.50,139.89,138.04,136.76,134.98,130.04,129.03,128.72(2C),127.07,126 .58(2C),123.17,121.55,118.86,113.18,112.74,49.07,22.81,14.40,8.28(2C).HRMS(ESI,m / z)for C 24 H 22 N 4 O 2 [M+Na] + :calcd,421.1641; found,421.1646.

[0238] Example 95 3-(Cyclopropanecarboxamido)-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-7-carboxamide (39)

[0239] 10i was used to replace 5a. The synthesis method was the same as compound 13. Yield: 32%, yellow solid. HPLC analysis: retention time, 5.023min; peak area, 95.02%. 1 H NMR (400 MHz, DMSO-d 6)δ11.66(s,1H),10.70(s,1H),9.21(t,J=6.0Hz,1H),8.76(s,1H),8.68( s,1H),8.25(d,J=8.3Hz,1H),8.09(d,J=1.5Hz,1H),7.74(dd,J=8.3,1.5 Hz,1H),7.39(td,J=7.9,6.1Hz,1H),7.24–7.13(m,3H),7.08(td,J=8.7, 2.8Hz,1H),4.55(d,J=5.5Hz,2H),2.08–1.97(m,1H),0.96–0.70(m,4H); 13 C NMR (151 MHz, DMSO-d 6 )δ172.19,167.12,163.54,144.21,143.33,141.57,134.49,132.13,130.77,130.72,129.47,123.69, 123.40,122.00,118.42,114.42,113.91,111.89,104.64,42.80,14.55,7.71(2C).HRMS(ESI,m / z)for C 23 H 19 FN 4 O 2 [M+Na] + :calcd,425.1390; found,425.1405.

[0240] Example 96 1-(Cyclopropanecarboxamido)-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-7-carboxamide (40)

[0241] 10i was used to replace 5a. The synthesis method was the same as compound 13. Yield: 22%, white solid. HPLC analysis: retention time, 4.290min; peak area, 98.46%. 1 H NMR (400 MHz, DMSO-d 6)δ10.98(s,1H),10.93(s,1H),9.15(t,J=6.0Hz,1H),8.30(d,J=8.3Hz,1H),8 .26(d,J=1.4Hz,1H),8.15(d,J=5.3Hz,1H),8.03(d,J=5.3Hz,1H),7.76(dd,J =8.3,1.5Hz,1H),7.40(td,J=7.9,6.1Hz,1H),7.25–7.14(m,2H),7.08(td,J= 8.4, 2.5Hz, 1H), 4.55 (d, J = 5.7Hz, 2H), 2.20–2.10 (m, 1H), 1.07–0.82 (m, 4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.17,167.38,161.54,143.34,139.94,138.07,136.84,134.57,130.76,130.00,129.10,123.73, 123.34,121.70,118.62,114.48,113.87,113.20,112.72,42.82,14.41,8.28(2C).HRMS(ESI,m / z)forC 23 H 19 FN 4 O 2 [M+Na] + :calcd,425.1390; found,425.1375.

[0242] Example 97 N-(3-chlorobenzyl)-3-(cyclopropanecarboxamido)-9H-pyrido[3,4-b]indole-7-carboxamide (41)

[0243] 10j was used to replace 5a. The synthesis method was the same as compound 13. Yield: 25%, yellow solid. HPLC analysis: retention time, 3.721min; peak area, 97.18%. 1 H NMR (400 MHz, DMSO-d 6)δ11.67(s,1H),10.70(s,1H),9.23(t,J=6.0Hz,1H),8.78(s,1H),8.69(s,1H),8.25(d,J=8.2Hz,1H),8.10(s,1 H),7.75(dd,J=8.3,1.5Hz,1H),7.44–7.29(m,4H),4.54(d,J=5.8Hz,2H),2.20–2.00(m,1H),0.90–0.76(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.18,167.13,144.25,142.88,141.57,134.64,134.43,133.45,132.17,130.69,129.46,127.56, 127.19,126.44,123.44,122.00,118.41,111.89,104.65,42.79,14.57,7.70(2C).HRMS(ESI,m / z)forC 23 H 19 C1N 4 O 2 [M+Na] + :calcd,441.1095; found,441.1104.

[0244] Example 98 N-(3-chlorobenzyl)-1-(cyclopropanecarboxamido)-9H-pyrido[3,4-b]indole-7-carboxamide (42)

[0245] 10j was used to replace 5a. The synthesis method was the same as compound 13. Yield: 19%, white solid. HPLC analysis: retention time, 3.852min; peak area, 97.67%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(s,1H),10.93(s,1H),9.17(t,J=6.0Hz,1H),8.30(d,J=8.3Hz,1H),8.26(d,J=1.5Hz,1H),8.15(d,J=5.3Hz,1H),8.03 (d,J=5.3Hz,1H),7.75(dd,J=8.3,1.5Hz,1H),7.53–7.20(m,4H),4.54(d,J=5.6Hz,2H),2.20–2.10(m,1H),1.04–0.87(m,4H); 13 C NMR (101 MHz, DMSO-d6 )δ173.14,167.33,142.88,139.94,138.06,136.85,134.46,133.45,130.71,129.96,129.14,127.56, 127.20,126.45,123.34,121.73,118.56,113.23,112.72,42.77,14.39,8.28(2C).HRMS(ESI,m / z)for C 23 H 19 C1N 4 O 2 [M+Na] + :calcd,441.1095; found,441.1102.

[0246] Example 99 3-(Cyclopropanecarboxamido)-N-(3-fluoro-4-methoxybenzyl)-9H-pyrido[3,4-b]indole-7-carboxamide (43)

[0247] 10k was used to replace 5a. The synthesis method was the same as compound 13. Yield: 31%, yellow solid. HPLC analysis: retention time, 3.060min; peak area, 99.69%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.66(s,1H),10.70(s,1H),9.15(t,J=6.0Hz,1H),8.77(s,1H),8.69(d,J=1.1Hz,1H),8.24(d,J=8.2Hz,1H),8.08(d,J=1.5Hz,1H),7. 73(dd,J=8.3,1.5Hz,1H),7.26–7.16(m,1H),7.16–7.08(m,2H),4.46(d,J=5.8Hz,2H),3.82(s,3H),2.11–2.00(m,1H),0.92–0.70(m,4H); 13 CNMR (101MHz, DMSO-d 6 )δ172.18,167.02,153.00,150.58,146.36,144.24,141.57,134.62,133.30,132.15,129.46,123.94,123 .37,121.95,118.42,115.51,114.21,111.86,104.64,56.50,42.42,14.56,7.70(2C).HRMS(ESI,m / z)for C 24H 21 FN 4 O 3 [M+Na] + :calcd,455.1856; found,455.1499.

[0248] Example 100 1-(Cyclopropanecarboxamido)-N-(3-fluoro-4-methoxybenzyl)-9H-pyrido[3,4-b]indole-7-carboxamide (44)

[0249] 10k was used to replace 5a. The synthesis method was the same as compound 13. Yield: 16%, white solid. HPLC analysis: retention time, 3.329min; peak area, 98.66%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(s,1H),10.92(s,1H),9.09(t,J=6.0Hz,1H),8.29(d,J=8.2Hz,1H),8.24(d,J=1.5Hz,1H),8.15(d,J=5.2Hz,1H),8.03(d,J=5.3Hz,1H ),7.74(dd,J=8.2,1.5Hz,1H),7.27–7.17(m,1H),7.17–7.11(m,2H),4. 46(d,J=5.7Hz,2H),3.82(s,3H),2.20–2.10(m,1H),1.04–0.87(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.15,167.22,150.59,146.37,139.94,138.04,136.81,134.65,133.24,129.99,129.10,123.96,123 .27,121.68,118.59,115.52,114.24,113.22,112.69,56.52,42.40,14.40,8.28(2C).HRMS(ESI,m / z)for C 24 H 21 FN 4 O 3 [M+Na] + :calcd,455.1856; found,455.1505.

