A quinazoline-azaindole compound, its preparation method, and its application in treating Alzheimer's disease.

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a quinazoline-azaindole compound, its preparation method, and its application in treating Alzheimer's disease. The quinazoline-azaindole compound of this invention regulates NF-κB by inhibiting DYRK1A. k B. A series of signaling pathways, including PI3k-Akt, achieve anti-neuroinflammatory effects; quinazoline-azaindole compounds can reduce the expression of inflammatory factor-related genes in an LPS-induced BV2 microglial inflammation model, thereby reducing the levels of inflammatory factors in the hippocampus and cortex, alleviating neuronal pathological damage caused by neuroinflammation, and improving cognitive impairment caused by neuroinflammation; in summary, quinazoline compounds inhibit DYRK1A and downregulate NF-κB signaling pathways. k It can reduce the expression and release of inflammatory factors, improve brain tissue pathology, and alleviate cognitive impairment through signaling pathways such as B, and has significant clinical application value.

Description

Technical Field

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

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disease that has become one of the most critical public health challenges globally. The pathological mechanisms of AD are complex, involving multiple factors, and various hypotheses have been proposed over the years. Currently, the most widely accepted hypotheses are the Aβ hypothesis and the tau protein hypothesis. β The hypothesis states that A β Abnormal aggregation and deposition of peptides trigger neurotoxicity, while the tau hypothesis emphasizes that neurofibrillary tangles caused by hyperphosphorylation of tau protein are a key cause of neuronal dysfunction. Furthermore, neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic damage are considered key drivers of disease progression.

[0003] Neuroinflammatory disease is now considered to connect A β A key step in driving and tau-driven pathological cascades. β Triggering a neuroinflammatory response exacerbates disease progression by directly promoting the development of neurotoxic tau pathology. Tau pathology-induced neuronal death and axonal degeneration release additional damage-related signals, further activating microglia and astrocytes, thereby perpetuating and aggravating neuroinflammatory activity. Neuroinflammatory activity is a core driving force in the pathogenesis of Alzheimer's disease (AD), and is closely related to A... β This creates a vicious cycle with tau pathology, jointly driving disease progression. Notably, DYRK1A also plays a crucial role in regulating microglia-mediated neuroinflammation. Studies have shown that DYRK1A is overexpressed and overactivated in polarized glial cells. DYRK1A can also act as a regulator of NF-κB. κ DYRK1A is a key target for nucleocytoplasmic shuttle, affecting its accumulation in the nucleus and regulating its transcriptional activity. This, in turn, influences the activation state of microglia and the neuroinflammatory response it mediates, potentially leading to earlier onset of AD pathology. Given that DYRK1A activation is related to NF-κB... κ It is closely related to the activation of neuroinflammatory pathways such as B-cell neurotransmitters, and its inhibitors can downregulate key inflammatory mediators such as NO and TNF-α in microglia (e.g., BV2 cells). α And the production of IL-6.

[0004] Currently available Alzheimer's disease treatments have significant limitations: traditional symptomatic medications (such as cholinesterase inhibitors) can only temporarily improve symptoms and cannot slow disease progression; while recently approved monoclonal antibody drugs targeting Aβ (such as lencanemab and donepemab) can slow cognitive decline to some extent, their efficacy is limited, and they may cause side effects such as cerebral edema or microbleeds. They are also expensive and mainly suitable for early-stage patients, with poor efficacy in mid-to-late-stage patients. Furthermore, existing therapies mostly target single pathological proteins (such as Aβ). β The pathogenesis of Alzheimer's disease is complex, involving multiple factors such as Tau protein abnormalities and neuroinflammation, making it difficult for single-target drugs to comprehensively block disease progression. In summary, the fundamental reason is that AD is a multifactorial disease, while existing therapies mostly target single pathological proteins (such as Tau protein). β It is difficult to completely block A β A complex network composed of tau pathology and neuroinflammation.

[0005] Therefore, the development of novel drugs capable of multi-target intervention of core pathologies is urgently needed. Among them, DYRK1A inhibitors have shown unique potential: studies have shown that overexpression of DYRK1A not only promotes Tau protein phosphorylation and neurofibrillary tangles, but also exacerbates A β The production of toxic peptides is directly linked to neuroinflammatory responses and key pathogenic pathways in Alzheimer's disease. This means that targeting DYRK1A holds promise for regulating neuroinflammation, tau pathology, and A... β Through multiple mechanisms including toxicity, this approach overcomes the limitations of existing drugs and provides a new direction for developing anti-Alzheimer's therapies with greater potential for disease modification. Summary of the Invention

[0006] Purpose of the Invention: This invention provides a quinazoline-azaindole compound, its preparation method, and its application in treating Alzheimer's disease. The purpose is to provide a quinazoline-azaindole compound with DYRK1A inhibitory activity, a method for preparing the novel quinazoline-azaindole compound, and to indicate its application in the preparation of drugs for treating Alzheimer's disease.

[0007] To achieve the above objectives, the present invention provides the following solution: The first aspect of this invention proposes the following compounds or pharmaceutically acceptable salts thereof, selected from: ; .

[0008] Beneficial effects The quinazoline-azaindole compounds proposed in this invention are developed by introducing a piperidine group at the 4-position of quinazoline and adding various substituents at the 5-position of azaindole, resulting in compounds with low IC50. 50 These are potent DYRK1A inhibitors. Preferred compounds exhibit low cytotoxicity and acute toxicity in C57 mice, and can significantly reduce the expression and release of LPS-induced microglial inflammatory factors at low concentrations. Therefore, these compounds can effectively target neuroinflammatory pathologies and play an important role in the preparation of drugs for the prevention or treatment of Alzheimer's disease. Attached Figure Description

[0009] Figure 1 This is the synthetic route diagram for compound ZRMQ1-3; Figure 2 This is the synthetic route diagram for compound ZRMQ4-5; Figure 3 This is the synthetic route diagram for compound ZRMQ6-8; Figure 4 This is the first synthetic route diagram for compound ZRMQ9-23; Figure 5 This is the second synthetic route diagram for compound ZRMQ9-23; Figure 6 This study evaluated the inhibitory effects of compounds ZRMQ-6,8,9,15,22,23 on LPS-induced inflammatory factors in BV2 cells; (A) represents the concentration of TNF-α in LPS-induced BV2 cells at a concentration of 1 μM (detected by ELISA); (B) represents the concentration of TNF-α in LPS-induced BV2 cells at a concentration of 1 μM. μ The concentration of IL-6 in BV2 cells induced by LPS at the concentration of compound M (detected by ELISA); the results in the figure are expressed as mean ± standard deviation, n≥4, ns represents no significance, #### represents p<0.0001 between LPS group and control group; * represents p<0.05 between experimental group and LPS group, ** represents p<0.01 between experimental group and LPS group, **** represents p<0.0001 between experimental group and LPS group; Figure 7 Evaluation of the cytotoxicity of compounds ZRMQ-8 and ZRMQ-22 to BV2 cells; where (A) is the cytotoxicity of ZRMQ-8 to BV2 cells, (B) is the cytotoxicity of ZRMQ-22 to BV2 cells, and (C) is the cytotoxicity of dexamethasone to BV2 cells. Figure 8This figure shows the acute toxicity evaluation of compounds ZRMQ-8 and ZRMQ-22 in C57 mice. (A) shows the survival rate of mice in each experimental group over 14 days; (B) shows the body weight change of each experimental group over 14 days after the first day of administration; and (C) shows the representative H&E staining results of major organs in each experimental group, with no abnormalities observed in these organs. (Scale bar = 50) μ m, the result is expressed as mean ± standard error, n=10. Detailed Implementation

[0010] The present invention will be described below through specific embodiments, but the present invention is not limited thereto.

