Selective HPK1 inhibitor as well as preparation method and application thereof

Abstract

The invention discloses a selective HPK1 inhibitor as well as a preparation method and application thereof. The invention provides a compound with a structure as shown in a formula (1), and isotope derivatives, chiral isomers, allosteric bodies, different salts, prodrugs, preparations and the like of the compounds. The compound provided by the invention has an HPK1 inhibition effect, can be used in the form of a single drug, and also can be used in combination with other drugs to treat or prevent related diseases mediated by HPK1. For example, when being combined with a chemotherapeutic drug or a targeted anti-tumor drug, the medicine has a certain treatment effect on breast cancer, esophageal cancer, glioblastoma, melanoma, ovarian cancer, pancreatic cancer, squamous cell carcinoma of head and neck, cervical cancer, chronic myelogenous leukemia and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a selective HPK1 inhibitor and a preparation method and application thereof. Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase 1 (MAP4K1), is a serine / threonine kinase. It was originally cloned from hematopoietic progenitor cells and is mainly expressed in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils and mast cells (Chen H, GuanX, He C, et al., Expert opinion on therapeutic targets, 2024, 28(4): 237-250). Its kinase activity can be induced when T cell receptor (TCR), B cell receptor (BCR), transforming growth factor receptor (TGF-βR) or Gs-coupled PGE2 receptor (EP2 and EP4) is activated, thereby regulating various immune cell functions and playing an important role in the immune regulation process.

[0003] HPK1 has a regulatory effect on the TCR signaling pathway. When the T cell receptor recognizes the pMHC complex, HPK1 quickly participates in a series of complex and orderly phosphorylation cascade reactions, regulates the threshold of T cell activation, and then affects the proliferation of T cells and the secretion spectrum of cytokines (Duan Y, Guo Z, Zhong W, et al., Future medicinal chemistry, 2024, 16 (22): 21-20). In addition, HPK1 participates in the molecular regulation of the cytotoxic effect of NK cells and the formation of immune synapses, helping NK cells to efficiently exert cytotoxicity (Choi SW, Kwon JH, Yi E, et al., Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024, 11 (29): e2400920), and ensures effective information transmission and collaboration between immune cells.

[0004] In the tumor microenvironment, HPK1 mediates the transduction of immunosuppressive signals, which is a key mechanism leading to T / NK cell exhaustion. In the tumor microenvironment, HPK1 is overactivated, thereby inhibiting the activity of T cells and NK cells. Inhibitors targeting HPK1 can reverse immune checkpoint blockade, enhance the infiltration ability of effector lymphocytes into tumor tissues, and enhance their activity in killing tumor cells. It is worth noting that the synergistic effect of HPK1 inhibitors and PD-1 / CTLA-4 inhibitors has been confirmed in preclinical models, providing a theoretical basis for the development of combined treatment options (Cheng B, Li H, Hong Y, et al., European Journal of Medicinal Chemistry, 2025, 286: 117289).

[0005] In the field of autoimmune diseases, the pathological mechanism of HPK1 is opposite to tumor immunity. Taking rheumatoid arthritis as an example, HPK1 is abnormally activated during the onset of the disease, leading to excessive proliferation of T cells, releasing a large number of pro-inflammatory factors, and attacking the body's own tissues and organs. The development of selective inhibitors is expected to reshape the immune balance and inhibit the production of pathological autoantibodies.

[0006] Rational drug design is based on the three-dimensional structure of the drug target. The structure of HPK1 drugs generally includes three parts: 1) the mother core part that binds to the key hinge of HPK1, 2) the hydrophobic structure deep inside the enzyme active pocket, and 3) the side chain facing the solvent end (Vara, BA, Levi, SM, Achab, A, et al., ACS Medicinal Chemistry Letters, 2021, 12: 653-661). It is worth noting that HPK1 belongs to the MAP4K family and negatively regulates the TCR pathway, while its family member GLK (MAP4K3) has the opposite effect and can promote TCR pathway activation. Although many HPK1 small molecule inhibitors reported in the literature have good HPK1 inhibitory activity, their inhibitory activity on GLK is often ignored. For example, the substituted amino-aza-heteroaryl compound of an inhibitor of hematopoietic progenitor cell kinase 1 (HPK1) disclosed in the patent (CN202280047006.7) has an unknown inhibitory effect on GLK. As kinases of the same family, the structures of the enzyme active centers of HPK1 and GLK are very similar, making it difficult to improve their enzyme selectivity. Summary of the invention

[0007] The first object of the present invention is to provide a compound having a selective HPK1 inhibitory effect, or an optical isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated derivative thereof, a hydrate thereof or a solvate thereof, characterized in that the selective HPK1 inhibitor has a structural formula as shown in formula (1):

[0008]

[0009] Wherein, R is selected from C 1～10 Alkoxy, -COOH, -CONH 2 、-CONHC 1～6 Alkyl, C 3～8 Cycloalkyl, C 3～8 Heterocycloalkyl, C 6～14 Aryl, C 6～14 Heteroaryl, CN, -CC-C 1～6 Alkyl, -CC-C 6～14 Aryl, -CC-C 6～14 A type of heteroaryl group.

