EGFR (epidermal growth factor receptor) inhibitor, preparation method, application and pharmaceutical composition

Abstract

The invention provides an EGFR (epidermal growth factor receptor) inhibitor, a preparation method, application and a pharmaceutical composition, the inhibitor is a compound represented by a structural formula I, a stereoisomer of the structural formula I or a pharmaceutically acceptable salt, hydrate or solvate of the structural formula I, and # imgabs0 # (I). The invention aims to overcome the defects of the existing inhibitor in the aspects of inhibition effect and side effect, especially in the aspect of drug resistance, so that more effective and safer treatment options are provided.

Description

Technical Field

[0001] The present invention relates to the fields of biomedicine and pharmacy, and in particular to an EGFR inhibitor and a preparation method, application and pharmaceutical composition thereof. Background Art

[0002] Non-small cell lung cancer (NSCLC) is a type of lung cancer that accounts for approximately 80%-85% of all lung cancers. Approximately 10% to 50% of patients with NSCLC have activating mutations in the epidermal growth factor receptor (EGFR), such as in-frame deletions in exon 19 (Ex19del) or missense mutations in exon 21 (L858R). The treatment of NSCLC is complex and depends on the stage of cancer development in patients, usually including surgery, radiotherapy, and / or chemotherapy. Studies have found that patients with EGFR mutations are more sensitive to tyrosine kinase inhibitors (TKIs), such as gefitinib and afatinib, which have strong anti-tumor effects but inevitably lead to drug resistance. The acquisition of drug resistance has promoted the renewal of EGFR-TKIs.

[0003] To date, the development of EGFR-TKIs has achieved encouraging results. T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR-TKIs. The emergence of new resistance leads to the emergence of pyrimidine backbone ( ) has emerged as a third-generation irreversible inhibitor. A representative drug is the inhibitor osimertinib (AZD-9291), which was approved by the FDA in 2015 for EGFR-T790M-positive mutation-positive non-small cell lung cancer. In addition, Sullivan et al. reviewed the clinical trial data of osimertinib in the treatment of non-small cell lung cancer and confirmed its effectiveness. Unfortunately, during osimertinib treatment, a new C797S mutation appeared in exon 20 of EGFR, which significantly reduced the therapeutic effect of the drug. EGFR acquired mutation is one of the main mechanisms of EGFR-TKIs resistance. At present, three generations of mature inhibitors have been developed for different types of resistance, and the treatment methods for acquired resistance to the third-generation EGFR-TKIs have been exhausted. However, the resistance of C797S to the third-generation EGFR inhibitors has not been resolved. The third-generation EGFR-TKIs exhibit excellent anti-tumor properties due to the covalent bond between their acrylamide (Michael receptor) site and the active thiol group in the EGFR kinase domain. However, the C797S mutation weakens the covalent bond between the EGFR cysteine ​​residue at position 797 and osimertinib, which can induce resistance to osimertinib. The C797S mutation is the main cause of resistance to third-generation inhibitors, and about 40% of resistant cases are attributed to the C797S mutation. In priority studies, del19 / T790M / C797S or L858R / T790M / C797S triple mutations were found in 20-40% of patients after taking third-generation EGFR-TKIs. In addition, a large number of these new drugs target the C797S mutation, but their in vivo and in vitro efficacy is still unclear, and some of them need to be used in combination with other therapies (such as antibody drugs) to achieve tumor suppression effects. The third-generation inhibitors are mainly used for L858R / T790M / C797S triple mutations, but are less effective against del19 / T790M / C797S triple mutations.

[0004] Therefore, the prior art needs to be further developed. Summary of the invention

[0005] In view of the various deficiencies of the prior art and in order to solve the above problems, an EGFR inhibitor, a preparation method, an application and a pharmaceutical composition are proposed, and the following technical solutions are provided: An EGFR inhibitor, wherein the inhibitor is a compound represented by structural formula I, a stereoisomer of structural formula I, or a pharmaceutically acceptable salt, hydrate or solvate of structural formula I, (I) Wherein, R1 is phenyl or aromatic heterocyclic group which is optionally mono- or poly-substituted by CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, NHSO2 (C1-C4 alkyl); R2 is selected from absent, H or C1-C4 alkyl; R3 is optionally substituted by CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, SO2(C1- C4 alkyl), CO(C1- C4 alkyl), NHSO2(C1- C4 alkyl), mono- or poly-substituted phenyl or aromatic heterocyclic group; Alternatively, R2 and R3 together form a substituted four-membered ring, five-membered ring or six-membered ring.