[0011] The structure of the compound was determined by nuclear magnetic resonance (NMR). The NMR measurements were performed using a Bruker AVANCE-300 / 500 NMR spectrometer, and the solvent was DMSO. d 6 The internal standard is TMS.

[0012] Preparation method of the compound of the present invention: Suzuki's general preparation method for coupling: The starting material (1.0 equivalent) and key intermediate 1 (1.2 equivalent) were added to a solution of dioxane / water (4:1, v / v) with Cs₂CO₃ (3.0 equivalent) and Pd(dppf)Cl₂ (5 mol%). The resulting mixture was heated at 95°C for 12 hours under a N₂ atmosphere (corresponding to...). Figure 1-5 Reaction conditions d). After the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by rapid silica gel column chromatography, with petroleum ether and ethyl acetate as the eluent, to give the corresponding product.

[0013] A general method for removing p-toluenesulfonyl groups: Dissolve the starting material (1.0 equivalent) in methanol / dichloromethane (1:1, v / v), and add sodium hydroxide solid (4 equivalents). Heat the resulting mixture at 50 °C for 2 hours (corresponding to...). Figure 1-5 Reaction condition e). After the reaction is complete, remove the solvent under reduced pressure. Dissolve the residue in water and adjust the pH of the solution to 6-7 with dilute hydrochloric acid. Extract with a suitable solvent (ethyl acetate or dichloromethane) depending on the solubility, noting whether the product is distributed in the aqueous or organic phase. Separate and concentrate the solvent, and obtain the product by column chromatography using a petroleum ether-acetone system.

[0014] like Figure 1-5 As shown, the preparation steps are as follows: (1) The synthesis of the target compound ZRMQ1-3 is described in Scheme 1, and the preparation method is as follows: Figure 1As shown. Intermediate 1 is obtained by nucleophilic substitution of commercially available A (6-bromo-4-chloroquinazoline) and piperidine, followed by a Miyaura reaction with dipinalyl borate; D1, D2, and D3 can be obtained by sulfonation of commercially available C1, C2, and C3, and then D1, D2, and D3 are coupled with intermediate 1 by Suzuki to obtain E1, E2, and E3, respectively. Finally, the synthesis of the target compound ZRMQ1-3 requires the removal of the p-toluenesulfonyl group under alkaline hydrolysis conditions.

[0015] (2) The synthesis of the target compound ZRMQ4-5 is shown in Scheme 2, and the preparation method is as follows: Figure 2 As shown. Commercially available raw materials C4 and C5 can be purchased, eliminating the need for sulfonation and removal of the p-toluenesulfonyl group.

[0016] (3) The synthesis of the target compound ZRMQ6-8 is described in Scheme 3, and the preparation method is as follows: Figure 3 As shown. D4-D6 can be prepared by sulfonation of commercially available C6-C8, and then D4-D6 are coupled with intermediate 1 by Suzuki to obtain E4-E6. Finally, the synthesis of the target compound ZRMQ6-8 requires the removal of p-toluenesulfonyl group under alkaline hydrolysis conditions.

[0017] (4) The synthesis of the target compound ZRMQ9-23 is shown in Scheme 4, and it can be synthesized by two methods: like Figure 4 As shown, one method involves using commercially available C9, first sulfonating it to obtain D7, then selectively coupling it with an intermediate via Suzuki, reacting it with intermediate 1 at the iodine atom site at position 3 to obtain intermediate 2. Intermediate 2 can react with pinacol arylboronic acid ester to obtain the corresponding intermediates E7-E21, and then removing the p-toluenesulfonyl group to obtain the corresponding final product.

[0018] like Figure 5 As shown, another method uses commercially available C3, first undergoing sulfonation protection to obtain D3, then coupling D3 with the corresponding arylboronic acid pinacol ester to prepare intermediate D8-D22, followed by selective bromination at the 3-position of azidoindole: D8-D22 is dissolved in anhydrous DMF, NBS (1.2 equivalents) is added while stirring, and then the mixture is slowly heated for 12 hours at room temperature under a N2 atmosphere. After the reaction is complete, ice water is added and stirred, resulting in the precipitation of a powdery white solid. The solid precipitate is collected by filtration and dried to obtain the target product.

[0019] The final product was obtained by further coupling with intermediate 1 and removing the p-toluenesulfonyl group.

[0020] Example 1: Preparation of 4-piperidin-6-bromo-4-(piperidin-1-yl)quinazoline (compound B): By means of a nucleophilic substitution reaction, commercially available starting material 4-chloro-6-bromoquinazoline (A) (1 equivalent) was dissolved in anhydrous isopropanol, and piperidine (1.5 equivalent) and triethylamine (2-3 equivalent) were added under stirring. The mixture was heated to 85°C and refluxed for 6 hours (corresponding to...). Figure 1-5 Reaction conditions a). After the reaction was complete, the reaction solution was concentrated and purified by column chromatography using petroleum ether:ethyl acetate = 4:1, yielding yellow crystals in approximately 91% yield.

[0021] Example 2: Preparation of key intermediate 1: 4-(piperidin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclo-2-yl)quinazoline: The reaction was carried out via the Miyaura reaction, in which KOAC (3.0 equivalents) and Pd(PPh3)2Cl2 (5 mol%) were added to an anhydrous dioxane solution of compound B (1 equivalent) and diphenoxylate (1.5 equivalents). The resulting mixture was heated at 100 °C for 12 hours under a N2 atmosphere (corresponding to...). Figure 1-5 Reaction condition b). After the reaction is complete, the solvent is carefully removed under reduced pressure, and then water and ethyl acetate are added to the reaction flask. The organic phase is separated and concentrated to obtain a brownish-brown oily liquid; the product is a brownish-brown oily substance.

[0022] Example 3: Preparation of D1-D7 The starting material, 1H-pyrrolo[2,3-b]pyridine derivatives (C1-C3, C6-C9) (1.0 equivalent), was dissolved in anhydrous DMF, and NaH (60% suspension in mineral oil) (2.0 equivalent) was added in portions at 0°C (ice bath cooling). After stirring the mixture for approximately 30 minutes, TsCl (1.2 equivalent) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, followed by a slow heating at room temperature for 12 hours (corresponding to...). Figure 1-5 Reaction condition c). After the reaction is complete, immediately quench with ice water. Collect the solid precipitate by filtration, and dry to obtain the target products D1-D7 (yellowish-white solids, yield 70-90%), without further purification. The compounds are C1-C3, C6-C9, and the structural formulas of the target products D1-D7 are as follows:

[0023] Example 4 Intermediates E1-E6 3-Bromoazaindole starting materials D1-D6 (1 equivalent) and the key intermediate 1-quinazolin-6-boronate (1.2 equivalent) were coupled via Suzuki to obtain the corresponding intermediates and final products E1-E6:

[0024] Example 5: Compound ZRMQ-4 was prepared by coupling raw material C4 with intermediate 1 via Suzuki coupling.

