Azaindole compound as well as preparation method and application thereof

Abstract

The invention relates to an azaindole compound as well as a preparation method and application thereof, and belongs to the field of medicines. The invention provides a compound shown in a general formula I or a pharmaceutically acceptable salt thereof. The azaindole compound provided by the invention has a novel chemical structure, most of the compounds have high-level inhibitory activity on TNIK in vitro, and the inhibitory activity of most of the compounds on TNIK is superior to that of the disclosed compounds and a TNIK inhibitor INS018055 entering a clinical II stage at present. The compound can be used for preventing and / or treating various diseases such as cancers, nervous system diseases, fibrotic diseases or metabolic diseases, and has a very wide application prospect.

Description

Technical Field

[0001] This invention relates to an azaindole compound, its preparation method, and its application, belonging to the pharmaceutical field. Background Technology

[0002] Traf2-and-Nck-interacting kinase (TNIK) is a member of the germinal center kinase family (GCKs) and is an important interacting protein kinase found in various organs and tissues of the human body. TNIK is mainly composed of conserved N-terminal kinase domains, intermediate domains, and C-terminal kinase domains from the GCK family. These domains endow it with a variety of functions, enabling it to participate in biological processes such as cell motility, survival, proliferation, and differentiation.

[0003] TNIK, as an integrative regulator of multiple signaling pathways, plays a central role in tumorigenesis and development. Abnormal expression of TNIK is associated with cancer occurrence and prognosis. Previous studies have reported that TNIK is a downstream signaling protein of the Wnt / β-catenin signaling pathway and an important regulator of the TCF4-β-catenin transcription complex. TNIK directly phosphorylates the TCF4 / LEF1 transcription factor, stabilizes the nuclear localization of β-catenin, and drives stem cell characteristics and cell cycle progression in colorectal cancer and breast cancer (Shitashige M et al. Cancer Research, 2010, 70(12):5024-33). In addition, TNIK is located in a region of high-frequency amplification at the distal end of chromosome 3q, and is frequently amplified in tumors such as lung squamous cell carcinoma and head and neck squamous cell carcinoma (approximately 40%–50%). Studies have reported that TNIK can directly phosphorylate key sites (such as S13 and S315) of the tumor suppressor protein Merlin (encoded by the NF2 gene), altering Merlin's conformation and weakening its function, thereby activating phosphorylation of focal adhesion kinase (FAK) at the Y397 site. Phosphorylated FAK promotes tumor cell survival, proliferation, and migration through downstream PI3K / AKT and RAS / MAPK signaling pathways (Torres-Ayuso P et al. Cancer Discovery, 2021, 11(6):1411-23).

[0004] TNIK plays a crucial role in neural development by regulating the cytoskeleton, neuronal polarity, and axonal guidance. Studies have found that neurogenesis in the dentate gyrus is impaired in TNIK knockout mice, suggesting that TNIK is essential for maintaining cognitive function. Furthermore, abnormal TNIK expression may disrupt synaptic plasticity and neuronal differentiation, leading to an increased risk of diseases such as schizophrenia, depression, and bipolar disorder. Previous studies have reported that TNIK can synergize with CNK 2, a kinase inhibitor highly expressed in dendrites, to regulate TNIK expression levels in dendritic spines, ensuring normal dendritic growth and development (Zieger HL et al. Scientific Reports, 2020, 10(1):5709). In addition, the neural progenitor cell Nedd4-1 forms a spatially colocalized ternary complex with TNIK and Rap 2A in neurons, regulating neuronal maturation and differentiation (Kawabe H et al. Neuron, 2010, 65(3):358-72). Abnormalities in these functions can lead to synaptic plasticity damage and impaired neural differentiation, significantly increasing susceptibility to mental illnesses such as schizophrenia, major depressive disorder, and bipolar disorder.

[0005] Furthermore, TNIK can inhibit EMT / FMT processes, inflammatory responses, and extracellular matrix deposition by integrating and regulating multiple fibrosis-related pathways, such as TGF-β / SMAD, Wnt / β-catenin, Hippo / YAP-TAZ, JNK, and NF-κB, thereby achieving anti-fibrotic effects on multiple organs (Ren F et al. Nature Biotechnology, 2025, 43(1):63-75). TNIK also plays a central role in the metabolic regulation of obesity and type 2 diabetes. Studies have found that TNIK may regulate cellular glucose sensing and lipid synthesis by regulating DHAP levels and affecting mTORC1 pathway activity (Pham TCP et al. Science Advances, 9(32):eadf7119).

[0006] TNIK, as an emerging target associated with various diseases, has attracted widespread attention. Currently, the chemical structures of some reported TNIK inhibitors are shown below. The TNIK inhibitor NCB-0846 has shown potent anti-tumor activity in xenograft models of colorectal cancer and lung squamous cell carcinoma, but its target specificity is insufficient. The research team of Sichuan University disclosed a selective TNIK inhibitor in patent CN113773316B, in which the preferred compound 6 achieved a significant improvement in target specificity compared to NCB-0846, but its kinase inhibitory activity and cell activity still need to be optimized (LI Y et al. Journal of Medicinal Chemistry, 2022, 65(3):1786-807). Incheon Intelligent Technology Co., Ltd. has developed INS018_055 using an AI platform, which has a high level of inhibitory activity against TNIK and exhibits excellent kinase selectivity. This inhibitor has entered phase II clinical trials as a treatment for idiopathic pulmonary fibrosis (IPF), and its pharmacodynamic characteristics in multiple indications need to be further validated clinically. Therefore, the research and development of novel TNIK inhibitors is of great significance for the treatment of various diseases, including cancer, neurological disorders, fibrotic diseases, and metabolic diseases.

[0007] Summary of the Invention

[0008] This invention provides an aza-indole compound, its preparation method, and its applications. Studies have shown that this class of compounds can significantly inhibit TNIK activity. This invention relates to compounds containing an aza-indole structure of general formula I, their stereoisomers, and pharmaceutically acceptable salts, methods for their preparation, and pharmaceutical compositions containing said compounds, wherein the substituent R... 1 R 2 R 3 R 4 R 5 R 6 The meanings of 'n' and 'n' are explained in the specification. This invention relates to compounds with high levels of inhibitory activity against TNIK, and the azaindole compounds, their stereoisomers, and pharmaceutically acceptable salts can be used to prepare drugs for the prevention and / or treatment of various diseases such as cancer, nervous system diseases, fibrotic diseases, or metabolic diseases.

[0009] This invention relates to azaindole compounds of general formula I, their stereoisomers, and pharmaceutically acceptable salts.

[0010]

[0011] in,

[0012] n is selected from 1, 2, 3, or 4;

[0013] R 1 Selected from hydrogen, hydroxyl, (C1–C6)alkyl, (C1–C6)alkoxy, (C1–C6)alkoxyformyl or

[0014] R a and R b Each is independently selected from hydrogen, (C1–C6)alkyl, (C3–C8)cycloalkyl or (C3–C8)cycloalkyl(C1–C4)alkylene;

[0015] Or R a R b Together with the nitrogen atoms attached to them, they form a 3–7-membered nitrogen-containing heterocycle, which contains 1–3 heteroatoms selected from N, O, or S; the nitrogen-containing heterocycle may optionally be separated by 1–3 R atoms. 7 replace;

[0016] R 2 R 3 R 4 R 5 R 6 Each is independently selected from hydrogen, halogen, cyano, (C1–C4)alkylsulfonylamino or (C3–C8)cycloalkylsulfonylamino;

[0017] Or R 3 R 4 Together with the carbon atoms attached to them, they form a 5–6-membered aromatic ring or heteroaromatic ring, the heteroaromatic ring containing 1–3 heteroatoms selected from N, O, or S; the aromatic ring or heteroaromatic ring may optionally be surrounded by 1–3 R atoms. 8 replace;

[0018] R 7 Selected from hydrogen, halogens, (C1–C6) alkyl or (C3–C8) cycloalkyl;

[0019] R 8 It is selected from hydrogen, (C1–C6)alkyl, (C1–C4)alkylsulfonyl or (C3–C8)cycloalkylsulfonyl.

[0020] This invention preferably relates to azaindole compounds of general formula I and their stereoisomers, as well as pharmaceutically acceptable salts, wherein,

[0021] n is selected from 2 or 3;

[0022] R 1 Selected from hydrogen, (C1–C6)alkoxy or

[0023] R a and R bEach is independently selected from hydrogen, (C1–C6)alkyl, (C3–C6)cycloalkyl, or (C3–C6)cycloalkyl(C1–C4)alkylene;

[0024] Or R a R b Together with the nitrogen atoms attached to them, they form a 4–6-membered nitrogen-containing heterocycle, which contains 1–3 heteroatoms selected from N or O; the nitrogen-containing heterocycle may optionally be separated by 1–3 R atoms. 7 replace;

[0025] R 2 R 6 All are hydrogen;

[0026] R 5 It is hydrogen or cyano;

[0027] R 3 R 4 Each is independently selected from hydrogen, cyano, (C1–C4)alkylsulfonylamino or (C3–C8)cycloalkylsulfonylamino;

[0028] Or R 3 R 4 Together with the carbon atoms attached to them, they form a 5–6-membered aromatic ring or heteroaromatic ring, the heteroaromatic ring containing 1–3 heteroatoms selected from N or O; the aromatic ring or heteroaromatic ring may optionally be surrounded by 1–3 R atoms. 8 replace;

[0029] R 7 Selected from hydrogen, fluorine, or (C1–C6) alkyl groups;

[0030] R 8 It is selected from hydrogen, (C1–C4)alkylsulfonyl or (C3–C8)cycloalkylsulfonyl.

[0031] The present invention more preferably relates to azaindole compounds of general formula I and their stereoisomers, as well as pharmaceutically acceptable salts, wherein,

[0032] n is selected from 2 or 3;

[0033] R 1 Selected from (C1–C6) alkoxy or in, Selected from:

[0034] Selected from:

[0035] The azaindole compounds and their stereoisomers represented by general formula I of this invention, as well as pharmaceutically acceptable salts, are preferably selected from the following compounds, but these compounds do not imply any limitation on this invention:

[0036]

[0037]

[0038]

[0039]

[0040] Furthermore, the present invention also includes prodrugs of the compounds of the present invention. The prodrugs of the compounds of the present invention are derivatives of general formula I, which may have weak or no activity on their own, but are converted into the corresponding biologically active form under physiological conditions (e.g., through metabolism, solvation or other means) after administration.

[0041] The present invention also provides a method for preparing azaindole compounds of general formula I, their stereoisomers, and pharmaceutically acceptable salts.

[0042] The method for preparing the azaindole compound represented by general formula I of this invention includes the following steps:

[0043]

[0044] (a) Intermediate 2 was prepared by substitution reaction of 5-bromo-7-azaindole with N-iodosuccinimide;

[0045] (b) Using intermediate 2 as a raw material, react with p-toluenesulfonyl chloride to prepare intermediate 3;

[0046] (c) Using intermediate 3 as a raw material, react with the corresponding arylboronic acid or borate ester. Intermediate 4 was prepared by the Suzuki-Miyaura coupling reaction;

[0047] (d) Using intermediate 5 as a raw material, react with the corresponding haloalkanes (R1-(CH2)). n Intermediate 6 was prepared by nucleophilic substitution reaction of -X (where X is a halogen);

[0048] (e) Using intermediate 6 as a raw material, intermediate 7 was prepared by coupling reaction with pinacol diboronic acid ester;

[0049] (f) Intermediate 8 was prepared by the Suzuki-Miyaura coupling reaction of intermediates 4 and 7;

[0050] (g) Using intermediate 8 as a raw material, the target compound in general formula I was prepared by removing the protecting group under alkaline conditions;

[0051] Alternatively, the compound can be prepared by the following steps:

[0052]

[0053] (a) Using intermediate 5 as a raw material, intermediate 9 was prepared by reacting it with 3-bromopropene in the presence of sodium hydride;

[0054] (b) Using intermediate 9 as a raw material, intermediate 10 was prepared by coupling reaction with pinacol diboronic acid ester;

[0055] (c) Intermediate 11 was prepared by Suzuki-Miyaura coupling reaction of intermediate 4 and intermediate 10;

[0056] (d) Using intermediate 11 as raw material, intermediate 12 was prepared under the action of osmium reagent and oxidant;

[0057] (e) Starting from intermediate 12, intermediate 8 is prepared by reductive amination of an amine compound with sodium cyanoborohydride or sodium triacetoxyborohydride.

[0058] (f) Using intermediate 8 as the starting material, the target compound in general formula I was prepared by removing the protecting group under alkaline conditions.

[0059] The above-described azaindole compounds of general formula I and their stereoisomers, as well as pharmaceutically acceptable salts, include salts formed with inorganic acids, organic acids, and alkali metal ions; the inorganic acids are selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, or phosphoric acid; the organic acids are selected from succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, or p-toluenesulfonic acid; and the alkali metal ions are selected from lithium ions, sodium ions, or potassium ions.

