A selective HPK1 inhibitor, its preparation method and application

Abstract

This invention discloses a selective HPK1 inhibitor, its preparation method, and its applications. This invention provides compounds with the structure shown in formula (1), as well as isotope derivatives, chiral isomers, allosteres, different salts, prodrugs, formulations, etc., of these compounds. The compounds provided by this invention have HPK1 inhibitory activity and can be used as monotherapy or in combination with other drugs to treat or prevent HPK1-mediated diseases. For example, when used in combination with chemotherapy drugs or targeted antitumor drugs, they have certain therapeutic effects on breast cancer, esophageal cancer, glioblastoma, melanoma, ovarian cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, cervical cancer, and chronic myeloid leukemia.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a selective HPK1 inhibitor, its preparation method, and its application. Background Technology

[0002] Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase 1 (MAP4K1), belongs to the serine / threonine kinase family. Originally cloned from hematopoietic progenitor cells, it is primarily expressed in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Chen H, Guan X, He C, et al., Expert opinion on therapeutic targets, 2024, 28(4):237-250). Its kinase activity can be induced upon activation of the T cell receptor (TCR), B cell receptor (BCR), transforming growth factor receptor (TGF-βR), or Gs-coupled PGE2 receptors (EP2 and EP4), thereby regulating the functions of various immune cells and playing a crucial role in immune regulation.

[0003] HPK1 plays a regulatory role in the TCR signaling pathway. When T cell receptors recognize the pMHC complex, HPK1 rapidly participates in a series of complex and orderly phosphorylation cascades, regulating the threshold of T cell activation and thus affecting T cell proliferation and cytokine secretion profiles (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 NK cell cytotoxicity and immune synapse formation, helping NK cells to exert cytotoxicity efficiently (Choi SW, Kwon JH, Yi E, et al., Advancedscience (Weinheim, Baden-Wurttemberg, Germany), 2024, 11(29):e2400920), and ensuring effective information transmission and cooperation between immune cells.

[0004] In the tumor microenvironment, HPK1 mediates the transduction of immunosuppressive signals, 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 of effector lymphocytes into tumor tissue, and increase their activity in killing tumor cells. Notably, the synergistic effect of HPK1 inhibitors and PD-1 / CTLA-4 inhibitors has been demonstrated in preclinical models, providing a theoretical basis for the development of combination therapy regimens (Cheng B, Li H, Hong Y, et al., European Journal of Medicinal Chemistry, 2025, 286:117-289).

[0005] In the field of autoimmune diseases, the pathological mechanism of HPK1 is the opposite of that of tumor immunity. Taking rheumatoid arthritis as an example, during the pathogenesis, HPK1 is abnormally activated, leading to excessive proliferation of T cells, releasing a large number of pro-inflammatory factors that attack the body's own tissues and organs. The development of selective inhibitors holds promise for reshaping immune balance and inhibiting 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) a core portion that binds to the key hinge of HPK1; 2) a hydrophobic structure deep within the enzyme's active pocket; and 3) a side chain facing the solvent end (Vara, BA; Levi, SM; Achab, A, et al., ACS Medicinal Chemistry Letters, 2021, 12:653-661). It is noteworthy that HPK1 belongs to the MAP4K family and negatively regulates the TCR pathway, while its family member GLK (MAP4K3) has the opposite effect, promoting TCR pathway activation. Many small molecule HPK1 inhibitors reported in the literature, while exhibiting good HPK1 inhibitory activity, often neglect their inhibitory activity against GLK. For example, the substituted amino-aza-heteroaryl compound disclosed in patent (CN202280047006.7) as an inhibitor of hematopoietic progenitor kinase 1 (HPK1) still has unknown inhibitory activity against GLK. As kinases in the same family, HPK1 and GLK have very similar structures of their active sites, 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 selective HPK1 inhibitory activity, 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 the structural formula shown in formula (1):

[0008]

[0009] Wherein, R is selected from C 1～10 Alkyl group, -COOH, -CONH2, -CONHC 1～6 Alkyl, C 3～8 cycloalkyl, C 3～8 Heterocyclic alkyl, C 6～14 Aryl, C 6～14 heteroaryl, CN, -CC-C 1～6 Alkyl, -CC-C 6～14 Aryl, -CC-C 6～14 One of the heteroaryl groups.

