1h-pyrrolo[2,3-b]pyridine compound and synthesis method and application thereof

Abstract

The application discloses a 1H-pyrrole[2,3-b]pyridine compound (formula I) and a synthesis method and application thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, and application of the same in preparation of a pharmaceutical preparation for preventing or treating diseases caused by mediation of a T cell receptor signal path related protein (including HPK1, LCK, GLK, PCKθ, ITK protein), such as a malignant tumor.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of small molecule drugs, in particular, the present application relates to a 1H-pyrrolo[2,3-b]pyridine compound and a method of using such a compound. BACKGROUND

[0002] Immunotherapy is the hottest cancer treatment today, and is hailed as the third revolution in cancer treatment. So far, immunotherapy has developed in various forms: targeted antibodies, cancer vaccines, adoptive cell therapy, oncolytic viruses, immune checkpoint inhibitors, cytokines and immune adjuvants. In the immune system, T cells play a key role. Mature T lymphocytes enter the human peripheral immune organs with blood flow and can be recycled through lymphatic vessels and peripheral blood to play the functions of cellular immunity and immune regulation.

[0003] The surface of T cells carries a special receptor, T cell receptor (TCR), which can recognize small protein fragments on the surface of antigens such as bacteria, viruses and infected or cancerous somatic cells, and convert extracellular recognition into signals that can be transmitted to the cell interior. By inducing TCR adjacent tyrosine kinase activation, promoting signal transmission complex assembly, activating downstream MAPK, PKC and calcium ion signal pathways, and finally activating corresponding transcription factors, the expression of effector protein molecules is regulated to complete the activation of T cells.

[0004] The initiation and transmission of TCR signals are finely regulated, including positive and negative regulation methods, and the balance will be affected if it is broken, which will affect the effect of immune response or induce autoimmunity. The most studied negative regulation mechanism is mediated by inhibitory receptors, such as CTLA4 and PD-1, which have been hot in the past few years as targets for anti-tumor therapy. TCR-related proteins, including HPK1, LCK, GLK, PCKθ, ITK, etc., have become the focus of pharmaceutical workers.

[0005] Hematopoietic progenitor kinase 1 (HPK1) is an immunosuppressive regulatory kinase and a negative regulator of T cell receptor (TCR), which can destroy the stability of TCR signal complex. HPK1 kinase can mediate T cell dysfunction and inhibit the immune function of various cells, and inactivation of its domain is sufficient to trigger the effect of anti-tumor immune response. Therefore, HPK1 is an extremely important candidate target for tumor immunotherapy, and HPK1 inhibitors are expected to become a new star of tumor immunotherapy and a new partner of immune checkpoint inhibitors.

[0006] More than ten years ago, researchers found that HPK1 might be a potential cancer immunotherapy target, and several compounds have entered clinical studies, such as CFI-402411, BGB-15025, PRJ1-3024, etc., but so far there is no related drug on the market. The main challenge in the development of HPK1 inhibitors is that the functions of HPK family members are different, and it is difficult to design compounds with high selectivity and high inhibitory activity. Therefore, new drugs targeting TCR-related proteins are still an urgent need for people's health and medical research. SUMMARY

[0007] The purpose of the present application is to overcome the deficiencies of the prior art, and provide a 1H-pyrrolo[2,3-b]pyridine compound, a preparation method of the compound, and an application of the compound in preparing a drug for targeting and inhibiting TCR negative regulatory factors.

[0008] The purpose of the present application is achieved by the following technical solutions: a 1H-pyrrolo[2,3-b]pyridine compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same, having the following formula I structure:

[0009]

[0010] Among them,

[0011] R1, R2 are independently H, methyl, ethyl, propyl, or fluorine, chlorine, bromine, or methoxy, ethoxy, amido, N,N-dimethyl amido;

[0012] X is C or N.