[0025] 6-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazolin (6-(1-Methyl-1-yl)pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazolin (6-(1-Methyl-1-yl)pyrrolo[2,3-b]pyridin-3-yl)pyrrolo[2,3-b] ... H -pyrrolo[2,3- b ]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-4), a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.20 (s, 1H), 8.71-8.42 (m, 3H), 8.32-8.07 (m, 3H), 7.94-7.70 (m, 3H), 7.51 (t, J = 7.7 Hz, 2H), 7.45-7.30 (m, 1H), 3.92-3.58 (m, 4H), 1.72 (s, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 164.45, 153.58,150.38, 149.24, 142.76, 139.39, 132.59, 132.34, 129.63, 129.43, 129.13,127.64, 126.37, 125.72, 121.25, 117.63, 117.04, 114.33, 50.83, 26.13, 24.64.HR-ESI-MS: m / z 344.1871 [M+H] + , (calcd for C 21 H 21 N5, 343.1870) Example 6: ZRMQ-5: 6-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(piperidin-1-yl)quinazoline 6-(1-Methyl-1-yl) ...pyrrolo[2,3-b]pyridin-1-yl)pyrrolo[2,3-b]pyrrolo[2,3-b]pyrrolo[2,3-b]pyrrolo[2,3-b]pyrrolo[2,3-b]pyrrolo[ H -pyrrolo[2,3- b pyridin-4-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-5). White solid. 1 H NMR (400 MHz, DMSO- d6) δ 8.63 (s, 1H), 8.38 (d, J = 4.9 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 2.0, 8.7 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 7.33(d, J = 5.0 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H), 3.89 (s, 3H), 3.75 (t, J = 4.4Hz, 4H), 1.70 (d, J = 2.6 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 164.28,153.60, 150.31, 148.48, 143.57, 132.28, 131.95, 129.16, 129.12, 127.76,121.10, 117.84, 116.94, 112.86, 50.85, 31.53, 26.04, 24.73.HR-ESI-MS: m / z344.1871 [M+H] + , (calcd for C 21 H 21 N5, 343.1870).

[0026] Example 7: Key Intermediate 2: 6-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline.

[0027]

[0028] Iodine-selective Suzuki coupling, D7 (1 equivalent) and key intermediate 1 (1.2 equivalent) were added to a solution of dioxane / water (4:1, v / v) with K2CO3 (2.0 equivalent) and Pd(dppf)Cl2 (5 mol%). The resulting mixture was heated at 75 °C for 3–5 hours under a N2 atmosphere (corresponding to...). Figure 1-5 Reaction conditions f). After the reaction is complete, remove the solvent under reduced pressure. Add water and ethyl acetate, sonicate to dissolve, extract, and concentrate the organic phase to obtain an orange solid, which requires no further purification; concentrate the reaction solution, extract with water and ethyl acetate, and concentrate the organic phase to obtain an orange-yellow solid, which also requires no further purification.

[0029] Example 8: E7-E21: Prepared by Suzuki coupling of key intermediate 2 (1 equivalent) with different arylboronic esters (1.2 equivalents): (corresponding to) Figure 1-5 Reaction conditions g) General structural formula of arylboronic acid esters: Where R is: , , , , , , , , , , , , , , .

[0030] E7-E21 general structural formula: The R in E7 is: The R in E8 is: The R in E9 is: Where R in E10 is: Where R in E11 is: Where R in E12 is: Where R in E13 is: Where R in E14 is: Where R in E15 is: Where R in E16 is: Where R in E17 is: Where R in E18 is: In E19, R is: Where R in E20 is: Where R in E21 is: .

[0031] Example 9: Preparation method of intermediates D8-D22 from method 2 Suzuki coupling: Cs₂CO₃ (2.0 equivalents) and Pd(dppf)Cl₂ (5 mol%) were added to a solution of intermediate D₃ (1 equivalent) and various arylboronic esters (1.2 equivalents) in dioxane / water (4:1, v / v). The resulting mixture was heated at 95 °C for 12 hours under a N₂ atmosphere (corresponding to...). Figure 1-5 Reaction conditions g). After the reaction was complete, the solvent was removed under reduced pressure. The residue was purified by rapid silica gel column chromatography to obtain the corresponding intermediate; D8-D22 structural formula: Where R in D8 is Where R in D9 is: Where R of D10 is: Where R in D11 is: Where R of D12 is: Where R in D13 is: Where R in D14 is: Where R in D15 is: Where R in D16 is: Where R in D17 is: Where R in D18 is: Where R in D19 is: Where R for D20 is: Where R of D21 is: Where R of D22 is: .

[0032] Example 10: Preparation of intermediates F1-F15 from Method 2: D8-D22 were dissolved in anhydrous DMF, and NBS (1.2 equivalents) was added while stirring. The mixture was reacted at room temperature to obtain the product (corresponding to...). Figure 1-5 Reaction conditions h); F1-F15 structural formula: Where R in F1 is Where R of F2 is: Where R of F3 is: The R of F4 is: The R in F5 is: The R of F6 is: The R in F7 is: The R of F8 is: The R in F9 is: Where R in F10 is: Where R in F11 is: Where R in F12 is: Where R in F13 is: The R of F14 is: The R in F15 is: .

[0033] Example 11: Preparation of the final product ZRMQ-1: In a round-bottom flask, E1 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 4-(piperidin-1-yl)-6-(1H-pyrrolo[2,3-b]pyrimidin-3-yl)quinazoline 4-(Piperidin-1-yl)-6-(1 H -pyrrolo[2,3- b ]pyridin-3-yl)quinazoline (ZRMQ-1), a white, flocculent solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.09 (s, 1H), 8.59 (s, 1H), 8.36-8.28 (m, 2H), 8.19 (dd, J = 1.9, 8.7 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.24(dd, J = 4.7, 7.9 Hz, 1H), 3.78-3.72 (m, 4H), 1.80-1.73 (m, 6H). 13 C NMR (101MHz, DMSO- d 6) δ 164.29, 153.57, 150.29, 149.67, 143.70, 132.64, 132.19,129.06, 127.46, 125.41, 121.15, 117.57, 116.91, 116.86, 113.97, 50.85, 26.05,24.75. HR-ESI-MS: m / z 330.1711 [M+H] + , (calcd for C 20 H 19 N5, 329.1711).

