Benzopyrimidine compound, preparation method therefor, pharmaceutical composition and use thereof

Abstract

Disclosed are a benzopyrimidine compound, a preparation method therefor, a pharmaceutical composition and the use thereof. Specifically disclosed is a benzopyrimidine compound as represented by formula (I) or a pharmaceutically acceptable salt thereof. The benzopyrimidine compound has good inhibitory activity against EGFR C797S mutation and selectivity for EGFR C797S mutation, and has one or more of the following advantages: good brain penetration ability and oral pharmacokinetic properties.

Description

Benzopyrimidine compounds, preparation methods, pharmaceutical compositions and applications thereof

[0001] This application claims the benefit of Chinese patent application No. 2024100589946, filed on January 15, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a benzopyrimidine compound, a preparation method, a pharmaceutical composition and application thereof. Background Art

[0003] EGFR (epidermal growth factor receptor, also known as ErbB-1 or HER1) is a member of the epidermal growth factor receptor (HER) family and a member of the receptor tyrosine kinase family. Upon ligand binding, it dimerizes and undergoes autotyrosine phosphorylation, thereby regulating downstream signaling pathways, including the PI3K-AKT-mTOR signaling pathway, which regulates cell survival, and the RAS-RAF-MEK-ERK signaling pathway, which regulates cell proliferation. EGFR regulates cell growth and division in normal cells, but in certain tumors, overexpression or mutations (such as exon 19 deletion or L858R) can lead to abnormal proliferation and spread of tumor cells. Therefore, inhibiting EGFR kinase activity has become an important strategy for treating EGFR mutation-positive tumors.

[0004] Over the past few decades, significant breakthroughs have been made in the development of EGFR inhibitors. First-generation EGFR inhibitors, such as erlotinib and gefitinib, inhibit EGFR activity by reversibly binding to the tyrosine kinase domain. However, tumor cells can develop resistance during treatment, with the most common mutation being the T790M mutation (accounting for approximately 50%).

[0005] Second-generation EGFR inhibitors, such as afatinib and dacomitinib, covalently bind to EGFR and inhibit its kinase activity. These inhibitors show higher anti-tumor activity in certain drug-resistant tumors, but still have problems of drug resistance and poor selectivity.

[0006] Third-generation EGFR inhibitors were developed to target the EGFR T790M mutation. This mutation is a common mechanism of EGFR resistance, conferring resistance to first- and second-generation EGFR inhibitors. Osimertinib was the first drug approved for the treatment of EGFR T790M mutation-positive non-small cell lung cancer.

[0007] Although third-generation EGFR inhibitors have achieved some success in treating EGFR T790M-resistant tumors, the problem of inducing further resistance remains. One of the most prominent mechanisms of resistance is the emergence of the EGFR C797S mutation, which accounts for nearly 20%. Therefore, the development of inhibitors targeting the EGFR C797S mutation has become a new target for treating resistant tumors.

[0008] Currently, fourth-generation EGFR-TKIs, such as TQB3804, U3-1402, BLU-945, CH7233163, JNJ-61186372, OBX02-011, BI-732, and H002, are still in clinical trials and hold promise for overcoming EGFR-TKI resistance. However, sufficient clinical efficacy data for these drugs remains to be obtained, and new inhibitors that can effectively inhibit the EGFR C797S mutation are still needed to provide more treatment options for drug-resistant tumors. Summary of the Invention

[0009] This invention addresses the shortage of existing EGFR C797S mutation inhibitors by providing novel benzopyrimidine compounds, preparation methods, pharmaceutical compositions, and applications thereof. These benzopyrimidine compounds exhibit excellent inhibitory activity and selectivity against the EGFR C797S mutation, and possess one or more of the following advantages: good brain penetration and oral pharmacokinetic properties.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

[0012] in,

[0013] The carbon atom marked with "*" indicates that when it is a chiral carbon atom, it is in the R configuration, S configuration or a mixture thereof;

[0014] R 1 and R 2 are each independently H or halogen;

[0015] R 3 is a C1-C6 alkyl group;

[0016] R 4 is a C1-C6 alkoxy group;

[0017] R 5 It is a halogen.

[0018] In certain preferred embodiments of the present invention, certain groups in the compound of formula (I) or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0019] In one embodiment of the present invention, R 1 and R 2 wherein the halogen is independently F, Cl, Br or I, for example, F.

[0020] In one embodiment of the present invention, R 3 In the embodiment, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl.

[0021] In one embodiment of the present invention, R 4 In the embodiment, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, such as methoxy.

[0022] In one embodiment of the present invention, R 5 wherein the halogen is F, Cl, Br or I, for example, F.

[0023] In one embodiment of the present invention, R 1 It is H or F, for example, F.

[0024] In one embodiment of the present invention, R 2 It is H or F, for example, F.

[0025] In one embodiment of the present invention, R 3 It is a methyl group.

[0026] In one embodiment of the present invention, R 4 It is a methoxy group.

[0027] In one embodiment of the present invention, R 5 For F.

[0028] In one embodiment of the present invention,

[0029] R 1 H or F;

[0030] R 2 H or F;

[0031] R 3 is methyl;

[0032] R 4 is methoxy;

[0033] R 5 For F.

[0034] In one embodiment of the present invention,

[0035] R 1 is F;

[0036] R 2 is F;

[0037] R 3 is methyl;

[0038] R 4 is methoxy;

[0039] R 5 For F.

[0040] In one embodiment of the present invention,

[0041] R 1 is H;

[0042] R 2 is H;

[0043] R 3 is methyl;

[0044] R 4 is methoxy;

[0045] R 5 For F.

