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

TECHNICAL FIELD

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to an inhibitor compound and use thereof, and a drug for treating cancer. BACKGROUND

[0002] Epidermal growth factor receptor (EGFR), as an expression product of a proto-oncogene, is a transmembrane glycoprotein consisting of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain having a tyrosine kinase structure. When a ligand binds to the extracellular domain of EGFR, it activates downstream signaling pathways such as PI3K-AKT and MAPK-Erk, leading to physiological processes such as cell growth, proliferation, and differentiation. However, when EGFR function is lost or its activity is abnormal, it continually activates 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 targeted EGFR tyrosine kinase inhibitors can act in the intracellular kinase domain of EGFR, and by competing with adenosine triphosphate molecules for the binding site on the tyrosine kinase residue, can prevent EGFR autophosphorylation, thereby blocking the transmission of EGFR signaling molecules, 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 resulting EGFR mutations promote drug resistance in tumor cells. Moreover, because these inhibitors cannot effectively cross the blood-brain barrier, they show limited efficacy in treating patients with non-small cell lung cancer having 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 the phosphorylation of EGF, HER-2, and HER-4 receptors and their subsequent kinase activities. However, cancer patients experience adverse reactions such as rash and diarrhea during use (Ramalingam SS,etal.Randomized Phase II Study of Dacomitinib(PF-00299804),an Irrever-sible 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,etal.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-Lung1): a phase2b / 3randomised trial[J].Lancet Oncology,2012,13(5): 528-538.).

[0006] Zoriftinib, as a new generation irreversible EGFR tyrosine kinase inhibitor, can form a covalent bond with the tyrosine kinase binding domain to inhibit the transmission of signaling pathways, thereby achieving the effect of inhibiting tumor cell growth, but it also has the adverse reaction of abnormal liver function (WU YL , et al.Randomized phase 3study 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.2023.41.1 6_suppl.9001.). SUMMARY

[0007] In view of the deficiencies of the prior art, the present invention provides an inhibitor compound with strong activity, low toxicity, and more effective inhibition of tumor growth. At the same time, the inhibitor compound can maintain strong brain penetration characteristics, enabling it to exert a good therapeutic effect in cancers that have metastasized to the central nervous system, particularly those that have metastasized to the brain, as well as cancers causing leptomeningeal metastasis.

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

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

[0010] The present invention also provides the use of the above inhibitor compound or the pharmaceutically acceptable salt thereof in the preparation of an EGFR kinase inhibitor.

[0011] The present invention also provides a drug for treating cancer, the drug comprising the above inhibitor compound or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] Further, the pharmaceutically acceptable salt is any one or more of phosphate, camphorsulfonate, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate,     malate,     tartrate,     citrate,     picrate,     methanesulfonate, trifluoromethanesulfonate, benzenemethanesulfonate, and benzenesulfonate of the inhibitor compound.

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

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

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

[0016] Further, the drug further comprises pharmaceutically acceptable adjuvants.

[0017] Compared with the prior art, the beneficial effects of the present solutions are:

[0018] 1. The present invention 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 invention, or the pharmaceutically acceptable salts thereof, are highly effective, low-toxicity EGFR inhibitors. They not only have high anti-tumor activity, effectively inhibit cancer cell growth, and show significant inhibitory effects on a variety of tumor cells, but also maintain strong brain penetration characteristics. They can exert good therapeutic effects in cancers that have metastasized to the central nervous system, particularly those that have metastasized to the brain as well as cancers causing leptomeningeal metastasis, and have broad application prospects. BRIEF DESCRIPTION OF DRAWINGS

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

[0021] FIG. 2 shows results of tumor growth inhibition in control group mice after 21 days of feeding;

[0022] FIG. 3 shows results of tumor growth inhibition in almonertinib group mice after 21 days of feeding;

[0023] FIG. 4 shows results of tumor growth inhibition in zoriftinib group mice after 21 days of feeding;

[0024] FIG. 5 shows results of tumor growth inhibition in BBB-7 group mice after 21 days of feeding;