[0060] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine; "alkyl" refers to a straight-chain or branched alkyl group; "aromatic ring" refers to a monocyclic or polycyclic cyclic system containing only carbon atoms; "heteroaromatic ring" refers to a monocyclic or polycyclic cyclic system containing nitrogen, oxygen, or sulfur atoms; "nitrogen-containing heterocyclic ring" refers to a monocyclic or polycyclic cyclic system containing nitrogen atoms; the cyclic system may be aromatic or non-aromatic. This represents the junction of substituents.

[0061] The definitions given above for compounds of general formula I, and the terms used, have the following meanings:

[0062] (C1–C6)alkoxyformyl: (C1–C6)alkyl-O-CO-; (C3–C8)cycloalkyl(C1–C4)alkylene: (C3–C8)cycloalkyl linked to the structure via (C1–C4)alkylene; (C1–C4)alkylsulfonylamino: (C1–C4)alkyl-SO2-NH-; (C3–C8)cycloalkylsulfonylamino: (C3–C8)cycloalkyl-SO2-NH-; (C1–C4)alkylsulfonyl: (C1–C4)alkyl-SO2-; (C3–C8)cycloalkylsulfonyl: (C3–C8)cycloalkyl-SO2-.

[0063] This invention can contain a zazaindole compound of general formula I and its stereoisomers, as well as a pharmaceutically acceptable salt, as an active ingredient, and can be mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition. The carrier or excipient includes diluents, binders, wetting agents, disintegrants, lubricants, and flow aids known in the art. Diluents include, but are not limited to, starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, and dicalcium phosphate; wetting agents include, but are not limited to, water, ethanol, and isopropanol; binders include, but are not limited to, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, and polyethylene glycol; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, sodium carboxymethyl starch, and sodium dodecyl sulfonate; lubricants and flow aids include, but are not limited to, talc, silica, and polyethylene glycol.

[0064] The pharmaceutical composition of the present invention can be formulated into several dosage forms, including but not limited to injections, tablets, capsules, etc.

[0065] The azaindole compounds and their stereoisomers, as well as pharmaceutically acceptable salts of the present invention, can be used in combination with other active ingredients to achieve better therapeutic effects.

[0066] This invention also provides the use of azidoindo compounds of general formula I and their stereoisomers, as well as pharmaceutically acceptable salts, in the preparation of medicaments for the prevention and / or treatment of TNIK-related diseases. The TNIK-related diseases are selected from cancer, neurological diseases, fibrotic diseases, or metabolic diseases. The cancers are selected from lymphoma, non-small cell lung cancer, small cell lung cancer, head and neck cell carcinoma, glioma, neuroblastoma, squamous cell carcinoma of the lung, adenocarcinoma of the lung, bladder cancer, gastric cancer, colorectal cancer, colon cancer, kidney cancer, bile duct cancer, gastric cancer, esophageal squamous cell carcinoma, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, brain cancer, melanoma, multiple myeloma, skin cancer, epithelial cell carcinoma, leukemia, or cervical cancer; the neurological diseases are selected from schizophrenia, depression, Alzheimer's disease, or bipolar disorder; the fibrotic diseases are selected from idiopathic pulmonary fibrosis, myocardial fibrosis, renal fibrosis, liver fibrosis, or skin fibrosis; and the metabolic diseases are selected from obesity or diabetes.

[0067] The positive and progressive effects of this invention are as follows: the azaindole compounds provided by this invention have novel chemical structures, most of which exhibit high levels of inhibitory activity against TNIK in vitro, and most of which have superior inhibitory activity against TNIK compared to CN113773316B-compound 6 and the TNIK inhibitor INS018_055, which is currently in Phase II clinical trials. They can be used for the prevention and / or treatment of various diseases such as cancer, neurological diseases, fibrotic diseases, or metabolic diseases. Detailed Implementation

[0068] The examples provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation examples does not limit the scope of the invention in any way, and all raw materials are prepared by the methods described in the examples and preparation examples, by methods well known to those skilled in the art of organic chemistry, or are commercially available. The derivatives of the present invention are prepared by the methods described in the examples and preparation examples or by similar methods well known to those skilled in the art of organic chemistry.

[0069] Example 1: 3-(5-(4-(2-methoxyethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-1)

[0070]

[0071] Step 1: 5-Bromo-3-iodo-7-azaindole

[0072]

[0073] At room temperature, 5-bromo-7-azaindole (5 g, 25.37 mmol) was dissolved in acetone (100 mL). While stirring, NIS (6.28 g, 27.91 mmol) was added to the reaction solution. The reaction was carried out at room temperature for 1.5 h, during which white crystals precipitated. After the reaction was complete, the mixture was filtered, the filter cake was washed with acetone, and dried to give 7.13 g of a white solid, with a yield of 87%. ESI-MS m / z: 321.4 [M+H] + .

[0074] Step 2: 5-Bromo-3-iodo-1-p-toluenesulfonyl-1H-indole

[0075]

[0076] 5-Bromo-3-iodo-7-azaindole (7.13 g, 22.15 mmol) was dissolved in 70 mL of dry DMF solution at room temperature. Sodium hydride (0.79 g, 32.91 mmol) was slowly added to the reaction solution at 0 °C, and the reaction was carried out for 30 min at 0 °C. Then, p-toluenesulfonyl chloride (4.65 g, 24.39 mmol) was added to the reaction solution, and the reaction was carried out for 3 h at room temperature. After the reaction was complete, the reaction solution was poured into 250 mL of water, precipitating a yellowish-brown solid. The solid was filtered, and the filter cake was dried to give 9.86 g of the yellowish-brown solid, with a yield of 93%. ESI-MS m / z: 475.2 [M+H] + .

[0077] Step 3: 3-(5-bromo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzonitrile

[0078]

[0079] 5-Bromo-3-iodo-1-p-toluenesulfonyl-1H-indole (4.12 g, 8.66 mmol), 3-cyanobenzoboronic acid (1.39 g, 9.52 mmol), K₂CO₃ (2.39 g, 17.29 mmol), and Pd(dppf)Cl₂·CH₂Cl₂ (0.71 g, 0.86 mmol) were added sequentially to a mixed solution of 1,4-dioxane (40 mL) and water (10 mL), and reacted at 90 °C for 3 h under N₂ protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth sieve, the filter cake was washed with ethyl acetate (5 mL × 2), the filtrate was concentrated, water was added and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness and purified by column chromatography (DCM / PE, 1 / 50–1 / 20) to obtain 2.86 g of white solid, yield 73%. 1H NMR (600MHz, DMSO-d6) δ8.66(d,J=2.2Hz,1H),8.55(d,J=2.1Hz,1H),8.34(d,J=1.8Hz,1H),8.16(dt,J=7.9,1.4Hz,1H),8.05 (d,J=8.2Hz,2H),7.86–7.83(m,1H),7.70(dt,J=18.2,7.8Hz,2H),7.45(d,J=8.1Hz,2H),2.36(s,3H).ESI-MSm / z:451.8[M+H] + .

[0080] Step 4: Methyl 4-bromo-2-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate

[0081]

[0082] Methyl 4-bromo-2-hydroxybenzoate (5 g, 21.64 mmol), N-Boc-ethanolamine (3.49 g, 21.65 mmol), PPh3 (8.51 g, 32.43 mmol), and DIAD (5.47 g, 21.5 mmol) were added sequentially to a dry THF (50 mL) solution at room temperature under N2 protection. The reaction was carried out for 10 h at room temperature. After the reaction was completed as monitored by TLC, the reaction solution was concentrated, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (PE / EA, 1 / 25–1 / 20) to obtain 6.64 g of a yellow oil, with a yield of 82%. ESI-MS m / z: 373.5 [M+H] + .

[0083] Step 5: Methyl 2-(2-aminoethoxy)-4-bromobenzoate

[0084]

[0085] Methyl 4-bromo-2-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate (5 g, 13.36 mmol) was added to a solution of dichloromethane (50 mL) at room temperature. Trifluoroacetic acid (15 mL) was added with stirring at room temperature, and the reaction was allowed to proceed for 1 h at room temperature. After the reaction was complete, the reaction solution was concentrated and added to 50 mL of water. The pH of the reaction solution was adjusted to approximately 7 using 2N NaOH solution at 0 °C. The reaction solution was extracted with dichloromethane (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness to obtain 3.29 g of a yellow solid, with a yield of 91%. ESI-MS m / z: 273.4 [M+H] + .

[0086] Step 6: 8-Bromo-3,4-dihydrobenzo[f][1,4]oxazapyro-5(2H)-one

[0087]

[0088] Methyl 2-(2-aminoethoxy)-4-bromobenzoate (2 g, 7.29 mmol) was dissolved in toluene (40 mL) at room temperature. Triethylamine (1.5 g, 14.82 mmol) was added to the reaction solution at 0 °C, and the reaction solution was refluxed for 6 h. After the reaction was completed, the reaction solution was concentrated and added to 30 mL of water. The solution was extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (DCM / PE, 1 / 50–1 / 20) to give 1.50 g of white solid, with a yield of 85%. 1 HNMR(600MHz,DMSO-d6)δ8.43(t,J=5.5Hz,1H),7.73(d,J=8.4Hz,1H),7.31(dd,J=8.5,2.0Hz ,1H),7.25(d,J=2.0Hz,1H),4.33–4.31(m,2H),3.33(d,J=5.3Hz,2H).ESI-MSm / z:241.3[M+H] + .

[0089] Step 7: 8-Bromo-4-(2-methoxyethyl)3,4-dihydrobenzo[f][1,4]oxazapine-5(2H)-one

[0090]

[0091] At room temperature, 1 g (4.73 mmol) of 8-bromo-3,4-dihydrobenzo[f][1,4]oxazetaphen-5(2H)-one was dissolved in 20 mL of dry DMF. NaH (0.2 g, 8.33 mmol) was slowly added to the reaction solution at 0 °C, and the mixture was stirred for 20 min at 0 °C. Then, 0.8 g (8.37 mmol) of 2-chloroethyl methyl ether was added to the reaction solution, and the reaction was carried out at room temperature for 5 h. After the reaction was complete, the reaction solution was added to 40 mL of water and extracted with ethyl acetate (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give 1.19 g of a pale yellow solid, with a yield of 92%. ESI-MS m / z: 313.6 [M+H] + .

[0092] Step 8: 4-(2-methoxyethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)3,4-dihydrobenzo[f][1,4]oxazapyrone-5(2H)-one

[0093]

[0094] 8-Bromo-4-(2-methoxyethyl)3,4-dihydrobenzo[f][1,4]oxazapyro-5(2H)-one (1 g, 3.19 mmol), pinacol diboronate (1.21 g, 4.79 mmol), potassium acetate (0.94 g, 9.58 mmol), and Pd(dppf)Cl2·CH2Cl2 (0.25 g, 0.32 mmol) were sequentially added to a dry 1,4-dioxane (20 mL) solution and reacted at 90 °C for 4 h under N2 protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth liner, the filter cake was washed with ethyl acetate (5 mL × 2), the filtrate was concentrated, water was added and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness and purified by column chromatography (DCM / PE, 1 / 50) to give 0.71 g of white solid, yield 62%. ESI-MS m / z: 361.4 [M+H] + .

[0095] Step 9: 3-(5-(4-(2-methoxyethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile

[0096]

[0097] 4-(2-methoxyethyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)3,4-dihydrobenzo[f][1,4]oxazapyro-5(2H)-one (1 g, 2.77 mmol), 3-(5-bromo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzonitrile (1.49 g, 3.32 mmol), K2CO3 (1.14 g, 8.31 mmol) and Pd(dppf)Cl2·CH2Cl2 (0.22 g, 0.27 mmol) were added sequentially to a mixed solution of 1,4-dioxane (20 mL) and water (4 mL), and reacted at 90 °C for 3 h under N2 protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate (5 mL × 2). The filtrate was concentrated, water was added, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (DCM / MeOH, 1 / 70) to obtain 0.91 g of a white solid, yield 54%. ESI-MS m / z: 606.2 [M+H] + .

[0098] Step 10: 3-(5-(4-(2-methoxyethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile

[0099]

[0100] At room temperature, 0.1 g (0.16 mmol) of 3-(5-(4-(2-methoxyethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazono-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (4 mL) and 2 mL of 2N NaOH solution were added. The reaction was carried out at room temperature for 1 h. After the reaction was completed by TLC, the reaction solution was concentrated and added to 50 mL of water. The solution was extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and separated by column chromatography (DCM / MeOH, 1 / 35) to give 0.046 g of white solid, with a yield of 62%. 1 H NMR(600MHz,DMSO-d6)δ12.24(s,1H),8.65(s,1H),8.58(s,1H),8.27(s,1H),8.20(d ,J=7.8Hz,1H),8.13(s,1H),7.77(d,J=8.0Hz,1H),7.71(d,J=7.6Hz,1H),7.66(d,J= 7.8Hz,1H),7.62(d,J=8.3Hz,1H),7.50(s,1H),4.40(t,J=5.1Hz,2H),3.60–3.58(m, 4H),3.38(d,J=6.3Hz,2H),3.25(s,3H),1.83(t,J=6.8Hz,2H).ESI-MSm / z:451.1[MH] + .