[0034] Example 12: Preparation of the final product ZRMQ-2: In a round-bottom flask, E2 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 4-(piperidin-1-yl)-6-(1H-pyrrolo[2,3-b]pyrimidin-4-yl)quinazoline 4-(Piperidin-1-yl)-6-(1 H -pyrrolo[2,3- b pyridin-4-yl)quinazoline (ZRMQ-2), yellow crystals. 1 H NMR (400 MHz, DMSO- d 6) δ 11.91(s, 1H), 8.64 (s, 1H), 8.34 (d, J = 4.9 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.19 (dd, J = 1.9, 8.6 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 2.5, 3.5 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 6.68 (dd, J = 1.7, 3.5 Hz, 1H), 3.76(t, J = 4.3 Hz, 4H), 1.72 (d, J = 4.7 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ164.35, 154.60, 151.74, 149.72, 143.54, 139.62, 135.57, 132.96, 129.20,127.61, 125.09, 117.60, 116.46, 114.96, 98.91, 50.81, 26.04, 24.60. HR-ESI-MS: m / z 330.1711 [M+H] + , (calcd for C 20 H 19 N5, 329.1711).

[0035] Example 13: Preparation of the final product ZRMQ-3: In a round-bottom flask, E3 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 4-(piperidin-1-yl)-6-(1H-pyrrolo[2,3-b]pyrimidin-5-yl)quinazoline 4-(Piperidin-1-yl)-6-(1 H -pyrrolo[2,3- b pyridin-5-yl)quinazoline (ZRMQ-3), pale yellow crystals. 1 H NMR (400 MHz, DMSO- d 6) δ11.80 (s, 1H), 8.64-8.58 (m, 2H), 8.32 (d, J = 2.2 Hz, 1H), 8.16 (dd, J =2.0, 8.7 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 2.5, 3.4 Hz, 1H), 6.55 (dd, J = 1.8, 3.4 Hz, 1H), 3.77 (t, J = 4.4Hz, 4H), 1.72 (d, J = 4.9 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 164.28, 154.02,150.92, 148.65, 142.14, 136.44, 132.38, 129.08, 127.91, 127.71, 126.94,122.98, 120.26, 116.62, 100.79, 50.78, 25.97, 24.67. HR-ESI-MS: m / z 330.1711[M+H] + , (calcd for C 20 H 19 N5, 329.1711).

[0036] Example 14: Preparation of the final product ZRMQ-6: In a round-bottom flask, E6 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-Methyl-1-yl)H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-6), a pale yellow powder. 1 H NMR (400 MHz, DMSO- d 6) δ 12.08-11.75 (m, 1H), 8.59 (s, 1H), 8.19 (dd, J = 1.9, 8.6 Hz, 2H), 8.12(d, J = 2.0 Hz, 2H), 8.02 (d, J = 2.6 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 3.74(t, J = 4.9 Hz, 4H), 2.45 (s, 3H), 1.93-1.58 (m, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 164.46, 153.51, 150.18, 148.36, 144.48, 132.87, 132.10, 129.05, 127.30,125.60, 125.36, 120.85, 117.39, 116.97, 113.28, 50.92, 26.11, 24.80, 18.73.HR-ESI-MS: m / z 344.1871 [M+H] + , (calcd for C 21 H 21 N5, 343.1870).

[0037] Example 15: Preparation of the final product ZRMQ-7: In a round-bottom flask, E7 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 4-(piperidin-1-yl)-6-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline 4-(Pi ... H -pyrrolo[2,3- b pyridin-3-yl)quinazoline (ZRMQ-7), white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 12.66 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.63-8.53 (m, 2H), 8.29 (d, J = 1.8 Hz, 1H), 8.21 (dd, J = 1.9, 8.6 Hz, 1H), 8.12(d, J = 2.1 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 3.74 (t, J = 4.8 Hz, 4H), 1.75(dp, J = 5.5, 6.5, 11.6 Hz, 6H). 19 F NMR (377 MHz, DMSO- d 6) δ -58.26. 13 C NMR (101 MHz, DMSO-) d 6) δ 164.42, 153.78, 150.91, 150.57, 140.36, 132.14, 131.49,129.24, 128.08, 126.91, 124.98, 124.21, 121.69, 118.50, 118.19, 116.90,116.63, 115.08, 50.87, 25.99, 24.72. HR-ESI-MS: m / z 398.1580 [M+H] + , (calcdfor C 21 H 18 F3N5, 397.1580).

[0038] Example 16: Preparation of the final product ZRMQ-8: In a round-bottom flask, E8 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-Methoxy-1-yl) H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-8), a white flocculent solid. 1 H NMR (400 MHz, DMSO-) d6) δ 11.99 (s, 1H), 8.59 (s, 1H), 8.18 (dd, J = 1.9, 8.7 Hz, 1H), 8.10 (dd, J = 2.3, 4.1 Hz, 2H), 8.01 (d, J = 2.4 Hz, 1H), 7.91-7.75 (m,2H), 3.91 (s, 3H), 3.82-3.67 (m, 4H), 1.74 (q, J = 7.6, 9.7 Hz, 6H). 13 C NMR (101 MHz, DMSO-) d 6) δ 164.27, 153.48, 151.76, 150.23, 144.99, 133.98, 132.84,132.22, 129.06, 126.20, 120.99, 117.39, 116.98, 113.69, 110.09, 56.50, 50.78,26.12, 24.68. HR-ESI-MS: m / z 360.1821 [M+H] + , (calcd for C 21 H 21 N5O, 359.1821).

[0039] Example 17: Preparation of the final product ZRMQ-9: In a round-bottom flask, E9 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-phenyl-1H-pyrrolopyrimidin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-Phenyl-1-yl) H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-9), a gray solid. 1 H NMR (400 MHz, DMSO- d 6) δ12.20 (s, 1H), 8.71-8.42 (m, 3H), 8.32-8.07 (m, 3H), 7.94-7.70 (m, 3H), 7.51(t, J = 7.7 Hz, 2H), 7.45-7.30 (m, 1H), 3.92-3.58 (m, 4H), 1.72 (s, 6H). 13CNMR (101 MHz, DMSO- d 6) δ 164.45, 153.58, 150.38, 149.24, 142.76, 139.39,132.59, 132.34, 129.63, 129.43, 129.13, 127.64, 126.37, 125.72, 121.25,117.63, 117.04, 114.33, 50.83, 26.13, 24.64. HR-ESI-MS: m / z 406.2027 [M+H] + ,(calcd for C 26 H 23 N5, 405.2027).

[0040] Example 18: Preparation of the final product ZRMQ-10: In a round-bottom flask, E10 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 4-(piperidin-1-yl)-6-(5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazoline 4-(Piperidin-1-yl)-6-(5-(pyridin-3-yl)-1 H -pyrrolo[2,3- b pyridin-3-yl)quinazoline (ZRMQ-10), white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.27 (s, 1H), 9.02 (dd, J = 0.8, 2.4 Hz, 1H),8.84-8.46 (m, 4H), 8.34-8.04 (m, 4H), 7.87 (d, J = 8.6 Hz, 1H), 7.53 (ddd, J = 0.9, 4.8, 8.0 Hz, 1H), 3.75 (t, J = 4.8 Hz, 4H), 1.87-1.51 (m, 6H). 13 C NMR (101 MHz, DMSO-) d6) δ 164.40, 153.61, 150.42, 149.47, 148.66, 148.50, 142.71,135.00, 134.97, 132.41, 132.39, 129.11, 126.55, 126.46, 126.15, 124.29,121.46, 117.70, 116.99, 114.50, 50.81, 26.08, 24.65. HR-ESI-MS: m / z 407.1980[M+H] + , (calcd for C 25 H 23 N6, 406.1980).