[0025] FIG. 6 shows results of tumor growth inhibition in BBB-8 group mice after 21 days of feeding;

[0026] FIG. 7 shows brain photon flux results of control group and experimental group mice after 7 days of feeding;

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035] FIG. 8 shows brain photon flux results of control group and experimental group mice after 14 days of feeding; FIG. 9 shows brain photon flux results of control group and experimental group mice after 21 days of feeding; FIG. 10 is a chemical structure diagram of BBB series compounds; FIG. 11 shows results of mouse organ tissue staining after 21 days of feeding. DETAILED DESCRIPTION The present invention is further illustrated by the following examples, which are intended to clarify the technical solutions of the present invention and should not be construed as limiting. Preparation of BBB-7 compound Step 1: Preparation of BBB-3 3-bromo-2-fluoroaniline (BBB-2, 3.04g) was added to a solution of 4-chloro-7-methoxyquinazolin-6-yl acetate (BBB-1, 4g) in acetonitrile (160 mL). The reaction mixture was heated to reflux for 4 hours with stirring, then cooled to room temperature. After filtration, the filter cake was washed with acetonitrile (50 mL) and dried under vacuum to obtain the HCl salt of 5 as a white solid (6g, 86%). Step 2: Preparation of BBB-4 BBB-3

[0036]

[0037] Potassium carbonate (4.12g) was added to a solution of the HCl salt of BBB-3 (6g) in methanol (40 mL). The reaction mixture was stirred at 10°C for 2 hours. After filtration, the solid was washed with methanol (20 mL). The filtrate was concentrated under vacuum to a residue, treated with methyl tert-butyl ether (40 mL). The resulting mixture was filtered, and the solid was dried at 40°C to obtain a potassium salt of compound BBB-4 (4.8g, 92%). Step 3: Preparation of BBB-5

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

[0039] Step 4: Preparation of BBB-6

[0040] Hydrogen chloride in 1,4-dioxane solution (4M, 2 mL) was added to a solution of BBB-5 (0.58g) 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 neutralized to a pH of 7 with saturated sodium bicarbonate solution. After filtration, the collected solid was treated with toluene (10 mL), and the toluene was 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] Step 5: 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). The reaction mixture was stirred at room temperature overnight, then concentrated under vacuum. The residue was treated with water and extracted with ethyl acetate (3 x 8 mL). The

[0043]

[0044]

[0045]

[0046] combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Finally, purification was performed by column chromatography with dichloromethane:methanol from 100:1 to 15:1. 1H NMR (400 MHz, DMSO-d6) 6 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). 13C NMR (101 MHz, DMSO-d6) 6 158.1, 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. Preparation of BBB-8 compound Step 1: Preparation of BBB-3

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

[0048] Step 2: Preparation of BBB-4

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

[0050] Step 3: Preparation of BBB-5

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

[0052] Step 4: Preparation of BBB-6

[0053] Hydrogen chloride in 1,4-dioxane solution (4M, 2 mL) was added to a solution of BBB-5 (0.58g) 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 neutralized to a pH of 7 with saturated sodium bicarbonate solution. After filtration, the collected solid was treated with toluene (10 mL), and the toluene was 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.

[0054] Step 5: Preparation of BBB-8 (HCHO)n NaBH3CN MeOH

[0055] Sodium cyanoborohydride (41 mg) was added to a mixture of BBB-6 (147 mg) and paraformaldehyde (19.3 mg) in methanol (2 mL). The reaction mixture was stirred at room temperature overnight, 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 sulfate, and concentrated under reduced pressure. Finally, purification was performed by column chromatography with dichloromethane:methanol from 100:1 to 15:1.

