Quinazoline compound containing urea structure and application thereof

Abstract

The invention discloses a quinazoline compound containing a urea structure and application of the quinazoline compound, and relates to the technical field of medicines. The invention provides a quinazoline compound containing a urea structure, and the compound with the general formula structure has relatively strong capability of inhibiting EGFR and c-Met kinase, so that the quinazoline compound can be used as an active component for preparing a medicine for treating diseases caused by abnormal activation of EGFR and / or c-Met kinase. In addition, the derivative also shows potential application value in preparation of drugs for treating and / or preventing proliferative diseases and cancers. The invention provides important technical support for developing high-efficiency anti-cancer drugs with better selectivity.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a urea-structured quinazoline compound and application thereof. Background Art

[0002] Non-small-cell lung cancer (NSCLC) is synonymous with "non-small cell cancer". Non-small cell lung cancer, including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, has slower growth and division of cancer cells than small cell carcinoma, and its spread and metastasis are relatively late. Non-small cell lung cancer accounts for about 80-85% of the total number of lung cancers. With the progress of molecular medicine and the continuous emergence of targeted drugs, the treatment of advanced NSCLC has entered the era of personalized treatment. The personalized targeted therapy currently used in clinical practice is mainly aimed at EGFR mutation and ALK (Anaplasticymphomakinase) fusion genotype lung cancer. Both of these genetic variant lung cancers have clear molecular targets, target detection technologies and marketed targeted drugs, and the clinical efficacy has been significantly improved.

[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 different receptors: EGFR (also known as ErbB-1 / HER1), ErbB-2 (neu, HER2), ErbB-3 (HER3) and ErbB-4 (HER4). The ErbB family all have an extracellular ligand binding domain, a single hydrophobic transmembrane domain and a cytoplasmic domain containing a tyrosine kinase. When a ligand is present, the conformation of a single EGFR receptor changes, from a single receptor pairing to form a dimer. The dimer located in the extracellular ligand binding domain is then cross-linked and phosphorylated, activating the cytoplasmic domain containing a tyrosine kinase, which then randomly binds to a molecule of adenosine triphosphate in this region to phosphorylate the tyrosine at the end of the C-terminal domain. The tyrosine at the end of the C-terminal domain then recruits substrate proteins (such as Gab1, Crk and Grb2) and provides them with docking sites. Signals at the membrane-proximal sites regulate gene expression and cell cycle in the nucleus through the cascade reaction of these substrate proteins. Currently, the two most common signaling pathways are the Ras / ERK pathway and the PI3K / mTOR pathway. The former mainly controls cell growth and differentiation, while the latter regulates cell apoptosis. In a variety of cancer cells, including NSCLC cells, it has been detected that the EGFR-mediated signaling pathway is constantly activated, leading to the continuous proliferation and activation of cancer cells and the continuous growth and spread of tumors.

[0004] c-Met is a member of another RTKs small subtype family (this subtype family also includes Ron and Sea) and is a receptor for hepatocyte growth factor (HGF / SF). c-Met is a heterodimer (composed of 1390 AARs) connected by disulfide bonds outside the cell and disulfide bonds on the transmembrane structure, with a total molecular weight of 195kDa. c-Met has the same structural characteristics as the RTKs family, with 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: the semaphorin domain, the plexins-semaphorins-integrins domain and the immunoglobulin-plexin-transcription domain; the hydrophobic transmembrane domain is a single structure with a Tyr1003 phosphorylation site; the cytoplasmic domain of the tyrosine kinase consists of a kinase domain and a multifunctional docking site region. Among them, Tyr-1234 and Tyr-1235 are the key AARs responsible for phosphorylation in the kinase domain, which can positively regulate the activity of c-Met kinase, while Tyr-1349 and Tyr-1356 are signal-energy converters in the multifunctional docking site region. After phosphorylation, AARs in the multifunctional docking site region will recruit a variety of substrate proteins (such as Gab1 and Grb2), which will lead to the activation of intracellular signal transduction pathways after phosphorylation. For example, the activated Gab1 protein will continue to become a binding site for downstream proteins, and then activate PI3K / Akt, Ras / MAPK and IKK / NFк-B pathways to regulate gene expression and cell cycle in the 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 signaling pathway 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 and directly activate the PI3K / mTOR signaling pathway.

