Benzopyrimidine compound, and preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a benzopyrimidine compound as well as a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention relates to a compound shown as a formula (I) or pharmaceutically acceptable salt thereof. The benzopyrimidine compound provided by the invention has good inhibitory activity and EGFR C797S mutation selectivity on EGFR C797S mutation, and has one or more of the following advantages: good brain entering ability and oral pharmacokinetic properties. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a benzopyrimidine compound, a preparation method thereof, a pharmaceutical composition and an application. Background Art

[0002] EGFR (epidermal growth factor receptor, also abbreviated as ErbB-1 or HER1) is one of the members of the epidermal growth factor receptor (HER) family and also belongs to the receptor tyrosine kinase family. After binding to ligands, it dimerizes and autophosphorylates tyrosine, and then regulates downstream signaling pathways, including the PI3K-AKT-mTOR signaling pathway that regulates cell survival and the RAS-RAF-MEK-ERK signaling pathway that regulates cell proliferation, etc. EGFR regulates cell growth and division in normal cells, but is overexpressed or mutated (such as exon 19 deletion or L858R, etc.) in some tumors, leading to abnormal proliferation and spread of tumor cells. Therefore, inhibiting EGFR kinase activity has become an important strategy for treating EGFR mutation-positive tumors.

[0003] In the past few decades, significant breakthroughs have been made in EGFR inhibitors. The first-generation EGFR inhibitors, such as erlotinib and gefitinib, inhibit their activity by reversibly binding to the EGFR tyrosine kinase domain. However, during use, tumor cells will develop drug resistance, and the most common one is the T790M mutation (about 50%).

[0004] The second-generation EGFR inhibitors, such as afatinib and dacomitinib, inhibit their kinase activity by covalently binding to EGFR. These inhibitors show higher anti-tumor activity in some drug-resistant tumors, but there are still problems of drug resistance and poor selectivity.

[0005] The third-generation EGFR inhibitors are developed for the EGFR T790M mutation. This mutation is a common EGFR drug resistance mechanism, which makes tumor cells resistant to the first-generation and second-generation EGFR inhibitors. Osimertinib is the first drug approved for the treatment of EGFR T790M mutation-positive non-small cell lung cancer.

[0006] Although the third-generation EGFR inhibitors have achieved certain success in treating EGFR T790M drug-resistant tumors, there are still problems of further inducing drug resistance. One of the most important drug resistance mechanisms is the emergence of the EGFR C797S mutation, accounting for nearly 20%. Therefore, developing inhibitors against the EGFR C797S mutation has become a new goal for treating drug-resistant tumors.

[0007] Currently, the fourth-generation EGFR-TKIs are still in the clinical trial stage, such as TQB3804, U3-1402, BLU-945, CH7233163, JNJ-61186372, OBX02-011, BI-732, H002, etc., which are expected to overcome the problem of EGFR-TKI resistance. However, the above drugs still lack sufficient clinical effective information, and new inhibitors that can effectively inhibit the EGFR C797S mutation still need to be developed to provide more treatment options for treating drug-resistant tumors. Summary of the Invention

[0008] In view of the deficiency of the existing types of EGFR C797S mutation inhibitors, the present invention provides a benzopyrimidine compound with a novel structure, its preparation method, pharmaceutical composition and application. The benzopyrimidine compound of the present invention has good inhibitory activity and EGFR C797S mutation selectivity against the EGFR C797S mutation, and has one or more of the following advantages: good brain penetration ability and oral pharmacokinetic properties.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0011]

[0012] wherein,

[0013] 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;

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

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

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

[0017] R 5 is a halogen.

[0018] In certain preferred embodiments of the present invention, some groups in the compound of formula (I) or a pharmaceutically acceptable salt thereof are defined as follows, and the groups not mentioned are the same as those described in any embodiment of the present invention (abbreviated as "in a certain embodiment of the present invention").

[0019] In a certain embodiment of the present invention, R 1 and R 2Among them, each of the halogens is independently F, Cl, Br or I, such as F.

[0020] In a certain embodiment of the present invention, R 3 Among them, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl.

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

[0022] In a certain embodiment of the present invention, R 5 Among them, the halogen is F, Cl, Br or I, such as F.

[0023] In a certain embodiment of the present invention, R 1 is H or F, such as F.