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

[0011]

[0012] A second objective of this invention is to provide a method for preparing the above-mentioned selective HPK1 inhibitor, the method comprising the following steps:

[0013] Raw material a and raw material b were 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(diphenylphosphine)ferrocene]palladium(II) (Pd(dppf)Cl2) were added. The reaction was carried out in a microwave synthesizer to obtain the compound shown in formula (1).

[0014] The synthetic route is shown below:

[0015]

[0016] Preferably, the reaction temperature is 160°C and the reaction time is 1.5 h. The compound represented by general formula (I) of this invention can be prepared by the method described above; however, the conditions of this method, such as reactants, solvent, amount of compound used, reaction temperature, and reaction time, are not limited to the explanations above. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

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

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

[0019] Preferably, the tumors include 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 (ALL), chronic myeloid leukemia, and promyelocytic leukemia.

[0020] A fourth object of the present invention is to provide an antitumor drug containing a safe and effective amount of the above-mentioned 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.

[0021] Preferably, pharmaceutically acceptable excipients are 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-mentioned HPK1 inhibitor and at least one other pharmaceutical agent, wherein the other pharmaceutical agent is an anticancer agent, a chemotherapeutic agent or an antiproliferative compound.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] This invention clarifies the conformation of lead compound 6 at the enzyme active site, then retains the parent core structure (2-aminopyrazine) and the side chain structure (phenylmorpholine) facing the solvent end. By optimizing the hydrophobic structure of the compound to penetrate deep into the enzyme active pocket, the enzyme selectivity of the compound is altered, thereby obtaining a selective HPK1 inhibitor. The HPK1 inhibitor of this invention can be used to treat or prevent HPK1-mediated diseases, exhibiting good anti-tumor activity and showing potential application value in the treatment or prevention of HPK1-mediated diseases. Its preparation method is simple, feasible, and easy to operate, employing a microwave-assisted method for compound synthesis. The reaction can be carried out at temperatures above the solvent boiling point, enabling rapid and efficient acquisition of the target compound. Detailed Implementation

[0025] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Operating methods not specifically specified in the following embodiments are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, the raw materials used in the embodiments are commercially available or prepared using conventional methods.

[0026] Example 1: Preparation of Compound 1

[0027]

