Pyrrolopyridine heterocyclic compound, preparation method thereof and application of pyrrolopyridine heterocyclic compound in preparation of medicine for treating Alzheimer disease

Abstract

The invention relates to the technical field of organic synthesis, in particular to a pyrrolopyridine heterocyclic compound, a preparation method and application thereof, a derivative of the pyrrolopyridine heterocyclic compound, application of the derivative, a pharmaceutical composition and application of the pharmaceutical composition. According to the pyrrolopyridine heterocyclic compound provided by the invention, the median inhibitory concentration (IC50) of the pyrrolopyridine heterocyclic compound to a target GSK-3beta is as low as 0.22 + / -0.03 nM, and the pyrrolopyridine heterocyclic compound has excellent target inhibitory activity; moreover, the pyrrolopyridine heterocyclic compound provided by the invention can effectively promote the growth of neuronal cell SH-SY5Y cell protrusions, can also effectively promote the expression of nerve growth markers GAP43 and MAP-2, can also significantly improve the movement retardation of an AlCl3-induced zebrafish AD model, has good in-vivo and in-vitro anti-AD activity, and can be used for preparing a new drug for preventing and treating AlCl3-induced zebrafish AD. The compound can be used as an anti-AD candidate drug for further research and development, and a basis is provided for research and development of novel anti-AD drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to pyrrolopyridine heterocyclic compounds and preparation methods and applications thereof, derivatives of pyrrolopyridine heterocyclic compounds and applications thereof, and pharmaceutical compositions and applications thereof. Background Art

[0002] Alzheimer's disease (AD) is an irreversible neurodegenerative disease. Its clinical pathological manifestations are mainly characterized by amyloid plaques formed by the deposition of β-amyloid protein (Aβ) in the brain, neurofibrillary tangles (NFTs) formed by the hyperphosphorylated aggregation of tau protein, oxidative stress damage to nerve cells, imbalance of metal ion homeostasis, neuroinflammation, and cholinergic neuron degeneration. At present, the main drugs for the treatment of AD include galantamine, rivastigmine, huperzine A, and donepezil, which inhibit cholinesterase activity, increase acetylcholine levels, and treat mild and moderate AD; memantine hydrochloride, which reduces glutamate concentration to treat moderate to severe AD; Aducanumab and Lecanemab, which inhibit β-amyloid protein deposition and improve cognitive impairment in patients with mild AD; and mannitol sodium, which improves cognition in patients with mild to moderate AD by reshaping the balance of intestinal flora and reducing the accumulation of peripheral metabolites phenylalanine and isoleucine. However, current AD treatment drugs can only slightly alleviate the memory and cognitive functions of AD patients and cannot effectively delay or even reverse the progression of AD. There is an urgent need to develop more effective new anti-AD drugs.

[0003] Glycogen synthase kinase-3 (GSK-3β) is a serine / threonine kinase, whose overactivation is closely related to the occurrence and malignant progression of AD. Activation of GSK-3β can induce the hyperphosphorylation of tau protein, causing it to form paired helical filaments and eventually form neurofibrillary tangles (NFTs) in the cytoplasm; it can also cause tau protein to lose its function of assembling and stabilizing microtubules, affecting the structure, transport function and release of neurotransmitters of axons, leading to neuronal degeneration; it can regulate the activity of β-secretase and γ-secretase, and induce toxic Aβ 1-40 / Aβ 1-42 It can also promote the production and release of inflammatory factors IL-1β, IL-6 and TNF-α, mediate neuroinflammatory response, and downregulate the activity of transcription factors that promote cell survival, activate apoptotic proteins such as caspase-3, and induce neuronal apoptosis. It can be seen that GSK-3β is a key factor connecting tau protein, Aβ, inflammation, neurotransmitters and neuronal apoptosis, and inhibiting GSK-3β is an effective target for AD treatment.

[0004] Existing GSK-3β inhibitors mainly include ATP competitive inhibitors, non-ATP competitive inhibitors, metal ion inhibitors, allosteric inhibitors and irreversible inhibitors, etc. However, the half-maximal inhibitory concentration of existing GSK-3β inhibitors on the target GSK-3β is generally at the level of 10 to 1000 nM. Therefore, it is urgent to develop a new GSK-3β inhibitor with a lower half-maximal inhibitory concentration on the target GSK-3β. Summary of the invention

[0005] In view of this, the object of the present invention is to provide a pyrrolopyridine heterocyclic compound and a preparation method and application thereof, a derivative of a pyrrolopyridine heterocyclic compound and an application thereof, a pharmaceutical composition and an application thereof. The pyrrolopyridine heterocyclic compound provided by the present invention has a half-maximal inhibition concentration of sub-nanomolar (nM) level for the target GSK-3β, and has significant target inhibition activity.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a pyrrolopyridine heterocyclic compound, the structural formula of which is shown in Formula SL:

[0008]

[0009] Wherein, R1 includes hydrogen, alkyl, alkoxy or halogen; R2 includes hydrogen, alkyl, alkoxy, unsubstituted aryl, substituted aryl, halogen or heterocyclic group; R3 includes unsubstituted aryl, substituted aryl or heterocyclic group; R2 and R3 are not phenyl at the same time.

[0010] Preferably, in R1 and R2, the alkyl group includes C1 to C 12 Alkyl; the alkoxy group includes C1~C 12 Alkoxy;

[0011] In R2 and R3, the aryl groups in the unsubstituted aryl group and the substituted aryl group independently include phenyl or naphthyl; the substituents in the substituted aryl group include alkyl, alkoxy, halogen or halogenated alkyl;

[0012] The heterocyclic group includes an aromatic heterocyclic group or an aliphatic heterocyclic group.

[0013] Preferably, the pyrrolopyridine heterocyclic compound has a structure shown in any one of Formulas SL01 to SL32:

[0014]

[0015]

[0016] The present invention provides a method for preparing the pyrrolopyridine heterocyclic compound described in the above technical solution, comprising the following steps:

[0017] Mixing 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, compound 1, an acid amine condensation agent, an organic base and a first organic solvent, and performing a condensation acylation reaction to obtain compound 2;

[0018] The compound 2, the compound 3, the catalyst, the inorganic base and the second organic solvent are mixed, and a Suzuki reaction is performed under a protective atmosphere to obtain the pyrrolopyridine heterocyclic compound;

[0019]

[0020] Wherein, R1 to R3 are the same as those in the formula SL.

[0021] Preferably, the molar ratio of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid to compound 1 is 1:0.4-1.2;

[0022] The acid amine condensing agent includes one or more of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

[0023] The molar ratio of the 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid to the acid amine condensation agent is 1:0.8-3;

[0024] The organic base includes N,N-diisopropylethylamine and / or triethylamine;

[0025] The molar ratio of the 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid to the organic base is 1:1.5-4;

[0026] The first organic solvent includes one or more of N,N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone.

[0027] Preferably, the condensation acylation reaction is carried out at a temperature of 60 to 100° C. and for a time of 3 to 48 hours.

[0028] Preferably, the catalyst comprises one or more of tetrakistriphenylphosphine palladium, bis(diphenylphosphino)ferrocene palladium dichloride and bistriphenylphosphine palladium dichloride;

[0029] The inorganic base includes one or more of potassium carbonate, sodium carbonate and cesium carbonate;

[0030] The molar ratio of compound 2 to compound 3 is 1:1.1-3;

[0031] The molar ratio of the compound 2 to the catalyst is 1:0.01-0.5;

[0032] The molar ratio of the compound 2 to the inorganic base is 1:1.1-10;

[0033] The second organic solvent includes 1,4-dioxane;

[0034] The temperature of the Suzuki reaction is 95-105° C., and the time is 6-24 hours.

[0035] The present invention provides derivatives of the pyrrolopyridine heterocyclic compounds described in the above technical solution, wherein the derivatives include one or more of isomers, pharmaceutically acceptable salts and solvates.

[0036] The present invention provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable excipient;

[0037] The active component is the pyrrolopyridine heterocyclic compound described in the above technical solution and / or a derivative of the pyrrolopyridine heterocyclic compound described in the above technical solution.

[0038] The present invention provides use of the pyrrolopyridine heterocyclic compound described in the above technical solution, the derivative of the pyrrolopyridine heterocyclic compound described in the above technical solution, or the pharmaceutical composition described in the above technical solution in the preparation of a drug for treating Alzheimer's disease.

[0039] The present invention provides a pyrrolopyridine heterocyclic compound, the structural formula of which is shown in Formula SL. The half inhibitory concentration (IC 50 ) is as low as 0.22±0.03nM, and has excellent target inhibitory activity; moreover, the pyrrolopyridine heterocyclic compound provided by the present invention can effectively promote the growth of SH-SY5Y cell processes of nerve cells, and can also effectively promote the expression of nerve growth markers GAP43 and MAP-2, and can also significantly improve the bradykinesia of AlCl3-induced zebrafish AD model, and has good in vivo and in vitro anti-AD activity, and can be used as an anti-AD candidate drug for further research and development, providing a basis for the research and development of new anti-AD drugs.

[0040] The method for preparing the pyrrolopyridine heterocyclic compound described in the above technical solution provided by the present invention is simple to operate, low in cost, and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Figure 2 shows the promoting effect of blank control, SL15 and RA on SH-SY5Y cell neurite outgrowth;

[0042] Figure 2 Figure 2 is the promoting effect of blank control, SL15 and RA on the expression of nerve growth markers in SH-SY5Y cells;

[0043] Figure 3 (Left) Graph showing the effects of donepezil hydrochloride and SL15 on improving AlCl3-induced zebrafish locomotion and (right) bar graph showing the distance traveled by zebrafish. DETAILED DESCRIPTION

[0044] The present invention provides a pyrrolopyridine heterocyclic compound, the structural formula of which is shown in Formula SL:

[0045]

[0046] In the present invention, R1 includes hydrogen, alkyl, alkoxy or halogen; R2 includes hydrogen, alkyl, alkoxy, unsubstituted aryl, substituted aryl, halogen or heterocyclic group; R3 includes unsubstituted aryl, substituted aryl or heterocyclic group; R2 and R3 are not phenyl at the same time.

[0047] In the present invention, in R1 and R2, the alkyl group preferably includes C1 to C 12 Alkyl, more preferably C1 to C 12 Straight chain alkyl, C1~C 12 Branched alkyl, C1~C 12 In a specific embodiment, the alkyl group may be C1 alkyl (methyl), C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl or C 12 Alkyl; the alkoxy group preferably includes C1~C 12 Alkoxy, more preferably C1 to C 12 Straight chain alkoxy, C1~C 12 Branched alkoxy, C1~C 12 Cycloalkoxy, in a specific embodiment, the alkoxy may be C 12 Alkoxy (methoxy), C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, C7 alkoxy, C8 alkoxy, C9 alkoxy, C 10 Alkoxy, C 11 Alkoxy or C 12 Alkoxy; the halogen preferably includes fluorine, chlorine, bromine or iodine.

[0048] In the present invention, in R2 and R3, the aryl groups in the unsubstituted aryl group and the substituted aryl group independently preferably include phenyl or naphthyl; the substituents in the substituted aryl group preferably include alkyl, alkoxy, halogen or halogenated alkyl; the heterocyclic group preferably includes an aromatic heterocyclic group or an alicyclic group; the aromatic heterocyclic group preferably includes a pyridyl, thienyl or furyl; the alicyclic group preferably includes a morpholine ring, a tetrahydropyrrole ring, a piperidine ring, N-methylpiperazine or a nitrogen-containing seven-membered heterocyclic ring.

