8-cyano-9-anilino-dioxinoquinoline derivatives, processes for their preparation and use

Abstract

The application belongs to the field of biological medicine, and particularly relates to a 8-cyano-9-aniline dioxane quinoline derivative. The application provides a 8-cyano-9-aniline dioxane quinoline derivative or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer or prodrug thereof, wherein the 8-cyano-9-aniline dioxane quinoline derivative is a compound having a structure shown in a general formula I. The synthesized 8-cyano-9-aniline dioxane quinoline derivative has EGFR kinase inhibitory activity, and has strong inhibitory activity on intracranial malignant glioblastoma and other malignant tumors.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to an 8-cyano-9-aniline dioxanequinoline derivative, its preparation method, and its application. Background Technology

[0002] Glioblastoma (GBM) is a highly aggressive intracranial malignant tumor, accounting for 50.9% of all malignant central nervous system tumors, ranking first among all types of brain tumors. According to the World Health Organization (WHO) glioma classification system, GBM is classified as grade IV. WHO grade I and II gliomas are considered low-grade brain tumors, but as the disease progresses, low-grade tumors not only have a high risk of recurrence but may also develop into WHO grade III anaplastic gliomas, and eventually transform into WHO grade IV secondary GBM.

[0003] Surgical resection is considered the primary treatment for GBM, but due to the highly diffuse nature of the tumor, complete removal of lesions is difficult. Currently, clinical treatment options for GBM are extremely limited, with only TMZ (tumor sulfadiazine) used as a DNA alkylating agent for first-line therapy. TMZ inhibits tumor proliferation by damaging DNA, but it lacks specificity, causes significant damage to normal cells, and long-term use easily leads to treatment resistance. Existing treatments result in poor patient prognosis, with a median survival of only 12-15 months, and approximately 70% of GBM patients have a five-year survival rate as low as 6.9% after diagnosis. Therefore, there is an urgent clinical need to explore new treatment strategies, such as small molecule targeted drug therapy.

[0004] Epidermal growth factor receptor (EGFR) belongs to the ERBB tyrosine kinase family. Clinicopathological analysis shows that approximately 60% of GBM cases exhibit EGFR amplification and / or mutation. Studies have found that in GBM patients with abnormal EGFR signaling pathways, about 50% show wild-type EGFR amplification, while the majority of the remaining mutations involve extracellular domain deletion. EGFRvIII is the most prevalent mutation type in GBM, and EGFR is considered a key driver of GBM.

[0005] Since the first-generation EGFR inhibitor gefitinib was launched in Japan in July 2002, significant progress has been made in EGFR kinase inhibitor research. However, to date, no EGFR kinase inhibitor has been successfully approved for the clinical treatment of GBM. Specifically, in the development of EGFR-targeted drugs, each generation of small molecule inhibitors has shown significant limitations in early clinical trials. Taking first-generation drugs characterized by reversible binding (such as gefitinib and erlotinib), second-generation drugs with covalent binding (such as dacomitinib and afatinib), and third-generation drugs that overcome acquired resistance (such as osimertinib) as examples, they generally face the following key challenges in Phase I / II clinical trials: insufficient intracranial exposure, significant adverse reactions, and poor inhibitory activity against EGFRvIII mutations. Therefore, there is an urgent need to develop anti-GBM drugs that can overcome the above defects. This invention aims to develop an innovative anti-GBM drug that is an EGFR inhibitor with strong inhibitory activity against EGFRvⅢ mutations, high intracranial exposure, and low adverse reactions. The present invention improves the physicochemical properties of the drug through reasonable molecular structure design and optimization, further enhances the drug's ability to penetrate the blood-brain barrier, and enhances the inhibitory activity against EGFR amplification and EGFRvⅢ mutations. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide an 8-cyano-9-aniline dioxanequinoline derivative or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug thereof, which can be used as a tyrosine kinase inhibitor targeting EGFR / EGFRvIII mutations and exhibits good anti-GBM proliferation effects.

[0007] This invention provides an 8-cyano-9-aniline dioxanequinoline derivative or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein the 8-cyano-9-aniline dioxanequinoline derivative is a compound having the structure shown in general formula I.

[0008]

[0009] In the formula,

[0010] R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkylester, C1-C6 alkylcarboxyl, etc.

[0011] R3 and R4 are independently selected from hydrogen, hydroxyl, amino, carboxyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkylester, C1-C6 alkylcarboxyl or selected from the following structures (where n = 1-6): wait.

[0012] Preferably, the 8-cyano-9-aniline dioxanequinoline derivative is selected from any one of the following compounds:

[0013] 9-(phenylamino)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(4-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-chlorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-bromophenyl)amino] -2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-(o-tolylamino)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(2-fluoro-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(3-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(2-chloro-6- [(2-bromo-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-dimethylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-dimethylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,4-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,4-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon 9-[(2-chloro-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2-bromo-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2,3-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2-fluoro-3-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(3-chloro-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile,3-g]quinoline-8-carboxynitrile, 9-[(3-bromo-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-amino-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-nitro-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(3-chloro-2-fluorophenyl)amino]-2-(piperidin-1-ylmethyl) ... [Phenyl)amino]-2-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-chloro-2-fluorophenyl)amino]-2-(morpholinemethyl)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-chloro-2-fluorophenyl)amino]-3-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(4-amino-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon.

[0014] The present invention also provides a method for preparing an 8-cyano-9-aniline dioxanequinoline derivative.

[0015] The preparation method of this 8-cyano-9-aniline dioxanequinoline derivative is shown below, including one of the following methods:

[0016] Method 1

[0017]

[0018] Reaction conditions and reagents: (a) N,N-dimethylformamide, 175℃, 6–10 h; (b) tetrahydrofuran, n-butyllithium, -60℃ to -80℃, 1–3 h; (c) phosphorus oxychloride, 90℃ to 110℃, 2–4 h; (d) N,N-dimethylformamide, sodium hydride, 170℃, 1–2 h; (e) pyridine hydrochloride, 220℃, 0.5–1 h; (f) N,N-dimethylformamide, potassium carbonate, 90℃ to -110℃, 1–3 h.

[0019] Method 2

[0020]

[0021] Reaction conditions and reagents: (g) N,N-dimethylformamide, potassium carbonate, 50℃~80℃, 4~8h; (h) N,N-dimethylformamide, cesium carbonate, 100℃~130℃, 4~8h; (i) N,N-dimethylformamide, dimethyl sulfoxide, room temperature, overnight; (j) different basic hydrophilic groups, 80℃~110℃, overnight; (k) Pb / C, isopropanol, room temperature, overnight; (m) isopropanol, 95℃, overnight; (n) phosphorus oxychloride, acetonitrile, 100℃, overnight.

[0022] Method 3

[0023]

[0024] Reaction conditions and reagents: (o) N,N-dimethylformamide, potassium carbonate, 50℃~80℃, 4~8h; (p) N,N-dimethylformamide, cesium carbonate, 100℃~130℃, 4~8h; (q) N,N-dimethylformamide, dimethyl sulfoxide, room temperature, overnight; (r) different basic hydrophilic groups, 80℃~110℃, overnight; (s) Pb / C, isopropanol, room temperature, overnight; (t) tetrahydrofuran, 75℃, 2~4h; (u) isopropanol, 95℃, overnight; (v) phosphorus oxychloride, acetonitrile, 100℃, overnight.

[0025] This invention provides the use of 8-cyano-9-aniline dioxanequinoline derivatives or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs thereof in the preparation of epidermal growth factor receptor inhibitor drugs.

[0026] Furthermore, the epidermal growth factor receptor is a tyrosine protein receptor kinase that drives GBM, such as EGFR amplification and / or EGFRvIII mutation.

[0027] This invention provides the use of 8-cyano-9-aniline dioxanequinoline derivatives or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs thereof in the preparation of drugs for the treatment and / or prevention and / or delay and / or adjuvant treatment and / or treatment of kinase-mediated diseases such as epidermal growth factor receptor (EGFR) amplification and / or EGFRvIII mutation.

[0028] This invention provides the use of the above-mentioned 8-cyano-9-aniline dioxanequinoline derivative or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer or prodrug in the preparation of antitumor drugs.

[0029] This invention provides a pharmaceutical composition.

[0030] The pharmaceutical composition includes an active ingredient and pharmaceutical excipients, wherein the active ingredient is selected from at least one of a) to i):

[0031] a) 8-cyano-9-aniline dioxanequinoline derivatives;

[0032] b) Pharmaceutically acceptable salts of the 8-cyano-9-aniline dioxanequinoline derivative;

[0033] c) The hydrate of the 8-cyano-9-aniline dioxanequinoline derivative;

[0034] d) The solvate of the 8-cyano-9-aniline dioxanequinoline derivative;

[0035] e) The polymorph of this 8-cyano-9-aniline dioxanequinoline derivative;

[0036] f) Tautomers of the 8-cyano-9-aniline dioxanequinoline derivative;

[0037] g) Stereomers of the 8-cyano-9-aniline dioxanequinoline derivative;

[0038] h) The prodrug of the 8-cyano-9-aniline dioxanequinoline derivative;

[0039] i) Isotopic derivatives of the 8-cyano-9-aniline dioxanequinoline derivative;

[0040] Among them, the above-mentioned 8-cyano-9-aniline dioxanequinoline derivatives are compounds represented by general formula I.

[0041] Preferably, the pharmaceutical excipients include at least one of the following substances: solvents, propellants, solubilizers, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculation agents, filter aids, and release inhibitors.