[0250] Example 101 N-(3-cyanobenzyl)-3-(cyclopropanecarboxamido)-9H-pyrido[3,4-b]indole-7-carboxamide (45)

[0251] 101 was used to replace 5a. The synthesis method was the same as compound 13. Yield: 25%, yellow solid. HPLC analysis: retention time, 2.885min; peak area, 98.90%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.67(s,1H),10.70(s,1H),8.77(s,1H),8.69(d,J=1.1Hz,1H),8.26(d,J=8.3Hz,1H),8.10(d,J=1.4Hz,1H),7.80( d,J=1.8Hz,1H),7.78–7.68(m,3H),7.57(t,J=7.7Hz,1H),4.58(d,J=5.7Hz,2H),2.11–2.00(m,1H),0.96–0.73(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.19,167.24,144.25,141.96,141.57,134.64,134.34,132.73,132.17,131.29,131.11,130.09,129 .46,123.47,122.00,119.33,118.43,111.93,111.72,104.65,42.71,14.56,7.70(2C).HRMS(ESI,m / z)for C 24 H 19 N 5 O 2 [M+Na] + :calcd,432.1437; found,432.1444.

[0252] Example 102 N-(3-cyanobenzyl)-1-(cyclopropanecarboxamido)-9H-pyrido[3,4-b]indole-7-carboxamide (46)

[0253] 101 was used to replace 5a. The synthesis method was the same as compound 13. Yield: 13%, white solid. HPLC analysis: retention time, 2.904min; peak area, 99.24%. 1 H NMR (400 MHz, DMSO-d 6)δ10.99(s,1H),10.93(s,1H),9.20(t,J=6.0Hz,1H),8.31(d,J=8.3Hz,1H),8.26(d,J=1.4Hz,1H),8.16(d,J=5.2Hz,1H),8.04(d,J=5. 2Hz,1H),7.81(d,J=1.8Hz,1H),7.77–7.69(m,3H),7.58(t,J=7.7Hz,1H),4.58(d,J=5.5Hz,2H),2.20–2.10(m,1H),1.07–0.78(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.15,167.45,141.96,139.93,138.06,136.85,134.37,132.75,131.29,131.13,130.10,129.96,129 .04,123.38,121.73,119.34,118.60,113.25,112.76,111.72,42.70,14.39,8.29(2C).HRMS(ESI,m / z)for C 24 H 19 N 5 O 2 [M+Na] + :calcd,432.1437; found,432.1445.

[0254] Example 103 3-(Cyclopropanecarboxamido)-N-(3-(trifluoromethyl)benzyl)-9H-pyrido[3,4-b]indole-7-carboxamide (47)

[0255] 10m was used to replace 5a. The synthesis method was the same as compound 13. Yield: 35%, yellow solid. HPLC analysis: retention time, 3.864min; peak area, 95.53%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.68(s,1H),10.72(s,1H),9.29(t,J=6.0Hz,1H),8.77(s,1H),8.69(d,J=1.1Hz,1H),8.26(d,J=8.2Hz,1H),8.10 (d,J=1.4Hz,1H),7.80–7.66(m,3H),7.65–7.53(m,2H),4.63(d,J=5.8Hz,2H),2.10–2.00(m,1H),0.91–0.76(m,4H);13 C NMR (101 MHz, DMSO-d 6 )δ172.21,167.20,144.21,141.78,141.60,134.63,134.40,132.11,131.93,129.89(2C),129.50,1 24.23,124.03,123.45,122.05,118.40,111.89,104.66,42.91,14.56,7.71(2C).HRMS(ESI,m / z)for C 24 H 19 F 3 N 4 O 2 [M+Na] + :calcd,475.1358; found,475.1367.

[0256] Example 104 1-(Cyclopropanecarboxamido)-N-(3-(trifluoromethyl)benzyl)-9H-pyrido[3,4-b]indole-7-carboxamide (48)

[0257] 10m was used to replace 5a. The synthesis method was the same as compound 13. Yield: 19%, white solid. HPLC analysis: retention time, 5.213min; peak area, 95.62%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(s,1H),10.94(s,1H),9.23(t,J=6.0Hz,1H),8.16(d,J=5.3Hz,1H),8.03(d,J=5.2Hz,1H),7.76(dd,J=8. 3,1.5Hz,1H),7.74–7.67(m,2H),7.66–7.55(m,2H),4.63(d,J=5.8Hz,2H),2.20–2.10(m,1H),1.04–0.80(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.15,167.42,141.78,139.94,138.07,136.86,134.41,131.95,129.96,129.89,129.68,129.36,129 .14,124.26,123.99,123.37,121.74,118.55,113.22,112.72,42.91,14.40,8.28(2C).HRMS(ESI,m / z)for C24 H 19 F 3 N 4 O 2 [M+Na] + :calcd,475.1358; found,475.1370.

[0258] Example 105 N-(Benzo[d][1,3]dioxolan-5-ylmethyl)-3-(cyclopropanecarboxamido)-9H-pyrido[3,4-b]indole-7-carboxamide (49)

[0259] 10n was used to replace 5a. The synthesis method was the same as compound 13. Yield: 24%, yellow solid. HPLC analysis: retention time, 3.122min; peak area, 99.59%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.66(s,1H),10.71(s,1H),9.12(t,J=6.0Hz,1H),8.77(s,1H),8.69(d,J=1.1Hz,1H),8.24(d,J=8.2Hz,1H),8.09(d,J=1.4Hz,1H),7.73 (dd,J=8.3,1.5Hz,1H),6.94(d,J=1.5Hz,1H),6.91–6.81(m,2H),5.99(s,2H),4.44(d,J=5.8Hz,2H),2.10–2.00(m,1H),0.91–0.76(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.20,166.96,147.72,146.52,144.22,141.59,134.73,134.63,134.16,132.11,129.51,123.34,12 1.93,120.98,118.44,111.87,108.47(2C),104.65,101.28,43.08,14.58,7.71(2C).HRMS(ESI,m / z)for C 24 H 20 N 4 O 4 [M+Na] + :calcd,451.1383; found,451.1393.

[0260] Example 106 N-(Benzo[d][1,3]dioxolan-5-ylmethyl)-1-(cyclopropanecarboxamido)-9H-pyrido[3,4-b]indole-7-carboxamide (50)

[0261] 10n was used to replace 5a. The synthesis method was the same as compound 13. Yield: 11%, white solid. HPLC analysis: retention time, 4.273min; peak area, 99.73%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(d,J=3.3Hz,1H),10.92(s,1H),9.05(t,J=6.0Hz,1H),8.28(d,J= 8.3Hz,1H),8.25(d,J=1.4Hz,1H),8.15(d,J=5.3Hz,1H),8.02(d,J=5.3Hz, 1H),7.74(dd,J=8.3,1.5Hz,1H),6.95(d,J=1.5Hz,1H),6.91–6.81(m,2H) ,5.99(s,2H),4.44(d,J=5.8Hz,2H),2.22–2.09(m,1H),1.04–0.80(m,4H); 13 CNMR (101MHz, DMSO-d 6 )δ173.15,167.16,147.73,146.53,139.93,138.04,136.83,134.75,134.15,129.99,129.10,123.24, 121.65,120.99,118.60,113.20,112.68,108.48,101.28,43.06,14.41,8.29(2C).HRMS(ESI,m / z)for C 24 H 20 N 4 O 4 [M+Na] + :calcd,451.1383; found,451.1392.