[0046] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (I-1), formula (I-2), formula (I-3) or formula (I-4):

[0047] Among them, in the above formulas, R 1 、R 2 、R 3 、R 4 and R 5 The definition of is as described in any embodiment of the present invention, Indicates the relative configuration of a stereocenter.

[0048] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (I-5), formula (I-6), formula (I-7) or formula (I-8):

[0049] Among them, in the above formulas, R 1 、R 2 、R 3 、R 4 and R 5 The definition of is as described in any embodiment of the present invention.

[0050] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0051] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0052] The compound that elutes first under the following chiral analysis conditions: a chiral chromatographic column, an elution phase of CO2 (A): ethanol containing 0.05% ethylenediamine (B), a gradient of 5% B to 40% B over 4 minutes, 40% B to 5% B over 0.2 minutes, and a hold of 5% B for 1.8 minutes, at a flow rate of 2.5 mL / min; preferably, under the conditions, the chiral chromatographic column is a Chiralpak AS-3 column having specifications of 150 mm by 4.6 mm, a filler particle size of 3 μm, a Waters UPCC instrument with a PDA detector, and a column temperature of 35° C.; and / or, preferably, the retention time of the compound that elutes first is approximately 3.71 min;

[0053] The compound eluting later under the following chiral analysis conditions: chiral chromatographic column, elution phase is CO2 (A): ethanol containing 0.05% ethylenediamine (B), gradient: 5% B to 40% B 4 minutes, 40% B to 5% B 0.2 minutes, hold 5% B 1.8 minutes, flow rate 2.5 mL / min; preferably, under the said conditions, the chiral chromatographic column is a chiral column Chiralpak AS-3, its specifications are 150 mm*4.6 mm, the filler particle size is 3 μm, the instrument is Waters UPCC with PDA detector, and the column temperature is 35°C; and / or, preferably, the retention time of the compound eluting later is about 4.24 min.

[0054] The present invention also provides a pharmaceutical composition comprising (i) a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, and (ii) a pharmaceutically acceptable excipient.

[0055] The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the use of the above-mentioned pharmaceutical composition in the preparation of an EGFR inhibitor, preferably, the EGFR inhibitor is an EGFR C797S inhibitor (e.g., an EGFR C797S single mutation or L858R / C797S double mutation inhibitor).

[0056] The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition as described in any of the above schemes, for use in the preparation of a medicament for preventing and / or treating EGFR-related diseases; preferably, the EGFR-related disease is a disease associated with the EGFR C797S mutation (e.g., EGFR C797S single mutation or L858R / C797S double mutation), such as a tumor, further such as non-small cell lung cancer or non-small cell lung cancer brain metastasis.

[0057] The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition according to any of the above schemes, for use in the preparation of a medicament for preventing and / or treating a disease resistant to osimertinib; preferably, the osimertinib resistance is resistance caused by an EGFR C797S mutation (e.g., an EGFR C797S single mutation or an L858R / C797S double mutation); and / or, preferably, the osimertinib-resistant disease is an osimertinib-resistant tumor, such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer; more preferably, the osimertinib-resistant disease is a resistant tumor caused by an EGFR C797S mutation (e.g., an EGFR C797S single mutation or an L858R / C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.

[0058] The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, as described in any of the above schemes, for use in the preparation of a drug for preventing and / or treating a disease resistant to drug caused by an EGFR C797S mutation (e.g., an EGFR C797S single mutation or an L858R / C797S double mutation).

[0059] The present invention also provides a method for preventing and / or treating EGFR-related diseases, comprising administering to a patient a therapeutically effective amount of a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; preferably, the EGFR-related disease is a disease associated with EGFR C797S (e.g., EGFR C797S single mutation or L858R / C797S double mutation), such as non-small cell lung cancer or non-small cell lung cancer brain metastasis.

[0060] The present invention also provides a method for preventing and / or treating a disease caused by drug resistance due to an EGFR C797S mutation (e.g., an EGFR C797S single mutation or an L858R / C797S double mutation), comprising administering to a patient a therapeutically effective amount of a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0061] The present invention also provides a method for preventing and / or treating a disease that is resistant to osimertinib, comprising administering a therapeutically effective amount of a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition to a patient; preferably, the osimertinib resistance is resistance caused by an EGFR C797S mutation (e.g., an EGFR C797S single mutation or an L858R / C797S double mutation); and / or, preferably, the osimertinib-resistant disease is an osimertinib-resistant tumor, such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer; more preferably, the osimertinib-resistant disease is a resistant tumor caused by an EGFR C797S mutation (e.g., an EGFR C797S single mutation or an L858R / C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.

[0062] The present invention also provides a method for preparing the compound represented by formula (I) according to any of the above schemes, which is the following method 1 or method 2:

[0063] Method 1 comprises the following steps: in a solvent, in the presence of a base, subjecting the compound represented by formula (IA) to a deprotection reaction to prepare the compound represented by formula (I);

[0064] Among them, "*", R 1 、R 2 、R 3 、R 4 and R 5 The definition of R is as described in any embodiment of the present invention, a is an alkynyl protecting group;

[0065] Method 2 comprises the following steps: in a solvent, under the action of an acid, condensing a compound represented by formula (IB) with a compound represented by formula (IC) to prepare a compound represented by formula (I);

[0066] Among them, "*", R 1 、R 2 、R 3 、R 4 and R 5 The definition of is as described in any embodiment of the present invention.

[0067] In one embodiment of the present invention, in method 1, the solvent is an ether solvent, such as a cyclic ether solvent, further such as tetrahydrofuran.

[0068] In one embodiment of the present invention, in method 1, the base is a quaternary ammonium base, such as a tetraalkylammonium halide, and further such as tetrabutylammonium fluoride.

[0069] In one embodiment of the present invention, in the method 1, the R a It is TMS (ie trimethylsilyl).