[0006] Therefore, in the clinical treatment of EGFR inhibitors, in addition to the common drug-resistant mutations of EGFR itself, there are also many EGFR mutations caused by c-Met amplification. Therefore, the development of new EGFR / c-Met dual-target inhibitor drugs for the treatment of cancer, which is safer and more efficient, has great social value and economic benefits, and is also a research hotspot for major pharmaceutical companies. By modifying the structure of the compound to design a new compound structure, improving its drug resistance and drugability, and improving its biological activity and bioavailability, to find a new class of EGFR / c-Met inhibitors is of great significance for the clinical treatment of diseases caused by EGFR / c-Met mutations. The current EGFR or c-Met inhibitors that have been marketed usually only target one target and still need to be improved. Summary of the invention

[0007] The purpose of the present invention is to provide a urea-structured quinazoline compound and its application to solve the problems existing in the above-mentioned prior art.

[0008] To achieve the above object, the present invention provides the following solutions:

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

[0010]

[0011] Among them, Z is selected from One of;

[0012] R 1 Selected from One of;

[0013] R 2 Selected from One of them.

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

[0015] [1] N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-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)ureido)ethyl methacrylate;

[0018] [4] N-(4-((6-(3-butylureido)-7-isopropoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide;

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

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

[0021] [7] N-(4-((7-butoxy-6-(3-butylureido)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-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)ureido)ethyl methacrylate;

[0024]

[10] N-(4-((6-(3-butylureido)-7-(pentyloxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxopiperidine-3-carboxamide;

[0025]

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

[0026]

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

[0027]

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

[0028]

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

[0029]

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

[0030]

[16] N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide;

[0031]

[17] ethyl ((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)quinazolin-6-yl)formamido)glycinate;

[0032]

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

[0033]

[19] N-(4-((6-(3-butylureido)-7-isopropoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide;

[0034]

[20] ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)formamido)glycinate;

[0035]

[21] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)ureido)ethyl methacrylate;

[0036]

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

[0037]

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

[0038]

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

[0039]

[25] N-(4-((6-(3-butylureido)-7-(pentyloxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide;

[0040]

[26] ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7-(pentyloxy)quinazolin-6-yl)carboxamido)glycinate;

[0041]

[27] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7-(pentyloxy)quinazolin-6-yl)ureido)ethyl methacrylate;

[0042]

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

[0043]

[29] ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-imidazole-4-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycinate;

[0044]

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

[0045]

[31] N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide;

[0046]

[32] ethyl ((7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-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-triazole-3-carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate;

[0048]

[34] N-(4-((6-(3-butylureido)-7-isopropoxyquinazolin-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-triazole-3-carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)formamido)glycinate;

[0050]

[36] 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)ureido)ethyl methacrylate;

[0051]

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

[0052]

[38] ethyl ((7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-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-triazole-3-carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate;

[0054]

[40] N-(4-((6-(3-butylureido)-7-(pentyloxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide;

[0055]

[41] Ethyl ((4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamido)phenoxy)-7-(pentyloxy)quinazolin-6-yl)carboxamido)glycinate;

[0056]

[42] 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;

[0057]

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

[0058]

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

[0059]

[45] 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.

[0060] The second object of the present invention is to provide a pharmaceutical composition, which uses the above-mentioned urea-containing quinazoline compound as an active ingredient.

[0061] The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0062] The third technical solution of the present invention is to provide the use of the above-mentioned urea-containing quinazoline compound or pharmaceutical composition in the preparation of EGFR and / or c-Met anti-tumor inhibitors.

[0063] A fourth technical solution of the present invention is to provide the use of the above-mentioned urea-containing quinazoline compound or pharmaceutical composition in the preparation of EGFR and c-Met dual-target anti-tumor inhibitors.