[0101] Following the synthesis method in steps 7-10 of Example 1, 8-bromo-4-(2-methoxyethyl)3,4-dihydrobenzo[f][1,4]oxazaphene-5(2H)-one was reacted with 3-chloropropyl methyl ether to prepare the target compound in Example 2.

[0102] Example 2: 3-(5-(4-(2-methoxypropyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-2)

[0103]

[0104] 1 H NMR (600MHz, DMSO-d6) δ12.29(d,J=2.8Hz,1H),10.28(s,1H),8.65(d,J=2.1Hz,1 H),8.56(d,J=2.1Hz,1H),8.17(d,J=2.8Hz,1H),7.98(dd,J=27.5,1.8Hz,2H),7. 80(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.9Hz,1H),7.47–7.41(m,2H),4.41(t,J=5. 1Hz,2H),3.25(s,3H),3.18(s,3H),1.83(p,J=6.6Hz,2H).ESI-MSm / z:544.2[MH] + .

[0105] Following the synthetic method in steps 9-10 of Example 1, N-(3-(5-bromo-1-tolyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanophenyl)methanesulfonamide was reacted with the corresponding borate ester to prepare the target compounds in Examples 3-4.

[0106] Example 3: N-(3-cyano-5-(5-(4-(3-methoxyethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-3)

[0107]

[0108] 1 H NMR (600MHz, DMSO-d6) δ12.25(s,1H),8.64(d,J=2.1Hz,1H),8.58(d,J=2.2Hz,1H),8.28(d,J=1.8 Hz,1H),8.21–8.19(m,1H),8.13(d,J=2.7Hz,1H),7.77(d,J=8.1Hz,1H),7.71(d,J=7.6Hz,1H),7.6 6(t,J=7.7Hz,1H),7.62(dd,J=8.2,1.8Hz,1H),7.50(d,J=1.9Hz,1H),4.42(t,J=5.0Hz,2H),3.73 (t,J=5.5Hz,2H),3.63(t,J=4.9Hz,2H),3.55(t,J=5.5Hz,2H),3.31(s,3H).ESI-MSm / z:437.4[MH] + .

[0109] Example 4: N-(3-cyano-5-(5-(4-(3-methoxypropyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-4)

[0110]

[0111] 1 H NMR (600MHz, DMSO-d6) δ12.30(d,J=2.8Hz,1H),10.30(s,1H),8.66(d,J=2.1Hz,1H),8.56(d,J=2.3Hz, 1H),8.17(d,J=2.8Hz,1H),8.00(d,J=1.5Hz,1H),7.96(t,J=1.8Hz,1H),7.79(d,J=8.1Hz,1H),7.60(d d,J=8.1,1.8Hz,1H),7.46(d,J=1.8Hz,1H),7.43(t,J=1.7Hz,1H),4.42(t,J=4.9Hz,2H),3.73(t,J=5. 6Hz,2H),3.64(t,J=5.0Hz,2H),3.55(t,J=5.5Hz,2H),3.31(s,3H),3.18(s,3H).ESI-MSm / z:530.3[MH] + .

[0112] Example 5: 3-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-5)

[0113]

[0114] Step 1: 4-Allyl-8-bromo-3,4-dihydrobenzo[f][1,4]oxazapyro-5(2H)-one

[0115]

[0116] Following the synthesis method in step 7 of Example 1, 1.10 g of a pale yellow solid was prepared from 8-bromo-3,4-dihydrobenzo[f][1,4]oxazazepone-5(2H)-one and 3-bromopropene, with a yield of 92%. 1H NMR(400MHz,Chloroform-d)δ7.80(d,J=8.3Hz,1H),7.40–7.34(m,1H),5.95(ddt,J=16.6,10.1,6.1Hz,1H), 5.40–5.28(m,2H),4.43(t,J=5.0Hz,2H),4.31(d,J=6.1Hz,2H),3.56(t,J=5.0Hz,2H).ESI-MSm / z:281.3[M+H ]+ .

[0117] Step 2: 4-Allyl-8-(4,4,5,5-Tetramethyl-1,3,2-dioxoborane-2-yl)3,4-dihydrobenzo[f][1,4]oxazapyrone-5(2H)-one

[0118]

[0119] Following the synthesis method in step 8 of Example 1, 0.65 g of a white solid was prepared from 4-allyl-8-bromo-3,4-dihydrobenzo[f][1,4]oxazazepone-5(2H)-one, with a yield of 63%. 1 H NMR(400MHz,Chloroform-d)δ7.78(d,J=7.6Hz,1H),7.58(d,J=7.6Hz,1H),7.45(s,1H),5.98–5.79(m,1H),5. 24(d,J=8.3Hz,2H),4.32(t,J=5.3Hz,2H),4.25(d,J=6.1Hz,2H),3.43(t,J=5.3Hz,2H),1.34(s,12H).ESI-MS m / z:329.3[M+H] + .

[0120] Step 3: 3-(5-(4-allyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile

[0121]

[0122] 4-Allyl-8-(4,4,5,5-Tetramethyl-1,3,2-dioxoborane-2-yl)3,4-dihydrobenzo[f][1,4]oxazapyro-5(2H)-one (1 g, 3.03 mmol), 3-(5-bromo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzonitrile (1.64 g, 3.63 mmol), K2CO3 (1.26 g, 9.11 mmol) and Pd(dppf)Cl2 (0.22 g, 0.30 mmol) were added sequentially to a mixed solution of 1,4-dioxane (20 mL) and water (4 mL), and reacted at 90 °C for 3 h under N2 protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate (5 mL × 2). The filtrate was concentrated, water was added, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (DCM / MeOH, 1 / 80) to obtain 1.04 g of a pale yellow solid, with a yield of 60%. ESI-MS m / z: 574.3 [M+H] + .

[0123] Step 4: 3-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile

[0124]

[0125] At room temperature, 1 g (1.74 mmol) of 3-(5-(4-allyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazono-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (1 g) was dissolved in a mixture of 8 mL of 1,4-dioxane and 2 mL of water. Then, 0.06 g (0.17 mmol) of K₂O₄·2H₂O was added, and the mixture was stirred at room temperature for 20 min. Subsequently, 0.56 g (2.61 mmol) of NaIO₄ was added to the reaction mixture, and the reaction was carried out at room temperature for 1 h. After the reaction was complete, the reaction solution was added to 100 mL of water and extracted with dichloromethane (50 mL × 3). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (DCM / MeOH, 1 / 50) to give 0.62 g of white solid, with a yield of 62%. 1H NMR (600MHz, DMSO-d6) δ8.78(dd,J=7.3,2.1Hz,1H),8.57(dd,J=8.6,2.1Hz,1H),8.48(d,J=3.0Hz,1H),8.41(t ,J=1.9Hz,1H),8.26(dq,J=8.0,1.7Hz,1H),8.10(d,J=1.7Hz,1H),8.08(d,J=1.8Hz,1H),7.86(dd,J=7.7,1.5Hz ,1H),7.82(d,J=8.2Hz,1H),7.71(t,J=7.8Hz,1H),7.60(dd,J=8.1,1.9Hz,1H),7.54(d,J=1.8Hz,1H),7.46(s,1 H),7.45(s,1H),4.47(s,2H),3.66(t,J=4.9Hz,2H),3.51(d,J=1.9Hz,2H),2.36(s,3H).ESI-MSm / z:576.3[M+H] + .

[0126] Step 5: 3-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-5)

[0127]

[0128] At room temperature, 0.1 g (0.17 mmol) of 3-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazono-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (4 mL) was dissolved in dry dichloromethane. Isopropylamine (0.038 g, 0.52 mmol), STAB (0.18 g, 0.87 mmol), and 2 drops of acetic acid were added, and the mixture was stirred for 2 h at room temperature. After the reaction was complete as detected by TLC, the reaction solution was evaporated to dryness, and a mixture of methanol (4 mL) and water (1 mL) was added and stirred for 10 min. Then, 2 mL of 2NNaOH aqueous solution was added to the reaction solution at 0 °C, and the reaction was carried out at room temperature for 30 min. After the reaction was completed, the reaction solution was concentrated and added to 50 mL of water. The solution was extracted with dichloromethane (10 mL × 3). The filtrate was dried with anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (DCM / MeOH, 1 / 30) to obtain a white solid (0.027 g, 36%). 1H NMR(600MHz,DMSO-d6)δ12.28(s,1H),8.65(s,1H),8.59(s,1H),8.29(s,1H),8.21 (d,J=7.8Hz,1H),8.15(s,1H),7.80(d,J=8.1Hz,1H),7.71(d,J=7.6Hz,1H),7.68–7 .61(m,2H),7.51(s,1H),4.46(t,J=5.0Hz,2H),3.66(q,J=6.6,6.1Hz,4H),2.89(q, J=6.1Hz,1H),2.84(t,J=6.3Hz,2H),1.06(d,J=6.2Hz,6H).ESI-MSm / z:466.0[M+H] + .

[0129] Following the synthetic method in step 5 of Example 5, the compounds in Examples 6 to 13 were prepared by reductive amination and deprotection under alkaline conditions using 3-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapheno-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile as the starting material and the corresponding small molecule amine.

[0130] Example 6: 3-(5-(4-(2-((cyclopropylmethyl)amino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-6)

[0131]

[0132] 1 H NMR (600MHz, DMSO-d6) δ12.27(s,1H),8.65(s,1H),8.59(s,1H),8.28(s,1H),8.21(d,J=7.8Hz, 1H),8.14(s,1H),7.79(d,J=8.1Hz,1H),7.71(d,J=7.6Hz,1H),7.68–7.61(m,2H),7.51(s,1H), 4.45(t,J=5.1Hz,2H),3.66–3.63(m,4H),2.82(t,J=6.5Hz,2H),2.51(s,2H),1.09(t,J=7.0Hz, 1H),0.90(p,J=6.3Hz,1H),0.42(d,J=7.6Hz,2H),0.13(d,J=5.1Hz,2H).ESI-MSm / z:478.3[M+H] + .

[0133] Example 7: 3-(5-(4-(2-(cyclopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-7)

[0134]

[0135] 1 H NMR(600MHz,DMSO-d6)δ12.26(s,1H),8.66–8.63(m,1H),8.60–8.57(m,1H),8.28(s,1H),8.21(d,J=7 .8Hz,1H),8.14(s,1H),7.79(d,J=8.1Hz,1H),7.71(d,J=7.6Hz,1H),7.66(t,J=7.7Hz,1H),7.62(d,J= 8.2Hz,1H),7.50(s,1H),4.43(t,J=5.1Hz,2H),3.63(dt,J=10.5,5.9Hz,4H),2.85(t,J=6.5Hz,2H),2 .19(tt,J=7.0,3.8Hz,1H),0.40(dq,J=6.3,4.1Hz,2H),0.27(p,J=4.0Hz,2H).ESI-MSm / z:464.0[M+H] + .

[0136] Example 8: 3-(5-(4-(2-(isobutylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-8)

[0137]

[0138] 1H NMR (600MHz, DMSO-d6) δ12.25(s,1H),8.64(s,1H),8.58(s,1H),8.28(s,1H),8.20(d,J=7.8Hz, 1H),8.14(s,1H),7.78(d,J=8.1Hz,1H),7.71(d,J=7.6Hz,1H),7.67–7.61(m,2H),7.50(s,1H),4 .45(t,J=5.0Hz,2H),3.68(t,J=6.3Hz,2H),3.64(t,J=5.1Hz,2H),2.85(t,J=6.6Hz,2H),2.48( d,J=6.2Hz,2H),1.73(dt,J=13.5,7.0Hz,1H),0.90(s,3H),0.89(s,3H).ESI-MSm / z:480.3[M+H] + .

[0139] Example 9: 3-(5-(5-oxo-4-(2-(pyrrolidine-1-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-9)

[0140]

[0141] 1 H NMR (600MHz, DMSO-d6) δ12.25(d,J=2.8Hz,1H),8.64(d,J=2.1Hz,1H),8.58(d,J=2.0Hz,1H),8.28(d,J=1 .8Hz,1H),8.20(dt,J=7.8,1.5Hz,1H),8.14(d,J=2.7Hz,1H),7.78(d,J=8.1Hz,1H),7.72–7.70(m,1H),7 .66(t,J=7.8Hz,1H),7.61(dd,J=8.1,1.9Hz,1H),7.49(d,J=1.8Hz,1H),4.44(t,J=4.9Hz,2H),3.69(t,J =6.7Hz,2H),3.63(t,J=5.0Hz,2H),2.72(s,2H),2.60(s,4H),1.73–1.70(m,4H).ESI-MSm / z:478.1[M+H] + .