[0070] In one embodiment of the present invention, in method 1, the equivalent ratio of the base to the compound represented by formula (IA) is (1-1.5):1.

[0071] In one embodiment of the present invention, in method 1, the reaction temperature of the deprotection reaction is 25-35°C, for example, 30°C.

[0072] In one embodiment of the present invention, in method 2, the solvent is an alkylbenzene solvent, such as toluene.

[0073] In one embodiment of the present invention, in method 2, the acid is an organic acid, such as acetic acid.

[0074] In one embodiment of the present invention, in method 2, the equivalent ratio of the compound represented by formula (IC) to the compound represented by formula (IB) is (2-3):1, for example, 2.5:1.

[0075] In one embodiment of the present invention, in method 2, the equivalent ratio of the acid to the compound represented by formula (IB) is (4-6):1, for example, 5:1.

[0076] In one embodiment of the present invention, in method 2, the reaction temperature of the condensation reaction is 15-25°C, for example, 20°C.

[0077] The present invention also provides a compound represented by formula (IA) or formula (IB):

[0078] Among them, "*", R 1 、R 2 、R 3 、R 4 、R 5 and R a is defined as in any of the above schemes.

[0079] In one embodiment of the present invention, the compound represented by formula (IA) is:

[0080] In one embodiment of the present invention, the compound represented by formula (IB) is any one of the following compounds:

[0081] Indicates the relative configuration of a stereocenter.

[0082] Unless otherwise specified, the terms used in this application have the following definitions. Definitions of terms not mentioned below are as commonly understood by those skilled in the art to which the present invention belongs.

[0083] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively nontoxic, pharmaceutically acceptable acid or base. When a compound contains relatively acidic functional groups, a base addition salt can be obtained by contacting a neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When a compound of the present invention contains relatively basic functional groups, an acid addition salt can be obtained by contacting a neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0084] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0085] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having a specified number of carbon atoms. 1-6 Alkyl (C1, C2, C3, C4, C5, C6), such as C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0086] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0087] Unless otherwise specified, use a solid wedge key. and dotted wedge key Indicates the absolute configuration of a stereocenter. Use a straight solid bond and straight dashed key represents the relative configuration of the stereocenter, for example, in the compound shown in formula (I-2), R 1 The connection is a straight solid bond, and R 2 The connection is a straight dotted bond, which means R 1 and R 2 are located on opposite sides of the piperidine ring; for example, in the compound shown in formula (I-1), R 1 The connection is a straight solid bond, and R 2 The connection is also a straight solid line bond, which means R1 and R 2 They are located on the same side of the piperidine ring, and the straight solid line bond and the straight dotted line bond do not represent R 1 and R 2 The absolute configuration of the attached carbon atoms.

[0088] In the aforementioned applications, the inhibitors can be used in mammalian organisms; they can also be used in vitro, mainly for experimental purposes, for example, as standard or control samples for comparison, or prepared into kits according to conventional methods in the art to provide rapid detection of EGFR C797S inhibitory effects.

[0089] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances contained in pharmaceutical preparations, other than the active ingredient. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0090] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0091] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0092] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0093] The reagents and raw materials used in the present invention are commercially available.

[0094] The positive progress of the present invention is that the benzopyrimidine compounds of the present invention have good inhibitory activity and EGFR C797S mutation selectivity, and have one or more of the following advantages: good brain penetration ability and oral pharmacokinetic properties. DETAILED DESCRIPTION

[0095] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0096] Example 1 Synthesis of Compound I-1

[0097] Step 1 Synthesis of Intermediate 1-2

[0098] Compound 1-1 (100 mg, 474.80 μmol, 1 eq) and compound 1-1a (65.62 mg, 569.76 μmol, 66.62 μL, 1.2 eq) were dissolved in 3 mL of tetrahydrofuran, and triphenylphosphine (149.44 mg, 569.76 μmol, 1.2 eq) and diisopropyl azodicarboxylate (124.81 mg, 617.23 μmol, 119.66 μL, 1.3 eq) were added. The reaction system was stirred at 20 ° C for 1 hour. LCMS monitoring showed that the raw material was completely consumed and the main product was generated. The reaction solution was concentrated under reduced pressure to a residue and chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0-15% methanol / dichloromethane; flow rate: 30 mL / min) to prepare intermediate 1-2 (120 mg, yield: 82.12%). LCMS (ESI): m / z calculated value C 15 H 19 ClN3O2 + .[M+H] + =308.12, measured value [M+H] + =308.0.

[0099] Step 2 Synthesis of Intermediates 1-4

[0100] Compound 1-3 (3 g, 15.79 mmol, 1 eq) and compound 1-3a (2.32 g, 23.64 mmol, 3.28 mL, 1.50 eq) were dissolved in 30 mL of toluene, and copper iodide (300.69 mg, 1.58 mmol, 0.1 eq), bis(triphenylphosphine)palladium dichloride (1.11 g, 1.58 mmol, 0.1 eq), triphenylphosphine (414.11 mg, 1.58 mmol, 0.1 eq) and diisopropylethylamine (10.20 g, 78.94 mmol, 13.75 mL, 5 eq) were added in sequence. The system was evacuated and replaced with nitrogen three times, and the reaction was stirred at 110 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 1-4 (2.8 g, yield: 85.54%). LCMS (ESI): m / z calculated value C 11 H 15 FNSi + .[M+H] + =208.10, measured value [M+H] + =208.1.

[0101] .