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

[0065] Furthermore, the cancer includes lung cancer, liver cancer, stomach cancer, colon cancer or breast cancer.

[0066] The present invention can prepare a composition by mixing the urea-containing quinazoline compound having the above-mentioned formula I structure with a pharmaceutically acceptable excipient, and prepare it into a clinically acceptable pharmaceutical dosage form. A pharmaceutically acceptable excipient refers to any diluent, adjuvant and / or carrier that can be used in the pharmaceutical field. The derivative of the present invention can be used in combination with other active ingredients.

[0067] The clinical dosage of the urea-containing quinazoline compound of the formula I structure of the present invention for patients can be appropriately adjusted according to the therapeutic efficacy and bioavailability, metabolism and excretion rate of the active ingredient in the body, and the age, gender, and disease stage of the patient; the daily dosage for adults should generally be 10 to 500 mg, preferably 50 to 300 mg. According to the guidance of a doctor or pharmacist, the pharmaceutical preparation of the present invention can be administered several times (preferably 1 to 6 times) at certain intervals.

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

[0069] Several dosage forms as mentioned above can adopt injection, tablet, capsule, aerosol, suppository, film, drop pill, external dressing, ointment and other dosage forms. The carrier used for the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: adhesive, lubricant, disintegrant, solubilizer, diluent, stabilizer, suspending agent, pigment-free, flavoring agent, preservative, solubilizing agent and matrix etc. The pharmaceutical preparation can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or locally), and if some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

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

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

[0072] The present invention provides important technical support for developing highly effective and more selective anticancer drugs. DETAILED DESCRIPTION

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

[0074] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0075] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0076] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

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

[0078] It should be pointed out that the matters not described in detail in the present invention are conventional operating means in the art and are not the focus of the present invention.

[0079] The raw materials and intermediates used in the present invention are prepared by the methods described in the synthesis routes or by methods well known to those skilled in the art of organic chemistry, and can also be purchased commercially.

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

[0081] The general structure of the urea-containing quinazoline compound of the present invention is shown in Formula I:

[0082]

[0083] Z, R 1 and R 2 As defined above, that is, Z is selected from One of;

[0084] R 1 Selected from One of;

[0085] R 2 Selected from One of them.

[0086] The urea-containing quinazoline compounds of formula I of the present invention can be prepared by the method of route 1, route 2 or route 3:

[0087] Route 1:

[0088]

[0089] Route 2:

[0090]

[0091] Route 3:

[0092]

[0093] In the above three routes of the present invention, the substituent R in the compound structure 1 and R 2 The substituent R in the compound of formula I 1 and R 2 Same definition.

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

[0095] The H NMR spectra of the compounds in the examples of the present invention were measured using Bruker ARX-400, and the mass spectra were measured using Agilent 1100 LC / MSD; all reagents used were analytically pure or chemically pure.

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

[0097] Table 1

[0098]

[0099]

