7-AZAINDOLE COMPOUNDS, METHODS FOR THEIR PREPARATION, AND USE THEREOF

Abstract

The present invention discloses 7-azaindole compounds, their preparation methods, and their uses, which belong to the field of drug synthesis. The present invention particularly relates to 7-azaindole compounds containing pyrazole or indole substitutions represented by general formula (I), as well as their preparation methods and pharmaceutical uses. The compounds of the present invention alleviate cancer cachexia skeletal muscle atrophy by inhibiting the ActRIIB protein in the MSTN pathway, thereby achieving significant anti-cancer cachexia effects. Experimental results show that the compounds have good anti-cachexia activity and can therefore be further used to prepare novel anti-cachexia drugs. TIFF2025537427000068.tif3144

Description

[Technical Field]

[0001] The present invention is in the field of drug synthesis and relates to novel 7-azaindole compounds, their preparation methods, and their uses. Specifically, the present invention relates to 7-azaindole compounds containing pyrazole or indole substitution, as well as their preparation methods and their use in medicine. [Background technology]

[0002] Cachexia is a progressive wasting syndrome accompanied by systemic dysfunction, including wasting, anemia, and mental depression. It is most often caused by cancer and other serious chronic diseases, such as chronic obstructive pulmonary disease, chronic heart failure, and AIDS. Cachexia, particularly caused by cancer, is called cancer cachexia. It affects nearly 80% of advanced cancer patients and accounts for approximately 30% of cancer-related deaths. It not only severely impacts the quality of life of cancer patients, but also weakens the effectiveness of chemotherapy and radiation therapy, significantly reducing patient survival. Cancer cachexia has gradually attracted widespread attention. However, the pathology of cancer cachexia is highly complex, which has led to the fact that most recommended treatments for cachexia today are limited to appetite stimulation and nutritional interventions. Currently, the only approved drug for the treatment of cancer cachexia is anamorelin (a ghrelin receptor agonist), leaving very limited options.

[0003] Suppressing muscle atrophy is currently considered one of the key approaches to treating and alleviating cancer cachexia. Recent studies have shown that the myostatin (MSTN)-related pathway plays an important role in cancer cachexia, and high myostatin expression is positively correlated with skeletal muscle atrophy in patients with cancer cachexia. Myostatin, also known as growth differentiation factor 8 (GDF-8), is a protein secreted primarily by skeletal muscle and plays a negative regulatory role in muscle growth and development. MSTN is also expressed in adipose tissue and plays an important regulatory role in fat deposition. The C-terminus of the MSTN homodimer first binds to activin type II receptors (ActRII, mainly ActRIIB) on the cell membrane surface, then recruits ActRI type I receptors to form a receptor complex, which then phosphorylates the cytoplasmic transcription factors Smad2 / 3. The activated Smad complex enters the nucleus and activates various forms of protein degradation. Inhibition of any part of the MSTN-ActRIIB-Smad signaling pathway can effectively affect the biological function of MSTN. Furthermore, after binding to the ActRIIB receptor, MSTN also regulates the expression of its downstream target genes through various non-Smad protein signaling pathways, such as MAPK, Erk1 / 2, and JNK, thereby producing biological functions.

[0004] Currently, drugs under development targeting the MSTN-related pathway mainly include the following types of drugs: (1) myostatin antibody inhibitors: landgrozumab (LY2495655), domagrozumab (PF-06252616), and stamuroumab (Myo-029); (2) myostatin propeptide: AMG-745; (3) ActRIIB-Fc recombinant fusion protein: ramatorcept (ACE-031); (4) ActRIIB receptor antibody inhibitor: bimagrumab (BYM338); and (5) gene therapy using follistatin (a natural MSTN inhibitor). Several peptide inhibitors of MSTN have also been reported in the literature. The ActRIIB antibody inhibitor CDD866 can effectively block the myostatin-ActRIIB signaling pathway. In animal experiments, it can effectively counteract cancer cachexia caused by the CT26 mouse colon cancer model. In combination with chemotherapy, it can reduce chemotherapy-induced muscle wasting and significantly prolong survival. Bimagrumab, an antibody inhibitor of ActRIIB under development by Novartis, has been shown in multiple phase II clinical trials to effectively increase muscle mass (5.0-7.8%) and exercise capacity in cachectic patients at a dose of 30 mg / kg.

[0005] The above research results confirm that inhibition of the ActRIIB receptor has significant clinical benefits in delaying cancer cachexia, but the related drugs currently under development are all protein or gene drugs. The difficulty and overall cost of researching such macromolecular drugs are relatively high, which makes their application in clinical treatment difficult. Therefore, research on small molecule inhibitors of the ActRIIB protein is sure to bring new hope and opportunities to research on anti-cancer cachexia drugs. Summary of the Invention

[0006] An object of the present invention is to provide novel 7-azaindole compounds having good ActRIIB inhibitory effects, and specifically, the present invention relates to 7-azaindole compounds containing a pyrazole or indole substituent.

[0007] Another object of the present invention is to provide a method for preparing the above 7-azaindole compounds, in particular a method for preparing 7-azaindole compounds containing a pyrazole ring.

[0008] The 7-azaindole compounds of the present invention have the following general formula (I): [ka] (In the formula, Ar is pyrazole, indole, or a pyrazole-containing substituent, wherein the substituents in the pyrazole-containing substituent are selected from C1-4 hydrocarbon groups and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, [ka] and Optionally, with the following restrictions: a) When R is morpholine, Ar is [ka] isn't it, b) R is [ka] If Ar is [ka] isn't it, c) When Ar is indole, R is [ka] isn't it).

[0009] In some embodiments of the present invention, the structural formula of the 7-azaindole compound is as shown in formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, or 3-pyridyl, and in the pyrazole-containing substituent or isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, [ka] is selected from Optionally, with the following restrictions: a) When R is morpholine, Ar is [ka] isn't it, b) R is [ka] If Ar is [ka] isn't it, c) When Ar is indole, R is [ka] isn't it).

[0010] In some embodiments of the present invention, the 7-azaindole compound is a compound represented by structural formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, or 3-pyridine, and in the pyrazole-containing substituent or isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, [ka] (selected from).

[0011] The present invention further provides a compound of structural formula (IV): [ka] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, preferably selected from a pharmaceutically acceptable carrier, diluent, or excipient, wherein Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, or 3-pyridine, and in the pyrazole-containing substituent or isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, [ka] is selected from Optionally, with the following restrictions: a) When R is morpholine, Ar is [ka] isn't it, b) R is [ka] If Ar is [ka] isn't it, c) When Ar is indole, R is [ka] isn't it).

[0012] The present invention further relates to the use of a compound represented by structural formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, pyridine, or phenyl, and in the pyrazole-containing substituent or the isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of the substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, [ka] is selected from Optionally, with the following restrictions: a) When R is morpholine, Ar is [ka] isn't it, b) R is [ka] If Ar is [ka] isn't it, c) When Ar is indole, R is [ka] isn't it).

[0013] In some preferred embodiments of the present invention, in Formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof, Ar is indole. More preferably, indole is [ka] is.

[0014] In some preferred embodiments of the present invention, in Formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof, Ar is a pyrazole or a pyrazole-containing substituent.

[0015] In some preferred embodiments of the present invention, in Formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof, Ar is [ka] More preferably, Ar is selected from: [ka] is.

[0016] In some preferred embodiments of the present invention, in Formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof, R is 4-methylpiperazine. More preferably, R is [ka] is.

[0017] The 7-azaindole compounds of the present invention include the following compounds: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0018] The present invention further relates to a 7-azaindole compound of formula (I), (II), (III), (IV), (V), or any one of compounds 1 to 25, or a pharmaceutically acceptable salt thereof, for use in inhibiting ActRIIB activity in a subject in need thereof.

[0019] The present invention further relates to a 7-azaindole compound of formula (I), (II), (III), (IV), (V), or any one of compounds 1-25, or a pharmaceutically acceptable salt thereof, for use in treating cachexia. Preferably, it is used to treat cancer cachexia.

[0020] The present invention further relates to a pharmaceutical composition comprising any one of (I), (II), (III), (IV), (V), or compounds 1 to 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0021] In some embodiments of the present invention, the pharmaceutically acceptable additive is selected from a pharmaceutically acceptable carrier, diluent, or excipient.

[0022] The present invention further relates to the use of a 7-azaindole compound of formula (I), (II), (III), (IV), (V), or any one of compounds 1 to 25, or a pharmaceutically acceptable salt thereof, or the composition of the present invention as described above, in the preparation of an ActRIIB inhibitor.

[0023] The present invention further relates to the use of a 7-azaindole compound of formula (I), (II), (III), (IV), (V), or any one of compounds 1 to 25, or a pharmaceutically acceptable salt thereof, in the preparation of an anti-cachexia medicament, in particular an anti-cancer cachexia medicament.

[0024] Using compound 2 as an example, the preparation process of compounds 1-11 of the present invention is as follows: [ka]

[0025] Using compound 12 as an example, the preparation process of compounds 12-17 of the present invention is as follows: [ka]

[0026] The preparation process of compound 18 of the present invention is as follows: [ka]

[0027] The present invention further relates to the use of a 7-azaindole compound, or a pharmaceutically acceptable salt thereof, in the preparation of an anti-cachexia medicament.

[0028] The present invention provides a composition and use of the composition in the preparation of an anti-cachexia medicament, the composition comprising a 7-azaindole compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a pharmaceutically acceptable carrier, diluent, or excipient.

[0029] Additionally, the anti-cachexia agent is selected from anti-cancer cachexia agents.

[0030] The compounds of the present invention have been subjected to in vivo and in vitro experiments, and found to be able to reduce the muscle atrophy caused by cancer cachexia, and animal experiments have shown that they can significantly alleviate the weight loss caused by cancer cachexia.This shows that azaindole compounds have anti-cancer cachexia effects, can be used to treat cancer cachexia and related diseases, and are the ideal drug for treating cancer cachexia. [Brief explanation of the drawings]