[0102] Step 3 Synthesis of Intermediate 1-5

[0103] Intermediate 1-2 (100 mg, 324.91 μmol, 1 eq) and intermediate 1-4 (202.08 mg, 974.74 μmol, 3 eq) were dissolved in 9 mL of isopropanol. 37% hydrochloric acid solution (160.09 mg, 1.62 mmol, 156.95 μL, 5 eq) was added dropwise to the system. The reaction system was stirred at 100 ° C for 2 hours. LCMS monitoring showed that the raw material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO rapid liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-30% (acetone:methanol=8:1) / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 1-5 (120 mg, yield: 77.17%). LCMS (ESI): m / z calculated value C 26 H 32 FN4O2Si + .[M+H] + =479.23, measured value [M+H] + =479.2.

[0104] Step 4 Synthesis of Compound I-1

[0105] Intermediate 1-5 (210 mg, 438.75 μmol, 1 eq) was dissolved in 2 mL of tetrahydrofuran and TBAF (1 M, 438.75 μL, 1 eq) was added. The reaction system was stirred at 30°C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-15% methanol / dichloromethane; flow rate: 30 mL / min) to prepare compound I-1 (70 mg, yield: 37.68%, purity: 96%). LCMS (ESI): m / z calculated value C 23 H 24 FN4O2 + .[M+H] + =407.19, measured value [M+H] + =407.1. 1 H NMR(400MHz,DMSO-d6)δppm 9.57(s,1H),8.41(s,1H),7.87(s,1H),7.70-7.61(m,1H),7.57-7.49(m,1H),7.33(t,J=7.9Hz, 1H),7.27(s,1H),4.64-4.55(m,1H),3.99(s,3H),2.82-2.71(m,2H),2.31-2.28(m,5H),2.10(br d,J=10.7Hz,2H),1.84-1.71(m,2H).

[0106] Example 2 Synthesis of Compound I-2:

[0107] Step 1 Synthesis of Intermediate 2-2

[0108] Compound 2-1 (15 g, 58.30 mmol, 1 eq) was dissolved in 50 mL of tetrahydrofuran, and sodium hydride (2.47 g, 61.80 mmol, 60% purity, 1.06 eq) was added at 0°C. The reaction system was stirred at 0°C for 30 minutes, then slowly warmed to 20°C and stirred for another 30 minutes. A solution of N-fluorobisbenzenesulfonamide (NFSI) (18.38 g, 58.30 mmol, 1 eq) in tetrahydrofuran (200 mL) was slowly added to the above mixture. The reaction system was stirred at 20°C for 2 hours. TLC (petroleum ether:ethyl acetate = 10:1) confirmed complete consumption of the starting material and the formation of the product. The reaction solution was diluted with 100 mL of saturated sodium chloride aqueous solution, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was then purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column type: 60g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 60 mL / min) to prepare intermediate 2-2 as a colorless oil (6.5 g, yield: 40.5%). LCMS (ESI): m / z calculated value C 12 H 19 FNO5 + .[M+H] + =276.12, measured value [Mt-Bu+H] + =220.0.

[0109] Step 2 Synthesis of Intermediate 2-3

[0110] Intermediate 2-2 (3.8 g, 13.80 mmol, 1 eq) was dissolved in 35 mL of DMF, and triethylamine (4.19 g, 41.41 mmol, 5.76 mL, 3 eq) and triethylsilyl chloride (4.58 g, 30.37 mmol, 5.17 mL, 2.2 eq) were added. The reaction system was stirred at 60°C for 30 minutes. TLC (petroleum ether: ethyl acetate = 8:1) monitored the complete consumption of the starting material and the formation of product spots. After the reaction was cooled to 20°C, it was quenched with saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with cyclohexane (50 mL*2). After the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue and chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 120 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 90 mL / min) to obtain intermediate 2-3 as a colorless oil (3.1 g, yield: 57.65%). 1 H NMR(400MHz,CD3Cl)δppm 5.11(br s,1H),4.40(br d,J=13.9Hz,1H),4.23(t,J=13.6Hz,1H),3.89-3.34(m,5H),1.45-1.32(m,9H),0.96-0.81(m,9H),0.67-0.55(m,6H).

[0111] Step 3 Synthesis of Intermediate 2-4

[0112] Intermediate 2-3 (3.3 g, 8.47 mmol, 1 eq) was dissolved in 60 mL of acetonitrile, and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectfluor) (4.50 g, 12.71 mmol, 1.5 eq) was added. The reaction system was stirred at 20 ° C for 17 hours. TLC (petroleum ether: ethyl acetate = 7:1) monitored the complete consumption of the starting material and the formation of product spots. The reaction solution was evaporated to dryness under reduced pressure to obtain a residue, which was then chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 80 g Silica Flash Column; mobile phase gradient: 0-100% ethyl acetate / petroleum ether; flow rate: 80 mL / min) to prepare intermediate 2-4 as a colorless oil (2.2 g, yield: 88.55%). LCMS (ESI): m / z calculated value C 12 H 18 F2NO5 + .[M+H] + =294.11, measured value [Mt-Bu+H] + =238.0.

[0113] Step 4 Synthesis of Intermediate 2-5

[0114] Intermediate 2-4 (2.2 g, 7.50 mmol, 1 eq) was dissolved in 30 mL of ethanol and potassium hydroxide solution (1 M, 8.25 mL, 1.1 eq) was added dropwise. The reaction system was stirred at 80 ° C for 3 hours. TLC (petroleum ether: ethyl acetate = 4: 1) monitored the complete consumption of the raw materials and the formation of products. The reaction solution was diluted with 80 mL of ethyl acetate and 80 mL of water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (80 mL * 2). After the organic phases were combined, they were washed with saturated brine (30 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue and chromatographed on a silica gel column (ISCO rapid liquid preparative chromatograph; column model: 50 g Silica Flash Column; mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediate 2-5 as a colorless oil (1.4 g, yield: 79.34%). LCMS (ESI): m / z calculated value C 10 H 16 F2NO3 + .[M+H] + =236.11, measured value [Mt-Bu+H] + =180.0.