[0042] Furthermore, pharmaceutical compositions can be formulated into various dosage forms: Classified by the dispersion system: Specifically, they can be formulated into the following dosage forms: solutions, colloidal solutions, emulsions, suspensions, gaseous dispersions, particulate dispersions, and solid dispersions; Classified by form: Specifically, they can be formulated into the following dosage forms: liquid dosage forms (such as aromatic aqueous solutions, solutions, injections, mixtures, lotions, liniments, etc.), gaseous dosage forms (such as aerosols, sprays, etc.), solid dosage forms (such as powders, pills, tablets, films, etc.), and semi-solid dosage forms (such as ointments, suppositories, pastes, etc.); Classified by route of administration: Specifically, they can be formulated into the following dosage forms: dosage forms administered via the gastrointestinal tract and dosage forms administered without the gastrointestinal tract.

[0043] The present invention has the following advantages over the prior art:

[0044] The 8-cyano-9-aniline dioxanequinoline derivatives or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs synthesized in this invention have high EGFR ex20ins mutant kinase inhibitory activity and strong inhibitory activity against solid tumors such as non-small cell lung cancer, breast cancer, and digestive system tumors. They can be used to prepare drugs for the treatment and / or prevention and / or delay and / or adjuvant treatment and / or treatment of diseases associated with excessive kinase activity such as EGFR amplification and / or EGFRvIII mutation. Attached Figure Description

[0045] Figure 1 The effect of target compound 20 on the growth of GBM tumors in nude mice in which U87MG-EGFRvⅢ-Luc cells were inoculated into the brain. In the figure, (A) and (B) are bar graphs and line graphs showing the change in fluorescence signal intensity of U87MG-EGFRvⅢ-Luc cell xenografts in nude mice over time, respectively; (C) is a graph showing the change in body weight of nude mice over time; and (D) is a survival curve of nude mice. All p-values ​​were compared with the control group (n=5), with (*) p<0.05 and (**) p<0.01. Detailed Implementation

[0046] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings, but this should not be construed as limiting the scope of the present invention.

[0047] An 8-cyano-9-aniline dioxane-quinoline derivative, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug thereof, wherein the 8-cyano-9-aniline dioxane-quinoline derivative is a compound having the structure shown in general formula I.

[0048]

[0049] In the formula,

[0050] R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkylester, C1-C6 alkylcarboxyl, etc.

[0051] R3 and R4 are independently selected from hydrogen, hydroxyl, amino, carboxyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkylester, C1-C6 alkylcarboxyl or selected from the following structures (where n = 1-6): wait.

[0052] This invention provides a synthetic route for 8-cyano-9-aniline dioxanequinoline derivatives.

[0053] Preferably, the 8-cyano-9-aniline dioxanequinoline derivative is selected from any one of the following compounds:

[0054] 9-(phenylamino)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(4-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-chlorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-bromophenyl)amino] -2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-(o-tolylamino)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(2-fluoro-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(3-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(2-chloro-6- [(2-bromo-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-dimethylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-dimethylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,4-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,4-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon 9-[(2-chloro-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2-bromo-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2,3-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2-fluoro-3-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(3-chloro-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile,3-g]quinoline-8-carboxynitrile, 9-[(3-bromo-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-amino-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-nitro-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(3-chloro-2-fluorophenyl)amino]-2-(piperidin-1-ylmethyl) ... [Phenyl)amino]-2-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-chloro-2-fluorophenyl)amino]-2-(morpholinemethyl)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-chloro-2-fluorophenyl)amino]-3-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(4-amino-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon.

[0055] This invention provides three synthetic methods for 8-cyano-9-aniline dioxanequinoline derivatives, along with the reaction conditions and reagents involved.

[0056] Method 1

[0057]

[0058] Reaction conditions and reagents: (a) N,N-dimethylformamide, 175℃, 6–10 h; (b) tetrahydrofuran, n-butyllithium, -60℃ to -80℃, 1–3 h; (c) phosphorus oxychloride, 90℃ to 110℃, 2–4 h; (d) N,N-dimethylformamide, sodium hydride, 170℃, 1–2 h; (e) pyridine hydrochloride, 220℃, 0.5–1 h; (f) N,N-dimethylformamide, potassium carbonate, 90℃ to -110℃, 1–3 h.

[0059] Method 2

[0060]

[0061] Reaction conditions and reagents: (g) N,N-dimethylformamide, potassium carbonate, 50℃~80℃, 4~8h; (h) N,N-dimethylformamide, cesium carbonate, 100℃~130℃, 4~8h; (i) N,N-dimethylformamide, dimethyl sulfoxide, room temperature, overnight; (j) different basic hydrophilic groups, 80℃~110℃, overnight; (k) Pb / C, isopropanol, room temperature, overnight; (m) isopropanol, 95℃, overnight; (n) phosphorus oxychloride, acetonitrile, 100℃, overnight.

[0062] Method 3

[0063]

[0064] Reaction conditions and reagents: (o) N,N-dimethylformamide, potassium carbonate, 50℃~80℃, 4~8h; (p) N,N-dimethylformamide, cesium carbonate, 100℃~130℃, 4~8h; (q) N,N-dimethylformamide, dimethyl sulfoxide, room temperature, overnight; (r) different basic hydrophilic groups, 80℃~110℃, overnight; (s) Pb / C, isopropanol, room temperature, overnight; (t) tetrahydrofuran, 75℃, 2~4h; (u) isopropanol, 95℃, overnight; (v) phosphorus oxychloride, acetonitrile, 100℃, overnight.

[0065] This invention provides the use of 8-cyano-9-aniline dioxanequinoline derivatives or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs thereof in the preparation of epidermal growth factor receptor inhibitor drugs.

[0066] Furthermore, the epidermal growth factor receptor is a tyrosine protein receptor kinase that drives GBM, such as EGFR amplification and / or EGFRvIII mutation.

[0067] This invention provides the use of 8-cyano-9-aniline dioxanequinoline derivatives or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs thereof in the preparation of medicaments for the treatment and / or prevention and / or delay and / or adjunctive treatment and / or management of diseases mediated by epidermal growth factor receptor exon 20 insertion mutant kinase.

[0068] This invention provides the use of the above-mentioned 8-cyano-9-aniline dioxanequinoline derivatives or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs in the preparation of antitumor drugs.

[0069] A pharmaceutical composition comprising an active ingredient and pharmaceutical excipients, wherein the active ingredient is selected from at least one of a) to i):

[0070] a) 8-cyano-9-aniline dioxanequinoline derivatives;

[0071] b) Pharmaceutically acceptable salts of the 8-cyano-9-aniline dioxanequinoline derivative;

[0072] c) The hydrate of this 8-cyano-9-aniline dioxanequinoline derivative;

[0073] d) The solvate of this 8-cyano-9-aniline dioxanequinoline derivative;

[0074] e) Polymorphs of this 8-cyano-9-aniline dioxanequinoline derivative;

[0075] f) Tautomers of the 8-cyano-9-aniline dioxanequinoline derivative;

[0076] g) Stereomers of the 8-cyano-9-aniline dioxanequinoline derivative;

[0077] h) The prodrug of this 8-cyano-9-aniline dioxanequinoline derivative;

[0078] i) Isotopic derivatives of this 8-cyano-9-aniline dioxanequinoline derivative;

[0079] The 2-amino-4-imidazolidine derivatives mentioned above are compounds represented by general formula I.

[0080] The compound mentioned above is the compound represented by general formula I.

[0081] Preferably, the pharmaceutical excipients include at least one of the following substances: solvent, propellant, solubilizer, stabilizer, flow aid, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesion agent, binding agent, penetration enhancer, pH adjuster, buffer, plasticizer, solubilizer, emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, surfactant, foaming agent, defoamer, thickener, encapsulating agent, humectant, absorbent, diluent, flocculant and anti-flocculation agent, filter aid, and release inhibitor.

[0082] Furthermore, pharmaceutical compositions can be formulated into various dosage forms: Classified by the dispersion system: Specifically, they can be formulated into the following dosage forms: solutions, colloidal solutions, emulsions, suspensions, gaseous dispersions, particulate dispersions, and solid dispersions; Classified by form: Specifically, they can be formulated into the following dosage forms: liquid dosage forms (such as aromatic aqueous solutions, solutions, injections, mixtures, lotions, liniments, etc.), gaseous dosage forms (such as aerosols, sprays, etc.), solid dosage forms (such as powders, pills, tablets, films, etc.), and semi-solid dosage forms (such as ointments, suppositories, pastes, etc.); Classified by route of administration: Specifically, they can be formulated into the following dosage forms: dosage forms administered via the gastrointestinal tract and dosage forms administered without the gastrointestinal tract.

[0083] The definitions of specific functional groups and chemical terms are described in more detail below.

[0084] When listing numerical ranges, each value and subranges within that range are included. For example, “C1-C6 alkyl” includes C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0085] It should be understood that, as described herein, any group defined below may be substituted by a number of substituents, and the corresponding definitions are listed below within their range, including the substituted group. Unless otherwise stated, the term "substitution" is defined below.

[0086] "C1-C6 alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C1-C4 alkyl is particularly preferred. Examples of said alkyl include, but are not limited to: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Unless otherwise stated, each alkyl group is optionally independently substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"); for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl is an unsubstituted C1-C6 alkyl (e.g., -CH3). In some implementations, the alkyl group is a substituted C1-C6 alkyl group.

[0087] "C1-C6 alkoxy" refers to the group -OR, where R is a substituted or unsubstituted C1-C6 alkyl group. In some embodiments, C1-C4 alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0088] "C1-C6 alkylamino" refers to the group -NHR or -NR2, where R is an optionally substituted C1-C6 alkyl group. In some embodiments, C1-C4 alkylamino is particularly preferred. Specific C1-C6 alkylamino groups include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino, dimethylamino, methylethylamino, and diethylamino.