[0142] Example 10: 3-(5-(5-oxo-4-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazon-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-10)

[0143]

[0144] 1 H NMR (600MHz, DMSO-d6) δ12.26(d,J=2.8Hz,1H),8.64(d,J=2.1Hz,1H),8.58(d,J=2.1Hz,1H),8.28(d,J=1 .9Hz,1H),8.20(d,J=7.9Hz,1H),8.14(d,J=2.7Hz,1H),7.78(d,J=8.1Hz,1H),7.71(d,J=7.6Hz,1H),7.6 6(t,J=7.7Hz,1H),7.61(dd,J=8.1,1.8Hz,1H),7.49(d,J=1.8Hz,1H),4.46(t,J=4.9Hz,2H),3.68(s,2H) ,3.62(t,J=5.0Hz,2H),3.40–3.34(m,2H),2.45(s,4H),1.52(s,4H),1.40(s,2H).ESI-MSm / z:492.1[M+H] + .

[0145] Example 11: 3-(5-(4-(2-(4-methylpiperazin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (Compound I-11)

[0146]

[0147] 1H NMR(600MHz,Chloroform-d)δ11.58(s,1H),8.58–8.57(m,1H),8.26(d,J=2.1Hz,1H),7 .90(d,J=8.1Hz,1H),7.84(s,1H),7.81(dd,J=7.2,1.9Hz,1H),7.58(s,1H),7.52–7.48( m,2H),7.34(dd,J=8.1,1.8Hz,1H),4.46(t,J=4.9Hz,2H),3.71(t,J=6.4Hz,2H),3.58(t ,J=4.9Hz,2H),2.61(d,J=6.3Hz,2H),2.43(s,8H),2.25(s,3H).ESI-MSm / z:507.6[M+H] + .

[0148] Example 12: 3-(5-(5-oxo-4-(2-(pentan-3-ylamino)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-12)

[0149]

[0150] 1 H NMR (600MHz, DMSO-d6) δ12.26(s,1H),8.64(d,J=2.1Hz,1H),8.59(d,J=2.2Hz,1H),8.28(d,J=1.9Hz,1H),8.2 1(dt,J=7.9,1.6Hz,1H),8.14(s,1H),7.78(d,J=8.1Hz,1H),7.71(d,J=7.6Hz,1H),7.66(t,J=7.7Hz,1H),7.6 2(dd,J=8.1,1.8Hz,1H),7.51(d,J=1.8Hz,1H),4.45(t,J=5.0Hz,2H),3.66(d,J=6.3Hz,2H),3.64(d,J=4.6Hz ,2H),2.81(t,J=6.4Hz,2H),2.47(s,1H),1.40(t,J=7.0Hz,4H),0.85(t,J=7.4Hz,6H).ESI-MSm / z:494.6[M+H] + .

[0151] Example 13: 3-(5-(4-(2-(4,4-difluoropiperidin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile (compound I-13)

[0152]

[0153] 1 H NMR (600MHz, DMSO-d6) δ12.13(d,J=2.7Hz,1H),8.63(d,J=2.1Hz,1H),8.52(d,J=2.1Hz,1H),8.2 3(d,J=2.3Hz,1H),8.02(d,J=2.7Hz,1H),7.98(d,J=7.7Hz,1H),7.78(dd,J=8.1,2.9Hz,2H),7.5 9–7.53(m,2H),7.44(d,J=1.8Hz,1H),4.45(t,J=4.9Hz,2H),3.67(t,J=6.4Hz,2H),3.63(t,J=5. 0Hz,2H),2.60(dt,J=9.6,5.8Hz,6H),1.95(dq,J=14.4,7.2,6.2Hz,4H).ESI-MSm / z:528.5[M+H] + .

[0154] Example 14: N-(3-cyano-5-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-14)

[0155]

[0156] Step 1: N-(3-(5-bromo-1-tolyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanophenyl)methanesulfonamide

[0157]

[0158] 5-Bromo-3-iodo-1-p-toluenesulfonyl-1H-indole (4.12 g, 8.66 mmol), N-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)methanesulfonamide (4.04 g, 12.54 mmol), Na2CO3 (2.22 g, 20.95 mmol) and Pd(PPh3)4 (1.21 g, 1.04 mmol) were added sequentially to a mixed solution of 1,4-dioxane (40 mL) and water (10 mL), and reacted at 90 °C for 5 h under N2 protection. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, the filter cake was washed with ethyl acetate (5 mL × 2), the filtrate was concentrated, water was added and extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness and purified by column chromatography (DCM / PE, 1 / 50-1 / 20) to obtain 3.98 g of white solid, yield 73%. 1 H NMR (600MHz, DMSO-d6) δ10.26(s,1H),8.58(d,J=2.2Hz,1H),8.56(d,J=2.2Hz,1H),8.54(s,1H),8.12(d,J=1.6Hz,1H),8.06–8.04(m,2H),7.8 5(t,J=1.9Hz,1H),7.59(t,J=1.7Hz,1H),7.45(d,J=8.2Hz,2H),2.92–2.89(m,1H),2.36(s,3H),1.00(d,J=6.3Hz,3H).ESI-MSm / z:542.9[MH] + .

[0159] Step 2: N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphen-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide

[0160]

[0161] The compound was prepared as a white solid using N-(3-(5-bromo-1-tolyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanophenyl)methanesulfonamide as the starting material, following the same method as steps 3-4 in Example 5. 1H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.60(s,1H),8.17(d,J=21.9Hz,2H), 8.07(d,J=8.0Hz,2H),7.93(s,1H),7.86(d,J=8.0Hz,1H),7.76(s,1H),7.62(s,1 H),7.47(s,1H),7.24(d,J=8.6Hz,2H),7.15(s,1H),4.49(s,4H),3.60(d,J=2.7H z,2H),3.40(d,J=14.5Hz,2H),3.03(s,3H),2.31(s,3H).ESI-MSm / z:669.2[M+H] + .

[0162] Step 3: N-(3-cyano-5-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrole[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide

[0163]

[0164] The compound was prepared from N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphen-8-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide as a starting material, following the same method as step 5 in Example 5. The compound was a white solid. 1 H NMR(600MHz,DMSO-d6)δ12.32(s,1H),8.68–8.65(m,1H),8.59–8.56(m,1H),8.17(s ,1H),7.97(s,2H),7.83(d,J=8.1Hz,1H),7.61(d,J=8.3Hz,1H),7.48(s,1H),7.42(s ,1H),4.47(t,J=5.0Hz,2H),3.73(t,J=6.6Hz,2H),3.67(s,2H),3.16(s,3H),3.04(p ,J=6.5Hz,1H),2.95(t,J=6.6Hz,2H),1.13(d,J=6.3Hz,6H).ESI-MSm / z:559.0[M+H] + .

[0165] Following the synthetic method in step 5 of Example 5, N-(3-cyano-5-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazeta-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide was used as a starting material and the corresponding small molecule amine was subjected to reductive amination and deprotection under alkaline conditions to obtain the compounds in Examples 15-23.

[0166] Example 15: N-(3-cyano-5-(5-(4-(2-(((cyclopropylmethyl)amino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-15)

[0167]

[0168] 1 H NMR (600MHz, DMSO-d6) δ12.32(s,1H),8.67(d,J=2.1Hz,1H),8.56(d,J=2.1Hz,1H),8.17(s,1H),7.99(d,J=1.8Hz,1H) ,7.96(t,J=1.9Hz,1H),7.83(d,J=8.1Hz,1H),7.61(dd,J=8.2,1.8Hz,1H),7.48(d,J=1.8Hz,1H),7.42(d,J=1.8Hz,1H ),4.46(t,J=4.9Hz,2H),3.75(t,J=6.4Hz,2H),3.65(t,J=4.9Hz,2H),3.51–3.50(m,1H),3.17(s,3H),3.02(t,J=6.6H z,2H),2.70(d,J=7.1Hz,2H),1.23(s,1H),0.52(dd,J=8.0,1.9Hz,2H),0.27(d,J=5.0Hz,2H).ESI-MSm / z:571.0[M+H] + .

[0169] Example 16: N-(3-cyano-5-(5-(4-(2-(cyclopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-16)

[0170]

[0171] 1H NMR (600MHz, DMSO-d6) δ12.30(s,1H),8.66(d,J=2.1Hz,1H),8.56(d,J=2.1Hz,1H),8.17(d,J=2.2Hz,1H),8.00( s,1H),7.96(d,J=1.9Hz,1H),7.80(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.46(d,J=1.8Hz,1H),7.43(s, 1H),4.42(t,J=5.0Hz,2H),3.64(d,J=6.5Hz,2H),3.61(d,J=5.0Hz,2H),3.51(s,1H),3.18(s,3H),2.85(t,J=6. 5Hz,2H),2.19(dt,J=6.7,3.2Hz,1H),0.40(dd,J=6.6,2.2Hz,2H),0.27(p,J=4.0Hz,2H).ESI-MSm / z:557.8[M+H] + .

[0172] Example 17: N-(3-cyano-5-(5-(4-(2-(isobutylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-17)

[0173]

[0174] 1 H NMR (600MHz, DMSO-d6) δ12.32(s,1H),8.66(d,J=2.0Hz,1H),8.56(d,J=2.1Hz,1H),8.18(s,1H),7.99(t,J=1 .5Hz,1H),7.96(d,J=1.9Hz,1H),7.81(d,J=8.1Hz,1H),7.61(dd,J=8.1,1.8Hz,1H),7.47(d,J=1.8Hz,1H),7 .42(t,J=1.7Hz,1H),4.45(t,J=4.9Hz,2H),3.70(t,J=6.5Hz,2H),3.65(t,J=5.0Hz,2H),3.17(s,3H),2.88( t,J=6.5Hz,2H),2.53(s,2H),1.76(dt,J=13.4,6.7Hz,1H),0.91(s,3H),0.90(s,3H).ESI-MSm / z:573.3[M+H] + .

[0175] Example 18: N-(3-cyano-5-(5-(5-oxo-4-(2-(pyrrolidine-1-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-18)

[0176]

[0177] 1 H NMR (600MHz, DMSO-d6) δ8.66(d,J=2.1Hz,1H),8.56(d,J=2.2Hz,1H),8.17(d,J=2.7Hz,1H),8.00 (d,J=1.7Hz,1H),7.96(t,J=1.9Hz,1H),7.80(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.9Hz,1H),7.45 (d,J=1.9Hz,1H),7.43(t,J=1.7Hz,1H),4.44(t,J=4.9Hz,2H),3.70(t,J=6.7Hz,2H),3.63(t,J= 4.9Hz,2H),3.18(s,3H),2.77(s,2H),2.65(s,4H),1.73(q,J=3.5Hz,4H).ESI-MSm / z:571.0[M+H] + .

[0178] Example 19: N-(3-cyano-5-(5-(5-oxo-4-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazeta-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-19)

[0179]

[0180] 1H NMR(600MHz,DMSO-d6)δ12.31(s,1H),8.66(s,1H),8.57(s,1H),8.18(s,1H),7.99(d ,J=18.1Hz,2H),7.81(d,J=8.1Hz,1H),7.59(d,J=8.1Hz,1H),7.45(d,J=8.7Hz,2H), 4.47(t,J=4.9Hz,2H),3.69(t,J=6.6Hz,2H),3.62(t,J=5.0Hz,2H),3.42–3.27(m,2H ),3.19(s,3H),2.59(s,4H),1.56–1.51(m,4H),1.41(s,2H).ESI-MSm / z:585.0[M+H] + .

[0181] Example 20: N-(3-cyano-5-(5-(4-(2-(4-methylpiperazin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-20)

[0182]

[0183] 1 H NMR (600MHz, DMSO-d6) δ12.29(d,J=2.8Hz,1H),8.65(d,J=2.1Hz,1H),8.55(d,J=2.1Hz,1H),8. 17(d,J=2.7Hz,1H),8.00(d,J=1.8Hz,1H),7.96(d,J=2.0Hz,1H),7.79(d,J=8.1Hz,1H),7.58(dd ,J=8.1,1.8Hz,1H),7.46–7.42(m,2H),4.46(t,J=4.9Hz,2H),3.66(t,J=6.5Hz,2H),3.62(t,J=5 .0Hz,2H),3.17(s,3H),2.54(d,J=6.5Hz,2H),2.46(s,8H),2.23(s,3H).ESI-MSm / z:600.4[M+H] + .

[0184] Example 21: N-(3-cyano-5-(5-(5-oxo-4-(2-(3-pentylamino)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-21)

[0185]

[0186] 1 H NMR (600MHz, DMSO-d6) δ12.31(s,1H),8.66(d,J=2.1Hz,1H),8.57(d,J=2.2Hz,1H),8.17(s,1H),7.99(q, J=1.3Hz,1H),7.97(t,J=1.9Hz,1H),7.81(d,J=8.1Hz,1H),7.60(dd,J=8.1,1.8Hz,1H),7.47(d,J=1.8Hz, 1H),7.43(t,J=1.7Hz,1H),4.46(t,J=5.0Hz,2H),3.66(dd,J=9.9,5.5Hz,4H),3.17(s,3H),2.84(t,J=6.5 Hz,2H),2.52(d,J=6.6Hz,1H),1.42(dd,J=7.7,6.1Hz,4H),0.85(d,J=7.4Hz,6H).ESI-MSm / z:587.4[M+H] + .