[0031] [Figure 1] 1 shows an HE staining image of the control group in Example 26. [Figure 2]1 shows HE staining images of the model group in Example 26. [Figure 3] 1 shows HE staining images of experimental group 1 in Example 26. [Figure 4] 1 shows HE staining images of experimental group 2 in Example 26. [Figure 5] 1 shows HE staining images of experimental group 3 in Example 26. [Figure 6] 1 shows HE staining images of experimental group 4 in Example 26. [Figure 7] 1 shows HE staining images of experimental group 5 in Example 26. [Figure 8] 1 shows HE staining images of experimental group 6 in Example 26. [Figure 9] 1 shows HE staining images of experimental group 7 in Example 26. [Figure 10] 1 shows HE staining images of experimental group 8 in Example 26. [Figure 11] 1 shows HE staining images of experimental group 9 in Example 26. [Figure 12] 1 shows HE staining images of experimental group 10 in Example 26. [Figure 13] 1 shows HE staining images of experimental group 11 in Example 26. [Figure 14] 1 shows HE staining images of experimental group 12 in Example 26. [Figure 15] 1 shows HE staining images of experimental group 13 in Example 26. [Figure 16] 1 shows HE staining images of experimental group 14 in Example 26. [Figure 17] 1 shows HE staining images of experimental group 15 in Example 26. [Figure 18] 1 shows HE staining images of experimental group 16 in Example 26. [Figure 19] 1 shows HE staining images of experimental group 17 in Example 26. [Figure 20] 1 shows HE staining images of experimental group 18 in Example 26. [Figure 21] 1 shows HE staining images of experimental group 19 in Example 26. [Figure 22] 1 shows HE staining images of experimental group 20 in Example 26. [Figure 23] 1 shows HE staining images of experimental group 21 in Example 26. [Figure 24] 1 shows HE staining images of experimental group 22 in Example 26. [Figure 25] 1 shows HE staining images of experimental group 23 in Example 26. [Figure 26] 1 shows HE staining images of experimental group 24 in Example 26. [Figure 27] 1 shows HE staining images of experimental group 25 in Example 26. [Figure 28] 1 shows an HE staining image of experimental group 26 in Example 26. [Figure 29] 1 shows HE staining images of experimental group 27 in Example 26. [Figure 30] 1 shows HE staining images of experimental group 28 in Example 26. [Figure 31] 1 shows HE staining images of experimental group 29 in Example 26. [Figure 32] 1 shows HE staining images of experimental group 30 in Example 26. [Figure 33] 1 shows the weight change curve of tumor-bearing mice treated with Compound 2 in Example 28. [Figure 34] 1 shows the weight change curve of tumor-free mice treated with Compound 2 in Example 28. [Figure 35] 1 shows the body weight change rate curve of mice treated with Compound 2 in Example 28. [Figure 36] 1 shows the tumor volume change curve of mice treated with Compound 2 in Example 28. [Figure 37] 1 shows a photograph of a tumor in a mouse treated with Compound 2 in Example 28. [Figure 38] 1 shows the average cumulative food intake change curve of mice treated with Compound 2 in Example 28. [Figure 39] 1 shows the results of a mouse muscle grip strength test for Compound 2 in Example 28. [Figure 40]1 shows the results of a mouse right hind paw mass test for Compound 2 in Example 28. [Figure 41] 1 shows a photograph of the right hind leg of a mouse treated with Compound 2 in Example 28. [Figure 42] 1 shows the results of a mouse gastrocnemius muscle mass test for Compound 2 in Example 28. [Figure 43] 1 shows a photograph of the gastrocnemius muscle of a mouse treated with Compound 2 in Example 28. [Figure 44] 1 shows the results of a mouse tibialis anterior muscle mass test of Compound 2 in Example 28. [Figure 45] 1 shows a photograph of the tibialis anterior muscle of a mouse treated with Compound 2 in Example 28. [Figure 46] 1 shows the weight change curves of tumor-bearing mice treated with compounds 3 and 10 in Example 28. [Figure 47] 1 shows the weight change curves of tumor-free mice treated with compounds 3 and 10 in Example 28. [Figure 48] 1 shows the body weight change rate curves of mice treated with Compounds 3 and 10 in Example 28. [Figure 49] 1 shows tumor volume change curves in mice for compounds 3 and 10 in Example 28. [Figure 50] 1 shows tumor images of mice treated with compounds 3 and 10 in Example 28. [Figure 51] 1 shows the average cumulative food intake change curves of mice treated with Compounds 3 and 10 in Example 28. [Figure 52] 1 shows the results of a mouse muscle grip strength test for Compounds 3 and 10 in Example 28. [Figure 53] 1 shows the results of a mouse right hind paw mass test for Compounds 3 and 10 in Example 28. [Figure 54] Photographs of the right hind legs of mice treated with Compounds 3 and 10 in Example 28 are shown. [Figure 55] 1 shows the results of a mouse tibialis anterior muscle mass test for Compounds 3 and 10 in Example 28. [Figure 56] 1 shows photographs of the tibialis anterior muscle of mice treated with Compounds 3 and 10 in Example 28. [Figure 57] 1 shows the results of a mouse gastrocnemius muscle mass test for Compounds 3 and 10 in Example 28. [Figure 58] 1 shows photographs of the gastrocnemius muscles of mice treated with Compounds 3 and 10 in Example 28. [Figure 59] 1 is a schematic diagram of mouse gastrocnemius muscle tissue sections of compounds 3 and 10 in Example 28. FIG. [Figure 60] FIG. 13 is a statistical diagram of the cross-sectional distribution of gastrocnemius muscle fibers in mice treated with Compounds 3 and 10 in Example 28. DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention will be further described below in conjunction with specific embodiments. The following embodiments are used only to explain the present invention, and do not limit the scope of the present invention. It should be understood that those skilled in the art can make some non-essential improvements and adjustments based on the above content of the present invention.

[0033] The pharmacodynamic testing methods used in the present invention are well known to those skilled in the art.

[0034] In the present invention, the C2C12 cells, C26 cells, and Balb / c mice used can be obtained commercially by those skilled in the art.

[0035] Example 1: Synthesis of compound 1·3-(1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0036] 1) Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine: A 50 mL two-neck flask was charged with 5-bromo-7-azaindole (1.0 equiv., 10.15 mmol, 2.00 g), 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester (1.5 equiv., 15.23 mmol, 4.60 g), potassium carbonate (3.0 equiv., 30.45 mmol, 4.21 g), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.51 mmol, 368 mg), followed by 15 mL of 1,4-dioxane and 5 mL of water. The atmosphere was replaced with argon three times, and the system was then heated under reflux and reacted overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 1.87 g of 5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 63.2% yield.

[0037] 2) Synthesis of 3-iodo-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine: To a 50 mL two-neck flask, 5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (1.0 equiv., 5.13 mmol, 1.50 g) was added, followed by 15 mL of anhydrous DMF. N-iodosuccinimide (1.1 equiv., 5.64 mmol, 1.27 g) was slowly added in batches, and the system was allowed to react for 30 minutes. After the reaction stopped, saturated sodium thiosulfate solution was added to quench the reaction, followed by the addition of a large amount of water to precipitate the product. The product was directly filtered without any further workup, yielding 2.04 g of crude product: 3-iodo-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 95.9% yield.

[0038] 3) 3-Iodo-1-[(4-methylphenyl)dioxo-λ 6Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine: In a 50 mL two-neck flask, 3-iodo-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine (1.0 equivalent, 4.78 mmol, 2.00 g) was added, followed by 15 mL of anhydrous DMF. Sodium hydride (60%, dispersed in liquid paraffin) (1.1 equivalent, 5.26 mmol, 126 mg) was slowly added in an ice bath, and the system was allowed to react for 30 minutes. Then, p-toluenesulfonyl chloride (1.3 equivalent, 6.22 mmol, 1.19 g) was slowly added, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the reaction was quenched by adding ice water. The product precipitated and was directly filtered to obtain the crude product. This was recrystallized to give 2 g of 3-iodo-1-[(4-methylphenyl)dioxo-λ]pyridine. 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine was obtained in 74.6% yield.

[0039] 4) 3-(1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6[-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1-Boc-pyrazole-4-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 116 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 87 mg of 3-(1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine was obtained in 65.4% yield. 1 H NMR(600MHz,chloroform-d) δ 8.63 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 2.0 Hz, 1H), 7.92 (s, 2H), 7.80 (s, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.27 (s, 2H), 6.97 (d, J = 8.3 Hz, 2H), 3.36 (t, J = 4.9 Hz, 4H), 2.81 (t, J = 4.8 Hz, 4H), 2.52 (s, 3H), 2.35 (s, 3H). 13 C NMR(151MHz,CDCl3) δ 150.30, 146.39, 145.27, 144.06, 135.33, 132.52, 131.86, 129.74, 129.60, 128.12, 127.96, 126.15, 122.15, 121.89, 116.54, 112.95, 111.89, 54.53, 48.07, 45.38, 21.64.

[0040] 5) Synthesis of 3-(1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.17 mmol, 87 mg) and potassium carbonate (3.0 equiv., 0.51 mmol, 70 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 44 mg of 3-(1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 72.4% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.48 (s, 1H), 8.29 (s, 1H), 8.09 (s, 2H), 7.70 (s, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 3.25 (s, 4H), 2.66 (s, 4H), 2.36 (s, 3H). 13 C NMR(151MHz,DMSO) δ 145.08, 143.23, 136.70, 125.04, 123.62, 123.41, 122.98, 120.87, 119.82, 117.88, 112.89, 111.25, 109.77, 102.25, 49.43, 42.90, 40.38.

[0041] Example 2: Synthesis of compound 2·3-(1H-pyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0042] 1) 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1H-pyrazole-3-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 76 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 83 mg of 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine was obtained in 62.4% yield. 1 H NMR(600 MHz,chloroform-d) δ 8.66 (d, J = 2.5 Hz, 1H), 8.59 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.25 (d, J = 6.7 Hz, 2H), 7.00 - 6.94 (m, 2H), 6.62 (d, J = 2.5 Hz, 1H), 3.29 (t, J = 5.0 Hz, 4H), 2.64 (t, J = 5.0 Hz, 4H), 2.39 (s, 3H), 2.34 (s, 3H). 13C NMR(151MHz,CDCl3) δ 150.61, 146.49, 145.21, 144.16, 135.36, 132.74, 130.30, 129.69, 129.38, 128.23, 128.07, 128.01, 123.30, 121.29, 116.23, 113.27, 103.04, 54.90, 48.58, 45.94, 21.63.

[0043] 2) Synthesis of 3-(1H-pyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 83 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 67 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 40 mg of 3-(1H-pyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 69.4% yield. 1 H NMR (600 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.50 (s, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.68 (s, 1H), 3.21 (s, 4H), 2.53 (s, 3H), 2.28 (d, J = 8.0 Hz, 4H). 13C NMR(151MHz,DMSO) δ 149.90, 147.75, 141.44, 137.45, 129.21, 128.53, 127.92, 127.27, 125.39, 123.81, 115.69, 101.27, 54.39, 47.81, 45.56.

[0044] Example 3: Synthesis of Compound 3·3-(1H-indol-5-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0045] 1) 3-(1H-indol-5-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 5-indoleboronic acid pinacol ester (1.5 equiv., 0.39 mmol, 95 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 88 mg of 3-(1H-indol-5-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine was obtained in 59.6% yield. 1H NMR (600 MHz, Chloroform-d) δ 8.70 - 8.62 (m, 1H), 8.34 (s, 1H), 8.23 ​​(d, J = 2.3 Hz, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 13.0 Hz, 2H), 7.50 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 10.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.65 - 6.58 (m, 1H), 3.31 (d, J = 5.3 Hz, 4H), 2.68 (s, 4H), 2.42 (s, 3H), 2.37 (s, 3H). 13 C NMR(151 MHz,CDCl3) δ 150.53, 146.73, 145.03, 143.87, 135.62, 135.38, 132.52, 129.67, 128.43, 128.18, 128.02, 126.65, 125.12, 124.32, 122.54, 122.28, 122.10, 121.83, 119.77, 116.37, 111.70, 102.94, 54.80, 48.49, 45.81, 21.65.

[0046] 2) Synthesis of 3-(1H-indol-5-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(1H-indol-5-yl)-1-[(4-methylphenyl)dioxo-λ 6[1H-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 88 mg) and potassium carbonate (3.0 equiv., 0.47 mmol, 65 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 41 mg of 3-(1H-indol-5-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 63.8% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.49 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.48 (s, 2H), 7.35 (t, J = 2.7 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.48 (t, J = 2.5 Hz, 1H), 3.21 (d, J = 5.7 Hz, 4H), 2.61 - 2.51 (m, 4H), 2.28 (s, 3H). 13 C NMR(151MHz,DMSO) δ 149.81, 148.09, 141.20, 134.54, 129.54, 128.38, 128.16, 127.43, 125.69, 125.49, 124.34, 122.98, 120.69, 117.65, 116.09, 115.76, 111.70, 101.12, 54.27, 47.74, 45.38.

[0047] Example 4: Synthesis of compound 4·3-(3-methyl-1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0048] 1) 3-(3-methyl-1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 3-methylpyrazole-4-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 82 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 82 mg of 3-(3-methyl-1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine was obtained in 59.6% yield. 1 H NMR(600MHz, DMSO-d6) δ 8.65 (d, J = 2.2 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.83 (s, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 3.20 (t, J = 4.9 Hz, 4H), 2.48 (t, J = 4.8 Hz, 4H), 2.39 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H). 13C NMR(151MHz,DMSO) δ 150.45, 145.50, 145.39, 143.09, 134.55, 131.99, 129.91, 127.74, 127.35, 127.25, 125.94, 122.07, 121.76, 115.45, 112.69, 108.96, 54.34, 47.58, 45.57, 20.98.

[0049] 2) Synthesis of 3-(3-methyl-1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(3-methyl-1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 82 mg) and potassium carbonate (3.0 equiv., 0.47 mmol, 65 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 38 mg of 3-(3-methyl-1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 66.3% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.48 (d, J = 2.2 Hz, 1H), 8.10 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 6.8 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 8.3 Hz, 2H), 3.19 (t, J = 5.0 Hz, 4H), 2.34 (s, 3H), 2.26 (s, 3H). 13C NMR(151MHz,DMSO) δ 149.84, 147.54, 145.64, 141.25, 137.45, 129.35, 128.11, 127.91, 127.37, 125.38, 124.26, 122.89, 118.27, 115.67, 106.74, 54.38, 47.84, 45.54, 20.67.