[0089] "C1-C6 alkyl acyl" refers to the group -(=O)R, where R is an optionally substituted C1-C6 alkyl group. In some embodiments, C1-C4 alkyl acyl is particularly preferred. Exemplary C1-C6 alkyl acyl groups include, but are not limited to: -(=O)CH3, -(=O)CH2CH3, -(=O)CH2CH2CH3, and -(=O)CH(CH3)2.

[0090] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, -Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

[0091] Therefore, "C1-C6 haloalkyl" and "C1-C6 haloalkoxy" refer to the aforementioned "C1-C6 alkyl" and "C1-C6 alkoxy" substituted with one or more halogen groups. In some embodiments, C1-C4 haloalkyl is particularly preferred, and more preferably C1-C2 haloalkyl. In some embodiments, C1-C4 haloalkoxy is particularly preferred, and more preferably C1-C2 haloalkoxy. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary haloalkoxy groups include, but are not limited to: -OCH2F, -OCHF2, -OCF3, etc.

[0092] Other definitions

[0093] The term "pharmaceutically acceptable salt" refers to those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; or salts formed using methods used in the art, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0094] The “subject” to which the drug is administered includes, but is not limited to: humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0095] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0096] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0097] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a response in the target organism. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include both therapeutic and prophylactic effective amounts.

[0098] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is the amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of other therapeutic agents.

[0099] Unless otherwise stated, the term "preventively effective amount" of a compound as used herein is a quantity sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or a quantity sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the quantity of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term "preventively effective amount" may include quantities that improve overall prevention or enhance the preventive efficacy of other preventive agents.

[0100] The term "combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form.

[0101] "EGFR-induced cancers" refer to cancers characterized by inappropriate high expression of the EGFR gene or by EGFR gene mutations that alter the biological activity of the EGFR nucleic acid molecule or polypeptide. EGFR-induced cancers can occur in any tissue, including the brain, blood, connective tissue, liver, mouth, muscles, spleen, stomach, testes, and trachea. EGFR-induced cancers include, but are not limited to, GBM, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, and nasopharyngeal carcinoma.

[0102] An “EGFR mutation” or “EGFR mutant” includes one or more deletions, substitutions, or additions in the amino acid or nucleotide sequence encoding the EGFR protein or EGFR. EGFR mutations may also include one or more deletions, substitutions, or additions, or fragments thereof, provided that the mutant retains or increases tyrosine kinase activity relative to wild-type EGFR. In a specific EGFR mutation, the kinase or phosphorylation activity may be increased or decreased relative to wild-type EGFR (e.g., at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 100%). Exemplary EGFR mutations include, but are not limited to, anomalous amplification, vIII mutation, 19del mutation, T790M mutation, L858R mutation, L858R / T790M double mutation, and L858R / T790M / C797S, etc.

[0103] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the principles described herein fall within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make selections within a suitable range based on the description herein, and are not intended to be limited to the specific data in the examples below.

[0104] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0105] In some embodiments of the present invention, the starting materials or reagents used in the reaction may be commercially available or prepared by those skilled in the art using methods known in the chemical field. All solvents used in the present invention are commercially available and can be used without further purification. All operations involving experiments sensitive to water and / or oxygen are performed in pre-dried glassware under a nitrogen atmosphere. Reaction times are typically 0.1 h to 60 h, preferably 0.5 h to 24 h. Compounds are named manually or using ChemDraw software; commercially available compounds are named according to the supplier's catalog.

[0106] Compound Synthesis Examples

[0107] Examples 1 to 22 were carried out according to synthesis method one.

[0108] Example 1

[0109] Synthesis of 9-(phenylamino)-2,3-dihydro-[1,4]dioxanehexa[2,3-g]quinoline-8-carboxynitrile (1)

[0110] Step 1: Synthesize the target product (E)-2-(((dimethylamino)methylene)amino)-4,5-dimethoxybenzoate (1-1)

[0111]

[0112] In a 100 mL round-bottom flask, methyl 2-amino-4,5-dimethoxybenzoate (2.0 g, 9.5 mmol), N,N-dimethylformamide dimethyl acetal (DMF-DMA, 15.8 g, 132.7 mmol), and N,N-dimethylformamide (DMF, 20 mL) were added. The reaction mixture was stirred thoroughly to dissolve the reactants, and the temperature was raised to 175 °C. The reaction was continued for at least 8 hours. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted mixture was transferred to a separatory funnel, and 400 mL of ethyl acetate was added for extraction. The combined organic phases were washed twice with saturated NaCl solution (2 × 100 mL). The treated organic phase was dehydrated and dried using anhydrous sodium sulfate. After separating the solid-liquid mixture with filter paper, the clear filtrate was concentrated by rotary evaporation under reduced pressure to obtain a pale blue unpurified product. Subsequently, silica gel column chromatography was used for separation and purification (eluent ratio: petroleum ether-ethyl acetate volume ratio 10:1), and 1.7 g of white crystalline target product was successfully obtained, with a calculated reaction yield of 68%. 1H NMR (400MHz, DMSO-d6) δ8.47(s,1H),8.22(s,1H),7.40(s,1H),3.86(s,3H),3.81(s,3H),3.77(s,3H),3.39(s,3H),3.38(s,3H).ESI-MS: m / z 267.13[M+H] + .

[0113] Step 2: Synthesize the target product 4-hydroxy-6,7-dimethoxyquinoline-3-carboxynitrile (1-2)

[0114]

[0115] In a 250 mL round-bottom flask, 15 mL of anhydrous tetrahydrofuran was added, followed by the slow addition of n-butyllithium (2.5 M dissolved in n-hexane, 7 mL, 17.5 mmol). The reaction mixture was cooled at -78 °C for 15 minutes. Acetonitrile (1.8 g, 44.7 mmol) was dissolved in 5 mL of tetrahydrofuran and slowly added dropwise to the reaction mixture at -78 °C. After half an hour, methyl (E)-2-(((dimethylamino)methylene)amino)-4,5-dimethoxybenzoate (1-1, 1.7 g, 6.4 mmol) was mixed and dissolved with 15 mL of tetrahydrofuran and then injected into the reaction system at a constant rate through a constant-pressure dropping funnel. The entire reaction was carried out under continuous nitrogen purging and stirred continuously at -78 °C for 1 hour. After the reaction system reached the predetermined time, accurately measure 3 mL of glacial acetic acid (50 mmol) and add it to the reaction vessel. Then remove the low-temperature bath and allow the mixture to naturally warm to an ambient temperature of 25 ± 2 °C. Add 100 mL of water and stir continuously overnight. Filter the reaction solution and dry the resulting solid to obtain 1.2 g of a yellow solid, with a yield of 82%. 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),7.99(s,1H),7.45(s,1H),7.14(s,1H),3.91(s,3H),3.88(s,3H).ESI-MS: m / z 231.07[M+H] + .

[0116] Step 3: Synthesize the target product 4-chloro-6,7-dimethoxyquinoline-3-carboxynitrile (1-3)

[0117]

[0118] In a 250 mL round-bottom flask, 4-hydroxy-6,7-dimethoxyquinoline-3-carboxynitrile (1-2, 1.0 g, 4.4 mmol) and phosphorus oxychloride (20 mL, 78 mmol) were added, and the mixture was reacted in an oil bath at 105 °C for 2 hours. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the reaction mixture was carefully poured into a beaker containing ice to quench the phosphorus oxychloride. The reaction mixture, adjusted to pH ≈ 9 with saturated potassium carbonate aqueous solution, was injected into 400 mL of dichloromethane solvent for liquid-liquid extraction. The organic extract phases were collected and combined, and washed repeatedly with saturated sodium chloride solution (100 mL × 2). The organic extract was then dehydrated and dried using anhydrous sodium sulfate, filtered through a sintered glass funnel, and the volatile solvent was removed by vacuum distillation to obtain the primary purified product. Fine separation was performed using silica gel column chromatography (eluent ratio: petroleum ether / ethyl acetate = 5:1), ultimately yielding 0.9 g of a white crystalline product, with a calculated yield of 84%. 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),7.54(s,1H),7.45(s,1H),7.39(s,1H),4.03(s,3H),4.01(s,3H).ESI-MS: m / z 249.04[M+H] + .

[0119] Step 4: Synthesize the target product 4-[(2-fluorophenyl)amino]-6,7-dimethoxyquinoline-3-carboxynitrile (1-4)

[0120]

[0121] Aniline (1 g, 10.9 mmol) was dissolved in 15 mL of LDM and added to a 100 mL round-bottom flask. The reaction mixture was cooled in an ice-water bath for 10 minutes, followed by the slow addition of sodium hydride (0.9 g, 21.8 mmol), and the reaction was maintained at the ice bath condition for half an hour. Next, 4-chloro-6,7-dimethoxyquinoline-3-carboxynitrile (1-3, 0.9 g, 3.6 mmol) was added to the reaction mixture, and the temperature was raised to 170 °C and the reaction was continued for 1 hour. The reaction progress was monitored by TLC. After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted reaction mixture was quantitatively transferred to a separatory funnel, and 400 mL of ethyl acetate was added for liquid-liquid extraction. The combined organic extract layers were collected and washed with saturated sodium chloride solution (100 mL × 2) in two separate washes. The organic phase, dehydrated with anhydrous sodium sulfate, was filtered through a sintered glass funnel to remove the desiccant, followed by vacuum distillation to remove the low-boiling solvent, yielding the primary product. Purification was achieved using silica gel column chromatography (eluent ratio: petroleum ether / ethyl acetate, volume ratio 4:1), ultimately yielding 0.8 g of a pale yellow powder, with a calculated yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ9.45(s,1H),8.44(s,1H),7.82(s,1H),7.45(t,J=7.8Hz,1H),7.36(d,J=4.3Hz ,1H),7.35(s,1H),7.33(d,J=3.7Hz,1H),7.27(t,J=8.1Hz,1H),3.96(s,3H),3.94(s,3H).ESI-MS:m / z 324.11[M+H] + .