[0049] In the present invention, the pyrrolopyridine heterocyclic compound preferably has a structure shown in any one of Formulas SL01 to SL32:

[0050]

[0051]

[0052]

[0053] The present invention provides a method for preparing the pyrrolopyridine heterocyclic compound described in the above technical solution, comprising the following steps:

[0054] Mixing 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, compound 1, an acid amine condensation agent, an organic base and a first organic solvent, and performing a condensation acylation reaction to obtain compound 2;

[0055] The compound 2, the compound 3, the catalyst, the inorganic base and the second organic solvent are mixed, and a Suzuki reaction is performed under a protective atmosphere to obtain the pyrrolopyridine heterocyclic compound;

[0056]

[0057] Wherein, R1 to R3 are the same as those in the formula SL.

[0058] In the present invention, unless otherwise specified, the reagents used are commercially available products well known to those skilled in the art.

[0059] The preparation route of the pyrrolopyridine heterocyclic compound in the present invention is as follows.

[0060]

[0061] The present invention mixes 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid, compound 1, an acid amine condensation agent, an organic base and a first organic solvent (referred to as a first mixture) and performs a condensation acylation reaction to obtain compound 2.

[0062] In the present invention, the molar ratio of 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid to compound 1 is preferably 1:0.4-1.2. In a specific embodiment, the molar ratio of 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid to compound 1 can be 1:0.4, 1:0.6, 1:0.8, 1:0.9, 1:1, 1:1.1 or 1:1.2.

[0063] In the present invention, the acid amine condensing agent preferably includes 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBT), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC); the molar ratio of the 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid and the acid amine condensation agent is preferably 1:0.8-3. In a specific embodiment, the molar ratio of the 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid and the acid amine condensation agent can be 1:0.8, 1:1, 1:1.2, 1:1.3, 1:1.5, 1:2 or 1:3.

[0064] In the present invention, the organic base preferably includes N,N-diisopropylethylamine (DIPEA) and / or triethylamine; the molar ratio of the 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid to the organic base is preferably 1:1.5-4. In a specific embodiment, the molar ratio of the 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid to the organic base can be 1:1.5, 1:1.7, 1:1.8, 1:2, 1:3 or 1:4.

[0065] In the present invention, the first organic solvent preferably includes one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); the ratio of the amount of the substance of 5-bromo-1H-pyrrole [2,3-b] pyridine-3-carboxylic acid to the volume of the first organic solvent is preferably 1mmol: 3 to 6mL. In a specific embodiment, the ratio of the amount of the substance of 5-bromo-1H-pyrrole [2,3-b] pyridine-3-carboxylic acid to the volume of the first organic solvent can be 1mmol: 3mL, 1mmol: 3.3mL, 1mmol: 4.5mL or 1mmol: 4.8mL.

[0066] In the present invention, the first mixing preferably comprises the following steps: premixing 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid, an acid amine condensing agent, an organic base and a first organic solvent, and then adding compound 1 for final mixing. In the present invention, the final mixing is preferably stirring mixing, and the temperature of the final mixing is preferably 10 to 30°C. In a specific embodiment, the temperature of the final mixing can be 10°C, 15°C, 20°C, 25°C, 28°C or 30°C; the time of the final mixing is preferably 5 to 15 minutes. In a specific embodiment, the time of the final mixing can be 5 minutes, 8 minutes, 10 minutes or 15 minutes.

[0067] In the present invention, the temperature of the condensation acylation reaction is preferably 60-100°C. In a specific embodiment, the temperature of the condensation acylation reaction can be 60°C, 65°C, 85°C, 90°C or 100°C; the time of the condensation acylation reaction is preferably 3-48h. In a specific embodiment, the time of the condensation acylation reaction can be 3h, 6h, 10h, 30h or 48h.

[0068] After completing the condensation acylation reaction, the present invention preferably further comprises mixing the reaction liquid obtained by the condensation acylation reaction with a third organic solvent, sequentially performing a first washing, a first drying and a first solid-liquid separation, and sequentially performing a first concentration and a first purification on the obtained liquid component to obtain compound 2. In the present invention, the third organic solvent preferably comprises ethyl acetate and / or dichloromethane (CH2Cl2); the volume ratio of the reaction liquid obtained by the condensation acylation reaction to the third organic solvent is preferably 1:3 to 8. In a specific embodiment, the volume ratio of the reaction liquid obtained by the condensation acylation reaction to the third organic solvent may be 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.

[0069] In the present invention, the first washing preferably includes sequentially performing a first water wash and a first saturated sodium chloride aqueous solution wash; the number of the first water wash is preferably 2 to 3 times; the number of the first saturated sodium chloride solution wash is preferably 1 to 2 times. In the present invention, the first drying preferably includes drying with a desiccant; the desiccant preferably includes anhydrous sodium sulfate (Na2SO4) drying and / or anhydrous magnesium sulfate (MgSO4); the first drying time is preferably 0.5 to 2 hours, more preferably 1 to 1.5 hours. The present invention does not specifically limit the first solid-liquid separation method, and conventional solid-liquid separation methods in the art may be used, such as filtration. In the present invention, the temperature of the first concentration is preferably 30 to 40°C, more preferably 35 to 38°C; the first concentration preferably includes reduced pressure concentration. In the present invention, the first purification preferably includes a first silica gel column chromatography; the eluent used in the first silica gel column chromatography preferably includes a dichloromethane-methanol mixed solvent or an ethyl acetate-methanol mixed solvent; the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 10 to 100:1. In a specific embodiment, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent may be 10:1, 13:1, 20:1, 25:1, 27:1, 40:1 or 50:1; the volume ratio of ethyl acetate to methanol in the ethyl acetate-methanol mixed solvent is preferably 20 to 100:1.

[0070] After obtaining the compound 2, the present invention mixes the compound 2, compound 3, a catalyst, an inorganic base and a second organic solvent (referred to as the second mixture), and performs a Suzuki reaction (Suzuki coupling reaction) under a protective atmosphere to obtain the pyrrolopyridine heterocyclic compound.

[0071] In the present invention, the molar ratio of compound 2 to compound 3 is preferably 1:1.1-3. In specific embodiments, the molar ratio of compound 2 to compound 3 can be 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:2 or 1:3.

[0072] In the present invention, the catalyst preferably includes one or more of tetrakistriphenylphosphine palladium (Pd(PPh3)4), bis(diphenylphosphino)ferrocene palladium dichloride (Pd(dppf)Cl2, wherein dppf is bis(diphenylphosphino)ferrocene) and bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2); the molar ratio of the compound 2 to the catalyst is preferably 1:0.01 to 0.5. In specific embodiments, the molar ratio of the compound 2 to the catalyst can be 1:0.01, 1:0.02, 1:0.05, 1:0.1, 1:0.2 or 1:0.5.

[0073] In the present invention, the inorganic base preferably includes one or more of potassium carbonate, sodium carbonate and cesium carbonate; the molar ratio of the compound 2 to the inorganic base is preferably 1:1.1-10. In a specific embodiment, the molar ratio of the compound 2 to the inorganic base can be 1:1.1, 1:2, 1:3, 1:5, 1:8 or 1:10.

[0074] In the present invention, the second organic solvent preferably includes 1,4-dioxane; the ratio of the amount of the substance of the compound 2 to the volume of the second organic solvent is preferably 1mmol:10-100mL. In a specific embodiment, the ratio of the amount of the substance of the compound 2 to the volume of the second organic solvent can be 1mmol:19mL, 1mmol:24mL, 1mmol:30mL, 1mmol:31mL, 1mmol:33mL, 1mmol:40mL, 1mmol:41mL, 1mmol:46mL, 1mmol:48mL, 1mmol:60mL, 1mmol:63mL, 1mmol:70mL or 1mmol:80mL.

[0075] In the present invention, the second mixing preferably also includes adding water for mixing; the volume ratio of the second organic solvent to water is preferably 4 to 20:1. In a specific embodiment, the volume ratio of the second organic solvent to water can be 4:1, 5:1, 6:1, 10:1, 16:1 or 20:1.

[0076] In the present invention, the protective atmosphere preferably includes nitrogen and / or an inert gas; the inert gas preferably includes argon.

[0077] In the present invention, the temperature of the Suzuki reaction is preferably 95-105°C. In a specific embodiment, the temperature of the Suzuki reaction can be 95°C, 98°C, 100°C, 102°C or 105°C; the time of the Suzuki reaction is preferably 6-24h. In a specific embodiment, the time of the Suzuki reaction can be 6h, 8h, 12h, 16h or 20h.

[0078] After completing the Suzuki reaction, the present invention preferably further comprises mixing the reaction liquid obtained by the Suzuki reaction with a fourth organic solvent, sequentially performing a second washing, a second drying and a second solid-liquid separation, and sequentially performing a second concentration and a second purification on the obtained liquid component to obtain the pyrrolopyridine heterocyclic compound.

[0079] In the present invention, the fourth organic solvent preferably includes ethyl acetate and / or dichloromethane (CH2Cl2). In the present invention, the second washing preferably includes sequentially performing a second water wash and a second saturated sodium chloride aqueous solution wash; the number of the second water wash is preferably 2 to 3 times; the number of the second saturated sodium chloride solution wash is preferably 1 to 2 times. In the present invention, the second drying preferably includes drying with a desiccant; the desiccant preferably includes drying with anhydrous sodium sulfate (Na2SO4) and / or anhydrous magnesium sulfate (MgSO4); the second drying time is preferably 0.5 to 2 hours, more preferably 1 to 1.5 hours. The present invention does not specifically limit the second solid-liquid separation method, and the conventional solid-liquid separation method in the art can be used, such as filtration. In the present invention, the temperature of the second concentration is preferably 30 to 40°C, more preferably 35 to 38°C; the second concentration preferably includes reduced pressure concentration. In the present invention, the second purification preferably includes a second silica gel column chromatography; the eluent used in the second silica gel column chromatography preferably includes a dichloromethane-methanol mixed solvent or an ethyl acetate-methanol mixed solvent; the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 10 to 80:1, and in a specific embodiment, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent may be 10:1, 13:1, 16:1, 20:1 or 27:1; the volume ratio of ethyl acetate to methanol in the ethyl acetate-methanol mixed solvent is preferably 15 to 100:1.

[0080] The present invention provides a derivative of the pyrrolopyridine heterocyclic compound described in the above technical solution, wherein the derivative includes one or more of isomers, pharmaceutically acceptable salts and solvates.

[0081] In the present invention, the pharmaceutically acceptable salt of the pyrrolopyridine heterocyclic compound preferably includes one or more of the sulfate, acetate, citrate, tartrate, maleate and hydrochloride of the pyrrolopyridine heterocyclic compound; the solvent used for the solvate of the pyrrolopyridine heterocyclic compound preferably includes one or more of water, glycerol, ethanol, polyethylene glycol, fatty oil and liquid paraffin.

[0082] The present invention provides a pharmaceutical composition, comprising an active component and a pharmaceutically acceptable excipient; the active component is the pyrrolopyridine heterocyclic compound described in the above technical solution and / or a derivative of the pyrrolopyridine heterocyclic compound described in the above technical solution.