[0187] Example 22: N-(3-cyano-5-(5-(4-(2-(4,4-difluoropiperidin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphenanthrene-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-22)

[0188]

[0189] 1H NMR (600MHz, DMSO-d6) δ12.31(d,J=2.7Hz,1H),8.66(d,J=2.1Hz,1H),8.56(d,J=2.1Hz,1H),8.17(d ,J=2.6Hz,1H),7.99–7.92(m,2H),7.79(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.46(d,J=1.8 Hz,1H),7.41(d,J=1.7Hz,1H),4.45(t,J=4.9Hz,2H),3.68(t,J=6.5Hz,2H),3.63(t,J=5.0Hz,2H),3 .15(s,3H),2.61(d,J=6.4Hz,2H),2.59(d,J=7.0Hz,4H),1.98–1.91(m,4H).ESI-MSm / z:621.6[M+H] + .

[0190] Example 23: N-(3-cyano-5-(5-(4-(2-(3,3-difluoropyrrolidine-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapheno-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanesulfonamide (compound I-23)

[0191]

[0192] 1 H NMR (600MHz, DMSO-d6) δ12.31(d,J=2.8Hz,1H),8.66(d,J=2.1Hz,1H),8.56(d,J=2.1Hz,1H),8.17( d,J=2.6Hz,1H),8.02–7.89(m,3H),7.79(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.51–7.37(m ,3H),4.44(t,J=4.9Hz,2H),3.67(t,J=6.5Hz,2H),3.63(t,J=5.0Hz,2H),3.16(s,3H),2.98(t,J=1 3.4Hz,2H),2.78(t,J=7.0Hz,2H),2.68(t,J=6.5Hz,2H),2.29–2.20(m,3H).ESI-MSm / z:607.2[M+H] + .

[0193] Example 24: N-(3-cyano-5-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-24)

[0194]

[0195] Step 1: 3-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)benzonitrile

[0196]

[0197] 5-Amino-3-bromobenzonitrile (2 g, 10.2 mmol), pinacol diboronate (3.11 g, 12.24 mmol), potassium acetate (2.0 g, 20.4 mmol), and Pd(dppf)Cl2·CH2Cl2 (0.25 g, 0.37 mmol) were sequentially added to a dry 1,4-dioxane (20 mL) solution and reacted at 80 °C for 4 h under N2 protection. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filter cake was washed with ethyl acetate (5 mL × 2). The filtrate was concentrated, and the reaction solution was poured into 30 mL of water and washed with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (PE / EA, 1 / 10) to give 1.84 g of a pale yellow solid, with a yield of 76.0%. 1 H NMR(600MHz, DMSO-d6)δ7.21(dd,J=2.4,0.9Hz,1H),7.04(t,J=1.3Hz,1H),6.96–6.95(m,1H),5.65(s,2H),1.28(s,12H).ESI-MSm / z:245.1[M+H] + .

[0198] Step 2: N-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl)ethanesulfonamide

[0199]

[0200] At room temperature, 1.8 g (7.37 mmol) of 3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile was dissolved in 25 mL of DCM. Pyridine (0.58 g, 11.1 mmol) was slowly added to the reaction solution at 0 °C. The mixture was then cooled to room temperature, and ethylsulfonyl chloride (1.58 g, 12.3 mmol) was added. After the reaction was complete as monitored by TLC, the reaction solution was poured into 30 mL of saturated citric acid aqueous solution and stirred continuously. The solution was then washed with 5 mL × 5 mL of DCM. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 2.25 g of a pale yellow solid, with a yield of 82.0%. ESI-MS m / z: 337.1 [M+H] + .

[0201] Step 3: N-(3-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanophenyl)ethanesulfonamide

[0202]

[0203] The compound was prepared from 5-bromo-3-iodo-1-p-toluenesulfonyl-1H-indole (2.8 g, 5.94 mmol) and N-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethanesulfonamide (2.0 g, 5.94 mmol) according to the synthetic method in step 3 of Example 1. The compound was a white solid, 2.46 g, in yield 70.4%. ESI-MS m / z: 558.8 [MH] + .

[0204] Step 4: N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide

[0205]

[0206] The compound was prepared from N-(3-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanophenyl)ethanesulfonamide as a raw material, following the same method as steps 3-4 in Example 5. It was a grayish-white solid. 1H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 7.9 Hz,2H),7.93(s,1H),7.88(d,J=8.0Hz,1H),7.77(s,1H),7.59(s,1H),7.46 (s,1H),7.20(s,2H),7.17(s,1H),4.49(s,4H),3.62(d,J=19.5Hz,3H),3.1 5(q,J=7.3Hz,2H),2.32(s,4H),1.34(t,J=7.3Hz,3H),1.19(s,3H).ESI-MS m / z:682.0[MH] + .

[0207] Step 5: N-(3-cyano-5-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide

[0208]

[0209] N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) The compound was prepared from 8-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide as a raw material, and was a white solid, according to the same method as step 5 in Example 5. 1 H NMR (600MHz, DMSO-d6) δ12.32(s,1H),8.67(d,J=2.0Hz,1H),8.56(d,J=2.1Hz,1H),8.17(s,1H),8 .00(d,J=2.1Hz,1H),7.98(s,1H),7.85(d,J=8.1Hz,1H),7.61(dd,J=8.2,1.8Hz,1H),7.48(d,J=1 .9Hz,1H),7.42(d,J=1.7Hz,1H),4.47(t,J=4.8Hz,2H),3.80(t,J=6.5Hz,2H),3.68(t,J=5.0Hz,2 H),3.24(s,1H),3.08(t,J=6.6Hz,2H),1.25(s,3H),1.21(d,J=6.4Hz,6H).ESI-MSm / z:571.1[MH] + .

[0210] Following the synthesis method in step 5 of Example 5, N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxaza The compounds in Examples 25-31 were prepared by reductive amination and deprotection under alkaline conditions using 8-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide as a starting material and the corresponding small molecule amine.

[0211] Example 25: N-(3-cyano-5-(5-(4-(2-(isobutylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) 8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-25)

[0212]

[0213] 1 H NMR (600MHz, DMSO-d6) δ12.31(s,1H),8.66(d,J=2.0Hz,1H),8.55(d,J=2.1Hz,1H),8.16(s,1H),7.98(dt,J=7.1, 1.7Hz,2H),7.80(d,J=8.1Hz,1H),7.60(dd,J=8.1,1.8Hz,1H),7.46(d,J=1.8Hz,1H),7.42(t,J=1.7Hz,1H),4.45( t,J=4.9Hz,2H),3.67(t,J=6.5Hz,2H),3.64(t,J=5.0Hz,2H),3.29(d,J=7.3Hz,2H),2.84(t,J=6.5Hz,2H),2.47( d,J=6.8Hz,2H),1.73(dp,J=13.4,6.7Hz,1H),1.25(t,J=7.3Hz,3H),0.90(d,J=6.6Hz,6H).ESI-MSm / z:585.2[MH] + .

[0214] Example 26: N-(3-cyano-5-(5-(4-(2-(cyclopropylmethyl)amino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-26)

[0215]

[0216] 1 H NMR (600MHz, DMSO-d6) δ12.32(s,1H),8.67(d,J=2.1Hz,1H),8.56(d,J=2.1Hz,1H),8.17(s,1H),8.00(t,J=1.9Hz,1H),7 .99–7.98(m,1H),7.85(d,J=8.1Hz,1H),7.62(dd,J=8.2,1.9Hz,1H),7.48(d,J=1.9Hz,1H),7.42(t,J=1.7Hz,1H),4.47(t ,J=4.9Hz,2H),3.83(t,J=6.3Hz,2H),3.67(t,J=4.9Hz,2H),3.29(t,J=7.3Hz,2H),3.14(t,J=6.4Hz,2H),2.84(d,J=7.3 Hz,2H),1.25(s,3H),1.06(dt,J=7.7,3.7Hz,1H),0.60–0.56(m,2H),0.36(dt,J=6.1,4.4Hz,2H).ESI-MSm / z:585.1[M+H] + .

[0217] Example 27: N-(3-cyano-5-(5-(4-(2-(cyclopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-27)

[0218]

[0219] 1H NMR (600MHz, DMSO-d6) δ12.29(s,1H),8.66(d,J=2.1Hz,1H),8.54(d,J=2.1Hz,1H),8.16(s,1H),7.97(d,J=1 .8Hz,2H),7.79(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.45(d,J=1.8Hz,1H),7.41(t,J=1.8Hz,1H),4. 41(t,J=5.0Hz,2H),3.61(q,J=5.6,4.6Hz,4H),3.28(s,2H),2.82(t,J=6.6Hz,2H),2.15(tt,J=6.7,3.6Hz,1H ),1.25(t,J=7.3Hz,3H),1.22(s,1H),0.37(dt,J=6.2,3.1Hz,2H),0.24–0.22(m,2H).ESI-MSm / z:571.2[M+H] + .

[0220] Example 28: N-(3-cyano-5-(5-(5-oxo-4-(2-(pyrrolidine-1-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-28)

[0221]

[0222] 1 H NMR (600MHz, DMSO-d6) δ12.30(d,J=2.8Hz,1H),8.66(d,J=2.1Hz,1H),8.55(d,J=2.1Hz,1H),8.17(d,J=2. 6Hz,1H),7.98(d,J=1.7Hz,2H),7.80(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.45(d,J=1.8Hz,1H),7 .42(t,J=1.7Hz,1H),4.44(t,J=4.9Hz,2H),3.69(t,J=6.7Hz,2H),3.63(t,J=4.9Hz,2H),3.29(s,2H),2.72 (t,J=6.8Hz,2H),2.61(d,J=10.2Hz,4H),1.73–1.71(m,4H),1.26(d,J=7.3Hz,3H).ESI-MSm / z:585.7[M+H] + .

[0223] Example 29: N-(3-cyano-5-(5-(5-oxo-4-(2-(piperidin-1-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-29)

[0224]

[0225] 1 H NMR (600MHz, DMSO-d6) δ12.30(d,J=2.8Hz,1H),8.66(d,J=2.1Hz,1H),8.54(d,J=2.1Hz,1H),8.16(d,J=2. 6Hz,1H),7.98(d,J=1.5Hz,2H),7.79(d,J=8.1Hz,1H),7.58(dd,J=8.1,1.8Hz,1H),7.45(d,J=1.8Hz,1H),7 .42(t,J=1.7Hz,1H),4.47(d,J=4.8Hz,2H),3.67(t,J=6.5Hz,2H),3.62(t,J=4.9Hz,2H),2.53(s,2H),2.46 (s,2H),1.51(t,J=5.7Hz,4H),1.39(dd,J=10.6,4.7Hz,2H),1.25(t,J=7.3Hz,5H).ESI-MSm / z:599.3[M+H] + .

[0226] Example 30: N-(3-cyano-5-(5-(5-oxo-4-(2-(3-pentylamino)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-30)

[0227]

[0228] 1H NMR (600MHz, DMSO-d6) δ12.31(s,1H),8.67(d,J=2.1Hz,1H),8.55(d,J=2.1Hz,1H),8.17(s,1H),7.99(dt,J =5.5,1.7Hz,2H),7.81(d,J=8.1Hz,1H),7.60(dd,J=8.1,1.8Hz,1H),7.47(d,J=1.9Hz,1H),7.42(t,J=1.7H z,1H),4.45(t,J=4.9Hz,2H),3.71(t,J=6.5Hz,2H),3.66(t,J=5.0Hz,2H),3.29(s,2H),2.91(t,J=6.5Hz,2 H),2.63(s,1H),1.47(p,J=7.1Hz,4H),1.25(t,J=7.3Hz,3H),0.87(t,J=7.5Hz,6H).ESI-MSm / z:601.7[M+H] + .

[0229] Example 31: N-(3-cyano-5-(5-(4-(2-(4,4-difluoropiperidin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)ethanesulfonamide (compound I-31)

[0230]

[0231] 1H NMR (600MHz, DMSO-d6) δ12.30(d,J=2.7Hz,1H),10.32(s,1H),8.66(d,J=2.1Hz,1H),8.54(d,J=2.1Hz,1H),8.17(d,J =2.8Hz,1H),7.98(p,J=1.7Hz,2H),7.80(d,J=8.1Hz,1H),7.58(dd,J=8.1,1.8Hz,1H),7.45(d,J=1.8Hz,1H),7.42(t ,J=1.7Hz,1H),4.45(t,J=4.9Hz,2H),3.68(t,J=6.4Hz,2H),3.63(t,J=5.0Hz,2H),3.29(d,J=7.3Hz,2H),2.62(d,J= 6.4Hz,2H),2.59(d,J=8.2Hz,4H),1.95(ddd,J=14.1,10.5,5.8Hz,6H),1.26(d,J=7.2Hz,3H).ESI-MSm / z:633.1[MH] + .