[0006] Furthermore, R1 is a phenyl or aromatic heterocyclic group which is optionally mono- or poly-substituted by OH, OMe, Cl, Br, F, CF3, CONH2, SO2NH2, NHSO2 (C1-C4 alkyl).

[0007] Furthermore, the R2 is H or absent.

[0008] Furthermore, R2 and R3 together form a substituted four-membered ring, five-membered ring or six-membered ring, and the four-membered ring, five-membered ring or six-membered ring contains 1-2 heteroatoms.

[0009] Furthermore, R2 and R3 together constitute a substituted four-membered ring, five-membered ring or six-membered ring, and the substituent of the four-membered ring, five-membered ring or six-membered ring is selected from at least one of alkyl, CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, SO2(C1-C4 alkyl), CO(C1-C4 alkyl) or NHSO2(C1-C4 alkyl).

[0010] Furthermore, the inhibitor is , , , , , , , , , , or .

[0011] In addition, the present application also provides a method for preparing the above-mentioned EGFR inhibitor, and the preparation process is as follows: .

[0012] The present application also provides the use of an EGFR inhibitor for preparing a medicament for treating or preventing lung cancer, wherein the lung cancer is non-small cell lung cancer.

[0013] The present application also provides a pharmaceutical composition, comprising an excipient and the above-mentioned EGFR inhibitor.

[0014] Beneficial effects: 1. The present invention develops new EGFR inhibitors to overcome the deficiencies of existing inhibitors in terms of inhibitory effects and side effects, especially drug resistance, thereby providing a more effective and safe treatment option.

[0015] 2. The EGFR inhibitor of the present invention has EGFR kinase inhibitory activity, is particularly sensitive to tyrosine kinase inhibitors (TKIs), and can be used to treat cancer. DETAILED DESCRIPTION

[0016] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention is clearly and completely described below in conjunction with the embodiments of the present invention. Based on the embodiments in this application, other similar embodiments obtained by ordinary technicians in this field without making any creative work should all fall within the scope of protection of this application.

[0017] According to an embodiment of the present invention, an EGFR inhibitor is provided, wherein the inhibitor is a compound represented by structural formula I, a stereoisomer of structural formula I, or a pharmaceutically acceptable salt, hydrate or solvate of structural formula I, (I) "Pharmaceutically acceptable salts" refer to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include: acid addition salts, which are obtained by reacting the free base of the parent compound with an inorganic acid or with an organic acid: the inorganic acid is such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, etc.: the organic acid is such as acetic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, maleic acid, malic acid, tartaric acid, etc.: preferably hydrochloric acid or malic acid: or when the acid proton present in the parent compound is replaced by a metal ion or coordinated with an organic base, a salt is formed, the metal ion is such as an alkali metal ion, an alkaline earth ion or an aluminum ion: the organic base is such as ethanolamine, diethanolamine, etc. and the like.

[0018] The compounds represented by Structural Formula I in the present invention may have one or more asymmetric centers and can therefore be prepared as individual (R)-stereoisomers or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or name of a specific compound in the present invention is intended to include individual enantiomers and racemic mixtures or other mixtures thereof.

[0019] Wherein, R1 is phenyl or aromatic heterocyclic group which is optionally substituted or polysubstituted by CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, NHSO2 (C1-C4 alkyl); for example, R1 is One of the four structures above.

[0020] R2 is selected from absent, H or C1-C4 alkyl; R3 is optionally substituted by CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, SO2(C1- C4 alkyl), CO(C1- C4 alkyl), NHSO2(C1- C4 alkyl), mono- or poly-substituted phenyl or aromatic heterocyclic group; Alternatively, R2 and R3 together form a substituted four-membered ring, five-membered ring or six-membered ring.

[0021] Preferably, R1 is phenyl or aromatic heterocyclic group which is optionally mono- or poly-substituted by OH, OMe, Cl, Br, F, CF3, CONH2, SO2NH2, NHSO2 (C1-C4 alkyl).

[0022] Preferably, R2 is H or absent.