[0115] Step 5 Synthesis of Intermediates 2-6, 2-7 and 2-8

[0116] Intermediate 2-5 (1.4 g, 5.95 mmol, 1 eq) was dissolved in 20 mL of tetrahydrofuran, and a toluene solution of diisobutylaluminum hydride (1 M, 5.95 mL, 1 eq) was slowly added dropwise at 0°C. The reaction system was stirred at 0°C for 1 hour. TLC monitored the complete reaction of the raw materials, and the developing solvent was (petroleum ether (containing 0.2% formic acid) / ethyl acetate (containing 10% methanol) = 3:1. The resulting product intermediates were three isomers, with an Rf value of approximately 0.31 for intermediate 2-6, an Rf value of approximately 0.30 for intermediate 2-7, and an Rf value of approximately 0.18 for intermediate 2-8. The reaction solution was concentrated to a residue and purified by silica gel column chromatography (ISCO rapid liquid preparative chromatograph; column model: 60 g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediate 2-6 as a colorless oil (120 mg, yield: 8.5%). 1 H NMR(400MHz,DMSO-d6)δppm 5.94-5.81(m,1H),4.50-4.34(m,1H),4.33-4.24(m,1H),3.84-3.71(m,1H),3.71-3.57(m,2H),3.55-3.43(m,2H),1.47-1.33(m,9H). 19 F NMR (376 MHz, DMSO-d6) δ ppm -192.21 (d, J = 59.0 Hz). Intermediate 2-7 was obtained as a colorless oil (510 mg, yield: 36.12%). 1 HNMR (400MHz, CD3Cl) δppm 4.93-4.53(m,2H),4.18-3.72(m,3H),3.68-3.18(m,2H),2.49-2.38(m,1H),1.53-1.43(m,9H). 19 F NMR (376 MHz, CD3Cl) δ ppm -198.00 (br d, J = 215.0 Hz), -204.46 (br d, J = 211.5 Hz). Meanwhile, intermediate 2-8 was obtained as a colorless oil (505 mg, yield: 35.76%). 1 H NMR(400MHz,CD3Cl)δppm 4.80-4.67(m,1H),4.63-4.52(m,1H),4.22-4.05(m,2H),4.02-3.84(m,1H),3.49-3.29(m,2H),2.72-2.56(m,1H),1.55-1.43(m,9H). 19F NMR (376MHz, CD3Cl) δppm-202.45 (br d, J=69.4Hz).

[0117] Step 6 Synthesis of Intermediate 2-10

[0118] Intermediate 2-8 (250.00 mg, 1.05 mmol, 1 eq) and intermediate 2-9 (206.68 mg, 1.05 mmol, 1 eq) (preparation method reference patent CN110343090A, 2019) were dissolved in 5 mL of tetrahydrofuran and potassium tert-butoxide (153.72 mg, 1.37 mmol, 1.3 eq) was added. The reaction system was stirred at 20 ° C for 1 hour. TLC (petroleum ether: ethyl acetate = 1: 1) monitored the complete reaction of the raw materials and the formation of the main product. The reaction solution was concentrated under reduced pressure to a residue and chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 12g Silica Flash Column; mobile phase gradient: 0-90% ethyl acetate / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 2-10 as a yellow solid (308 mg, yield: 70.71%). LCMS (ESI): m / z calculated value C 18 H 22 F2N3O6 + .[M+H] + =414.15, measured value [Mt-Bu+H] + =358.1.

[0119] Step 7 Synthesis of Intermediate 2-11

[0120] Intermediate 2-10 (308 mg, 745.09 μmol, 1 eq) was dissolved in 4 mL of dichloromethane and 4 mL of trifluoroacetic acid was added dropwise. The reaction system was stirred at 25°C for 1 hour. LCMS monitoring showed that the starting material was completely consumed and product was generated. The reaction solution was concentrated under reduced pressure to obtain intermediate 2-11 as a light yellow oil (305 mg, crude product, trifluoroacetate salt). LCMS (ESI): m / z calculated value: C 13 H 14 F2N3O4 + .[M+H] + =314.09, measured value [M+H] + =314.1.

[0121] Step 8 Synthesis of Intermediate 2-12

[0122] Intermediate 2-11 (305 mg, 713.81 μmol, 1 eq) was dissolved in 2 mL of methanol, and 37% aqueous formaldehyde solution (116.06 mg, 1.43 mmol, 2 eq) and sodium cyanoborohydride (93.63 mg, 1.49 mmol, 2 eq) were added in sequence. The reaction system was stirred at 20°C for 2 hours. TLC (ethyl acetate: methanol = 20:1) monitored the complete reaction of the raw materials and the formation of the main product. The reaction solution was concentrated under reduced pressure to a residue and purified by silica gel column chromatography (ISCO fast liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-100% (acetone:methanol=10:1) / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 2-12 as a yellow solid (192 mg, yield: 82.18%). LCMS (ESI): m / z calculated value C 14 H 16 F2N3O4 + .[M+H] + =328.11, measured value [M+H] + =328.1.