[0041] Example 19: Preparation of the final product ZRMQ-11: In a round-bottom flask, E11 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give 4-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide 4-(3-(4-(Piperidin-1-yl)quinazolin-6-yl)-1 H -pyrrolo[2,3- b pyridin-5-yl)benzamide (ZRMQ-11), white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.24 (d, J = 2.7 Hz, 1H), 8.69 (d, J = 2.1 Hz,1H), 8.64-8.55 (m, 2H), 8.27 (dd, J = 1.9, 8.7 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.07 (s, 1H), 8.04-7.98 (m, 2H), 7.94-7.83 (m,3H), 3.76 (t, J = 4.9 Hz, 4H), 1.72 (s, 6H). 13 C NMR (101 MHz, DMSO- d6) δ168.00, 164.41, 153.61, 150.42, 149.45, 142.86, 142.06, 133.16, 132.47,132.40, 129.13, 128.65, 128.62, 127.25, 126.50, 125.90, 121.42, 117.67,117.02, 114.52, 50.82, 26.13, 24.67. HR-ESI-MS: m / z 449.2082 [M+H] + , (calcdfor C 27 H 24 N6O,448.2082).

[0042] Example 20: Preparation of the final product ZRMQ-12: In a round-bottom flask, E12 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give N-(4-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acetamide. N -(4-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1 H -pyrrolo[2,3- b pyridin-5-yl)phenyl)acetamide (ZRMQ-12), yellow powder. 1 H NMR (400 MHz, DMSO- d 6) δ 12.16 (d, J = 2.7 Hz,1H), 10.05 (s, 1H), 8.63-8.57 (m, 2H), 8.48 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 1.9, 8.7 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.86(d, J = 8.7 Hz, 1H), 7.72 (s, 4H), 3.76 (t, J = 5.2 Hz, 4H), 2.08 (s, 3H), 1.75-1.71 (m, 6H). 13 C NMR (101 MHz, DMSO-d 6) δ 168.81, 164.43, 153.57,150.35, 149.03, 142.53, 139.05, 133.85, 132.64, 132.34, 129.28, 129.10,127.76, 126.28, 125.14, 121.20, 119.85, 117.63, 117.03, 114.24, 50.82, 26.14,24.66, 24.53. HR-ESI-MS: m / z 463.2237 [M+H] + , (calcd for C 28 H 26 N6O, 462.2237).

[0043] Example 21: Preparation of the final product ZRMQ-13: In a round-bottom flask, E13 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product N-(5-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acetamide N-(5-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1 H -pyrrolo[2,3- b pyridin-5-yl)pyridin-2-yl)acetamide (ZRMQ-13), white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.22 (d, J = 2.7Hz, 1H), 10.62 (s, 1H), 8.75 (t, J = 1.7 Hz, 1H), 8.68-8.50 (m, 3H), 8.32-8.07 (m, 5H), 7.86 (d, J = 8.7 Hz, 1H), 3.76 (t, J = 4.9 Hz, 4H), 2.13 (s, 3H), 1.70 (d, J = 16.0 Hz, 6H). 13 C NMR (101 MHz, DMSO- d6) δ 169.79, 164.36,153.57, 151.67, 150.35, 149.25, 146.44, 142.47, 136.98, 132.49, 132.42,130.33, 129.07, 126.45, 126.31, 125.43, 121.45, 117.69, 116.98, 114.42,113.64, 50.81, 26.10, 24.68, 24.41. HR-ESI-MS: m / z 464.2192 [M+H] + , (calcdfor C 27 H 25 N7O, 463.2193).

[0044] Example 22: Preparation of the final product ZRMQ-14: In a round-bottom flask, E14 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 4-(piperidin-1-yl)-6-(5-(4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)quinazolin 4-(Piperidin-1-yl)-6-(5-(4-(trifluoromethyl)phenyl)-1H- H -pyrrolo[2,3- b pyridin-3-yl)quinazoline (ZRMQ-14), a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.31-12.14 (m, 1H), 8.69 (d, J =2.1 Hz, 1H), 8.59 (d, J = 1.7 Hz, 2H), 8.28 (dd, J = 1.9, 8.7 Hz, 1H), 8.17(dd, J = 2.3, 15.3 Hz, 2H), 8.08-8.00 (m, 2H), 7.86 (t, J = 8.5 Hz, 3H), 3.75(t, J = 4.8 Hz, 4H), 1.70 (s, 6H). 13 C NMR (101 MHz, DMSO- d6) δ 164.38,153.63, 150.44, 149.59, 143.57, 142.86, 132.38, 129.11, 128.34, 128.02,126.64, 126.32, 126.23, 126.19, 121.52, 117.67, 116.99, 114.61, 50.81, 26.09,24.62. 19 F NMR (377 MHz, DMSO- d 6) δ -60.80. HR-ESI-MS: m / z 474.1901 [M+H] + ,(calcd for C 27 H 22 F3N5, 473.1901).

[0045] Example 23: Preparation of the final product ZRMQ-15: In a round-bottom flask, E15 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 4-(piperidin-1-yl)-6-(5-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrrolidin[2,3-b]pyridin-3-yl)quinazolin 4-(piperidin-1-yl)-6-(5-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1 H -pyrrolo[2,3- b pyridin-3-yl)quinazoline (ZRMQ-15), a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.13 (s, 1H), 8.56 (d, J = 17.8 Hz, 2H), 8.45 (d, J = 30.8 Hz, 2H), 8.31-8.02 (m, 3H), 7.88(dd, J = 8.7, 18.9 Hz, 2H), 6.55 (d, J = 8.7 Hz, 1H), 3.75 (s, 4H), 3.43 (s, 4H), 1.97 (s, 4H), 1.72 (s, 6H). 13 C NMR (101 MHz, DMSO- d6) δ 164.39, 156.66,153.55, 148.76, 146.62, 142.04, 136.20, 132.71, 132.34, 129.09, 127.67,126.13, 124.40, 121.21, 117.01, 114.10, 106.82, 50.83, 46.95, 26.12, 25.50,24.67. HR-ESI-MS: m / z 476.2556 [M+H] + , (calcd for C 29 H 29 N7, 475.2556).

[0046] Example 24: Preparation of the final product ZRMQ-16: In a round-bottom flask, E16 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-(6-Methylpyridin-3-yl)-1 H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-16), a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.24 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H),8.68 – 8.46 (m, 3H), 8.32-8.00 (m, 4H), 7.86 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 3.75 (t, J = 4.6 Hz, 4H), 2.54 (s, 3H), 1.71 (d, J = 10.2 Hz, 6H). 13 C NMR (101 MHz, DMSO- d6) δ 164.37, 157.02, 153.60, 150.40, 149.33,147.65, 142.58, 135.25, 132.46, 132.40, 132.04, 129.10, 126.56, 126.46,125.76, 123.57, 121.44, 117.69, 116.99, 114.43, 50.80, 26.09, 24.66, 24.17.HR-ESI-MS: m / z 421.2134 [M+H] + , (calcd for C 26 H 24 N6, 420.2134).