[0100] Example 1

[0101] Preparation of N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-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] 2.68g of NaOH was added to 100mL of anhydrous ethanol solution and placed in a 250mL round-bottomed flask as a reaction vessel. The reaction vessel was placed in an oil bath and heated to 70°C. 2g of raw material 7-fluoro-6-nitroquinazoline-4(3H)-one (1) was added thereto and stirred. After 2h of reaction, yellow solid was observed to precipitate, confirming that the reaction was complete. The reaction solution was poured into a mixture of 300mL of ice water and stirred at room temperature. The pH of the reaction solution was adjusted to 2 with 37% hydrochloric acid, and white solid was observed to precipitate. After the product was completely precipitated, it 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, and 250mL of thionyl chloride and three drops of DMF were added thereto. The reaction vessel was placed in an oil bath and heated to 90°C for five hours. After the reaction was completed, the excess thionyl chloride was evaporated under reduced pressure, and 100ml of ethyl acetate was added to the reaction vessel, dissolved and evaporated under reduced pressure, and repeated three times. Finally, it 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] 3.0g of compound 3 was placed in a 100mL round-bottom flask, a small amount of THF was added, and then a large amount of 1,4-Dio was added and placed in a refrigerator. 4-amino-2-fluorophenol was dissolved in THF, and then stirred in an ice bath with ultrasonic nitrogen protection. Potassium tert-butoxide was added in batches (do not shake, it is easy to stick to the wall) and stirred for 1h. Then, the compound 3 system was dripped into the reaction system of 4-amino-2-fluorophenol, and the reaction was protected by nitrogen vacuum for 2.5h. After the reaction was completed, an equal volume of DCM was added to the system with stirring, and then filtered, the filtrate was collected and dried, and DCM was added to dissolve (suspension) after drying, and the product was extracted twice with dilute NaOH aqueous solution and DCM, and the organic phase was distilled under reduced pressure. The product was taken off with isopropanol and then recrystallized with n-hexane to obtain 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] Dissolve the compound 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid in ultra-dry DCM, add 2dDMF and stir, drip oxalyl chloride dissolved in DMC into the system, and stir at room temperature for 0.5 hours. 3 In ultra-dry DCM, after stirring, the compound 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid system was added dropwise to the compound 4 system, and stirred at room temperature for three hours with a platen monitor. After the reaction was completed, it was distilled under reduced pressure, a small amount of ethanol was added and ultrasonicated, and then a large amount of precipitated solid was added.

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

[0115]

[0116] First, Fe was dissolved in ethanol, ammonium chloride was completely dissolved in water, and added to the Fe system and refluxed at 90°C for 1h. Compound 5 was then dissolved in ethanol and added to the Fe system and refluxed at 90°C for 2h. After the reaction was completed, methanol of the same volume as the reaction solution was added, and the mixture was filtered while hot on a Buchner funnel covered with diatomaceous earth. The filtrate was distilled under reduced pressure and the product was separated by column chromatography. DCM / CH 3 OH (v / v, from 300:1 to 70:1) was used as the eluent to afford compound 6.

[0117] Step 6: Preparation of N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-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 isocyanobutyl ester and stir at room temperature. After the reaction is complete, distill under reduced pressure to obtain a crude product. The crude product is purified by column chromatography and purified by DCM / CH 3 OH (v / v, from 300:1 to 50:1) was used as the eluent to obtain the final compound.

[0120] ESI-MS / (m / z):516.2433(M+H) +1 ; H NMR (400 MHz, DMSO-d 6)δ10.63(s,1H),9.04(s,1H),8.50(s,1H),8.27(s,1H),7.84(d,J=12.8Hz,1H),7.7 7-7.66(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). 13 C 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] According to the method of Example 1, in step 6, n-butyl isocyanate is replaced 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)ureido)ethyl methacrylate:

[0126] According to the method of Example 1, in step six, n-butyl isocyanate is replaced with isocyanoethyl methacrylate.

[0127] Example 4

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

[0129] The method of Example 1 can be followed, except that the ethanol in step 1 is replaced with isopropanol.

[0130] Example 5

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

[0132] According to the method of Example 4, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0133] Example 6

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

[0135] According to the method of Example 4, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0136] Example 7

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

[0138] The method of Example 1 can be followed, except that the ethanol in step 1 is replaced 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] According to the method of Example 7, the isocyanobutyl ester in step 6 is replaced 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)ureido)ethyl methacrylate:

[0144] According to the method of Example 7, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0145] Example 10

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

[0147] The method of Example 1 can be followed, except that the ethanol in step 1 is replaced with n-pentanol.

[0148] Embodiment 11

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

[0150] According to the method of Example 10, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0151] Example 12

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

[0153] According to the method of Example 10, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0154] Embodiment 13

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

[0156] The method of Example 1 is followed, except that the ethanol in step 1 is replaced with 3-methoxypropan-1-ol.

[0157] Embodiment 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] According to the method of Example 13, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0160] Embodiment 15

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

[0162] According to the method of Example 13, the isocyanobutyl ester in step 6 is replaced with isocyanoethyl methacrylate.