[0024] In a certain embodiment of the present invention, R 2 is H or F, such as F.

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

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

[0027] In a certain embodiment of the present invention, R 5 is F.

[0028] In a certain embodiment of the present invention,

[0029] R 1 is H or F;

[0030] R 2 is H or F;

[0031] R 3 is methyl;

[0032] R 4 is methoxy;

[0033] R 5 is F.

[0034] In a certain embodiment of the present invention,

[0035] R 1 is F;

[0036] R 2 is F;

[0037] R3 is methyl;

[0038] R 4 is methoxy;

[0039] R 5 is 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 is 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]

[0048] wherein, in each of the above formulas, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention, represents the relative configuration of the stereocenter.

[0049] 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):

[0050]

[0051]

[0052] wherein, in each of the above formulas, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention.

[0053] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0054]

[0055] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0056] 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, with a specification of 150 mm * 4.6 mm, packing particle size 3 μm, instrument Waters UPCC equipped with a PDA detector, column temperature 35°C; and / or, preferably, the retention time of the compound that elutes first is about 3.71 min;

[0057] under the following chiral analysis conditions eluted later The compound of the peak: 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, with a specification of 150 mm * 4.6 mm, packing particle size 3 μm, instrument Waters UPCC equipped with a PDA detector, column temperature 35°C; and / or, preferably, the retention time of the compound that elutes later is about 4.24 min.

[0058] The present invention also provides a pharmaceutical composition, which comprises (i) the compound represented by formula (I) according to any one of the above embodiments or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient.

[0059] The present invention also provides the use of the compound represented by formula (I) according to any one of the above embodiments or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of an EGFR inhibitor, preferably, the EGFR inhibitor is an EGFR C797S inhibitor (such as an EGFR C797S single mutation or L858R / C797S double mutation inhibitor).

[0060] The present invention also provides an application of a compound represented by formula (I) as described in any one of the above-mentioned solutions, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition 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 EGFR C797S single mutation or L858R / C797S double mutation), such as tumors, and further such as non-small cell lung cancer or brain metastases of non-small cell lung cancer.

[0061] The present invention also provides an application of a compound represented by formula (I) as described in any one of the above-mentioned solutions, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases resistant to osimertinib; preferably, the resistance to osimertinib is caused by EGFR C797S mutation (such as EGFR C797S single mutation or L858R / C797S double mutation); and / or, preferably, the diseases resistant to osimertinib are tumors resistant to osimertinib, such as non-small cell lung cancer or brain metastases of non-small cell lung cancer; more preferably, the diseases resistant to osimertinib are tumors caused by EGFR C797S mutation (such as EGFR C797S single mutation or L858R / C797S double mutation) resulting in resistance, such as non-small cell lung cancer or brain metastases of non-small cell lung cancer.

[0062] The present invention also provides an application of a compound represented by formula (I) as described in any one of the above-mentioned solutions, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases resistant to EGFR C797S mutation (such as EGFR C797S single mutation or L858R / C797S double mutation).

[0063] The present invention also provides a method for preventing and / or treating diseases related to EGFR, including administering a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition to a patient; preferably, the diseases related to EGFR are diseases related to EGFR C797S (such as EGFR C797S single mutation or L858R / C797S double mutation), such as non-small cell lung cancer or brain metastases of non-small cell lung cancer.

[0064] The present invention also provides a method for preventing and / or treating diseases resistant to EGFR C797S mutation (such as EGFR C797S single mutation or L858R / C797S double mutation), including administering a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition to a patient.

[0065] The present invention also provides a method for preventing and / or treating a disease resistant to osimertinib, which comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; 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.

[0066] The present invention also provides a method for preparing a compound represented by formula (I) according to any one of the above-mentioned schemes, which is Method 1 or Method 2 as follows:

[0067] Method 1 comprises the following steps: in a solvent, under the action of a base, the compound represented by formula (I-A) undergoes a deprotection reaction to prepare the compound represented by formula (I); that is, it is okay.

[0068]

[0069] Among them, the definitions of “*”, R 1 , R 2 , R 3 , R 4 and R 5 are as described in any one of the schemes of the present invention, and R a is an alkynyl protecting group;

[0070] Method 2 comprises the following steps: in a solvent, under the action of an acid, the compound represented by formula (I-B) and the compound represented by formula (I-C) undergo a condensation reaction to prepare the compound represented by formula (I); that is, it is okay.

