A quinazoline compound containing a urea structure and application thereof

Abstract

The application discloses a quinazoline compound containing a urea structure and an application thereof, and relates to the technical field of medicines. The application provides a quinazoline compound containing a urea structure. The compound with the general structure has strong inhibiting ability on EGFR and c-Met kinases, and therefore can be used as an active ingredient to prepare a therapeutic drug for diseases caused by abnormal activation of EGFR and / or c-Met kinases, and also shows potential application value in preparation of a drug for treating and / or preventing proliferative diseases and cancers. The application provides important technical support for development of an anticancer drug with high efficiency and better selectivity.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a urea-containing quinazoline compound and its applications. Background Technology

[0002] Non-small-cell lung cancer (NSCLC) is synonymous with "non-small cell carcinoma." NSCLC includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Compared to small cell carcinoma, its cancer cells grow and divide more slowly, and metastasize relatively late. NSCLC accounts for approximately 80-85% of all lung cancers. With advancements in molecular medicine and the emergence of targeted therapies, the treatment of advanced NSCLC has entered the era of personalized medicine. Currently, clinically applied personalized targeted therapies mainly target EGFR-mutant and ALK (Anaplastic ymphomakinase) fusion gene lung cancers. Both of these gene mutation types of lung cancer have clearly defined molecular targets, target detection technologies, and marketed targeted drugs, resulting in significantly improved clinical efficacy.

[0003] Epidermal growth factor receptor (EGFR) is a cell surface receptor for EGF family ligands and a member of the ErbB family of tyrosine kinases. The ErbB family of receptor tyrosine kinases (RTKs) includes four distinct receptors: EGFR (also known as ErbB-1 / HER1), ErbB-2 (neu, HER2), ErbB-3 (HER3), and ErbB-4 (HER4). All ErbB family receptors possess an extracellular ligand-binding domain, a single hydrophobic transmembrane domain, and a cytoplasmic domain containing the tyrosine kinase. In the presence of a ligand, the conformation of a single EGFR receptor changes, forming a dimer by pairing two receptors. The dimer in the extracellular ligand-binding domain then undergoes cross-linking phosphorylation, activating the cytoplasmic domain containing the tyrosine kinase. Subsequently, one molecule of adenosine triphosphate (ATP) randomly binds to this region, phosphorylating a tyrosine residue at the end of the C-terminal domain. The tyrosine residue at the end of the C-terminal domain then recruits substrate proteins (such as Gab1, Crk, and Grb2) and provides them with docking sites. Signaling at juxtamembranous sites regulates gene expression and the cell cycle within the cell nucleus through a cascade of substrate proteins. Currently, two common signaling pathways are the Ras / ERK pathway and the PI3K / mTOR pathway; the former primarily controls cell growth and differentiation, while the latter regulates apoptosis. In various cancer cells, including NSCLC cells, continuous activation of the EGFR-mediated signaling pathway has been detected, leading to continuous proliferation and activation of cancer cells, as well as continuous tumor growth and spread.

[0004] c-Met is a member of another small subfamily of RTKs (which also includes Ron and Sea) and is a receptor for hepatocyte growth factor (HGF / SF). c-Met is a heterodimer (composed of 1390 AARs) linked by extracellular disulfide bonds to disulfide bonds on a transmembrane structure, with a total molecular weight of 195 kDa. c-Met shares the same structural features as other RTKs, possessing an extracellular ligand-binding domain, a single hydrophobic transmembrane domain, and a cytoplasmic domain containing a tyrosine kinase. The c-Met extracellular ligand-binding domain consists of three parts: a semaphorin domain, a plexins-semaphorins-integrins domain, and an immunoglobulin-plexin-transcription domain; the hydrophobic transmembrane domain is a single structure with a Tyr1003 phosphorylation site; and the cytoplasmic domain of the tyrosine kinase consists of a kinase domain and a multifunctional docking site region. Tyr-1234 and Tyr-1235 are key AARs responsible for phosphorylation within the kinase domain, positively regulating c-Met kinase activity. Tyr-1349 and Tyr-1356 are signal-to-energy converters in the multifunctional docking site region. Phosphorylation of AARs in the multifunctional docking site region recruits various substrate proteins (such as Gab1 and Grb2). Phosphorylation of these substrate proteins leads to the activation of intracellular signal transduction pathways. For example, activated Gab1 protein continues to become a binding site for downstream proteins, thereby activating pathways such as PI3K / Akt, Ras / MAPK, and IKK / NFκ-B to regulate gene expression and cell cycle in the cell nucleus.

