Inhibitor compound and use thereof and drug for treating cancer

Abstract

The present invention relates to the technical field of drug synthesis, and specifically relates to an inhibitor compound and the use thereof and a drug for treating cancer. Provided is an inhibitor compound or a pharmaceutically acceptable salt thereof, which can be used for preparing an EGFR kinase inhibitor and preparing a drug for treating or preventing cancer. Further provided is a drug containing the inhibitor compound or the pharmaceutically acceptable salt thereof for treating cancer. The compound or drug is highly effective and has low toxicity. The compound or drug not only exhibits potent antitumor activity and effectively inhibits the growth of cancer cells, but also maintains strong brain-penetrating properties, and thus has broad application prospects.

Description

Inhibitor compound and application and medicine for treating cancer TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to an inhibitor compound and application and medicine for treating cancer. BACKGROUND

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein as an expression product of a proto-oncogene, which is composed of an extracellular ligand binding region, a transmembrane region and an intracellular region with a tyrosine kinase domain. When a ligand binds to the extracellular region of EGFR, it can activate downstream signaling pathways such as PI3K-AKT and MAPK-Erk, leading to physiological processes such as cell growth, proliferation and differentiation. However, when the function of EGFR is lost or abnormal, it can continuously activate genes related to tumor proliferation and differentiation, thereby inducing the formation and development of tumors such as lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, liver cancer and glioblastoma.

[0003] Small molecule EGFR tyrosine kinase inhibitors can act on the intracellular kinase region of EGFR, and can prevent EGFR autophosphorylation by competing with adenosine triphosphate molecules for the binding site of tyrosine kinase residues, thereby blocking the transmission of EGFR signaling molecules and achieving the effect of inhibiting cancer cell proliferation.

[0004] Gefitinib and erlotinib, as reversible quinazoline EGFR inhibitors, cannot completely inhibit the growth of tumor cells, and the emergence of EGFR mutations promotes the drug resistance of tumor cells; also such inhibitors cannot effectively cross the blood-brain barrier, showing limited effect in treating non-small cell lung cancer patients with brain metastases (Jackman DM, et al. Response and Resistance in a Non-Small-Cell Lung Cancer Patient With an Epidermal Growth Factor Receptor Mutation and Leptomeningeal Metastases Treated With High-Dose Gefitinib [J]. Journal of Clinical Oncology, 2006, 24(27): 4517-4520. Grommes C, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer [J]. Neuro-Oncology, 2011, 13(12): 1364-9.).

[0005] Afatinib and dacomitinib, as irreversible quinazoline EGFR inhibitors, can inhibit EGF, HER-2 and HER-4 receptor phosphorylation and its subsequent kinase activity, but cancer patients will have adverse reactions such as skin rash and diarrhea during use (Ramalingam SS, et al. Randomized Phase II Study of Dacomitinib (PF-00299804), an Irreversible Pan–Human Epidermal Growth Factor Receptor Inhibitor, Versus Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer [J]. Journal of Clinical Oncology, 2012, 30(27): 3337-3344. Miller VA, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b / 3 randomised trial [J]. Lancet Oncology, 2012, 13(5): 528-538.).

[0006] Zoritifinib is a new generation irreversible EGFR tyrosine kinase inhibitor, which can inhibit the transmission of signal pathway by forming a covalent bond with the tyrosine kinase binding domain, and then inhibit the growth of tumor cells, but there is an adverse reaction of abnormal liver function (WU YL, et al. Randomized phase 3 study of first-line BBB3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non-small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis [J]. Journal of Clinical Oncology, 2023, 41(16_suppl):9001. doi:10.1200 / JCO.2023.41.16_suppl.9001.). SUMMARY

[0007] In view of the deficiencies of the prior art, the present application provides an inhibitor compound which has strong activity, low toxicity and can more effectively inhibit tumor growth. At the same time, the inhibitor compound can maintain strong brain penetration characteristics, so that it can play a better therapeutic effect on those cancers that have metastasized to the central nervous system, especially those that have metastasized to the brain and caused leptomeningeal metastasis.

