[go: up one dir, main page]

WO2025152954A1 - Benzopyrimidine compound, preparation method therefor, pharmaceutical composition and use thereof - Google Patents

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

Info

Publication number
WO2025152954A1
WO2025152954A1 PCT/CN2025/072438 CN2025072438W WO2025152954A1 WO 2025152954 A1 WO2025152954 A1 WO 2025152954A1 CN 2025072438 W CN2025072438 W CN 2025072438W WO 2025152954 A1 WO2025152954 A1 WO 2025152954A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
egfr
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/072438
Other languages
French (fr)
Chinese (zh)
Inventor
杨康敏
孙启明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Pulsing Industry Co Ltd
Original Assignee
Shanghai Pulsing Industry Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Pulsing Industry Co Ltd filed Critical Shanghai Pulsing Industry Co Ltd
Publication of WO2025152954A1 publication Critical patent/WO2025152954A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a benzopyrimidine compound, a preparation method thereof, a pharmaceutical composition and application thereof.
  • Second-generation EGFR inhibitors such as afatinib and dacomitinib, inhibit EGFR kinase activity by covalently binding to EGFR. These inhibitors show higher anti-tumor activity in certain drug-resistant tumors, but still have problems of drug resistance and poor selectivity.
  • R5 is F.
  • R1 is H or F
  • R1 is H
  • R2 is H
  • the compound represented by formula (I) is a compound represented by formula (I-1), formula (I-2), formula (I-3) or formula (I-4):
  • R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention, Indicates the relative configuration of a stereocenter.
  • the compound represented by formula (I) is a compound represented by formula (I-5), formula (I-6), formula (I-7) or formula (I-8):
  • the compound represented by formula (I) is any one of the following compounds:
  • the compound represented by formula (I) is any one of the following compounds:
  • chiral chromatographic column eluting phase is CO 2 (A): ethanol containing 0.05% ethylenediamine (B), 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 conditions, the chiral chromatographic column is a chiral column Chiralpak AS-3, with a specification of 150 mm*4.6 mm, a filler particle size of 3 ⁇ m, an instrument Waters UPCC with a PDA detector, and a column temperature of 35°C; and/or, preferably, the retention time of the compound that elutes first is about 3.71 min;
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, and (ii) a pharmaceutically acceptable excipient.
  • the present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or use of the above pharmaceutical composition in the preparation of an EGFR inhibitor.
  • the EGFR inhibitor is an EGFR C797S inhibitor (e.g., an EGFR C797S single mutation or L858R/C797S double mutation inhibitor).
  • the present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or the use of the above pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease associated with EGFR; preferably, the disease associated with EGFR is a disease associated with 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 brain metastasis of non-small cell lung cancer.
  • EGFR C797S mutation e.g. EGFR C797S single mutation or L858R/C797S double mutation
  • the present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or the use of the above pharmaceutical composition in the preparation of a drug for preventing and/or treating a disease resistant to osimertinib; preferably, the osimertinib resistance is resistance caused by EGFR C797S mutation (e.g.
  • 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 EGFR C797S mutation (e.g. EGFR C797S single mutation or L858R/C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.
  • EGFR C797S mutation e.g. EGFR C797S single mutation or L858R/C797S double mutation
  • the present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or the use of the above pharmaceutical composition in the preparation of a drug for preventing and/or treating diseases caused by drug resistance due to EGFR C797S mutation (such as EGFR C797S single mutation or L858R/C797S double mutation).
  • EGFR C797S mutation such as EGFR C797S single mutation or L858R/C797S double mutation.
  • 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 shown in 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.
  • EGFR C797S e.g., EGFR C797S single mutation or L858R/C797S double mutation