[0056] 1H NMR (400 MHz, DMSO-d6) 6 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] 13C NMR (101 MHz, DMSO-d6) 6 158.1, 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] Experiment on the inhibitory effect of drugs on lung cancer brain xenograft tumors

[0059] Balb / c-nude mice (5 weeks old) were routinely fasted and deprived of water before surgery. Anesthesia was induced with isoflurane. The mice were placed in a prone position and fixed on a brain stereotaxic instrument. After routine disinfection, the skull was carefully drilled at the right parietal lobe (3 mm lateral to the sagittal suture, 1 mm anterior to the coronal suture) using a dental drill with a diameter of 1 mm. A 10-^1 microsyringe was used to draw 5 pl of prepared PC-9-LUC cell suspension (6*104 cells / ^l). The needle was slowly inserted perpendicularly to the skull plate to a depth of 3.5 mm, then withdrawn 0.5 mm. 3 pl of cell suspension was slowly injected (approximately 1 ^l / min). After leaving the needle in place for 1 min, it was slowly withdrawn. The surgical field was rinsed with normal saline, and the scalp was sutured. The mice were routinely raised. On days 7, 14, and 21, in vivo small animal imaging was used to track the brain tumor size in the control group and experimental groups (15 mg / kg) (almonertinib group, zoriftinib group, BBB-7 group, and BBB-8 group). Drug efficacy was reflected by the fluorescence signal intensity, where a stronger fluorescence signal indicates a greater number of tumor cells and also represents a larger tumor volume.

[0060] FIG. 2 shows results of tumor growth inhibition in the control group mice after 21 days of feeding; FIG. 3 shows results of tumor growth inhibition in the almonertinib group mice after 21 days of feeding; FIG. 4 shows results of tumor growth inhibition in the zoriftinib group mice after 21 days of feeding; FIG. 5 shows results of tumor growth inhibition in the BBB-7 group mice after 21 days of feeding; FIG. 6 shows results of tumor growth inhibition in the BBB-8 group mice after 21 days of feeding; FIG. 7 shows brain photon flux results of the control group and experimental group mice after 7 days of feeding; FIG. 8 shows brain photon flux results of the control group and experimental group mice after 14 days of feeding; and FIG. 9 shows brain photon flux results of the control group and experimental group mice after 21 days of feeding.

[0061] As shown in FIGs. 2 to 6, after 21 days of drug treatment, the fluorescence signal intensity in the experimental groups was weaker compared to the control group mice, indicating that all four groups of drugs could inhibit the growth of lung cancer brain xenograft tumors in mice.

[0062] During the feeding and drug administration sampling period, further analysis was performed on the photon flux values of the mouse brains. As shown in FIGs. 7 to 9, the brain photon flux of the control group mice increased with inoculation time, indicating good tumor growth. The brain photon flux of the experimental group mice decreased with inoculation time, indicating that drug administration could inhibit tumor growth.

[0063] Among the four drug groups, almonertinib is an irreversible third-generation EGFR tyrosine kinase inhibitor that has been approved for marketing in China in 2020. It has higher selectivity for EGFR T790M and stronger blood-brain barrier penetration, and can inhibit tumor proliferation by competitively binding to the EGFR tyrosine region. Zoriftinib is an EGFR inhibitor that can effectively penetrate the central nervous system and has excellent blood-brain barrier permeability. Clinical studies have shown that zoriftinib can achieve drug concentrations in the brain equivalent to those in plasma, effectively inhibit tumor growth in the brain, reduce the area of brain tumors, and prevent the formation of brain tumors. In the drug efficacy inhibition experiment of the present invention, compared with the almonertinib group and the zoriftinib group, the brain photon flux values in the BBB-7 group and BBB-8 group mice were lower, indicating that the BBB-7 and BBB-8 drugs prepared by the present invention have a better inhibitory effect on mouse lung cancer brain xenograft tumors than almonertinib and zoriftinib. Furthermore, compared with the BBB-7 group, the tumor inhibition level in the BBB-8 group mice was significantly higher (on day 7, p < 0.01; on day 14, p < 0.001; on day 21, p < 0.05).

[0064] The data obtained from the lung cancer brain xenograft model experiments indicate that, compared to almonertinib and zoriftinib, the BBB-7 and BBB-8 compounds prepared by the present invention can better inhibit tumor growth in mice, with BBB-8 showing a stronger tumor inhibitory effect, as tumors in mice hardly grew.