[0008] The present application provides an inhibitor compound as shown below or a pharmaceutically acceptable salt thereof:

[0009] The present application also provides the use of the above-mentioned inhibitor compound or its pharmaceutically acceptable salt in the preparation of a drug for treating or preventing cancer.

[0010] The present application also provides the use of the above-mentioned inhibitor compound or its pharmaceutically acceptable salt in the preparation of an EGFR kinase inhibitor.

[0011] The present application also provides a drug for treating cancer, which contains the above-mentioned inhibitor compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0012] Further, the pharmaceutically acceptable salt is any one or more of a phosphate salt, a camphorsulfonic acid salt, a hydrobromic acid salt, a hydrofluoric acid salt, a sulfuric acid salt, a nitric acid salt, a formic acid salt, an acetic acid salt, a propionic acid salt, an oxalic acid salt, a malonic acid salt, a succinic acid salt, a fumaric acid salt, a maleic acid salt, a lactic acid salt, a malic acid salt, a tartaric acid salt, a citric acid salt, a picric acid salt, a methanesulfonic acid salt, a trifluoromethanesulfonic acid salt, a benzenesulfonic acid salt, or a benzenesulfonic acid salt of the inhibitor compound.

[0013] Further, the pharmaceutically acceptable salt is a hydrochloric acid salt of the inhibitor compound.

[0014] Further, the cancer is lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, liver cancer, glioblastoma, a solid tumor, non-small cell lung cancer, papillary renal cell carcinoma, or melanoma.

[0015] Further, the inhibitor compound or a pharmaceutically acceptable salt thereof is a main active ingredient.

[0016] Further, the medicine further comprises a pharmaceutically acceptable excipient.

[0017] Compared with the prior art, the present scheme has the beneficial effects that:

[0018] 1. The present application provides BBB-7 and BBB-8 compounds which are structurally different from existing quinazoline EGFR inhibitors;

[0019] 2. The BBB-7 and BBB-8 compounds provided by the present application, or a pharmaceutically acceptable salt thereof, are a high-efficiency and low-toxicity EGFR inhibitor, which not only has high antitumor activity and effectively inhibits the growth of cancer cells, has obvious inhibitory effect on a variety of tumor cells, but also can maintain strong brain penetration characteristics, can play a good therapeutic effect on those cancers that have metastasized to the central nervous system, especially the brain and cause leptomeningeal metastasis, and has a wide application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0020] FIG. 1 is a structural general structural diagram of the BBB compound;

[0021] FIG. 2 is a result diagram of the tumor growth inhibition condition of the control group of mice after 21 days of feeding;

[0022] FIG. 3 is a result diagram of the tumor growth inhibition condition of the mice in the amuvirtin group after 21 days of feeding;

[0023] FIG. 4 is a result diagram of the tumor growth inhibition condition of the mice in the sorafenib group after 21 days of feeding;

[0024] FIG. 5 is a result diagram of the tumor growth inhibition condition of the mice in the BBB-7 group after 21 days of feeding;

[0025] Figure 6 is a result graph of tumor growth inhibition of BBB-8 group mice after feeding for 21 days;

[0026] Figure 7 is a result graph of brain photon flux of control group and experimental group mice after feeding for 7 days;

[0027] Figure 8 is a result graph of brain photon flux of control group and experimental group mice after feeding for 14 days;

[0028] Figure 9 is a result graph of brain photon flux of control group and experimental group mice after feeding for 21 days;

[0029] Figure 10 is a chemical structure diagram of BBB series compounds;

[0030] Figure 11 is a result graph of mouse organ tissue staining after feeding for 21 days. DETAILED DESCRIPTION

[0031] The present application is further illustrated by the following examples, which are intended to be more concretely illustrative of the technical solutions of the present application, and should not be understood as a limitation.

[0032] Preparation of BBB-7 compound

[0033] First step: preparation of BBB-3

[0034] To a solution of 4-chloro-7-methoxyquinazoline-6-yl acetate (BBB-1, 4 g) in acetonitrile (160 mL) was added 3-bromo-2-fluoroaniline (BBB-2, 3.04 g), and the reaction mixture was heated to reflux with stirring for 4 hours, then cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (50 mL) and dried under vacuum to give the HCl salt of 5 (6 g, 86%) as a white solid.