[0122] Step 5: Synthesize the target product 4-[(2-fluorophenyl)amino]-6,7-dihydroxyquinoline-3-carboxynitrile (1-5)

[0123]

[0124] In a 500 mL round-bottom flask, 4-[(2-fluorophenyl)amino]-6,7-dimethoxyquinoline-3-carboxynitrile (1-4, 0.8 g, 2.5 mmol) and pyridine hydrochloride (57.3 g, 495.4 mmol) were added. The reaction mixture was heated to 220 °C and reacted for 1 hour. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with saturated brine (200 mL), and extracted with tetrahydrofuran (400 mL). The resulting organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by recrystallization from dichloromethane to give 0.7 g of a deep yellow solid, with a yield of 96%. 1 HNMR(400MHz,DMSO-d6)δ10.95(s,1H),10.02(s,1H),9.64(s,1H),8.52(s,1H),7.60(s,1H),7.36(s,1 H),7.32(d,J=7.6Hz,1H),7.01-6.95(m,1H),6.93(d,J=2.5Hz,1H),6.88(t,J=8.0Hz,1H).ESI-MS:m / z 296.08[M+H] + .

[0125] Step 6: Synthesize the target product 9-[(2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (1)

[0126]

[0127] 4-[(2-fluorophenyl)amino]-6,7-dihydroxyquinoline-3-carboxynitrile (1-5, 0.7 g, 2.4 mmol) was dissolved in DMF and added to a 100 mL round-bottom flask. Potassium carbonate (0.98 g, 7.1 mmol) was then added, and the mixture was reacted at room temperature for half an hour. Next, 1,2-dibromoethane (308 μL, 3.6 mmol) was added, and the reaction mixture was heated to 100 °C and reacted for another hour. The reaction progress was monitored by TLC. After the reaction was terminated, the mixture was allowed to cool naturally to 25 °C, and then diluted with 200 mL of saturated sodium chloride solution. The diluted mixture was transferred to a separatory funnel, and 400 mL of ethyl acetate was accurately added for liquid-liquid extraction. The combined organic extract layers were washed twice with saturated sodium chloride solution (100 mL each time). The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a Buchner funnel, and the organic solvent was removed using a vacuum evaporator to obtain a preliminarily purified product. This product was then purified by silica gel column chromatography (eluent ratio: petroleum ether-ethyl acetate, volume ratio 3:1), ultimately yielding 220 mg of a light yellow crystalline powder. The calculated yield after purification was 29%. 1 H NMR (400MHz, DMSO-d6) δ9.45(s,1H),8.39(s,1H),7.99(s,1H),7.43(t,J=7.9Hz,1H),7.37(s,1H),7.3 4(d,J=3.3Hz,1H),7.31(d,J=8.6Hz,1H),7.26(t,J=7.2Hz,1H),4.42(s,2H),4.41(s,2H).ESI-MS:m / z 322.09[M+H] + .

[0128] Example 2

[0129] Synthesis of 9-(phenylamino)-2,3-dihydro-[1,4]dioxanehexa[2,3-g]quinoline-8-carboxynitrile (2)

[0130]

[0131] The synthesis method is as described in 1, yielding 200 mg of a white solid with a yield of 27%. 1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.42(s,1H),7.92(s,1H),7.42-7.39(m,1H),7.39-7.37(m,1H),7 .33(s,1H),7.25(d,J=2.4Hz,1H),7.23(d,J=2.4Hz,1H),7.22-7.19(m,1H),4.42(s,2H),4.40(s,2H). 13 CNMR(101MHz,DMSO-d6)δ151.57,150.16,148.67,145.66,144.39,140.27,129.38, 125.59,124.12,117.56,114.91,114.55,108.82,87.65,64.91,64.60.ESI-MS:m / z 304.10[M+H] + .

[0132] Example 3

[0133] Synthesis of 9-[(3-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (3)

[0134]

[0135] The synthesis method is as described in 1, yielding 195 mg of a white solid with a yield of 26%. 1 H NMR (400MHz, DMSO-d6) δ9.57(s,1H),8.50(s,1H),7.87(s,1H),7.42(d,J=7.5Hz,1H),7.37(d,J=2 .1Hz,1H),7.05(s,1H),7.03(s,1H),6.99(t,J=8.5Hz,1H),4.43(s,2H),4.41(s,2H).ESI-MS:m / z 322.09[M+H] + .

[0136] Example 4

[0137] Synthesis of 9-[(4-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (4)

[0138]

[0139] The synthesis method is as described in 1, yielding 195 mg of a white solid with a yield of 26%. 1H NMR (400MHz, DMSO-d6) δ9.54(s,1H),8.37(s,1H),7.97(s,1H),7.33(d,J=5.0Hz,1H),7.32(s,1H),7.30(d,J =4.3Hz,1H),7.26(d,J=2.5Hz,1H),7.23(d,J=8.8Hz,1H),4.42(s,2H),4.40(s,2H).ESI-MS:m / z322.09[M+H] + .

[0140] Example 5

[0141] Synthesis of 9-[(2-chlorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (5)

[0142]

[0143] The synthesis method is as described in 1, yielding 249 mg of a white solid with a yield of 33%. 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.35(s,1H),8.01(s,1H),7.57(d,J=7.7Hz,1H),7.51-7.46(m ,1H),7.42(s,1H),7.41-7.38(m,1H),7.32(d,J=4.5Hz,1H),4.43(s,2H),4.39(s,2H).ESI-MS:m / z 338.07[M+H] + .

[0144] Example 6

[0145] Synthesis of 9-[(2-bromophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (6)

[0146]

[0147] The synthesis method is as described in 1, yielding 158 mg of a white solid, with a yield of 21%. 1 H NMR (400MHz, DMSO-d6) δ9.59(s,1H),8.33(s,1H),8.03(s,1H),7.75(s,1H),7.52(d,J=16.4Hz,1H),7.45( d,J=11.5Hz,1H),7.39-7.33(m,1H),7.33-7.22(m,1H),4.43(s,2H),4.40(s,2H).ESI-MS:m / z382.01[M+H]+ .

[0148] Example 7

[0149] Synthesis of 9-(o-tolylamino)-2,3-dihydro-[1,4]dioxanehexa[2,3-g]quinoline-8-carboxynitrile (7)

[0150]

[0151] The synthesis method is as described in 1, yielding 177 mg of a white solid, with a yield of 23%. 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.29(s,1H),8.02(s,1H),7.33(d,J=6.9Hz,1H),7.31(d,J=4.3Hz,1H),7.3 0(s,1H),7.27-7.26(m,1H),7.26-7.24(m,1H),4.41(s,2H),4.41(s,2H),2.19(s,3H).ESI-MS:m / z318.12[M+H] + .

[0152] Example 8

[0153] Synthesis of 9-[(2-fluoro-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (8)

[0154]

[0155] The synthesis method is as described in 1, yielding 130 mg of a white solid with a yield of 44%. 1 H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.32(s,1H),8.05(s,1H),7.39-7.34(m,1H),7.32(s,1H), 7.20(d,J=4.8Hz,1H),7.17(d,J=5.2Hz,1H),4.43(s,2H),4.41(s,2H),2.24(s,3H).ESI-MS:m / z 336.11[M+H] + .

[0156] Example 9

[0157] Synthesis of 9-[(3-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (9)

[0158]

[0159] The synthesis method is as described in 1, yielding 136 mg of a white solid with a yield of 40%. 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.33(s,1H),8.01(s,1H),7.32(s,1H),7.27(d,J=7.5Hz,1H) ,7.19(t,J=8.8Hz,1H),7.12(d,J=7.6Hz,1H),4.42(s,2H),4.41(s,2H),2.09(s,3H).ESI-MS:m / z 336.14[M+H] + .

[0160] Example 10

[0161] Synthesis of 9-[(4-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (10)

[0162]

[0163] The synthesis method is as described in 1, yielding 119 mg of a white solid, with a yield of 34%. 1 H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.28(s,1H),8.01(s,1H),7.33(s,1H),7.30(s,1H),7.2 1(d,J=6.9Hz,1H),7.09(d,J=14.2Hz,1H),4.41(s,2H),4.41(s,2H),2.18(s,3H).ESI-MS:m / z 336.22[M+H] + .

[0164] Example 11

[0165] Synthesis of 9-[(2-chloro-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (11)

[0166]

[0167] The synthesis method is as described in 1, yielding 167 mg of a white solid with a yield of 52%. 1H NMR (400MHz, DMSO-d6) δ9.42(s,1H),8.30(s,1H),8.05(s,1H),7.44(d,J=7.2Hz,1H),7.37(d,J=7 .6Hz,1H),7.34(s,1H),7.32(t,J=1.0Hz,1H),4.43(s,2H),4.41(s,2H),2.25(s,3H).ESI-MS:m / z 352.08[M+H] + .

[0168] Example 12

[0169] Synthesis of 9-[(2-bromo-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (12)

[0170]

[0171] The synthesis method is as described in 1, yielding 112 mg of a white solid, with a yield of 27%. 1 H NMR (400MHz, DMSO-d6) δ9.47(s,1H),8.29(s,1H),8.05(s,1H),7.59(d,J=7.7Hz,1H),7.37(d,J=7 .3Hz,1H),7.31(s,1H),7.28(t,J=5.7Hz,1H),4.43(s,2H),4.41(s,2H),2.25(s,3H).ESI-MS:m / z 352.08[M+H] + .