[0047] Example 25: Preparation of the final product ZRMQ-17: In a round-bottom flask, E17 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-(4-Meth ... H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-17), a gray solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.15 (d, J = 2.8 Hz, 1H), 8.66-8.51 (m, 2H), 8.44 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 1.9, 8.7 Hz, 1H), 8.19 (d, J = 2.0Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.76-7.66 (m,2H), 7.13-6.98 (m, 2H), 3.82 (s, 3H), 3.75 (t, J = 4.9 Hz, 4H), 1.85-1.55 (m,6H). 13 C NMR (101 MHz, DMSO- d6) δ 164.42, 159.18, 153.53, 150.28, 148.92,142.53, 132.68, 132.32, 131.75, 129.42, 129.06, 128.72, 126.22, 125.12,121.19, 117.60, 117.01, 114.88, 114.18, 55.68, 50.83, 26.13, 24.65. HR-ESI-MS: m / z 436.2131 [M+H] + , (calcd for C 27 H 25 N5O, 435.2131).

[0048] Example 26: Preparation of the final product ZRMQ-18: In a round-bottom flask, E18 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-(2,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyrimidin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-(2,4-Dimethoxyphenyl)-1 H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-18), a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.11 (d, J = 2.7 Hz, 1H), 8.58(s, 1H), 8.34 (dd, J = 1.9, 15.0 Hz, 2H), 8.23 ​​(dd, J = 1.9, 8.7 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.76-6.62 (m, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.70(d, J = 5.7 Hz, 4H), 1.67 (s, 6H). 13C NMR (101 MHz, DMSO- d 6) δ 164.44,160.64, 157.75, 153.50, 150.27, 148.46, 144.61, 132.78, 132.16, 131.86,129.09, 127.81, 127.16, 125.83, 121.01, 120.77, 117.08, 116.97, 113.86,105.74, 99.37, 56.05, 55.79, 55.38, 50.82, 26.04, 24.68. HR-ESI-MS: m / z466.2236 [M+H] + , (calcd for C 28 H 27 N5O2, 465.2236).

[0049] Example 27: Preparation of the final product ZRMQ-19: In a round-bottom flask, E19 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give 4-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzaldehyde 4-(3-(4-(Piperidin-1-yl)quinazolin-6-yl)-1 H -pyrrolo[2,3- b pyridin-5-yl)benzaldehyde (ZRMQ-19), a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.29 (d, J = 2.7 Hz, 1H), 10.08 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 8.27 (dd, J = 1.9, 8.7 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 2.6 Hz, 1H), 8.12-7.98 (m, 4H), 7.87 (d, J = 8.7 Hz, 1H), 3.76 (t, J= 5.0 Hz, 4H), 1.74 (d, J = 22.8 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 193.23, 164.37, 153.62, 150.44,149.64, 145.29, 142.98, 135.25, 132.39, 132.34, 130.62, 129.12, 128.13,128.10, 126.66, 126.27, 121.51, 117.71, 116.99, 114.67, 50.80, 26.10, 24.65.HR-ESI-MS: m / z 434.1976 [M+H] + , (calcd for C 27 H 23 N5O, 433.1976).

[0050] Example 28: Preparation of the final product ZRMQ-20: In a round-bottom flask, E20 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 1-(4-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acetone 1-(4-(3-(4-(Pi ... H -pyrrolo[2,3- b pyridin-5-yl)phenyl)ethan-1-one (ZRMQ-20), white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.27 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.60 (d, J = 5.4 Hz, 2H), 8.27 (dd, J = 1.9, 8.6 Hz, 1H), 8.20 (d, J =2.0 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.97 (d, J =8.3 Hz, 2H), 7.87 (d,J = 8.7 Hz, 1H), 3.76 (t, J = 4.8 Hz, 4H), 2.64 (s, 3H), 1.71 (s, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 197.94, 164.36, 153.59,150.40, 149.56, 143.89, 142.87, 135.76, 132.38, 132.34, 129.33, 129.09,128.25, 127.59, 126.57, 126.02, 121.44, 117.68, 116.98, 114.61, 50.80, 27.22,26.10, 24.64. HR-ESI-MS: m / z 448.2132 [M+H] + , (calcd for C 28 H 25 N5O, 447.2132).

[0051] Example 29: Preparation of the final product ZRMQ-21: In a round-bottom flask, E21 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 1-(5-(3-(4-(piperidin-1-yl)quinazolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acetone 1-(5-(3-(4-(Piperidin-1-yl)quinazolin-6-yl)-1 H -pyrrolo[2,3- b pyridin-5-yl)pyridin-2-yl)ethan-1-one (ZRMQ-21), a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.34 (s, 1H), 9.20 (d, J = 2.3 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.59(s, 1H), 8.44 (dd, J = 2.3, 8.2 Hz, 1H), 8.29 (dd, J= 1.9, 8.7 Hz, 1H),8.22-8.13 (m, 2H), 8.06 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 3.76(t, J = 4.8 Hz, 4H), 2.69 (s, 3H), 1.78-1.60 (m, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 199.53, 164.32, 153.63, 151.88, 150.45, 149.73, 147.93, 142.88, 138.45,135.78, 132.40, 132.23, 129.09, 126.73, 126.59, 125.39, 121.74, 121.64,117.78, 116.95, 114.74, 50.79, 26.16, 26.06, 24.64. HR-ESI-MS: m / z 449.2083[M+H] + , (calcd for C 27 H 25 N6O, 448.2083).

[0052] Example 30: Preparation of the final product ZRMQ-22: In a round-bottom flask, E22 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-(2-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazoline 6-(5-(2-Methoxypyridin-3-yl)-1 H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-22), a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.22 (s, 1H), 8.59 (s, 1H), 8.47 (dd, J = 2.0, 13.4 Hz, 2H), 8.27-8.21 (m, 2H), 8.16 (d, J = 4.8 Hz, 2H), 7.91 (dd, J= 1.9, 7.3 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.15(dd, J = 5.0, 7.3 Hz, 1H), 3.90 (s, 3H), 3.72 (dd, J = 3.3, 5.3 Hz, 4H), 1.66(d, J = 6.1 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 164.43, 160.88, 153.55,150.34, 148.92, 146.25, 144.29, 139.71, 132.54, 132.20, 129.11, 127.96,126.20, 125.32, 122.61, 120.96, 117.98, 117.09, 116.95, 114.10, 53.82, 50.79,26.01, 24.66. HR-ESI-MS: m / z 437.2085 [M+H] + , (calcd for C 26 H 24 N6O, 436.2084).