  • the present invention also provides a method for preventing and/or treating a drug-resistant disease caused by 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 shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.
  • an EGFR C797S mutation e.g., an EGFR C797S single mutation or an L858R/C797S double mutation
  • the present invention also provides a method for preventing and/or treating a disease resistant to osimertinib, comprising administering to a patient a therapeutically effective amount of a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; preferably, the osimertinib resistance is resistance caused by EGFR C797S mutation (e.g.
  • 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 EGFR C797S mutation (e.g. EGFR C797S single mutation or L858R/C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.
  • EGFR C797S mutation e.g. EGFR C797S single mutation or L858R/C797S double mutation
  • the present invention also provides a method for preparing the compound as shown in formula (I) described in any of the above schemes, which is the following method 1 or method 2:
  • Method 1 comprises the following steps: in a solvent, under the action of a base, a compound as represented by formula (IA) is subjected to a deprotection reaction to prepare a compound as represented by formula (I);
  • Ra is an alkynyl protecting group
  • Method 2 comprises the following steps: in a solvent, under the action of an acid, a compound represented by formula (IB) and a compound represented by formula (IC) undergo a condensation reaction to prepare a compound represented by formula (I);
  • R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention.
  • the solvent is an ether solvent, such as a cyclic ether solvent, and further such as tetrahydrofuran.
  • the base is a quaternary ammonium base, such as a tetraalkylammonium halide, and further such as tetrabutylammonium fluoride.
  • the Ra is TMS (i.e., trimethylsilyl).
  • the reaction temperature of the deprotection reaction is 25-35°C, for example, 30°C.
  • the solvent is an alkylbenzene solvent, such as toluene.
  • the acid is an organic acid, such as acetic acid.
  • the equivalent ratio of the acid to the compound represented by formula (I-B) is (4-6):1, for example, 5:1.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • the key is a solid wedge. and dotted wedge key Indicates the absolute configuration of a stereocenter. Use a straight solid bond and straight dashed key Indicates the relative configuration of the stereocenter. For example, in the compound shown in formula (I-2), R1 is connected by a straight solid bond, while R2 is connected by a straight dotted bond, which means that R1 and R2 are located on the different sides of the piperidine ring.
  • pharmaceutically acceptable excipients refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • treatment refers to therapeutic treatment.
  • treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing 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.
  • prevent refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • the reagents and raw materials used in the present invention are commercially available.
  • the intermediate 1-5 (210 mg, 438.75 ⁇ mol, 1 eq) was dissolved in 2 mL of tetrahydrofuran, and TBAF (1 M, 438.75 ⁇ L, 1 eq) was added. The reaction system was stirred at 30 ° C for 1 hour. LCMS monitored that the raw material was completely consumed and the product was generated.
  • the 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.
  • the intermediate 2-11 (305 mg, 713.81 ⁇ mol, 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.
  • the intermediate 2-13 (72 mg, 242.18 ⁇ mol, 1 eq) was dissolved in 2 mL of toluene, and acetic acid (72.71 mg, 1.21 mmol, 69.32 ⁇ L, 5 eq) and intermediate 2-13a (169.69 mg, 605.45 ⁇ mol, 2.5 eq) (CN115260153A, 2022) were added in sequence.
  • the reaction system was stirred at 20 ° C for 2 hours. LCMS monitored that the raw material was completely consumed and the product was generated.
  • Chiral analysis conditions instrument Waters UPCC with PDA detector, chiral column Chiralpak AS-3 (specification: 150 mm*4.6 mm, particle size 3 ⁇ m), elution phase CO 2 (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 per minute, column temperature 35°C; compound I-3, retention time: 3.71 minutes; compound I-4, retention time: 4.24 minutes.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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