[0163] Example 16

[0164] Preparation of N-(4-((6-(3-butylureido)-7-ethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide:

[0165] The method of Example 1 was followed except that 1-(4-fluorophenyl)-2-oxo-3-pyrrolidone-4-carboxylic acid was replaced with 1-(4-fluorophenyl)-1H-imidazole-4-carboxylic acid.

[0166] Embodiment 17

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

[0168] The method of Example 16 can be followed, except that n-butyl isocyanate in step 6 is replaced with ethyl isocyanate.

[0169] Embodiment 18

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

[0171] According to the method of Example 16, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0172] Embodiment 19

[0173] Preparation of N-(4-((6-(3-butylureido)-7-isopropoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide:

[0174] The method of Example 16 is followed, except that ethanol is replaced with isopropanol.

[0175] Embodiment 20

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

[0177] The method of Example 19 can be followed, except that n-butyl isocyanate in step 6 is replaced with ethyl isocyanate.

[0178] Embodiment 21

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

[0180] According to the method of Example 19, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0181] Embodiment 22

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

[0183] The method of Example 16 is followed, except that ethanol is replaced with n-butanol.

[0184] Embodiment 23

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

[0186] According to the method of Example 22, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0187] Embodiment 24

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

[0189] According to the method of Example 22, the isocyanobutyl ester in step 6 is replaced with isocyanoethyl methacrylate.

[0190] Embodiment 25

[0191] Preparation of N-(4-((6-(3-butylureido)-7-(pentyloxy)quinazolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide:

[0192] According to the method of Example 16, the ethanol in step 1 is replaced with n-pentanol.

[0193] Embodiment 26

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

[0195] According to the method of Example 25, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0196] Embodiment 27

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

[0198] According to the method of Example 25, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0199] Embodiment 28

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

[0201] Follow the method of Example 16, except that the ethanol in step 1 is replaced with 3-methoxypropan-1-ol.

[0202] Embodiment 29

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

[0204] According to the method of Example 28, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0205] Embodiment 30

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

[0207] According to the method of Example 28, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0208] Embodiment 31

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

[0210] The method of Example 1 is followed except that 1-(4-fluorophenyl)-2-oxo-3-pyrrolidone-4-carboxylic acid is replaced with 1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid.

[0211] Embodiment 32

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

[0213] According to the method of Example 31, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0214] Embodiment 33

[0215] Preparation of 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:

[0216] According to the method of Example 31, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0217] Embodiment 34

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

[0219] Follow the method of Example 31, except that the ethanol in step 1 is replaced with isopropanol.

[0220] Embodiment 35

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

[0222] According to the method of Example 34, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0223] Embodiment 36

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

[0225] According to the method of Example 34, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0226] Embodiment 37

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

[0228] According to the method of Example 31, the ethanol in step 1 is replaced with n-butanol.

[0229] Embodiment 38

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

[0231] According to the method of Example 37, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0232] Embodiment 39

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

[0234] According to the method of Example 37, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0235] Embodiment 40

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

[0237] According to the method of Example 31, the ethanol in step 1 is replaced with n-pentanol.

[0238] Embodiment 41

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

[0240] According to the method of Example 40, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0241] Embodiment 42

[0242] Preparation of 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:

[0243] According to the method of Example 40, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0244] Embodiment 43

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

[0246] According to the method of Example 31, the ethanol in step 1 is replaced by 3-methoxypropan-1-ol.

[0247] Embodiment 44

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

[0249] According to the method of Example 43, the isocyanobutyl ester in step 6 is replaced with ethyl isocyanate.

[0250] Embodiment 45

[0251] Preparation of 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:

[0252] According to the method of Example 43, the isocyanobutyl ester in step 6 is replaced by isocyanoethyl methacrylate.

[0253] In vitro anti-tumor cell activity verification:

[0254] The urea-containing quinazoline derivatives of the general formula I of the present invention were tested for their in vitro inhibitory activity on lung cancer cells H1975, with Afatinib as the reference substance.