[0083] In the present invention, the mass of the active component is preferably 10-80% of the mass of the pharmaceutical composition. In a specific embodiment, the mass of the active component can be 10%, 20%, 40%, 50%, 60% or 80% of the mass of the pharmaceutical composition; the pharmaceutically acceptable excipients preferably include one or more of calcium phosphate, magnesium stearate, talc, dextrin, starch, gel cellulose, methyl cellulose, sodium carboxymethyl cellulose and polyvinyl pyrrolidone; the pharmaceutically acceptable excipients preferably include excipients and / or carriers; the excipients preferably include binders, fillers or disintegrants; the carrier preferably includes drug-loaded nanomaterials; the dosage form of the pharmaceutical composition preferably includes oral preparations, more preferably tablets, pills or capsules.

[0084] The present invention provides the use of the pyrrolopyridine heterocyclic compound described in the above technical solution, the derivative of the pyrrolopyridine heterocyclic compound described in the above technical solution, or the pharmaceutical composition described in the above technical solution in the preparation of a drug for treating Alzheimer's disease. The half inhibitory concentration (IC50) of the pyrrolopyridine heterocyclic compound provided by the present invention on the target GSK-3β 50 ) is as low as 0.22±0.03nM, and has excellent target inhibitory activity; moreover, the pyrrolopyridine heterocyclic compound provided by the present invention can effectively promote the growth of SH-SY5Y cell processes of nerve cells, and can also effectively promote the expression of nerve growth markers GAP43 and MAP-2, and can also significantly improve the bradykinesia of AlCl3-induced zebrafish AD model, and has good in vivo and in vitro anti-AD activity, and can be used as an anti-AD candidate drug for further research and development, providing a basis for the research and development of new anti-AD drugs.

[0085] In order to further illustrate the present invention, a pyrrolopyridine heterocyclic compound and its preparation method and application, a derivative of the pyrrolopyridine heterocyclic compound and its application, a pharmaceutical composition and its application provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0086] Example 1

[0087] 3mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3.6mmol HATU and 6.0mmol DIPEA were added to 10mL DMF, and 3.3mmol 3-aminopyridine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 3h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed with water twice and saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column, eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1, and 0.49g of brown powder solid 5-bromo-N-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2a) was obtained, and the yield was 51.2%.

[0088] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2a are as follows: melting point is 303-305°C;

[0089] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),10.09(s,1H),8.91(d,J=2.5Hz,1H),8.63(d,J=2.3Hz,1H),8.51(d,J=2.9Hz,1 H),8.40(d,J=2.3Hz,1H),8.28(dd,J=4.7,1.5Hz,1H),8.18(ddd,J=8.4,2.5,1.5Hz,1H),7.38(dd,J=8.4,4.7Hz,1H);

[0090] HRMS(ESI):Calcd.for C 13 H9BrN4O[M+H] + :317.0032,found:317.0043.

[0091] 0.3 mmol of intermediate 2a, 0.36 mmol of phenylboronic acid, 0.015 mmol of catalyst Pd(PPh3)4 and 0.9 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and stirred for 6 h under a nitrogen atmosphere at 100°C. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a mixed solvent of dichloromethane and methanol in a volume ratio of 20:1 to obtain 88 mg of yellow-white powdery solid 5-phenyl-N-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL01, with a structure as shown in formula SL01), with a yield of 93.3%.

[0092] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL01 are as follows: melting point is 306-308°C;

[0093] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.07(s,1H),8.94(d,J=2.5Hz,1H),8.71(d,J=2.3Hz,1H),8.63(d,J=2.3Hz,1H),8.50(d ,J=2.9Hz,1H),8.28(dd,J=4.7,1.6Hz,1H),8.25-8.17(m,1H),7.73(d,J=7.7Hz,2H),7.51(t,J=7.7Hz,2H),7.44-7.33(m,2H);

[0094] HRMS(ESI):Calcd.for C 19 H 14 N4O[M+H] + :315.1240,found:315.1251.

[0095] Example 2

[0096] 3mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3.6mmol HATU and 6.0mmol DIPEA were added to 10mL DMF, and 3.3mmol 5-methylpyridin-3-amine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 3h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed with water twice and saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column, eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1, and 0.15g of yellow-white powder solid 5-bromo-N-(5-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2b) was obtained, and the yield was 15.1%.

[0097] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2b are as follows: melting point is 284-286°C;

[0098] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),10.01(s,1H),8.70(d,J=2.4Hz,1H),8.62(d,J=2.3Hz,1H ),8.50(d,J=3.0Hz,1H),8.40(d,J=2.3Hz,1H),8.13(d,J=2.4Hz,1H),8.03(s,1H),2.31(s,3H);

[0099] HRMS(ESI):Calcd.for C 14 H 11 BrN4O[M+H] + :331.0189,found:331.0196.

[0100] 0.3 mmol of intermediate 2b, 0.36 mmol of phenylboronic acid, 0.015 mmol of catalyst Pd(PPh3)4 and 0.9 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and stirred for 6 h under a nitrogen atmosphere at 100°C. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a mixed solvent of dichloromethane and methanol in a volume ratio of 16:1 to obtain 41 mg of yellow-white powdery solid N-(5-methylpyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL02, with a structure as shown in formula SL02), with a yield of 41.6%.

[0101] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL02 are as follows:

[0102] Melting point>330℃;

[0103] 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),10.02(s,1H),8.73(d,J=2.4Hz,1H),8.72(d,J=2.3Hz,1H),8.63(d,J=2.3Hz,1H),8.51(d ,J=3.0Hz,1H),8.13(d,J=2.4Hz,1H),8.09(s,1H),7.73(d,J=7.7Hz,2H),7.51(t,J=7.7Hz,2H),7.42-7.36(m,1H),2.31(s,3H);

[0104] HRMS(ESI):Calcd.for C 20 H 16 N4O[M+H] + :329.1397,found:329.1404.

[0105] Example 3

[0106] 3.3mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3.9mmol HATU and 6.0mmol DIPEA were added to 10mL DMF, and 3mmol 5-methoxypyridin-3-amine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 3h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed with water twice and saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column, eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1, and 0.38g of yellow-white powder solid 5-bromo-N-(5-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2c) was obtained, and the yield was 36.5%.

[0107] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2c are as follows: melting point is 258-260°C;

[0108] 1 HNMR(400MHz,DMSO-d6)δ12.61(s,1H),10.09(s,1H),8.63(d,J=2.4Hz,1H),8.55-8.5 1(m,2H),8.41(d,J=2.4Hz,1H),8.02(d,J=2.7Hz,1H),7.92-7.85(m,1H),3.85(s,3H);

[0109] HRMS(ESI):Calcd.for C 14 H 11 BrN4O2[M+H] + :347.0138,found:347.0147.

[0110] 0.3 mmol of intermediate 2c, 0.36 mmol of phenylboronic acid, 0.015 mmol of catalyst Pd(PPh3)4 and 0.9 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and stirred for 6 h under a nitrogen atmosphere at 100°C. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a mixed solvent of dichloromethane and methanol in a volume ratio of 16:1 to obtain 81 mg of yellow-white powdery solid N-(5-methoxypyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL03, with a structure as shown in formula SL03), with a yield of 78.4%.

[0111] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL03 are as follows:

[0112] Melting point 318~320℃;

[0113] 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),10.08(s,1H),8.72(d,J=2.3Hz,1H),8.64(d,J=2.3Hz,1H),8.56(d,J=2.0Hz,1H),8.51(d,J= 2.9Hz,1H),8.02(d,J=2.7Hz,1H),7.94(t,J=2.4Hz,1H),7.75-7.72(m,2H),7.51(t,J=7.7Hz,2H),7.44-7.36(m,1H),3.85(s,3H);

[0114] HRMS(ESI):Calcd.for C 20 H 16 N4O2[M+H] + :345.1346,found:345.1357.

[0115] Example 4

[0116] 3.3mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3.9mmol HATU and 6.0mmol DIPEA were added to 10mL DMF, and 3mmol 5-fluoropyridin-3-amine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 3h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed with water twice and saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. A dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 was used for elution to obtain 0.26g of yellow-white powdery solid 5-bromo-N-(5-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2d) with a yield of 25.9%.

[0117] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2d are as follows: melting point is 242-244°C;

[0118] 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),10.34(s,1H),8.72(s,1H),8.61(d,J=2.3Hz,1H) ,8.53(d,J=2.5Hz,1H),8.40(d,J=2.3Hz,1H),8.27(d,J=2.7Hz,1H),8.23-8.18(m,1H);

[0119] HRMS(ESI):Calcd.for C 13 H8BrFN4O[M+H] + :334.9938,found:334.9948.

[0120] 0.3 mmol of intermediate 2d, 0.36 mmol of phenylboronic acid, 0.015 mmol of catalyst Pd(PPh3)4 and 0.9 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and stirred for 6 h under a nitrogen atmosphere at 100°C. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a mixed solvent of dichloromethane and methanol in a volume ratio of 16:1 to obtain 42 mg of yellow-white powdery solid N-(5-fluoropyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL04, with a structure as shown in formula SL04), with a yield of 44.1%.

[0121] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL04 are as follows: melting point 311-313°C;

[0122] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),10.29(s,1H),8.75(s,1H),8.70(d,J=2.3Hz,1H),8.64(d,J=2.3Hz,1H ),8.51(d,J=2.8Hz,1H),8.29-8.22(m,2H),7.73(d,J=7.6Hz,2H),7.51(t,J=7.6Hz,2H),7.43-7.35(m,1H);

[0123] HRMS(ESI):Calcd.for C 19 H 13 FN4O[M+H] + :333.1146,found:333.1154.

[0124] Example 5

[0125] 3.3mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3.9mmol HATU and 6.0mmol DIPEA were added to 10mL DMF, and 3mmol 4-methylpyridin-3-amine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 3h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. A dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 was used for elution to obtain 0.29g of yellow-white powdery solid 5-bromo-N-(4-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2e) with a yield of 29.2%.

[0126] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2e are as follows: melting point, 290-292°C;

[0127] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),9.75(s,1H),8.58(d,J=2.3Hz,1H),8.51(s,1H),8.4 6(s,1H),8.39(d,J=2.3Hz,1H),8.30(d,J=4.9Hz,1H),7.31(d,J=4.9Hz,1H),2.27(s,3H);

[0128] HRMS(ESI):Calcd.for C 14 H 11 BrN4O[M+H] + :331.0189,found:331.0195.

[0129] 0.4 mmol of intermediate 2e, 0.48 mmol of phenylboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and stirred for 6 h under a nitrogen atmosphere at 100°C. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. A mixed solvent of dichloromethane and methanol with a volume ratio of dichloromethane to methanol of 16:1 was used for elution to obtain 60 mg of yellow-white powdery solid N-(4-methylpyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL05, with a structure as shown in formula SL05), with a yield of 45.7%.

[0130] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL05 are as follows: melting point 245-247°C;

[0131] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),9.72(s,1H),8.69(d,J=2.3Hz,1H),8.63(d,J=2.3Hz,1H),8.57(s,1H),8.46(d,J=2.8Hz, 1H),8.31(d,J=4.8Hz,1H),7.72(d,J=7.6Hz,2H),7.50(t,J=7.6Hz,2H),7.41-7.36(m,1H),7.32(d,J=4.8Hz,1H),2.31(s,3H);

[0132] HRMS(ESI):C 20 H 16 N4O[M+H] + :329.1397,found:329.1405.

[0133] Example 6

[0134] 3.3mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3.9mmol HATU and 6.0mmol DIPEA were added to 10mL DMF, and 3mmol 4-methoxypyridin-3-amine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 3h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed with water twice and saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column, eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1, and 0.49g of yellow-white powder solid 5-bromo-N-(4-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2f) was obtained, and the yield was 47.1%.