[0262] Example 107 N-(7-(2-(3-methoxybenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-3-yl)cyclopropanecarboxamide (51)

[0263] 12a was used to replace 5a. The synthesis method was the same as compound 13. Yield: 24%, yellow solid. HPLC analysis: retention time, 3.381min; peak area, 97.95%.1 H NMR (400 MHz, DMSO-d 6 )δ12.00(s,1H),11.72(s,1H),10.72(s,1H),8.79(s,1H),8.71(s,1H),8.49(s,1H),8.31(d,J=8.7Hz,1H),8.12(s,1H),7 .76(d,J=8.2Hz,1H),7.40(t,J=8.0Hz,1H),7.32(s,2H),7.07–6.95(m,1H),3.83(s,3H),2.10-2.00(m,1H),0.83(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.21,160.07,148.15,144.28,141.46,136.34,134.67,133.55,132.26,130.47,129.44,123.70, 122.18,120.56,118.69,116.73,112.26,111.70,104.69,55.68,14.56,7.71(2C).HRMS(ESI,m / z)for C 24 H 21 N 5 O 3 [M+Na] + :calcd,450.1542; found,450.1534.

[0264] Example 108 N-(7-(2-(3-methoxybenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-1-yl)cyclopropanecarboxamide (52)

[0265] 12a was used to replace 5a. The synthesis method was the same as compound 13. Yield: 17%, yellow solid. HPLC analysis: retention time, 10.428min; peak area, 98.716%. 1 H NMR (400 MHz, DMSO-d 6)δ11.97(s,1H),11.01(s,1H),8.48(s,1H),8.35(d,J=8.4Hz,1H),8.29(s,1H),8.11(s,1H),8.11–8.03(m,1H),7.77(d,J=8.0Hz,1H ),7.58–7.50(m,1H),7.39(d,J=7.8Hz,1H),7.34–7.25(m,2H),7.03(d,J=8.1Hz,1H),3.83(s,3H),2.13(brs,1H),0.96–0.79(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ173.14,164.14,160.06,148.18,139.80,138.18,136.91,136.38,133.37,130.47(2C),129.82,129.0 6,123.68,121.86,120.58,119.02,116.74,113.23,111.60,55.68,14.47,8.32(2C).HRMS(ESI,m / z)for C 24 H 21 N 5 O 3 [M+Na] + :calcd,450.1542; found,450.1549.

[0266] Example 109 N-(7-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-3-yl)cyclopropanecarboxamide (53)

[0267] 12b was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18%, yellow solid. HPLC analysis: retention time, 9.898min; peak area, 98.378%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.86(s,1H),11.71(s,1H),10.71(s,1H),8.78(s,1H),8.71(s,1H),8.46(s,1H),8.30(d,J=8.2H z,1H),8.10(s,1H),7.73(m,3H),7.05(d,J=8.3Hz,2H),3.83(s,3H),2.07–1.98(m,1H),0.83(m,4H); 13 C NMR (151 MHz, DMSO-d6 )δ172.20,163.75,161.34,148.14,144.28,141.47,134.65,133.74,132.25,129.44,129.19(2C),127 .45,123.64,122.13,118.64,114.86(2C),112.18,104.66,55.79,14.56,7.72(2C).HRMS(ESI,m / z)for C 24 H 21 N 5 O 3 [M+Na] + :calcd,450.1542; found,450.1552.

[0268] Example 110 N-(7-(2-(4-methoxybenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-1-yl)cyclopropanecarboxamide (54)

[0269] 12b was used to replace 5a. The synthesis method was the same as compound 13. Yield: 14%, yellow solid. HPLC analysis: retention time, 3.186min; peak area, 98.28%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.83(s,1H),11.01(s,1H),10.97(s,1H),8.44(s,1H),8.35(d,J=8.2Hz,1H),8.28(s,1H),8.17(d,J=5.3Hz,1H),8.06(d,J= 5.3Hz,1H),7.76(d,J=8.3Hz,1H),7.70(d,J=8.3Hz,2H),7.08–7.02(m,2H),3.83(s,3H),2.20–2.10(m,1H),1.08–0.86(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.18,163.95,161.34,148.08,139.87,138.11,136.89,133.75,129.98,129.17(2C),129.13,127 .46,123.55,121.83,118.81,114.86(2C),113.25,113.04,55.80,14.41,8.31(2C).HRMS(ESI,m / z)for C 24 H 21 N5 O 3 [M+Na] + :calcd,450.1542; found,450.1549.

[0270] Example 111 N-(7-(2-(3-cyanobenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-3-yl)cyclopropanecarboxamide (55)

[0271] 12c was used to replace 5a. The synthesis method was the same as compound 13. Yield: 22%, yellow solid. HPLC analysis: retention time, 2.971min; peak area, 95.86%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.22(s,1H),11.74(s,1H),10.73(s,1H),8.79(s,1H),8.72(s,1H),8.55(s,1H),8.32(d,J=8.3Hz,1H),8.20–8. 00(m,3H),7.91(d,J=7.8Hz,1H),7.77(d,J=8.3Hz,1H),7.70(t,J=7.8Hz,1H),2.10–2.00(m,1H),0.95–0.75(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.24,164.11,145.93,144.26,141.45,136.26,134.68,133.76,133.27,132.26,131.49,131.23(2 C),130.63(2C),129.45,123.86,122.24,118.89,112.54,104.71,14.56,7.74(2C).HRMS(ESI,m / z)for C 24 H 18 N 6 O 2 [M+Na] + :calcd,445.1389; found,445.1392.

[0272] Example 112 N-(7-(2-(3-cyanobenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-1-yl)cyclopropanecarboxamide (56)

[0273] 12c was used to replace 5a. The synthesis method was the same as compound 13. Yield: 13%, yellow solid. HPLC analysis: retention time, 2.986min; peak area, 99.20%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.19(s,1H),11.02(s,1H),10.99(s,1H),8.54(s,1H),8.40–8.29(m,2H),8.20–8.10(m,3H),8.06(d,J=5.3H z,1H),7.91(d,J=7.7Hz,1H),7.79(d,J=8.3Hz,1H),7.69(t,J=7.8Hz,1H),2.20–8.10(m,1H),1.08–0.80(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.18,164.33,145.85,139.81,138.15,136.94,136.26,133.73,133.22,131.47,131.22(2C),130. 61(2C),129.91,129.19,123.78,121.90,118.88,113.29,112.54,14.41,8.32(2C).HRMS(ESI,m / z)for C 24 H 18 N 6 O 2 [M+Na] + :calcd,445.1389; found,445.1390.