[0053] Example 31: Preparation of the final product ZRMQ-23: In a round-bottom flask, E23 (1.0 equivalent) was deprotected from the p-toluenesulfonyl group to give the product 6-(5-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(piperidin-1-yl)quinazolin 6-(5-(2-Methoxypyridin-4-yl)-1 H -pyrrolo[2,3- b pyridin-3-yl)-4-(piperidin-1-yl)quinazoline (ZRMQ-23), a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.31 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H),8.66-8.54 (m, 2H), 8.31-8.09 (m, 4H), 7.87 (d, J = 8.6 Hz, 1H), 7.46 (dd, J=1.6, 5.4 Hz, 1H), 7.27 (d, J = 1.5 Hz, 1H), 3.92 (s, 3H), 3.85-3.65 (m, 4H), 1.87-1.52 (m, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 164.91, 164.38, 153.59,150.43, 149.98, 149.67, 147.80, 142.65, 132.31, 132.25, 129.07, 126.66,126.40, 126.16, 121.45, 117.59, 116.97, 115.86, 114.68, 108.14, 53.69, 50.79,26.10, 24.62. HR-ESI-MS: m / z 437.2083 [M+H] + , (calcd for C 26 H 24 N6O,436.2083).

[0054] Example 32: Single-concentration NO release level test and MTT cytotoxicity test BV-2 cells were packed at 4 × 10⁶ cells per well. 4 Cells were seeded at a density of [number] cells per well in 96-well plates and incubated overnight at 37°C. After cell adhesion and growth, the drug-treated groups were treated with the corresponding final concentration of the test compound, while the blank control group was treated with an equal volume of DMSO-containing medium. Incubation was continued for 24 hours. Subsequently, 20 [units of a specific chemical compound] was added to each well. μ Incubate with 5 mg / mL MTT solution for 4 hours. After incubation, discard the MTT-containing culture medium and add 150 mL of MTT solution to each well. μ L DMSO was placed on a horizontal shaker and shaken for 5 minutes to dissolve the crystals. The absorbance was measured at 490 nm using a microplate reader, and the cell viability was calculated based on the absorbance.

[0055] BV-2 cells were packed at 4 × 10⁶ cells per well. 4 Cells were seeded at a density of [number] cells per well in 96-well plates and incubated overnight at 37°C. After cell adhesion and growth, the drug-treated groups were treated with the corresponding concentration of the test compound, while the blank control and model groups were treated with an equal volume of DMSO-containing medium and incubated for 1 h. The model group and drug-treated groups were treated with a final concentration of 0.5 [units unclear]. μ Add g / mL LPS to the blank control group and add an equal volume of culture medium, and continue incubation for 24 h. Take 50 g / mL of LPS... μAdd L of supernatant and diluted standard to a 96-well plate, and add 50 μL of supernatant to each well sequentially. μ After mixing the samples with Griess Reagent I and Griess Reagent II, the absorbance was immediately measured at 562 nm using a microplate reader. A standard curve was plotted based on the absorbance values ​​of the diluted standards and blank wells, and the sample concentration was calculated accordingly. The results are shown in Table 1.

[0056] Table 1. Compounds ZRMQ-1 to ZRMQ-5 in 1 μ Evaluation of the inhibition rate of LPS-induced cytotoxicity and NO release in BV2 cells under M-mode

[0057] a The anti-inflammatory activity of the compounds was expressed as the NO inhibition rate in BV2 cells, and the results are expressed as mean ± standard deviation (n=3). b Compound treatment of BV2 cells in 1 μ Survival rate (%) under M, results are expressed as mean ± standard deviation (n=3).

[0058] As shown in Table 1, some of the compounds prepared in this invention have a [result in] 1 [unit / percentage]. μ At a concentration of M, it can effectively inhibit LPS-induced NO release in BV2 cells and has low cytotoxicity.

[0059] The following preferred compounds ZRMQ-6, ZRMQ-8, ZRMQ-9, ZRMQ-15, ZRMQ-22, and ZRMQ-23 will be further studied, while other compounds still have similar technical effects.

[0060] Example 33: TNF- α Release level detection BV-2 cells were planted at a rate of 1 × 10⁶ cells per well. 4 Cells were seeded at a density of [number] cells per well in 96-well plates and incubated overnight at 37°C. After cell adhesion and growth, the drug-treated groups were treated with the corresponding final concentration of the test compound, while the blank control and model groups were incubated with an equal volume of DMSO-containing medium for 1 h. The model and drug-treated groups were then treated with LPS at a final concentration of 10 ng / mL, while the blank control group was incubated with an equal volume of medium for another 2 h. The cell supernatant was collected and diluted 1:5 with diluent, and then the ELISA kit was used strictly according to the instructions. The results are shown in Table 2. Figure 6 .

[0061] Example 34: Detection of IL-6 Release Levels BV-2 cells were distributed at a rate of 2 × 10⁶ cells per well. 4Cells were seeded at a density of [number] cells per well in 96-well plates and incubated overnight at 37°C. After cell adhesion and growth, the drug-treated groups were treated with the corresponding final concentration of the test compound, while the blank control group and model group were treated with an equal volume of DMSO-containing medium and incubated for 1 hour. The model group and drug-treated groups were treated with a final concentration of 0.5 [units of chemical compound]. μ Add g / mL LPS to the blank control group and add an equal volume of culture medium, and continue incubation for 6 hours. Take the cell supernatant, dilute it with diluent at a ratio of 1:5, and then strictly follow the ELISA kit instructions. The detection results are shown in Table 2 and [Table data missing]. Figure 6 .

[0062] Table 2. Inhibition rate of LPS-induced inhibition of inflammatory release in BV2 cells after treatment with 1 μM compound.

[0063] From Table 2 and Figure 6 The results showed that compounds ZRMQ-6, ZRMQ-8, ZRMQ-9, ZRMQ-15, ZRMQ-22 and ZRMQ-23 all exhibited excellent IL-6 inhibitory effects compared to the control group.

[0064] Example 35: Kinase Activity Assay The IC50 of the target compound was determined using the ADP-Glo™ kinase assay kit. 50 Value. The specific experimental steps are as follows: First, use the Echo 655 dispensing system to accurately transfer 20 nL of the test compound into a 384-well sample preparation plate, then add 2 μ L 2× kinase was gently mixed with a metal ion mixture (kinase working concentration: DYRK1A, 0.9 nM) and incubated at 25°C for 10 min. Then, 2 μ L 2× substrate and ATP mixed solution (working substrate concentration: 0.1 mg / mL; working ATP concentration: DYRK1A, 30) μ M; ), centrifuged at 1000 rpm for 1 min, then incubated at 25°C for 60 min. Subsequently, 4 μ L ADP-Glo ​​reagent, centrifuged at 1000 rpm for 1 min, and incubated at 25 °C for 40 min. Finally, add 8 μ The L-kinase assay reagent was centrifuged at 1000 rpm for 1 min and incubated at 25°C for 40 min. After incubation, the luminescence signal was recorded using a BMG multi-mode microplate reader. The results are shown in Table 3.

[0065] Table 3. DYRK1A enzyme inhibition of compounds measured using the DYRK1A ADP-Glo ​​assay (ATP concentration = 30). μM), Staurosporine was used as a positive control.

[0066] As shown in Table 3, compounds ZRMQ-6, ZRMQ-8, ZRMQ-9, ZRMQ-15, ZRMQ-22 and ZRMQ-23 all exhibited nanomolar-level inhibitory effects on DYRK1A.