[0255] The test steps are as follows:

[0256] (1) After the cells have recovered and been passaged 2-3 times to stabilize, use trypsin solution (0.25%) to digest them from the bottom of the culture bottle. After the cell digestion solution is aspirated into a centrifuge tube, the culture medium is added to terminate the digestion. The centrifuge tube is centrifuged at 1000r / min for 3min, the supernatant is discarded, and 3mL of culture medium is added. The cells are mixed by pipetting, and 10μL of the cell suspension is aspirated and added to a cell counting plate for counting. The cell concentration is adjusted to 10 4 180 μL of cell suspension was added to all the blank wells except the top, bottom and leftmost wells in the 96-well plate. The 96-well plate was placed in an incubator and cultured for 24 h.

[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. Then dilute the sample in an EP tube to 1, 0.333, 0.111, 0.037, and 0.012 μg / mL.

[0258] Each concentration was added to 3 wells, 20 μL per well, and the growth of cells in the two rows and two columns around was greatly affected by the environment, so they were only used as blank cell wells. The 96-well plate was placed in an incubator and cultured for 72 hours.

[0259] (3) The drug-containing culture medium in the 96-well plate was discarded, and the cells were rinsed twice with phosphate buffer solution (PBS). 100 μL of MTT (tetrazolium) (0.5 mg / mL) was added to each well and placed in the incubator for 4 hours. The MTT solution was discarded and 100 μL of dimethyl sulfoxide was added. The surviving cells were shaken on a magnetic oscillator to fully dissolve the formazan reaction product of MTT, and the result was measured in an ELISA reader at a wavelength of 492 nM. The IC value of the drug can be calculated by the Bliss method. 50 value.

[0260] The results of the inhibitory activity of the compounds on lung cancer cells H1975 are shown in Table 2, where NA represents IC 50 Greater than 1000, ND means not detected.

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

[0262]

[0263]

[0264] EGFR kinase activity (IC 50 and inhibition rate determination)

[0265] Take a 384-well plate, set up test compound wells, blank control wells and positive drug control wells on the plate. Add 2.5μL kinase solution to the test compound wells, 2.5μL kinase buffer to the blank control wells, and 2.5μL kinase solution to the positive drug control wells. Add 2.5μL of different concentrations of compounds to the test compound wells, add 10μL EGFR kinase antibody and EDTA reaction reagent to each well, centrifuge and mix, and place at room temperature for 60 minutes. The final concentration of the antibody is 2nM, and the final concentration of EDTA is 8mM. Envision reads the fluorescence value. Calculate the percentage inhibition rate of the compound.

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

[0267] Min: Lance signal value without enzyme; Max-DMSO control Lance signal value, data were analyzed by SPSS, MSExcel and Graphpad5.0 to get IC 50 .

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

[0269] Same method as above

[0270] Afatinib and Foretinib were used as positive controls, and Kinase-Glo and Ultra enzyme activity evaluation method was used to test the inhibitory activity of the compounds on EGFR and c-Met kinases. The results are shown in Table 3, wherein NA means the inhibition rate is less than 1% and ND means not detected.

[0271] Table 3EGFR and c-Met kinase activity (IC 50 Determination)

[0272]

[0273]

[0274] It can be seen from the above test results that the compounds of general formula I to be protected by the present invention have good in vitro anti-cell proliferation activity and anti-EGFR and c-Met kinase activity, among which Examples 2, 5, 14, 32, 36, 38, 44, and 45 show excellent inhibition rates on EGFR and c-Met kinases. By further performing kinase IC on the compounds with higher inhibition rates, 50 The results showed that Example 44 showed excellent cytotoxic activity against all selected cell lines and was comparable to that of positive drugs. It can be seen that the compound of Formula I of the present invention is expected to become a potential inhibitor of EGFR and c-Met kinase.

[0275] Although the present invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of the present invention.

[0276] Application example 1: Tablets

[0277] According to the general tableting method in pharmacy, 10 g of the compound of Example 1 was added with 20 g of auxiliary materials and mixed evenly, and then compressed into 100 tablets, each weighing 300 mg.