[0274] Example 113 N-(7-(2-(4-cyanobenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-3-yl)cyclopropanecarboxamide (57)

[0275] 12d was used to replace 5a. The synthesis method was the same as compound 13. Yield: 26%, yellow solid. HPLC analysis: retention time, 2.950min; peak area, 99.90%. 1 H NMR (400 MHz, DMSO-d 6)δ12.24(s,1H),11.74(s,1H),10.73(s,1H),8.79(s,1H),8.72(s,1H),8.57(s,1H),8.32(d,J=8 .3Hz,1H),8.13(s,1H),7.94(s,4H),7.77(d,J=8.3Hz,1H),2.10–2.00(m,1H),0.88–0.80(m,4H); 13 CNMR (151MHz, DMSO-d 6 )δ172.22,164.14,146.22,144.30,141.44,139.39,134.69,133.29(4C),133.19,132.30,129.4 1,128.13,123.91,122.26,119.17,118.72,112.37,104.69,14.56,7.73(2C).HRMS(ESI,m / z)for C 24 H 18 N 6 O 2 [M+Na] + :calcd,445.1389; found,445.1401.

[0276] Example 114 N-(7-(2-(4-cyanobenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-1-yl)cyclopropanecarboxamide (58)

[0277] 12d was used to replace 5a. The synthesis method was the same as compound 13. Yield: 17%, yellow solid. HPLC analysis: retention time, 2.986min; peak area, 97.59%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.21(s,1H),11.01(d,J=7.9Hz,2H),8.55(d,J=5.2Hz,1H),8.37(d,J=8.1Hz,1H),8.30(s,1H),8.17(d,J=5. 3Hz,1H),8.06(d,J=5.3Hz,1H),7.95(d,J=6.4Hz,4H),7.82–7.70(m,1H),2.20–2.00(m,1H),1.04–0.89(m,4H); 13 C NMR (151 MHz, DMSO-d 6)δ173.17,164.36,148.88,146.15,139.39,138.14,136.94,133.32,133.29(2C),129.90,129.21,1 28.13,123.82,121.95,119.16,118.86,113.31,112.36,14.41,8.32,8.27(2C).HRMS(ESI,m / z)forC 24 H 18 N 6 O 2 [M+Na] + :calcd,445.1389; found,445.1396.

[0278] Example 115 N-(7-(2-(4-chlorobenzylidene)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indol-1-yl)cyclopropanecarboxamide (59)

[0279] 12e was used to replace 5a. The synthesis method was the same as compound 13. Yield: 23%, yellow solid. HPLC analysis: retention time, 4.086min; peak area, 98.71%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.04(s,1H),11.02(s,1H),10.98(s,1H),8.49(s,1H),8.36(d,J=8.3Hz,1H),8.29(s,1H),8.17(d,J=5.3Hz ,1H),8.06(d,J=5.3Hz,1H),7.79(d,J=7.5Hz,3H),7.55(d,J=8.1Hz,2H),2.20–2.10(m,1H),1.05–0.89(m,4H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.18,164.19,146.83,139.84,138.13,136.93,134.97,133.86,133.43,129.94,129.46 (4C),129.20,123.70,121.90,118.84,113.28,113.15,14.41,8.31(2C).HRMS(ESI,m / z)for C 23 H 18 C1N 5 O 2 [M+Na] +:calcd,454.1047; found,454.1055.

[0280] Example 116 (R)-1-Acetamido-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (60)

[0281] 10o was used to replace 5a. The synthesis method was the same as compound 13. Yield: 12.33%, white solid. HPLC analysis: retention time, 3.333min; peak area, 98.05%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.06(s,1H),10.67(s,1H),8.95(d,J=8.1Hz,1H),8.29(d,J=8.2Hz,1H),8.21–8.11(m,2H),8.04(d,J=5.3Hz,1H),7.76(dd,J=8.2,1 .5Hz,1H),7.48–7.41(m,2H),7.35(dd,J=8.4,6.9Hz,2H),7.27–7.21(m,1H),5.23(p,J=7.2Hz,1H),2.24(s,3H),1.52(d,J=7.1Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ169.70,166.60,145.53 139.95,137.95,136.81,134.95,129.77,129.57,128.74(2C),127.08,126.58(2C) ,123.15,121.61,118.81,113.41,112.57,49.08,23.71,22.83.HRMS(ESI,m / z)for C 22 H 21 N 4 O 2 [M+H] + :calcd,373.1665; found,373.1670.

[0282] Example 117 (R)-1-(Cyclobutanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (61)

[0283] 10p was used to replace 5a. The synthesis method was the same as compound 13. Yield: 16.2%, white solid. HPLC analysis: retention time, 5.578min; peak area, 98.01%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(s,1H),10.49(s,1H),8.92(d,J=8.1Hz,1H),8.32–8.23(m,2H),8.14(d,J=5.3Hz,1H),8.0 3(d,J=5.3Hz,1H),7.76(dd,J=8.2,1.5Hz,1H),7.49–7.42(m,2H),7.35(t,J=7.6Hz,2H),7.29–7.2 0(m,1H),5.24(p,J=7.2Hz,1H),3.51(p,J=8.5Hz,1H),2.40(pd,J=9.1,2.4Hz,2H),2.20(qd,J=8.8 ,4.5Hz,2H),2.01(dq,J=10.8,8.8Hz,1H),1.88(tq,J=9.7,5.9,4.6Hz,1H),1.52(d,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ174.21,166.62,145.52,139.94,138.01,136.83,134.95,129.88,129.31,128.74(2C),127.08,126 .59(2C),123.17,121.58,118.83,113.30,112.74,49.09,25.16(2C),22.85,18.20.HRMS(ESI,m / z)for C 25 H 25 N 4 O 2 [M+H] + :calcd,413.1978; found,413.1982.

[0284] Example 118 (R)-1-(Cyclopentanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (62)

[0285] 10q was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18.8%, white solid. HPLC analysis: retention time, 5.006min; peak area, 98.89%. 1H NMR (400 MHz, DMSO-d 6 )δ10.88(s,1H),10.63(s,1H),8.91(d,J=8.1Hz,1H),8.35–8.22(m,2H),8.14(d,J=5 .3Hz,1H),8.03(d,J=5.2Hz,1H),7.75(dd,J=8.2,1.6Hz,1H),7.50–7.41(m,2H),7.4 0–7.30(m,2H),7.28–7.16(m,1H),5.23(p,J=7.2Hz,1H),3.08(p,J=8.1Hz,1H),2.02 –1.82(m,4H),1.75(dt,J=11.6,4.5Hz,2H),1.66–1.56(m,2H),1.52(d,J=7.1Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ175.8,166.6,145.5,139.9,138.1,136.8,134.9,130.0,129.2,128.7(2C),127.1,126.6(2C ),123.2,121.6,118.8,113.3,112.8,49.1,44.8,30.6(2C),26.4(2C),22.9.HRMS(ESI,m / z)for C 26 H 27 N 4 O 2 [M+H] + :calcd,427.2134; found,427.2136.

[0286] Example 119 (R)-1-(Cyclopropanecarboxamido)-6-fluoro-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (63)

[0287] 10r was used to replace 5a. The synthesis method was the same as compound 13. Yield: 13.4%, white solid. HPLC analysis: retention time, 4.201min; peak area, 98.73%. 1 H NMR (400 MHz, DMSO-d 6)δ11.08–10.95(m,1H),10.85(s,1H),8.89(d,J=8.0Hz,1H),8.21–8.10(m,2H),8.02(d,J=5.3Hz,1H),7.93(d,J=5.8Hz,1H),7.49–7.40(m,2H ),7.36(dd,J=8.4,6.8Hz,2H),7.30–7.13(m,1H),5.18(p,J=7.2Hz,1H),2.13(tt,J=8.0,4.5Hz,1H),1.47(d,J=7.0Hz,3H),1.04–0.87(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ173.13,164.19,152.71,145.14,138.19,136.61,136.20,129.57,128.79(2C),127.16,126.47(2C) ,125.94,122.57,114.02,113.39,108.08,107.83,49.10,23.00,14.38,8.28(2C).HRMS(ESI,m / z)for C 24 H 22 FN 4 O 2 [M+H] + :calcd,417.1727; found,417.1732.