[0013] Further, the 1H-pyrrolo[2,3-b]pyridine compound provided by the present application has the following structure:

[0014]

[0015] The present application also provides a preparation method of the above-mentioned 1H-pyrrolo[2,3-b]pyridine compound, and the synthetic route is as follows:

[0016]

[0017] Specifically comprising the following steps:

[0018] Step a: 5-bromo-3-iodo-7-azaindole reacts with di-tert-butyl dicarbonate in the presence of triethylamine to obtain tert-butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (II);

[0019] Step b: the above obtained (II) is reacted with 4-(1-methyl-4-piperidyl)benzene boronic acid pinacol ester or 4-(4-methylpiperazin-1-yl)benzene boronic acid pinacol ester in the presence of Pd(dppf)2Cl2 and K2CO3 to obtain 5-bromo-3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine or 5-bromo-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (III).

[0020] Step c: the above obtained product (III) is reacted with a benzene boronic acid ester compound containing different substituents in the presence of Pd(dppf)2Cl2 and K2CO3 to obtain the corresponding 1H-pyrrolo[2,3-b]pyridine compound (I).

[0021] The present application also provides a pharmaceutical use of the 1H-pyrrolo[2,3-b]pyridine compound, which is specifically used for preparing a drug for preventing or treating a disease caused by mediation of a T cell receptor signal pathway related protein. The T cell receptor signal pathway related protein includes HPK1, LCK, GLK, PCKθ, ITK protein. The disease caused by mediation of the T cell receptor signal pathway related protein is lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia or lymphoid malignancy, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, adenocarcinoma lung cancer, lung squamous carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumor, head and neck cancer and hematological malignancy. The hematological malignancy includes acute T lymphoblastic leukemia, chronic T lymphoblastic leukemia, acute B lymphoblastic leukemia, chronic B lymphoblastic leukemia, plasma cell tumor, multiple myeloma, macroglobulinemia, Jejunal lymphoma, non-Hodgkin's lymphoma, primary thrombocytosis, polycythemia vera.

[0022] Compared with the prior art, the present application has the following beneficial effects:

[0023] The application discloses a novel 1H-pyrrolo[2,3-b]pyridine compound, pharmacological activity of the compound shows obvious inhibiting effect on TCR related protein HPK1 kinase, the compound or a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same have potential application value in targeting HPK1 target related diseases. In addition, the application also discloses a synthesis method of the novel 1H-pyrrolo[2,3-b]pyridine compound, and the method has the characteristics of simple synthesis and convenient operation. BRIEF DESCRIPTION OF DRAWINGS DETAILED DESCRIPTION

[0024] The structure, preparation method and application of the application are further described below with reference to examples, but the application is not limited by the examples.

[0025] The analysis data of the sample are determined by the following instruments:

[0026] The thermometer is not calibrated; the Bruker DRX400 nuclear magnetic resonance instrument; the Agilent 5975 mass spectrometer; the Bruker Vector 22 infrared spectrometer.

[0027] Example 1: synthesis of compound 1

[0028] The synthesis route is as follows:

[0029]

[0030] Step a: Boc protection

[0031] A round-bottom flask is added with 5-bromo-3-iodo-7-azaindole (15.5 mmol), THF is added to dissolve the solid, triethylamine (46.5 mmol) is added, and finally di-tert-butyl dicarbonate (31 mmol) is added. The reaction is carried out at 50 DEG C for 5 h. After the reaction is completed, extraction is carried out, and concentration is carried out to dryness to obtain 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester, which is directly used in the next reaction.

[0032] Step b: synthesis of an intermediate

[0033]

[0034] A round-bottom flask was charged with the above obtained 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1.2 mmol), and 4-(1-methyl-4-piperidinyl)benzeneboronic acid pinacol ester (1.2 mmol), Pd(dppf)2Cl2(0.06 mmol), K2CO3(3.6 mmol), appropriate amount of 1,4-dioxane: water (5:1), under N2protection at 90 °C for 8 h. After reaction, extraction, concentrated to dryness, to obtain 5-bromo-3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine.