[0135] The melting point, H NMR spectrum, and high-resolution mass spectrometry data of intermediate 2f are as follows: melting point > 330 °C;

[0136] 1 H NMR (400MHz, DMSO-d6) δ12.57(s,1H),9.42(s,1H),8.69(s,1H),8.59(d,J=2.3Hz,1H),8.5 2(s,1H),8.40(d,J=2.3Hz,1H),8.32(d,J=5.6Hz,1H),7.16(d,J=5.6Hz,1H),3.91(s,3H);

[0137] HRMS(ESI):Calcd.for C 14 H 11 BrN4O2[M+H] + :347.0138,found:347.0148.

[0138] 0.4 mmol of intermediate 2f, 0.48 mmol of phenylboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and stirred for 6 h under a nitrogen atmosphere at 100°C. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. A mixed solvent of dichloromethane and methanol with a volume ratio of dichloromethane to methanol of 16:1 was used for elution to obtain 46 mg of white powdery solid N-(4-methoxypyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL06, with a structure as shown in formula SL06), with a yield of 33.4%.

[0139] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL06 are as follows: melting point is 148-150°C;

[0140] 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),9.35(s,1H),8.76(s,1H),8.67(d,J=2.2Hz,1H),8.62(d,J=2.2Hz,1H),8.50(s,1H), 8.31(d,J=5.7Hz,1H),7.72(d,J=7.6Hz,2H),7.51(t,J=7.6Hz,2H),7.43-7.34(m,1H),7.16(d,J=5.7Hz,1H),3.91(s,3H);

[0141] HRMS(ESI):Calcd.for C 20 H 16 N4O2[M+H] + :345.1346,found:345.1357.

[0142] Example 7

[0143] 6mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 8mmol HATU and 12mmol DIPEA were added to 18mL DMF, and 4mmol 4-(4-methylphenyl)pyridin-3-amine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 24h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed with water twice and a saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column, eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1, and 0.32g of white powder solid 5-bromo-N-(4-(4-methylphenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2g) was obtained, and the yield was 19.9%.

[0144] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2g are as follows: melting point is 272-274°C;

[0145] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),9.67(s,1H),8.66(s,1H),8.50(d,J=5.0Hz,1H),8.46(d,J=2. 3Hz,1H),8.38(d,J=2.3Hz,1H),8.28(s,1H),7.49-7.38(m,3H),7.24(d,J=7.9Hz,2H),2.30(s,3H);

[0146] HRMS(ESI):Calcd.for C 20 H 15 BrN4O[M+H] + :407.0502,found:407.0511.

[0147] 0.5 mmol of the intermediate 2 g, 0.75 mmol of phenylboric acid, 0.025 mmol of catalyst Pd(PPh3)4 and 1.5 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 108 mg of a white powdery solid 5-phenyl-N-(4-(4-tolyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL07, with a structure as shown in formula SL07) in a yield of 53.4%.

[0148] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL07 are as follows: melting point 278-280°C;

[0149] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),9.63(s,1H),8.72(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=2.3Hz,1H),8.50(d,J=5.0Hz, 1H),8.28(d,J=2.5Hz,1H),7.68(d,J=7.6Hz,2H),7.53-7.42(m,5H),7.38(t,J=7.4Hz,1H),7.22(d,J=7.4Hz,2H),2.25(s,3H);

[0150] HRMS(ESI):Calcd.for C 26 H 20 N4O[M+H] + :405.1710,found:405.1719.

[0151] Example 8

[0152] 3.3 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3.9 mmol HATU and 6.0 mmol DIPEA were added to 10 mL DMF, and 3 mmol 4-(4-methoxyphenyl)pyridin-3-amine was added, and the mixture was stirred at 20°C for 5 min, then the temperature was raised to 80°C and the reaction was stirred for 16 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 0.25 g of a yellow-white powdery solid 5-bromo-N-(4-(4-methoxyphenyl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2h) in a yield of 19.7%.

[0153] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2h are as follows: melting point 264-266°C;

[0154] 1 HNMR(400MHz,DMSO-d6)δ12.50(s,1H),9.68(s,1H),8.64(s,1H),8.50-8.48(m,2H),8.38(d,J=2.3Hz,1H ),8.29(d,J=3.0Hz,1H),7.50(d,J=8.8Hz,2H),7.44(d,J=5.0Hz,1H),7.00(d,J=8.8Hz,2H),3.75(s,3H);

[0155] HRMS(ESI):Calcd.for C 20 H 15 BrN4O2[M+H] + :423.0451,found:423.0457.

[0156] 0.25 mmol of intermediate 2h, 0.3 mmol of phenylboric acid, 0.013 mmol of catalyst Pd(PPh3)4 and 0.75 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 56 mg of yellow-white powdery solid N-(4-(4-methoxyphenyl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL08, with a structure as shown in formula SL08), with a yield of 53.3%.

[0157] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL08 are as follows: melting point is 270-272°C;

[0158] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),9.63(s,1H),8.68(s,1H),8.61(d,J=2.3Hz,1H),8.56(d,J=2.3Hz,1H),8.48(d,J=5.0Hz,1H),8.28( d,J=2.9Hz,1H),7.68(d,J=7.6Hz,2H),7.53-7.47(m,4H),7.43(d,J=5.0Hz,1H),7.38(t,J=7.6Hz,1H),6.98(d,J=8.4Hz,2H),3.71(s,3H);

[0159] HRMS(ESI):Calcd.for C 26 H 20 N4O2[M+H] + :421.1659,found:421.1667.

[0160] Example 9

[0161] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 7.5 mmol HATU and 9 mmol DIPEA were added to 18 mL DMF, and 3 mmol 4-(3-methoxyphenyl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the mixture was stirred for 24 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 87 mg of a yellow-white powdery solid 5-bromo-N-(4-(3-methoxyphenyl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2i) in a yield of 6.9%.

[0162] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2i are as follows: melting point 282-284°C;

[0163] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),9.71(s,1H),8.69(s,1H),8.53(d,J=5.1Hz,1H),8.47(d,J=2.4Hz,1H),8.38(d,J=2.4Hz,1H ),8.27(d,J=3.1Hz,1H),7.50(d,J=5.1Hz,1H),7.35(t,J=8.2Hz,1H),7.12-7.06(m,2H),6.95(dd,J=8.2,2.6Hz,1H),3.68(s,3H);

[0164] HRMS(ESI):Calcd.for C 20 H 15 BrN4O2[M+H] + :423.0451,found:423.0461.

[0165] 0.17 mmol of intermediate 2i, 0.2 mmol of phenylboronic acid, 0.009 mmol of catalyst Pd(PPh3)4 and 0.51 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100 °C under nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 40 mg of yellow-white powdery solid N-(4-(3-methoxyphenyl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL09, with a structure as shown in formula SL09), with a yield of 56%.

[0166] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL09 are as follows: melting point 258-260°C;

[0167] 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),9.66(s,1H),8.72(s,1H),8.61(d,J=2.3Hz,1H),8.56(d,J=2.3Hz,1H),8.53(d,J=5.0Hz,1H) ,8.26(d,J=3.0Hz,1H),7.71-7.65(m,2H),7.53-7.46(m,3H),7.42-7.31(m,2H),7.18-7.07(m,2H),6.98-6.89(m,1H),3.66(s,3H);

[0168] HRMS(ESI):Calcd.for C 26 H 20 N4O2[M+H] + :421.1659,found:421.1669.

[0169] Example 10

[0170] 2.1 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 2.5 mmol HATU and 3.8 mmol DIPEA were added to 10 mL DMF, and 1.9 mmol 4-(4-fluorophenyl)pyridin-3-amine was added, and the mixture was stirred at 20°C for 5 min, then the temperature was raised to 80°C and the reaction was stirred for 16 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 70 mg of a yellow-white powdery solid 5-bromo-N-(4-(4-fluorophenyl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2j) in a yield of 8.9%.

[0171] The high resolution mass spectrometry data of intermediate 2j are as follows: HRMS (ESI): Calcd.for C 19 H 12 BrFN4O[M+H] + :411.0251,found:411.0259.

[0172] 0.17 mmol of intermediate 2j, 0.2 mmol of phenylboronic acid, 0.009 mmol of catalyst Pd(PPh3)4 and 0.51 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 29 mg of yellow-white powdery solid N-(4-(4-fluorophenyl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL10, with a structure as shown in formula SL10), with a yield of 41.8%.

[0173] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL10 are as follows: melting point 250-252°C;

[0174] 1H NMR (400MHz, DMSO-d6) δ12.36(s,1H),9.68(s,1H),8.72(s,1H),8.60(d,J=2.3Hz,1H),8.54(d,J=2.3Hz,1H),8.52(d,J=5.0Hz ,1H),8.26(d,J=3.0Hz,1H),7.73-7.65(m,2H),7.63-7.56(m,2H),7.53-7.43(m,3H),7.41-7.35(m,1H),7.27(t,J=8.9Hz,2H);

[0175] HRMS(ESI):Calcd.for C 25 H 17 FN4O[M+H] + :409.1459,found:409.1469.

[0176] Embodiment 11

[0177] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 7.5 mmol HATU and 9 mmol DIPEA were added to 18 mL DMF, and 3 mmol 4-(2-fluorophenyl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the mixture was stirred for 12 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 95 mg of a yellow-white powdery solid 5-bromo-N-(4-(2-fluorophenyl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2k) in a yield of 7.7%.

[0178] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2k are as follows: melting point is 236-238°C;

[0179] 1 HNMR (400MHz, DMSO-d6) δ12.47(s,1H),9.69(s,1H),8.77(s,1H),8.58-8.31(m,3H),8.21(s,1H),7.52-7.14(m,5H);

[0180] HRMS(ESI):Calcd.for C 19 H 12 BrFN4O[M+H]+ :411.0251,found:411.0262.

[0181] 0.17 mmol of intermediate 2k, 0.2 mmol of phenylboronic acid, 0.009 mmol of catalyst Pd(PPh3)4 and 0.51 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 51 mg of yellow-white powdery solid N-(4-(2-fluorophenyl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL11, with a structure as shown in formula SL11), and the yield was 73.5%.

[0182] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL11 are as follows: melting point 248-250°C;

[0183] 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),9.64(s,1H),8.80(s,1H),8.59(d,J=2.3Hz,1H),8.52(d,J=5.1Hz,1H),8.49(d,J=2.3Hz,1H) ,8.19(d,J=3.0Hz,1H),8.04(s,1H),7.84-7.78(m,1H),7.69-7.66(m,2H),7.52-7.44(m,3H),7.41-7.38(m,2H),7.28-7.23(m,1H);

[0184] HRMS(ESI):Calcd.for C 25 H 17 FN4O[M+H] + :409.1459,found:409.1468.

[0185] Example 12

[0186] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 6 mmol HATU and 9 mmol DIPEA were added to 18 mL DMF, and 3 mmol 4-(3-fluorophenyl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the mixture was stirred for 24 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 0.218 g of a white powdery solid 5-bromo-N-(4-(3-fluorophenyl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2l) with a yield of 17.7%.

[0187] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2l are as follows: melting point 282-284°C;

[0188] 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),9.78(s,1H),8.70(d,J=2.6Hz,1H),8.55(d,J=5.0Hz,1H), 8.45(d,J=2.3Hz,1H),8.38(d,J=2.3Hz,1H),8.28(s,1H),7.52-7.31(m,4H),7.28-7.15(m,1H);

[0189] HRMS(ESI):Calcd.for C 19 H 12 BrFN4O[M+H] + :411.0251,found:411.0262.