[0005] Studies have shown that both EGFR and c-Met receptors on cells can regulate cell growth, differentiation, and apoptosis by mediating the same Ras / ERK or PI3K / mTOR signaling pathway. When EGFR is inhibited, the c-Met receptor can bypass the phosphorylation process at the end of the C-terminal domain of EGFR through its own phosphorylation, directly activating the PI3K / mTOR signaling pathway.

[0006] Therefore, in the clinical treatment of EGFR-mediated diseases, besides the common drug resistance mutations of EGFR itself, c-Met amplification-induced EGFR mutations are also quite common. Thus, developing safer and more effective novel EGFR / c-Met dual-target inhibitors for cancer treatment has significant social and economic value and is currently a research hotspot for major pharmaceutical companies. Designing new compound structures by modifying their structures to improve drug resistance and drugability, thereby enhancing bioactivity and bioavailability, is crucial for finding a new class of EGFR / c-Met inhibitors and is of great significance for the clinical treatment of diseases caused by EGFR / c-Met mutations. Currently marketed EGFR or c-Met inhibitors typically target only one target and still require improvement. Summary of the Invention

[0007] The purpose of this invention is to provide a urea-containing quinazoline compound and its application, in order to solve the problems existing in the prior art.

[0008] To achieve the above objectives, the present invention provides the following solution:

[0009] One objective of this invention is to provide a quinazoline compound containing a urea structure, which has the structure shown in general formula I:

[0010]

[0011] Z is selected from One of them;

[0012] R1 is selected from One of them;

[0013] R2 is selected from One of them.

[0014] Furthermore, the quinazoline compounds containing urea structures include the following compounds:

[0015] [1]N-(4-((6-(3-butylureo)-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiridine-3-carboxamide;

[0016] [2] Ethyl((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)carbamoyl)glycine ester;

[0017] [3] 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0018] [4]N-(4-((6-(3-butylureo)-7-isopropoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidin-3-carboxamide;

[0019] [5] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)carbamoyl)glycine ester;

[0020] [6] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)ureo)ethyl methacrylate;

[0021] [7]N-(4-((7-butoxy-6-(3-butylureo)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiridine-3-carboxamide;

[0022] [8] Ethyl((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)formyl)glycine ester;

[0023] [9] 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0024]

[10] N-(4-((6-(3-butylureo)-7-(pentoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiridine-3-carboxamide;

[0025]

[11] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)carbamoyl)glycine ester;

[0026]

[12] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0027]

[13] N-(4-((6-(3-butylurea)-7-(3-methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiridine-3-carboxamide;

[0028]

[14] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycine ester;

[0029]

[15] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0030]

[16] N-(4-((6-(3-butylurea)-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide;

[0031]

[17] Ethyl((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)formamido)glycine ester;

[0032]

[18] 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0033]

[19] N-(4-((6-(3-butylureo)-7-isopropoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide;

[0034]

[20] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)formamido)glycine ester;

[0035]

[21] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)ureo)ethyl methacrylate;

[0036]

[22] N-(4-((7-butoxy-6-(3-butylureo)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide;

[0037]

[23] Ethyl((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)formyl)glycine ester;

[0038]

[24] 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0039]

[25] N-(4-((6-(3-butylurea)-7-(pentoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide;

[0040]

[26] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)formamido)glycine ester;

[0041]

[27] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0042]

[28] N-(4-((6-(3-butylurea)-7-(3-methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide;

[0043]

[29] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycine ester;

[0044]

[30] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0045]

[31] N-(4-((6-(3-butylurea)-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamide;

[0046]

[32] Ethyl((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)carbamoyl)glycine ester;

[0047]

[33] 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0048]

[34] N-(4-((6-(3-butylurea)-7-isopropoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide;

[0049]

[35] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)formamido)glycine ester;

[0050]

[36] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)ureo)ethyl methacrylate;

[0051]

[37] N-(4-((7-butoxy-6-(3-butylureo)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamide;

[0052]

[38] Ethyl((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)formyl)glycine ester;

[0053]

[39] 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0054]

[40] N-(4-((6-(3-butylurea)-7-(pentoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamide;

[0055]

[41] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)formamido)glycine ester;

[0056]

[42] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)ureo)ethyl methacrylate;

[0057]

[43] N-(4-((6-(3-butylurea)-7-(3-methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamide;

[0058]

[44] Ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycine ester;

[0059]

[45] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)ureo)ethyl methacrylate.

[0060] A second objective of this invention is to provide a pharmaceutical composition using the aforementioned quinazoline compounds containing a urea structure as the active ingredient.

[0061] The pharmaceutical composition of the present invention also includes pharmaceutically acceptable excipients.

[0062] The third technical solution of the present invention is to provide the application of the above-mentioned urea-containing quinazoline compounds or pharmaceutical compositions in the preparation of EGFR and / or c-Met antitumor inhibitors.