[0071]

[0072] Among them, the definitions of “*”, R 1 , R 2 , R 3 , R 4 and R 5 are as described in any one of the schemes of the present invention.

[0073] In a certain scheme of the present invention, in Method 1, the solvent is an ether solvent, such as a cyclic ether solvent, and further such as tetrahydrofuran.

[0074] In a certain embodiment of the present invention, in Method 1, the base is a quaternary ammonium base, such as tetraalkylammonium halide, and further such as tetrabutylammonium fluoride.

[0075] In a certain embodiment of the present invention, in Method 1, the R a is TMS (i.e., trimethylsilyl).

[0076] In a certain embodiment of the present invention, in Method 1, the equivalent ratio of the base to the compound represented by formula (I-A) is (1 to 1.5):1.

[0077] In a certain embodiment of the present invention, in Method 1, the reaction temperature of the deprotection reaction is 25 to 35 °C, such as 30 °C.

[0078] In a certain embodiment of the present invention, in Method 2, the solvent is an alkylbenzene solvent, such as toluene.

[0079] In a certain embodiment of the present invention, in Method 2, the acid is an organic acid, such as acetic acid.

[0080] In a certain embodiment of the present invention, 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.

[0081] In a certain embodiment of the present invention, 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.

[0082] In a certain embodiment of the present invention, in Method 2, the reaction temperature of the condensation reaction is 15 to 25 °C, such as 20 °C.

[0083] The present invention also provides a compound represented by formula (I-A) or formula (I-B):

[0084]

[0085] Wherein, "*", R 1 , R 2 , R 3 , R 4 , R 5 and R a are defined as described in any of the above embodiments.

[0086] In a certain embodiment of the present invention, the compound represented by formula (I-A) is:

[0087]

[0088] In one embodiment of the present invention, the compound represented by formula (I-B) is any one of the following compounds:

[0089]

[0090] represent the relative configuration of the stereocenter.

[0091] Unless otherwise specified, the terms used in this application have the following definitions. For terms not covered below, their definitions are as commonly understood by those skilled in the art to which the present invention pertains.

[0092] In this application, the term "pharmaceutically acceptable salt" refers to a salt prepared by reacting a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of such a 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 a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a 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.

[0093] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0094] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having a specified number of carbon atoms. In some embodiments, the alkyl is C 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups.

[0095] The term "alkoxy" refers to the group -O-R X , where R X is alkyl as defined above.

[0096] Unless otherwise specified, the absolute configuration of a stereocenter is represented by a solid wedge bond and a dashed wedge bond . The relative configuration of a stereocenter is represented by a solid straight bond and a dashed straight bond . For example, in the compound represented by formula (I-2), the bond connecting R 1 is a solid straight bond, while the bond connecting R2 The connected one is a straight dotted line bond, which represents R 1 and R 2 are respectively on the opposite sides of the piperidine ring; for another example, in the compound shown in formula (I-1), R 1 is connected by a straight solid line bond, while R 2 is also connected by a straight solid line bond, which represents R 1 and R 2 are respectively on the same side of the piperidine ring. The straight solid line bond and the straight dotted line bond therein do not represent the absolute configuration of the carbon atoms to which R 1 and R 2 are connected.

[0097] In the described application, the inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes. For example, it can be provided as a standard sample or a control sample for comparison, or made into a kit according to the conventional methods in the art to provide a rapid detection of the inhibitory effect of EGFR C797S.

[0098] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the formulation of prescriptions, and are all substances included in pharmaceutical preparations except the active ingredient. Reference can be made to the fourth part of the Chinese Pharmacopoeia (2020 edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0099] The term "treatment" refers to therapeutic treatment. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that cause or give rise to the disorder or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects or side effects related to the disorder, or one or more symptoms, effects or side effects related to the disorder or its treatment, or (4) slowing down the development of the disorder or one or more biological manifestations of the disorder.

[0100] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0101] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0102] The reagents and raw materials used in the present invention are all commercially available.