[0123] Step 9 Synthesis of Intermediate 2-13

[0124] Intermediate 2-12 (192 mg, 586.65 μmol, 1 eq) was dissolved in 5 mL of ethanol and sodium dithionite (612.84 mg, 3.52 mmol, 6 eq) was added. The reaction system was stirred at 20 ° C for 16 hours. TLC (petroleum ether: ethyl acetate = 3:1) monitored the complete reaction of the raw materials and the generation of the main product. The reaction system was diluted with 10 mL of ethyl acetate and 10 mL of water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mL * 2). After the organic phases were combined, they were washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue and chromatographed on a silica gel column (ISCO rapid liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-100% (ethyl acetate:methanol = 20:1) / petroleum ether; flow rate: 30 mL / min) to prepare intermediate 2-13 as a colorless oil (72 mg, yield: 41.28%). LCMS (ESI): m / z calculated value C 14 H 18 F2N3O2 + .[M+H] + =298.14, measured value [M+H] + =298.1.

[0125] Step 10 Synthesis of Compound I-2

[0126] Intermediate 2-13 (72 mg, 242.18 μmol, 1 eq) was dissolved in 2 mL of toluene, and acetic acid (72.71 mg, 1.21 mmol, 69.32 μL, 5 eq) and intermediate 2-13a (169.69 mg, 605.45 μmol, 2.5 eq) (CN115260153A, 2022) were added in sequence. The reaction system was stirred at 20 ° C for 2 hours. LCMS monitoring showed that the raw material was completely consumed and the product was generated. The reaction solution was concentrated to obtain a residue, which was chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-100% (ethyl acetate:methanol = 10:1) / petroleum ether; flow rate: 30 mL / min) to prepare compound I-2 as a white solid (23 mg, yield: 21.04%, purity: 98%). LCMS (ESI): m / z calculated value C 23 H 22 F3N4O2 + .[M+H] + =443.17, measured value [M+H] + =443.2. 1 HNMR(400MHz,DMSO-d6)δppm 9.54(s,1H),8.39(s,1H),7.99(s,1H),7.62(br dd,J=8.3,15.8Hz,1H),7.47(t,J=6.9Hz,1H),7.31-7.23(m,2H),5.12-4.67(m,3H),4.55(s,1H),3.98(s,3H),2.93(br s,2H),2.72-2.53(m,2H),2.32(s,3H).

[0127] Example 3 Synthesis of Compound I-3 and Compound I-4:

[0128] Step 1 Synthesis of Compound 3-6

[0129] Referring to the synthesis method of Example 2, the corresponding raw materials were replaced and intermediates 2-7 and 2-9 were used as raw materials to prepare compound 3-6 as a white solid. LCMS (ESI): m / z calculated value C 23 H 22 F3N4O2 + .[M+H] + =443.17, measured value [M+H] + =443.2.

[0130] Step 2 Chiral preparation of compound I-3 and compound I-4

[0131] Compound 3-6 (70 mg) was further separated by chiral SFC using the following chiral preparation conditions: chiral column DAICEL CHIRALPAK AS (size: 250 mm x 30 mm, particle size 10 μm), elution phase: CO2 (A): ethanol containing 0.1% ammonia (B), isocratic (A / B = 70 / 30). Compound I-3 was isolated as the front peak, a white solid (30 mg, yield: 42.85%, ee% value: 98%). LCMS (ESI): m / z calculated: C 23 H 22 F3N4O2 + .[M+H] + =443.17, measured value [M+H] + =443.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 6.9 Hz, 1H), 7.31-7.25 (m, 2H), 5.28-5.10 (m, 1H), 5.09-4.88 (m, 1H), 4.82-4.66 (m, 1H), 4.55 (s, 1H), 3.97 (s, 3H), 3.21-3.00 (m, 2H), 2.45-2.25 (m, 5H). Compound I-4 was isolated as a white solid (29 mg, yield: 41.42%, ee% value: 98%). LCMS (ESI): m / z calculated value: C 23 H 22 F3N4O2 + .[M+H] + =443.17, measured value [M+H] + =443.2. 1 H NMR(400MHz,DMSO-d6)δppm 9.49(s,1H),8.39(s,1H),7.97(s,1H),7.61(t,J=7.5Hz,1H),7.46(t,J=6.8Hz,1H),7.32-7.22(m,2H),5.27-5. 09(m,1H),5.08-4.87(m,1H),4.81-4.66(m,1H),4.54(s,1H),3.97(s,3H),3.20-3.00(m,2H),2.45-2.25(m,5H).

[0132] Chiral analysis conditions: Instrument: Waters UPCC with PDA detector, chiral column: Chiralpak AS-3 (specifications: 150 mm*4.6 mm, particle size: 3 μm), elution phase: CO2 (A): ethanol containing 0.05% ethylenediamine (B), gradient: 5% B to 40% B over 4 minutes, 40% B to 5% B over 0.2 minutes, hold at 5% B for 1.8 minutes); flow rate: 2.5 mL / min, column temperature: 35°C; compound I-3, retention time: 3.71 minutes; compound I-4, retention time: 4.24 minutes.

[0133] Example 4 Synthesis of Compound I-5:

[0134] Referring to the synthesis method of Example 2, the corresponding raw materials were replaced and intermediates 2-6 and 2-9 were used as raw materials to prepare compound I-5, which was a white solid. LCMS (ESI): m / z calculated value C 23 H 22 F3N4O2 + .[M+H] + =443.17, measured value [M+H] + =443.2. 1 H NMR(400MHz,DMSO-d6)δppm 9.49(s,1H),8.39(s,1H),8.04(s,1H),7.63(br t,J=7.0Hz,1H),7.47(t,J=6.3Hz,1H),7.31-7.23(m,2H),4.92-4.81(m,2H),4. 78-4.68(m,1H),4.55(s,1H),3.97(s,3H),3.19-3.09(m,2H),2.41-2.29(m,5H).

[0135] Compound structure

[0136] Biological Test Example 1: Cell Proliferation Inhibition Data

[0137] The Ba / F3 cell line stably carrying the EGFR-C797S mutation and the A431 cell line with wild-type EGFR were used to evaluate the inhibitory activity of the compounds against EGFR-C797S-driven cell proliferation and against wild-type EGFR cells.