[0063] The fourth technical solution of the present invention is to provide the application of the above-mentioned urea-containing quinazoline compounds or pharmaceutical compositions in the preparation of EGFR and c-Met dual-target antitumor inhibitors.

[0064] The fifth technical solution of the present invention is to provide the use of the above-mentioned urea-containing quinazoline compounds or pharmaceutical compositions in the preparation of medicaments for treating and / or preventing proliferative diseases and cancer.

[0065] Furthermore, the cancers mentioned include lung cancer, liver cancer, stomach cancer, colon cancer, or breast cancer.

[0066] This invention relates to the preparation of compositions by mixing urea-containing quinazoline compounds having the structure of Formula I with pharmaceutically acceptable excipients, and to the formulation of clinically acceptable pharmaceutical dosage forms. Pharmaceutically acceptable excipients refer to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The derivatives of this invention can be used in combination with other active ingredients.

[0067] The clinical dosage of the urea-containing quinazoline compound of Formula I described above can be appropriately adjusted for patients based on the therapeutic efficacy and bioavailability of the active ingredient in vivo, its metabolism and excretion rate, as well as the patient's age, sex, and disease stage. The daily dose for adults should generally be 10–500 mg, preferably 50–300 mg. Under the guidance of a doctor or pharmacist, the pharmaceutical preparation of this invention can be administered in several divided doses at certain intervals (preferably 1 to 6 times).

[0068] The pharmaceutical compositions of the present invention can be formulated into several dosage forms, wherein they contain some commonly used excipients in the pharmaceutical field.

[0069] The dosage forms described above can be injections, tablets, capsules, aerosols, suppositories, films, pellets, topical dressings, ointments, etc. The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, preservatives, solvents, and matrices. The pharmaceutical formulations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0070] The present invention discloses the following technical effects:

[0071] This invention provides a quinazoline compound containing a urea structure. This compound has a strong ability to inhibit EGFR and c-Met kinases, and therefore can be used as an active ingredient in the preparation of therapeutic drugs for diseases caused by abnormal activation of EGFR and / or c-Met kinases. It also shows potential application value in the preparation of drugs for the treatment and / or prevention of proliferative diseases and cancer.

[0072] This invention provides important technical support for the development of more efficient and selective anticancer drugs. Detailed Implementation

[0073] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0074] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0075] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0076] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0077] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0078] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0079] The raw materials and intermediates used in this invention are prepared by the methods described in the synthetic route or by methods well known to those skilled in the art of organic chemistry, and are also commercially available.

[0080] All urea-containing quinazoline compounds of this invention were prepared by the methods described in the synthetic routes or by similar methods, which are well known to those skilled in the art of organic chemistry. All variable factors used in the synthetic routes are defined below.

[0081] The general formula of the urea-containing quinazoline compounds of this invention is shown in Formula I:

[0082]

[0083] Z, R1, and R2 are defined as above, that is: Z is selected from... One of them;

[0084] R1 is selected from One of them;

[0085] R2 is selected from One of them.

[0086] The urea-containing quinazoline compounds of Formula I of this invention can be prepared by methods 1, 2, or 3:

[0087] Route 1:

[0088]

[0089] Route 2:

[0090]

[0091] Route 3:

[0092]

[0093] In the above three routes of the present invention, the substituents R1 and R2 in the compound structure have the same definition as the substituents R1 and R2 in the compound with the same formula I structure.

[0094] The present invention will be described in more detail below with reference to embodiments:

[0095] In the embodiments of the present invention, the proton NMR spectra of the compounds were measured using a Bruker ARX-400, and the mass spectra were measured using an Agilent 1100 LC / MSD; all reagents used were analytical grade or chemically pure.

[0096] The structural formulas of the compounds prepared in Examples 1-45 of this invention are shown in Table 1.

[0097] Table 1

[0098]

[0099]

[0100] Example 1

[0101] Preparation of N-(4-((6-(3-butylurea)-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide:

[0102] Step 1: Preparation of 7-ethoxy-6-nitroquinazoline-4-ol (2):

[0103]

[0104] 2.68 g of NaOH was added to 100 mL of anhydrous ethanol solution and placed in a 250 mL round-bottom flask. The flask was then placed in an oil bath and heated to 70 °C. 2 g of the starting material 7-fluoro-6-nitroquinazoline-4(3H)-one (1) was added and stirred. After 2 hours of reaction, a yellow solid precipitated, confirming the complete reaction. The reaction solution was then poured into a 300 mL mixture of ice and water and stirred at room temperature. The pH of the reaction solution was adjusted to 2 with 37% hydrochloric acid, resulting in the precipitation of a white solid. After complete precipitation, the product was filtered and dried to obtain compound 2.