[0050] Example 5: Synthesis of compound 5·3-(3,5-dimethyl-1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0051] 1) 3-(3,5-dimethyl-1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 3,5-dimethylpyrazole-4-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 87 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 90 mg of 3-(3,5-dimethyl-1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine was obtained in 63.8% yield. 1 H NMR(600MHz,chloroform-d) δ 8.65 (s, 1H), 8.13 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.60 (s, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 3.40 - 3.25 (m, 4H), 2.73 (s, 4H), 2.46 (s, 3H), 2.39 (s, 3H), 2.23 (s, 6H). 13 C NMR(151MHz,CDCl3) δ 150.46, 146.32, 145.22, 143.97, 135.48, 132.40, 129.73, 129.53, 128.09, 128.07, 126.35, 124.61, 123.15, 116.45, 111.77, 108.79, 58.48, 54.74, 48.31, 45.68, 21.69.

[0052] 2) Synthesis of 3-(3,5-dimethyl-1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(3,5-dimethyl-1H-pyrazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine (1.0 equiv., 0.17 mmol, 90 mg) and potassium carbonate (3 equiv., 0.50 mmol, 69 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 42 mg of 3-(3,5-dimethyl-1H-pyrazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 65.2% yield.1 H NMR (600MHz, methanol-d4) δ 8.44 (d, J = 2.4 Hz, 1H), 7.88 (t, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.2, 2.3 Hz, 2H), 7.55 (dd, J = 8.9, 2.4 Hz, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 8.3, 2.2 Hz, 2H), 7.11 (dd, J = 8.9, 2.4 Hz, 2H), 3.45 (s, 3H), 3.21 (qd, J = 7.4, 2.4 Hz, 3H), 2.87 (d, J = 2.3 Hz, 3H), 2.36 (d, J = 2.3 Hz, 3H), 2.21 (d, J = 2.3 Hz, 6H). 13 C NMR(151MHz,DMSO) δ 148.39, 147.72, 145.57, 141.08, 137.51, 130.47, 127.94, 127.71, 127.40, 125.38, 124.10, 119.04, 116.33, 109.52, 54.81, 52.13, 45.51, 45.48.

[0053] Example 6: Synthesis of Compound 6·5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine

[0054] 1) 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6[-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 82 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 86 mg of 1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine was obtained in 62.2% yield. 1 H NMR(600MHz,chloroform-d) δ 8.70 (d, J = 2.8 Hz, 1H), 8.20 - 8.13 (m, 2H), 7.93 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.46 (dt, J = 8.6, 4.0 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.04 - 6.96 (m, 2H), 6.47 - 6.41 (m, 1H), 3.94 (d, J = 2.3 Hz, 3H), 3.32 (s, 4H), 2.68 (s, 4H), 2.42 (s, 3H), 2.40 (d, J = 2.2 Hz, 3H). 13C NMR(151MHz,CDCl3) δ 150.75, 145.82, 145.62, 144.71, 138.99, 135.09, 134.11, 133.05, 129.82, 128.26, 128.09, 126.22, 124.79, 121.90, 116.32, 109.22, 107.80, 106.99, 54.82, 48.41, 45.87, 37.62, 37.28.

[0055] 2) Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 86 mg) and potassium carbonate (3.0 equiv., 0.49 mmol, 68 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 41 mg of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine in 66.9% yield. 1 H NMR(600MHz,chloroform-d) δ 8.62 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.54 (s, 1H), 7.53 (s, 1H), 7.49 (s, 1H), 7.05 (s, 1H), 7.03 (s, 1H), 6.45 (d, J = 1.8 Hz, 1H), 3.95 (s, 3H), 3.31 (t, J = 5.0 Hz, 4H), 2.65 (t, J = 4.9 Hz, 4H). 13C NMR(151MHz,CDCl3) δ 150.55, 147.59, 142.86, 138.83, 136.36, 130.56, 130.09, 128.06, 125.98, 124.55, 119.35, 116.38, 106.32, 105.27, 54.97, 48.78, 46.04, 37.44.

[0056] Example 7: Synthesis of Compound 7·3-(2-ethylpyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0057] 1) 3-(2-ethylpyrazol-3-yl)-1-[4-methylphenyl]dioxo-λ 6 Synthesis of -thio-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1-ethylpyrazole-5-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 87 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 87 mg of 3-(2-ethylpyrazol-3-yl)-1-[4-methylphenyl]dioxo-λ 6 -thio-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine was obtained in 61.7% yield.1 H NMR(600MHz,chloroform-d) δ 8.68 (s, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.90 (s, 1H), 7.81 (s, 1H), 7.63 (s, 1H), 7.48 (s, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.00 (s, 2H), 6.40 (s, 1H), 4.32 - 4.14 (m, 2H), 3.72 (s, 4H), 3.07 (s, 3H), 2.89 (s, 3H), 2.40 (s, 4H), 1.45 (d, J = 7.9Hz, 3H). 13 C NMR(151MHz,CDCl3) δ 146.01, 145.70, 144.71, 139.19, 135.04, 132.55, 131.19, 129.86, 128.42, 128.29, 126.36, 124.93, 117.80, 109.28, 107.21, 53.93, 46.87, 44.80, 21.73, 15.83.

[0058] 2) Synthesis of 3-(2-ethylpyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(2-ethylpyrazol-3-yl)-1-[4-methylphenyl]dioxo-λ 6 1H-thio-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 87 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 67 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 40 mg of 3-(2-ethylpyrazol-3-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 64.7% yield. 1H NMR(600MHz,DMSO-d6) δ 8.56 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 1.8 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.23 (s, 4H), 2.63 (s, 4H), 2.34 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13 C NMR(151MHz,DMSO) δ 150.35, 147.98, 142.61, 138.75, 135.72, 129.70, 129.48, 128.02, 126.16, 124.48, 118.86, 116.34, 106.11, 103.95, 54.58, 47.97, 44.41, 15.98.

[0059] Example 8: Synthesis of Compound 8: 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-(prop-2-yl)pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine

[0060] 1) 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-(prop-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6[-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1-isopropylpyrazole-5-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 93 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 91 mg of 1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-(prop-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine was obtained in 62.5% yield. 1 H NMR(600MHz,chloroform-d) δ 8.69 (s, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.87 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 6.35 (s, 1H), 4.56 (p, J = 6.7 Hz, 1H), 3.31 (t, J = 5.1 Hz, 4H), 2.67 (s, 4H), 2.42 (s, 3H), 2.40 (s, 3H), 1.50 (d, J = 6.5 Hz, 6H). 13C NMR(151MHz,CDCl3) δ 150.72, 145.82, 145.59, 144.65, 139.10, 135.12, 133.02, 132.51, 129.81, 128.90, 128.28, 128.03, 125.94, 124.86, 122.41, 116.31, 109.36, 106.92, 54.82, 50.43, 48.40, 45.86, 23.02, 21.71.

[0061] 2) Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-(prop-2-yl)pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-(prop-2-yl)pyrazol-3-yl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 91 mg) and potassium carbonate (3.0 equiv., 0.49 mmol, 68 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 44 mg of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-(prop-2-yl)pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine in 66.4% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.56 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 2.6 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 2H), 7.08 - 6.99 (m, 2H), 6.44 (d, J = 1.7 Hz, 1H), 4.66 (p, J = 6.5 Hz, 1H), 3.23 (s, 4H), 2.60 (s, 4H), 2.33 (s, 3H), 1.39 (d, J = 6.5 Hz, 6H).13 C NMR(151MHz,DMSO) δ 149.78, 147.39, 142.00, 138.14, 134.58, 128.97, 128.88, 127.36, 125.75, 123.63, 118.53, 115.73, 105.51, 103.33, 54.06, 49.21, 47.42, 45.07, 22.82.

[0062] Example 9: Synthesis of Compound 9: 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine

[0063] 1) 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1-methylpyrazol-4-yl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxopentaboran-2-yl)-1H-pyrazole (1.5 equiv., 0.39 mmol, 82 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 10 mg) were added to a mixture, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was taken, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to obtain 84 mg of 1-[(4-methylphenyl)dioxo-λ 6-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1-methylpyrazol-4-yl)pyrrolo[2,3-b]pyridine was obtained in 60.7% yield. 1 H NMR(600MHz,chloroform-d) δ 8.65 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 8.3, 2.3 Hz, 2H), 8.03 (d, J = 2.6 Hz, 1H), 7.77 (t, J = 3.1 Hz, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.05 - 6.97 (m, 2H), 3.99 (d, J = 2.3 Hz, 3H), 3.37 (s, 4H), 2.75 (s, 3H), 2.48 (s, 3H), 2.37 (d, J = 2.3 Hz, 3H). 13 C NMR(151MHz,CDCl3) δ 146.42, 145.16, 144.11, 137.50, 135.43, 132.52, 129.68, 128.17, 128.02, 127.50, 126.10, 121.97, 121.82, 116.51, 113.65, 111.81, 58.47, 54.67, 48.27, 39.18, 21.64.

[0064] 2) Synthesis of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6[-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1-methylpyrazol-4-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 84 mg) and potassium carbonate (3.0 equiv., 0.4 mmol, 66 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 39 mg of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1-methylpyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine in 65.3% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.47 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.22 (s, 4H), 2.57 (s, 4H), 2.30 (s, 3H). 13 C NMR(151MHz,DMSO) δ 149.78, 147.71, 141.25, 135.96, 129.39, 128.22, 127.48, 126.86, 124.24, 122.30, 117.26, 115.70, 115.17, 106.48, 54.20, 47.69, 45.30, 38.38.

[0065] Example 10: Synthesis of compound 10·3-(1H-pyrazol-3-yl)-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)-1H-pyrrolo[2,3-b]pyridine:

[0066] 1) 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-(4-{[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy}phenyl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1H-pyrazole-3-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 76 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and Pd(dppf)Cl (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was removed, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 83 mg of 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)pyrrolo[2,3-b]pyridine was obtained in 62.4% yield. 1 H NMR(600MHz,chloroform-d) δ 8.64 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.11 (dd, J = 8.5, 2.0 Hz, 2H), 8.03 (s, 1H), 7.66 (s, 1H), 7.53 - 7.47 (m, 2H), 7.28 (s, 2H), 7.00 - 6.95 (m, 2H), 6.64 (s, 1H), 4.20 (d, J = 5.9 Hz, 2H), 3.79 (d, J = 5.2 Hz, 4H), 2.89 (s, 2H), 2.67 (s, 4H), 2.36 (d, J = 1.9 Hz, 3H). 13C NMR(151MHz,CDCl3) δ 158.36, 146.60, 145.25, 144.27, 143.57, 135.34, 132.61, 131.24, 129.70, 128.56, 128.49, 128.05, 124.82, 123.46, 121.22, 115.10, 113.17, 103.13, 66.66, 65.62, 57.58, 54.01, 21.64. 54.90, 48.58, 45.94, 21.63.

[0067] 2) Synthesis of 3-(1H-pyrazol-3-yl)-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 [1H-thio]-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 83 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 67 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 24 mg of 3-(1H-pyrazol-3-yl)-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)-1H-pyrrolo[2,3-b]pyridine in 59.4% yield. 1H NMR(600MHz, methanol-d4) δ 7.64 (s, 1H), 7.56 (d, J = 2.1 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.77 - 6.70 (m, 2H), 6.18 (d, J = 8.6 Hz, 2H), 5.77 (d, J = 2.2 Hz, 1H), 3.31 (t, J = 5.4 Hz, 2H), 2.84 (t, J = 4.6 Hz, 4H), 1.96 (t, J = 5.4 Hz, 2H), 1.75 (t, J = 4.6 Hz, 4H). 13 C NMR(151MHz,DMSO) δ 157.65, 147.87, 141.59, 131.35, 128.30, 127.91, 125.99, 123.92, 117.02, 114.98, 101.30, 66.09, 65.32, 56.93, 53.55.

[0068] Example 11: Synthesis of compound 11·5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)-3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine:

[0069] 1) 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 5-(4-{[2-(hexahydropyridin-1-yl)ethyl]oxy}phenyl)-3-iodine-1-[(4-methylphenyl)dioxo-λ 6[-thio]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1H-pyrazole-3-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 76 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and Pd(dppf)Cl (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was removed, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 65 mg of 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]pyrrolo[2,3-b]pyridine was obtained in 42.3% yield. 1 H NMR 600MHz,chloroform-d) δ 8.62 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.10 (d, J = 8.1 Hz, 2H), 8.02 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.27 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 2.3 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.75 (s, 4H), 2.36 (s, 3H), 1.72 (p, J = 5.6 Hz, 4H), 1.52 (s, 2H). 13C NMR(151MHz,CDCl3) δ 158.13, 146.59, 145.26, 144.24, 135.31, 132.57, 131.28, 129.70, 128.55, 128.03, 123.39, 121.24, 115.05, 103.05, 65.06, 57.37, 54.72, 25.01, 23.51, 21.64.