[0023] Preferably, R2 and R3 together form a substituted four-membered ring, five-membered ring or six-membered ring, wherein the four-membered ring, five-membered ring or six-membered ring contains 1-2 heteroatoms.

[0024] Preferably, R2 and R3 together constitute a substituted four-membered ring, five-membered ring or six-membered ring, and the substituent of the four-membered ring, five-membered ring or six-membered ring is selected from at least one of alkyl, CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, SO2(C1-C4 alkyl), CO(C1-C4 alkyl) or NHSO2(C1-C4 alkyl).

[0025] The inhibitor may have one of the following structures (1)-(12): "Pharmaceutical composition" refers to a mixture of one or more EGFR inhibitors described herein with other chemical components (such as physiologically acceptable carriers and excipients). The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. "Excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, diluents, granulating agents, lubricants, binders, disintegrants, and similar agents. The present invention can prepare a pharmaceutical composition by mixing an EGFR inhibitor with a physiologically acceptable carrier and excipient.

[0026] The preparation method of the EGFR inhibitor, the preparation process is as follows: (1) Preparation of Intermediate IV: Compound II reacts with compound III under the action of a catalyst and a ligand, and the reaction is carried out under base catalysis at 20°C-100°C, the catalyst is selected from PdCb(PPh3)2, Pd(PPh3)4, Pd(dba)2, Pd(OAc)2 or Pd(dppf)2Cb; the ligand is selected from 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl or 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; the base in the preparation process of intermediate IV is selected from cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate or sodium acetate; the reaction solvent in the preparation process of intermediate IV is 1,4-dioxane, DMF, toluene or xylene; (2) Preparation of Intermediate VI: Compound IV reacts under the action of a base, the reaction is carried out at a temperature of 20°C-100°C, the base in the preparation process of intermediate VI is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; the reaction solvent in the preparation process of intermediate VI is N,N-dimethylformamide, tetrahydrofuran or toluene.

[0027] (3) Preparation of Intermediate VII: Compound VI reacts under the action of a base, the reaction is carried out at a temperature of 20°C-100°C, the base in the preparation process of intermediate VII is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; the reaction solvent in the preparation process of intermediate VII is methanol, ethanol, tetrahydrofuran, toluene, methanol aqueous solution, ethanol aqueous solution, tetrahydrofuran aqueous solution or toluene aqueous solution; (4) Preparation of intermediate VIII: Compound VII reacts under the action of DPPA, the reaction is carried out at a temperature of 80°C-100°C, the base in the preparation process of intermediate VIII is selected from triethylamine or diisopropylethylamine; the reaction solvent in the preparation process of intermediate VIII is toluene, 1,4-dioxane or xylene; (5) Preparation of Structural Formula I: Compound VIII reacts with compound IX under the action of a condensing agent, the reaction is carried out under base catalysis at a temperature of 20°C-100°C, the condensing agent is selected from CDI or phenyl chloroformate; the base in the preparation process of intermediate I is selected from triethylamine, diisopropylethylamine, N-methylmorpholine or DMAP; the reaction solvent in the preparation process of structural formula I is dichloromethane, DMF, tetrahydrofuran, toluene or xylene.

[0028] Embodiment 1: The preparation process of EGFR inhibitors is as follows: According to the above preparation process: first step: Compound la (15.3 g, 0.1 mol), compound lb 16.52 g, 0.1 mol), cesium carbonate (65.0 g, 0.2 mol), Pd(dba) 2 (4.5 g, 0.005 mol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (2.9 g, 0.005 mol) were dissolved in DMF (100 ml), heated to 100 ° C and stirred for 12 hours. The reaction was detected by TLC. After the reaction was completed, the reaction solution was poured into water (300 ml), extracted with ethyl acetate (200 mlX2), the organic phases were combined, dried, filtered, concentrated, and separated by column chromatography to obtain 14.4 g of an off-white solid with a yield of 51.1%.

[0029] Step 2: Compound 1c (14.0 g, 0.05 mol) and compound 1d (12.4 g, 0.05 mol) were dissolved in DMF (70 ml) solvent, potassium carbonate (13.8 g, 0.1 mol) was added, the temperature was raised to 80-100 °C, and the mixture was stirred for 4 hours. The reaction was monitored by TLC. After the reaction was completed, water (350 ml) was added, the mixture was stirred for crystallization, filtered, concentrated, and separated by column chromatography to obtain 34.2 g of a yellow solid with a yield of 78.2%.