[0232] Example 32: N-(3-cyano-5-(5-(4-(2-(isobutylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide (compound I-33)

[0233]

[0234] Step 1: N-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)cyclopropanesulfonamide

[0235]

[0236] The compound was prepared from 3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzonitrile (1.8 g, 7.37 mmol) and cyclopropylmethanesulfonyl chloride (1.58 g, 12.3 mmol) according to the synthetic method in step 2 of Example 21. The compound was a pale yellow solid, 2.36 g, with a yield of 91%. 1H NMR (600MHz, DMSO-d6) δ10.18(s,1H),7.81(s,1H),7.69(d,J=14.9Hz,2H),2.76(h,J=5.5,5.1Hz,1H),1.31(s,12H),0.96(t,J=6.6Hz,4H).ESI-MS m / z:349.1[MH] + .

[0237] Step 2: N-(3-(5-bromo-1-tolyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanophenyl)cyclopropanesulfonamide

[0238]

[0239] The compound was prepared from 5-bromo-3-iodo-1-p-toluenesulfonyl-1H-indole (2.8 g, 5.94 mmol) and N-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)cyclopropanesulfonamide (2.0 g, 5.94 mmol) according to the synthetic method in step 3 of Example 1. The compound was a white solid, 2.34 g, with a yield of 71.2%. 1 H NMR (600MHz, DMSO-d6) δ10.26(s,1H),8.58(d,J=2.2Hz,1H),8.56(d,J=2.2Hz,1H),8.54(s,1H),8.12(d,J=1.6Hz,1H),8.06–8.04(m,2H), 7.85(t,J=1.9Hz,1H),7.59(t,J=1.7Hz,1H),7.45(d,J=8.3Hz,2H),2.91(s,1H),2.36(s,3H),1.00(d,J=6.3Hz,4H).ESI-MSm / z:571.8[MH] + .

[0240] Step 3: N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1-tolyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide

[0241]

[0242] The compound was prepared from N-(3-(5-bromo-1-tolyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyanophenyl)cyclopropanesulfonamide as a starting material, following the same method as steps 3-4 in Example 5. It was a grayish-white solid. ESI-MS m / z: 695.2 [MH] + .

[0243] Step 4: N-(3-cyano-5-(5-(4-(2-(isobutylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) -8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide

[0244]

[0245] N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazine) The compound was prepared from pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide as a raw material, and was a white solid, following the same method as step 5 in Example 5. 1 HNMR(600MHz,DMSO-d6)δ12.53–12.16(m,1H),8.68(s,1H),8.57(s,1H),8.17(s,1H),8.02(d,J=20.0Hz,2H),7.81(s,1H),7.61(s,1H),7 .47(s,2H),4.46(s,2H),3.69(d,J=34.7Hz,4H),3.51(s,2H),2.89(s,2H),1.78(s,1H),1.02(s,4H),0.91(s,6H).ESI-MSm / z:597.4[M+H] + .

[0246] Following the synthesis method in step 5 of Example 5, N-(3-cyano-5-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxaza The compounds in Examples 33-35 were prepared by reductive amination and deprotection under alkaline conditions using (-8-yl)-1-tolyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide as a starting material and the corresponding small molecule amine.

[0247] Example 33: N-(3-cyano-5-(5-(4-(2-(4-methylpiperazin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide (compound I-36)

[0248]

[0249] 1 H NMR (600MHz, DMSO-d6) δ12.32(d,J=2.7Hz,1H),8.67(d,J=2.1Hz,1H),8.56(d,J=2.1Hz,1H),8.17 (d,J=2.4Hz,1H),8.02(dt,J=10.1,1.7Hz,2H),7.80(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.9Hz,1H) ,7.47–7.45(m,2H),4.46(t,J=4.9Hz,2H),3.66(t,J=6.5Hz,2H),3.62(t,J=5.0Hz,2H),2.53(d,J =6.4Hz,2H),2.41(s,8H),2.21(s,3H),1.02(ddd,J=10.8,5.1,2.5Hz,4H).ESI-MSm / z:626.5[M+H] + .

[0250] Example 34: N-(3-cyano-5-(5-(4-(2-(3,3-difluoropyrrolidine-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapheno-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide (Compound I-38)

[0251]

[0252] 1H NMR (600MHz, DMSO-d6) δ12.30(d,J=2.8Hz,1H),10.28(s,1H),8.66(d,J=2.1Hz,1H),8.55(d,J=2.1Hz,1H),8.17(d,J =2.7Hz,1H),8.01(d,J=1.7Hz,2H),7.79(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.45(d,J=2.0Hz,2H),4.44(t, J=4.9Hz,2H),3.67(t,J=6.6Hz,2H),3.63(t,J=5.0Hz,2H),2.98(t,J=13.4Hz,2H),2.88(ddd,J=7.7,4.8,2.6Hz,1H), 2.78(t,J=7.0Hz,2H),2.69(t,J=6.6Hz,2H),2.24(dt,J=15.3,8.0Hz,2H),1.03–0.99(m,4H).ESI-MSm / z:633.6[M+H] + .

[0253] Example 35: N-(3-cyano-5-(5-(4-(2-(4,4-difluoropiperidin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphenanthrene-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclopropanesulfonamide (Compound I-39)

[0254]

[0255] 1H NMR (600MHz, DMSO-d6) δ12.30(d,J=2.8Hz,1H),10.28(s,1H),8.67(d,J=2.0Hz,1H),8.55(d,J=2.1Hz,1H),8. 17(d,J=2.7Hz,1H),8.01(d,J=2.2Hz,2H),7.80(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.45(d,J=1.9Hz ,2H),4.45(t,J=4.9Hz,2H),3.68(t,J=6.4Hz,2H),3.63(t,J=5.0Hz,2H),2.88(tt,J=7.7,5.0Hz,1H),2.60(d t,J=10.4,6.0Hz,6H),1.95(td,J=13.8,12.7,5.6Hz,4H),1.01(tt,J=7.9,2.5Hz,4H).ESI-MSm / z:647.2[M+H] + .

[0256] Example 36: 8-(3-(benzo(c)[1,2,5]oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(isopropylamino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-ketone (compound I-40)

[0257]

[0258] Step 1: 5-Bromobenzo[c][1,2,5]oxadiazole

[0259]

[0260] 4-Bromo-2-nitroaniline (5.0 g, 23.04 mmol) and potassium hydroxide (2.58 g, 46.08 mmol) were dissolved in anhydrous ethanol. At 0 °C, 5% NaClO solution was slowly added to the reaction solution until the red color disappeared, and then the mixture was allowed to react at room temperature for 1 h. After the reaction was complete, the solution was poured into water and washed with ethyl acetate to obtain a pale yellow solid (4.45 g, 90.0%). The above pale yellow solid (4.0 g, 18.60 mmol) and PPh3 (5.84 g, 22.32 mmol) were dissolved in toluene and reacted at 110 °C under N2 protection. After the reaction was complete, the reaction solution was concentrated, poured into water, washed with ethyl acetate, evaporated to dryness, and purified by column chromatography (EA / PE, 1 / 100) to obtain a pale pink solid of 2.95 g, yield 79.0%. ESI-MS m / z: 198.4 [M+H]+ .

[0261] Step 2: 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentane-2-yl)benzo[c][1,2,5]oxadiazole

[0262]

[0263] The compound was prepared from 5-bromobenzo[c][1,2,5]oxadiazole (3 g, 15.07 mmol) according to the synthetic method in step 1 of Example 21. The compound was a white solid, 3.07 g, in yield of 83.0%. ESI-MS m / z: 247.2 [M+H] + .

[0264] Step 3: 5-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzo[c][1,2,5]oxadiazole

[0265]

[0266] The compound was prepared from 5-bromo-3-iodo-1-p-toluenesulfonyl-1H-indole (5.8 g, 12.19 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzo[c][1,2,5]oxadiazole (3.0 g, 12.19 mmol) according to the synthetic method in step 3 of Example 1. The compound was a grayish-white solid, 3.88 g, in yield of 68.0%. ESI-MS m / z: 468.5 [M+H] + .

[0267] Step 4: 2-(8-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-oxo-2,3-dihydrobenzo[f][1,4]oxonitrile -4(5H)-yl)acetaldehyde

[0268]

[0269] The compound was prepared from 5-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzo[c][1,2,5]oxadiazole as a starting material, and was a grayish-white solid prepared by the same method as steps 3-4 in Example 5. 1H NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.82–8.80(m,1H),8.73(dd,J=8.7,2.1Hz,1H),8.68(d,J=2.8Hz,1H) ,8.62(s,1H),8.22(d,J=9.4Hz,1H),8.17(d,J=9.3Hz,1H),8.12(d,J=8.0Hz,2H),7.81(dd,J=30.7,8.1Hz ,1H),7.64(t,J=7.3Hz,1H),7.58(d,J=19.4Hz,1H),7.47(d,J=8.1Hz,2H),4.48(s,1H),4.43(q,J=5.2Hz, 1H),3.65(dt,J=18.7,5.1Hz,2H),3.50(dq,J=17.6,12.1,8.8Hz,2H),2.36(s,3H).ESI-MSm / z:592.1[MH] + .

[0270] Step 5: 8-(3-(benzo(c)[1,2,5]oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(isopropylamino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-keto

[0271]

[0272] 2-(8-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-oxo-2,3-dihydrobenzo[f][1,4]oxonitrile The compound was prepared from 0.1 g (0.17 mmol) of 4(5H)-yl)acetaldehyde and 0.03 g (0.51 mmol) of isopropylamine according to the same method as step 5 in Example 5. The compound was a white solid, 0.03 g, with a yield of 37.5%. 1H NMR (600MHz, DMSO-d6) δ8.76(d,J=2.1Hz,1H),8.69(d,J=2.0Hz,1H),8.43(s,1H),8.39(s ,1H),8.19(dd,J=9.4,1.5Hz,1H),8.09(d,J=9.4Hz,1H),7.80(d,J=8.1Hz,1H),7.68(dd,J =8.1,1.8Hz,1H),7.58(d,J=1.7Hz,1H),4.46(t,J=5.0Hz,2H),3.65(dt,J=7.8,4.5Hz,4H ),2.90–2.86(m,1H),2.84(t,J=6.7Hz,2H),1.05(d,J=6.2Hz,6H).ESI-MSm / z:483.0[M+H] + .

[0273] Following the synthesis method in step 5 of Example 5, 2-(8-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-oxo-2,3-dihydrobenzo[f][1,4]oxonitrile The compounds in Examples 37-39 were prepared by using 4(5H)-yl)acetaldehyde as a raw material and reacting it with the corresponding small molecule amines through reductive amination and deprotection under alkaline conditions.

[0274] Example 37: 8-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(isobutylamino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-keto (compound I-41)

[0275]

[0276] 1H NMR (600MHz, DMSO-d6) δ8.76(d,J=2.1Hz,1H),8.68(d,J=2.1Hz,1H),8.43(t,J=1.3Hz,1H),8.39 (s,1H),8.18(dd,J=9.5,1.5Hz,1H),8.09(dd,J=9.4,1.0Hz,1H),7.79(d,J=8.1Hz,1H),7.67(dd, J=8.1,1.9Hz,1H),7.57(d,J=1.8Hz,1H),4.46(t,J=5.0Hz,2H),3.66–3.63(m,4H),2.80(t,J=6. 4Hz,2H),2.43(d,J=6.7Hz,2H),1.72–1.67(m,1H),0.89(d,J=6.6Hz,6H).ESI-MSm / z:497.0[M+H] + .

[0277] Example 38: 8-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(cyclopropylmethyl)amino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-keto (compound I-42)

[0278]

[0279] 1 H NMR (600MHz, DMSO-d6) δ8.77(d,J=2.1Hz,1H),8.70(d,J=2.0Hz,1H),8.44(s,1H),8.40(s,1H),8.19(dd,J =9.5,1.5Hz,1H),8.10(d,J=9.4Hz,1H),7.84(d,J=8.1Hz,1H),7.70(dd,J=8.1,1.8Hz,1H),7.60(d,J=1.8 Hz,1H),4.48(t,J=4.9Hz,2H),3.83(t,J=6.4Hz,2H),3.69(t,J=4.9Hz,2H),3.12(t,J=6.4Hz,2H),2.81(d ,J=7.2Hz,2H),1.09–1.05(m,1H),0.58–0.55(m,2H),0.35(dd,J=4.7,1.6Hz,2H).ESI-MSm / z:495.1[M+H] + .

[0280] Example 39: 8-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-ketone (compound I-43)

[0281]

[0282] 1 H NMR (600MHz, DMSO-d6) δ12.46(d,J=2.9Hz,1H),8.76(d,J=2.1Hz,1H),8.68(d,J=2.0Hz,1H),8.43( s,1H),8.39(d,J=2.8Hz,1H),8.18(dd,J=9.4,1.5Hz,1H),8.09(d,J=9.4Hz,1H),7.79(d,J=8.0Hz,1 H),7.67(dd,J=8.1,1.8Hz,1H),7.56(d,J=1.8Hz,1H),4.46(t,J=4.9Hz,2H),3.69(t,J=6.4Hz,2H) ,3.64(t,J=5.0Hz,2H),2.61(d,J=8.9Hz,6H),1.96(dd,J=18.5,10.3Hz,4H).ESI-MSm / z:545.4[MH] + .