[0070] 2) Synthesis of 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)-3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 [1H-thio]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 83 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 67 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 32 mg of 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)-3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine in 53.4% ​​yield. 1 H NMR(600MHz,DMSO-d6) δ 8.56 (s, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.68 - 7.57 (m, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.68 (s, 1H), 4.12 (t, J = 6.1 Hz, 2H), 2.69 (d, J = 7.8 Hz, 2H), 2.46 (s, 4H), 1.51 (p, J = 5.6 Hz, 4H), 1.39 (q, J = 6.1, 5.7 Hz, 2H). 13C NMR(151MHz,DMSO) δ 157.69, 147.86, 141.56, 131.29, 128.30, 127.89, 123.91, 114.97, 101.30, 65.57, 57.26, 54.31, 25.47, 23.82.

[0071] Example 12: Synthesis of Compound 12: 3-(2-methylpyrazol-3-yl)-5-(4-{[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy}phenyl)-1H-pyrrolo[2,3-b]pyridine

[0072] 1) Synthesis of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine: To a 50 mL two-neck flask, 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 equiv., 25.38 mmol, 5.00 g) was added, followed by 60 mL of anhydrous THF. N-iodosuccinimide (1.1 equiv., 27.91 mmol, 6.28 g) was added slowly in batches, and the mixture was allowed to react for 60 minutes. After the reaction had stopped, saturated sodium thiosulfate solution was added to quench the reaction, and then a large amount of water was added to precipitate the product. The product was directly filtered without any further workup, yielding 7.57 g of crude product: 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine in 92.4% yield.

[0073] 2) 5-Bromo-3-iodo-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]pyrrolo[2,3-b]pyridine: In a 50 mL two-neck flask, 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.0 equivalent, 18.58 mmol, 6.00 g) and 40 mL of anhydrous THF were added. Sodium hydride (60%, dispersed in liquid paraffin) (1.1 equivalent, 20.44 mmol, 817 mg) was slowly added in an ice bath, and the mixture was allowed to react for 30 minutes. Then, p-toluenesulfonyl chloride (1.3 equivalent, 24.15 mmol, 4.60 g) was slowly added, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the reaction was quenched by adding ice water. The product precipitated and was directly filtered to obtain the crude product. This was recrystallized to give 6.43 g of 5-bromo-3-iodo-1-[(4-methylphenyl)dioxo-λ]pyridine. 6 -thio]pyrrolo[2,3-b]pyridine was obtained in 72.5% yield.

[0074] 3) 5-Bromo-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine: In a 50 mL two-neck flask, add 5-bromo-3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]pyrrolo[2,3-b]pyridine (1.0 equiv., 12.58 mmol, 6.00 g), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1.5 equiv., 18.86 mmol, 3.92 g), potassium carbonate (3.0 equiv., 37.73 mmol, 5.21 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.63 mmol, 456 mg) were added, followed by 45 mL of 1,4-dioxane and 15 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated at 80 °C and reacted for 72 h. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 2.93 g of 5-bromo-1-[(4-methylphenyl)dioxo-λ 6-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine was obtained in 54.1% yield.

[0075] 4) 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)-5-(4-{[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy}phenyl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 5-bromo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 100 mg), 4-(2-morpholinethoxy)phenylboronic acid pinacol ester (1.5 equiv., 0.35 mmol, 116 mg), potassium carbonate (3.0 equiv., 0.70 mmol, 96 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 8 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 84 mg of 1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)-5-(4-{[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy}phenyl)pyrrolo[2,3-b]pyridine was obtained in 65.1% yield. 1H NMR(600MHz,chloroform-d) δ 8.68 (s, 1H), 8.16 (dd, J = 8.4, 2.1 Hz, 2H), 7.93 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.60 (s, 1H), 7.46 (dd, J = 8.6, 2.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.00 (dd, J = 8.6, 2.2 Hz, 2H), 6.44 (s, 1H), 4.21 (s, 2H), 3.94 (d, J = 2.0 Hz, 3H), 3.79 (s, 4H), 2.96 - 2.81 (m, 2H), 2.66 (s, 4H), 2.40 (s, 3H). 13 C NMR(151MHz,CDCl3) δ 145.95, 145.66, 144.79, 139.00, 135.05, 134.02, 132.89, 130.75, 129.83, 128.54, 128.28, 126.55, 124.89, 121.89, 115.27, 109.20, 107.00, 57.52, 53.98, 37.62, 21.71.

[0076] 5) Synthesis of 3-(2-methylpyrazol-3-yl)-5-(4-{[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy}phenyl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6[-thio]-3-(2-methylpyrazol-3-yl)-5-(4-{[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy}phenyl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.17 mmol, 84 mg) and potassium carbonate (3.0 equiv., 0.51 mmol, 70 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 28 mg of 3-(2-methylpyrazol-3-yl)-5-(4-{[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy}phenyl)-1H-pyrrolo[2,3-b]pyridine in 45.3% yield. 1 H NMR(600MHz,DMSO-d6) δ 7.72 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.02 (d, J = 2.7 Hz, 1H), 6.86 - 6.80 (m, 2H), 6.67 (t, J = 1.8 Hz, 1H), 6.24 - 6.17 (m, 2H), 5.76 (t, J = 1.7 Hz, 1H), 3.35 - 3.27 (m, 2H), 3.11 - 3.04 (m, 3H), 2.75 (q, J = 3.6, 2.6 Hz, 4H), 1.88 (t, J = 5.8 Hz, 2H), 1.65 (s, 4H). 13 C NMR(151MHz,DMSO) δ 157.85, 147.61, 142.25, 137.98, 135.94, 131.15, 128.82, 128.19, 125.96, 124.61, 118.11, 115.05, 105.24, 103.65, 66.17, 65.42, 57.01, 53.63, 37.41.

[0077] Example 13: Synthesis of Compound 13·5-(4-{[2-(hexahydropyridin-1-yl)ethyl]oxy}phenyl)-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine

[0078] 1) 5-(4-{[2-(hexahydropyridin-1-yl)ethyl]oxy}phenyl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 5-bromo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 100 mg), 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid pinacol ester (1.5 equiv., 0.35 mmol, 115 mg), potassium carbonate (3.0 equiv., 0.70 mmol, 96 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 8 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 80 mg of 5-(4-{[2-(hexahydropyridin-1-yl)ethyl]oxy}phenyl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine was obtained in 62.1% yield. 1H NMR(600MHz,chloroform-d) δ 8.87 (s, 1H), 8.21 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.53 (s, 1H), 7.26 (d, J = 8.2 Hz, 2H),7.01 (d, J = 8.1 Hz, 2H), 6.45 (d, J = 2.4 Hz, 1H), 4.27 (s, 2H), 3.95 (d, J = 2.3 Hz, 3H), 3.06 (s, 2H), 2.69 (s, 4H), 2.37 (s, 3H), 1.84 (s, 4H), 1.52 (s, 2H).

[0079] 2) Synthesis of 5-(4-{[2-(hexahydropyridin-1-yl)ethyl]oxy}phenyl)-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 5-(4-{[2-(hexahydropyridin-1-yl)ethyl]oxy}phenyl)-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.14 mmol, 80 mg) and potassium carbonate (3.0 equiv., 0.43 mmol, 60 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 27 mg of 5-(4-{[2-(hexahydropyridin-1-yl)ethyl]oxy}phenyl)-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine in 47.2% yield. 1H NMR(600MHz,chloroform-d) δ 8.60 (s, 1H), 8.06 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.48 (s, 1H), 7.01 (d, J = 8.1 Hz, 2H), 6.45 (d, J = 2.4 Hz, 1H), 4.27 (s, 2H), 3.95 (d, J = 2.3 Hz, 3H), 2.96 (s, 2H), 2.69 (s, 4H), 1.73 (s, 4H), 1.51 (s, 2H). 13 C NMR(151MHz,CDCl3) δ 147.64, 143.27, 138.85, 136.19, 130.47, 128.51, 126.12, 124.82, 124.39, 119.16, 115.17, 106.36, 105.49, 58.47, 57.58, 54.87, 37.44.

[0080] Example 14: Synthesis of Compound 14·(4-methylpiperazin-1-yl){4-[3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}ketone

[0081] 1)(4-{1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)(4-methylpiperazin-1-yl) ketone In a 50 mL two-neck flask, add 5-bromo-1-[(4-methylphenyl)dioxo-λ 6[-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 100 mg), 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid pinacol ester (1.5 equiv., 0.35 mmol, 115 mg), potassium carbonate (3.0 equiv., 0.70 mmol, 96 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 8 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 82 mg of (4-{1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)(4-methylpiperazin-1-yl)ketone was obtained in 63.7% yield. 1 H NMR(600MHz,chloroform-d) δ 8.72 (d, J = 2.0 Hz, 1H), 8.21 - 8.14 (m, 2H), 8.00 (d, J = 2.2 Hz, 1H), 7.88 (t, J = 1.4 Hz, 1H), 7.63 - 7.57 (m, 3H), 7.51 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.45 (q, J = 1.7 Hz, 1H), 3.95 (t, J = 1.5 Hz, 3H), 3.93 - 3.47 (m, 4H), 2.57 (s, 3H), 2.41 (s, 4H), 2.40 (s, 3H). 13C NMR(151MHz,CDCl3) δ 169.78, 146.43, 145.82, 144.89, 139.56, 139.05, 134.94, 133.81, 132.32, 129.89, 128.35, 128.03, 127.56, 127.13, 125.17, 121.96, 109.20, 107.04, 54.66, 45.75, 41.76, 37.62, 24.88, 21.73.

[0082] 2) Synthesis of (4-methylpiperazin-1-yl){4-[3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}ketone In a 10 mL one-neck flask, add (4-{1-[(4-methylphenyl)dioxo-λ 6 [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)(4-methylpiperazin-1-yl)ketone (1.0 equiv., 0.15 mmol, 82 mg) and potassium carbonate (3.0 equiv., 0.44 mmol, 61 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 27 mg of (4-methylpiperazin-1-yl){4-[3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}ketone in 46.1% yield. 1 H NMR(600MHz,chloroform-d) δ 8.66 (s, 1H), 8.14 (s, 1H), 7.71 - 7.65 (m, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 7.4 Hz, 3H), 6.46 (d, J = 2.5 Hz, 1H), 3.96 (d, J = 2.6 Hz, 3H), 3.92 - 3.55 (m, 4H), 2.50 (d, J = 68.0 Hz, 4H), 2.38 (d, J = 2.5 Hz, 3H). 13C NMR(151MHz,CDCl3) δ 170.03, 148.16, 143.16, 140.57, 138.89, 135.99, 134.55, 129.85, 127.95, 127.48, 126.72, 124.85, 119.36, 106.42, 105.61, 58.44, 55.22, 54.71, 45.92, 37.43.

[0083] Example 15: Synthesis of Compound 15: 5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine

[0084] 1) 1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 5-bromo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 100 mg), 4-(4-methyl-1-piperazinemethyl)phenylboronic acid pinacol ester (1.5 equiv., 0.35 mmol, 110 mg), potassium carbonate (3.0 equiv., 0.70 mmol, 96 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 8 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 77 mg of 1-[(4-methylphenyl)dioxo-λ 6-thio]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine was obtained in 61.5% yield. 1 H NMR(600MHz,chloroform-d) δ 8.85 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.53 - 7.49 (m, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H),6.49 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H), 3.68 (s, 2H), 2.69 (s, 8H), 2.62 (s, 3H), 2.52 (s, 3H).

[0085] 2) Synthesis of 5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.14 mmol, 77 mg) and potassium carbonate (3.0 equiv., 0.43 mmol, 59 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 25 mg of 5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine in 45.3% yield.