[0105] Step 2: Preparation of 4-chloro-7-ethoxy-6-nitroquinazoline (3):

[0106]

[0107] 2g of compound 2 was added to a 500mL round-bottom flask, along with 250mL of thionyl chloride and three drops of DMF. The reaction vessel was placed in an oil bath and heated to 90°C, and the reaction was carried out for five hours. After the reaction was completed, excess thionyl chloride was distilled off under reduced pressure. Then, 100mL of ethyl acetate was added to the reaction vessel, dissolved, and distilled off under reduced pressure. This process was repeated three times. Finally, the mixture was washed with ice water and filtered to obtain compound 3.

[0108] Step 3: Preparation of 4-((7-ethoxy-6-nitroquinazolin-4-yl)oxy)-3-fluoroaniline (4):

[0109]

[0110] 3.0 g of compound 3 was placed in a 100 mL round-bottom flask, a small amount of THF was added, followed by a large amount of 1,4-Dio, and the flask was placed in a refrigerator. 4-Amino-2-fluorophenol was dissolved in THF and stirred under nitrogen protection in an ice bath. Potassium tert-butoxide was then added in portions (do not shake, as it easily sticks to the walls), and the mixture was stirred for 1 h. Then, the compound 3 system was added dropwise to the 4-amino-2-fluorophenol reaction system, and the reaction was carried out under nitrogen vacuum for 2.5 h. After the reaction was complete, an equal volume of DCM was added to the system while stirring. The mixture was then filtered, and the filtrate was collected and evaporated to dryness. DCM was added to dissolve the filtrate (resin), and the mixture was extracted twice with dilute NaOH aqueous solution and DCM, followed by double-extraction under reduced pressure. The organic phase was distilled off under reduced pressure. The product was carried down with isopropanol and then recrystallized from n-hexane to give a yellow solid.

[0111] Step 4: Preparation of N-(4-((7-ethoxy-6-nitroquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamide (5):

[0112]

[0113] Compound 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid was dissolved in ultra-dry DCM, and 2dDMF was added with stirring. Oxaloyl chloride dissolved in DMC was then added dropwise to the system, and the mixture was stirred at room temperature for 0.5 hours. Compound 4 and NaHCO3 were dissolved in ultra-dry DCM, and the mixture was stirred. The mixture of compound 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid was then added dropwise to the mixture of compound 4, and the mixture was stirred at room temperature for three hours. The reaction was monitored by TLC. After the reaction was completed, the mixture was distilled under reduced pressure, a small amount of ethanol was added, and the mixture was sonicated. A large amount of the precipitated solid was then added.

[0114] Step 5: Preparation of N-(4-((6-amino-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamide (6):

[0115]

[0116] First, Fe was dissolved in ethanol, and ammonium chloride was completely dissolved in water. These solutions were then added to the Fe system and refluxed at 90°C for 1 hour. Next, compound 5 was dissolved in ethanol and added to the Fe system, refluxed at 90°C for 2 hours. After the reaction was complete, an equal volume of methanol was added to the reaction solution, and the mixture was filtered while hot through a Buchner funnel lined with diatomaceous earth. The filtrate was then distilled under reduced pressure, and the products were separated by column chromatography using DCM / CH3OH (v / v, from 300:1 to 70:1) as the eluent to obtain compound 6.

[0117] Step Six: Preparation of N-(4-((6-(3-butylurea)-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide:

[0118]

[0119] Weigh 0.1 g of compound 6, add an appropriate amount of DCM solution and 1 ml of isocyanate n-butyl ester, and stir at room temperature. After the reaction is complete, distill under reduced pressure to obtain the crude product. The crude product is purified by column chromatography using DCM / CH3OH (v / v, from 300:1 to 50:1) as the eluent to obtain the final compound.

[0120] ESI-MS / (m / z): 516.2433(M+H) +1 ;H NMR (400MHz, DMSO-d6) δ10.63(s,1H),9.04(s,1H),8.50(s,1H),8.27(s,1H),7.84(d,J=1 2.8Hz,1H),7.77-7.66(m,2H),7.53-7.34(m,3H),7.34-7.19(m,3H),4.37(q,J=7.0Hz,2H ),3.92(h,J=7.0,6.3Hz,2H),3.79(t,J=8.7Hz,1H),3.13(q,J=6.5Hz,2H),2.42(dd,J=25 .3,8.1Hz,2H),1.48(dt,J=22.8,7.2Hz,5H),1.34(h,J=7.2Hz,2H),0.91(t,J=7.3Hz,3H). 13C NMR(151MHz,DMSO-d6)δ170.72,168.57,164.72,155.35,153.52,152.25,148.82,138.14,135.99,132.05,124.96,122.25,122.19,115 .99,115.97,115.95,115.80,109.81,108.06,107.91,107.39,106.55,65.40,51.48,47.49,39.10,32.14,21.81,20.05,14.79,14.13.