[0035] Second step: preparation of BBB-4

[0036] Potassium carbonate (4.12 g) was added to a solution of the HCl salt of BBB-3 (6 g) in methanol (40 mL), and the reaction mixture was stirred at 10°C for 2 hours, then filtered, and the solid was washed with methanol (20 mL), the filtrate was concentrated under vacuum to a residue, and treated with methyl tert-butyl ether (40 mL), the resulting mixture was filtered, and the solid was dried at 40°C to give the potassium salt of compound BBB-4 (4.8 g, 92%).

[0037] Third step: preparation of BBB-5

[0038] BBB-4 (346 mg), acyl chloride (270 mg) and potassium carbonate (276 mg) were added to a reaction flask followed by dry N,N-dimethylformamide (7 mL) and the mixture was stirred at room temperature overnight. The reaction was checked by TLC and the mixture was poured into water (20 mL) and filtered. The filter cake was dried under vacuum to give crude product BBB-5 (0.58 g) as a yellow solid which was used without purification in the next step.

[0039] Fourth step: Preparation of BBB-6

[0040] Hydrogen chloride 1,4 dioxane solution (4 M, 2 mL) was added to a solution of BBB-5 (0.58 g) in methanol (2 mL) and the mixture was stirred at room temperature for 1 hour and then concentrated. The residue was diluted with water (5 mL) and neutralised to pH 7 with saturated sodium bicarbonate solution. The solid was collected by filtration and treated with toluene (10 mL) and the toluene evaporated under reduced pressure. This process was repeated twice and the crude product BBB-6 (412 mg, yellow solid, 86% yield) was used without further purification.

[0041] Fifth step: Preparation of BBB-7

[0042] Sodium cyanoborohydride (41 mg) was added to a mixture of BBB-6 (147 mg) and acetaldehyde (28.3 mg) in methanol (2 mL) and the reaction mixture was stirred at room temperature overnight and then concentrated under vacuum. The residue was treated with water and extracted with ethyl acetate (3 x 8 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The final purification was carried out by column chromatography using dichloromethane:methanol 100:1 to 15:1.

[0043] 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.34 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 4.33 (br, 1H), 3.95 (s, 3H), 3.85 (br. 1H), 3.23 (br. 1H), 2.90 (d, J = 11.2 Hz, 1H), 2.78 (d, J = 11.2 Hz, 1H), 2.39 - 2.30 (m, 2H), 2.11 (m, 1H), 1.92 (t, J = 11.2 Hz, 1H), 1.34 (br 3H), 1.03 (t, J = 7.1 Hz, 3H).

[0044] 13 C NMR (101 MHz, DMSO-d6) δ 158.1, 156.7, 155.2, 153.8 (d, JCF= 247 Hz), 152.9, 150.4, 140.4, 130.7, 128.3 (d, JCF= 13 Hz), 128.1, 126.0 (d, JCF= 4 Hz), 116.9, 109.2 (d, JCF= 20 Hz), 108.8, 108.5, 57.2, 56.9, 52.8, 52.0, 48.5, 16.8, 12.4.

[0045] Preparation of BBB-8 compound

[0046] First step: Preparation of BBB-3

[0047] To a solution of 4-chloro-7-methoxyquinazoline-6-yl acetate (BBB-1, 4 g) in acetonitrile (160 mL) was added 3-bromo-2-fluoroaniline (BBB-2, 3.04 g) and the reaction mixture was heated to reflux with stirring for 4 h, then cooled to room temperature, filtered and the filter cake was washed with acetonitrile (50 mL) and dried under vacuum to give the HCI salt of 5 (6 g, 86%) as a white solid.

[0048] Second step: Preparation of BBB-4

[0049] Potassium carbonate (4.12 g) was added to a solution of the HCI salt of BBB-3 (6 g) in methanol (40 mL) and the reaction mixture was stirred at 15 °C for 2 h, filtered and the solid was washed with methanol (20 mL), the filtrate was concentrated under vacuum to a residue and treated with methyl tert-butyl ether (40 mL), the resulting mixture was filtered and the solid was dried at 45 °C to give the potassium salt of compound BBB-4 (4.8 g, 92%).