[0086] 1H NMR(600MHz,chloroform-d) δ 8.65 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.53 - 7.49 (m, 1H), 7.43 (d, J = 7.8 Hz, 2H), 6.46 (d, J = 1.8 Hz, 1H), 3.95 (s, 3H), 3.62 (s, 2H), 2.69 (s, 8H), 2.48 (s, 3H). 13 C NMR(151MHz,CDCl3) δ 147.90, 143.38, 138.86, 136.12, 130.52, 129.89, 128.89, 127.39, 126.52, 125.98, 124.53, 119.22, 106.38, 105.57, 62.23, 54.69, 51.86, 45.21, 37.44.

[0087] Example 16: Synthesis of Compound 16: 3-(2-methylpyrazol-3-yl)-5-[4-(1,4-oxazacyclohexan-4-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0088] 1) 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)-5-[4-(1,4-oxazacyclohexan-4-yl)phenyl]pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 5-bromo-1-[(4-methylphenyl)dioxo-λ 6[-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 100 mg), 4-morpholinylphenylboronic acid pinacol ester (1.5 equiv., 0.35 mmol, 101 mg), potassium carbonate (3.0 equiv., 0.70 mmol, 96 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 8 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 74 mg of 1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)-5-[4-(1,4-oxazacyclohexan-4-yl)phenyl]pyrrolo[2,3-b]pyridine was obtained in 62.2% yield. 1 H NMR(600MHz,chloroform-d) δ 8.70 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 2.2 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.13 (s, 2H), 6.44 (d, J = 2.4 Hz, 1H), 4.01 - 3.89 (m, 7H), 3.26 (s, 4H), 2.40 (s, 3H). 13 C NMR(151MHz,CDCl3) δ 145.95, 145.67, 144.72, 138.99, 135.06, 134.06, 129.84, 128.30, 126.39, 124.91, 121.92, 109.18, 107.01, 66.40, 58.49, 37.62, 21.72.

[0089] 2) Synthesis of 3-(2-methylpyrazol-3-yl)-5-[4-(1,4-oxazacyclohexan-4-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6 [-thio]-3-(2-methylpyrazol-3-yl)-5-[4-(1,4-oxazacyclohexan-4-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.14 mmol, 74 mg) and potassium carbonate (3.0 equiv., 0.43 mmol, 59 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 24 mg of 3-(2-methylpyrazol-3-yl)-5-[4-(1,4-oxazacyclohexan-4-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 45.3% yield. 1 H NMR(600MHz,chloroform-d) δ 8.62 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.61 (s, 1H), 7.60 - 7.53 (m, 2H), 7.51 (d, J = 2.4 Hz, 1H), 7.08 - 6.96 (m, 2H), 6.45 (s, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.90 (dt, J = 5.7, 2.8 Hz, 4H), 3.23 (p, J = 2.6 Hz, 4H). 13 C NMR(151MHz,CDCl3) δ 150.72, 146.60, 141.89, 138.88, 135.95, 130.66, 129.99, 128.14, 126.76, 124.77, 119.86, 116.05, 106.46, 105.65, 66.83, 49.14, 37.45.

[0090] Example 17: Synthesis of Compound 17: 3-(2-methylpyrazol-3-yl)-5-[4-(piperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0091] 1) 2-Methylprop-2-yl 4-(4-{1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)piperazine-1-formate In a 50 mL two-neck flask, add 5-bromo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 100 mg), 4-[4-(N-BOC)piperazin-1-yl]phenylboronic acid pinacol ester (1.5 equiv., 0.35 mmol, 135 mg), potassium carbonate (3.0 equiv., 0.70 mmol, 96 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.01 mmol, 8 mg) were added to the reaction mixture. Then, 4 mL of 1,4-dioxane and 1 mL of water were added. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was separated, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=20:1) to give 98 mg of 2-methylprop-2-yl 4-(4-{1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)piperazine-1-formate was obtained in 69.1% yield.

[0092] 2) Synthesis of 2-methylprop-2-yl 4-{4-[3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazine-1-formate In a 10 mL one-neck flask, add 2-methylprop-2-yl 4-(4-{1-[(4-methylphenyl)dioxo-λ 6[-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)piperazine-1-formate (1.0 equiv., 0.16 mmol, 98 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 66 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 47 mg of 2-methylprop-2-yl 4-{4-[3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazine-1-formate in 63.6% yield. 1 H NMR(600MHz,chloroform-d) δ 8.55 (s, 1H), 8.30 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 6.47 (d, J = 3.1 Hz, 1H), 3.94 (t, J = 1.7 Hz, 3H), 3.64 (s, 4H), 3.24 (d, J = 6.0 Hz, 4H), 1.50 (t, J = 1.7 Hz, 9H).

[0093] 3) Synthesis of 3-(2-methylpyrazol-3-yl)-5-[4-(piperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, 47 mg of 2-methylprop-2-yl 4-{4-[3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}piperazine-1-formate was added, and DCM containing 10% trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the product was centrifuged and dried to obtain 34 mg of the final product: 3-(2-methylpyrazol-3-yl)-5-[4-(piperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 92.3% yield. 1H NMR(600MHz,DMSO-d6) δ 8.57 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.64 (s, 2H), 7.51 (s, 1H), 7.07 (s, 2H), 6.59 (s, 1H), 3.92 (s, 3H), 3.16 (d, J = 67.6 Hz, 8H). 13 C NMR (151 MHz, DMSO) δ 147.43, 142.05, 137.88, 135.89, 128.81, 127.55, 125.81, 124.17, 118.03, 116.08, 105.11, 103.48, 46.65, 43.48, 37.31.

[0094] Example 18: Synthesis of Compound 18·5-(4-{[2-(diethylamino)ethyl]oxy}phenyl)-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine

[0095] 1) 4-{1-[(4-methylphenyl)dioxo-λ 6 Synthesis of {-thio}-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenol In a 100 mL three-neck flask, add 5-bromo-1-[(4-methylphenyl)dioxo-λ 6[-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 1.62 mmol, 700 mg), 4-hydroxyphenylboronic acid pinacol ester (1.5 equiv., 2.43 mmol, 536 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equiv., 0.081 mmol, 59 mg), and potassium carbonate (3.0 equiv., 4.86 mmol, 672 mg) were added, followed by 20 mL of 1,4-dioxane and 5 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux at 100 °C and allowed to react overnight. After cooling, water and DCM were added for extraction. The organic phase was collected, washed three times with water, washed three times with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=30:1) to give 418 mg of 4-{1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenol was obtained in a yield of 58.0%.

[0096] 2) 2-[(4-{1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)oxy]ethan-1-ol In a 50 mL flask, add 4-{1-[(4-methylphenyl)dioxo-λ 6-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenol (1.0 equiv., 0.90 mmol, 400 mg), 2-bromoethanol (1.2 equiv., 1.08 mmol, 135 mg), potassium carbonate (3.0 equiv., 2.70 mmol, 373 mg), and 10 mL of acetone were added and heated at 55°C overnight. After cooling the reaction, the solvent was concentrated under reduced pressure to dryness by centrifugation, and water and DCM were added for extraction. The organic phase was collected, washed three times with water, washed three times with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=30:1) to give 237 mg of 2-[(4-{1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)oxy]ethan-1-ol was obtained in a yield of 54.0%.

[0097] 3) 4-Methylbenzenesulfonic acid-2-[(4-{1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)oxy]ethyl ester In a 50 mL flask, add 2-[(4-{1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)oxy]ethan-1-ol (1.0 equiv., 0.41 mmol, 200 mg), p-toluenesulfonyl chloride (1.2 equiv., 0.49 mmol, 94 mg), triethylamine (5.0 equiv., 2.05 mmol, 207 mg), and 10 mL of DCM were added, and the mixture was stirred and reacted at room temperature for 8 hours. After completion of the reaction, the system was washed with water. The organic phase was separated and washed three times with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the system was purified by column chromatography (DCM:MeOH=30:1) to obtain 218 mg of 4-methylbenzenesulfonic acid-2-[(4-{1-[(4-methylphenyl)dioxo-λ 6-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)oxy]ethyl ester was obtained in a yield of 83.0%.

[0098] 4) 5-(4-{[2-(diethylamino)ethyl]oxy}phenyl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine In a 25 mL flask, add 4-methylbenzenesulfonic acid-2-[(4-{1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridin-5-yl}phenyl)oxy]ethyl ester (1.0 equivalent, 0.23 mmol, 150 mg), diethylamine (2.2 equivalent, 0.51 mmol, 37.55 mg), potassium carbonate (1.1 equivalent, 0.26 mmol, 36 mg) were added, and then 5 mL of acetonitrile was added, and then the mixture was heated under reflux and reacted overnight. After cooling, the reaction mixture was concentrated under reduced pressure and centrifuged to dryness without any other workup to obtain the crude compound: 5-(4-{[2-(diethylamino)ethyl]oxy}phenyl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine was obtained, which was carried on directly to the next step of the reaction.

[0099] 5) Synthesis of 5-(4-{[2-(diethylamino)ethyl]oxy}phenyl)-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine In a 25 mL one-neck flask, add 5-(4-{[2-(diethylamino)ethyl]oxy}phenyl)-1-[(4-methylphenyl)dioxo-λ 6[-thio]-3-(2-methylpyrazol-3-yl)pyrrolo[2,3-b]pyridine and potassium carbonate (2.0 equivalents, 0.46 mmol, 65 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80°C for 16 hours. After cooling the reaction, water and DCM were added for extraction. The organic phase was separated, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 30:1) to obtain 40 mg of 5-(4-{[2-(diethylamino)ethyl]oxy}phenyl)-3-(2-methylpyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine. The overall yield of the two-step reaction was 44.0%. 1 H NMR (600MHz, methanol-d4) δ 8.54 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.77 (s, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.49 - 7.44 (m, 2H), 6.94 - 6.86 (m, 2H), 6.53 (d, J = 2.0 Hz, 1H), 4.52 (t, J = 6.7 Hz, 2H), 3.95 (d, J = 2.1 Hz, 3H), 3.05 (t, J = 6.6 Hz, 2H), 2.72 (q, J = 7.1 Hz, 4H), 1.05 (t, J = 7.2 Hz, 6H). 13 C NMR (151 MHz, methanol-d₄) δ 158.36, 147.65, 143.42, 139.66, 138.25, 132.07, 131.49, 130.51, 129.48, 126.84, 121.01, 116.94, 106.98, 104.45, 53.37, 49.43, 49.28, 49.14, 49.00, 48.86, 48.72, 48.57, 48.40, 43.71, 37.57, 11.76.

[0100] Example 19: Synthesis of Compound 19: 3-(3,5-dimethylisoxazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine

[0101] 1) The compound 3-(3,5-dimethylisoxazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 88 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and Pd(dppf)Cl (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling the reaction mixture, it was purified by column chromatography (DCM:MeOH=20:1) to obtain 90 mg of the compound: 3-(3,5-dimethylisoxazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine was obtained in 63.6% yield. 1H NMR(600MHz,chloroform-d) δ 8.68 (d, J = 2.5 Hz, 1H), 8.19 - 8.13 (m, 2H), 7.71 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.03 - 6.98 (m, 2H), 3.30 (t, J = 4.9 Hz, 4H), 2.63 (s, 4H), 2.40 (d, J = 5.1 Hz, 6H), 2.37 (d, J = 2.1 Hz, 3H), 2.22 (d, J = 2.0 Hz, 3H). 13 C NMR(151MHz,CDCl3) δ 166.89, 159.44, 150.84, 146.03, 145.49, 144.43, 135.22, 132.78, 129.79, 128.78, 128.23, 128.01, 125.78, 125.22, 122.37, 116.24, 108.30, 107.63, 54.92, 48.51, 46.01, 21.71, 11.79, 10.78.

[0102] 2) Synthesis of the compound 3-(3,5-dimethylisoxazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(3,5-dimethylisoxazol-4-yl)-1-[(4-methylphenyl)dioxo-λ 6[-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-pyrrolo[2,3-b]pyridine (1.0 equiv., 0.17 mmol, 90 mg) and potassium carbonate (3.0 equiv., 0.50 mmol, 69 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 42 mg of the compound: 3-(3,5-dimethylisoxazol-4-yl)-5-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridine in 64.6% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.53 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.64 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 3.32 (s, 3H), 3.26 (s, 4H), 2.72 (s, 4H), 2.41 (s, 3H), 2.20 (d, J = 2.1 Hz, 3H). 13 C NMR(151MHz,DMSO) δ 165.12, 159.12, 149.54, 147.55, 141.58, 140.97, 128.41, 127.40, 127.24, 126.15, 123.77, 118.54, 115.80, 109.23, 53.76, 47.15, 11.42, 10.36. ESI-MS m / z 388.4 [M+H] + ESI-HRMS (m / z): [C 23 H 25 NO] + Calculated value: 388.4274, measured value: 388.4276.