[0010] Preferably, the selective HPK1 inhibitor has a structural formula of any one of the following formulas 1 to 7:

[0011]

[0012] The second object of the present invention is to provide a method for preparing the above selective HPK1 inhibitor, the method comprising the following steps:

[0013] Raw materials a and b were dissolved in 1,4-dioxane and purified water, and potassium carbonate, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (XphosPdG3) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (Pd(dppf)Cl 2 ), reacting in a microwave synthesizer to obtain a compound represented by formula (1);

[0014] Its synthetic route is as follows:

[0015]

[0016] Preferably, the reaction temperature is 160°C and the reaction time is 1.5h. The compound represented by the general formula (I) of the present invention can be prepared by the above method, however, the conditions of the method, such as reactants, solvents, the amount of the compound used, reaction temperature, reaction time, etc. are not limited to the above explanation. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily performed by a technician in the field to which the present invention belongs.

[0017] The selective HPK1 inhibitor of the present invention and the solvent used in its preparation process are commonly used reaction solvents, and there are no special requirements.

[0018] The third object of the present invention is to provide the use of the above-mentioned compound having HPK1 inhibitory effect, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate or solvate in the preparation of anti-tumor drugs.

[0019] Preferably, the tumor includes cervical cancer, liver cancer, fibrosarcoma, gastric cancer, genitourinary tract cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, breast, lymphoma, squamous cell carcinoma of the head and neck, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, and myeloid leukemia.

[0020] The fourth object of the present invention is to provide an anti-tumor drug containing a safe and effective amount of the above-mentioned selective HPK1 inhibitor, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates or solvates.

[0021] Preferably, a pharmaceutically acceptable excipient is also included.

[0022] A fifth object of the present invention is to provide a pharmaceutical composition comprising a safe and effective amount of the above HPK1 inhibitor and at least one other agent, wherein the other agent is an anticancer agent, a chemotherapeutic agent or an antiproliferative compound.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention clarifies the conformation of the lead compound 6 at the enzyme active site, then retains the compound's core structure (2-aminopyrazine) and the side chain structure (phenylmorpholine) toward the solvent end, and changes the compound's enzyme selectivity by optimizing the compound's hydrophobic structure that penetrates deep into the enzyme active pocket, thereby obtaining a selective HPK1 inhibitor. The HPK1 inhibitor of the present invention can be used to treat or prevent HPK1-mediated related diseases, has good anti-tumor activity, and has potential application value in treating or preventing HPK1-mediated related diseases; its preparation method is simple and feasible, easy to operate, and uses a microwave-assisted method to synthesize the compound. The reaction can be carried out at a temperature higher than the boiling point of the solvent, and the target compound can be obtained quickly and efficiently. DETAILED DESCRIPTION

[0025] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods in the following examples where specific conditions are not specified are usually performed under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the examples are all commercially available or prepared using conventional methods.

[0026] Example 1: Preparation of Compound 1

[0027]

[0028] 5-Bromo-3-methoxypyrazin-2-amine (75 mg, 0.368 mmol, 1.00 equiv), 4-(4-morpholinyl)phenylboronic acid pinacol ester (127.56 mg, 0.441 mmol, 1.20 equiv), potassium carbonate (152.18 mg, 1.103 mmol, 3.00 equiv), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'- Amino-1,1'-biphenyl-2-yl) palladium (II) (30.895 mg, 0.037 mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) 27.073 mg, 0.037 mmol, 0.10 equivalent), 1,4-dioxane (2 ml), purified water (0.5 ml), added to a 10 mL microwave reaction tube, and microwaved at 160 ° C for 1.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a light yellow solid with a yield of 38%. 1 HNMR (500MHz, CDCl 3 )δ7.86(s,1H),7.75(d,J=8.9Hz,2H),6.90(d,J=8.8Hz,2H),4.93(s,2H),4.02(s,3H),3.84–3.79(m,4H),3.17–3.12(m,4H).