[0103] The positive and progressive effects of the present invention are as follows: The benzopyrimidine compounds of the present invention have good inhibitory activity against EGFR C797S mutation and EGFR C797S mutation selectivity, and have one or more of the following advantages: good brain penetration ability and oral pharmacokinetic properties. Detailed implementation manners

[0104] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0105] Example 1 Synthesis of Compound I-1

[0106]

[0107] Step 1 Synthesis of Intermediate 1-2

[0108] Dissolve 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) in 3 mL of tetrahydrofuran, and add 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). The reaction system was stirred at 20 °C for 1 hour. LCMS monitored that the raw materials were completely consumed and the main product was formed. The reaction solution was concentrated under reduced pressure to a residue, and was prepared by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0-15% methanol / dichloromethane; flow rate: 30 mL / min) to obtain 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.

[0109] Step 2 Synthesis of Intermediate 1-4

[0110] Compounds 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 cuprous iodide (300.69 mg, 1.58 mmol, 0.1 eq), bis(triphenylphosphine)palladium(II) 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 successively. After the system was evacuated, it was purged with nitrogen three times and stirred at 110 °C for 1 hour. The reaction solution was concentrated under reduced pressure to a residue, and intermediate 1-4 (2.8 g, yield: 85.54%) was prepared by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 20 g Silica Flash Column; mobile phase gradient: 0-20% ethyl acetate / petroleum ether; flow rate: 30 mL / min). LCMS (ESI): calculated m / z for C 11 H 15 FNSi + .[M+H] + = 208.10, found [M+H] + = 208.1.

[0112] Synthesis of Intermediate 1-5 in Step 3

[0113] 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. A 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 monitored that the raw materials were completely consumed and the product was formed. The reaction solution was concentrated under reduced pressure to a residue, and intermediate 1-5 (120 mg, yield: 77.17%) was prepared by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 12 g Silica FlashColumn; mobile phase gradient: 0-30% (acetone:methanol = 8:1) / petroleum ether; flow rate: 30 mL / min). LCMS (ESI): calculated m / z for C 26 H 32 FN4O2Si + .[M+H] + = 479.23, found [M+H] + = 479.2.

[0114] Synthesis of Compound I-1 in Step 4

[0115] The 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 monitored that the raw materials were completely consumed and the product was formed. The reaction solution was concentrated under reduced pressure to a residue, and compound I-1 (70 mg, yield: 37.68%, purity: 96%) was prepared by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0-15% methanol / dichloromethane; flow rate: 30 mL / min). LCMS (ESI): m / z calculated value for C 23 H 24 FN4O2 + .[M+H] + = 407.19, measured value [M+H] + = 407.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 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 = 7.9 Hz, 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 = 10.7 Hz, 2H), 1.84 - 1.71 (m, 2H).

[0116] Example 2 Synthesis of Compound I-2:

[0117]

[0118]

[0119] Step 1 Synthesis of Intermediate 2-2

[0120] Dissolve compound 2-1 (15 g, 58.30 mmol, 1 eq) in 50 mL of tetrahydrofuran, and add sodium hydride (2.47 g, 61.80 mmol, 60% purity, 1.06 eq) 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. Slowly add a solution of N-fluorobenzenesulfonimide (NFSI) (18.38 g, 58.30 mmol, 1 eq) in tetrahydrofuran (200 mL) to the above mixture. The reaction system was stirred at 20 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 10:1) monitored the complete consumption of the starting materials 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 * 2). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was then purified by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 60 g Silica FlashColumn; mobile phase gradient: 0 - 30% ethyl acetate / petroleum ether; flow rate: 60 mL / minute) to obtain 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 [M - t-Bu + H] + = 220.0.

[0121] Synthesis of Intermediate 2-3 in Step 2

[0122] Dissolve intermediate 2-2 (3.8 g, 13.80 mmol, 1 eq) in 35 mL of DMF, and add triethylamine (4.19 g, 41.41 mmol, 5.76 mL, 3 eq) and triethylchlorosilane (4.58 g, 30.37 mmol, 5.17 mL, 2.2 eq). 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 materials and the formation of the product spot. After the reaction was cooled to 20 °C, it was quenched with saturated sodium bicarbonate aqueous solution (100 mL). The mixture was extracted with cyclohexane (50 mL * 2). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue, which was then purified by silica column chromatography (ISCO rapid liquid-phase preparative chromatograph; column model: 120 g Silica Flash Column; mobile phase gradient: 0 - 30% ethyl acetate / petroleum ether; flow rate: 90 mL / minute) to obtain intermediate 2-3 as a colorless oil (3.1 g, yield: 57.65%). 11H NMR (400 MHz, CD3Cl) δ ppm 5.11 (br s, 1H), 4.40 (br d, J = 13.9 Hz, 1H), 4.23 (t, J = 13.6 Hz, 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).