[0028] The following were added: 5-bromo-3-methoxypyrazine-2-amine (75 mg, 0.368 mmol, 1.00 equivalent), 4-(4-morpholino)phenylboronic acid pinacol ester (127.56 mg, 0.441 mmol, 1.20 equivalent), potassium carbonate (152.18 mg, 1.103 mmol, 3.00 equivalent), and methanesulfonic acid (2-dicyclohexylphosphine-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), and purified water (0.5 mL) were added to a 10 mL microwave-safe reaction tube and reacted at 160 °C for 1.5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography to obtain a pale yellow solid in 38% yield. 1 HNMR (500MHz, CDCl3) 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] The following were added: 5-bromo-3-ethoxypyrazine-2-amine (37 mg, 0.17 mmol, 1.00 equivalent), 4-(4-morpholino)phenylboronic acid pinacol ester (58.88 mg, 0.20 mmol, 1.20 equivalent), potassium carbonate (70.25 mg, 0.51 mmol, 3.00 equivalent), and methanesulfonic acid (2-dicyclohexylphosphine-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), and purified water (0.5 mL) were added to a 10 mL microwave-safe reaction tube and reacted at 160 °C for 1.5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography to obtain a pale yellow solid with a yield of 71%. 1HNMR (500MHz, CDCl3) 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] The following were added: 3-amino-6-bromopyrazin-2-carboxamide (92.9 mg, 0.43 mmol, 1.00 equivalent), 4-(4-morpholino)phenylboronic acid pinacol ester (148.5 mg, 0.51 mmol, 1.20 equivalent), potassium carbonate (177.2 mg, 1.28 mmol, 3.00 equivalent), and methanesulfonic acid (2-dicyclohexylphosphine-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-safe reaction tube and reacted at 160 °C for 1.5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography to obtain a pale yellow solid with a yield of 29%. 1 HNMR (500MHz, CDCl3) 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] The following were added: 5-bromo-3-phenylpyrazine-2-amine (250 mg, 0.28 mmol, 1.00 equivalent), 4-(4-morpholino)phenylboronic acid pinacol ester (98.32 mg, 0.34 mmol, 1.20 equivalent), potassium carbonate (115.92 mg, 0.84 mmol, 3.00 equivalent), and methanesulfonic acid (2-dicyclohexylphosphine-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), and purified water (0.5 mL) were added to a 10 mL microwave-safe reaction tube and reacted at 160 °C for 1.5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography to obtain a yellow solid with a yield of 76.13%. 1 HNMR(500MHz, CDCl3)δ8.38(s,1H),7.93–7.87(m,2H),7.85–7.79(m,2H),7.55–7.49(m,2H), 7.48–7.43(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] The following were added: 3-amino-6-bromopyrazin-2-carboxylonitrile (90 mg, 0.45 mmol, 1.00 equivalent), 4-(4-morpholino)phenylboronic acid pinacol ester (156.93 mg, 0.543 mmol, 1.20 equivalent), potassium carbonate (187.23 mg, 1.36 mmol, 3.00 equivalent), and methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'- Amino-1,1'-biphenyl-2-yl)palladium(II) (37.36 mg, 0.045 mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.1 mg, 0.045 mmol, 0.10 equivalent), 1,4-dioxane (2 mL), and purified water (0.5 mL) were added to a 10 mL microwave-safe reaction tube and reacted at 160 °C for 1.5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography to obtain a yellow solid with a yield of 23.6%. 1HNMR (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-Dibromopyrazin-2-amine (485.7 mg, 1.92 mmol, 1.50 equivalents), 4-acetyleneaniline (150 mg, 1.28 mmol, 1.00 equivalents), cuprous iodide (24.39 mg, 0.13 mmol, 0.1 equivalents), tetrahydrofuran (15.36 ml), and triethylamine (0.54 ml) were added to a 50 ml round-bottom flask under nitrogen protection. The mixture was stirred overnight at 60 °C. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a yellow solid in 13% yield.

[0044]

[0045] Step 2: 3-((4-aminophenyl)ethynyl)-5-bromopyrazine-2-amine (74.1 mg, 0.26 mmol, 1.00 equivalent), 4-(4-morpholinyl)phenylboronic acid pinacol ester (88.93 mg, 0.31 mmol, 1.20 equivalent), potassium carbonate (106.1 mg, 0.77 mmol, 3.00 equivalent), and methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-bicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-bicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-bicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-bicyclohexylphosphine-2',1',6'-triisopropyl-1' ... 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), and purified water (0.5 mL) were added to a 10 mL microwave-safe reaction tube and reacted at 160 °C for 1.5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography to obtain a yellow solid with a yield of 25.9%. 1HNMR(500MHz, CDCl3)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,1 H),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: 3,5-Dibromopyrazin-2-amine (253 mg, 1 mmol, 1.00 equivalent), 4-acetyleneaniline (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) were added to a 50 ml round-bottom flask. Under nitrogen protection, bis(triphenylphosphine)palladium dichloride (70 mg, 0.1 mmol, 0.10 equivalent) was added. The mixture was stirred overnight at 40 °C. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a yellow solid with a yield of 51%.