[0029] Example 2: Preparation of Compound 2

[0030]

[0031] 5-Bromo-3-ethoxypyrazin-2-amine (37 mg, 0.17 mmol, 1.00 equiv), 4-(4-morpholinyl)phenylboronic acid pinacol ester (58.88 mg, 0.20 mmol, 1.20 equiv), potassium carbonate (70.25 mg, 0.51 mmol, 3.00 equiv), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino -1,1'-biphenyl-2-yl) palladium (II) (14.17 mg, 0.026 mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) 12.42 mg, 0.017 mmol, 0.10 equivalent), 1,4-dioxane (2 ml), purified water (0.5 ml), added to a 10 mL microwave reaction tube, and microwaved at 160 ° C for 1.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a light yellow solid with a yield of 71%.1 HNMR (500MHz, CDCl 3 )δ7.95(s,1H),7.81(d,J=8.9Hz,2H),6.95(d,J=8.9Hz,2H),4.82(s,2H),4.53 (q,J=7.1Hz,2H),3.91–3.85(m,4H),3.24–3.17(m,4H),1.46(t,J=7.1Hz,3H).

[0032] Example 3: Preparation of Compound 3

[0033]

[0034] 3-Amino-6-bromopyrazine-2-carboxamide (92.9 mg, 0.43 mmol, 1.00 equiv), 4-(4-morpholinyl)phenylboronic acid pinacol ester (148.5 mg, 0.51 mmol, 1.20 equiv), potassium carbonate (177.2 mg, 1.28 mmol, 3.00 equiv), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'- Amino-1,1'-biphenyl-2-yl)palladium(II) (35.74 mg, 0.043 mmol, 0.10 equivalents), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.32 mg, 0.042 mmol, 0.10 equivalents), 1,4-dioxane (2 mL), and purified water (0.5 mL) were added to a 10 mL microwave reaction tube and microwaved at 160°C for 1.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a light yellow solid with a yield of 29%. 1 HNMR (500MHz, CDCl 3 )δ8.61(s,1H),7.80(d,J=8.8Hz,2H),7.02(d,J=8.4Hz,2H),3.93–3.87(m,4H),3.27–3.22(m,4H).

[0035] Example 4: Preparation of Compound 4

[0036]

[0037] 5-Bromo-3-phenylpyrazin-2-amine (250 mg, 0.28 mmol, 1.00 equiv), 4-(4-morpholinyl)phenylboronic acid pinacol ester (98.32 mg, 0.34 mmol, 1.20 equiv), potassium carbonate (115.92 mg, 0.84 mmol, 3.00 equiv), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino -1,1'-biphenyl-2-yl) palladium (II) (23.38 mg, 0.028 mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (20.49 mg, 0.028 mmol, 0.10 equivalent), 1,4-dioxane (2 ml), purified water (0.5 ml), added to a 10 mL microwave reaction tube, and microwaved at 160 ° C for 1.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid with a yield of 76.13%. 1 HNMR (500MHz, CDCl 3 )δ8.38(s,1H),7.93–7.87(m,2H),7.85–7.79(m,2H),7.55–7.49(m,2H),7.48–7.4 3(m,1H),6.98(d,J=8.8Hz,2H),4.80(s,2H),3.91–3.84(m,4H),3.26–3.19(m,4H).

[0038] Example 5: Preparation of Compound 5

[0039]

[0040] 3-Amino-6-bromopyrazine-2-carbonitrile (90 mg, 0.45 mmol, 1.00 equiv), 4-(4-morpholinyl)phenylboronic acid pinacol ester (156.93 mg, 0.543 mmol, 1.20 equiv), potassium carbonate (187.23 mg, 1.36 mmol, 3.00 equiv), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2'- Amino-1,1'-biphenyl-2-yl)palladium(II) (37.36mg, 0.045mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.1mg, 0.045mmol, 0.10 equivalent), 1,4-dioxane (2ml), purified water (0.5ml), added to a 10mL microwave reaction tube, and microwaved at 160°C for 1.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid with a yield of 23.6%. 1 HNMR (500MHz, CDCl3 )δ8.57(s,1H),7.78(d,J=8.4Hz,2H),7.04(s,2H),5.11(s,2H),3.88(s,4H),3.22(t,J=4.8Hz,4H).

[0041] Example 6: Preparation of Compound 6

[0042]

[0043] Step 1: 3,5-dibromopyrazine-2-amine (485.7 mg, 1.92 mmol, 1.50 equivalents), 4-ethynylaniline (150 mg, 1.28 mmol, 1.00 equivalents), cuprous iodide (24.39 mg, 0.13 mmol, 0.1 equivalents), tetrahydrofuran (15.36 ml), triethylamine (0.54 ml), under nitrogen protection, add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (9.37 mg, 0.013 mmol, 0.010 equivalents) into a 50 ml round-bottom flask and stir at 60°C overnight. After the reaction is completed, the solvent is evaporated under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain a yellow solid with a yield of 13%.