[0278] Application example 2: Capsules

[0279] 5 g of the compound of Example 10 was mixed with 10 g of auxiliary materials according to the requirements of pharmaceutical capsules, and then filled into hollow capsules. Each capsule weighed 300 mg.

[0280] Application example 3: Ointment

[0281] The compound of Example 12 (10 g) was ground into powder and then mixed with 500 g of an oily base such as vaseline.

[0282] Application example 4: Aerosol

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

[0284] Application example 5: Suppository

[0285] Grind 10 g of the compound of Example 20 into powder, add an appropriate amount of glycerin, grind evenly, add melted glycerin gelatin, grind evenly, and pour into a mold coated with a lubricant to prepare 50 suppositories.

[0286] Application example 6: pills

[0287] 5 g of the compound of Example 22 and 25 g of a matrix such as gelatin were heated to melt and mixed, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.

[0288] Application Example 7: External Liniment

[0289] The compound of Example 23 (10 g) was mixed and ground with 2.5 g of auxiliary materials such as an emulsifier according to conventional pharmaceutical methods, and then distilled water was added to 200 mL to obtain the product.

[0290] Application example 8: Injection

[0291] 6 g of the compound of Example 26 was adsorbed on activated carbon according to conventional pharmaceutical methods. After filtering through a 0.65 μm microporous filter membrane, it was filled into a nitrogen tank to prepare an aqueous injection preparation, each containing 2 mL, and a total of 100 bottles were filled.

[0292] Application example 9: Film

[0293] Polyvinyl alcohol, medicinal glycerin, water, etc. were stirred and expanded, and then heated to dissolve. The mixture was filtered through an 80-mesh sieve. The compound of Example 15 was added to the filtrate and stirred to dissolve. 100 films were made by a film coating machine.

[0294] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A quinazoline compound containing a urea structure, characterized in that: It has the structure shown in general formula I: Among them, Z is selected from One of; R1 is selected from One of; R2 is selected from One of them.

2. The quinazoline compound containing a urea structure according to claim 1, characterized in that: Includes the following compounds: 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-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)carbamoyl)glycine ester, 2-(3-(7-ethoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)quinazolin-6-yl)ureido)ethyl methacrylate, N-(4-((6-(3-butylureido)-7-isopropoxyquinazolin-4-yl)oxy)-3 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-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 ((4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)carbamoyl)glycine ester, 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxamido)phenoxy)-7-isopropoxyquinazolin-6-yl)ureido)ethyl methacrylate, 2-(3-(7-butoxy-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-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-oxopyrrolidine-3-carboxamido)phenoxy)-7- 2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-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-oxopyrrolidine-3-carboxamido)phenoxy)-7-(3-methoxypropoxy)quinazolin-6-yl)formamido)glycine ester,2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxopyrrolidine-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)glycine ester, 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 ester, 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)glycine ester, 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)glycine ester, 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)glycine ester, 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- 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)ureido)ethyl methacrylate 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)ureido)ethyl methacrylate,2-(3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxamide)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)glycine ester 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 in that The urea-structured quinazoline compound according to any one of claims 1 to 2 is used as an active ingredient.

4. The pharmaceutical composition according to claim 3, characterized in that A pharmaceutically acceptable excipient is included.

5. Use of the urea-containing quinazoline compound according to any one of claims 1 to 2 or the pharmaceutical composition according to any one of claims 3 to 4 in the preparation of EGFR and / or c-Met anti-tumor inhibitors.

6. Use of the urea-containing quinazoline compound according to any one of claims 1 to 2 or the pharmaceutical composition according to any one of claims 3 to 4 in the preparation of an EGFR and c-Met dual-target anti-tumor inhibitor.

7. Use of the urea-containing quinazoline compound according to any one of claims 1 to 2 or the pharmaceutical composition according to any one of claims 3 to 4 in the preparation of drugs for treating and / or preventing proliferative diseases and cancer.

8. The use according to claim 7, characterized in that The cancer includes lung cancer, liver cancer, stomach cancer, colon cancer or breast cancer.

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