[0172] Example 13

[0173] Synthesis of 9-[(2,6-dimethylphenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (13)

[0174]

[0175] The synthesis method is as described in 1, yielding 153 mg of a white solid with a yield of 43%. 1H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.29 (s, 1H), 7.25-7.21 (m, 1H), 7.17 (d, J = 1. 5Hz,1H),7.15(d,J=0.9Hz,1H),4.42(s,2H),4.40(s,2H),2.16(s,3H),2.15(s,3H).ESI-MS:m / z352.08[M+H] + .

[0176] Example 14

[0177] Synthesis of 9-[(2,6-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (14)

[0178]

[0179] The synthesis method is as described in 1, yielding 114 mg of a white solid, with a yield of 19%. 1 H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.41(s,1H),8.04(s,1H),7.51-7.45(m,1H),7.36(s ,1H),7.28(d,J=5.1Hz,1H),7.26(d,J=6.4Hz,1H),4.44(s,2H),4.42(s,2H).ESI-MS:m / z 352.08[M+H] + .

[0180] Example 15

[0181] Synthesis of 9-[(2,4-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (15)

[0182]

[0183] The synthesis method is as described in 1, yielding 155 mg of a white solid with a yield of 44%. 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.38(s,1H),7.98(s,1H),7.53(d,J=6.2Hz,1H), 7.44(d,J=8.5Hz,1H),7.33(s,1H),7.18(s,1H),4.42(s,2H),4.42(s,2H).ESI-MS:m / z 352.08[M+H] + .

[0184] Example 16

[0185] Synthesis of 9-[(2-chloro-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (16)

[0186]

[0187] The synthesis method is as described in 1, yielding 213 mg of a white solid with a yield of 34%. 1 H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 7.51 (d, J = 3.5Hz, 1H), 7.4 8(d,J=4.0Hz,1H),7.43-7.38(m,1H),7.35(s,1H),4.44(s,2H),4.42(s,2H).ESI-MS:m / z 352.08[M+H] + .

[0188] Example 17

[0189] Synthesis of 9-[(2-bromo-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (17)

[0190]

[0191] The synthesis method is as described in 1, yielding 189 mg of a white solid, with a yield of 51%. 1 H NMR (400MHz, DMSO-d6) δ9.49(s,1H),8.36(s,1H),8.05(s,1H),7.62(t,J=9.3Hz,1H),7.45( d,J=11.0Hz,1H),7.39(d,J=11.3Hz,1H),7.34(s,1H),4.43(s,2H),4.41(s,2H).ESI-MS:m / z 352.08[M+H] + .

[0192] Example 18

[0193] Synthesis of 9-[(2,3-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (18)

[0194]

[0195] The synthesis method is as described in 1, yielding 123 mg of a white solid with a yield of 32%. 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.46(s,1H),7.97(s,1H),7.42-7.37(m,1H),7.36(s ,1H),7.27(d,J=5.0Hz,1H),7.23(d,J=4.7Hz,1H),4.44(s,2H),4.42(s,2H).ESI-MS:m / z 352.08[M+H] + .

[0196] Example 19

[0197] Synthesis of 9-[(2-fluoro-3-methylphenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (19)

[0198]

[0199] The synthesis method is as described in 1, yielding 98 mg of a white solid with a yield of 27%. 1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.38(s,1H),7.99(s,1H),7.33(s,1H),7.25(d,J=5.0Hz,1H) ,7.22(d,J=4.7Hz,1H),7.13(t,J=7.7Hz,1H),4.42(s,2H),4.41(s,2H),2.28(s,3H).ESI-MS:m / z 336.11[M+H] + .

[0200] Example 20

[0201] Synthesis of 9-[(3-chloro-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (20)

[0202]

[0203] The synthesis method is as described in 1, yielding 186 mg of a white solid with a yield of 42%. 1 H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.44(s,1H),7.95(s,1H),7.50(s,1H),7.39(d,J=6.8 Hz,1H),7.33(d,J=4.9Hz,1H),7.26(t,J=7.8Hz,1H),4.43(s,2H),4.42(s,2H).ESI-MS:m / z 356.06[M+H] + .

[0204] Example 21

[0205] Synthesis of 9-[(3-bromo-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (21)

[0206]

[0207] The synthesis method is as described in 1, yielding 159 mg of a white solid, with a yield of 44%. 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),9.01(s,1H),8.49(s,1H),7.82(d,J=6.8Hz,1H),7.62 (d,J=7.5Hz,1H),7.60(s,1H),7.30(t,J=8.1Hz,1H),4.51(s,2H),4.46(s,2H).ESI-MS:m / z 401.00[M+H] + .

[0208] Example 22

[0209] Synthesis of 9-[(2-fluoro-4-nitrophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (22)

[0210]

[0211] The synthesis method is as described in 1, yielding 386 mg of the target compound, which is a light yellow crystalline compound, with a yield of 42%. 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.20(d,J=9.9Hz,1H),8.06(d,J=8.6Hz,1H ),7.76(s,1H),7.36(s,1H),7.28(s,1H),4.43(s,2H),4.40(s,2H).ESI-MS:m / z 368.08[M+H] + .

[0212] Example 23

[0213] Synthesis of 9-[(4-amino-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-formonitrile (23)

[0214]

[0215] In a 100 mL round-bottom flask, 9-[(2-fluoro-4-nitrophenyl)amino]-2,3-dihydro-[1,4]dioxane-[2,3-g]quinoline-8-carboxynitrile (22,386 mg, 1.0 mmol), 10% Pb / C (40 mg), and 20 mL of methanol were added. The reaction mixture was stirred continuously at 25 °C for 12 hours, and the reaction progress was monitored in real time using thin-layer chromatography (TLC). After the reaction was completed, the volatile solvent was removed by vacuum distillation to obtain the primary reaction product. The product was separated and purified by silica gel column chromatography (eluent ratio: dichloromethane / methanol 50:1, v / v), and 297 mg of the target compound as a white crystalline powder was finally obtained, with a calculated yield of 88%. 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.25(s,1H),7.98(s,1H),7.27(d,J=15.7Hz,1H),7.00(d,J=9. 0Hz,1H),6.41(s,1H),6.39(s,1H),5.56(s,1H),5.54(s,1H),4.41(s,2H),4.34(s,2H).ESI-MS:m / z 337.11[M+H] + .

[0216] Example 24

[0217] Synthesis of 9-[(3-chloro-2-fluorophenyl)amino]-2-(piperidin-1-ylmethyl)-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile

[0218] Step 1: Synthesize the target product 2-[(2-chloro-5-nitrophenoxy)methyl]ethylene oxide (24-1)

[0219]

[0220] In a 100 mL round-bottom flask, 2-chloro-5-nitrophenol (2 g, 11.5 mmol), epichlorohydrin (2.7 mL, 34.5 mmol), potassium carbonate (4.8 g, 34.5 mmol), and 30 mL LDM were added. The reaction mixture was heated to 80 °C and reacted for 4 hours. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted reaction mixture was transferred to a separatory apparatus, and 400 mL of ethyl acetate was accurately measured for extraction. The combined organic extract layers were collected and washed twice with saturated sodium chloride solution (100 mL × 2). The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a sintered glass funnel to remove solid impurities, and then the solvent was evaporated using a vacuum distillation apparatus to obtain the primary purified product. Purification was carried out using silica gel column chromatography (eluent ratio: petroleum ether / ethyl acetate volume ratio 20:1), and 2.4 g of pale yellow crystalline product was finally obtained, with a calculated yield of 91%. 1 H NMR (400MHz, DMSO-d6) δ7.96(s,1H),7.87(d,J=11.2Hz,1H),7.77(d,J=8.7Hz,1H),4.67(d,J=13.7Hz,1 H),4.11(d,J=18.2Hz,1H),3.44-3.39(m,1H),2.89(d,J=9.4Hz,1H),2.79(d,J=7.7Hz,1H).ESI-MS:m / z 230.02[M+H] + .

[0221] Step 2: Synthesize the target product (6-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol(24-2)

[0222]

[0223] In a 250 mL round-bottom flask, 2-[(2-chloro-5-nitrophenoxy)methyl]ethylene oxide (24-1, 2.4 g, 10.5 mmol), cesium carbonate (6.8 g, 21 mmol), and 60 mL LDM were added. The reaction mixture was heated to 110 °C and reacted overnight. The reaction progress was monitored by TLC. After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted mixture was transferred to a separatory funnel, and 400 mL of ethyl acetate was added for extraction. The combined organic phases were washed twice with saturated NaCl solution (2 × 100 mL). The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a sintered glass funnel, and concentrated by rotary evaporation under reduced pressure to obtain a preliminarily purified product. Fine purification was performed using silica gel column chromatography (eluent ratio: petroleum ether / ethyl acetate volume ratio 10:1), and 1.9 g of pale yellow crystalline product was finally obtained. The product yield was calculated to be 85%. 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=8.9Hz,1H),7.75(s,1H),7.11(d,J=8.9Hz,1H),5.15(d,J=5.6Hz,1H ),4.44(d,J=13.4Hz,1H),4.35(t,J=8.5Hz,1H),4.15-4.09(m,1H),3.68(t,J=5.3Hz,2H).ESI-MS:m / z 212.05[M+H] + .