[0123] Synthesis of Intermediate 2 - 4 in Step 3

[0124] Dissolve Intermediate 2 - 3 (3.3 g, 8.47 mmol, 1 eq) in 60 mL of acetonitrile, and add 1 - (chloromethyl)-4 - fluoro - 1,4 - diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) (4.50 g, 12.71 mmol, 1.5 eq). The reaction system is stirred at 20 °C for 17 h. TLC (petroleum ether:ethyl acetate = 7:1) monitors the complete consumption of the raw materials and the formation of product spots. The reaction solution is evaporated to dryness under reduced pressure to obtain a residue, which is then purified by silica gel column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 80 g Silica Flash Column; mobile phase gradient: 0 - 100% ethyl acetate / petroleum ether; flow rate: 80 mL / min) to obtain Intermediate 2 - 4 as a colorless oil (2.2 g, yield: 88.55%). LCMS (ESI): m / z calculated value for C 12 H 18 F2NO5 + . [M + H] + = 294.11, measured value [M - t - Bu + H] + = 238.0.

[0125] Synthesis of Intermediate 2 - 5 in Step 4

[0126] Dissolve Intermediate 2 - 4 (2.2 g, 7.50 mmol, 1 eq) in 30 mL of ethanol, and dropwise add potassium hydroxide solution (1 M, 8.25 mL, 1.1 eq). The reaction system is stirred at 80 °C for 3 h. TLC (petroleum ether:ethyl acetate = 4:1) monitors the complete consumption of the raw materials and the formation of product. The reaction solution is diluted with 80 mL of ethyl acetate and 80 mL of water. The organic phase is separated, and the aqueous phase is extracted with ethyl acetate (80 mL × 2). The combined organic phases are washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to a residue under reduced pressure, and then purified by silica gel column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 50 g Silica Flash Column; mobile phase gradient: 0 - 90% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain Intermediate 2-5 as a colorless oil (1.4 g, yield: 79.34%). LCMS (ESI): m / z calculated for C 10 H 16 F2NO3 + .[M + H] + = 236.11, found [M - t-Bu + H] + = 180.0.

[0127] Step 5 Synthesis of Intermediates 2-6, 2-7 and 2-8

[0128] Dissolve Intermediate 2-5 (1.4 g, 5.95 mmol, 1 eq) in 20 mL of tetrahydrofuran, and slowly add a toluene solution of diisobutylaluminum hydride (1 M, 5.95 mL, 1 eq) at 0 °C. The reaction system was stirred at 0 °C for 1 hour. TLC monitoring showed complete reaction of the starting material, and the eluent was (petroleum ether (containing 0.2% formic acid) / ethyl acetate (containing 10% methanol) = 3:1. The resulting product intermediates were three isomers. The Rf value of Intermediate 2-6 was approximately 0.31, the Rf value of Intermediate 2-7 was approximately 0.30, and the Rf value of Intermediate 2-8 was approximately 0.18. The reaction solution was concentrated to a residue and purified by silica column chromatography (ISCO rapid liquid chromatography preparative instrument; column model: 60 g Silica Flash Column; mobile phase gradient: 0 - 30% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to obtain Intermediate 2-6 as a colorless oil (120 mg, yield: 8.5%). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 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 19F 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 1H NMR (400 MHz, CD3Cl) δ ppm 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). 1919F 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 prepared as a colorless oil (505 mg, yield: 35.76%). 1 1H NMR (400 MHz, CD3Cl) δ ppm 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). 19 19F NMR (376 MHz, CD3Cl) δ ppm -202.45 (br d, J = 69.4 Hz).

[0129] Step 6 Synthesis of Intermediate 2-10

[0130] Intermediate 2-8 (250.00 mg, 1.05 mmol, 1 eq) and intermediate 2-9 (206.68 mg, 1.05 mmol, 1 eq) (the preparation method refers to 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 that the raw materials reacted completely and the main product was formed. The reaction solution was concentrated under reduced pressure to a residue, and intermediate 2-10 was prepared by silica column chromatography (ISCO rapid liquid phase preparation chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0 - 90% ethyl acetate / petroleum ether; flow rate: 30 mL / minute) as a yellow solid (308 mg, yield: 70.71%). LCMS (ESI): m / z calculated value for C 18 H 22 F2N3O6 + .[M + H] + = 414.15, measured value [M - t-Bu + H] + = 358.1.