[0067] Based on the above tests, compounds ZRMQ-8 and ZRMQ-22 were further selected and subjected to the following experiments. Other compounds still have similar technical effects.

[0068] Example 36: Multi-concentration cell viability assay BV-2 cells: BV-2 cells were packed at a rate of 4 × 10⁶ cells per well. 4 Cells were seeded at a density of [number] cells per well in 96-well plates and incubated overnight at 37°C. After cell adhesion and growth, the drug-treated groups were treated with the corresponding final concentration of the test compound, while the blank control group was treated with an equal volume of DMSO-containing medium. Incubation was continued for 24 hours. Subsequently, 20 [units of a specific chemical compound] was added to each well. μ Add 5 mg / mL MTT solution to each well and incubate for another 4 hours. After incubation, discard the MTT-containing culture medium and add 150 μL of the solution to each well. μ L DMSO was placed on a horizontal shaker and shaken for 5 min to dissolve the crystals. The absorbance was measured at 490 nm using a microplate reader, and the cell viability was calculated based on the absorbance.

[0069] The results are as follows Figure 7 As shown, compared with the positive control drug dexamethasone, both compounds showed some toxicity to BV2 cells after 24 hours of treatment. However, compared with the two experimental groups, ZRMQ-22 had weaker cytotoxicity than ZRMQ-8.

[0070] Example 37: In vivo acute toxicity test C57BL / 6 mice were used to study the acute toxicity of compounds ZRMQ-8 and ZRMQ-22. Mice were administered the drugs by gavage once and then observed for two weeks, with daily changes in body weight recorded for each group. During the experiment, the animals had free access to food and water. The experimental protocol was reviewed and approved by the Animal Ethics Committee of the Northern Theater General Hospital of the Chinese People's Liberation Army (Ethics Review No.

[2024] 052).

[0071] The results are as follows Figure 8As shown in Figure A, all mice in the ZRMQ-22 group treated at a dose of 500 mg / kg survived within 14 days, while mice in the other experimental groups died. Figure B shows that the body weight of mice in the ZRMQ-22 group treated at a dose of 500 mg / kg did not change significantly compared to the control group during the 14-day period. Figure C shows representative H&E staining results of major organs in mice in the control group and the ZRMQ-22 group treated at a dose of 500 mg / kg; no tissue abnormalities were observed in either group. The experiment demonstrates that ZRMQ-22 has lower toxicity and better in vivo safety than ZRMQ-8.

[0072] In summary, the quinazoline-azaindole compounds proposed in this invention achieve anti-neuroinflammatory effects by inhibiting DYRK1A; quinazoline-azaindole compounds can reduce the expression of inflammatory factor-related genes in an LPS-induced BV2 microglial inflammation model, thereby reducing the levels of inflammatory factors in the hippocampus and cortex, alleviating neuronal pathological damage caused by neuroinflammation, and improving cognitive impairment caused by neuroinflammation; in summary, quinazoline compounds inhibit DYRK1A and downregulate NF-κB... κ It can penetrate signaling pathways such as B, reduce the expression and release of inflammatory factors, improve brain tissue pathology, and alleviate cognitive impairment, thus possessing significant clinical application value. In particular, compound ZRMQ-22 has an IC50 of DYRK1A. 50 =0.35 nM, in LPS-induced BV2 cells, the IC50 inhibitory concentration of NO release was 0.35 nM. 50 It is 1.05 μ M; 1 μ At M dosage concentration, TNF-α α The inhibition rate of release was 64.99%, and the inhibition rate of IL-6 was 114.35%; at an oral dose of 30 mg / kg, it could exert a good in vivo anti-neuroinflammatory effect.

[0073] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. Quinazoline-azaindole compounds and their pharmaceutically acceptable salts, selected from: ； 。 2. A method for preparing the quinazoline-azaindole compound as described in claim 1, characterized in that, The steps are as follows: (1) After the nucleophilic substitution reaction of A (6-bromo-4-chloroquinazoline) and piperidine, the intermediate 1 was obtained by the Miyaura reaction with bipinnatrol boronic acid ester; compounds C1, C2, and C3 were sulfonated to obtain compounds D1, D2, and D3, and then D1, D2, and D3 were coupled with intermediate 1 by Suzuki to obtain E1, E2, and E3, respectively. Finally, the p-toluenesulfonyl group was removed under alkaline hydrolysis to obtain the target compound ZRMQ1-3. Compound C1 is C2 is C3 is ; (2) Compounds C4 and C5, by omitting the sulfonation and removal of p-toluenesulfonyl groups, yield the target compound ZRMQ4-5; Compound C4 is C5 is ; (3) Compounds C6-C8 were sulfonated to obtain compounds D4-D6. Then, compounds D4-D6 were coupled with intermediate 1 via Suzuki coupling to obtain compounds E4-E6. Finally, the p-toluenesulfonyl group was removed under alkaline hydrolysis to obtain the target compound ZRMQ6-8. Compound C6 is C7 is C8 is ; (4) Using compound C9, first sulfonate to obtain D7, selectively Suzuki couple with intermediate, react with intermediate 1 at the 3-iodine atom site to obtain intermediate 2, intermediate 2 can react with arylboronic acid pinacol ester to obtain the corresponding intermediates E7-E21, and then remove the p-toluenesulfonyl group to obtain the target compound ZRMQ9-23; Among them, compound C9 is ; Alternatively, compound C3 is first sulfonated to obtain D3, and then D3 is coupled with the corresponding arylboronic acid pinacol ester to obtain intermediate D8-D22. Selective bromination at the 3-position of azidoindole is then performed: D8-D22 is dissolved in anhydrous DMF, NBS is added while stirring, and then the temperature is slowly increased at room temperature under N2 atmosphere. After the reaction is completed, ice water is added and stirred, and a powdery white solid precipitates. The solid precipitate is collected by filtration, dried to obtain the target product, and then coupled with intermediate 1 and the removal of the p-toluenesulfonyl group to obtain the target compound ZRMQ9-23.

3. The preparation method according to claim 2, characterized in that, The general structural formula of the arylboronic acid pinacol ester is: Where R is: , , , , , , , , , , , , , , .

4. The use of a quinazoline-azaindole compound as described in claim 1 in the preparation of an anti-Alzheimer's disease drug.

5. The use of a quinazoline-azaindole compound as described in claim 1 in the preparation of a drug that inhibits DYRK1A.

6. The use of a quinazoline-azaindole compound as described in claim 1 in the preparation of a drug for inhibiting the expression of inflammatory factors in brain tissue.

7. The use of a quinazoline-azaindole compound as described in claim 1 in the preparation of drugs that inhibit DYRK1A and drugs that inhibit the expression of inflammatory factors in brain tissue.

8. The application according to any one of claims 6-7, characterized in that, The inflammatory factors include TNF-α. α IL-6 and iNOS.

9. An application as described in any one of claims 4-7, characterized in that, The quinazoline-azaindole compound is the active ingredient of the drug.

10. The application according to claim 9, characterized in that, The drug may also include pharmaceutically acceptable carriers or adjuvants.

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