[0103] Example 20: Synthesis of Compound 20: 3-(1H-pyrazol-3-yl)-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)-1H-pyrrolo[2,3-b]pyridine

[0104] 1) The compound 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)pyrrolo[2,3-b]pyridine To a 50 mL two-neck flask were added 4-(2-(4-(3-iodo-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenoxy)ethyl)morpholine (1.0 equiv., 0.26 mmol, 150 mg), 1H-pyrazole-3-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 76 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), Pd(dppf)Cl (0.05 equiv., 0.01 mmol, 10 mg), followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling the reaction mixture, it was purified by column chromatography (DCM:MeOH=20:1) to give 83 mg of 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)pyrrolo[2,3-b]pyridine was obtained in 62.4% yield. 1 H NMR(600MHz,chloroform-d) δ 8.64 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.11 (dd, J = 8.5, 2.0 Hz, 2H), 8.03 (s, 1H), 7.66 (s, 1H), 7.53 - 7.47 (m, 2H), 7.28 (s, 2H), 7.00 - 6.95 (m, 2H), 6.64 (s, 1H), 4.20 (d, J = 5.9 Hz, 2H), 3.79 (d, J = 5.2 Hz, 4H), 2.89 (s, 2H), 2.67 (s, 4H), 2.36 (d, J = 1.9 Hz, 3H). 13C NMR(151MHz,CDCl3) δ 158.36, 146.60, 145.25, 144.27, 143.57, 135.34, 132.61, 131.24, 129.70, 128.56, 128.49, 128.05, 124.82, 123.46, 121.22, 115.10, 113.17, 103.13, 66.66, 65.62, 57.58, 54.01, 21.64. ESI-MS m / z 544.4 [M+H] + .

[0105] 2) Synthesis of the compound 3-(1H-pyrazol-3-yl)-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 [1H-thio]-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 83 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 67 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 24 mg of 3-(1H-pyrazol-3-yl)-5-(4-[[2-(1,4-oxazacyclohexan-4-yl)ethyl]oxy]phenyl)-1H-pyrrolo[2,3-b]pyridine in 59.4% yield. 1H NMR(600MHz, methanol-d4) δ 7.64 (s, 1H), 7.56 (d, J = 2.1 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.77 - 6.70 (m, 2H), 6.18 (d, J = 8.6 Hz, 2H), 5.77 (d, J = 2.2 Hz, 1H), 3.31 (t, J = 5.4 Hz, 2H), 2.84 (t, J = 4.6 Hz, 4H), 1.96 (t, J = 5.4 Hz, 2H), 1.75 (t, J = 4.6 Hz, 4H). 13 C NMR(151MHz,DMSO) δ 157.65, 147.87, 141.59, 131.35, 128.30, 127.91, 125.99, 123.92, 117.02, 114.98, 101.30, 66.09, 65.32, 56.93, 53.55. ESI-MS m / z 390.2 [M+H] + ESI-HRMS (m / z): [C 22 H 23 N5O2] + Calculated value: 390.1852, measured value: 390.1853.

[0106] Example 21: Synthesis of Compound 21·5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)-3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine

[0107] 1) The compound 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]pyrrolo[2,3-b]pyridine To a 50 mL two-neck flask were added 3-iodo-5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 1H-pyrazole-3-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 76 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), Pd(dppf)Cl (0.05 equiv., 0.01 mmol, 10 mg), followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling the reaction mixture, it was purified by column chromatography (DCM:MeOH=20:1) to give 65 mg of 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 -thio]pyrrolo[2,3-b]pyridine was obtained in 42.3% yield. 1 H NMR 600MHz,chloroform-d) δ 8.62 (d, J = 2.1 Hz, 1H), 8.57 (s, 1H), 8.10 (d, J = 8.1 Hz, 2H), 8.02 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.27 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 2.3 Hz, 1H), 4.23 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.75 (s, 4H), 2.36 (s, 3H), 1.72 (p, J = 5.6 Hz, 4H), 1.52 (s, 2H). 13C NMR(151MHz,CDCl3) δ 158.13, 146.59, 145.26, 144.24, 135.31, 132.57, 131.28, 129.70, 128.55, 128.03, 123.39, 121.24, 115.05, 103.05, 65.06, 57.37, 54.72, 25.01, 23.51, 21.64. ESI-MS m / z 542.2 [M+H] + .

[0108] 2) Synthesis of 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)-3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 5-(4-[[2-(hexahydropyridin-1-yl)ethyl]oxy]phenyl)3-(1H-pyrazol-3-yl)-1-[(4-methylphenyl)dioxo-λ 6 [4-(4-(2-(hexahydropyridin-1-yl)ethyl)oxy]phenyl)-3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 83 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 67 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80° C. for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH=10:1) to obtain 32 mg of 5-(4-(2-(hexahydropyridin-1-yl)ethyl)oxy)phenyl)-3-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine in 53.4% ​​yield. 1H NMR (600 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.51 (s, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.68 - 7.57 (m, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.68 (s, 1H), 4.12 (t, J = 6.1 Hz, 2H), 2.69 (d, J = 7.8 Hz, 2H), 2.46 (s, 4H), 1.51 (p, J = 5.6 Hz, 4H), 1.39 (q, J = 6.1, 5.7 Hz, 2H). 13C NMR(151MHz,DMSO) δ 157.69, 147.86, 141.56, 131.29, 128.30, 127.89, 123.91, 114.97, 101.30, 65.57, 57.26, 54.31, 25.47, 23.82. ESI-MS m / z 388.2 [M+H] + ESI-HRMS (m / z): [C 23 H 25 NO] + Calculated value: 388.2259, measured value: 388.2259.

[0109] Example 22: Synthesis of compound 22·5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine:

[0110] 1) Compound 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-3-yl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 3-pyridineboronic acid pinacol ester (1.5 equiv., 0.39 mmol, 80 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), Pd(dppf)Cl2 (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, the reaction mixture was purified by column chromatography (DCM:MeOH=20:1) to obtain 83 mg of compound 1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-3-yl)pyrrolo[2,3-b]pyridine was obtained in 60.9% yield. 1H NMR(600MHz,chloroform-d) δ 8.91 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.66 - 8.59 (m, 1H), 8.16 (s, 1H), 8.14 (t, J = 2.5 Hz, 2H), 7.93 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.41 (dt, J = 7.5, 3.3 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.01 (dd, J = 8.8, 2.5 Hz, 2H), 3.33 (s, 4H), 2.69 (s, 4H), 2.43 (s, 3H), 2.39 (d, J = 2.3 Hz, 3H). 13 C NMR(151MHz,CDCl3) δ 150.69, 148.83, 148.45, 146.43, 145.48, 144.47, 135.21, 134.67, 132.94, 129.78, 129.14, 128.91, 128.22, 128.14, 126.00, 123.91, 123.72, 121.16, 116.89, 116.37, 54.80, 48.40, 45.82, 21.69. ESI-MS m / z 524.4 [M+H] + .

[0111] 2) Synthesis of the compound 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6[-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-3-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 83 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 66 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 38 mg of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine in 65.3% yield. 1 H NMR(600MHz,DMSO-d6) δ 9.02 (s, 1H), 8.54 (s, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.46 (dd, J = 7.9, 4.8 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 3.19 (t, J = 4.8 Hz, 4H), 2.48 (d, J = 6.2 Hz, 4H), 2.24 (s, 3H). 13 C NMR(151MHz,CDCl3) δ 150.41, 147.77, 146.97, 142.39, 134.48, 131.28, 130.46, 130.40, 130.22, 128.15, 125.98, 125.69, 124.04, 123.66, 118.48, 116.61, 112.66, 54.86, 48.71, 45.84. ESI-MS m / z 370.3 [M+H] + ESI-HRMS (m / z): [C 23 H 23 N5] + Calculated value: 370.3245, measured value: 370.3242.

[0112] Example 23: Synthesis of Compound 23: 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine

[0113] 1) Compound 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyrimidin-5-yl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), pyrimidine-5-boronic acid pinacol ester (1.5 equiv., 0.39 mmol, 81 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), Pd(dppf)Cl2 (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, the reaction mixture was purified by column chromatography (DCM:MeOH=20:1) to obtain 84 mg of compound 1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyrimidin-5-yl)pyrrolo[2,3-b]pyridine was obtained in 60.9% yield. 1 H NMR(600MHz,DMSO-d6) δ 9.27 (s, 2H), 9.07 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 3.23 (s, 4H), 2.60 (d, J = 20.1 Hz, 4H), 2.32 (s, 3H). 13C NMR(151MHz,DMSO) δ 155.32, 153.60, 148.06, 142.01, 129.18, 127.63, 125.96, 124.54, 116.82, 115.64, 107.50, 97.43, 54.13, 47.61, 41.17, 31.17, 28.90. ESI-MS m / z 525.4 [M+H] + .

[0114] 2) Synthesis of the compound 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyrimidin-5-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 84 mg) and potassium carbonate (3.0 equiv., 0.47 mmol, 66 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 39 mg of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine in 67.3% yield. 1 H NMR(600MHz,DMSO-d6) δ 9.27 (s, 2H), 9.07 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.18 (s, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 3.23 (s, 4H), 2.58 (s, 4H), 2.30 (d, J = 13.0 Hz, 3H). 13C NMR(151MHz,DMSO) δ 155.33, 153.61, 149.91, 148.08, 142.03, 129.22, 128.98, 127.90, 127.64, 125.97, 125.38, 124.55, 116.83, 115.64, 107.51, 54.19, 47.60, 45.24. ESI-MS m / z 371.3 [M+H] + ESI-HRMS (m / z): [C 22 H 22 N6] + Calculated value: 371.2904, measured value: 371.2906.

[0115] Example 24: Synthesis of Compound 24: 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine

[0116] 1) Compound 1-[(4-methylphenyl)dioxo-λ 6 Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-4-yl)pyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), 4-pyridineboronic acid pinacol ester (1.5 equiv., 0.39 mmol, 81 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), Pd(dppf)Cl2 (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, the reaction mixture was purified by column chromatography (DCM:MeOH = 20:1) to obtain 85 mg of the compound: 1-[(4-methylphenyl)dioxo-λ 6-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-4-yl)pyrrolo[2,3-b]pyridine was obtained in 62.6% yield. 1 H NMR(600MHz,chloroform-d) δ 8.70 (s, 1H), 8.70 - 8.67 (m, 2H), 8.20 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 8.4, 2.1 Hz, 2H), 8.05 (d, J = 2.1 Hz, 1H), 7.54 (q, J = 2.2 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.02 (dd, J = 8.6, 2.2 Hz, 2H), 3.33 (s, 4H), 2.69 (s, 4H), 2.43 (s, 3H), 2.39 (d, J = 2.2 Hz, 3H). 13 C NMR(151MHz,CDCl3) δ 150.78, 150.58, 146.47, 145.62, 144.60, 140.66, 135.07, 133.10, 129.81, 128.31, 128.18, 126.15, 124.67, 121.72, 120.69, 117.47, 116.37, 54.82, 48.43, 45.86, 21.70. ESI-MS m / z 540.4 [M+H] + .

[0117] 2) Synthesis of the compound 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6[-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-4-yl)pyrrolo[2,3-b]pyridine (1.0 equiv., 0.16 mmol, 85 mg) and potassium carbonate (3.0 equiv., 0.48 mmol, 67 mg) were added, followed by 5 mL of methanol. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 39 mg of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine in 66.1% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.56 (d, J = 5.4 Hz, 3H), 8.48 (s, 1H), 8.22 (s, 1H), 7.83 (d, J = 5.2 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 3.22 (s, 4H), 2.53 (s, 4H), 2.29 (s, 3H). 13 C NMR(151MHz,DMSO) δ 149.83, 148.23, 142.25, 141.85, 129.26, 128.91, 127.56, 126.78, 124.60, 120.23, 116.88, 115.62, 111.41, 54.22, 47.65, 45.36. ESI-MS m / z 370.3 [M+H] + ESI-HRMS (m / z): [C 23 H 23 N5] + Calculated value: 370.3231, measured value: 370.3234.