[0190] 0.4 mmol of intermediate 2l, 0.48 mmol of phenylboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 120 mg of a yellow-white powdery solid N-(4-(3-fluorophenyl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL12, with a structure as shown in formula SL12), with a yield of 73.5%.

[0191] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL12 are as follows: melting point 236-238°C;

[0192] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),9.74(s,1H),8.74(s,1H),8.61(d,J=2.2Hz,1H),8.56- 8.51(m,2H),8.27(d,J=2.9Hz,1H),7.70-7.65(m,2H),7.54-7.33(m,7H),7.24-7.14(m,1H);

[0193] HRMS(ESI):Calcd.for C 25 H 17 FN4O[M+H] + :409.1459,found:409.1467.

[0194] Example 13

[0195] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 6 mmol HATU and 9 mmol DIPEA were added to 18 mL DMF, and 3 mmol 4-(2,4-difluorophenyl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the mixture was stirred for 24 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 0.112 g of a white powdery solid 5-bromo-N-(4-(2,4-difluorophenyl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2m) in a yield of 8.7%.

[0196] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2m are as follows: melting point is 206-208°C;

[0197] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),9.71(s,1H),8.77(s,1H),8.52(d,J=5.0Hz,1H),8.43- 8.34(m,2H),8.22(d,J=3.0Hz,1H),7.55-7.42(m,2H),7.39-7.32(m,1H),7.20-7.14(m,1H);

[0198] HRMS(ESI):Calcd.for C 19 H 11 BrF2N4O[M+H] + :429.0157,found:429.0168.

[0199] 0.19 mmol of intermediate 2m, 0.22 mmol of phenylboric acid, 0.009 mmol of catalyst Pd(PPh3)4 and 0.56 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 27:1 to obtain 46 mg of yellow-white powdery solid N-(4-(2,4-difluorophenyl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL13, with a structure as shown in formula SL13), with a yield of 56.8%.

[0200] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL13 are as follows: melting point 212-214°C;

[0201] 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),9.66(s,1H),8.80(s,1H),8.60(d,J=2.3Hz,1H),8.52(d,J=5.0Hz,1H),8.49(d,J=2.3Hz,1H ),8.20(d,J=3.0Hz,1H),7.68(d,J=7.6Hz,2H),7.50(t,J=7.6Hz,3H),7.45(d,J=5.0Hz,1H),7.41-7.31(m,2H),7.17-7.13(m,1H);

[0202] HRMS(ESI):Calcd.for C 25 H 16 F2N4O[M+H] + :427.1365,found:427.1374.

[0203] Embodiment 14

[0204] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 7.5 mmol HATU and 9 mmol DIPEA were added to 18 mL DMF, and 3 mmol 4-(4-(trifluoromethyl)phenyl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the reaction was stirred for 24 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 0.15 g of a white powdery solid 5-bromo-N-(4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2n) in a yield of 10.8%.

[0205] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2n are as follows: melting point is 298-300°C;

[0206] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),9.82(s,1H),8.73(s,1H),8.57(d,J=5.1Hz,1H),8.43(d,J=2.3Hz,1H),8 .37(d,J=2.3Hz,1H),8.26(d,J=3.1Hz,1H),7.81(d,J=8.0Hz,2H),7.74(d,J=8.0Hz,2H),7.51(d,J=5.1Hz,1H);

[0207] HRMS(ESI):Calcd.for C 20 H 12 BrF3N4O[M+H] + :461.0219,found:461.0232.

[0208] 0.26 mmol of intermediate 2n, 0.31 mmol of phenylboronic acid, 0.013 mmol of catalyst Pd(PPh3)4 and 0.78 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 27:1 to obtain 45 mg of a white powdery solid 5-phenyl-N-(4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL14, with a structure as shown in formula SL14) in a yield of 37.8%.

[0209] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL14 are as follows: melting point 292-294°C;

[0210] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),9.80(s,1H),8.77(s,1H),8.61(d,J=2.2Hz,1H),8.58(d,J=5.0Hz,1H),8.54(d,J=2.2Hz,1H), 8.27(d,J=2.7Hz,1H),7.82(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H),7.69(d,J=7.2Hz,2H),7.55-7.47(m,3H),7.39(t,J=7.2Hz,1H);

[0211] HRMS(ESI):Calcd.for C 26 H 17 F3N4O[M+H] + :459.1427,found:459.1440.

[0212] Embodiment 15

[0213] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 7.5 mmol HATU and 9 mmol DIPEA were added to 18 mL DMF, and 3 mmol 4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the reaction was stirred for 24 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 0.321 g of a white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2o) in a yield of 24.5%.

[0214] The melting point, H NMR spectrum, and high-resolution mass spectrometry data of intermediate 2o are as follows: melting point is 306-308°C;

[0215] 1 HNMR(400MHz,DMSO-d6)δ12.52(s,1H),9.68(s,1H),8.66(s,1H),8.51-8.45(m,2H),8.39(d,J=2.3Hz,1 H),8.30(d,J=3.0Hz,1H),7.43(d,J=5.0Hz,1H),7.11(d,J=1.8Hz,1H),7.05-6.95(m,2H),6.03(s,2H);

[0216] HRMS(ESI):Calcd.for C 20 H 13 BrN4O3[M+H] + :437.0244,found:437.0253.

[0217] 0.4 mmol of intermediate 2o, 0.48 mmol of phenylboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 130 mg of a yellow-white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL15, with a structure as shown in formula SL15), with a yield of 74.8%.

[0218] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL15 are as follows: melting point 272-274°C;

[0219] 1 H NMR (400MHz, DMSO-d6) δ12.37(s,1H),9.63(s,1H),8.70(s,1H),8.61(d,J=2. 3Hz,1H),8.57(d,J=2.3Hz,1H),8.48(d,J=5.1Hz,1H),8.29(s,1H),7.69(d,J= 7.6Hz,2H),7.49(t,J=7.6Hz,2H),7.43(d,J=5.1Hz,1H),7.38(t,J=7.6Hz,1H) ,7.14(s,1H),7.05(dd,J=8.1,1.8Hz,1H),6.97(d,J=8.1Hz,1H),5.98(s,2H);

[0220] HRMS(ESI):Calcd.for C 26 H 18 N4O3[M+H] + :435.1452,found:435.1463.

[0221] Example 16

[0222] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 8 mmol HATU and 12 mmol DIPEA were added to 18 mL DMF, and 4 mmol 4-(thiophen-3-yl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the reaction was stirred for 24 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 and 25:1, respectively, to obtain 0.243 g of off-white powdery solid 5-bromo-N-(4-(thiophen-3-yl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2p) in a yield of 15.2%.

[0223] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2p are as follows: melting point 298-300°C;

[0224] 1 H NMR (400MHz, DMSO-d6) δ12.55(s,1H),9.82(s,1H),8.65(s,1H),8.54(d,J=2.3Hz,1H),8.48(d,J=5.1Hz,1H),8.39(d,J= 2.3Hz,2H),7.94(dd,J=2.9,1.4Hz,1H),7.63(dd,J=5.0,2.9Hz,1H),7.60(d,J=5.1Hz,1H),7.46(dd,J=5.0,1.4Hz,1H);

[0225] HRMS(ESI):Calcd.for C 17 H 11 BrN4OS[M+H] + :398.9910,found:398.9919.

[0226] 0.5 mmol of intermediate 2p, 0.75 mmol of phenylboronic acid, 0.025 mmol of catalyst Pd(PPh3)4 and 1.5 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 27:1 to obtain 96 mg of white powdery solid 5-phenyl-N-(4-(thiophene-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL16, with a structure as shown in formula SL16) in a yield of 48.4%.

[0227] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL16 are as follows: melting point 252-254°C;

[0228] 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),9.78(s,1H),8.69(s,1H),8.62(s,2H),8.49(d,J=5.1Hz,1H),8.38(d,J=2.5Hz,1H),7.96(dd,J =3.0,1.3Hz,1H),7.70(d,J=7.3Hz,2H),7.63(dd,J=5.1,3.0Hz,1H),7.60(d,J=5.1Hz,1H),7.53-7.44(m,3H),7.38(t,J=7.3Hz,1H);

[0229] HRMS(ESI):Calcd.for C 23 H 16 N4OS[M+H] + :397.1118,found:397.1127.

[0230] Embodiment 17

[0231] 3.6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 4.8 mmol HATU and 7.2 mmol DIPEA were added to 12 mL DMF, and 2.4 mmol [4,4'-bipyridine]-3-amine was added, and the mixture was stirred at 20°C for 5 min, then the temperature was raised to 80°C and stirred for 24 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 40:1 and 13:1, respectively, to obtain 0.1 g of a brown powdery solid N-([4,4'-bipyridine]-3-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2q) in a yield of 10.6%.

[0232] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2q are as follows: melting point, 316-318°C;

[0233] 1 HNMR(400MHz,DMSO-d6)δ12.53(s,1H),9.89(s,1H),8.72(s,1H),8.63-8.60(m,2H),8.58(d ,J=5.0Hz,1H),8.44(d,J=2.3Hz,1H),8.38(d,J=2.3Hz,1H),8.29(s,1H),7.57-7.49(m,3H);

[0234] HRMS(ESI):Calcd.for C 18 H 12 BrN5O[M+H] + :394.0298,found:394.0308.

[0235] 0.2 mmol of intermediate 2q, 0.3 mmol of phenylboronic acid, 0.01 mmol of catalyst Pd(PPh3)4 and 0.6 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and stirred for 6 h under a nitrogen atmosphere at 100°C. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column, eluted with a mixed solvent of dichloromethane-methanol with a volume ratio of dichloromethane to methanol of 10:1, and 52 mg of white powdery solid N-([4,4'-bipyridine]-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL17, with a structure as shown in formula SL17) was obtained, with a yield of 66.4%.

[0236] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL17 are as follows: melting point 188-190°C;

[0237] 1 HNMR (400MHz, DMSO-d6) δ12.33(s,1H),9.79(s,1H),8.69(s,1H),8.57-8.50(m,4H),8.46(d,J=2.3Hz,1H),8.22(d,J=2.8 Hz,1H),7.61(d,J=7.6Hz,2H),7.49(d,J=6.1Hz,2H),7.46(d,J=5.1Hz,1H),7.42(t,J=7.6Hz,2H),7.31(t,J=7.6Hz,1H);

[0238] HRMS(ESI):Calcd.for C 24 H 17 N5O[M+H] + :392.1506,found:392.1510.

[0239] Embodiment 18

[0240] 3.6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 4.8 mmol HATU and 7.2 mmol DIPEA were added to 12 mL DMF, and 2.4 mmol [3,4'-bipyridine]-3'-amine was added, and the mixture was stirred at 20°C for 5 min, then the temperature was raised to 80°C and the reaction was stirred for 24 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then eluted with a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 40:1 and 13:1, respectively, to obtain 80 mg of a brown powdery solid N-([3,4'-bipyridine]-3'-yl)-5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2r) in a yield of 8.5%.

[0241] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2r are as follows: melting point, 164-166°C;

[0242] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),9.86(s,1H),8.72(d,J=2.3Hz,1H),8.70(s,1H),8.57(d,J=5.0Hz,1H),8.55(dd,J=4.9,2.0Hz, 1H),8.44(d,J=2.3Hz,1H),8.37(d,J=2.0Hz,1H),8.27(s,1H),7.93(dt,J=8.0,2.0Hz,1H),7.54(d,J=5.0Hz,1H),7.47-7.43(m,1H);

[0243] HRMS(ESI):Calcd.for C 18 H 12 BrN5O[M+H] + :394.0298,found:394.0306.