[0224] Step 3: Synthesize the target product 2-(chloromethyl)-6-nitro-2,3-dihydrobenzo[b][1,4]dioxane(24-3)

[0225]

[0226] (6-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol (24-2) (1.9 g, 9.0 mmol) was dissolved in 30 mL of DMF and added to a 250 mL round-bottom flask. The flask was cooled in an ice-water bath for 10 minutes. Then, thionyl chloride (13 mL, 180 mmol) was dissolved in 10 mL of DMF and slowly added dropwise to the cooled reaction solution. After the addition was complete, the ice-water bath was removed, and the reaction mixture was stirred continuously at 25 °C for 12 hours, during which the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was slowly poured into a container containing crushed ice to achieve cryogenic quenching of thionyl chloride. The pH of the mixture was adjusted to the alkaline range (pH≈9) by adding saturated potassium carbonate aqueous solution, and then 400 mL of ethyl acetate was injected for liquid-liquid extraction. The combined organic extract layers were collected and washed several times (100 mL each time) with saturated sodium chloride solution. The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a Buchner funnel, and then the volatile solvent was removed by vacuum distillation to obtain the primary purified product. Fine purification was then performed using silica gel column chromatography (eluent ratio: petroleum ether / ethyl acetate 15:1, v / v), ultimately yielding 1.4 g of a pale yellow oily product, with a calculated yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ7.80(d,J=6.9Hz,1H),7.75(s,1H),7.16(d,J=8.9Hz,1H),4.65(d,J=5.5Hz ,1H),4.50(d,J=11.7Hz,1H),4.18-4.13(m,1H),4.00(s,1H),3.94(s,1H).ESI-MS:m / z230.02[M+H] + .

[0227] Step 4: Synthesize the target product 1-[(6-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl]piperidine (24-4)

[0228]

[0229] In a 100 mL round-bottom flask, 2-(chloromethyl)-6-nitro-2,3-dihydrobenzo[b][1,4]dioxane (22-3, 1.4 g, 6.1 mmol) and piperidine (15.5 mL, 183 mmol) were added. The reaction mixture was heated to 90 °C and reacted overnight. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted mixture was transferred to a separatory funnel, and extracted with 400 mL of ethyl acetate. The combined organic phases were washed twice with saturated NaCl solution (2 × 100 mL). The dehydrated organic phase was dried with anhydrous sodium sulfate, filtered through a sintered glass funnel, and then the low-boiling solvent was removed by vacuum distillation to obtain a preliminarily purified product. Purification was carried out using silica gel column chromatography (eluent ratio: dichloromethane to methanol, volume ratio 50:1), and 1.2 g of pale yellow oily product was finally obtained. The yield of this separation step was calculated to be 70%. 1 HNMR (400MHz, DMSO-d6) δ7.78(d,J=8.9Hz,1H),7.74(d,J=2.6Hz,1H),7.10(s,1H),4.53(d,J=6.3Hz,1H),4.41(d,J=11.7Hz,1H),4.11-4.0 5(m,1H),2.57(d,J=9.2Hz,2H),2.49-2.44(m,2H),2.44-2.39(m,2H),1.53-1.50(m,2H),1.50-1.47(m,2H),1.41-1.36(m,2H).ESI-MS:m / z 279.13[M+H] + .

[0230] Step 5: Synthesize the target product 2-(piperidin-1-ylmethyl)-2,3-dihydrobenzo[b][1,4]dioxane-6-amine (24-5)

[0231]

[0232] In a 100 mL round-bottom flask, 1-[(6-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl]piperidine (24-4, 1.2 g, 4.3 mmol), 10% Pb / C (120 mg), and 20 mL isopropanol were added. The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a sintered glass funnel to remove the desiccant, and then the volatile solvent was removed by vacuum distillation to obtain a pre-purified product. Purification was performed using silica gel column chromatography (eluent ratio: dichloromethane / methanol 20:1, v / v), ultimately yielding 0.8 g of a white powder. The yield of this separation step was calculated to be 76%. 1 H NMR(400MHz,DMSO-d6)δ6.52(d,J=8.4Hz,1H),6.17(s,1H),6.06(d,J=8.5Hz,1H), 4.59(s,2H),4.19(d,J=11.4Hz,1H),4.12(d,J=8.3Hz,1H),3.88-3.80(m,1H),3.18 (d,J=4.7Hz,1H),2.47(d,J=2.5Hz,1H),2.46-2.45(m,1H),2.45-2.42(m,1H),2.41 -2.30(m,2H),1.52-1.49(m,2H),1.49-1.39(m,2H),1.39-1.22(m,2H).ESI-MS:m / z 249.16[M+H] + .

[0233] Step 6: Synthesize the target product (E)-N-(3-chloro-2-fluorophenyl)-2-cyano-3-[(2-(piperidin-1-ylmethyl)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino]acrylamide (24-6)

[0234]

[0235] In a 100 mL round-bottom flask, 2-(piperidin-1-ylmethyl)-2,3-dihydrobenzo[b][1,4]dioxane-6-amine (24-5, 0.8 g, 3.2 mmol), triethyl orthoformate (0.7 g, 4.8 mmol), and 20 mL of isopropanol were added. The reaction mixture was heated to 95 °C. After half an hour, N-(3-chloro-2-fluorophenyl)-2-cyanoacetamide (0.7 g, 3.2 mmol) was dissolved in 10 mL of isopropanol and slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred overnight. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted mixture was transferred to a separatory funnel, and 400 mL of ethyl acetate was added for extraction. The combined organic phases were washed twice with saturated NaCl solution (2 × 100 mL). The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a sintered glass funnel, and the volatile solvent was removed by vacuum distillation to obtain a preliminarily purified product. Fine purification was then performed using silica gel column chromatography (eluent ratio: dichloromethane to methanol 40:1, v / v), ultimately yielding 0.8 g of a pale yellow oily product. The yield of this separation step was calculated to be 54%. 1 H NMR (400MHz, DMSO-d6) δ11.29-10.37(m,1H),9.49(d,J=14.2Hz,1H),8.34(d,J=13.2Hz,1H),7.64 -7.46(m,1H),7.45-7.29(m,1H),7.28-7.13(m,1H),7.04(d,J=13.2Hz,1H),6.95-6.65(m,2H),4. 32(s,1H),4.30(d,J=1.5Hz,1H),4.10(dd,J=10.4,5.2Hz,1H),3.18(d,J=5.2Hz,2H),2.47(s,2H) ,2.37(d,J=12.0Hz,2H),1.51(s,2H),1.49(s,2H),1.38(d,J=3.7Hz,2H).ESI-MS:m / z471.16[M+H] + .

[0236] Step 7: Synthesize the target product 9-[(3-chloro-2-fluorophenyl)amino]-2-(piperidin-1-ylmethyl)-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (24)

[0237]

[0238] In a 100 mL round-bottom flask, (E)-N-(3-chloro-2-fluorophenyl)-2-cyano-3-[(2-(piperidin-1-ylmethyl)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino]acrylamide (24-6, 0.8 g, 1.7 mmol) and 20 mL acetonitrile were added. The reaction mixture was heated to reflux. After 10 minutes, phosphorus oxychloride (3.1 g, 20.4 mmol) was dissolved in acetonitrile and slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred overnight. The reaction progress was monitored in real time using thin-layer chromatography (TLC). After the reaction was complete, the mixture was allowed to cool naturally to 25 °C, and then the volatile solvent was removed by vacuum distillation. 100 mL of deionized water was added to the product, and the pH of the mixture was adjusted to a weakly alkaline range (pH≈9) using saturated potassium carbonate solution. Liquid-liquid separation was then performed using 400 mL of ethyl acetate as the extraction solvent. After combining the organic extract layers, the mixture was washed several times with saturated sodium chloride solution (2 × 100 mL). The dehydrated organic phase was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration through a Buchner funnel. The solvent was then concentrated under reduced pressure using a rotary evaporator. Finally, fine purification was performed using silica gel column chromatography (eluent: dichloromethane / methanol, volume ratio 20:1), successfully yielding 126 mg of the target compound as white crystalline powder, with a calculated yield of 35%. 1 HNMR(400MHz,DMSO-d6)δ9.60(s,1H),8.44(s,1H),7.99(s,1H),7.49(d,J=10.7Hz,1H), 7.38(d,J=5.8Hz,1H),7.35(s,1H),7.26(t,J=8.0Hz,1H),4.53(d,J=5.7Hz,1H),4.48(d ,J=11.6Hz,1H),4.20-4.14(m,1H),2.60(d,J=5.6Hz,2H),2.49-2.46(m,2H),2.46-2.40 (m,2H),1.52(d,J=4.1Hz,2H),1.50(d,J=2.9Hz,2H),1.39(d,J=4.5Hz,2H).ESI-MS:m / z 453.14[M+H] + .

[0239] Example 25

[0240] Synthesis of 9-[(3-chloro-2-fluorophenyl)amino]-2-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (25)

[0241]

[0242] The synthesis method is as described in 24, yielding 173 mg of a white solid, with a yield of 47%. 1 H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.44(s,1H),8.00(s,1H),7.50(t,J=6.9Hz,1 H),7.37(d,J=12.8Hz,2H),7.26(t,J=8.1Hz,1H),4.54(dd,J=10.9,5.5Hz,1H),4.4 8(dd,J=11.6,2.3Hz,1H),4.17(dd,J=11.6,7.6Hz,1H),2.65(s,1H),2.63(s,1H), 2.51(d,J=1.7Hz,2H),2.50(d,J=1.7Hz,2H),2.33(s,4H),2.16(s,3H).ESI-MS:m / z 468.16 [M+H] + .

[0243] Example 26

[0244] 9-[(3-chloro-2-fluorophenyl)amino]-2-(morpholinomethyl)-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (26)

[0245]

[0246] The synthesis method is as described in 24, yielding 205 mg of a white solid, with a yield of 59%. 1 H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.45(s,1H),8.01(s,1H),7.50(s,1H),7.3 9(d,J=4.6Hz,1H),7.36(d,J=1.9Hz,1H),7.26(t,J=7.8Hz,1H),4.58(d,J=5.3H z,1H),4.50(d,J=11.5Hz,1H),4.22-4.17(m,1H),3.62-3.60(m,2H),3.60-3.58 (m,2H),2.65(d,J=5.7Hz,2H),2.57-2.53(m,2H),2.53-2.52(m,2H).ESI-MS:m / z 455.12[M+H] + .