[0118] Example 25: Synthesis of Compound 25: 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridine

[0119] 1) Compound 1-[(4-methylphenyl)dioxo-λ 6Synthesis of [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-phenylpyrrolo[2,3-b]pyridine In a 50 mL two-neck flask, add 3-iodo-1-[(4-methylphenyl)dioxo-λ 6

[0047] To a mixture of [4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine (1.0 equiv., 0.26 mmol, 150 mg), (4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)benzene (1.5 equiv., 0.39 mmol, 80 mg), potassium carbonate (3.0 equiv., 0.79 mmol, 109 mg), and Pd(dppf)Cl (0.05 equiv., 0.01 mmol, 10 mg) were added, followed by 4 mL of 1,4-dioxane and 1 mL of water. The atmosphere was replaced with argon three times, and the mixture was heated under reflux and allowed to react overnight. After cooling, the reaction mixture was purified by column chromatography (DCM:MeOH=20:1) to obtain 88 mg of the compound: 1-[(4-methylphenyl)dioxo-λ 6 -thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-phenylpyrrolo[2,3-b]pyridine was obtained in 64.7% yield. 1 H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 8.5, 2.0 Hz, 2H), 7.84 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 3.31 (s, 4H), 2.70 (s, 3H), 2.35 (d, J = 2.1 Hz, 4H). 13C NMR (151 MHz, DMSO) δ 145.80, 145.56, 143.23, 134.47, 132.15, 131.94, 129.96, 129.00, 127.84, 127.54, 127.33, 125.93, 123.74, 120.62, 119.62, 115.68, 53.74, 47.02, 28.71, 21.00. ESI-MS m / z 523.4 [M+H] + .

[0120] 2) Synthesis of the compound 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridine In a 10 mL one-neck flask, add 1-[(4-methylphenyl)dioxo-λ 6 [-thio]-5-[4-(4-methylpiperazin-1-yl)phenyl]-3-phenylpyrrolo[2,3-b]pyridine (1.0 equiv., 0.17 mmol, 88 mg), potassium carbonate (3.0 equiv., 0.51 mmol, 70 mg), and 5 mL of methanol were added. The mixture was reacted at 80 °C for 4 hours. After concentration under reduced pressure, the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain 40 mg of 5-[4-(4-methylpiperazin-1-yl)phenyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridine in 65.4% yield. 1 H NMR(600MHz,DMSO-d6) δ 8.51 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.64 - 7.59 (m, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.09 - 7.02 (m, 2H), 3.21 (t, J = 4.8 Hz, 4H), 2.55 (s, 4H), 2.29 (s, 3H). 13C NMR(151MHz,DMSO) δ 149.87, 148.13, 141.48, 134.96, 129.29, 128.80, 128.72, 127.48, 126.26, 125.53, 124.33, 124.28, 117.19, 115.73, 114.35, 54.26, 47.71, 45.38. ESI-MS m / z 369.3 [M+H] + ESI-HRMS (m / z): [C 24 H 24 N4] + Calculated value: 369.3411, measured value: 369.3410.

[0121] Example 26: Experiment on 7-azaindole compounds attenuating atrophy of mouse myoblasts (C2C12) induced by mouse colon cancer cells (C26)

[0122] C2C12 cells were seeded into 24-well plates. The culture medium was high-glucose DMEM containing 10% FBS and 1% penicillin-streptomycin. The plates were maintained at 37°C with 5% CO2. When cell proliferation density reached 50%-60%, the culture medium was replaced with high-glucose DMEM containing 2% HS and 1% penicillin-streptomycin. Fresh 2% HS differentiation medium was replaced every 48 hours, and the cells differentiated into mature cells on day 5 or 6. Furthermore, C26 cells were seeded into T75 flasks. The culture medium was high-glucose DMEM containing 10% FBS and 1% penicillin-streptomycin. The flasks were maintained at 37°C with 5% CO2. For subculture, cells were subcultured at 6 million cells per flask. After 48 hours of culture in 20 mL of medium, the supernatant was collected and centrifuged at 1000 rpm for 3 minutes. The supernatant was collected and centrifuged at 4000 rpm for 10 minutes to obtain C26 supernatant. The C26 supernatant and 2% HS differentiation solution were mixed in a 1:1 ratio (volume ratio) to form a muscle atrophy induction solution. Except for the control group, which was added with 2% HS differentiation solution, the other groups were added with an equal volume of muscle atrophy induction solution. One group was used as a model group, and the other groups were used as treatment and experimental groups. [Table 1-1] [Table 1-2]

[0123] The diameter of myotubes after differentiation of mouse myoblasts (C2C12) was evaluated using a diameter measurement method. The myotube diameter measurement method was as follows: 48 hours after treatment, myotubes were fixed and stained for more than 1 hour with a fixative (absolute ethanol:formaldehyde:glacial acetic acid (volume ratio) = 20:2:1). The staining method used in the experiment was hematoxylin-eosin staining, abbreviated as HE staining. Hematoxylin stain is alkaline and positively charged, and can easily bind to negatively charged, acidic deoxyribonucleic acid (DNA) in the cell nucleus through ionic bonds, staining the DNA blue. Eosin is an acidic dye that dissociates into negatively charged anions in water and can easily bind to the positively charged amino groups of proteins in the cytoplasm, staining the amino groups red. The stained cells were placed under a high-power microscope and photographed (magnification: 200x), and the diameter of myotubes was statistically analyzed using Image J software. The muscle atrophy recovery rate was calculated according to the following formula: muscle atrophy recovery rate = (mean value of myotubes in the treatment group - mean value of myotubes in the model group) / (mean value of myotubes in the control group - mean value of myotubes in the model group) × 100%.

[0124] Results and Discussion: Figures 1-32 are exemplary HE staining images showing that 7-azaindole compounds attenuate C2C12 mature myotube atrophy induced by C26 cell culture medium, and Table 1 shows the statistical results of myotubes. As shown in Figures 1-32 and Table 2, the compounds statistically significantly and concentration-dependently reversed myocyte atrophy. [Table 2]

[0125] Example 27: Testing the inhibitory activity of 7-azaindole compounds on ActRIIB

[0126] The ATP and substrate concentrations recommended by the ADP-Glo™ Assay Kit were used, which were 25 μM and 0.1 mg / mL, respectively. A series of isocratic final ActRIIB concentrations were also established: 0, 0.47, 0.94, 1.88, 3.75, 7.5, 15, 30, and 60 ng / μL, respectively. An ActRIIB concentration titration curve was constructed according to the fluorescence values ​​obtained in the experiment. The ActRIIB concentrations corresponding to the signal-to-background ratio (i.e., signal-to-background ratio, SBR) in the range of 5-10 were suitable for screening compounds for inhibition of ActRIIB activity. From the ActRIIB concentration titration curve, the final ActRIIB concentrations corresponding to SB5 and SB10 were calculated to be 14.9 and 23.7 ng / μL, respectively. Finally, a final concentration of 20.0 ng / μL was selected as the experimental concentration for screening compounds for inhibitory activity against ActRIIB. The inhibitory efficiencies of 7-azaindole compounds on ActRIIB were detected at concentrations of 0.1, 1, 10, and 100 nM, respectively. As shown in Table 3, the inhibition curves were plotted and the IC 50 values ​​were calculated. [Table 3]

[0127] Example 28: Experimental results of the compound in treating cancer cachexia animal models

[0128] 1. Regarding the experimental results of 7-azaindole compound 2 in the treatment of cancer cachexia animal models, the methods were as follows: C26 cells were seeded in a T75 flask. The culture system was 1640DMEM medium containing 10% FBS with 1% penicillin-streptomycin. For expansion culture, the flask was placed in a 5% CO2, 37°C environment. The cells were collected by centrifugation at 1000 rpm for 3 minutes, and the medium was washed with ice-cold PBS buffer to prepare a cell suspension at 10 million / mL. To generate tumors, the cell suspension was seeded into the left and right axillae of BALB / c mice at a concentration of 1 million. Tumor volumes of 1000 mm3 were obtained. 3 When tumors grew to 100 μL / g, they were removed and homogenized in 3 mL of iced saline to obtain tumor tissue suspensions. Mice were divided into groups according to body weight, and the cell suspension was inoculated into the left axilla of Balb / c mice at an inoculation volume of 100 μL / mouse. Treatment began the day after inoculation. Compound 2 was dissolved in 3% DMSO, 2% solutol, and 95% saline, successively, to form a homogenous solution with the required concentration. The solution was prepared daily and used. The dose was 5 mg / kg, and the compound was administered intragastrically (ig). The body weight, body temperature, tumor size, and food intake of the mice were monitored daily. In the early stages of the experiment, the tumor volume of the mice in the model group was small and body weight did not decrease, indicating a pre-cachectic stage. When the tumor volume of the mice in the model group reached 2.0 × 10 3 mm 3 The mice were considered to have entered the cachexia stage when their body weight reached 10% or when their body weight decreased by 10%. The grip strength of the forelimb muscles of the mice was tested at these two stages. The grip strength of the limb muscles of the mice was tested at these two stages. At the end of the experiment, the mice were sacrificed by cervical dislocation, and the gastrocnemius muscle, tibialis anterior muscle, right hind limb, and tumor samples were obtained and weighed.

[0129] The muscle grip strength was measured using the following method: The muscle grip strength of mice was tested on day 5 (pre-cachectic stage) and day 22 (cachectic stage) of the experiment. Using the right hand, the mouse was stably placed on a YLS-13A Mouse and Rat Grasp Force Tester so that its forelimbs could firmly grasp the grip disc, which was stabilized by moving the left hand forward. When the left hand slowly released the grip disc, the right hand quickly and slowly pulled the mouse's tail backward until the forelimbs separated from the grip disc. The test was repeated eight times for each mouse, and the average of the eight measurements was used as the skeletal muscle strength index for each mouse.

[0130] Results and Discussion: See Figures 33 to 45. The three curves in the figures represent the healthy group, the C26 tumor model group, and the treatment group (the group of Compound 2 at a dose of 5 mg / kg), respectively.

[0131] Figures 31-35 show the weights of tumor-bearing mice (Figure 33), tumor-free weights (Figure 34), tumor-free weight change (%) (Figure 35), tumor volume (Figure 36), and tumor photographs of the mice on the final day (Figure 37) during the survival period. Here, tumor-bearing weight and tumor-free weight are the average weights of eight mice, tumor-free weight change (%) is the average weight change (%) of eight mice, tumor volume is the average tumor volume of eight mice, and tumor photographs are tumor photographs of eight mice. As shown in Figure 33, the weights of mice in the healthy group continued to increase. On the other hand, as shown in Figure 34, the weights of mice in the C26-treated group from the start of the experiment began to decrease on day 15 and continued to decrease until the end of the experiment. The same was true for tumor-free weights. The compound 2 group was able to significantly alleviate the weight loss of mice, and by the end of the experiment, both the tumor-bearing and tumor-free body weights were greater than those of the C26 tumor model group, with a statistically significant difference (p<0.05). However, as shown in Figures 36 and 37, the tumor volume of the compound 2 group was slightly reduced compared to that of the C26 tumor model group. However, the difference was not significant, indicating that compound 2 did not have a clear inhibitory effect on C26 tumors.

[0132] Figure 38 shows the average cumulative feeding of mice during survival, which is the average calculation result of 8 mice.The feeding of mice in C26 tumor model group is significantly less than that in healthy group.The feeding of compound 2 group is slightly more than that in C26 tumor model group, and appetite is slightly improved.

[0133] Figure 39 shows the muscle grip strength of mouse limbs.The muscle grip strength of mice in cachectic C26 tumor model group is significantly smaller than that of healthy group (p=0.06).Compound 2 significantly improves the muscle grip strength of cachectic mice (p=0.06).

[0134] Figures 40 and 41 show the weight of the right hind limbs of mice and photographs of the right hind limbs. The weight of the right hind limbs is the average value of 8 mice, and the photographs of the right hind limbs are the results of 8 mice per group. As shown in Figures 40 and 41, the weight of the right hind limbs of mice in the C26 tumor model group was significantly smaller than that of mice in the healthy group, and the difference was statistically significant (p<0.001). Compound 2 can improve skeletal muscle atrophy in cachectic mice to a certain extent.