[0244] 0.29 mmol of intermediate 2r, 0.44 mmol of phenylboronic acid, 0.015 mmol of catalyst Pd(PPh3)4 and 0.88 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 10:1 to obtain 76 mg of white powdery solid N-([3,4'-bipyridine]-3'-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL18, with a structure as shown in formula SL18), with a yield of 67%.

[0245] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL18 are as follows: melting point 180-182°C;

[0246] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),9.84(s,1H),8.75(s,2H),8.60(d,J=2.3Hz,1H),8.57(d,J=5.0Hz,1H),8.55-8.51(m,2H),8 .27(d,J=2.8Hz,1H),7.96(d,J=7.9Hz,1H),7.68(d,J=7.4Hz,2H),7.54(d,J=5.0Hz,1H),7.52-7.41(m,3H),7.38(t,J=7.4Hz,1H);

[0247] HRMS(ESI):Calcd.for C 24 H 17 N5O[M+H] + :392.1506,found:392.1512.

[0248] Embodiment 19

[0249] 8 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 8 mmol HATU and 16 mmol DIPEA were added to 24 mL DMF, and 4 mmol 4-(pyrrolidin-1-yl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the reaction was stirred for 24 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then subjected to silica gel column chromatography. Elution was performed using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 50:1 to obtain 336 mg of white powdery solid 5-bromo-N-(4-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2s) in a yield of 21.8%.

[0250] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2s are as follows: melting point 312-314°C;

[0251] 1 H NMR (400MHz, DMSO-d6) δ12.53 (s, 1H), 9.62 (s, 1H), 8.59 (d, J = 2.3Hz, 1H), 8.40-8.35 (m, 2H),8.03(d,J=5.8Hz,1H),7.95(s,1H),6.59(d,J=5.8Hz,1H),3.39(s,4H),1.81(s,4H);

[0252] HRMS(ESI):Calcd.for C 17 H 16 BrN5O[M+H] + :386.0611,found:386.0614.

[0253] 0.39 mmol of intermediate 2s, 0.58 mmol of phenylboronic acid, 0.019 mmol of catalyst Pd(PPh3)4 and 1.17 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 13:1 to obtain 75 mg of a white powdery solid 5-phenyl-N-(4-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL19, with a structure as shown in formula SL19) in a yield of 50.2%.

[0254] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL19 are as follows: melting point 275-277°C;

[0255] 1 H NMR (400MHz, DMSO-d6) δ9.59(s,1H),8.69(d,J=2.3Hz,1H),8.61(d,J=2.3Hz,1H),8.37(s,1H),8.04(d,J=5.8Hz,1H),7.98(s,1H) ,7.70(d,J=7.7Hz,2H),7.49(t,J=7.7Hz,2H),7.37(t,J=7.7Hz,1H),6.58(d,J=5.8Hz,1H),3.49-3.36(m,4H),1.88-1.65(m,4H);

[0256] HRMS(ESI):Calcd.for C 23 H 21 N5O[M+H] + :384.1819,found:384.1829.

[0257] Embodiment 20

[0258] 2.2mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 3mmol HATU and 4mmol DIPEA were added to 10mL DMF, and 2mmol 4-morpholinylpyridin-3-amine was added, and the mixture was stirred at 20°C for 5min, and then the temperature was raised to 80°C and stirred for 3h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, which was washed with water twice and with a saturated sodium chloride solution once, dried with anhydrous sodium sulfate for 1h, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. A dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 was used for elution to obtain 76mg of white powdery solid 5-bromo-N-(4-morpholinylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (intermediate 2t) with a yield of 9.5%.

[0259] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2t are as follows: melting point 256-258°C;

[0260] 1 H NMR (400MHz, DMSO-d6) δ12.56(s,1H),9.40(s,1H),8.62(d,J=2.3Hz,1H),8.50(s,2H),8.40(d,J =2.3Hz,1H),8.24(d,J=5.5Hz,1H),7.02(d,J=5.5Hz,1H),3.71-3.69(m,4H),3.09-3.06(m,4H);

[0261] HRMS(ESI):Calcd.for C 17 H 16 BrN5O2[M+H] + :402.0560,found:402.0562.

[0262] 0.15 mmol of intermediate 2t, 0.18 mmol of phenylboronic acid, 0.0075 mmol of catalyst Pd(PPh3)4 and 0.45 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 26 mg of white powdery solid N-(4-morpholinylpyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL20, with a structure as shown in formula SL20), with a yield of 43.4%.

[0263] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL20 are as follows: melting point 240-242°C;

[0264] 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),9.36(s,1H),8.70(d,J=2.3Hz,1H),8.62(d,J=2.3Hz,1H),8.55(s,1H),8.49(d,J=2.9Hz,1H),8.25(d,J= 5.5Hz,1H),7.72(d,J=7.7Hz,2H),7.51(t,J=7.7Hz,2H),7.39(t,J=7.7Hz,1H),7.03(d,J=5.5Hz,1H),3.72-3.67(m,4H),3.09(t,J=4.6Hz,4H);

[0265] HRMS(ESI):Calcd.for C 23 H 21 N5O2[M+H] + :400.1768,found:400.1773.

[0266] Embodiment 21

[0267] 8 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 8 mmol HATU and 16 mmol DIPEA were added to 24 mL DMF, and then 4 mmol 4-(4-methylpiperazin-1-yl)pyridin-3-amine was added. The mixture was stirred at 20° C. for 5 min, and then the temperature was raised to 80° C. and the reaction was stirred for 24 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 10:1 to obtain 156 mg of white powdery solid 5-bromo-N-(4-(4-methylpiperazine-1-yl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2u) in a yield of 9.4%.

[0268] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2u are as follows: melting point is 290-292°C;

[0269] 1 H NMR (400MHz, DMSO-d6) δ12.57(s,1H),9.33(s,1H),8.62(d,J=2.3Hz,1H),8.49(s,2H),8.40(d,J=2.3Hz,1 H),8.22(d,J=5.5Hz,1H),7.01(d,J=5.5Hz,1H),3.08(t,J=4.8Hz,4H),2.43(t,J=4.8Hz,4H),2.18(s,3H);

[0270] HRMS(ESI):Calcd.for C 18 H 19 BrN6O[M+H] + :415.0876,found:415.0887.

[0271] 0.29 mmol of intermediate 2u, 0.43 mmol of phenylboronic acid, 0.014 mmol of catalyst Pd(PPh3)4 and 0.87 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 13:1 and 10:1, respectively, to obtain 42 mg of white powdery solid N-(4-(4-methylpiperazine-1-yl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL21, with a structure as shown in formula SL21), with a yield of 35.1%.

[0272] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL21 are as follows: melting point 258-260°C;

[0273] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),9.28(s,1H),8.70(d,J=2.3Hz,1H),8.62(d,J=2.3Hz,1H),8.57(s,1H),8.48(s,1H),8.22(d,J=5.5Hz,1H),7 .73(d,J=7.6Hz,2H),7.50(t,J=7.6Hz,2H),7.39(t,J=7.6Hz,1H),7.02(d ,J=5.5Hz,1H),3.08(t,J=4.8Hz,4H),2.42(t,J=4.8Hz,4H),2.12(s,3H);

[0274] HRMS(ESI):Calcd.for C 24 H 24 N6O[M+H] + :413.2084,found:413.2096.

[0275] Embodiment 22

[0276] 6 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 7.5 mmol HATU and 9 mmol DIPEA were added to 18 mL DMF, and 3 mmol 4-(4,4-difluoropiperidin-1-yl)pyridin-3-amine was added, and the mixture was stirred at 20° C. for 5 min, then the temperature was raised to 80° C. and the reaction was stirred for 6 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then subjected to silica gel column chromatography. Elution was performed using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 27:1 to obtain 325 mg of a brown powdery solid 5-bromo-N-(4-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2v) in a yield of 24.8%.

[0277] The melting point, H NMR spectrum, and high-resolution mass spectrum data of intermediate 2v are as follows: melting point is 248-250°C;

[0278] 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),9.62(s,1H),8.61(d,J=2.4Hz,1H),8.58(s,1H),8.53(d,J=3.0Hz,1H ),8.41(d,J=2.4Hz,1H),8.30(d,J=6.2Hz,1H),7.23(d,J=6.2Hz,1H),3.49-3.37(m,4H),2.17-2.08(m,4H);

[0279] HRMS(ESI):Calcd.for C 18 H 16 BrF2N5O[M+H] + :436.0579,found:436.0590.

[0280] 0.64 mmol of intermediate 2v, 0.77 mmol of phenylboric acid, 0.03 mmol of catalyst Pd(PPh3)4 and 1.93 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 75 mg of white powdery solid N-(4-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL22, with a structure as shown in formula SL22) in a yield of 27%.

[0281] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL22 are as follows: melting point 272-274°C;

[0282] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),9.32(s,1H),8.72(d,J=2.3Hz,1H),8.66-8.60(m,2H),8.56(d,J=2.7Hz,1H),8.24(d,J=5.5Hz,1 H),7.72(d,J=7.6Hz,2H),7.50(t,J=7.6Hz,2H),7.39(t,J=7.6Hz,1H),7.08(d,J=5.5Hz,1H),3.21(t,J=5.5Hz,4H),2.13-2.06(m,4H);

[0283] HRMS(ESI):Calcd.for C 24 H 21 F2N5O[M+H] + :434.1787,found:434.1795.

[0284] Embodiment 23

[0285] 5 mmol 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, 5 mmol HATU and 10 mmol DIPEA were added to 15 mL DMF, and then 2.5 mmol 4-(azepan-1-yl)pyridin-3-amine was added. The mixture was stirred at 20° C. for 5 min, and then the temperature was raised to 80° C. and the reaction was stirred for 24 h. After the reaction was completed, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate for 1 hour, filtered, concentrated under reduced pressure at 35°C, and then subjected to silica gel column chromatography. Elution was performed using a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 13:1 to obtain 274 mg of yellow-white powdery solid N-(4-(azepan-1-yl)pyridin-3-yl)-5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxamide (intermediate 2w) in a yield of 26.5%.

[0286] The melting point, H NMR spectrum and high-resolution mass spectrum data of intermediate 2w are as follows: melting point is 248-250°C;

[0287] 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),9.59(s,1H),8.60(d,J=2.3Hz,1H),8.41(s,1H),8.39(d,J=2.3Hz,1H),8. 05(d,J=5.9Hz,1H),8.01(s,1H),6.80(d,J=5.9Hz,1H),3.53-3.34(m,4H),1.75-1.61(m,4H),1.55-1.35(m,4H);

[0288] HRMS(ESI):Calcd.for C 19 H 20 BrN5O[M+H] + :414.0924,found:414.0924.

[0289] 0.36 mmol of intermediate 2w, 0.54 mmol of phenylboric acid, 0.018 mmol of catalyst Pd(PPh3)4 and 1.09 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 13:1 to obtain 95 mg of yellow-white powdery solid N-(4-(azacycloheptane-1-yl)pyridin-3-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL23, with a structure as shown in formula SL23), with a yield of 64.1%.