[0050] Third step: Preparation of BBB-5

[0051] BBB-4 (346 mg), the acid chloride (270 mg) and potassium carbonate (276 mg) were added to a reaction flask followed by dry N,N-dimethylformamide (7 mL) and the mixture was stirred at room temperature overnight, the reaction was checked by TLC and the mixture was poured into water (20 mL) and filtered, the filter cake was dried under vacuum to give the crude product BBB-5 (0.58 g) as a yellow solid which was used without purification in the next step.

[0052] Fourth step: Preparation of BBB-6

[0053] Hydrogen chloride 1,4 dioxane solution (4 M, 2 mL) was added to a solution of BBB-5 (0.58 g) in methanol (2 mL) and the mixture was stirred at room temperature for 1 h before concentrating. The residue was diluted with water (5 mL) and neutralized to pH 7 with saturated sodium bicarbonate solution, filtered and the collected solid was treated with toluene (10 mL) and the toluene evaporated under reduced pressure. The process was repeated twice and the crude product BBB-6 (412 mg, yellow solid, 86% yield) was used without further purification.

[0054] Fifth step: Preparation of BBB-8

[0055] Sodium cyanoborohydride (41 mg) was added to a mixture of BBB-6 (147 mg) and paraformaldehyde (19.3 mg) in methanol (2 mL) and the reaction mixture was stirred at room temperature overnight before concentrating in vacuo, the residue was treated with water and extracted with ethyl acetate (3 x 8 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, finally purified by column chromatography, dichloromethane:methanol 100:1 to 15:1.

[0056] 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.48 (s, 1H), 8.23 (s, 1H), 7.60 (ddd, J = 8.6, 6.1, 1.6 Hz, 1H), 7.56 (m, 1H), 7.34 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H), 4.50 - 4.17 (br 1H), 4.00 - 3.70 (br, 1H), 3.40 - 3.17 (br, 1H), 2.81 (d, J = 11.2 Hz, 1H), 2.68 (d, J = 11.2 Hz, 1H), 2.21 (s, 3H), 2.11 (dd, J = 11.7, 4.0 Hz, 1H), 1.91 (m, 1H), 1.35 (br, 3H).

[0057] 13 C NMR (101 MHz, DMSO-d6) δ 158.1, 156.7, 155.2, 153.8 (d, JCF= 247 Hz), 153.0, 150.4, 140.4, 130.7, 128.3 (d, JCF= 13 Hz), 128.1, 126.0 (d, JCF= 4 Hz), 116.9, 109.1 (d, JCF= 20 Hz), 108.8, 108.5, 59.5, 56.9, 55.0, 48.4, 46.4, 16.6.

[0058] Lung cancer brain metastasis tumor drug inhibition experiment

[0059] Balb / c-nude mice (5 weeks old) were fasted and watered before the operation, and isoflurane was used for anesthesia. The mice were fixed in a prone position on a brain stereotaxic instrument, and the right parietal lobe (3 mm apart from the sagittal suture, 1 mm in front of the coronal suture) was carefully drilled with a 1 mm diameter dental drill after routine disinfection. A 10 μl microsyringe was used to extract the prepared PC-9-LUC cell suspension (6x10 4 / μl) 5 μl, and a slow vertical skull plate was used to inject 3.5 mm, retreat 0.5 mm, slowly (about 1 μl / min) inject 3 μl of cell suspension, and then slowly pull out the needle. The surgical field was washed with normal saline, the scalp was sutured, and the mice were routinely fed. On the 7th, 14th, and 21st days, the brain tumor size of the blank group and the experimental (15 mg / kg) group mice (amatinib group, zanolimumab group, BBB-7 group, and BBB-8 group) was tracked using small animal live imaging technology. The drug efficacy was reflected by the size of the fluorescence signal value, that is, the stronger the fluorescence signal, the more tumor cells, and the larger the tumor volume.