[0138] Assay Procedure: Centrifuge resuspended A431 cells or suspension-cultured Ba / F3-TEL-EGFR-C797S cells, resuspend in growth medium, and count using a cell counter. Dilute the cell suspension to the desired density in growth medium and transfer the cell suspension to a 96-well plate. Add various concentrations of the test compound to the 96-well plate and incubate at 37°C, 5% CO₂ for 72 hours.

[0139] After 72 hours, the cell culture plates were removed and each well was added Reagent, mix the contents on a shaker for 2 minutes to lyse the cells. Incubate at room temperature for 10 minutes to stabilize the luminescent signal and record the luminescence on a SpectraMax Paradigm multi-function fluorescence microplate reader. The anti-cell proliferation activity inhibition rate was calculated as follows: Inhibition rate (%) = 100-(RLU compound-RLU blank) / (RLU control-RLU blank)*100% (where RLU control wells are cells plus DMSO wells, and RLU blank wells are culture medium plus DMSO wells). The curve was fitted by compound concentration and inhibition rate to calculate IC 50 (half inhibitory concentration).

[0140] The compound test results are shown in Table 1 below:

[0141] Table 1. Inhibitory effects of compounds on the proliferation of EGFR wild-type A431 cells and EGFR-C797S mutant Ba / F3 cells

[0142] The compound of the present invention has a strong proliferation inhibitory activity on Ba / F3 cells stably transfected with EGFR-C797S, and the effect is significantly better than WSD-0922, the third-generation EGFR inhibitor AZD9291 and the fourth-generation inhibitor BLU-945; and has better EGFR C797S mutation selectivity.

[0143] Biological Test Example 2: Kinase Inhibition Data

[0144] The HTRF technique was used to evaluate the inhibitory effects of the compounds on the EGFR kinase activity of wild-type, C797S single mutation, and L858R / C797S double mutation.

[0145] Add the test compound to a 384 assay plate and a mixture of kinase and metal. Add substrate and ATP solution to the wells and incubate at 25°C for 40 minutes. Add 5 μL of kinase detection reagent and incubate at 25°C for 60 minutes. Read the fluorescence signal at 620 nm (Cryptate) and 665 nm (XL665) using a microtiter plate.

[0146] The % inhibition was calculated as follows: % inhibition = 100% - (compound - positive control) / (negative control - positive control) * 100%

[0147] The % inhibition rate and the logarithm of compound concentration were fitted to a nonlinear regression (dose response-variable slope) using GraphPad 7.0 to calculate the IC 50 .

[0148] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*hillslope))

[0149] X: logarithm of inhibitor concentration; Y: % inhibition rate.

[0150] The inhibitory activity of the compounds against EGFR-WT, EGFR-C797S, and EGFR-L858R / C797S kinases is shown in Table 2 below:

[0151] Table 2. IC inhibition of compounds on EGFR-WT, EGFR-C797S, and EGFR-L858R / C797S kinases 50 (nM) value

[0152] / : Not detected

[0153] The compound of the present invention has potent inhibitory activity against EGFR-C797S and EGFR-L858R / C797S double mutations.

[0154] Biological test example 3: rat brain test

[0155] SD rats were fasted for 12 hours before dosing, but not water. The test article was administered orally using a solvent consisting of 15:20% Solutol Hs and 6:94 Hp-β-CD (v:v). Food was resumed two hours after dosing. Four hours after dosing, rats were anesthetized and sacrificed, and venous blood and brain samples were collected. Plasma was separated from whole blood. The brain tissue was washed with ice-cold saline to remove any residual blood, blotted dry with filter paper, and homogenized with saline. Samples were stored at -80°C until analysis.

[0156] The concentrations of the compounds in plasma and brain tissue homogenate samples were analyzed by HPLC-MS / MS.

[0157] The plasma and brain concentrations and the brain-to-blood concentration ratio of the compound 4 hours after oral administration are shown in Table 3 below:

[0158] Table 3: Plasma, brain tissue and brain-blood concentration ratios of the compounds in rats 4 hours after oral administration

[0159] The compound of the present invention has good brain-penetrating ability.

[0160] Biological Test Example 4: Rat PK Test

[0161] SD rats were fasted for 12 hours prior to administration, but not water. The test article was administered orally at a dose of 5 mg / kg in a solvent consisting of 15:20% Solutol Hs Hp-β-CD (6:94 v:v). Food was resumed two hours after administration. Blood was collected via the jugular vein or appropriate site at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. Plasma was separated from whole blood and stored at -80°C until analysis.

[0162] The concentrations of the compounds in plasma samples were analyzed by HPLC-MS / MS.

[0163] The pharmacokinetic parameters of the test product after oral administration to rats are shown in Table 4 below:

[0164] Table 4 Pharmacokinetic parameters of the test products after oral administration in rats

[0165] The compounds of the present invention have good oral PK properties.

[0166] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, Among them, the carbon atom marked with "*" represents that when it is a chiral carbon atom, it is in the R configuration, S configuration or a mixture thereof; R 1 and R 2 each independently is H or a halogen; R 3 is a C1-C6 alkyl group; R 4 is a C1-C6 alkoxy group; R 5 is a halogen.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, it satisfies one or more of the following conditions: (1)R 1 and R 2 wherein each of said halogens is independently F, Cl, Br or I, such as F; (2)R 3 In which, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl; (3)R 4 In the formula, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example, methoxy; (4)R 5 In which, the halogen is F, Cl, Br or I, such as F.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, it satisfies one or more of the following conditions: (1)R 1 is H or F, for example F; (2)R 2 is H or F, such as F; (3)R 3 is methyl; (4)R 4 is methoxy; (5)R 5 is F.