[0030] Step 3: Compound le (30.0 g, 0.07 mol) was dissolved in ethanol (150 ml) and purified water (100 ml), and uranium hydroxide (5.6 g, 0.14 mol) was added at room temperature. The mixture was stirred for 12 hours and the reaction was monitored by TLC. After the reaction was completed, part of the ethanol was removed under reduced pressure, the mixture was cooled in an ice-water bath, the pH was adjusted to 1-2 with dilute hydrochloric acid, the mixture was stirred for 2 hours, and 21.5 g of an off-white solid was obtained by filtration. The yield was 75.2%.

[0031] Step 4: Compound 1f (20.0 g, 0.05 mol), DPPA (19.3 g, 0.07 mol), DIPEA (12.9 g, 0.1 mol) were dissolved in toluene (120 ml), and the mixture was stirred under reflux for 12 hours. The reaction was monitored by TLC. After the reaction was completed, water (20 ml) was added and stirred for 1 hour to stop the reaction. The organic layer was separated and dried, filtered, concentrated, and separated by column chromatography to obtain 9.5 g of an off-white solid with a yield of 50.1%.

[0032] Step 5: Compound 1g (3.8g, 0.01mol), CDI (1.6g, 0.01mol), DIPEA (3.9g, 0.03mol) were placed in toluene (50ml), stirred at room temperature for 1 hour, then compound 1h (1.7g, 0.01mol) was added, stirred for 6 hours, and the reaction was monitored by TLC. After the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 2.4g of off-white solid, with a yield of 41.2%. MS-ESI: m / z =578.1[M+1] Embodiment 2: 1-(4-acetylphenyl)-3-(2-(4-(2-(3-fluorophenyl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)urea, the structural formula is as follows: The first to fourth steps of Example 2 are the same as those of Example 1. The fifth step is to add compound 1g (3.8g, 0.01mol), CDI (1.6g, 0.01mol), DIPEA (3.9g, 0.03mol) was placed in toluene (50ml), stirred at room temperature for 1 hour, then added with compound 1-(4-aminophenyl)ethan-1-one (1.4g, 0.01mol), stirred for 6-8 hours, and the reaction was monitored by TLC. After the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 2.4g of off-white solid with a yield of 45.8%. MS-ESI: m / z =542.2[M+l] Embodiment three: 1-(2-(4-(2-(3-fluorophenyl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)-3-(4-methylpiperazin-1-yl)urea, the structural formula is as follows: The first to fourth steps of Example 3 are the same as those of Example 1. The fifth step is to add compound 1g (3.8g, 0.01mol), CDI (1.6g, 0.01mol), DIPEA (3.9g, 0.03mol) was placed in toluene (50ml), stirred at room temperature for 1 hour, then added with compound 1-methylpiperazine (1.0g, 0.01mol), stirred for 6-8 hours, and the reaction was monitored by TLC. After the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 2.1g of off-white solid with a yield of 40.1%. MS-ESI: m / z =522.6[M+l] Embodiment 4: 1-(4-isopropylpiperazin-1-yl)-3-(2-(4-(2-(6-methoxypyridin-2-yl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)urea, the structural formula is as follows: The R1 of the fourth embodiment is , a similar method to that in Example 1 was used to prepare the compound 2-(4-(1-(6-methoxypyridin-2-yl)ethyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-amine, the compound 2-(4-(1-(6-methoxypyridin-2-yl)ethyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-amine (1.9 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then the compound 1-isopropylpiperazine (0.6 g, 5 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 1.1 g of an off-white solid with a yield of 38.2%. MS-ESI: m / z =563.7[M+1] Embodiment five: 1-((S)-3-hydroxypiperidin-1-yl)-3-(2-(4-(2-(6-methoxypyridin-2-yl)pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)urea, the structural formula is as follows: The R1 of Example 5 is , a similar method to that in Example 1 was used to prepare the compound 2-(4-(1-(6-methoxypyridin-2-yl)ethyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-amine, compound 2-(4-(1-(6-methoxypyridin-2-yl)ethyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-amine (1.9 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then compound (S)-piperidin-3-ol (0.5 g, 5 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 0.9 g of a white solid with a yield of 33.2%. MS-ESI: m / z =537.2[M+1] Embodiment six: 1-((S)-3-aminopyrrolidin-1-yl)-3-(2-(4-(2-(6-methoxypyridin-2-yl)pyrrolidinyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)urea, the structural formula is as follows: The R1 of Example 6 is , a similar method to that in Example 1 was used to prepare the compound 2-(4-(1-(6-methoxypyridin-2-yl)ethyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-amine, compound 2-(4-(1-(6-methoxypyridin-2-yl)ethyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-amine (1.9 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then compound (S)-pyrrolidin-3-amine (0.5 g, 6 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, the mixture was concentrated under reduced pressure and separated by column chromatography to obtain 1.1 g of a white solid with a yield of 43.7%. MS-ESI: m / z =521.6[M+1] Embodiment seven: 1-(3,3-difluorocyclopentyl)-3-(2-(4-(2-(2,5-difluorophenyl)-4-oxopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)urea, the structural formula is as