[0288] Example 120 (R)-6-Chloro-1-(cyclopropanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (64)

[0289] 10s was used to replace 5a. The synthesis method was the same as compound 13. Yield: 12.6%, white solid. HPLC analysis: retention time, 4.955min; peak area, 98.21%. 1 H NMR (400 MHz, DMSO-d 6)δ11.05(s,1H),10.91(s,1H),9.02(d,J=8.1Hz,1H),8.42(s,1H),8.15(d,J=5.3Hz,1H),8.06(d,J=5.3Hz,1H),7.81(s,1H),7.46(d,J=7.2H z,2H),7.37(t,J=7.6Hz,2H),7.32–7.21(m,1H),5.18(p,J=7.2Hz,1H),2.13(tt,J=8.0,4.5Hz,1H),1.46(d,J=7.0Hz,3H),1.08–0.82(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ173.13,166.43,145.03,138.34,138.11,137.01,136.84,129.51,128.97,128.76(2C),127.16,126 .51(2C),122.61,122.51,121.11,113.43,113.32,48.85,22.98,14.38,8.29(2C).HRMS(ESI,m / z)for C 24 H 22 C1N 4 O 2 [M+H] + :calcd,433.1431; found,433.1436.

[0290] Example 121 (R)-1-(Cyclopropanecarboxamido)-6-fluoro-N-(1-(3-fluorophenyl)ethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (65)

[0291] 10t was used to replace 5a. The synthesis method was the same as compound 13. Yield: 17.6%, white solid. HPLC analysis: retention time, 5.257min; peak area, 99.53%. 1 H NMR (400 MHz, DMSO-d 6)δ11.56(s,2H),9.03(d,J=7.9Hz,1H),8.29(d,J=10.1Hz,1H),8.23–8.1 0(m,2H),8.00(d,J=5.7Hz,1H),7.42(td,J=8.0,6.0Hz,1H),7.27(dd,J=1 1.2,4.6Hz,2H),7.09(td,J=8.6,2.6Hz,1H),5.21(p,J=7.1Hz,1H),2.14( td,J=7.3,3.7Hz,1H),1.48(d,J=7.0Hz,3H),1.03(dd,J=8.1,2.7Hz,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ174.13,164.02,161.58,159.00,155.39,153.01,148.18,148.12,137.05,132.70,130.81,128.20,126 .86,122.67,114.29,114.07,113.46,108.63,108.38,48.88,22.83,14.84,9.09(2C).HRMS(ESI,m / z)for C 24 H 21 F 2 N 4 O 2 [M+H] + :calcd,435.1633; found,435.1637.

[0292] Example 122 (R)-N-(1-(3-chlorophenyl)ethyl)-1-(cyclopropanecarboxamido)-6-fluoro-9H-pyrido[3,4-b]indole-7-carboxamide (66)

[0293] 10u was used to replace 5a. The synthesis method was the same as compound 13. Yield: 13.2%, white solid. HPLC analysis: retention time, 6.271min; peak area, 97.43%. 1 H NMR (400 MHz, DMSO-d 6)δ11.03(s,1H),10.86(s,1H),8.96(d,J=7.9Hz,1H),8.26–8.09(m,2H),8.03(dd,J=5.3,1.8Hz,1H),7.93(dd,J=5.8,1.8Hz,1H),7.51(s,1 H),7.47–7.37(m,2H),7.38–7.28(m,1H),5.18(p,J=7.3Hz,1H),2.14(q,J=7.3,6.3Hz,1H),1.47(dd,J=7.0,1.8Hz,3H),1.05–0.86(m,4H). 13 CNMR (101MHz, DMSO-d 6 )δ173.14,164.31,152.68,147.81,138.21,136.62,136.20,133.52,130.74,129.59,127.16,126.42,125 .51,125.31,122.57,113.98,113.40,108.14,107.89,48.86,22.83,14.39,8.29(2C).HRMS(ESI,m / z)for C 24 H 21 CIF 4 O 2 [M+H] + :calcd,451.1337; found,451.1341.

[0294] Example 123 (R)-1-(Cyclopentanecarboxamido)-6-methoxy-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (67)

[0295] 10v was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18.4%, white solid. HPLC analysis: retention time, 7.812min; peak area, 97.93%. 1 H NMR (400 MHz, DMSO-d 6)δ10.61(d,J=15.6Hz,2H),8.71(d,J=8.0Hz,1H),8.10(d,J=5.3Hz,1H),8.0 8–8.00(m,2H),7.94(s,1H),7.49–7.42(m,2H),7.37(dd,J=8.4,6.8Hz,2H),7 .32–7.20(m,1H),5.19(p,J=7.1Hz,1H),4.00(s,3H),3.07(p,J=8.Hz,1H),2. 02–1.82(m,4H),1.80–1.68(m,2H),1.67–1.55(m,2H),1.49(d,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ175.69,165.35,151.42,145.26,138.11,136.16,134.71,129.97,129.52,128.82(2C),127.14,126.46(2C), 126.43,122.97,114.70,113.31,103.90,56.93,48.97,44.79,30.59(2C),26.36(2C),23.24.HRMS(ESI,m / z)for C 27 H 29 N 4 O 3 [M+H] + :calcd,457.2240; found,457.2242.

[0296] Example 124 (R)-1-(Cyclopentanecarboxamido)-6-fluoro-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (68)

[0297] 10w was used to replace 5a. The synthesis method was the same as compound 13. Yield: 11.9%, white solid. HPLC analysis: retention time, 6.811min; peak area, 98.06%. 1 H NMR (400 MHz, DMSO-d 6)δ10.83(s,1H),10.67(s,1H),8.90(d,J=8.0Hz,1H),8.21–8.08(m,2H),8.03 (d,J=5.3Hz,1H),7.96(d,J=5.8Hz,1H),7.45(d,J=7.2Hz,2H),7.37(t,J=7.5 Hz,2H),7.26(t,J=7.3Hz,1H),5.18(p,J=7.2Hz,1H),3.08(p,J=8.1Hz,1H),2 .02–1.82(m,4H),1.81–1.67(m,2H),1.68–1.54(m,2H),1.47(d,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ174.71,164.20,152.09,145.14,138.28,136.59,136.22,129.67,128.78(2C),127.15,126.46(2C),125. 92,122.56,114.06,113.42,108.08,107.83,49.08,44.79,30.58(2C),26.36(2C),23.02.HRMS(ESI,m / z)for C 26 H 26 FN 4 O 2 [M+H] + :calcd,445.2040; found,445.2043.

[0298] Example 125 (R)-6-Chloro-1-(cyclopentanecarboxamido)-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (69)

[0299] 10x was used to replace 5a. The synthesis method was the same as compound 13. Yield: 6.13%, white solid. HPLC analysis: retention time, 6.152min; peak area, 97.05%. 1 H NMR (400 MHz, DMSO-d 6)δ11.23(s,1H),10.96(s,1H),9.04(d,J=8.1Hz,1H),8.48(s,1H),8.15(q,J =5.5Hz,2H),7.87(s,1H),7.46(d,J=7.1Hz,2H),7.38(t,J=7.6Hz,2H),7.32 –7.21(m,1H),5.18(p,J=7.1Hz,1H),3.11(p,J=8.1Hz,1H),2.05–1.83(m,4H ),1.80–1.68(m,J=4.2,3.5Hz,2H),1.69–1.55(m,2H),1.47(d,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ176.24,166.31,144.97,138.71,137.80,137.30,129.95,128.76(2C),128.49,127.18(2C),126.53(2C) ,122.88,122.36,121.55,113.53,113.38,48.88,44.94,30.54(2C),26.33(2C),22.97.HRMS(ESI,m / z)forC 26 H 26 C1N 4 O 2 [M+H] + :calcd,461.1744; found,461.1748.