苯并嘧啶类化合物、其制备方法、药物组合物及应用Benzopyrimidine compound, preparation method, pharmaceutical composition and application thereof

本申请要求申请日为2024年1月15日的中国专利申请2024100589946的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese Patent Application No. 2024100589946, filed on January 15, 2024. This application cites the entire text of the above Chinese Patent Application.

技术领域Technical Field

本发明涉及一种苯并嘧啶类化合物、其制备方法、药物组合物及应用。The present invention relates to a benzopyrimidine compound, a preparation method thereof, a pharmaceutical composition and application thereof.

背景技术Background Art

EGFR(epidermal growth factor receptor，也简称为ErbB-1或HER1)是表皮生长因子受体(HER)家族成员之一，也属于受体酪氨酸激酶家族，与配体结合后发生二聚并发生自体酪氨酸磷酸化，进而调控下游信号通路，包括调控细胞存活的PI3K-AKT-mTOR信号通路和调控细胞增殖的RAS-RAF-MEK-ERK信号通路等。EGFR在正常细胞中调节细胞生长和分裂，但在某些肿瘤中过度表达或突变(如19外显子缺失或L858R等)，导致肿瘤细胞的异常增殖和扩散。因此，抑制EGFR激酶活性成为治疗EGFR突变阳性肿瘤的重要策略。EGFR (epidermal growth factor receptor, also referred to as ErbB-1 or HER1) is a member of the epidermal growth factor receptor (HER) family and also belongs to the receptor tyrosine kinase family. After binding to the ligand, it dimerizes and undergoes autotyrosine phosphorylation, thereby regulating 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. EGFR regulates cell growth and division in normal cells, but is overexpressed or mutated in certain tumors (such as exon 19 deletion or L858R, etc.), 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.

在过去的几十年里，针对EGFR的抑制剂已经取得了显著的突破。第一代EGFR抑制剂，如埃洛替尼和吉非替尼，是通过与EGFR酪氨酸激酶区可逆结合来抑制其活性。然而，使用过程中肿瘤细胞会产生耐药性，其中最常见为T790M突变(约占50％)。In the past few decades, inhibitors targeting EGFR have made significant breakthroughs. The first generation of EGFR inhibitors, such as erlotinib and gefitinib, inhibit the activity of EGFR by reversibly binding to the tyrosine kinase region of EGFR. However, tumor cells will develop drug resistance during use, the most common of which is T790M mutation (about 50%).

第二代EGFR抑制剂，如阿法替尼和达可替尼，通过与EGFR共价结合，抑制其激酶活性，这些抑制剂在某些耐药肿瘤中显示出更高的抗肿瘤活性，但仍然存在耐药问题和选择性差的问题。Second-generation EGFR inhibitors, such as afatinib and dacomitinib, inhibit EGFR kinase activity by covalently binding to EGFR. These inhibitors show higher anti-tumor activity in certain drug-resistant tumors, but still have problems of drug resistance and poor selectivity.

第三代EGFR抑制剂是针对EGFR T790M突变而开发的。这种突变是常见的EGFR耐药机制，它使肿瘤细胞对第一代和第二代EGFR抑制剂产生耐药性。奥希替尼是第一个获得批准用于治疗EGFR T790M突变阳性非小细胞肺癌的药物。The third generation of EGFR inhibitors was developed to target the EGFR T790M mutation. This mutation is a common EGFR resistance mechanism that renders tumor cells resistant to first and second generation EGFR inhibitors. Osimertinib is the first drug approved for the treatment of EGFR T790M mutation-positive non-small cell lung cancer.

尽管，第三代EGFR抑制剂在治疗EGFR T790M耐药肿瘤方面取得了一定的成功，但仍然存在进一步诱导耐药的问题。其中最主要的耐药机制之一是EGFR C797S突变的出现，占比近20％。因此，开发针对EGFR C797S突变的抑制剂成为治疗耐药肿瘤的新目标。Although the third-generation EGFR inhibitors have achieved some success in treating EGFR T790M-resistant tumors, there is still the problem of inducing further resistance. One of the most important resistance mechanisms is the emergence of EGFR C797S mutation, accounting for nearly 20%. Therefore, the development of inhibitors targeting EGFR C797S mutation has become a new goal for the treatment of resistant tumors.

目前第四代EGFR-TKI仍在临床试验阶段，如TQB3804、U3-1402、BLU-945、CH7233163、JNJ-61186372、OBX02-011、BI-732、H002等，有望克服EGFR-TKI耐药问题。但以上药物仍未获得足够的临床有效信息，仍需开发新型的能够有效抑制EGFR C797S突变的新型抑制剂，为治疗耐药肿瘤提供更多的治疗选择。Currently, the fourth-generation EGFR-TKI is 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 have not yet obtained sufficient clinical effective information, and new inhibitors that can effectively inhibit EGFR C797S mutations still need to be developed to provide more treatment options for the treatment of drug-resistant tumors.

发明内容Summary of the invention

本发明针对现有EGFR C797S突变抑制剂种类不足的缺陷，提供一种结构新颖的苯并嘧啶类化合物、其制备方法、药物组合物及应用。本发明的苯并嘧啶类化合物对EGFR C797S突变具有良好的抑制活性和EGFR C797S突变选择性，并具有以下一个或多个优点：良好的入脑能力和口服药代动力学性质。The present invention aims at the defect that the existing EGFR C797S mutation inhibitors are insufficient in variety, and provides a novel benzopyrimidine compound, a preparation method, a pharmaceutical composition and application thereof. The benzopyrimidine compound of the present invention has good inhibitory activity and EGFR C797S mutation selectivity, and has one or more of the following advantages: good brain penetration ability and oral pharmacokinetic properties.