[0060] Fig. 2 is a result graph of the tumor growth inhibition condition of the blank group mice after feeding for 21 days, Fig. 3 is a result graph of the tumor growth inhibition condition of the amatinib group mice after feeding for 21 days, Fig. 4 is a result graph of the tumor growth inhibition condition of the zanolimumab group mice after feeding for 21 days, Fig. 5 is a result graph of the tumor growth inhibition condition of the BBB-7 group mice after feeding for 21 days, and Fig. 6 is a result graph of the tumor growth inhibition condition of the BBB-8 group mice after feeding for 21 days. Fig. 7 is a result graph of the brain photon flux of the blank group and the experimental group mice after feeding for 7 days, Fig. 8 is a result graph of the brain photon flux of the blank group and the experimental group mice after feeding for 14 days, and Fig. 9 is a result graph of the brain photon flux of the blank group and the experimental group mice after feeding for 21 days.

[0061] As shown in Figs. 2 to 6, after the mice were treated with drugs for 21 days, the fluorescence signal intensity of the experimental group mice was weaker than that of the blank group mice, indicating that the four drugs could inhibit the growth of lung cancer brain metastasis tumors in mice.

[0062] During the feeding and sampling period, the photon flux value of the mouse brain was further analyzed. As shown in Figs. 7 to 9, the brain photon flux of the blank group mice increased with the increase of the inoculation time, indicating that the tumor grew well. The brain photon flux of the experimental group mice decreased with the increase of the inoculation time, indicating that taking the drug could inhibit the growth of the tumor.

[0063] Among the four groups of drugs, amatinib is an irreversible third-generation EGFR tyrosine kinase inhibitor, which has been approved for marketing in China in 2020, has higher selectivity and stronger blood-brain barrier penetration to EGFR T790M, and can inhibit tumor proliferation by competitive binding to the tyrosine region of EGFR. Sotorasib is an EGFR inhibitor that can effectively penetrate the central nervous system, has excellent blood-brain barrier penetration, and clinical studies have shown that sotorasib can reach the same drug concentration in the brain as in the plasma, effectively inhibit brain tumor growth, reduce brain tumor area, and prevent brain tumor formation. In the drug efficacy inhibition experiment, compared with the amatinib group and the sotorasib group, the brain photon flux value of the BBB-7 group and the BBB-8 group of mice is lower, indicating that the BBB-7 and BBB-8 drugs prepared by the present application have better inhibition effect on lung cancer brain metastasis tumors in mice than amatinib and sotorasib. In addition, compared with the BBB-7 group, the tumor inhibition level of the BBB-8 group of mice is significantly increased (p<0.01 on the 7th day, p<0.001 on the 14th day, and p<0.05 on the 21st day).

[0064] The data of the lung cancer brain metastasis tumor model obtained by the experiment show that, compared with amatinib and sotorasib, the BBB-7 and BBB-8 compounds prepared by the present application can better inhibit tumor growth in mice in vivo, and the BBB-8 has a stronger tumor inhibition effect on mice, and the tumor of the mice hardly grows.

[0065] Experiment of the influence of the BBB series of drugs on cancer cell proliferation

[0066] By testing the influence of the BBB series of drugs on cancer cell growth, the inhibition of the BBB series of compounds on cancer cell proliferation is further evaluated.

[0067] First, the structural general formula of the BBB compound of FIG. 1 is modified in multiple structures to obtain a series of BBB compounds, and then the obtained BBB series of compounds are added to human lung cancer cells PC-9 at different concentrations (25nM, 50nM, 100nM, 200nM, 400nM in DMSO) and incubated for 72h, and finally the OD value is obtained by detecting the 450nm absorbance in the enzyme marker with the Cell Counting Kit-8 (abbreviated as CCK-8) reagent, and the IC 50 .

[0068] FIG. 10 is a chemical structure diagram of the BBB series of compounds; as shown in the figure, the compound structural general formula of FIG. 1 is modified to obtain a variety of structural changes of compounds, wherein R1 and R2 can be independently selected from alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0069] Table 1 is a result table of the effect of the BBB series compounds on the proliferation of cancer cells. After treating human lung cancer cells PC-9 with the BBB series compounds synthesized above, the corresponding IC 50 values are obtained as shown in the table.