[0035] 1 H NMR (400 MHz, DMSO) δ 12.15 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 7.91 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 2.98 - 2.91 (m, J = 11.2 Hz, 2H), 2.27 (s, 3H), 2.09 (t, J = 10.5 Hz, 2H), 1.86 - 1.63 (m, J = 12.1, 7.6 Hz, 5H). 13 C NMR (101 MHz, DMSO) δ 147.84, 144.25, 143.31, 132.52, 129.76, 127.73, 126.90, 125.78, 119.51, 114.56, 111.73, 56.05, 46.27, 41.08, 33.15.

[0036] Step c: synthesis of compound 1

[0037]

[0038] A round-bottom flask was charged with the above obtained 5-bromo-3-(4-(1- methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (0.3 mmol), and 3,4- dimethoxybenzeneboronic acid pinacol ester (0.3 mmol), Pd(dppf)2Cl2(0.015 mmol), K2CO3(0.9 mmol), appropriate amount of 1,4-dioxane: water (5:1), under N2protection, 90 °C for 8 h. After reaction, extraction, concentrated to dryness, purified by column chromatography to obtain 5-(3,4-dimethoxyphenyl)-3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine.

[0039] 1H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 7.85 (s, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 6.9 Hz, 3H), 7.26 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.17 - 3.07 (m, J = 10.9 Hz, 2H), 2.67 - 2.56 (m, 1H), 2.48 - 2.38 (m, 5H), 1.90 - 1.76 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 149.64, 148.86, 148.68, 143.24, 142.44, 133.52, 132.42, 129.40, 127.68, 126.99, 125.54, 124.69, 119.81, 117.72, 114.95, 112.86, 111.58, 56.17, 56.09, 55.31, 45.04, 32.12.

[0040] Example 2: Synthesis of compound 2

[0041]

[0042] The target product was synthesized according to the method of Example 1.

[0043] 1 H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 7.85 (s, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 6.9 Hz, 3H), 7.26 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.17 - 3.07 (m, J = 10.9 Hz, 2H), 2.67 - 2.56 (m, 1H), 2.48 - 2.38 (m, 5H), 1.90 - 1.76 (m, 4H). 13C NMR (101 MHz, DMSO) δ 153.57, 151.15, 149.00, 146.82, 146.71, 143.82, 142.18, 133.24, 132.67, 132.60, 127.88, 127.68, 127.00, 125.63, 124.77, 123.60, 117.77, 115.12, 114.96, 114.81, 56.57, 55.92, 46.03, 40.94, 32.97.

[0044] Example 3: Synthesis of compound 3

[0045]

[0046] The target product was synthesized according to the method of Example 1.

[0047] 1 H NMR (400 MHz, DMSO) δ 12.06 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 8.48 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 3.18 - 3.11 (m, J = 10.7 Hz, 2H), 2.99 (s, 6H), 2.69 - 2.57 (m, J = 5.8 Hz, 1H), 2.49 - 2.39 (m, 5H), 1.91 - 1.82 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 170.42, 149.24, 143.32, 142.39, 140.43, 135.34, 133.34, 128.40, 128.23, 127.69, 127.32, 127.05, 126.03, 124.96, 117.83, 115.17, 63.07, 55.21, 52.49, 44.93, 35.27, 32.00.

[0048] Example 4: Synthesis of compound 4

[0049]

[0050] The target product was synthesized according to the method of Example 1.

[0051] 1H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 8.19 (d, J = 11.3 Hz, 2H), 7.86 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.99 - 2.91 (m, J = 10.9 Hz, 2H), 2.82 - 2.72 (m, J = 6.9 Hz, 2H), 2.50 - 2.44 (m, 1H), 2.27 (s, 3H), 2.11 (t, J = 10.5 Hz, 2H), 1.74 - 1.64 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 161.63, 159.23, 158.45, 158.39, 148.63, 144.74, 143.92, 133.20, 130.04, 129.93, 129.52, 127.71, 126.82, 124.28, 119.63, 117.32, 116.68, 116.50, 114.82, 108.53, 108.30, 108.10, 56.62, 55.98, 46.15, 46.10, 41.00, 33.06.

[0052] Example 5: Synthesis of compound 5

[0053]

[0054] The target product was synthesized according to the method of Example 1.