[0044]

[0045] Step 2: 3-((4-aminophenyl)ethynyl)-5-bromopyrazin-2-amine (74.1 mg, 0.26 mmol, 1.00 equiv), 4-(4-morpholinyl)phenylboronic acid pinacol ester (88.93 mg, 0.31 mmol, 1.20 equiv), potassium carbonate (106.1 mg, 0.77 mmol, 3.00 equiv), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) Phenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (21.4 mg, 0.026 mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) 18.75 mg, 0.026 mmol, 0.10 equivalent), 1,4-dioxane (2 ml), purified water (0.5 ml), added to a 10 mL microwave reaction tube, and microwaved at 160 ° C for 1.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid with a yield of 25.9%. 1 HNMR (500MHz, CDCl 3)δ8.33(s,1H),7.84(d,J=8.8Hz,1H),7.67(ddd,J=8.7,6.9,3.4Hz,2H),7.54(dt,J=8.8,5.2Hz,1H),7.43–7 .34(m,2H),7.02–6.95(m,2H),6.66(d,J=8.5Hz,2H),5.10(s,2H),3.91–3.86(m,4H),3.23(q,J=5.2Hz,4H).

[0046] Example 7: Preparation of Compound 7

[0047]

[0048] Step 1: Add 3,5-dibromopyrazine-2-amine (253 mg, 1 mmol, 1.00 equivalent), 4-ethynylaniline (175.7 mg, 1.5 mmol, 1.50 equivalent), cuprous iodide (19 mg, 0.1 mmol, 0.1 equivalent), tetrahydrofuran (10 ml), and triethylamine (0.41 ml) into a 50 ml round-bottom flask. Under nitrogen protection, add bistriphenylphosphine palladium dichloride (70 mg, 0.1 mmol, 0.10 equivalent). After stirring at 40 ° C overnight, the reaction is completed, and the solvent is evaporated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a yellow solid with a yield of 51%.

[0049]

[0050] Step 2: 3-((3-aminophenyl)ethynyl)-5-bromopyrazin-2-amine (148 mg, 0.51 mmol, 1.00 equiv), 4-(4-morpholinyl)phenylboronic acid pinacol ester (177 mg, 0.612 mmol, 1.20 equiv), potassium carbonate (211 mg, 1.53 mmol, 3.00 equiv), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) )(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (43.2mg, 0.051mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 37.3mg, 0.051mmol, 0.10 equivalent), 1,4-dioxane (2ml), purified water (0.5ml), added to a 10mL microwave reaction tube, and microwaved at 160°C for 1.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a golden solid with a yield of 51%. 1 HNMR (500MHz, CDCl 3)δ8.37(s,1H),7.84(d,J=8.9Hz,2H),7.67(ddd,J=12.0,8.3,1.4Hz,2H),7.58–7.52(m,1H),7.17(t,J=7.9Hz,1H),7.01(dt ,J=7.6,1.2Hz,1H),7.00–6.95(m,2H),6.72(ddd,J=8.1,2.4,0.9Hz,1H),5.08(s,2H),3.91–3.85(m,4H),3.25–3.20(m,4H).

[0051] Example 8: Activity inhibition test of compounds on HPK1 and GLK kinases

[0052] The test compound was tested for its inhibitory effect on the activity of HPK1 and GLK (MAP4K3) kinases. The specific experimental steps are as follows:

[0053] 1. Prepare 1× kinase buffer

[0054] Ingredients: 50mMHEPES (pH7.5), 10mMgCl2, 4mMDTT, 0.01% Tween-20, 0.01% BSA

[0055] 2. Compound treatment

[0056] 1) Compound gradient dilution and source plate preparation:

[0057] Dilute the compound to a final concentration of 100 using 100% DMSO, add 100 μl of 100% DMSO to two blank wells of the 96-well plate, as "no compound control" and "no enzyme control", respectively, and mark them as source plates. Transfer 40 μl of compound from the source plate to a new 384-well Echo plate (middle plate)

[0058] 2) Preparation of test plate

[0059] Using the Echo pipetting system, transfer 200 nl of the solution from each well of the 384-well Echo plate to the 384-well assay plate.

[0060] 3. Kinase reaction

[0061] 1) Prepare 2× kinase solution

[0062] Prepare kinase solution with 1× kinase buffer, with the concentration of each component being 2 times the final concentration of the reaction. Add 10 μl of kinase solution to each well of the assay plate, add 1× kinase buffer to the no-enzyme control wells, shake to mix, and incubate at room temperature for 10 minutes.