[0070] The results in Table 1 show that there is a strong uncertainty between the structural formula of the BBB compound and the measured IC 50 value. For example, the structural formula of the BBB-18 compound has ethyl as R1 and propyl as R2, and the structural formula of the BBB-19 compound has ethyl as R1 and butyl as R2, and the difference between the two is only one methylene group, but the IC 50 value of BBB-18 is 77.39nM, and the IC 50 value of BBB-19 is 19.99nM, which is nearly 3 times different; the structural formula of the BBB-13 compound has a heterocyclic ring as R, and the structural formula of the BBB-16 compound has a straight-chain alkyl as R, and the difference between the two is very large, but the IC 50 value of BBB-13 is 38.35nM, and the IC 50 value of BBB-16 is 36.21nM, which is very small.

[0071] The IC 50 values of BBB-7 and BBB-8 prepared by the present application are lower than the IC 50 values of other BBB compounds synthesized, indicating that the chemical structure of the BBB-7 and BBB-8 compounds has a better inhibitory effect on the proliferation of cancer cells, and the inhibitory effect of BBB-8 is the best.

[0072] Table 1: IC 50

[0073] Experiment of the effect of the BBB series drugs on the organs of mice

[0074] The effects of the BBB series drugs on the heart, liver, spleen, lung, and kidney of mice were evaluated by HE staining. After feeding the mice with the BBB series drugs for 21 days, the heart, liver, spleen, lung, and kidney of the mice were taken for embedding sectioning, hematoxylin staining, and finally observed under a microscope.

[0075] Figure 11 is a result graph of the staining of the organ tissues of mice. As shown in the figure, after treating the mice with the BBB series drugs, the heart, liver, spleen, lung, and kidney of the mice were not damaged, and the side effects of the BBB series drugs were small.

[0076] From the above experiment, the inhibitor compound provided by the application can be used to reduce or inhibit the activity of EGFR kinase or mutant EGFR kinase of cells or subjects, and then prevent or treat cell proliferation or EGFR related diseases, so the BBB-7 and BBB-8 compounds can be made into corresponding drugs.

[0077] Although the application is described in detail herein, the application is not limited thereto, and those skilled in the art can make modifications according to the principles of the application, therefore, all kinds of modifications made according to the principles of the application should be understood as falling within the protection scope of the application.

Claims

1. An inhibitor compound, or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the inhibitor compound is:

2. The inhibitor compound or pharmaceutically acceptable salt thereof according to claim 1 : characterized in that: The structure of the inhibitor compound is:

3. The inhibitor compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt is any one or more of a phosphate salt, a camphorsulfonic acid salt, a hydrobromic acid salt, a hydrofluoric acid salt, a sulfuric acid salt, a nitric acid salt, a formic acid salt, an acetic acid salt, a propionic acid salt, an oxalic acid salt, a malonic acid salt, a succinic acid salt, a fumaric acid salt, a maleic acid salt, a lactic acid salt, a malic acid salt, a tartaric acid salt, a citric acid salt, a picric acid salt, a methanesulfonic acid salt, a trifluoromethanesulfonic acid salt, a benzenesulfonic acid salt, a benzenesulfonic acid salt of the inhibitor compound.

4. The inhibitor compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt is a hydrochloric acid salt of the inhibitor compound.

5. The use of an inhibitor compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: for the preparation of a medicament for treating or preventing cancer.

6. Use according to claim 5, characterized in that: The cancer is lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, liver cancer, glioblastoma, a solid tumor, non-small cell lung cancer, papillary renal cell carcinoma, or melanoma.

7. The use of an inhibitor compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: for the preparation of an EGFR kinase inhibitor.

8. A medicament for treating cancer, characterized by: The medicament contains the inhibitor compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

9. The medicament for treating cancer according to claim 8, wherein: The medicament contains the inhibitor compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 as a main active ingredient.

10. The medicament according to claim 9, characterized in that: The medicament further comprises a pharmaceutically acceptable excipient. The medicament further comprises a pharmaceutically acceptable excipient.

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