[0055] 1 H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 8.19 (d, J = 11.3 Hz, 2H), 7.86 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.99 - 2.91 (m, J = 10.9 Hz, 2H), 2.82 - 2.72 (m, J = 6.9 Hz, 2H), 2.50 - 2.44 (m, 1H), 2.27 (s, 3H), 2.11 (t, J = 10.5 Hz, 2H), 1.74 - 1.64 (m, 2H). 13CNMR (101 MHz, DMSO) δ 162.81, 160.90, 159.67, 156.84, 152.25, 150.17, 149.22, 128.97, 121.81, 120.52, 118.89, 115.58, 112.12, 110.94, 107.21, 100.05, 56.62, 56.08, 55.83, 54.95, 48.59, 46.02.

[0056] Example 6: Synthesis of compound 6

[0057]

[0058] The target product was synthesized according to the method of Example 1.

[0059] 1 H NMR (400 MHz, DMSO) δ 11.86 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.35 (s, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 13.0, 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 8.8 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 3.89 (s, 3H), 3.23 - 3.11 (m, 4H), 2.59 - 2.50 (m, 4H), 2.26 (s, 3H). 13 CNMR (101 MHz, DMSO) δ 162.81, 160.90, 159.67, 156.84, 152.25, 150.17, 149.22, 128.97, 121.81, 120.52, 118.89, 115.58, 112.12, 110.94, 107.21, 100.05, 56.62, 56.08, 55.83, 54.95, 48.59, 46.02.

[0060] Example 7: Synthesis of compound 7

[0061]

[0062] The target product was synthesized according to the method of Example 1.

[0063] 1H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 1.5 Hz, 1H), 7.24 (dd, J = 8.2, 1.6 Hz, 1H), 7.04 (dd, J = 12.5, 8.6 Hz, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.20 - 3.16 (m, 4H), 2.61 - 2.52 (m, 4H), 2.28 (s, 3H). 13 CNMR (101 MHz, DMSO) δ 149.65, 149.51, 148.81, 148.65, 142.26, 132.50, 129.14, 127.61, 126.31, 125.49, 123.66, 119.73, 117.80, 116.45, 115.17, 112.87, 111.52, 56.16, 56.09, 54.89, 48.48, 45.92.

[0064] Example 8: Synthesis of compound 8

[0065]

[0066] The target product was synthesized according to the method of Example 1.

[0067] 1 H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.77 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 3.22 - 3.14 (m, 4H), 3.00 (s, 6H), 2.58 - 2.51 (m, 4H), 2.27 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 170.44, 149.60, 149.19, 142.22, 140.52, 135.30, 134.37, 128.24, 128.16, 127.66, 127.24, 126.26, 126.07, 125.97, 123.90, 117.93, 116.44, 115.42, 54.91, 48.50, 45.97.

[0068] Example 9: Synthesis of compound 9

[0069]

[0070] The target product was synthesized according to the method of Example 1.

[0071] 1 H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 16.8, 8.5 Hz, 4H), 7.26 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 3.22 - 3.12 (m, 4H), 3.03 (s, 3H), 2.82 (s, 3H), 2.60 - 2.51 (m, J = 4.6 Hz, 4H), 2.29 (s, 3H), 2.27 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 170.37, 149.60, 149.12, 142.22, 139.64, 136.04, 134.85, 129.16, 128.38, 127.66, 126.86, 126.11, 125.85, 124.88, 123.83, 117.89, 116.43, 115.36, 54.94, 48.53, 46.01, 38.32, 34.40, 19.10.

[0072] Example 10: Preparation of compound 5 hydrochloride

[0073] The target product obtained in Example 5 was dissolved in ethyl acetate with stirring, saturated with HC1 gas at 0-5 degrees, and a white solid was precipitated, which was the hydrochloride salt.

[0074] Application: Biological activity determination

[0075] Inhibition determination on HPK1 kinase

[0076] 1. Dilute the compound 3 times in dilution plate with DMSO, and the initial concentration of the compound is 1 10 μΜ.

[0077] 2. Dilute the compound 50 times in 1x kinase reaction buffer, and shake on a shaker for 20 minutes.