[0300] Example 126 (R)-1-(Cyclopentanecarboxamido)-6-fluoro-N-(1-(3-fluorophenyl)ethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (70)

[0301] 10y was used to replace 5a. The synthesis method was the same as compound 13. Yield: 18.1%, white solid. HPLC analysis: retention time, 6.682min; peak area, 97.52%. 1 H NMR (400 MHz, DMSO-d 6)δ10.84(s,1H),10.67(s,1H),8.95(d,J=7.9Hz,1H),8.22–8.11(m,2H),8.03 (d,J=5.3Hz,1H),7.97(d,J=5.7Hz,1H),7.42(td,J=8.0,6.1Hz,1H),7.33–7. 23(m,2H),7.14–7.03(m,1H),5.20(p,J=7.2Hz,1H),3.08(p,J=8.1Hz,1H),2. 06–1.82(m,4H),1.80–1.68(m,2H),1.67–1.56(m,2H),1.48(d,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ157.29,145.82,145.49,143.07,136.55,134.18,129.79,129.72,117.72,112.29,112.21,111.35,111.1 7,104.14,95.53,94.92,94.59,89.61,89.36,30.28,26.29,12.08(2C),7.86(2C),4.35.HRMS(ESI,m / z)forC 26 H 25 F 2 N 4 O 2 [M+H] + :calcd,463.1946; found,463.1949.

[0302] Example 127 (R)-N-(1-(3-chlorophenyl)ethyl)-1-(cyclopentanecarboxamido)-6-fluoro-9H-pyrido[3,4-b]indole-7-carboxamide (71)

[0303] 10z replaced 5a, the synthesis method was the same as compound 13. Yield 11.7%, off-white solid. HPLC analysis: retention time, 6.886min; peak area, 97.34%. 1 H NMR (400 MHz, DMSO-d 6)δ10.84(s,1H),10.67(s,1H),8.96(d,J=7.9Hz,1H),8.23–8.09(m,2H),8.03(d ,J=5.3Hz,1H),7.96(d,J=5.8Hz,1H),7.51(d,J=2.2Hz,1H),7.41(dd,J=4.3,1.8 Hz,2H),7.33(dt,J=5.4,3.3Hz,1H),5.18(p,J=7.2Hz,1H),3.08(p,J=8.1Hz,1H) ,2.02–1.81(m,4H),1.79–1.67(m,2H),1.68–1.55(m,2H),1.47(d,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ175.81,164.33,152.70,147.80,138.31,136.62,136.23,133.52,130.74,129.70,127.16,126.42(2C),125 .68,125.31,122.59,113.43,108.13,107.88,48.86,44.80,30.59(2C),26.36(2C),22.82.HRMS(ESI,m / z)for C 26 H 25 CIF 4 O 2 [M+H] + :calcd,479.165; found,479.1650.

[0304] Example 128 (R)-1-(Cyclopentanecarboxamido)-N-(1-phenylpropyl)-9H-pyrido[3,4-b]indole-7-carboxamide (72)

[0305] 10aa was used to replace 5a. The synthesis method was the same as compound 13. Yield: 7.08%, white solid. HPLC analysis: retention time, 13.571min; peak area, 98.75%. 1 H NMR (400 MHz, DMSO-d 6)δ10.89(s,1H),10.64(s,1H),8.85(d,J=8.4Hz,1H),8.33–8.23(m,2H),8.14(d,J =5.2Hz,1H),8.03(d,J=5.3Hz,1H),7.74(dd,J=8.2,1.5Hz,1H),7.49–7.40(m,2H) ,7.34(t,J=7.6Hz,2H),7.28–7.20(m,1H),5.08–4.87(m,1H),3.09(p,J=8.1Hz,1H ),2.02–1.81(m,6H),1.81–1.68(m,2H),1.67–1.55(m,2H),0.95(t,J=7.3Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ175.81,167.04,144.64,139.91,138.13,136.81,135.07,129.97,129.21,128.69(2C),127.12(3C),123. 14,121.56,118.87,113.25,112.74,55.53,44.80,30.59(2C),29.59,26.37(2C),11.91.HRMS(ESI,m / z)for C 27 H 29 N 4 O 2 [M+H] + :calcd,441.2291; found,441.2294.

[0306] Example 130 1-(Cyclopentanecarboxamido)-N-(1-phenylcyclopropyl)-9H-pyrido[3,4-b]indole-7-carboxamide (73)

[0307] 10ab was used to replace 5a. The synthesis method was the same as compound 13. Yield: 16.31%, white solid. HPLC analysis: retention time, 8.855min; peak area, 97.08%. 1 H NMR (400 MHz, DMSO-d 6)δ10.89(s,1H),10.63(s,1H),9.27(s,1H),8.32–8.21(m,2H),8.14(d,J=5.2Hz,1H),8.03(d,J=5.3Hz,1H),7.76(dd,J=8.2,1.6Hz,1H),7.41 –7.22(m,4H),7.22–7.03(m,1H),3.08(p,J=8.1Hz,1H),2.03–1.83(m,4 H),1.81–1.68(m,2H),1.68–1.50(m,2H),1.31(dt,J=12.7,2.4Hz,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ175.82,167.78,144.12,139.95,138.14,136.83,134.89,129.95,129.25,128.51(2C),126.01,125.14(2C) ,123.28,121.62,118.71,113.28,112.79,44.80,34.98,30.59(2C),26.36(2C),18.75(2C).HRMS(ESI,m / z)for C 27 H 27 N 4 O 2 [M+H] + :calcd,439.2134; found,439.2137.

[0308] Example 131 (R)-1-(Cyclopentanecarboxamido)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-9H-pyrido[3,4-b]indole-7-carboxamide (74)

[0309] 10ac was used to replace 5a. The synthesis method was the same as compound 13. Yield: 15.02%, white solid. HPLC analysis: retention time, 8.887min; peak area, 95.449%. 1 H NMR (400 MHz, DMSO-d 6)δ10.88(s,1H),10.64(s,1H),8.86(d,J=8.6Hz,1H),8.40–8.22(m,2H),8.14(d,J=5. 2Hz,1H),8.03(d,J=5.3Hz,1H),7.78(d,J=8.3Hz,1H),7.34–7.20(m,1H),7.21–7.07( m,3H),5.31(q,J=7.1,6.4Hz,1H),3.08(p,J=8.2Hz,1H),2.91–2.71(m,2H),2.02(q,J =5.0,4.6Hz,2H),1.99–1.81(m,5H),1.81–1.71(m,3H),1.60(q,J=14.5,10.5Hz,2H). 13 C NMR (101 MHz, DMSO-d 6 )δ175.81,166.99,139.94,138.26,138.12,137.69,136.81,134.92,129.96,129.24(2C),128.35,127.10,126.34,12 3.18,121.53,118.87,113.27,112.90,47.81,44.79,30.59(2C),30.36,29.41,26.36(2C),20.96.HRMS(ESI,m / z)for C 28 H 29 N 4 O 2 [M+H] + :calcd,453.2291; found,453.2295.