[0283] Example 40: 8-(3-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(isopropylamino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-ketone (compound I-45)

[0284]

[0285] Step 1: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-1H-indazole

[0286]

[0287] The compound was prepared from 5-bromoindazole (3 g, 15.23 mmol) according to the synthetic method in step 1 of Example 21, as a white solid, yielding 2.67 g in 72.4%. ESI-MS m / z: 245.4 [M+H] + .

[0288] Step 2: 5-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indazole

[0289]

[0290] The compound was prepared from 5-bromo-3-iodo-1-p-toluenesulfonyl-1H-indole (4.9 g, 10.24 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole (2.5 g, 10.24 mmol) according to the synthetic method in step 3 of Example 1. The compound was a white solid, 3.88 g, with a yield of 68.0%. 1 H NMR (400MHz, Chloroform-d) δ8.51(d,J=2.1Hz,1H),8.23(d,J=2.2Hz,1H),8.17(s,1H),8.10(d,J=8.4Hz,2H),7.93(t,J=1.2H z,1H),7.90(s,1H),7.65–7.62(m,1H),7.58(dd,J=8.7,1.6Hz,1H),7.31(d,J=8.1Hz,2H),2.39(s,3H).ESI-MSm / z:467.4[M+H] + .

[0291] Step 3: 2-(8-(3-(1H-indazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-oxo-2,3-dihydrobenzo[f][1,4]oxazine -4(5H)-yl)acetaldehyde

[0292]

[0293] The compound was prepared from 5-(5-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indazole as a starting material, following the same method as steps 3-4 in Example 5. It was a white solid. ESI-MS m / z: 592.6 [M+H] + .

[0294] Step 4: 8-(3-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(isopropylamino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-keto

[0295]

[0296] 2-(8-(3-(1H-indazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-oxo-2,3-dihydrobenzo[f][1,4]oxazine The compound was prepared from 0.1 g (0.17 mmol) of 4(5H)-yl)acetaldehyde and 0.015 g (0.26 mmol) of isopropylamine according to the same method as step 5 in Example 5. The compound was a white solid, 0.05 g, with a yield of 61.2%. 1 HNMR (600MHz, DMSO-d6) δ13.10(s,1H),12.03(d,J=2.6Hz,1H),8.63(d,J=2.1Hz,1H),8.53(d,J=2.1Hz,1H ),8.16(s,1H),8.12(s,1H),7.90(d,J=2.4Hz,1H),7.83(d,J=8.1Hz,1H),7.79(d,J=8.7Hz,1H),7.63(d,J= 8.6Hz,1H),7.61(dd,J=8.2,1.8Hz,1H),7.47(d,J=1.8Hz,1H),4.46(t,J=5.0Hz,2H),3.82(t,J=6.7Hz,2H ),3.69(t,J=5.0Hz,2H),3.24(s,1H),3.07(t,J=6.7Hz,2H),1.23(d,J=4.7Hz,6H).ESI-MSm / z:581.3[M+H] + .

[0297] Following the synthesis method in step 5 of Example 5, 2-(8-(3-(1H-indazol-5-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-oxo-2,3-dihydrobenzo[f][1,4]oxazine The compounds in Examples 41-43 were prepared by using 4(5H)-yl)acetaldehyde as a raw material and reacting it with the corresponding small molecule amines through reductive amination and deprotection under alkaline conditions.

[0298] Example 41: 8-(3-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(isobutylamino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-ketone (compound I-46)

[0299]

[0300] 1H NMR (600MHz, DMSO-d6) δ13.07(s,1H),12.01(d,J=2.6Hz,1H),8.62(d,J=2.1Hz,1H),8.52(d,J=2.1Hz,1H),8. 15(s,1H),8.12(s,1H),7.90(d,J=2.2Hz,1H),7.81–7.78(m,2H),7.63(d,J=8.6Hz,1H),7.60(dd,J=8.2,1.8H z,1H),7.46(d,J=1.8Hz,1H),4.45(t,J=4.9Hz,2H),3.75(t,J=6.5Hz,2H),3.66(t,J=5.0Hz,2H),2.96(t,J=6 .4Hz,2H),2.61(d,J=6.9Hz,2H),1.82(dd,J=13.8,7.1Hz,1H),0.92(d,J=6.7Hz,6H).ESI-MSm / z:495.4[M+H] + .

[0301] Example 42: 8-(3-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(cyclopropylmethyl)amino)ethyl)-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-ketone (compound I-47)

[0302]

[0303] 1H NMR (600MHz, DMSO-d6) δ13.09(s,1H),12.02(d,J=2.6Hz,1H),8.63(d,J=2.1Hz,1H),8.53(d,J=2.1Hz,1H),8.15(d,J=1.6Hz,1H) ,8.12(s,1H),7.90(d,J=2.1Hz,1H),7.82(d,J=8.1Hz,1H),7.79(dd,J=8.6,1.6Hz,1H),7.63(d,J=8.6Hz,1H),7.61(dd,J=8.1,1 .8Hz,1H),7.46(d,J=1.8Hz,1H),4.46(t,J=4.9Hz,2H),3.79(t,J=6.5Hz,2H),3.67(t,J=4.9Hz,2H),3.05(t,J=6.4Hz,2H),2.73 (d,J=7.1Hz,2H),1.03(ddd,J=12.7,7.5,4.4Hz,1H),0.53(dt,J=8.0,3.0Hz,2H),0.30(d,J=5.2Hz,2H).ESI-MSm / z:493.3[M+H] + .

[0304] Example 43: 8-[3-(1H-indazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-[2-(4,4-difluoropiperidin-1-yl)ethyl]-3,4-dihydrobenzo[f][1,4]oxazine -5(2H)-ketone (compound I-48)

[0305]

[0306] 1H NMR (600MHz, DMSO-d6) δ13.08(s,1H),12.02(d,J=2.7Hz,1H),8.62(d,J=2.2Hz,1H),8.53(d,J=2.2Hz,1 H),8.16(d,J=1.5Hz,1H),8.12(s,1H),7.91(d,J=2.5Hz,1H),7.81–7.77(m,2H),7.64(d,J=8.6Hz,1H),7 .59(dd,J=8.1,1.9Hz,1H),7.45(d,J=1.9Hz,1H),4.45(t,J=4.9Hz,2H),3.68(t,J=6.5Hz,2H),3.63(t, J=5.0Hz,2H),2.60(dt,J=10.1,5.8Hz,6H),1.95(ddd,J=19.7,11.8,5.4Hz,4H).ESI-MSm / z:543.4[M+H] + .

[0307] Example 44: 1-(cyclopropylsulfonyl)-6-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphen-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indole-4-carboxynitrile (Compound I-49)

[0308]

[0309] Step 1: 6-Bromo-1H-indole-4-carboxamide

[0310]

[0311] 6-Bromo-1H-indole-4-carboxylic acid (3 g, 12.49 mmol), EDCI (4.8 g, 25.04 mmol), and HOBT ammonium salt (3.8 g, 24.97 mmol) were dissolved in dry DMF. Triethylamine (5.1 g, 50.40 mmol) was added dropwise to the reaction solution at room temperature, and the reaction was allowed to proceed for 3 h at room temperature. After the reaction was complete, the solution was poured into water and washed with ethyl acetate (25 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 2.25 g of a white solid, yield 75.8%. ESI-MS m / z: 337.1 [M+H] + .

[0312] Step 2: 6-Bromo-1H-indole-4-carboxynitrile

[0313]

[0314] 6-Bromo-1H-indole-4-carboxamide (1 g, 4.18 mmol) was dissolved in phosphorus oxychloride (5 mL, 12.55 mmol) and reacted at 100 °C for 4 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated. The solution was then slowly added dropwise to 30 mL of ice water, stirred for 10 min, and washed with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (PE / EA, 1 / 1) to give 0.74 g of a pale yellow solid, yield 80.4%. ESI-MS m / z: 221.9 [M+H] + .

[0315] Step 3: 6-Bromo-1-(cyclopropylsulfonyl)-1H-indole-4-carboxynitrile

[0316]

[0317] The compound was prepared from 6-bromo-1H-indole-4-carboxynitrile (2.65 g, 11.98 mmol) and cyclopropylmethanesulfonyl chloride (2.03 g, 14.38 mmol) according to the synthetic method in step 2 of Example 21. The compound was a pale yellow solid, 3.22 g, in yield of 82.7%. ESI-MS m / z: 325.9 [M+H] + .

[0318] Step 4: 1-(cyclopropylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indole-4-carboxynitrile

[0319]

[0320] The compound was prepared from 2.8 g (5.94 mmol) of 6-bromo-1-(cyclopropylsulfonyl)-1H-indole-4-carboxynitrile according to the synthetic method in step 1 of Example 21. The compound was a pale yellow solid, 2.75 g, with a yield of 85.9%. ESI-MS m / z: 373.1 [M+H] + .

[0321] Step 5: 6-(5-bromo-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(cyclopropylsulfonyl)-1H-indole-4-carboxynitrile

[0322]

[0323] The compound was prepared from 5-bromo-3-iodo-1-p-toluenesulfonyl-1H-indole (2.3 g, 4.83 mmol) and 1-(cyclopropylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-indole-4-carboxynitrile (2.2 g, 5.91 mmol) according to the synthetic method in step 3 of Example 1. The compound was a white solid, 1.88 g, in yield of 65.3%. ESI-MS m / z: 596.0 [M+H] + .

[0324] Step 6: 1-(cyclopropylsulfonyl)-6-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphen-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indole-4-carboxynitrile

[0325]

[0326] The compound was prepared from 6-(5-bromo-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(cyclopropylsulfonyl)-1H-indole-4-carboxynitrile as a starting material, following the same method as steps 3-4 in Example 5. It was a white solid. ESI-MS m / z: 720.1 [M+H] + .

[0327] Step 7: 1-(cyclopropylsulfonyl)-6-(5-(4-(2-(isopropylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indole-4-carboxynitrile

[0328]

[0329] The compound was prepared from 1-(cyclopropylsulfonyl)-6-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphen-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indol-4-carboxynitrile (0.1 g, 0.17 mmol) and isopropylamine (0.03 g, 0.51 mmol) by the same method as step 5 in Example 5, as a white solid, in a yield of 37.4%. 1H NMR (600MHz, DMSO-d6) δ12.37(s,1H),8.76(d,J=2.0Hz,1H),8.63(d,J=2.8Hz,2H),8.38(s,1H),8.26(s,1H), 7.98(d,J=3.7Hz,1H),7.91(d,J=8.2Hz,1H),7.67(dd,J=8.1,1.9Hz,1H),7.54(d,J=1.8Hz,1H),7.08(d,J=3.7 Hz,1H),4.53(t,J=4.9Hz,2H),3.83(t,J=6.6Hz,2H),3.75(t,J=5.1Hz,2H),3.49(dq,J=7.9,4.0,3.4Hz,2H), 3.21(s,1H),3.08(t,J=6.7Hz,2H),1.41(dt,J=7.2,3.6Hz,2H),1.23(d,J=6.6Hz,8H).ESI-MSm / z:609.5[M+H] + .

[0330] Following the synthetic method in step 5 of Example 5, the compounds in Examples 45-49 were prepared by reductive amination and deprotection under alkaline conditions using 1-(cyclopropylsulfonyl)-6-(5-(5-oxo-4-(2-oxoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazono-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indole-4-carboxynitrile as the starting material and the corresponding small molecule amine.

[0331] Example 45: 1-(cyclopropylsulfonyl)-6-(5-(4-(2-(4-methylpiperazin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indole-4-carboxynitrile (Compound I-50)

[0332]

[0333] 1H NMR(600MHz,DMSO-d6)δ12.30(s,1H),8.68(d,J=2.1Hz,1H),8.55(s,2H),8.31(s,1H),8 .19(s,1H),7.91(d,J=3.7Hz,1H),7.79(d,J=8.1Hz,1H),7.59–7.56(m,1H),7.45(s,1H), 4.46(t,J=4.9Hz,2H),3.66(t,J=6.4Hz,2H),3.62(t,J=5.0Hz,2H),3.42(dq,J=7.9,4.0, 3.5Hz,2H),2.49–2.20(m,8H),2.15(s,3H),1.37–1.33(m,2H),1.18–1.14(m,2H).ESI-MS m / z:650.7[M+H] + .