[0078] 3. Prepare 2x kinase with lx enzyme reaction buffer.

[0079] 4. Add 2 μL of kinase (prepared in step 3) to each well of the reaction plate.

[0080] 5. Add 1 μL of compound diluted in buffer to each well, seal the plate with a plate sealer, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 10 minutes.

[0081] 6. Prepare 4x MBP Protein and ATP (final concentration of ATP is 10 μM) mixture with lx enzyme reaction buffer, add 1 μL of 4x MBP Protein / ATP mixture to the reaction plate.

[0082] 7. Seal the plate with a plate sealer, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 60 minutes.

[0083] 8. Transfer 4 μL of ADP Glo to the 384 reaction plate, centrifuge at 1000 rpm / min for 1 min, and incubate at 25°C for 40 min.

[0084] 9. Transfer 8 u L of Detection solution to the 384 reaction plate, centrifuge at 1000 rpm / min for 1 min, and incubate at 25°C for 40 min.

[0085] 10. Read the RLU (Relative luminescence unit) signal using a Biotek Multifunctional Plate Reader. The signal intensity is used to characterize the degree of activity of the kinase.

[0086] Data processing

[0087] Calculate the inhibition rate of each well, and calculate the IC 50 value.

[0088] The results are shown in the following table:

[0089]

[0090] IC 50 : A < 100 nM; 100 nM < B < 500 nM

[0091] It can be seen that the compounds all exhibit good HPK1 inhibitory activity (nM level), and most of the compounds have high inhibitory activity (IC 50 < 100 nM). Thus, the 1H-pyrrolo[2,3-b]pyridine compound disclosed in the present application can be applied in the preparation of a drug for preventing or treating diseases caused by the mediation of T cell receptor signal pathway related proteins.

Claims

1. A 1H-pyrrole[2,3-b]pyridine compound or a pharmaceutically acceptable salt thereof, characterized in that, The structure is as follows: Formula I; in, R1 and R2 are independently H, methyl, ethyl, propyl, fluorine, chlorine, bromine, methoxy, ethoxy, aminoacyl or N,N-dimethylaminoacyl; X is CH or N.

2. The 1H-pyrrole[2,3-b]pyridine compound or a pharmaceutically acceptable salt thereof as described in claim 1, characterized in that, Compounds with the following structures: ； 。 3. The method for synthesizing the 1H-pyrrole[2,3-b]pyridine compound as described in claim 1, characterized in that, Includes the following steps: ； The definitions of X, R1, and R2 are the same as before; Step a: 5-Bromo-3-iodo-7-azaindole reacts with ditert-butyl dicarbonate in the presence of triethylamine to give tert-butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate of formula II, i.e. product (II). Step b: The product (II) obtained in step a reacts with 4-(1-methyl-4-piperidinyl)phenylboronic acid pinacol ester or 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester in the presence of Pd(dppf)2Cl2 and K2CO3 to give 5-bromo-3-(4-(1-methylpiperidin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine or 5-bromo-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine of formula III, i.e., product (III); Step c: The product (III) obtained in step b reacts with phenylboronic acid esters containing different substituents in the presence of Pd(dppf)2Cl2 and K2CO3 to give a 1H-pyrrole[2,3-b]pyridine compound of formula I.

4. The use of the 1H-pyrrole[2,3-b]pyridine compound as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of diseases mediated by the HPK1 protein.

5. The application according to claim 4, characterized in that, The drugs mentioned are for diseases mediated by HPK1 protein, including lymphoma, blastoma, sarcoma, neuroendocrine tumors, mesothelioma, schwannoma, meningioma, adenocarcinoma, melanoma, lymphoid malignant tumors, squamous cell carcinoma, lung cancer, peritoneal cancer, gastric cancer, intestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumors, head and neck cancer, or hematologic malignancies.

6. The application according to claim 5, characterized in that, The hematologic malignancies mentioned are acute T-cell leukemia, chronic T-cell leukemia, acute B-cell leukemia, chronic B-cell leukemia, plasma cell tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, essential thrombocytosis, or polycythemia vera.

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