[0121] Example 2

[0122] Preparation of ethyl ((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)carbamoyl)glycine ester:

[0123] Following the method of Example 1, step six simply involves replacing n-butyl isocyanate with ethyl isocyanate.

[0124] Example 3

[0125] Preparation of 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0126] Following the method of Example 1, step six can be achieved by replacing n-butyl isocyanate with ethyl isocyanate methacrylate.

[0127] Example 4

[0128] Preparation of N-(4-((6-(3-butylurea)-7-isopropoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide:

[0129] The method of Example 1 can be followed by replacing ethanol in step 1 with isopropanol.

[0130] Example 5

[0131] Preparation of ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)carbamoyl)glycine ester:

[0132] Following the method in Example 4, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0133] Example 6

[0134] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)ureo)ethyl methacrylate:

[0135] Following the method of Example 4, the isocyanobutyl ester in step six was replaced with isocyanoethyl methacrylate.

[0136] Example 7

[0137] Preparation of N-(4-((7-butoxy-6-(3-butylureo)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide:

[0138] The method in Example 1 can be followed by replacing ethanol in step 1 with n-butanol.

[0139] Example 8

[0140] Preparation of ethyl ((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)formyl)glycine ester:

[0141] Following the method of Example 7, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0142] Example 9

[0143] Preparation of 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0144] Following the method of Example 7, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0145] Example 10

[0146] Preparation of N-(4-((6-(3-butylurea)-7-(pentoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide:

[0147] The method in Example 1 can be followed by replacing ethanol in step 1 with n-pentanol.

[0148] Example 11

[0149] Preparation of ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)carbamoyl)glycine ester:

[0150] Following the method of Example 10, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0151] Example 12

[0152] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0153] Following the method of Example 10, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0154] Example 13

[0155] Preparation of N-(4-((6-(3-butylurea)-7-(3-methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide:

[0156] The method of Example 1 can be followed by replacing the ethanol in step 1 with 3-methoxyprop-1-ol.

[0157] Example 14

[0158] Preparation of ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycine ester:

[0159] Following the method of Example 13, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0160] Example 15

[0161] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0162] Following the method of Example 13, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0163] Example 16

[0164] Preparation of N-(4-((6-(3-butylurea)-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide:

[0165] Following the method in Example 1, simply replace 1-(4-fluorophenyl)-2-oxo-3-pyrrolidone-4-carboxylic acid with 1-(4-fluorophenyl)-1H-imidazol-4-carboxylic acid.

[0166] Example 17

[0167] Preparation of ethyl ((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)formamido)glycine ester:

[0168] Following the method of Example 16, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0169] Example 18

[0170] Preparation of 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0171] Following the method of Example 16, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0172] Example 19

[0173] Preparation of N-(4-((6-(3-butylurea)-7-isopropoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide:

[0174] The method described in Example 16 can be followed by replacing ethanol with isopropanol.

[0175] Example 20

[0176] Preparation method of ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)formamido)glycine ester:

[0177] Following the method of Example 19, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0178] Example 21

[0179] Preparation of N-(4-((2-((5-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)amino)-7,8-dihydro-5H-thiaro[4,3-d]pyrimidin-4-yl)amino)phenyl)acetamide:

[0180] Following the method of Example 19, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0181] Example 22

[0182] Preparation of N-(4-((7-butoxy-6-(3-butylureo)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide:

[0183] The method described in Example 16 can be followed by replacing ethanol with n-butanol.

[0184] Example 23

[0185] Preparation of ethyl ((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)formyl)glycine ester:

[0186] Following the method of Example 22, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0187] Example 24

[0188] Preparation of 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0189] Following the method of Example 22, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0190] Example 25

[0191] Preparation of N-(4-((6-(3-butylurea)-7-(pentoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide:

[0192] Following the method of Example 16, simply replace the ethanol in step one with n-pentanol.

[0193] Example 26

[0194] Preparation of ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)formamido)glycine ester:

[0195] Following the method of Example 25, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0196] Example 27

[0197] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0198] Following the method of Example 25, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0199] Example 28

[0200] Preparation of N-(4-((6-(3-butylurea)-7-(3-methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazol-4-carboxamide:

[0201] Following the method of Example 16, simply replace the ethanol in step one with 3-methoxyprop-1-ol.