[0131] Step 7 Synthesis of Intermediate 2-11

[0132] The 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 monitored that the raw material was completely consumed and the product was formed. The reaction solution was concentrated under reduced pressure to obtain intermediate 2-11, a light yellow oil (305 mg, crude product, trifluoroacetate). LCMS (ESI): calculated m / z for C 13 H 14 F2N3O4 + .[M+H] + = 314.09, found [M+H] + = 314.1.

[0133] Synthesis of intermediate 2-12 in step 8

[0134] The 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 successively. The reaction system was stirred at 20 °C for 2 hours. TLC (ethyl acetate: methanol = 20:1) monitored that the raw material reaction was complete and the main product was formed. The reaction solution was concentrated under reduced pressure to the residue, and was prepared by silica column chromatography (ISCO rapid liquid phase preparative chromatograph; column model: 12 g Silica Flash Column; mobile phase gradient: 0 - 100% (acetone: methanol = 10:1) / petroleum ether; flow rate: 30 mL / minute) to obtain intermediate 2-12 as a yellow solid (192 mg, yield: 82.18%). LCMS (ESI): calculated m / z for C 14 H 16 F2N3O4 + .[M+H] + = 328.11, found [M+H] + = 328.1.

[0135] Synthesis of intermediate 2-13 in step 9

[0136] The 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 that the raw material reaction was complete and the main product was formed. 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, which was then subjected to silica column chromatography (ISCO rapid liquid phase 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 for C 14 H 18 F2N3O2 + .[M + H] + = 298.14, found [M + H] + = 298.1.

[0137] Synthesis of Compound I-2 in Step 10

[0138] The 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). The reaction body The system was stirred at 20 °C for 2 hours. LCMS monitored that the raw material was completely consumed and the product was formed. The reaction solution was concentrated to a residue, which was then subjected to silica column chromatography (ISCO rapid liquid phase 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 for C 23 H 22 F3N4O2 + .[M + H] + = 443.17, found [M + H] + = 443.2. 1HNMR(400 MHz, DMSO-d6) δ ppm 9.54 (s, 1H), 8.39 (s, 1H), 7.99 (s, 1H), 7.62 (br dd, J = 8.3, 15.8 Hz, 1H), 7.47 (t, J = 6.9 Hz, 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).

[0139] Synthesis of Compounds I-3 and I-4 in Example 3:

[0140]

[0141] Step 1 Synthesis of Compound 3-6

[0142] Referring to the synthesis method of Example 2, replacing the corresponding raw materials, using Intermediate 2-7 and Intermediate 2-9 as raw materials, Compound 3-6 was prepared and synthesized, which is a white solid. LCMS (ESI): m / z calculated value C 23 H 22 F3N4O2 + .[M + H] + = 443.17, measured value [M + H] + = 443.2.

[0143] Step 2 Chiral Preparation of Compound I-3 and Compound I-4

[0144] Compound 3-6 (70 mg) was further separated by chiral SFC. Chiral preparation conditions: Chiral column DAICEL CHIRALPAK AS (specification: 250 mm * 30 mm, particle size 10 μm), elution phase was CO2 (A): ethanol containing 0.1% ammonia water (B), isocratic gradient (A / B = 70 / 30). Compound I-3, the front peak, was obtained as a white solid (30 mg, yield: 42.85%, ee% value: 98%). LCMS (ESI): m / z calculated value C 23 H 22 F3N4O2 + .[M + H] + = 443.17, measured value [M + H] + = 443.2. 11H 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). The separated compound I-4, the later peak, was a white solid (29 mg, yield: 41.42%, ee% value: 98%). LCMS (ESI): m / z calculated for C 23 H 22 F3N4O2 + .[M + H] + = 443.17, found [M + H] + = 443.2. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 6.8 Hz, 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).