[0290] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL23 are as follows: melting point 188-190°C;

[0291] 1 H NMR (400MHz, DMSO-d6) δ12.37(s,1H),9.54(s,1H),8.68(d,J=2.3Hz,1H),8.61(d,J=2.3Hz,1H),8.39(s,1H),8.10-8.00(m,2H),7.70(d,J= 7.6Hz,2H),7.49(t,J=7.6Hz,2H),7.37(t,J=7.6Hz,1H),6.79(d,J=6.0Hz,1H),3.45(t,J=5.9Hz,4H),1.78-1.60(m,4H),1.53-1.37(m,4H);

[0292] HRMS(ESI):Calcd.for C 25 H 25 N5O[M+H] + :412.2132,found:412.2141.

[0293] Embodiment 24

[0294] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of p-hydroxyphenylboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 to obtain 105 mg of yellow-white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL24, with a structure as shown in formula SL24), with a yield of 58.3%.

[0295] The melting point, H NMR spectrum, and high-resolution mass spectrometry data of SL24 are as follows: melting point > 330°C;

[0296] 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),9.58(s,2H),8.68(s,1H),8.52(d,J= 2.3Hz,1H),8.48(d,J=5.1Hz,1H),8.46(d,J=2.3Hz,1H),8.24(s,1H),7.49 (d,J=8.6Hz,2H),7.43(d,J=5.1Hz,1H),7.13(d,J=1.8Hz,1H),7.05(dd,J= 8.1,1.8Hz,1H),6.97(d,J=8.1Hz,1H),6.88(d,J=8.6Hz,2H),5.99(s,2H);

[0297] HRMS(ESI):Calcd.for C 26 H 18 N4O4[M+H] + :451.1401,found:451.1396.

[0298] Embodiment 25

[0299] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of p-methoxyphenylboric acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 to obtain 93 mg of white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL25, with a structure as shown in formula SL25), with a yield of 50.1%.

[0300] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL25 are as follows: melting point 285-287°C;

[0301] 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),9.60(s,1H),8.69(s,1H),8.56(d,J= 2.2Hz,1H),8.50(d,J=2.2Hz,1H),8.48(d,J=5.0Hz,1H),8.26(d,J=2.9Hz, 1H),7.61(d,J=8.8Hz,2H),7.43(d,J=5.0Hz,1H),7.13(d,J=1.7Hz,1H),7. 05(dd,J=8.3,1.7Hz,3H),6.97(d,J=8.3Hz,1H),5.98(s,2H),3.80(s,3H);

[0302] HRMS(ESI):Calcd.for C 27 H 20 N4O4[M+H] + :465.1557,found:465.1561.

[0303] Embodiment 26

[0304] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of p-fluorophenylboric acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 to obtain 96 mg of white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL26, with a structure as shown in formula SL26), with a yield of 53%.

[0305] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL26 are as follows: melting point 310-312°C;

[0306] 1 H NMR (400MHz, DMSO-d6) δ12.37(s,1H),9.62(s,1H),8.69(s,1H),8.58(d,J= 2.3Hz,1H),8.53(d,J=2.3Hz,1H),8.48(d,J=5.1Hz,1H),8.28(d,J=2.9Hz,1 H),7.75-7.66(m,2H),7.43(d,J=5.1Hz,1H),7.35-7.27(m,2H),7.13(d,J= 1.8Hz,1H),7.05(dd,J=8.1,1.8Hz,1H),6.97(d,J=8.1Hz,1H),5.98(s,2H);

[0307] HRMS(ESI):Calcd.for C 26 H 17 FN4O3[M+H] + :453.1357,found:453.1366.

[0308] Embodiment 27

[0309] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of 2-furanboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 to obtain 105 mg of yellow-white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(furan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL27, with a structure as shown in formula SL27), with a yield of 52.5%.

[0310] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL27 are as follows: melting point 298-300°C;

[0311] 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),9.65(s,1H),8.73(d,J=2.2Hz,1H),8.68(s,1H),8.64(d,J=2.2Hz,1H),8.48(d,J=5.1Hz,1H),8.27(s,1H),7 .77(d,J=1.8Hz,1H),7.43(d,J=5.1Hz,1H),7.13(s,1H),7.05(dd,J=8.1 ,1.8Hz,1H),7.00-6.94(m,2H),6.61(dd,J=3.4,1.8Hz,1H),6.01(s,2H);

[0312] HRMS(ESI):Calcd.for C 24 H 16 N4O4[M+H] + :425.1244,found:425.1250.

[0313] Embodiment 28

[0314] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of 3-thiopheneboric acid, 0.025 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 20:1 to obtain 86 mg of white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(thiophene-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL28, with a structure as shown in formula SL28), with a yield of 41.6%.

[0315] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL28 are as follows: melting point 306-308°C;

[0316] 1 H NMR(400MHz,DMSO-d6)δ12.33(s,1H),9.60(s,1H),8.70(d,J=2.2Hz,1H),8.68(s,1H), 8.59(d,J=2.2Hz,1H),8.48(d,J=5.0Hz,1H),8.25(d,J=2.9Hz,1H),7.88(dd,J=2.9,1.4 Hz,1H),7.68(dd,J=5.0,2.9Hz,1H),7.57(dd,J=5.0,1.4Hz,1H),7.43(d,J=5.0Hz,1H) ,7.14(d,J=1.8Hz,1H),7.05(dd,J=8.1,1.8Hz,1H),6.97(d,J=8.1Hz,1H),5.99(s,2H);

[0317] HRMS(ESI):Calcd.for C 24 H 16 N4O3S[M+H] + :441.1016,found:441.1022.

[0318] Embodiment 29

[0319] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of 4-pyridineboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent having a volume ratio of dichloromethane to methanol of 13:1 to obtain 45 mg of a yellow-white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL29, with a structure as shown in formula SL29), with a yield of 25.8%.

[0320] The melting point, H NMR spectrum, and high-resolution mass spectrum data of SL29 are as follows: melting point 317-319°C;

[0321] 1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),9.67(s,1H),8.75(d,J=2.3Hz,1H),8 .69(s,1H),8.68(d,J=2.3Hz,1H),8.64(d,J=6.2Hz,2H),8.49(d,J=5.1Hz, 1H),8.32(s,1H),7.75(d,J=6.2Hz,2H),7.43(d,J=5.1Hz,1H),7.14(d,J=1 .8Hz,1H),7.05(dd,J=8.1,1.8Hz,1H),6.97(d,J=8.1Hz,1H),5.97(s,2H);

[0322] HRMS(ESI):Calcd.for C 25 H 17 N5O3[M+H] + :436.1404,found:436.1407.

[0323] Embodiment 30

[0324] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of 3-pyridineboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 13:1 to obtain 113 mg of yellow-white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL30, with a structure as shown in formula SL30), with a yield of 64.9%.

[0325] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL30 are as follows: melting point 296-298°C;

[0326] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),9.64(s,1H),8.92(d,J=2.3Hz,1H),8.69(s,1H), 8.66(d,J=2.3Hz,1H),8.59(dd,J=4.8,1.8Hz,2H),8.48(d,J=5.1Hz,1H),8.31(d,J=2.6 Hz,1H),8.11(dt,J=8.0,1.8Hz,1H),7.51(dd,J=8.0,4.8Hz,1H),7.43(d,J=5.1Hz,1H) ,7.14(d,J=1.8Hz,1H),7.05(dd,J=8.0,1.8Hz,1H),6.96(d,J=8.0Hz,1H),5.98(s,2H);

[0327] HRMS(ESI):Calcd.for C 25 H 17 N5O3[M+H] + :436.1404,found:436.1410.

[0328] Embodiment 31

[0329] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of 1-naphthylboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 to obtain 106 mg of yellow-white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(naphthalene-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL31, with a structure as shown in formula SL31), with a yield of 47.3%.

[0330] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL31 are as follows: melting point 306-308°C;

[0331] 1 HNMR(400MHz,DMSO-d6)δ12.46(s,1H),9.64(s,1H),8.66(s,1H),8.47-8.44(m,2H),8. 40(d,J=2.2Hz,1H),8.35(d,J=3.0Hz,1H),8.05-7.94(m,2H),7.79(d,J=8.2Hz,1H),7. 61(dd,J=8.2,7.0Hz,1H),7.57-7.54(m,1H),7.52-7.45(m,2H),7.40(d,J=5.1Hz,1H), 7.12(d,J=1.8Hz,1H),7.03(dd,J=8.1,1.8Hz,1H),6.94(d,J=8.1Hz,1H),5.99(s,2H);

[0332] HRMS(ESI):Calcd.for C 30 H 20 N4O3[M+H] + :485.1608,found:485.1619.

[0333] Embodiment 32

[0334] 0.4 mmol of the intermediate 2o prepared in Example 15, 0.48 mmol of 2-naphthylboronic acid, 0.02 mmol of catalyst Pd(PPh3)4 and 1.2 mmol of K2CO3 were added to a mixed solvent of 12 mL of 1,4-dioxane and 2 mL of water, and the reaction was stirred at 100°C under a nitrogen atmosphere for 6 h. After the reaction, ethyl acetate was added to the obtained reaction system to obtain a mixed solution, and the mixed solution was washed twice with water and once with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 35°C, and then chromatographed on a silica gel column. The mixture was eluted with a dichloromethane-methanol mixed solvent with a volume ratio of dichloromethane to methanol of 20:1 to obtain 80 mg of white powdery solid N-(4-(benzo[d][1,3]dioxol-5-yl)pyridin-3-yl)-5-(naphthalene-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (pyrrolopyridine heterocyclic compound, denoted as SL32, with a structure as shown in formula SL32) in a yield of 35.7%.

[0335] The melting point, H NMR spectrum and high-resolution mass spectrum data of SL32 are as follows: melting point 312-314°C;

[0336] 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),9.66(s,1H),8.78(d,J=2.3Hz,1H),8.73(d,J=2.3Hz,1H ),8.71(s,1H),8.49(d,J=5.1Hz,1H),8.31(d,J=3.0Hz,1H),8.26(s,1H),8.03(dd,J=8.5,5.6 Hz,2H),7.96(d,J=7.7Hz,1H),7.88(dd,J=8.5,1.8Hz,1H),7.57-7.51(m,2H),7.44(d,J=5.1H z,1H),7.15(d,J=1.8Hz,1H),7.07(dd,J=8.1,1.8Hz,1H),6.97(d,J=8.1Hz,1H),5.97(s,2H);

[0337] HRMS(ESI):Calcd.for C 30 H 20 N4O3[M+H] + :485.1608,found:485.1615.

[0338] Embodiment 33

[0339] The pyrrolopyridine heterocyclic compounds prepared in Examples 1 to 32 were tested for in vitro GSK-3β kinase inhibitory activity using Lance Ultra technology and 384-well culture plates. The specific operation is as follows: 10 μL of kinase-containing buffer was added to an aqueous solution containing 40 μL of pyrrolopyridine heterocyclic compounds of different concentrations, wherein the concentrations of each aqueous solution of pyrrolopyridine heterocyclic compounds were 1000 nM, 333.33 nM, 111.11 nM, 37.0370 nM, 12.3457 nM, 4.1152 nM, 1.3717 nM, 0.4572 nM, 0.1524 nM and 0.0508 nM, respectively. 10 μL of ULight-4E-BP1 / ATP buffer was added and stirred at room temperature for 60 min. 20 μL of Eu-anti-phospho-4E-BP1 antibody solution was added and incubated at room temperature for 60 min. EnVision multifunctional microplate reader was used to collect Lance signal data, and the data were converted into inhibition rate. XLfit software was used to calculate the half inhibitory concentration (IC 50 ), the results are shown in Table 1 (where Staurosporine is a positive drug).