[0310] Example 132 (R)-1-(Cyclopentanecarboxamido)-N-methyl-N-(1-phenylethyl)-9H-pyrido[3,4-b]indole-7-carboxamide (75)

[0311] 10ad replaced 5a, the synthesis method was the same as compound 13. Yield 4.29%, white solid. HPLC analysis: retention time, 8.424min; peak area, 96.06%. 1 H NMR (400 MHz, DMSO-d 6)δ10.83(s,1H),10.66(s,1H),8.29(d,J=8.1Hz,1H),8.14(d,J=5.2Hz,1H),8.02(d,J=5.2Hz,1H),7.86(s,1H),7.48–7.21(m,6 H),3.18(d,J=3.7Hz,1H),3.09(p,J=8.2Hz,1H),2.71–2.64(m,3H),2.03–1.82(m,4H),1.81–1.65(m,2H),1.61(t,J=6.7Hz,5H). 13 C NMR (151 MHz, DMSO-d 6 )δ175.81,171.54,140.89,139.84,138.03,136.88(2C),130.25,129.06(2C),128.56,127.76,127.39,1 22.24,121.71,118.40,118.02,113.01,111.21,49.08,44.82,30.61(3C),26.36(3C).HRMS(ESI,m / z)for C 27 H 29 N 4 O 2 [M+H] + :calcd,441.2291; found,441.2293.

[0312] Example 133: Evaluation of GSK-3β and DYRK1A inhibitory activity

[0313] Kinase Glo assay was performed in assay buffer using a yellow 96-well plate. 1 μL (10 μM) of the test compound (10q and 13-75) (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, and then 2 μL of an isomeric mixture containing 0.2 μg of substrate and 25 μM ATP was added. After incubation at room temperature for 60 minutes, 5 μL of Kinase Glo reagent was used to stop the enzymatic reaction and eliminate the remaining ATP. After incubation at room temperature for 40 minutes, the ADP generated by the reaction was converted into ATP using a kinase detection reagent, and the luminescence value was recorded using a multifunctional microplate reader after 30 minutes. Conclusion: The experiment shows that some of the compounds prepared by the present invention can effectively inhibit the activity of GSK-3β (Table 1) and have high selectivity for DYRK1A. Among them, the GSK3β inhibitory activities of compounds 14, 16, 18, 34, 36, 40, 42, 46, 48, 60-63, 66, 68, 69, 70, 71, 72 and 73 were better than those of ZDWX-25. The GSK3β inhibitory activities of compounds 13, 15, 17, 19-33, 35, 37-39, 41, 43-45, 47, 49-59, 64, 65, 67, 74 and 75 were comparable to those of ZDWX-25, and the selectivity of compounds 35, 44, 50, 52, 64, 65, 67, 74 and 75 were better than those of ZDWX-25. The GSK3β inhibitory activities of some compounds in compounds 13-75 were 191.89 times higher than those of the lead compound ZDWX-25, and the selectivity was increased by 17337 times.

[0314] Table 1 GSK3β / DYRK1A inhibitory activity of compounds 10q and 13-75

[0315]

[0316]

[0317]

[0318]

[0319] a IC 50 Values ​​were calculated from data points obtained from the average of duplicate wells. b ND.: Not determined. c Selectivity Index (SI) = IC 50 (DYRK1A) / IC 50 (GSK3β). Calculated using ADMETlab 3.0: https: / / admetlab3.scbdd.com / . Indicates IC 50≤50nM. Indicates IC 50 >50nM but ≤100nM; Indicates IC 50 >100nM but ≤1000nM; Indicates IC 50 >1000nM, but <10000nM; Indicates IC 50 is >10000nM.

[0320] One of the compounds 13-75 with stronger activity (14, 16, 18, 34, 36, 40, 42, 46, 48, 60-63, 66, 68, 69, 70, 71, 72 and 73) was selected as Z86 for further experiments as follows; other compounds have the same technical effects and are not described in detail here.

[0321] Example 134: Open Field Test (OFT) Experiment of Candidate Compound Z86

[0322] 2 μL of OKA (50 ng / μL) prepared with saline (Vehicle group) was injected into the lateral ventricle of C57BL6 / J mice (OA group, 2 ng / μL) to establish an acute Tau phosphorylation mouse model. Z86 (5 mg / kg and 25 mg / kg) and LiCl (25 mg / kg) were administered on the second day for 2 weeks, and behavioral experiments were performed.

[0323] The mice were placed in the center of the open field before the test and the timing was started. The total distance moved by the mice, the time of activity, the time spent in the central area (anxiety assessment), and the presence of abnormal behaviors (such as circling or irregular movements) were recorded. The test was performed for 30 minutes. The results showed that compared with the Vehicle group, the OA group and the drug-treated groups Z86 (5 mg / kg and 25 mg / kg) and LiCl (25 mg / kg) did not show significant behavioral abnormalities or side effects in the open field experiment, indicating that the drug was safe under the current experimental conditions and did not adversely affect the anxiety or activity level of the mice. This also supports the safety and efficacy of the drug at this dose, and can provide a strong experimental basis for subsequent drug research and clinical applications.

[0324] ( Figure 2 ).

[0325] Example 134: Novel Position Recognition (NPR) Experiment of Candidate Compound Z86

[0326] Place two identical objects in the test box and allow the mice to explore freely for 10 minutes. Test phase: After 2 hours, change the position of one of the objects and keep the position of the other object unchanged. The mice will freely explore the location of the objects during the test. Record the time the mice stay between the two objects. By comparing the exploration time of the mice on the new object and the old object, their memory and cognitive function are evaluated. The longer the exploration time of the new object, the stronger the mouse's memory preference for the new object, and vice versa, it may reflect memory impairment.

[0327] The experimental results showed that the model group showed obvious spatial memory impairment while having a faster activity speed, and its exploration time of new locations was significantly reduced. This may reflect the impairment of its cognitive function, especially the loss or impairment of spatial memory. The administration of Z86 (5mg / kg and 25mg / kg) and LiCl (25mg / kg) to the drug group restored normal activity levels, indicating that the drugs Z86 (5mg / kg and 25mg / kg) and LiCl (25mg / kg) have significant effects on the recovery and improvement of spatial memory. The drug may play a positive role by improving cognitive function, especially spatial memory and learning ability. This provides strong support for the potential of the drug in improving cognitive impairment ( Figure 3 ).

[0328] Example 135: Morris Water Maze Test of Candidate Compound Z86

[0329] A large circular pool with a diameter of about 1 meter, inconspicuous milky white dye was added to the pool, and there was a hidden platform at the bottom of the pool (lower than the water surface). The mice searched for the hidden escape platform in the pool (the platform was set 1 cm below the water surface), and it took 5 days of training (4 times a day, each time to find the platform within 60 seconds). After training, a memory test was conducted on the sixth day: the platform was removed, and the time, path, search area, etc. of the mice swimming in the pool were recorded. Observe whether the mice can remember the location of the platform and reduce the search time.