[0247] Example 27

[0248] Synthesis of 9-[(3-chloro-2-fluorophenyl)amino]-3-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (27)

[0249] Step 1: Synthesize the target product 2-(2-fluoro-4-nitrobenzyl)ethylene oxide (27-1)

[0250]

[0251] In a 100 mL round-bottom flask, 2-fluoro-4-nitrophenol (2 g, 12.7 mmol), epichlorohydrin (3.0 mL, 38.1 mmol), potassium carbonate (5.3 g, 38.1 mmol), and 30 mL LDM were added. The reaction mixture was heated to 70 °C and reacted for 4 hours. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted mixture was transferred to a separatory funnel, and 400 mL of ethyl acetate was added for extraction. The combined organic phases were washed twice with saturated NaCl solution (2 × 100 mL). The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a sintered glass funnel to remove solids, and then the residual solvent was removed by vacuum distillation to obtain the primary purified product. The target compound was separated and purified by silica gel column chromatography (eluent ratio: petroleum ether / ethyl acetate, volume ratio 20:1), and 1.9 g of pale yellow crystalline compound was finally obtained, with a product yield of 76%. 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=11.1Hz,1H),8.13(d,J=6.5Hz,1H),7.43(t,J=8.8Hz,1H),4.63(d,J=11.5Hz,1H) ,4.10(dd,J=11.5,6.7Hz,1H),3.42(d,J=4.3Hz,1H),2.90(t,J=4.7Hz,1H),2.76(dd,J=5.0,2.6Hz,1H).ESI-MS:m / z 198.05[M+H] + .

[0252] Step 2: Synthesize the target product (7-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol (27-2)

[0253]

[0254] In a 250 mL round-bottom flask, 2-(2-fluoro-4-nitrobenzyl)ethylene oxide (25-1, 1.9 g, 9.6 mmol), cesium carbonate (6.3 g, 19.3 mmol), and 60 mL LDM were added. The reaction mixture was heated to 120 °C and reacted overnight. The reaction progress was monitored by TLC. After the reaction was terminated, the mixture was allowed to cool naturally to room temperature (25 °C), and then diluted with 200 mL of saturated sodium chloride solution. The diluted mixture was transferred to a separatory funnel, and 400 mL of ethyl acetate was added for extraction. The combined organic phases were washed twice with saturated NaCl solution (2 × 100 mL). The dehydrated organic phase was dried over anhydrous sodium sulfate, filtered through a sintered glass funnel, and then the volatile solvent was removed by vacuum distillation to obtain the primary purified product. Fine purification was carried out using silica gel column chromatography (eluent ratio: petroleum ether to ethyl acetate, volume ratio 10:1), and 1.3 g of pale yellow crystalline target compound was finally obtained. The yield of this separation step was calculated to be 66%. 1 HNMR (400MHz, DMSO-d6) δ7.81-7.76(m,1H),7.73(dd,J=9.1,2.7Hz,1H),7.12(d,J=8.9Hz,1H),5.16(q,J=5.5Hz,1H ),4.50-4.42(m,1H),4.36-4.26(m,1H),4.20-4.11(m,1H),3.68(d,J=5.1Hz,1H),3.66(d,J=5.3Hz,1H).ESI-MS:m / z 212.05[M+H] + .

[0255] Steps 3-7: Synthesize the target products 2-(chloromethyl)-7-nitro-2,3-dihydrobenzo[b][1,4]dioxane (27-3), 1-methyl-4-((7-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl)piperazine (27-4), 1-methyl-4-((7-amino-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl)piperazine (27-5), ( E)-N-(3-chloro-2-fluorophenyl)-2-cyano-3-((3-((4-methylpiperazin-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)amino)acrylamide (27-6), 9-[(3-chloro-2-fluorophenyl)amino]-3-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxanehexano[2,3-g]quinoline-8-carboxynitrile (27)

[0256]

[0257]

[0258] The synthesis methods for steps 3 to 7 are as described in 24, yielding 79 mg of the target product 27, a white solid, with a yield of 26%. 1 HNMR(400MHz,DMSO-d6)δ9.60(s,1H),8.44(s,1H),8.00(s,1H),7.49(t,J=6.9Hz,1H),7 .38(d,J=7.0Hz,1H),7.35(s,1H),7.26(t,J=8.0Hz,1H),4.54(d,J=5.4Hz,1H),4.48(d, J=11.6Hz,1H),4.17(dd,J=11.4,7.6Hz,1H),2.64(d,J=5.6Hz,2H),2.52(d,J=5.5Hz,2H ),2.50(d,J=7.1Hz,2H),2.37(s,2H),2.32(s,2H),2.16(s,3H).ESI-MS:m / z468.16[M+H] + .

[0259] Compound activity evaluation

[0260] 1. Evaluation of kinase inhibition activity

[0261] The activity of the target compound EGFR kinase (CarnaBiosciences, Japan) was tested using an HTRF kinase assay kit (Cisbio, France). Prior to the kinase activity assay, EGFR... WT The conditions for isokinase activity assays were optimized.

[0262] The activity of inhibitors (8-cyano-9-aniline dioxanequinoline derivatives or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs prepared in Examples 1-27) against kinases was determined.

[0263] Prepare standard kinase buffer solution, 5× kinase solution, 5× ATP solution, 5× TK Substrate-biotin solution (5 μM), 4× TK-Antibody-Cryptate solution, and 4× Streptavidin-XL665 solution.

[0264] The inhibitor was serially diluted three-fold with DMSO solution, and finally diluted with prepared kinase buffer to a DMSO concentration of 2.5%. 4 μL of inhibitor solution was added to each well of a 384 microplate, with two replicates for each concentration. For the negative control wells (100% inhibition), no 4 μL of inhibitor solution or 2 μL of kinase solution was added; instead, 4 μL of 2.5% DMSO kinase buffer and 2 μL of kinase buffer were used as controls, with other conditions the same as the experimental wells. For the positive control wells (0% inhibition), no 4 μL of inhibitor solution was added; instead, 4 μL of 2.5% DMSO kinase buffer was used as a control; with other conditions the same as the experimental wells. Add 2 μL of kinase solution, 2 μL of substrate solution, and 2 μL of ATP solution sequentially to each well. Centrifuge at 800 rpm for 1 minute and incubate at 37°C for an appropriate time. After incubation, add 5 μL of Streptavidin-XL665 solution and 5 μL of TK-Antibody-Cryptate solution to terminate the reaction. Centrifuge again at 800 rpm for 1 minute and incubate at 37°C. After incubation, use a microplate reader (TECAN, M1000PRO) with an excitation wavelength of 317 nm to detect the fluorescence intensity at 665 nm and 620 nm wavelengths. Calculate the signal-to-light ratio (665 nm fluorescence intensity / 620 nm fluorescence intensity). Analyze and process the data to calculate the kinase activity inhibition rate of the test compound. The results are shown in Table 1.

[0265] 2. Evaluation of in vitro cell viability

[0266] The cell lines used in this invention include human glioblastoma cells U87MG, U251, and T98G, and murine glioblastoma cells GL261. U87MG and U251 cell lines were purchased from ATCC (American Type Culture Collection). The U87MG-EGFRvⅢ cell line was constructed by transfecting U87MG cells with an EGFRvⅢ mutant, and was kindly provided by Professor Zhang Xingmei of the School of Basic Medical Sciences, Southern Medical University. The U87MG-EGFRvⅢ-Luc cell line is a tool cell line carrying fluorescent markers constructed in our laboratory based on U87MG-EGFRvⅢ cells.

[0267] Experimental steps:

[0268] Weigh out the target compound and positive control drug from Examples 1-27, Gefitinib, Erlotinib, and JCN037 respectively, and dissolve them in DMSO to prepare a 20 mM stock solution, which is then stored at -20°C. Before use, dilute 3-fold with DMSO in a serial gradient, for a total of 10 dilutions.

[0269] Collect cells in the logarithmic growth phase, adjust the cell suspension concentration to 23,000 cells / mL, and add 100 μL of cell suspension (2,300 cells per well) to each well of a 96-well plate. Set up 3 replicates and control wells. Incubate the cells in an incubator, and administer the drug the day after cell adhesion.

[0270] Cells in 96-well plates were treated with the compound and cultured at 37°C and 5% CO2 for 72 hours. Then, 10 μL of MTT solution (5 mg / mL) was added to each well, and the same culture environment was maintained for another 4 hours. After terminating the culture, the culture medium and MTT solution were removed from each well, and 100 μL of dimethyl sulfoxide (DMSO) was added to each well. The plates were shaken at 300 rpm for 10 minutes to ensure complete dissolution of the formazan crystals. The absorbance (OD value) of each well was measured at 570 nm using a full-wavelength microplate reader. The cell proliferation inhibition rate was calculated using the formula: Inhibition rate (%) = [(OD value of experimental group - OD value of blank group) / (OD value of control group - OD value of blank group)] × 100%. Data analysis was performed using GraphPadPrism software. The results are shown in Tables 1 and 2.

[0271] Table 1. Effects of the target compounds on EGFR WT kinase and GBM cell inhibitory activity

[0272]

[0273]

[0274] a represents the percentage (%) of kinase activity inhibition at 1 μM, the average of at least two measurements.

[0275] b represents the half-concentration (IC50) at which the target compound inhibits cell proliferation. 50 ( ), the average of at least two measurements.

[0276] Table 2. Inhibitory activity of target compounds 19–21 against glioblastoma cells.