[0340] Table 1 Half-maximal inhibitory concentration of compounds SL01 to SL32 on GSK-3β (unit: (nM))

[0341] Compound <![CDATA[GSK-3βIC 50 ±SD]]> Compound <![CDATA[GSK-3βIC 50 ±SD]]> SL01 75.87±18.78 SL18 1.35±0.01 SL02 115.12±38.36 SL19 283.29±6.50 SL03 124.19±0.61 SL20 0.26±0.05 SL04 223.78±18.09 SL21 0.39±0.01 SL05 48.18±3.43 SL22 0.28±0.02 SL06 2.10±0.30 SL23 2.35±0.11 SL07 0.42±0.01 SL24 0.34±0.02 SL08 0.43±0.03 SL25 0.26±0.01 SL09 0.31±0.02 SL26 0.30±0.02 SL10 0.31±0.05 SL27 0.24±0.01 SL11 0.42±0.04 SL28 0.24±0.01 SL12 0.33±0.03 SL29 0.35±0.01 SL13 0.33±0.03 SL30 0.56±0.03 SL14 4.48±0.53 SL31 1.61±0.10 SL15 0.22±0.03 SL32 0.64±0.06 SL16 0.38±0.07 Staurosporine 4.89±0.97 SL17 0.85±0.15

[0342] As shown in Table 1, the pyrrolopyridine heterocyclic compounds provided by the present invention generally have good GSK-3β inhibitory activity, and the IC 50 Values ​​can be as low as sub-nanomolar levels.

[0343] Embodiment 34

[0344] Experiment on the promotion of neurite outgrowth by pyrrolopyridine heterocyclic compounds

[0345] AD patients have a large number of neuron loss in their brains, accompanied by pathological symptoms such as a decrease in newborn neurons and decreased differentiation ability. Promoting neuron regeneration and differentiation is considered to be one of the effective means of treating AD, and the inhibition of GSK-3β can promote the differentiation and extension of nerve cells. Human neuroblastoma cells (SH-SY5Y) have neuronal morphology and biochemical processes similar to mature human neurons and are widely used in in vitro neuronal activity studies. SH-SY5Y cells were cultured in MEM / F12 containing 10% fetal bovine serum (FBS) based on 6-well culture plates at a constant temperature of 5% CO2 / 37°C, with 2×10 cells seeded per well. 5The cells were cultured for 24 hours. Compounds SL01-SL32 (at a concentration of 1 μM) and retinoic acid (RA, at a concentration of 1 μM) were added and cultured for 72 hours. A 200-fold microscope was used to take photos and observe the growth of neuronal processes.

[0346] Taking compound SL15 as an example, Figure 1 Figure 2 shows the promoting effect of blank control, SL15 and RA on SH-SY5Y cell neurite outgrowth. Figure 1 It can be seen that compared with the positive drug RA, SL15 more effectively induced the growth and extension of SH-SY5Y cell processes, indicating that pyrrolopyridine heterocyclic compounds have effective anti-AD effects.

[0347] Embodiment 34

[0348] Experiment on promoting the expression of neural markers by pyrrolopyridine heterocyclic compounds

[0349] Differentiated SH-SY5Y cells express nerve growth markers, such as growth-associated protein 43 (GAP43) and microtubule-associated protein 2 (MAP-2). RT-PCR was used to detect the effect of pyrrolopyridine heterocyclic compounds on the mRNA expression of nerve growth markers (GAP43, MAP-2) in SH-SY5Y cells. 5 The cells were inoculated into 6-well plates and cultured at 5% CO2 / 37°C for 24 h. Compounds SL01 to SL32 (at a concentration of 10 μM) and RA (at a concentration of 10 μM) were added and cultured for another 24 h. Total RNA was extracted using TRIzol and its purity and concentration were determined. TM Perform reverse transcription according to the RTMaster Mix (Perfect Real Time) kit instructions and follow the OneStep TB Green TM PrimeScript TM RT-PCRKit II kit instructions for amplification. GAPDH was used as the internal reference gene for fluorescence quantitative detection. -ΔΔCt The relative expression of the target gene was calculated by PCR. The PCR primer sequences are shown in Table 2.

[0350] Table 2 Primer sequence related information

[0351]

[0352] Table 3 Results of RA and SL15 promoting the expression of GAP43 and MAP-2 in SH-SY5Y cells

[0353] sample GAP43 MAP-2 SH-SY5Y 1.01±0.13 1.00±0.08 SH-SY5Y+RA 2.48±0.15 1.71±0.15 SH-SY5Y+SL15 3.15±0.40 2.96±0.31

[0354] Taking compound SL15 as an example, Figure 2 Figure 2 is the promoting effect of blank control, SL15 and RA on the expression of nerve growth markers in SH-SY5Y cells. **** p<0.0001, *** p<0.001, ** p<0.01, * p<0.05; Table 3 shows the effects of RA and SL15 on the expression of GAP43 and MAP-2 in SH-SY5Y cells. Figure 2 As shown in Table 3, compound SL15 can significantly promote the expression of GAP43 and MAP-2, indicating that pyrrolopyridine heterocyclic compounds have the effect of promoting the growth of nerve cells.

[0355] Embodiment 35

[0356] Experimental study on the efficacy of pyrrolopyridine heterocyclic compounds in improving Alzheimer's disease

[0357] Zebrafish and humans have a variety of AD-related homologous genes, such as zebrafish psen1, psen2, APP genes, etc., and have become a popular model vertebrate for AD research. Aluminum chloride (AlCl3) can promote Aβ deposition and NFTs formation in the zebrafish brain, increase acetylcholinesterase activity, promote the release of inflammatory factors IL-1β and TNF-α, reduce acetylcholine, γ-aminobutyric acid, dopamine, norepinephrine and serotonin levels, and induce decreased motor ability. The bradykinesia induced by AlCl3 in zebrafish is used to simulate the movement disorder of AD, which has been widely used in preclinical anti-AD drug screening. Wild-type AB strain zebrafish 4 days after fertilization were randomly selected in 6-well plates, with 30 tails per well. After water dissolution, the positive control donepezil hydrochloride (8μM) and different concentrations of compounds SL01~SL32 were given, and a normal control group and a model control group were set up at the same time. The capacity of each well was 3mL. The normal control group did not add aluminum chloride hexahydrate, and the model control group, donepezil hydrochloride group and compound SL01-SL32 groups were all given aluminum chloride hexahydrate (160μM) in water to establish the zebrafish Alzheimer's disease model. After 24 hours of treatment at 28℃, 10 zebrafish were randomly selected from each experimental group, and the total movement distance of the zebrafish within 1 hour was measured using a behavioral analyzer. The statistical analysis results of this indicator were used to evaluate the efficacy of the sample in improving Alzheimer's disease.

[0358] Taking compound SL15 as an example (dosing concentrations were 1.95 μM, 3.91 μM and 7.81 μM, respectively), Figure 3 (Left) The effect of donepezil hydrochloride and SL15 on improving AlCl3-induced zebrafish movement and (right) the bar graph of zebrafish movement distance, where Figure 3In the middle left picture, the black line is slow motion, the green line is medium speed motion, and the red line is fast motion. Figure 3 It can be seen that AlCl3 induction can cause bradykinesia in zebrafish, and the positive drug donepezil hydrochloride can effectively improve this movement disorder, and the zebrafish AD model was successfully established. The compound SL15 can increase the movement distance of the AlCl3-induced zebrafish AD model in a dose-dependent manner. Compared with the 605mm of the AlCl3-induced model control group, the movement distance of the SL15-administered experimental group increased to 693mm, 826mm and 1365mm, respectively, indicating that pyrrolopyridine heterocyclic compounds have an effective effect in improving Alzheimer's disease.

[0359] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pyrrolopyridine heterocyclic compound, characterized in that: The structural formula is shown in Formula SL: Wherein, R1 includes hydrogen, alkyl, alkoxy or halogen; R2 includes hydrogen, alkyl, alkoxy, unsubstituted aryl, substituted aryl, halogen or heterocyclic group; R3 includes unsubstituted aryl, substituted aryl or heterocyclic group; R2 and R3 are not phenyl at the same time.

2. The pyrrolopyridine heterocyclic compound according to claim 1, characterized in that: In R1 and R2, the alkyl group includes C1 to C 12 Alkyl; the alkoxy group includes C1~C 12 Alkoxy; In R2 and R3, the aryl groups in the unsubstituted aryl group and the substituted aryl group independently include phenyl or naphthyl; the substituents in the substituted aryl group include alkyl, alkoxy, halogen or halogenated alkyl; The heterocyclic group includes an aromatic heterocyclic group or an aliphatic heterocyclic group.

3. The pyrrolopyridine heterocyclic compound according to claim 1 or 2, characterized in that: The pyrrolopyridine heterocyclic compound has a structure shown in any one of formulas SL01 to SL32:

4. The method for preparing the pyrrolopyridine heterocyclic compound according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: mixing 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid, compound 1, an acid amine condensation agent, an organic base and a first organic solvent, and performing a condensation acylation reaction to obtain compound 2; The compound 2, the compound 3, the catalyst, the inorganic base and the second organic solvent are mixed, and a Suzuki reaction is performed under a protective atmosphere to obtain the pyrrolopyridine heterocyclic compound; Wherein, R1 to R3 are the same as those in the formula SL.

5. The preparation method according to claim 4, characterized in that: The molar ratio of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid to compound 1 is 1:0.4-1.2; The acid amine condensing agent includes one or more of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; The molar ratio of the 5-bromo-1H-pyrrole[2,3-b]pyridine-3-carboxylic acid to the acid amine condensation agent is 1:0.8-3; The organic base includes N,N-diisopropylethylamine and / or triethylamine; The molar ratio of the 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid to the organic base is 1:1.5-4; The first organic solvent includes one or more of N,N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone.

6. The preparation method according to claim 4 or 5, characterized in that: The temperature of the condensation acylation reaction is 60-100° C. and the time is 3-48 hours.

7. The preparation method according to claim 4, characterized in that: The catalyst comprises one or more of tetrakistriphenylphosphine palladium, bis(diphenylphosphino)ferrocene palladium dichloride and bistriphenylphosphine palladium dichloride; The inorganic base includes one or more of potassium carbonate, sodium carbonate and cesium carbonate; The molar ratio of compound 2 to compound 3 is 1:1.1-3; The molar ratio of the compound 2 to the catalyst is 1:0.01-0.5; The molar ratio of the compound 2 to the inorganic base is 1:1.1-10; The second organic solvent includes 1,4-dioxane; The temperature of the Suzuki reaction is 95-105° C., and the time is 6-24 hours.

8. The derivative of the pyrrolopyridine heterocyclic compound according to any one of claims 1 to 3, wherein the derivative comprises one or more of isomers, pharmaceutically acceptable salts and solvates.

9. A pharmaceutical composition, characterized in that comprising active ingredients and pharmaceutically acceptable excipients; The active component is the pyrrolopyridine heterocyclic compound according to any one of claims 1 to 3 and / or the derivative of the pyrrolopyridine heterocyclic compound according to claim 8.

10. Use of the pyrrolopyridine heterocyclic compound according to any one of claims 1 to 3, the derivative of the pyrrolopyridine heterocyclic compound according to claim 8, or the pharmaceutical composition according to claim 9 in the preparation of a drug for treating Alzheimer's disease.

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