[0049]

[0050] Step 2: Dissolve 3-((3-aminophenyl)ethynyl)-5-bromopyrazine-2-amine (148 mg, 0.51 mmol, 1.00 equivalent), 4-(4-morpholinyl)phenylboronic acid pinacol ester (177 mg, 0.612 mmol, 1.20 equivalent), potassium carbonate (211 mg, 1.53 mmol, 3.00 equivalent), and methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (43.2 mg, 0.051 mmol, 0.10 equivalent), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (37.3 mg, 0.051 mmol, 0.10 equivalent), 1,4-dioxane (2 mL), and purified water (0.5 mL) were added to a 10 mL microwave-safe reaction tube and reacted at 160 °C for 1.5 hours. After the reaction was complete, the solvent was removed by vacuum distillation to obtain the crude product, which was purified by silica gel column chromatography to obtain a golden yellow solid with a yield of 51%. 1HNMR(500MHz, CDCl3)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: Inhibition test of compound activity against HPK1 and GLK kinases

[0052] The specific experimental steps for testing the inhibitory effects of the compounds on the activities of HPK1 and GLK (MAP4K3) kinases 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 a 96-well plate as the "compound-free control" and "enzyme-free control," respectively, and label them as the source plate. Transfer 40 μl of the compound from the source plate to a new 384-well Echo plate (intermediate plate).

[0058] 2) Preparation of detection plate

[0059] Using the Echo pipetting system, 200 nmol of solution from each well in the 384-well Echo plate was transferred to the 384-well detection plate.

[0060] 3. Kinase response

[0061] 1) Prepare 2× kinase solution

[0062] Prepare the kinase solution using 1× kinase buffer, with each component concentration being twice the final reaction concentration. Add 10 μl of kinase solution to each well of the test plate, and add 1× kinase buffer to the enzyme-free 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 using 1× kinase buffer, with each component concentration being twice the final reaction concentration. Add 10 μl of the substrate solution to all wells of the detection plate to start the reaction and vortex to mix.

[0065] 3) Incubation reaction

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

[0067] 4. Testing

[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] Fluorescence signals were 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 units (RFU) from Envision software and calculate the 520nm / 495nm fluorescence ratio.

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

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

[0075] “min”: Ratio of enzyme-free control wells

[0076] “max”: DMSO reference well Ratio

[0077] 3) Use MS Excel to organize the data, and fit the dose-response curve using the XLFit plugin (v5.4.0.8). Calculation formula:

[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 using the experimental methods described above. 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 the target compounds on HPK1 and GLK at 500 nM.

[0082]

[0083] “ND”: Not detected.

[0084] A selection of compounds with good activity were chosen, and their IC50 values ​​were determined using the experimental method described above. 50 The values ​​are shown in Table 2. The compound exhibits good inhibitory effects on HPK1.

[0085] Table 2. Half-maximal inhibitory concentrations of the target compounds against HPK1

[0086]

[0087] “ND”: Not detected.

[0088] The above description of the present invention is illustrative and not restrictive. Those skilled in the art will understand that many modifications, variations or equivalents may be made within the spirit and scope defined by the claims, but all of them will fall within the protection scope of the present invention.

Claims

1. A selective HPK1 inhibitor, characterized in that, The selective HPK1 inhibitor is selected from one of the following structures: 。 2. Use of the selective HPK1 inhibitor of claim 1 in the preparation of an antitumor drug.

3. Use according to claim 2, 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, lymphoma, squamous cell carcinoma of the head and neck, acute lymphoblastic leukemia, chronic myelogenous leukemia or myeloblastic leukemia.

4. An antitumor agent, characterized by comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof. A safe and effective amount of the selective HPK1 inhibitor of claim 1.

5. The antitumor drug according to claim 4, characterized by, Also included are pharmaceutically acceptable excipients.

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