[0145] Chiral analysis conditions: Instrument Waters UPCC equipped with a PDA detector, chiral column Chiralpak AS-3 (specification: 150 mm * 4.6 mm, particle size 3 μm), eluent phase was CO2 (A): ethanol containing 0.05% ethylenediamine (B), gradient: 5% B to 40% B in 4 minutes, 40% B to 5% B in 0.2 minutes, hold 5% B for 1.8 minutes); flow rate 2.5 mL per minute, column temperature 35 °C; for compound I-3, retention time: 3.71 minutes; for compound I-4, retention time: 4.24 minutes.

[0146] Example 4 Synthesis of compound I-5:

[0147]

[0148] Referring to the synthesis method of Example 2, replacing the corresponding raw materials, using Intermediate 2-6 and Intermediate 2-9 as raw materials, Compound I-5 was prepared, which is a white solid. LCMS (ESI): m / z calculated value C 23 H 22 F3N4O2 + .[M+H] + =443.17, found [M+H] + =443.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.63 (br t, J = 7.0 Hz, 1H), 7.47 (t, J = 6.3 Hz, 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).

[0149] Compound structure

[0150]

[0151] Biological Test Example 1: Cell Proliferation Inhibition Data

[0152] Using the stably transfected Ba / F3 cell line with EGFR-C797S mutation and the EGFR wild-type A431 cell line respectively, the inhibitory activity of the compound on EGFR-C797S-driven cell proliferation and the inhibitory activity on wild-type EGFR cell proliferation were evaluated.

[0153] Experimental procedure: Centrifuge the resuspended A431 cells or the suspended cultured Ba / F3-TEL-EGFR-C797S cells, resuspend them in the growth medium, and count them with a cell counter. Dilute the cell suspension to the required density in the growth medium, and transfer the cell suspension to a 96-well plate. Add different concentrations of the compound to be tested to the 96-well plate and incubate at 37 °C and 5% CO2 for 72 hours.

[0154] After 72 hours, take out the cell culture plate, add reagent to each well, mix the contents on a shaker for 2 minutes to lyse the cells. Incubate at room temperature for 10 minutes to stabilize the luminescence signal and record it on a SpectraMax Paradigm multi-functional fluorescence microplate reader luminescence. The calculation formula for the inhibition rate of anti-cell proliferation activity is: Inhibition rate (%) = 100 - (RLU of the compound - RLU of the blank) / (RLU of the control - RLU of the blank) blank) * 100% (where the RLU control well is the cell plus DMSO well, and the RLU blank well is the medium plus DMSO well), fit the curve of compound concentration and inhibition rate and calculate IC50 (Half maximal inhibitory concentration).

[0155] The test results of the compounds are shown in Table 1 below:

[0156] Table 1. Inhibitory effects of compounds on the proliferation of EGFR wild-type A431 cells and EGFR-C797S mutant Ba / F3 cells

[0157]

[0158] The compounds of the present invention have potent inhibitory activity on the proliferation of Ba / F3 cells stably transfected with EGFR-C797S, and the effect is significantly better than that of WSD-0922, the third-generation EGFR inhibitor AZD9291 and the fourth-generation inhibitor BLU-945; they have better EGFR C797S mutation selectivity.

[0159] Biological Test Example 2: Kinase Inhibition Data

[0160] The HTRF technology was used to evaluate the inhibitory effects of the compounds on the kinase activities of wild-type, C797S single mutant, and L858R / C797S double mutant EGFR.

[0161] The test compound was added to a 384-well assay plate, and a kinase and Metal mixed solution was added. A substrate and an ATP solution were added to the wells and incubated at 25 °C for 40 minutes. 5 μL of a kinase detection reagent was added and incubated at 25 °C for 60 minutes. The fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) were read using a microplate reader.

[0162] The % inhibition was calculated as follows: % inhibition rate = 100% - (compound - positive control) / (negative control - positive control) * 100%

[0163] The % inhibition rate and the logarithm of the compound concentration were fitted to a non-linear regression (dose response - variable slope) using GraphPad 7.0 to calculate the IC 50 .

[0164] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * hillslope))

[0165] X: logarithm of the inhibitor concentration; Y: % inhibition rate.

[0166] The kinase inhibitory activities of the compounds against EGFR-WT, EGFR-C797S, and EGFR-L858R / C797S are shown in Table 2 below:

[0167] Table 2. IC of the compound against EGFR-WT, EGFR-C797S, and EGFR-L858R / C797S kinase inhibition 50 (nM) value

[0168]

[0169]

[0170] / : Not detected

[0171] The compound of the present invention has potent inhibitory activity against the double mutations of EGFR-C797S and EGFR-L858R / C797S.