[0202] Example 29

[0203] Preparation of ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycine ester:

[0204] Following the method of Example 28, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0205] Example 30

[0206] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazol-4-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0207] Following the method of Example 28, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0208] Example 31

[0209] Preparation of N-(4-((6-(3-butylurea)-7-ethoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide:

[0210] Following the method in Example 1, simply replace 1-(4-fluorophenyl)-2-oxo-3-pyrrolidone-4-carboxylic acid with 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid.

[0211] Example 32

[0212] Preparation of ethyl ((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)carbamoyl)glycine ester:

[0213] Following the method of Example 31, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0214] Example 33

[0215] Preparation of 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0216] Following the method of Example 31, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0217] Example 34

[0218] Preparation of N-(4-((6-(3-butylurea)-7-isopropoxyquinazoline-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide:

[0219] Following the method of Example 31, simply replace the ethanol in step one with isopropanol.

[0220] Example 35

[0221] Preparation of ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)formamido)glycine ester:

[0222] Following the method of Example 34, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0223] Example 36

[0224] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-isopropoxyquinazoline-6-yl)ureo)ethyl methacrylate:

[0225] Following the method of Example 34, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0226] Example 37

[0227] Preparation of N-(4-((7-butoxy-6-(3-butylureo)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide:

[0228] Following the method of Example 31, simply replace the ethanol in step one with n-butanol.

[0229] Example 38

[0230] Preparation of ethyl ((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)formyl)glycine ester:

[0231] Following the method of Example 37, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0232] Example 39

[0233] Preparation method of 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0234] Following the method of Example 37, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0235] Example 40

[0236] Preparation of N-(4-((6-(3-butylurea)-7-(pentoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide:

[0237] Following the method of Example 31, simply replace the ethanol in step one with n-pentanol.

[0238] Example 41

[0239] Preparation of ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)formamido)glycine ester:

[0240] Following the method of Example 40, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0241] Example 42

[0242] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(pentoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0243] Following the method of Example 40, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0244] Example 43

[0245] Preparation of N-(4-((6-(3-butylurea)-7-(3-methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide:

[0246] Following the method of Example 31, simply replace the ethanol in step one with 3-methoxyprop-1-ol.

[0247] Example 44

[0248] Preparation of ethyl((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycine ester:

[0249] Following the method of Example 43, simply replace the isocyanobutyl ester in step six with ethyl isocyanate.

[0250] Example 45

[0251] Preparation of 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)ureo)ethyl methacrylate:

[0252] Following the method of Example 43, simply replace the isocyanobutyl ester in step six with isocyanoethyl methacrylate.

[0253] In vitro validation of anti-tumor cell activity:

[0254] The in vitro inhibitory activity of the urea-containing quinazoline derivatives of general formula I according to the present invention against H1975 lung cancer cells was tested, with Afatinib as the control standard.

[0255] The testing steps are as follows:

[0256] (1) After cell resuscitation and stabilization through 2-3 passages, digest the cells from the bottom of the culture flask using trypsin solution (0.25%). Transfer the digestion solution to a centrifuge tube, then add culture medium to stop the digestion. Centrifuge the tube at 1000 rpm for 3 minutes, discard the supernatant, add 3 mL of culture medium, mix the cells by pipetting, and add 10 μL of the cell suspension to a cell counting chamber for counting. Adjust the cell concentration to 102. 4 Cells / well. In a 96-well plate, except for the top, bottom, and leftmost wells which are blank (no cells added), 180 μL of cell suspension was added to all other wells. The 96-well plate was then incubated for 24 hours.

[0257] (2) Dissolve the test sample in 20 μL of dimethyl sulfoxide, then add 980 μL of culture medium to dissolve the sample into a 1 mg / mL solution, and then dilute the sample in an EP tube to 1, 0.333, 0.111, 0.037, 0.012 μg / mL.

[0258] Add 20 μL of each concentration to 3 wells. The two outer rows and two columns of cells are more susceptible to environmental influences and are used as blank cells. Incubate the 96-well plate in an incubator for 72 hours.

[0259] (3) Discard the drug-containing culture medium in the 96-well plate, wash the cells twice with phosphate-buffered saline (PBS), add 100 μL of MTT (tetrazazole) (0.5 mg / mL) to each well, incubate for 4 h, discard the MTT solution, and add 100 μL of dimethyl sulfoxide. Shake on a magnetic oscillator to fully dissolve the surviving cells and the MTT reaction product formazan, then measure the results at 492 nM using a microplate reader. The IC50 of the drug can be determined using the Bliss method. 50 value.

[0260] The results of the compounds inhibiting the activity of H1975 lung cancer cells are shown in Table 2, where NA represents IC50. 50 If the value is greater than 1000, ND indicates that no detection was performed.