[0277]

[0278] 'a' represents the half-concentration (IC50) at which the target compound inhibits cell proliferation. 50 ( ), the average of at least two measurements.

[0279] b indicates that no measurement was performed.

[0280] Table 1 shows that most compounds exhibited superior inhibitory activity against U87MG and U87MG-EGFRvIII cells compared to the positive controls Gefitinib and Erlotinib, with compounds 19, 20, and 21 showing the best inhibitory activity against GBM cells. Table 2 further indicates that compounds 19, 20, and 21, with the best activity, demonstrated strong inhibitory activity against several other GBM cell lines (U251, T98G, and GL261), showing superior activity compared to the positive control Gefitinib.

[0281] 3. In vivo activity evaluation

[0282] Male nude mice weighing approximately 25g were purchased and acclimatized for 7 days. An orthotopic glioblastoma model was constructed using U87MG-EGFRvⅢ-Luc cells. Cells in the logarithmic growth phase were harvested and diluted to 1×10⁻⁶ with sterile PBS. 7 A cell suspension of 5 μL / μL was injected into the hippocampus of nude mice to induce tumor formation.

[0283] Three days after inoculation, in vivo chemiluminescence imaging was performed. Nude mice were anesthetized with isoflurane gas for 5 minutes after intraperitoneal injection of 150 mg / kg of D-fluorescein sodium, followed by imaging in a darkroom using an in vivo imaging system. Fluorescence intensity was analyzed using Bruker MISE software, and mice were uniformly grouped according to tumor fluorescence intensity: Control group (injected with sterile PBS), low-dose compound 20 group (25 mg / kg), high-dose compound 20 group (50 mg / kg), and temozolomide (TMZ) group (25 mg / kg).

[0284] Drug administration began on the day of imaging (Day 0), with daily weighing and dosage calculations, and continued gavage for two weeks. In vivo imaging was performed on days 9 and 13 of administration, and intracranial tumor size was assessed by fluorescence intensity. After drug administration was discontinued, the survival time of nude mice was recorded, and tumor inhibition rate, experimental nude mouse survival rate, and survival time were calculated.

[0285] TGI calculation formula:

[0286] TGI = [1-(L TreatmentFinalDay -L PertreatmentDay ) / (L ControlFinalDay -L ControlpertreatmentDay )]×100%

[0287] L is an abbreviation for Luminescence.

[0288] The tumor growth inhibition rate (TGI) was calculated using the formula, and the tumor inhibition rates of the low-dose and high-dose groups of target compound 20 were 92.5% and 103.9%, respectively, while the TMZ positive control group showed 101.4%. These results indicate that compound 20, at a high dose, has a slightly better inhibitory effect on tumors than TMZ and can significantly promote tumor regression. The difference in the high-dose group of compound 20 compared to the control group was statistically significant (P<0.01). The results are as follows... Figure 1 As shown.

[0289] Figure 1 The effect of target compound 20 on the growth of GBM tumors in nude mice in an intracranial orthotopic transplantation model using U87MG-EGFRvⅢ-Luc cells was investigated. Figures (A) and (B) show the bar and line graphs, respectively, of the fluorescence signal intensity of U87MG-EGFRvⅢ-Luc cell xenografts in nude mice over time, representing the changes in mouse body weight over time. Figure (C) shows the mouse survival curve. All p-values ​​were compared with the control group (n=5), with p<0.05 for * and p<0.01 for **. Figures (A) and (B) show that compound 20 significantly inhibited the fluorescence signal intensity of intracranial xenografts in nude mice and significantly inhibited their proliferation. Figures (C) and (D) show that there was no significant decrease in mouse body weight after administration, and compound 20 significantly prolonged the median survival time of mice.

[0290] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. An 8-cyano-9-aniline dioxanequinoline derivative or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug thereof, characterized in that, The 8-cyano-9-aniline dioxanequinoline derivative is a compound having the structure shown in general formula I. In the formula, R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkylester, and C1-C6 alkylcarboxyl. R3 and R4 are independently selected from hydrogen, hydroxyl, amino, carboxyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkylester, C1-C6 alkylcarboxyl or selected from the following structures (where n = 1-6):

2. The 8-cyano-9-aniline dioxanequinoline derivative or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug according to claim 1, characterized in that, The 8-cyano-9-aniline dioxanequinoline derivative is selected from one or more of the following compounds: 9-(phenylamino)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(4-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-chlorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2-bromophenyl)amino] -2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-(o-tolylamino)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(2-fluoro-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(3-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-fluoro-2-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(2-chloro-6- [(2-bromo-6-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-dimethylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-dimethylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,6-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,4-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(2,4-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon 9-[(2-chloro-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2-bromo-6-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2,3-difluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(2-fluoro-3-methylphenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile, 9-[(3-chloro-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylonitrile,3-g]quinoline-8-carboxynitrile, 9-[(3-bromo-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-amino-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(4-nitro-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxynitrile, 9-[(3-chloro-2-fluorophenyl)amino]-2-(piperidin-1-ylmethyl) ... [Phenyl)amino]-2-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-chloro-2-fluorophenyl)amino]-2-(morpholinemethyl)-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(3-chloro-2-fluorophenyl)amino]-3-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon, 9-[(4-amino-2-fluorophenyl)amino]-2,3-dihydro-[1,4]dioxane-hexano[2,3-g]quinoline-8-carboxylon.

3. A method for preparing the 8-cyano-9-aniline dioxanequinoline derivative according to any one of claims 1-2, characterized in that, Includes one of the following methods: Method 1 Reaction conditions and reagents: (a) N,N-dimethylformamide, 175℃, 6-10h; (b) tetrahydrofuran, n-butyllithium, -60℃ to -80℃, 1-3h; (c) phosphorus oxychloride, 90℃ to 110℃, 2-4h; (d) N,N-dimethylformamide, sodium hydride, 170℃, 1-2h; (e) pyridine hydrochloride, 220℃, 0.5-1h; (f) N,N-dimethylformamide, potassium carbonate, 90℃ to -110℃, 1-3h. Method 2 Reaction conditions and reagents: (g) N,N-dimethylformamide, potassium carbonate, 50℃~80℃, 4~8h; (h) N,N-dimethylformamide, cesium carbonate, 100℃~130℃, 4~8h; (i) N,N-dimethylformamide, dimethyl sulfoxide, room temperature, overnight; (j) different basic hydrophilic groups, 80℃~110℃, overnight; (k) Pb / C, isopropanol, room temperature, overnight; (m) isopropanol, 95℃, overnight; (n) phosphorus oxychloride, acetonitrile, 100℃, overnight; Method 3 Reaction conditions and reagents: (o) N,N-dimethylformamide, potassium carbonate, 50℃~80℃, 4~8h; (p) N,N-dimethylformamide, cesium carbonate, 100℃~130℃, 4~8h; (q) N,N-dimethylformamide, dimethyl sulfoxide, room temperature, overnight; (r) different basic hydrophilic groups, 80℃~110℃, overnight; (s) Pb / C, isopropanol, room temperature, overnight; (t) tetrahydrofuran, 75℃, 2~4h; (u) isopropanol, 95℃, overnight; (v) phosphorus oxychloride, acetonitrile, 100℃, overnight.

4. The use of an 8-cyano-9-aniline dioxanequinoline derivative or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug as described in any one of claims 1-2 in the preparation of an epidermal growth factor receptor inhibitor drug.

5. The application according to claim 4, characterized in that, The epidermal growth factor receptor is an amplified EGFR and / or an EGFRvIII mutated epidermal growth factor receptor.

6. The use of an 8-cyano-9-aniline dioxanequinoline derivative or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug as described in any one of claims 1-2 in the preparation of a medicament for treating and / or preventing and / or delaying and / or adjuvant treatment and / or managing glioma, a neurological tumor disease mediated by epidermal growth factor receptor EGFR amplification and / or EGFRvIII mutation.

7. The use of an 8-cyano-9-aniline dioxanequinoline derivative or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, stereoisomer, or prodrug as described in any one of claims 1-2 in the preparation of an antitumor drug.

8. A pharmaceutical composition, characterized in that, Includes active ingredients and pharmaceutical excipients, wherein the active ingredient is selected from at least one of a) to i): a) 8-cyano-9-aniline dioxanequinoline derivatives; b) Pharmaceutically acceptable salts of the 8-cyano-9-aniline dioxanequinoline derivative; c) The hydrate of the 8-cyano-9-aniline dioxanequinoline derivative; d) The solvate of the 8-cyano-9-aniline dioxanequinoline derivative; e) The polymorphs of the 8-cyano-9-aniline dioxanequinoline derivative; f) Tautomers of the 8-cyano-9-aniline dioxanequinoline derivative; g) Stereomers of the 8-cyano-9-aniline dioxanequinoline derivative; h) the prodrug of the 8-cyano-9-aniline dioxanequinoline derivative; i) Isotopic derivatives of the 8-cyano-9-aniline dioxanequinoline derivative; Wherein, the 8-cyano-9-aniline dioxanequinoline derivative is the 8-cyano-9-aniline dioxanequinoline derivative according to any one of claims 1-2.

9. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical excipients include at least one of the following substances: solvents, propellants, solubilizers, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculation agents, filter aids, and release inhibitors.

10. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical composition can be formulated into various dosage forms: classified according to the dispersion system of the dosage form: the dosage forms include: solution type, colloidal solution type, emulsion type, suspension type, gas dispersion type, particulate dispersion type, and solid dispersion type; classified according to the form: the dosage forms include: liquid dosage forms, gas dosage forms, solid dosage forms, and semi-solid dosage forms; classified according to the route of administration: the dosage forms include: dosage forms administered via the gastrointestinal tract and dosage forms administered without the gastrointestinal tract.

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