本发明是通过以下技术方案来解决上述技术问题的。The present invention solves the above-mentioned technical problems through the following technical solutions.

本发明提供一种如式(I)所示的化合物或其药学上可接受的盐，
The present invention provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

其中，in,

标注“*”的碳原子表示当为手性碳原子时，其为R构型、S构型或它们的混合物；The carbon atom marked with "*" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof;

R1和R2各自独立地为H或卤素； R1 and R2 are each independently H or halogen;

R3为C1-C6烷基；R 3 is C 1 -C 6 alkyl;

R4为C1-C6烷氧基；R 4 is C 1 -C 6 alkoxy;

R5为卤素。 R5 is halogen.

在本发明某些优选实施方案中，所述的如式(I)所示的化合物或其药学上可接受的盐中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在本发明某一方案中”)。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").

在本发明某一方案中，R1和R2中，所述的卤素各自独立地为F、Cl、Br或I，例如F。In one embodiment of the present invention, in R1 and R2 , the halogen is independently F, Cl, Br or I, for example F.

在本发明某一方案中，R3中，所述的C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，例如甲基。In one embodiment of the present invention, in R 3 , the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl.

在本发明某一方案中，R4中，所述的C1-C6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基，例如甲氧基。In one embodiment of the present invention, in R 4 , the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example, methoxy.

在本发明某一方案中，R5中，所述的卤素为F、Cl、Br或I，例如F。In one embodiment of the present invention, in R 5 , the halogen is F, Cl, Br or I, for example, F.

在本发明某一方案中，R1为H或F，例如F。In one embodiment of the present invention, R 1 is H or F, for example F.

在本发明某一方案中，R2为H或F，例如F。In one embodiment of the present invention, R2 is H or F, for example F.

在本发明某一方案中，R3为甲基。In one embodiment of the present invention, R3 is methyl.

在本发明某一方案中，R4为甲氧基。In one embodiment of the present invention, R4 is methoxy.

在本发明某一方案中，R5为F。In one embodiment of the present invention, R5 is F.

在本发明某一方案中，In one embodiment of the present invention,

R1为H或F； R1 is H or F;

R2为H或F； R2 is H or F;

R3为甲基； R3 is methyl;

R4为甲氧基； R4 is methoxy;

R5为F。 R5 is F.

在本发明某一方案中，In one embodiment of the present invention,

R1为F； R1 is F;

R2为F； R2 is F;

R3为甲基； R3 is methyl;

R4为甲氧基； R4 is methoxy;

R5为F。 R5 is F.

在本发明某一方案中，In one embodiment of the present invention,

R1为H； R1 is H;

R2为H； R2 is H;

R3为甲基； R3 is methyl;

R4为甲氧基； R4 is methoxy;

R5为F。 R5 is F.

在本发明某一方案中，所述的如式(I)所示的化合物为如式(I-1)、式(I-2)、式(I-3)或式(I-4)所示的化合物：
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):

其中，上述各式中，R1、R2、R3、R4和R5的定义如本发明任一方案所述，表示立体中心的相对构型。Wherein, in the above formulae, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention, Indicates the relative configuration of a stereocenter.

在本发明某一方案中，所述的如式(I)所示的化合物为如式(I-5)、式(I-6)、式(I-7)或式(I-8)所示的化合物：
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):

其中，上述各式中，R1、R2、R3、R4和R5的定义如本发明任一方案所述。Wherein, in the above formulae, R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention.