[0135] Figures 42-45 show the gastrocnemius muscle mass, gastrocnemius muscle photographs, tibialis anterior muscle mass, and tibialis anterior muscle photographs for mice. The gastrocnemius muscle mass and tibialis anterior muscle mass are the average values ​​for eight mice, and the photographs of the gastrocnemius muscle and tibialis anterior muscle are the results for eight mice per mouse. As shown in Figures 42 and 43, the gastrocnemius muscle mass of mice in the C26 tumor model group was significantly lower than that of the healthy control group, with the difference being statistically significant (p<0.001). Compound 2 significantly alleviated gastrocnemius muscle atrophy in cachectic mice (p<0.05). As shown in Figures 44 and 45, the tibialis anterior muscle mass of mice in the C26 tumor model group was significantly lower than that of the healthy control group, with the difference being statistically significant (p<0.001). Compound 2 can significantly alleviate tibialis anterior muscle atrophy in cachectic mice (p<0.05).

[0136] The above results indicate that Compound 2 can alleviate weight loss, muscle atrophy, and muscle strength caused by cancer cachexia, without affecting tumor size, and can slightly improve appetite.

[0137] 2. Regarding the experimental results of 7-azaindole compounds 3 and 10 in the treatment of cancer cachexia animal models, the methods were as follows: C26 cells were seeded in a T75 flask. The culture system was 1640DMEM medium containing 10% FBS with 1% penicillin-streptomycin. For expansion culture, the flask was placed in a 5% CO2, 37°C environment. The cells were collected by centrifugation at 1000 rpm for 3 minutes, and the medium was washed with ice-cold PBS buffer to prepare a cell suspension at 10 million / mL. To generate tumors, the cell suspension was seeded into the left and right axillae of BALB / c mice at a concentration of 1 million. Tumor volumes of 1000 mm3 were obtained. 3 When tumors grew to 100 μL / g, they were removed and homogenized in 3 mL of iced saline solution to obtain tumor tissue suspensions. Mice were divided into groups according to body weight, and the cell suspension was inoculated into the left axilla of BaLB / c mice at an inoculation volume of 100 μL / mouse. Treatment began the day after inoculation. Compounds 3 and 10 were dissolved in 3% DMSO, 2% solutol, and 95% saline, respectively, to form homogenous solutions with the required concentrations. The solutions were prepared daily and used. The dose was 10 mg / kg, and the compounds were administered intraperitoneally (ip). The body weight, body temperature, tumor size, and food intake of the mice were monitored daily. In the early stage of the experiment, the tumor volume of the mice in the model group was small and they did not lose weight, which indicated a pre-cachectic stage. In the middle stage of the experiment, the mice in the model group began to lose weight, which indicated that they had entered the mid-cachectic stage. When the tumor volume of the mice in the model group reached 2.0 × 10 3 mm 3 Late cachexia was considered to have occurred when the mice reached a maximum body weight of 1000 or lost 10% of their body weight. The grip strength of the mice's forelimb muscles was tested at these three stages. At the end of the experiment, the mice were sacrificed by cervical dislocation, and the gastrocnemius, tibialis anterior, right hind limb, and tumor samples were obtained and weighed. Appropriately sized gastrocnemius muscle tissue was obtained and fixed, embedded, cut, and stained to prepare H&E-stained tissue sections. For photography, at least 10 fields were randomly selected for each slice group. The cross-sectional areas of all muscle fibers in the photographs were measured and statistically analyzed.

[0138] The muscle grip force was measured using the following method: The muscle grip force of mice was tested on days 3 (pre-cachexia stage), 11 (mid-cachexia stage), and 16 (late-cachexia stage) of the experiment. Using the right hand, the mouse was stably placed on a YLS-13A Mouse and Rat Grasp Force Tester so that its forelimbs could firmly grasp the grip disc, which was stabilized by moving the left hand forward. When the left hand slowly released the grip disc, the right hand quickly and slowly pulled the mouse's tail backward until the forelimbs separated from the grip disc. The test was repeated eight times for each mouse, and the average of the eight measurements was used as the skeletal muscle strength index for each mouse.

[0139] Results and Discussion: See Figures 46 to 58. The four curves in the figures represent the healthy group, the C26 tumor model group, the compound 3 treatment group (dose: 10 mg / kg), and the compound 10 treatment group (dose: 10 mg / kg).

[0140] Figures 46-48 show the weights of tumor-bearing mice (Figure 46), tumor-free weights (Figure 47), tumor-free weight change (%) (Figure 48), tumor volume (Figure 49), and tumor photographs of the mice on the final day (Figure 50) during the survival period. Here, tumor-bearing weight and tumor-free weight are the average weights of eight mice, tumor-free weight change (%) is the average weight change (%) of eight mice, tumor volume is the average tumor volume of eight mice, and tumor photographs are tumor photographs of eight mice. As shown in Figure 46, the weights of mice in the healthy group continued to increase. On the other hand, as shown in Figure 47, the weights of mice in the C26-treated group from the start of the experiment began to decrease on day 11 and continued to decrease until the end of the experiment. The same was true for tumor-free weights. The compound 3 group was able to alleviate the weight loss of the mice to a similar extent, and by the end of the experiment, both the tumor-bearing and tumor-free body weights were greater than those of the C26 tumor model group, but the difference was not statistically significant. The compound 10 group was able to significantly alleviate the weight loss of the mice. At the end of the experiment, both the tumor-bearing and tumor-free body weights were greater than those of the C26 tumor model group, and the difference was statistically significant (p<0.05). However, as shown in Figures 49 and 50, the tumor volumes of the compound 3 group and the compound 10 group were slightly reduced compared to those of the C26 tumor model group. However, there was no significant difference, indicating that compounds 3 and 10 did not have a clear inhibitory effect on C26 tumors.

[0141] Figure 51 shows the average cumulative feeding of mice during the survival period, which is the average calculation result of 8 mice. The feeding of mice in the C26 tumor model group was significantly less than that in the healthy group. The feeding of the compound 3 group and the compound 10 group was slightly more than that in the C26 tumor model group, and appetite was slightly improved.

[0142] Figure 52 shows the muscle grip strength of mouse limbs. The muscle grip strength of mice in the mid-stage and late-stage cachexia C26 tumor model group was significantly smaller than that of the healthy group (p<0.05). Compounds 3 and 10 significantly improved the muscle grip strength of cachexia mice (p<0.05).

[0143] Figures 53 and 54 show the weight of the right hind limbs of mice and photographs of the right hind limbs. The weight of the right hind limbs is the average value of 8 mice, and the photographs of the right hind limbs are the results of 8 mice per group. As shown in Figures 53 and 54, the weight of the right hind limbs of mice in the C26 tumor model group was significantly smaller than that of mice in the healthy group, and the difference was statistically significant (p<0.05). Compounds 3 and 10 can improve skeletal muscle atrophy in cachectic mice to a certain extent.

[0144] Figures 55-60 show the mass of mouse tibialis anterior muscle, photographs of the tibialis anterior muscle, mass of gastrocnemius muscle, photographs of the gastrocnemius muscle, a statistical graph of the cross-sectional distribution of gastrocnemius muscle fibers, and a schematic diagram of gastrocnemius muscle tissue sections. The mass of the tibialis anterior muscle and the gastrocnemius muscle are the average values ​​of eight mice. The photographs of the tibialis anterior muscle and the gastrocnemius muscle are the results of eight mice per group. The statistical graph of the cross-sectional distribution of gastrocnemius muscle fibers is the statistical result of three mice. As shown in Figures 55 and 56, the mass of the tibialis anterior muscle in the C26 tumor model group was significantly lower than that in the healthy control group, and the difference was statistically significant (p<0.001). Compounds 3 and 10 significantly alleviated gastrocnemius muscle atrophy in cachectic mice. As shown in Figures 57 and 58, the gastrocnemius muscle mass of mice in the C26 tumor model group was significantly lower than that of mice in the healthy group, and the difference was statistically significant (p<0.001). Compounds 3 and 10 can significantly alleviate the atrophy of the tibialis anterior muscle in cachectic mice. As shown in Figures 59 and 60, the cross-sectional area of ​​the gastrocnemius muscle fibers of mice in the C26 tumor model group was significantly smaller than that of mice in the healthy group, and compounds 3 and 10 can significantly alleviate the decrease in the cross-sectional area of ​​the gastrocnemius muscle in cachectic mice.

[0145] The above results indicate that compounds 3 and 10 can alleviate weight loss, muscle atrophy, and muscle strength caused by cancer cachexia without affecting tumor size, and can slightly improve appetite.

[0146] The above is a preferred embodiment of the present invention. It should be noted that those skilled in the art to which the present invention is directed may make some additions and improvements without departing from the method of the present invention. These additions and improvements should also be considered as within the protection scope of the present invention.

Claims

1. 7-Azaindole compounds having a structural formula represented by formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, Ar is selected from pyrazole, indole, or a pyrazole-containing substituent, wherein the substituents in the pyrazole-containing substituent are selected from C1-4 hydrocarbon groups and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, 【Chemistry 2】 (selected from).

2. A 7-azaindole compound having a structural formula represented by formula (II): 【Transformation 3】 or a pharmaceutically acceptable salt thereof, Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, or 3-pyridyl, wherein in the pyrazole-containing substituent or the isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, 【Chemistry 4】 is selected from With the following limitations: a) when R is morpholine, Ar is 【Transformation 5】 isn't it, b) R is 【Transformation 6】 When Ar is 【Transformation 7】 isn't it, c) When Ar is indole, R is 【Transformation 8】 isn't it).

3. 7-Azaindole compounds having a structural formula represented by formula (III): 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, or 3-pyridine, wherein in the pyrazole-containing substituent or the isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, 【Chemistry 10】 (selected from).

4. 4. The 7-azaindole compound according to claim 1, wherein Ar is indole, or a pharmaceutically acceptable salt thereof.

5. 4. The 7-azaindole compound according to claim 1, wherein Ar is pyrazole or a pyrazole-containing substituent, or a pharmaceutically acceptable salt thereof.

6. The Ar is 【Chemistry 11】 4. The 7-azaindole compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following:

7. 7. The 7-azaindole compound according to claim 1, wherein R is 4-methylpiperazine, or a pharmaceutically acceptable salt thereof.

8. 8. A 7-azaindole compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in inhibiting ActRIIB activity.

9. 8. A 7-azaindole compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of cachexia.

10. A pharmaceutical composition comprising the 7-azaindole compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10, wherein the pharmaceutically acceptable additive is selected from a pharmaceutically acceptable carrier, diluent, or excipient.

12. Use of the 7-azaindole compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claims 10 to 11, in the preparation of an ActRIIB inhibitor.

13. Use of a 7-azaindole compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition according to claims 10 to 11, in the preparation of an anti-cachexia drug, in particular an anti-cancer cachexia drug.

14. A compound represented by structural formula (IV): 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, preferably selected from a pharmaceutically acceptable carrier, diluent, or excipient, wherein Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, or 3-pyridine, wherein in the pyrazole-containing substituent or the isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, 【Chemistry 13】 is selected from With the following limitations: a) when R is morpholine, Ar is 【Chemistry 14】 isn't it, b) R is 【Chemistry 15】 When Ar is 【Chemistry 16】 isn't it, c) When Ar is indole, R is 【Chemistry 17】 isn't it).

15. The 7-azaindole compound is any one of the following compounds: 【Chemistry 18-1】 【Chemistry 18-2】 or a pharmaceutically acceptable salt thereof; the pharmaceutical composition according to any one of claims 10, 11 and 14; and the use according to any one of claims 12 and 13.

16. In preparing an anti-cachexia drug, a compound represented by structural formula (V): 【Chemistry 19】 or a pharmaceutically acceptable salt thereof, wherein Ar is selected from pyrazole, indole, a pyrazole-containing substituent, an isoxazole-containing substituent, pyrimidine, pyridine, or phenyl, and in the pyrazole-containing substituent or the isoxazole-containing substituent, the substituent is selected from a C1-4 hydrocarbon group, and the number of substituents is 1 or 2; R is 4-methylpiperazine, piperazine, morpholine, 【Chemistry 20】 is selected from With the following limitations: a) when R is morpholine, Ar is 【Chemistry 21】 isn't it, b) R is 【Chemistry 22】 When Ar is 【Chemistry 23】 isn't it, c) When Ar is indole, R is 【Chemistry 24】 isn't it).

17. The compound is any one of the following compounds: 【Chemistry 25-1】 【Chemistry 25-2】 17. The use of a compound according to claim 16, selected from: or a pharmaceutically acceptable salt thereof.

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