4. The compound represented by formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, it is any of the following cases: (1)R 1 is H or F; R 2 is H or F; R 3 is methyl; R 4 is methoxy; R 5 is F; (2)R 1 is F; R 2 is F; R 3 is methyl; R 4 is methoxy; R 5 is F; (3)R 1 is H; R 2 is H; R 3 is methyl; R 4 is methoxy; R 5 is F.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to at least one of claims 1-4, characterized in that The compound represented by formula (I) is a compound represented by formula (I-1), formula (I-2), formula (I-3) or formula (I-4): Among them, in the above formulas, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in at least one of claims 1-4, represents the relative configuration of the stereocenter.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to at least one of claims 1-4, characterized in that, The compound represented by formula (I) is a compound represented by formula (I-5), formula (I-6), formula (I-7) or formula (I-8): Among them, in the above formulas, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in at least one of claims 1-4.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, The compound represented by the formula (I) is any one of the following compounds:

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound represented by formula (I) is any of the following compounds: the compound that elutes first under the following chiral analysis conditions: chiral chromatographic column, eluent phase is CO2 (A): ethanol (B) containing 0.05% ethylenediamine, gradient: 5% B to 40% B for 4 minutes, 40% B to 5% B for 0.2 minutes, hold 5% B for 1.8 minutes, flow rate 2.5 mL / min; preferably, under the said conditions, the chiral chromatographic column is chiral column Chiralpak AS-3, its specification is 150 mm * 4.6 mm, packing particle size 3 μm, instrument Waters UPCC equipped with PDA detector, column temperature 35 °C; and / or, preferably, the retention time of the compound that elutes first is about 3.71 min; the compound that elutes later under the following chiral analysis conditions: chiral chromatographic column, eluent phase is CO2 (A): ethanol (B) containing 0.05% ethylenediamine, gradient: 5% B to 40% B for 4 minutes, 40% B to 5% B for 0.2 minutes, hold 5% B for 1.8 minutes, flow rate 2.5 mL / min; preferably, under the said conditions, the chiral chromatographic column is chiral column Chiralpak AS-3, its specification is 150 mm * 4.6 mm, packing particle size 3 μm, instrument Waters UPCC equipped with PDA detector, column temperature 35 °C; and / or, preferably, the retention time of the compound that elutes later is about 4.24 min.

9. A pharmaceutical composition, which comprises (i) a compound represented by formula (I) as described in at least one of claims 1-8 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient.

10. Use of a compound represented by formula (I) as described in at least one of claims 1-8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 9 in the preparation of an EGFR inhibitor; preferably, the EGFR inhibitor is an EGFR C797S inhibitor, such as an EGFR C797S single mutant inhibitor, an L858R / C797S double mutant inhibitor.

11. Use of a compound represented by formula (I) as described in at least one of claims 1-8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 9 in the preparation of a drug for preventing and / or treating diseases related to EGFR; preferably, the diseases related to EGFR are diseases related to EGFR C797S mutation, such as tumors, further such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.

12. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to at least one of claims 1-8, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for preventing and / or treating a disease resistant to osimertinib; preferably, the resistance to osimertinib is caused by an EGFR C797S mutation (such as an EGFR C797S single mutation or an L858R / C797S double mutation); and / or, preferably, the disease resistant to osimertinib is a tumor resistant to osimertinib, such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer; more preferably, the disease resistant to osimertinib is a tumor caused by an EGFR C797S mutation (such as an EGFR C797S single mutation or an L858R / C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.

13. A method for preparing a compound represented by formula (I) according to at least one of claims 1-8, which is method 1 or method 2 as follows: Method 1 comprises the following steps: in a solvent, under the action of a base, the compound shown by formula (I-A) undergoes a deprotection reaction to prepare the compound shown by formula (I), that's all; Among them, "*", R 1 , R 2 , R 3 , R 4 and R 5 is defined as described in at least one of claims 1 - 8, R a is an alkynyl protecting group; Method 2 comprises the following steps: in a solvent, under the action of an acid, the compound shown by formula (I-B) and the compound shown by formula (I-C) are subjected to a condensation reaction to prepare the compound shown by formula (I), and that's it; Among them, "*", R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in at least one of claims 1-8; Preferably, method 1 satisfies one or more of the following conditions: (1) The solvent is an ether solvent, such as a cyclic ether solvent, further such as tetrahydrofuran; (2) The base is a quaternary ammonium base, such as a tetraalkylammonium halide, further such as tetrabutylammonium fluoride; (3) The described R a is TMS; (4) The equivalent ratio of the base to the compound represented by formula (I-A) is (1 to 1.5):1; (5) In method 1, the reaction temperature of the deprotection reaction is 25 to 35 °C, such as 30 °C; Preferably, method 2 satisfies one or more of the following conditions: (1) The solvent is an alkylbenzene solvent, such as toluene; (2) In method 2, the acid is an organic acid, such as acetic acid; (3) In method 2, the equivalent ratio of the compound represented by formula (I-C) to the compound represented by formula (I-B) is (2 to 3):1, such as 2.5:1; (4) In method 2, the equivalent ratio of the acid to the compound represented by formula (I-B) is (4 to 6):1, such as 5:1; (5) In method 2, the reaction temperature of the condensation reaction is 15 to 25 °C, such as 20 °C.

14. A compound represented by formula (I-A) or formula (I-B): Among them, "*”, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in at least one of claims 1 - 8, R a is defined as described in claim 13; Preferably, the compound represented by formula (I-A) is: Preferably, the compound represented by formula (I-B) is any one of the following compounds: Represents the relative configuration of the stereocenter.

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