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

[0066] The inhibitory effect of BBB series compounds on cancer cell proliferation was further evaluated by testing the effect of BBB series drugs on cancer cell growth:

[0067] Initially, the general structural formula of BBB compounds shown in FIG. 1 was modified in various ways to obtain a series of BBB compounds. The resulting BBB series compounds were then added to human lung cancer cells PC-9 at different concentrations (25 nM, 50 nM, 100 nM, 200 nM, 400 nM in DMSO) and incubated for 72 hours. Finally, the Cell Counting Kit-8 (CCK-8) reagent was used to detect the absorbance at 450 nm using a microplate reader to obtain OD values, and the IC50 was measured.

[0068] FIG. 10 is a chemical structure diagram of the BBB series compounds. As shown, modifications were made to the general structural formula of the compound in FIG. 1 to obtain various structural changes, wherein R1 and R2 may each be independently selected from alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0069] Table 1 shows results of the effect of BBB series compounds on cancer cell proliferation. After treating human lung cancer cells PC-9 with the above synthesized BBB series compounds, the corresponding IC50 values were obtained as shown in the table.

[0070] The results in Table 1 show that there is a strong uncertainty between the structural formulas of BBB compounds and the measured IC50 values. For example, in compound BBB-18, R1 is ethyl and R2 is propyl; in compound BBB-19, R1 is ethyl and R2 is butyl. The two structures differ by only one methylene group, but the IC50 value of BBB-18 is 77.39 nM, while the IC50 value of BBB-19 is 19.99 nM, a difference of nearly 3-fold. In compound BBB-13, the R group is a heterocycle, while in compound BBB-16, the R group is a straight-chain alkane. The two structures are very different, but the IC50 value of BBB-13 is 38.35 nM, and the IC50 value of BBB-16 is 36.21 nM, a very small difference.

[0071] The IC50 values of BBB-7 and BBB-8 prepared by the present invention are lower than the IC50 values of other synthesized BBB compounds, indicating that the chemical structures of BBB-7 and BBB-8 compounds have a better inhibitory effect on cancer cell proliferation, with BBB-8 having the best inhibitory effect.

[0072] Table 1: IC50 of BBB series compounds Compound BBB-7 BBB-8 BBB-9 BBB-10 BBB-11 BBB-12 BBB-13 BBB-14 ic50 (bM) 18.05 9.71 29.85 50.18 32.48 114.6 38.35 105.7 Compound BBB-15 BBB-16 BBB-17 BBB-18 BBB-19 BBB-20 BBB-21 IC50 (11M) 114.6 36.21 34.39 77.39 19.99 24.62 19.83

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

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

[0075] FIG. 11 is a diagram showing results of mouse organ tissue staining. As shown, after feeding mice with BBB series drugs for treatment, the heart, liver, spleen, lung, and kidney of the mice were not damaged, indicating that the BBB series drugs have relatively few side effects.

[0076] From the above experiments, it can be seen that the inhibitor compound provided by the present invention can be used to reduce or inhibit the activity of EGFR kinase or mutant EGFR kinase in cells or a subject, thereby preventing or treating cell proliferative or EGFR-related diseases. Therefore, BBB-7 and BBB-8 compounds can be formulated into corresponding drugs.

[0077] Although the present invention has been described in detail herein, the present invention is not limited thereto. Those skilled in the art can make modifications according to the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood to fall within the protection scope of the present invention.

Claims

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

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

3. The inhibitor compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt is any one or more of phosphate, camphorsulfonate, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, trifluoromethanesulfonate, benzenemethanesulfonate, and benzenesulfonate of the inhibitor compound.

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

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

6. The use according to claim 5, characterized in that the cancer is lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, liver cancer, glioblastoma, solid tumor, nonsmall cell lung cancer, papillary renal cell carcinoma, or melanoma.

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

8. A drug for treating cancer, characterized in that the drug comprises the inhibitor compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

9. The drug for treating cancer according to claim 8, characterized in that the inhibitor compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 is a main active ingredient.

10. The drug according to claim 9, characterized in that the drug further comprises pharmaceutically acceptable adjuvants.

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