[0261] Table 2. Anti-H1975 cell proliferation activity (IC50 assay)

[0262]

[0263]

[0264] EGFR kinase activity (IC50) 50 (and inhibition rate measurement)

[0265] Prepare a 384-well plate with wells for the test compound, blank control, and positive control. Add 2.5 μL of kinase solution to the test compound wells, 2.5 μL of kinase buffer to the blank control wells, and 2.5 μL of kinase solution to the positive control wells. Add 2.5 μL of the compound at different concentrations to each test compound well. Add 10 μL of LEGFR kinase antibody and EDTA reagent to each well, centrifuge to mix, and incubate at room temperature for 60 min to equilibrate. The final antibody concentration is 2 nM, and the final EDTA concentration is 8 mM. Read the fluorescence values ​​using Envision. Calculate the percentage inhibition rate of the compound.

[0266] Percentage inhibition rate = (Lance signal value - Min) / (Max - Min) × 100;

[0267] Min: Lance signal value without enzyme; Lance signal value of Max-DMSO control. Data were analyzed using SPSS, MSExcel, and Graphpad 5.0 to obtain IC50. 50 .

[0268] c-Met kinase activity (IC) 50 (and inhibition rate measurement)

[0269] The method is the same as above.

[0270] Afatinib and Foretinib were used as positive controls, and Kinase-Glo and Kinase-Glo were used respectively. The Ultra enzyme activity evaluation method was used to test the inhibitory activity of the compounds against EGFR and c-Met kinases. The results are shown in Table 3, where NA indicates an inhibition rate of less than 1% and ND indicates no detection.

[0271] Table 3. EGFR and c-Met kinase activity (IC50) 50 (Measurement)

[0272]

[0273]

[0274] The above experimental results show that the compounds of general formula I protected by this invention have good in vitro anti-cell proliferation activity and anti-EGFR and c-Met kinase activity. Among them, Examples 2, 5, 14, 32, 36, 38, 44, and 45 showed excellent inhibition rates against EGFR and c-Met kinases. Further kinase IC50 assays were conducted on the compounds with higher inhibition rates. 50 The assays revealed that Example 44 exhibited excellent toxic activity against all selected cell lines, comparable to that of positive control drugs. This suggests that the compounds of general formula I of this invention hold promise as potential inhibitors of EGFR and c-Met kinases.

[0275] Although the invention has been described with reference to specific embodiments, modifications and equivalent variations will be apparent to those skilled in the art, and are all included within the scope of the invention.

[0276] Application Example 1: Tablets

[0277] 10g of compound 1 from Example 1 was mixed with 20g of excipients according to the general pharmaceutical tableting method and then compressed into 100 tablets, each weighing 300mg.

[0278] Application Example 2: Capsules

[0279] 5g of compound from Example 10 was mixed with 10g of excipients according to the requirements for pharmaceutical capsules, and then filled into empty capsules, each weighing 300mg.

[0280] Application Example 3: Ointment

[0281] The compound from Example 12 was prepared by grinding 10g of the compound into a fine powder and then mixing it with 500g of an oily matrix such as petrolatum.

[0282] Application Example 4: Aerosol

[0283] Dissolve 10g of compound 15 in an appropriate amount of propylene glycol, add distilled water and other additives, and prepare a 500mL clear solution.

[0284] Application Example 5: Suppositories

[0285] After grinding 10g of compound 20 into a fine powder, add an appropriate amount of glycerin and grind evenly. Then add melted glycerin gelatin and grind evenly. Pour the mixture into a mold coated with lubricant to obtain 50 suppositories.

[0286] Application Example 6: Droplets

[0287] 5g of the compound from Example 22 was heated and melted with 25g of a matrix such as gelatin and mixed evenly. The mixture was then dripped into low-temperature liquid paraffin to prepare 1000 pills.

[0288] Application Example 7: Topical Liniments

[0289] 10g of compound 23 was mixed and ground with 2.5g of excipients such as emulsifier according to conventional pharmaceutical methods, and then distilled water was added to 200mL to obtain the final product.

[0290] Application Example 8: Injectables

[0291] Using 6g of compound from Example 26, the compound was adsorbed onto activated carbon according to conventional pharmaceutical methods, filtered through a 0.65μm microporous membrane, and then filled into a nitrogen cylinder to prepare an aqueous injection formulation. Each injection contained 2mL, and a total of 100 bottles were filled.

[0292] Application Example 9: Film Formulation

[0293] Polyvinyl alcohol, pharmaceutical glycerin, water, etc. are stirred and expanded, then heated and dissolved. The mixture is filtered through an 80-mesh sieve. The compound from Example 15 is then added to the filtrate and stirred and dissolved. 100 films are made by coating the film.

[0294] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A quinazoline compound having a urea structure, characterized by, having the structure of Formula I: ； wherein Z is selected from , or . R1is selected from one of , , , or . R2is selected from , or .