follows: The R1 of Example 7 is , a similar method to that in Example 1 was used to prepare the compound 1-(7-(5-aminothiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-(2,5-difluorophenyl)pyrrolidin-3-one, compound 1-(7-(5-aminothiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-(2,5-difluorophenyl)pyrrolidin-3-one (2.1 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then compound 3,3-difluorocyclopentane-1-amine (0.7 g, 6 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 1.4 g of a white solid with a yield of 51.8%. .MS-ESI: m / z =560.5[M+1] Embodiment eight: 1-(2-(4-(2-(2,5-difluorophenyl)-4-oxopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)-3-(3-oxocyclopentyl)urea, the structural formula is as follows: The R1 of Example 8 is , a similar method to that in Example 1 was used to prepare the compound 1-(7-(5-aminothiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-(2,5-difluorophenyl)pyrrolidin-3-one, the compound 1-(7-(5-aminothiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-(2,5-difluorophenyl)pyrrolidin-3-one (2.1 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then the compound 3-aminocyclopentane-1-one (0.6 g, 6 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 1.0 g of a white solid with a yield of 40.8%. MS-ESI: m / z =538.6[M+1] Embodiment nine: 1-(2-(4-(2-(2,5-difluorophenyl)-4-oxopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)-3-(4-(methylsulfonyl)phenyl)urea, the structural formula is as follows: The R1 of Example 9 is , a similar method to that in Example 1 was used to prepare the compound 1-(7-(5-aminothiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-(2,5-difluorophenyl)pyrrolidin-3-one, compound 1-(7-(5-aminothiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-(2,5-difluorophenyl)pyrrolidin-3-one (2.1 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then compound 4-(methylsulfonyl)aniline (1.0 g, 6 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, the mixture was concentrated under reduced pressure and separated by column chromatography to obtain 1.3 g of a white solid with a yield of 44.1%. MS-ESI: m / z =610.6[M+1] Embodiment ten: 1-(2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)-3-(4-(methylsulfonyl)phenyl)urea, the structural formula is as follows: The R1 of Example 10 is , a similar method to that in Example 1 was used to prepare the compound 2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazole-5-amine, the compound 2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazole-5-amine (2.0 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then the compound 4-(methylsulfonyl)aniline (1.0 g, 6 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 1.5 g of a white solid with a yield of 50.5%. MS-ESI: m / z =606.7[M+1] Embodiment eleven: 1-(4-acetylphenyl)-3-(2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)urea, the structural formula is as follows: In Example 11, R1 is , a similar method to that in Example 1 was used to prepare the compound 2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazole-5-amine, the compound 2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazole-5-amine (2.0 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then the compound 1-(4-aminophenyl)ethan-1-one (0.7 g, 5 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 1.3 g of a white solid with a yield of 45.5%. .MS-ESI: m / z =570.3[M+1] Embodiment 12: 1-(2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazol-5-yl)-3-(4-methylpiperazin-1-yl)urea, the structural formula is as follows: In Example 12, R1 is , a similar method to that in Example 1 was used to prepare the compound 2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazole-5-amine, the compound 2-(4-(2-(3-fluorophenyl)-4,4-dimethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)thiazole-5-amine (2.0 g, 5 mmol), CDI (0.8 g, 5 mmol), DIPEA (1.8 g, 0.015 mol) were placed in toluene (30 ml), stirred at room temperature for 1 hour, then the compound 1-methylpiperazine (0.5 g, 5 mmol) was added, stirred for 6-8 hours, the reaction was detected by TLC, and after the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain 1.4 g of a white solid with a yield of 51.4%. MS-ESI: m / z =550.6[M+1] The products obtained in Examples 1 to 12 were subjected to pharmacological studies: 11-point serial dilutions of each compound were prepared in DMSO, and the final buffer conditions were 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [HEPES], 150 mM NaCl, 0.05% Tween 20, pH 7.4 and 5% DMSO. The final protein concentration in the assay was 20 nM, and the fluorescent probe was present at 10 nM. The experiment was incubated at 23°C for 2 hours, and then the fluorescence polarization was measured on a Biotek SynergyNeo plate reader (excitation 485 nm, emission 525 nm, parallel and perpendicular readings). Dose response curves were plotted using XL-Fit software using a 4-parameter logistic model (sigmoidal dose response model), and the inhibitory concentration (IC50) that increased the fluorescence intensity by 50% was determined. K was determined from the IC50 values ​​according to Cer et al., Nucleic Acids Res, 2009, Jul1;37 (Web Server Release): W441-W445. I value.