[0334] Example 46: 6-(5-(4-(2-((cyclopropylmethyl)amino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphen-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(cyclopropylsulfonyl)-1H-indole-4-carboxynitrile (Compound I-51)

[0335]

[0336] 1 H NMR (600MHz, DMSO-d6) δ12.30(s,1H),8.69(d,J=2.1Hz,1H),8.56(d,J=1.4Hz,2H),8.31(d,J=1.4Hz,1H),8.19(s,1H),7.9 1(d,J=3.7Hz,1H),7.81(d,J=8.1Hz,1H),7.60(dd,J=8.1,1.8Hz,2H),7.47(d,J=1.8Hz,1H),7.01(d,J=3.6Hz,1H),4.45(d ,J=5.0Hz,2H),3.71(s,2H),3.66(s,2H),3.43–3.41(m,1H),2.92(d,J=6.4Hz,2H),2.59(d,J=6.9Hz,2H),1.35–1.34(m,2H ),1.17(d,J=5.3Hz,2H),0.95(q,J=3.5,2.8Hz,1H),0.48–0.46(m,2H),0.21(dd,J=4.8,1.6Hz,2H).ESI-MSm / z:621.2[M+H] + .

[0337] Example 47: 1-(cyclopropylsulfonyl)-6-(5-(5-oxo-4-(2-(pyrrolidine-1-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indol-4-carboxynitrile (Compound I-52)

[0338]

[0339] 1 H NMR (600MHz, DMSO-d6) δ12.30(s,1H),8.69(d,J=2.1Hz,1H),8.56(d,J=2.4Hz,2H),8.31(s,1H),8.19(d,J= 2.6Hz,1H),7.91(d,J=3.7Hz,1H),7.80(d,J=8.1Hz,1H),7.59(dd,J=8.1,1.9Hz,1H),7.45(d,J=1.8Hz,1H), 7.01(d,J=3.7Hz,1H),4.44(t,J=4.9Hz,2H),3.71(t,J=6.7Hz,2H),3.64(t,J=5.0Hz,2H),2.77(s,2H),2.66 (s,4H),1.76–1.72(m,4H),1.34(dt,J=7.1,3.5Hz,2H),1.17(dd,J=7.7,2.6Hz,2H).ESI-MSm / z:621.7[M+H] + .

[0340] Example 48: 1-(cyclopropylsulfonyl)-6-(5-(4-(2-(4,4-difluoropiperidin-1-yl)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazapyro-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indole-4-carboxynitrile (Compound I-53)

[0341]

[0342] 1H NMR (600MHz, DMSO-d6) δ12.29(d,J=2.7Hz,1H),8.68(d,J=2.0Hz,1H),8.56(d,J=2.3Hz,2H),8.31(s,1H),8 .19(d,J=2.6Hz,1H),7.91(d,J=3.7Hz,1H),7.79(d,J=8.1Hz,1H),7.58(dd,J=8.1,1.8Hz,1H),7.45(d,J=1 .7Hz,1H),7.01(d,J=3.7Hz,1H),4.45(t,J=4.9Hz,2H),3.68(t,J=6.4Hz,2H),3.64(t,J=5.0Hz,2H),2.61( d,J=10.2Hz,6H),1.95(t,J=14.6Hz,4H),1.35(dd,J=4.7,2.6Hz,2H),1.22(s,2H).ESI-MSm / z:671.4[M+H] + .

[0343] Example 49: 1-(cyclopropylsulfonyl)-6-(5-(4-(2-(isobutylamino)ethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazaphen-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-indole-4-carboxynitrile (Compound I-54)

[0344]

[0345] 1 H NMR (600MHz, DMSO-d6) δ12.30(s,1H),8.69(d,J=2.1Hz,1H),8.56(d,J=2.4Hz,2H),8.31(d,J=1.5Hz,1H),8.19(s,1H),7 .91(d,J=3.7Hz,1H),7.82(d,J=8.1Hz,1H),7.60(dd,J=8.1,1.9Hz,1H),7.47(d,J=1.9Hz,1H),7.01(d,J=3.6Hz,1H),4. 46(t,J=5.0Hz,2H),3.76(t,J=6.4Hz,2H),3.66(t,J=4.9Hz,2H),3.42(tt,J=8.0,4.7Hz,2H),2.99(d,J=6.7Hz,2H),1.8 4(dd,J=13.7,7.0Hz,1H),1.35–1.33(m,2H),1.16(dd,J=7.8,2.5Hz,2H),0.93(d,J=6.6Hz,6H).ESI-MSm / z:671.4[M+H]+ .

[0346] Pharmacological activity studies of the compounds of this invention, specifically the evaluation of the inhibitory activity of the compounds in the examples against TNIK kinase:

[0347] The inhibitory activity of the compounds of this invention against TNIK kinase was tested using ADP-Glo ​​provided by ICE Bioscience Inc. TM The technology is complete. The experimental method is as follows:

[0348] 1. Prepare ATP & substrate solution and kinase & metal solution using detection buffer solution.

[0349] 2. Transfer 20 μL of the compound to a 384-well plate using an Echo 655, add 2 μL of kinase & metal solution, mix, and incubate at 25°C for 10 minutes in the 384-well plate.

[0350] 3. Add 2 μL of substrate & ATP solution to a 384-well plate and incubate at 25°C for 60 minutes.

[0351] 4. Add 4 μL of ADP-Glo ​​reagent to a 384-well plate and incubate at 25°C for 40 minutes.

[0352] 5. Add 8 μL of kinase detection reagent to a 384-well plate and incubate at 25°C for 40 minutes.

[0353] 6. Record the luminescence signal on the microtiter plate reader.

[0354] The results of the compounds of the present invention inhibiting the activity of TNIK kinase are shown in Table 1. Table 1 shows the activity range or IC50 of the compounds of the present invention inhibiting TNIK kinase. 50 The values ​​are as follows: A = 0.1nM ~ 20nM; B ≥ 20nM.

[0355] Table 1. Activity range or IC50 of the compounds of this invention inhibiting TNIK kinase. 50 value

[0356]

[0357] Experimental results show that the azaindole compounds provided by this invention have significant inhibitory activity against TNIK kinase in vitro, and most of the compounds have significantly better activity than CN113773316B-compound 6 and INS018_055.

Claims

1. An azaindole compound, its stereoisomers, and pharmaceutically acceptable salts, characterized in that: The general structural formula of the azaindole compounds is shown in Formula I: in, n is selected from 1, 2, 3, or 4; R 1 Selected from hydrogen, hydroxyl, (C1–C6)alkyl, (C1–C6)alkoxy, (C1–C6)alkoxyformyl or R a and R b Each is independently selected from hydrogen, (C1–C6)alkyl, (C3–C8)cycloalkyl or (C3–C8)cycloalkyl(C1–C4)alkylene; Or R a R b Together with the nitrogen atoms attached to them, they form a 3–7-membered nitrogen-containing heterocycle, which contains 1–3 heteroatoms selected from N, O, or S; the nitrogen-containing heterocycle may optionally be separated by 1–3 R atoms. 7 replace; R 2 R 3 R 4 R 5 R 6 Each is independently selected from hydrogen, halogen, cyano, (C1–C4)alkylsulfonylamino or (C3–C8)cycloalkylsulfonylamino; Or R 3 R 4 Together with the carbon atoms attached to them, they form a 5–6-membered aromatic ring or heteroaromatic ring, the heteroaromatic ring containing 1–3 heteroatoms selected from N, O, or S; the aromatic ring or heteroaromatic ring may optionally be surrounded by 1–3 R atoms. 8 replace; R 7 Selected from hydrogen, halogens, (C1–C6) alkyl or (C3–C8) cycloalkyl; R 8 It is selected from hydrogen, (C1–C6)alkyl, (C1–C4)alkylsulfonyl or (C3–C8)cycloalkylsulfonyl.

2. The azaindole compounds and their stereoisomers, as well as pharmaceutically acceptable salts, according to claim 1, characterized in that: n is selected from 2 or 3; R 1 Selected from hydrogen, (C1–C6)alkoxy or R a and R b Each is independently selected from hydrogen, (C1–C6)alkyl, (C3–C6)cycloalkyl, or (C3–C6)cycloalkyl(C1–C4)alkylene; Or R a R b Together with the nitrogen atoms attached to them, they form a 4–6-membered nitrogen-containing heterocycle, which contains 1–3 heteroatoms selected from N or O; the nitrogen-containing heterocycle may optionally be separated by 1–3 R atoms. 7 replace; R 2 R 6 All are hydrogen; R 5 It is hydrogen or cyano; R 3 R 4 Each is independently selected from hydrogen, cyano, (C1–C4)alkylsulfonylamino or (C3–C8)cycloalkylsulfonylamino; Or R 3 R 4 Together with the carbon atoms attached to them, they form a 5–6-membered aromatic ring or heteroaromatic ring, the heteroaromatic ring containing 1–3 heteroatoms selected from N or O; the aromatic ring or heteroaromatic ring may optionally be surrounded by 1–3 R atoms. 8 replace; R 7 Selected from hydrogen, fluorine, or (C1–C6) alkyl groups; R 8 It is selected from hydrogen, (C1–C4)alkylsulfonyl or (C3–C8)cycloalkylsulfonyl.

3. The azaindole compounds and their stereoisomers, as well as pharmaceutically acceptable salts, according to claim 1, characterized in that: n is selected from 2 or 3; R 1 Selected from (C1–C6) alkoxy or in, Selected from: Selected from:

4. The azaindole compounds and their stereoisomers, as well as pharmaceutically acceptable salts, according to claim 1, characterized in that: The azaindole compound is one of the compounds having the following chemical structural formulas I-1 to I-54:

5. A method for preparing the compound according to any one of claims 1 to 4, its stereoisomers, and pharmaceutically acceptable salts, characterized in that: The compound was prepared according to the following steps: (a) Intermediate 2 was prepared by substitution reaction of 5-bromo-7-azaindole with N-iodosuccinimide; (b) Using intermediate 2 as a raw material, react with p-toluenesulfonyl chloride to prepare intermediate 3; (c) Using intermediate 3 as a raw material, react with the corresponding arylboronic acid or borate ester. Intermediate 4 was prepared by the Suzuki-Miyaura coupling reaction; (d) Using intermediate 5 as a raw material, react with the corresponding haloalkanes (R1-(CH2)). n Intermediate 6 was prepared by nucleophilic substitution reaction of -X (where X is a halogen); (e) Using intermediate 6 as a raw material, intermediate 7 was prepared by coupling reaction with pinacol diboronic acid ester; (f) Intermediate 8 was prepared by the Suzuki-Miyaura coupling reaction of intermediates 4 and 7; (g) Using intermediate 8 as a raw material, the target compound in general formula I was prepared by removing the protecting group under alkaline conditions; Alternatively, the compound can be prepared by the following steps: (a) Using intermediate 5 as a raw material, intermediate 9 was prepared by reacting it with 3-bromopropene in the presence of sodium hydride; (b) Using intermediate 9 as a raw material, intermediate 10 was prepared by coupling reaction with pinacol diboronic acid ester; (c) Intermediate 11 was prepared by Suzuki-Miyaura coupling reaction of intermediate 4 and intermediate 10; (d) Using intermediate 11 as raw material, intermediate 12 was prepared under the action of osmium reagent and oxidant; (e) Starting from intermediate 12, intermediate 8 is prepared by reductive amination of an amine compound with sodium cyanoborohydride or sodium triacetoxyborohydride. (f) Using intermediate 8 as the starting material, the target compound in general formula I was prepared by removing the protecting group under alkaline conditions.

6. The compound according to any one of claims 1 to 4, its stereoisomers, and pharmaceutically acceptable salts, characterized in that: The pharmaceutically acceptable salts include salts formed with inorganic acids, organic acids, and alkali metal ions; the inorganic acids are selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, or phosphoric acid; the organic acids are selected from: succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, or p-toluenesulfonic acid; and the alkali metal ions are selected from lithium ions, sodium ions, or potassium ions.

7. A pharmaceutical composition comprising, as an active ingredient, any one of the compounds of claims 1 to 4 and their stereoisomers, as well as a pharmaceutically acceptable salt, carrier, or excipient.

8. The use of the compound of any one of claims 1 to 4 and its stereoisomers and pharmaceutically acceptable salts, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the prevention and / or treatment of diseases related to TNIK.

9. The application according to claim 8, characterized in that: The diseases associated with TNIK are selected from cancer, nervous system diseases, fibrotic diseases, or metabolic diseases.

10. The application according to claim 9, characterized in that: The cancers mentioned are selected from lymphoma, non-small cell lung cancer, small cell lung cancer, head and neck cell carcinoma, glioma, neuroblastoma, squamous cell carcinoma of the lung, adenocarcinoma of the lung, bladder cancer, gastric cancer, colorectal cancer, colon cancer, kidney cancer, bile duct cancer, gastric cancer, esophageal squamous cell carcinoma, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, brain cancer, melanoma, multiple myeloma, skin cancer, epithelial cell carcinoma, leukemia, or cervical cancer; the neurological diseases mentioned are selected from schizophrenia, depression, Alzheimer's disease, or bipolar disorder; the fibrotic diseases mentioned are selected from idiopathic pulmonary fibrosis, myocardial fibrosis, renal fibrosis, liver fibrosis, or skin fibrosis; the metabolic diseases mentioned are selected from obesity or diabetes.

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