2. The quinazoline compound containing a urea structure according to claim 1, characterized by, selected from the group consisting of: N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxopiperidine-3-carboxamide, ethyl ((7-ethoxy-4-(2-fluoro-4-(1-(4- fluorophenyl)-2-oxopyrrolidin-3-carboxamido)phenoxy)quinazolin-6-yl)carbamoyl) glycinate, 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidin-3- carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)- 7-isopropoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3- carboxamide, ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidin-3- carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)carbamoyl)glycinate, 2-(3-(4-(2-fluoro- 4-(1-(4-fluorophenyl)-2-oxopyrrolidin-3-carboxamido)phenoxy)-7-isopropoxyquinazolin-6- yl)ureido)ethyl methacrylate, N-(4-((7-butoxy-6-(3-butylureido)quinazolin-4-yl)oxy)-3- fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide, ethyl ((7-butoxy-4-(2- fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidin-3-carboxamido)phenoxy)quinazolin-6- yl)formamidyl)glycinate, 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2- oxopyrrolidin-3-carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4- ((6-(3-butylureido)-7-(pentyloxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)- 2-oxopiperidine-3-carboxamide, ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-2- oxopyrrolidin-3-carboxamido)phenoxy)-7-(pentyloxy)quinazolin-6-yl)carbamoyl)glycinate, 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidin-3-carboxamido)phenoxy)-7- (pentyloxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7-(3- methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3- carboxamide, ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidin-3- carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamidyl)glycinate,2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidin-3-carboxamido)phenoxy)-7- (3-methoxypropoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7- ethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4- carboxamide, ethyl ((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4- carboxamido)phenoxy)quinazolin-6-yl)formamido)glycinate, 2-(3-(7-ethoxy-4-(2-fluoro-4- (1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7-isopropoxyquinazolin-4-yl)oxy)-3- fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide, ethyl ((4-(2-fluoro-4-(1-(4- fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)formamido) glycinate, 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7- isopropoxyquinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((7-butoxy-6-(3-butylureido)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide, ethyl ((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)quinazolin-6-yl)formyl)glycinate, 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7-(pentyloxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide, ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7- (pentyloxy)quinazolin-6-yl)formamido)glycinate, 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7- (pentyloxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7-(3- methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4- carboxamide,ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7- (3-methoxypropoxy)quinazolin-6-yl)formamido)glycinate, 2-(3-(4-(2-fluoro-4-(1-(4- fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin- 6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-4-yl)oxy)-3- fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide, ethyl ((7-ethoxy-4-(2- fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamido)phenoxy)quinazolin-6-yl) carbamoyl)glycinate, 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4- triazole-3-carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3- butylureido)-7-isopropoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4- triazole-3-carboxamide, ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3- carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)formamido)glycinate, 2-(3-(4-(2-fluoro- 4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamido)phenoxy)-7-isopropoxyquinazolin-6- yl)ureido)ethyl methacrylate, N-(4-((7-butoxy-6-(3-butylureido)quinazolin-4-yl)oxy)-3- fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide, ethyl ((7-butoxy-4-(2- fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamido)phenoxy)quinazolin-6-yl) formamido)glycinate, 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3- carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)- 7-(pentyloxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3- carboxamide, ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3- carboxamido)phenoxy)-7-(pentyloxy)quinazolin-6-yl)formamido)glycinate,2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamido)phenoxy)-7- (pentyloxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7-(3- methoxypropoxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4- triazole-3-carboxamide, ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3- carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycinate, or 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamido)phenoxy)-7-(3- methoxypropoxy)quinazolin-6-yl)ureido)ethyl methacrylate.

3. A pharmaceutical composition, characterized by, A quinazoline compound having a urea structure according to any one of claims 1-2 as an active ingredient.

4. The pharmaceutical composition of claim 3, wherein, including pharmaceutically acceptable excipients.

5. Use of a quinazoline compound having a urea structure according to any one of claims 1-2 or a pharmaceutical composition according to any one of claims 3-4 in the manufacture of an EGFR and / or c-Met antitumor inhibitor.

6. Use of a quinazoline compound having a urea structure according to any one of claims 1-2 or a pharmaceutical composition according to any one of claims 3-4 in the manufacture of a dual-targeting antitumor inhibitor of EGFR and c-Met.

7. Use of a quinazoline compound having a urea structure according to any one of claims 1-2 or a pharmaceutical composition according to any one of claims 3-4 in the manufacture of a medicament for the treatment and / or prevention of cancer.

8. Use according to claim 7, characterized in that The cancer is selected from lung cancer, liver cancer, stomach cancer, colon cancer, or breast cancer.

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