[0063] 2) Prepare 2× substrate solution

[0064] Prepare a substrate solution containing Fluorescein-PKC and ATP with 1× kinase buffer. The concentration of each component is twice the final concentration of the reaction. Add 10 μl of substrate solution to all wells of the test plate to start the reaction and shake to mix.

[0065] 3) Incubation reaction

[0066] Cover the test plate and react at room temperature for 90 minutes.

[0067] 4. Detection

[0068] Prepare the detection solution (2× final concentration), add 20 μl of the detection solution to each well of the detection plate, centrifuge to mix, and incubate at room temperature in the dark for 60 minutes.

[0069] 5. Data Collection

[0070] The fluorescence signal was read using an Envision microplate reader: excitation wavelength 340 nm, emission wavelengths 520 nm and 495 nm

[0071] 6. Curve Fitting

[0072] 1) Export the relative fluorescence unit (RFU) value from Envision software and calculate the 520nm / 495nm fluorescence ratio (Ratio)

[0073] 2) Convert the Ratio value to inhibition percentage:

[0074] Inh%=(max-sample Ratio) / (max-min)*100

[0075] "min": Ratio of no enzyme control well

[0076] "max": DMSO control well Ratio

[0077] 3) Use MS Excel to organize the data, and fit the dose-response curve using the XLFit plug-in (v5.4.0.8). The calculation formula is:

[0078] Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)^HillSlope)

[0079] 7. Experimental Results

[0080] The inhibitory effects of some target compounds on HPK1 and GLK were determined according to the above experimental method. The results are shown in Table 1. At a concentration of 500 nM, the inhibitory effect of the compounds on HPK1 was stronger than that on GLK.

[0081] Table 1 Inhibitory effects of target compounds on HPK1 and GLK at 500 nM

[0082]

[0083] “ND”: Not detected.

[0084] Select some compounds with better activity and determine IC according to the above experimental method 50 The results are shown in Table 2. The compound has a good inhibitory effect on HPK1.

[0085] Table 2 Half-maximal inhibitory concentration of target compounds on HPK1

[0086]

[0087] “ND”: Not detected.

[0088] The above description of the present invention is illustrative rather than restrictive. Those skilled in the art will appreciate that many modifications, changes or equivalents may be made within the spirit and scope defined in the claims, but they will all fall within the scope of protection of the present invention.

Claims

1. A selective HPK1 inhibitor, or an optical isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated derivative thereof, a hydrate thereof or a solvate thereof, characterized in that: The selective HPK1 inhibitor has a structural formula as shown in formula (1): Where R is selected from C 1～10 Alkoxy, -COOH, -CONH2, -CONHC 1～6 Alkyl, C 3～8 Cycloalkyl, C 3～8 Heterocycloalkyl, C 6～14 Aryl, C 6～14 Heteroaryl, CN, -CC-C 1～6 Alkyl, -CC-C 6～14 Aryl, -CC-C 6～14 A type of heteroaryl group.

2. The selective HPK1 inhibitor according to claim 1, characterized in that The compound of formula (1) has the following structure:

3. A method for preparing a selective HPK1 inhibitor according to claim 1 or 2, characterized in that: The preparation method comprises the following steps: The raw materials a and b are dissolved in 1,4-dioxane and purified water, and potassium carbonate, methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (XphosPdG3) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (Pd(dppf)Cl2) are added, and the mixture is reacted at 160° C. for 1.5 h in a microwave synthesizer to obtain a compound represented by formula (1); Its synthetic route is as follows:

4. Use of the selective HPK1 inhibitor according to claim 1 or 2, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate or solvate in the preparation of anti-tumor drugs.

5. The use according to claim 4, characterized in that: The tumor is cervical cancer, liver cancer, fibrosarcoma, gastric cancer, genitourinary tract cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, breast cancer, lymphoma, squamous cell carcinoma of the head and neck, acute lymphoblastic leukemia, chronic myeloid leukemia or myeloid leukemia.

6. An anti-tumor drug, characterized in that: A composition comprising a safe and effective amount of the selective HPK1 inhibitor according to claim 1 or 2, or an optical isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated derivative thereof, a hydrate thereof or a solvate thereof.

7. The anti-tumor drug according to claim 6, characterized in that: Pharmaceutically acceptable excipients are also included.

8. A pharmaceutical composition comprising a safe and effective amount of the selective HPK1 inhibitor of claim 1 or 2 and at least one other agent, wherein the other agent is an anticancer agent, a chemotherapeutic agent or an antiproliferative compound.

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