[0330] The experimental results showed that: the latency was prolonged: the mice in the OA group showed a longer latency when trying to find the platform, that is, they spent more time locating the hidden platform. This indicates that the OA group had significant obstacles in spatial memory and positioning ability, which may be due to impaired cognitive function, resulting in their inability to effectively use environmental cues. Compared with the Vehicle group, the swimming path of the mice in the OA group was more tortuous and inefficient, indicating that they had difficulties in spatial navigation and may have failed to effectively form or call spatial memory. Reduced exploratory behavior: The model group mice spent significantly less time near the platform, reflecting their reduced ability to recognize and remember the target location, and were unable to effectively concentrate and perform purposeful exploratory behavior. Improvement effect of the drug group: ① Shortened latency: The latency of mice in the drug treatment group Z86 (5mg / kg and 25mg / kg) and LiCl (25mg / kg) to find the platform was significantly shortened, close to the level of the normal group, indicating that the drugs Z86 (5mg / kg and 25mg / kg) and LiCl (25mg / kg) restored spatial learning and memory abilities to a certain extent. ② More efficient swimming path: The swimming path of the drug group mice was more linear and the number of detours was reduced, indicating that they had restored higher efficiency and goal orientation in spatial navigation. ③ Increased residence time and number of shuttle platform crossings: The drug group's residence time in the platform area and number of shuttle platform crossings increased significantly, indicating that their memory and recognition ability of the target location was improved, and they were able to better use spatial cues to locate the platform ( Figure 4 ).

[0331] Through enzyme activity tests and behavioral experimental results, this type of β-carboline derivatives can provide a theoretical basis for the discovery of new AD therapeutic drugs.

[0332] In summary, the β-carboline compounds proposed in the present invention can be used to prepare GSK-3β inhibitors and drugs for treating Alzheimer's disease.

Claims

1. A β-carboline compound or a pharmaceutically acceptable salt thereof, characterized in that: The general structural formula of the derivative is shown in Formula I or Formula II: in: R1 is an amide substituent at position 1 or 3 of the β-carboline pyridine ring, selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl; R2 is a substituent on the 7-position benzene ring of the β-carboline core, and R2 is selected from: -OCH3, R3 is F, OCH3, H or Cl.

2. The following compounds or pharmaceutically acceptable salts thereof, selected from:

3. A method for preparing the compound as claimed in claim 2, characterized in that: The preparation method of the compound comprises the following steps: (1) Compound 1 is dissolved in tetrahydrofuran, pyridine is added, and the mixture is stirred under ice bath conditions, and then cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, cyclopentylcarbonyl chloride, cyclohexylcarbonyl chloride, benzoyl chloride, or acetyl chloride is slowly added dropwise to obtain compound 2a, 2b, 2c, 2d, 2e, or 2f; (2) Compound 2a, 2b, 2c, 2d, 2e, 2f is dissolved in anhydrous dioxane, potassium acetate, 4,4,4',4',5,5,5',5'-octamethyl-2,2-bi-1,3,2-dioxaborolane and bis(triphenylphosphine)palladium chloride are added, and the mixture is heated at 95° C. under nitrogen protection to obtain compound 3a, 3b, 3c, 3d, 3e or 3f; (3) Compound 3a, 3b, 3c, 3d, 3e, 3f is dissolved in anhydrous dioxane and water, cesium carbonate and bis(triphenylphosphine)palladium chloride are added, heated at 95° C., and reacted with compound 4a, 4b under nitrogen protection to obtain compound 5a, 5b, 5c, 5d or 5e; (4) dissolving compound 5a, 5b, 5c, 5d, or 5e in o-dichlorobenzene, adding triphenylphosphine, and reacting to obtain compound 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22; (5) Compounds 6a, 6b, 6c and KNO3 were mixed, and concentrated sulfuric acid was added dropwise under ice bath conditions to react to obtain compound 7a, 7b or 7d; (6) dissolving compound 7a, 7b, 7c, 7d, or 7e in SOCl2 and reacting under reflux to obtain compound 8a, 8b, 8c, 8d, or 8e; (7) Compound 8a, 8b, 8c, 8d, or 8e is dissolved in dichloromethane, and triethylamine and amines with different substituents are added to react to obtain compound 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t, 9u, 9v, 9w, 9x, or 9y; (8) Compounds 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t, 9u, 9v, 9w, and 9x were dissolved in dioxane and water, and potassium acetate, 4,4,4',4',5,5,5',5'-octamethyl-2,2-bi-1,3,2-dioxaborolane, and bis(triphenylphosphine)palladium chloride were added. , heating at 95° C. under nitrogen protection to obtain target compounds 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h, 10i, 10j, 10k, 10l, 10m, 10n, 10o, 10p, 10q, 10r, 10s, 10t, 10u, 10v, 10w, 10x, 10y, 10z, 10aa, 10ab, 10ac or 10ad; (9) Compounds 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h, 10i, 10j, 10k, 10l, 10m, 10n, 10o, 10p, 10q, 10r, 10s, 10t, 10u, 10v, 10w, 10x, 10y, 10z, 10aa, 10ab, 10ac, and 10ad were added to o-dichlorobenzene and heated at 110°C under nitrogen. Under the protection of atmospheric pressure, the target compound 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or 75 was obtained; (10) Compound 8c was mixed with methanol in an ice bath to form compound 9z through methylation; (11) Compound 9z was added to dioxane and water, heated at 95 °C, and reacted under nitrogen to produce compound 10ae via Suzuki coupling reaction; (12) Compound 10ae is added to ethanol, and then hydrazine monohydrate is added to obtain compound 11; (13) Compound 11 reacts with 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 3-cyanobenzaldehyde, 4-cyanobenzaldehyde or 3-chlorobenzaldehyde to obtain compound 12a, 12b, 12c, 12d or 12e; (14) Compounds 12a, 12b, 12c, 12d, or 12e were added to o-dichlorobenzene and heated at 95° C. under nitrogen protection to obtain target compounds 51, 52, 53, 54, 55, 56, 57, 58, or 59.

4. The method for preparing the compound according to claim 3, characterized in that: The acyl chloride with different substituents in step (1) is one of acetyl chloride, cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, cyclopentylcarbonyl chloride, cyclohexylcarbonyl chloride or phenylacetyl chloride.

5. The method for preparing the compound according to claim 3, characterized in that: The amine with different substituents in step (7) is one of cyclopropylamine, cyclohexylamine, aniline, 4-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline, benzylamine, (S)-1-phenylethylamine, (3-fluorophenyl)methylamine, (3-chlorophenyl)methylamine, (3-fluoro-4-methoxyphenyl)methylamine, 3-(aminomethyl)benzonitrile, benzo[d][1,3]dioxol-5-ylmethylamine, (3-(trifluoromethyl)phenyl)methylamine, (R)-1-phenylethylamine, (R)-1-(3-fluorophenyl)ethylamine, (R)-1-(3-chlorophenyl)ethylamine, (R)-1-phenylpropylamine, 1-phenylcyclopropylamine, (R)-1,2,3,4-tetrahydronaphthalene-1-amine or (R)-N-methyl-1-phenylethylamine.

6. The method for preparing the compound according to claim 3, characterized in that: The benzaldehyde with different substituents in step (13) is one of 3-methoxybenzaldehyde, 4-methoxybenzaldehyde, 3-cyanobenzaldehyde, 4-cyanobenzaldehyde or 3-chlorobenzaldehyde.

7. A pharmaceutical composition, characterized in that Containing the formula I or a pharmaceutically acceptable excipient thereof according to any one of claims 1 to 3.

8. The pharmaceutical composition according to claim 6, characterized in that The preparation is prepared by adding one or more pharmaceutically acceptable excipients to the formula I as described in any one of claims 1 to 3.

9. Use of the compound according to any one of claims 1 to 3 in the preparation of a drug for treating Alzheimer's disease.

10. Use of the compound according to any one of claims 1 to 3 in the preparation of a GSK-3β inhibitor.

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