[0033] The test results are shown in Table 1, which show that the compounds of the present invention inhibit the interaction between the EGFR protein and the fluorescence as described above.

[0034] Table 1 Pharmacological study test results of the products obtained from Example 1 to Example 12 K I The lower the value, the lower the drug concentration required to inhibit EGFR activity, which usually means that the drug is more effective. The lower the value, the lower the drug concentration required to inhibit EGFR activity, which usually means that the drug is more effective. It can be seen from the above table that the inhibitor prepared by the present invention is a potent inhibitor of EGFR protein.

[0035] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. An EGFR inhibitor, characterized in that The inhibitor is a compound represented by structural formula I, a stereoisomer of structural formula I, or a pharmaceutically acceptable salt, hydrate or solvate of structural formula I, （I） Wherein, R1 is phenyl or aromatic heterocyclic group which is optionally mono- or poly-substituted by CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, NHSO2 (C1-C4 alkyl); R2 is selected from absent, H or C1-C4 alkyl; R3 is optionally substituted by CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, SO2(C1- C4 alkyl), CO(C1- C4 alkyl), NHSO2(C1- C4 alkyl), mono- or poly-substituted phenyl or aromatic heterocyclic group; Alternatively, R2 and R3 together form a substituted four-membered ring, five-membered ring or six-membered ring.

2. An EGFR inhibitor according to claim 1, characterized in that: The R1 is a phenyl group or an aromatic heterocyclic group which is optionally mono- or poly-substituted by OH, OMe, Cl, Br, F, CF3, CONH2, SO2NH2, NHSO2 (C1-C4 alkyl).

3. An EGFR inhibitor according to claim 1, characterized in that: The R2 is H or absent.

4. An EGFR inhibitor according to claim 1, characterized in that: The R2 and R3 together form a substituted four-membered ring, five-membered ring or six-membered ring, and the four-membered ring, five-membered ring or six-membered ring contains 1-2 heteroatoms.

5. An EGFR inhibitor according to claim 1, characterized in that: The R2 and R3 together constitute a substituted four-membered ring, five-membered ring or six-membered ring, and the substituent of the four-membered ring, five-membered ring or six-membered ring is selected from at least one of alkyl, CN, OH, OMe, NH2, NHMe, N(Me)2, Cl, Br, F, CF3, CONH2, SO2NH2, SO2 (C1-C4 alkyl), CO (C1-C4 alkyl) or NHSO2 (C1-C4 alkyl).

6. An EGFR inhibitor according to claim 1, characterized in that: The inhibitor is , , , , , , , , , , or .

7. The method for preparing the EGFR inhibitor according to any one of claims 1 to 6, characterized in that: The preparation process is as follows: 。 8. Use of the EGFR inhibitor according to any one of claims 1 to 6 for preparing a medicament for treating or preventing lung cancer, characterized in that: The lung cancer is non-small cell lung cancer.

9. A pharmaceutical composition, characterized in that The composition comprises an excipient and the EGFR inhibitor according to any one of claims 1 to 6.

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