[0172] Biological Test Example 3: Rat Brain Penetration Test

[0173] SD rats were fasted for 12 h before dosing, with water not restricted. The test article was administered by gavage, and the solvent was Solutol Hs15: 20% Hp-β-CD = 6:94 (v:v). Food was restored 2 h after dosing. The rats were anesthetized and sacrificed 4 h after dosing, and venous blood and brain were collected. Plasma was separated from whole blood. The brain tissue was washed with ice-cold saline to remove the contents and residual blood, blotted dry with filter paper, and homogenized with saline. The samples were stored at -80 °C until analysis.

[0174] HPLC-MS / MS was used to analyze the concentration of the compound in plasma and brain tissue homogenate samples.

[0175] The plasma and brain concentrations and brain-blood concentration ratios of the compound in rats 4 h after oral administration are shown in Table 3 below:

[0176] Table 3: Plasma and brain tissue and brain-blood concentration ratios of rats 4 h after oral administration of the compound

[0177]

[0178] The compound of the present invention has good brain penetration ability.

[0179] Biological Test Example 4: Rat PK Test

[0180] SD rats were fasted for 12 h before dosing, with water not restricted. The test article was administered by gavage at a dose of 5 mg / kg, and the solvent was Solutol Hs15: 20% Hp-β-CD = 6:94 (v:v). Food was restored 2 h after dosing. Blood was collected from the jugular vein or appropriate site at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h after dosing. Plasma was separated from whole blood and stored at -80 °C until analysis.

[0181] HPLC-MS / MS was used to analyze the concentration of the compound in plasma samples.

[0182] The pharmacokinetic parameters of the test article after oral administration to rats are shown in Table 4 below:

[0183] Table 4 Pharmacokinetic parameters of the test article after oral administration to rats

[0184]

[0185] The compound of the present invention has good oral PK properties.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, 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 according to claim 1, wherein it satisfies one or more of the following conditions: (1)R 1 and R 2 wherein each of the 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 Among them, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, such as methoxy; (4)R 5 In the formula, the halogen is F, Cl, Br or I, for example, F.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to 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 of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein it is any of the following: (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 any one of claims 1-4, characterized in that, the compound of formula (I) is a compound of 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 any one of claims 1-4, or represents the relative configuration of the stereocenter.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, the compound of formula (I) is a compound of 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 any one of claims 1-4.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, the compound of formula (I) is any of the following compounds:

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein, the compound of 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, in the said conditions, the chiral chromatographic column is Chiralpak AS-3 chiral column, 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, in the said conditions, the chiral chromatographic column is Chiralpak AS-3, with a specification of 150 mm * 4.6 mm, packing particle size 3 μm, instrument Waters UPCC equipped with a 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 comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1-8, and (ii) a pharmaceutically acceptable excipient.

10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1-8, 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 of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1-8, 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 metastases of non-small cell lung cancer.

12. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in any one of claims 1-8, or the pharmaceutical composition as described in claim 9 in the preparation of a drug for preventing and / or treating diseases 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 diseases resistant to osimertinib are tumors resistant to osimertinib, such as non-small cell lung cancer or brain metastases of non-small cell lung cancer; more preferably, the diseases resistant to osimertinib are tumors 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 metastases of non-small cell lung cancer.

13. A method for preparing a compound of formula (I) as described in any one of claims 1-8, which is method 1 or method 2 below: Method 1 includes the following steps: in a solvent, under the action of a base, the compound shown in formula (I-A) undergoes a deprotection reaction to prepare the compound shown in formula (I), that's all; Among them, "*”, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any one of claims 1-8, R a is an alkynyl protecting group; Method 2 includes the following steps: in a solvent, under the action of an acid, the compound shown in formula (I-B) and the compound shown in formula (I-C) undergo a condensation reaction to prepare the compound shown in formula (I), that's all; Among them, "*", R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any 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 shown in 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 shown in formula (I-C) to the compound shown in 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 shown in 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 shown in 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 any one of claims 1 - 8, and R a is defined as described in claim 13; Preferably, the compound shown in formula (I-A) is: Preferably, the compound represented by formula (I-B) is any one of the following compounds: or represents the relative configuration of the stereocenter.

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