在本发明某一方案中，所述的如式(I)所示的化合物为以下化合物中的任一种：
In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

在本发明某一方案中，所述的如式(I)所示的化合物为以下化合物中的任一种：In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

中在以下手性分析条件下先出峰的化合物：手性色谱柱，洗脱相为CO2(A)：含0.05％乙二胺的乙醇(B)，梯度：5％ B至40％ B 4分钟，40％ B至5％ B 0.2分钟，保持5％ B 1.8分钟，流速2.5mL/min；较佳地，所述条件中，所述的手性色谱柱为手性柱Chiralpak AS-3，其规格为150mm*4.6mm，填料粒径3μm，仪器Waters UPCC配PDA检测器，柱温度35℃；和/或，较佳地，所述先出峰的化合物的保留时间约为3.71min； The compound that elutes first under the following chiral analysis conditions: chiral chromatographic column, eluting phase is CO 2 (A): ethanol containing 0.05% ethylenediamine (B), 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 conditions, the chiral chromatographic column is a chiral column Chiralpak AS-3, with a specification of 150 mm*4.6 mm, a filler particle size of 3 μm, an instrument Waters UPCC with a PDA detector, and a column temperature of 35°C; and/or, preferably, the retention time of the compound that elutes first is about 3.71 min;

中在以下手性分析条件下后出峰的化合物：手性色谱柱，洗脱相为CO2(A)：含0.05％乙二胺的乙醇(B)，梯度：5％ B至40％ B 4分钟，40％ B至5％ B 0.2分钟，保持5％ B 1.8分钟，流速2.5mL/min；较佳地，所述条件中，所述的手性色谱柱为手性柱Chiralpak AS-3，其规格为150mm*4.6mm，填料粒径3μm，仪器Waters UPCC配PDA检测器，柱温度35℃；和/或，较佳地，所述后出峰的化合物的保留时间约为4.24min。 The compound eluting later under the following chiral analysis conditions: chiral chromatographic column, eluting phase is CO2 (A): ethanol containing 0.05% ethylenediamine (B), 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 conditions, the chiral chromatographic column is a chiral column Chiralpak AS-3, with a specification of 150 mm*4.6 mm, a filler particle size of 3 μm, an instrument Waters UPCC with a PDA detector, and a column temperature of 35°C; and/or, preferably, the retention time of the compound eluting later is about 4.24 min.

本发明还提供一种药物组合物，其包含(i)上述任一方案所述的如式(I)所示的化合物或其药学上可接受的盐，和(ii)药学上可接受的辅料。The present invention also provides a pharmaceutical composition comprising (i) a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, and (ii) a pharmaceutically acceptable excipient.

本发明还提供一种上述任一方案所述的如式(I)所示的化合物或其药学上可接受的盐，或上述药物组合物在制备EGFR抑制剂中的应用，较佳地，所述的EGFR抑制剂为EGFR C797S抑制剂(例如EGFR C797S单突变或L858R/C797S双突变抑制剂)。The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or use of the above 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).

本发明还提供一种上述任一方案所述的如式(I)所示的化合物或其药学上可接受的盐，或上述药物组合物在制备预防和/或治疗与EGFR相关的疾病的药物中的应用；较佳地，所述的与EGFR相关的疾病为与EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)相关的疾病，例如肿瘤，进一步例如非小细胞肺癌或非小细胞肺癌脑转移。The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or the use of the above pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease associated with EGFR; preferably, the disease associated with EGFR is a disease associated with 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 brain metastasis of non-small cell lung cancer.

本发明还提供一种上述任一方案所述的如式(I)所示的化合物或其药学上可接受的盐，或上述药物组合物在制备预防和/或治疗对奥希替尼耐药的疾病的药物中的应用；较佳地，所述的对奥希替尼耐药为由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)所导致的耐药；和/或，较佳地，所述对奥希替尼耐药的疾病为对奥希替尼耐药的肿瘤，例如非小细胞肺癌或非小细胞肺癌脑转移；更佳地，所述对奥希替尼耐药的疾病为由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)所导致的耐药的肿瘤，例如非小细胞肺癌或非小细胞肺癌脑转移。The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or the use of the above pharmaceutical composition in the preparation of a drug for preventing and/or treating a disease resistant to osimertinib; preferably, the osimertinib resistance is resistance caused by EGFR C797S mutation (e.g. EGFR C797S single mutation or 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 EGFR C797S mutation (e.g. EGFR C797S single mutation or L858R/C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.

本发明还提供一种上述任一方案所述的如式(I)所示的化合物或其药学上可接受的盐，或上述药物组合物在制备预防和/或治疗由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)导致耐药的疾病的药物中的应用。The present invention also provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in any of the above schemes, or the use of the above pharmaceutical composition in the preparation of a drug for preventing and/or treating diseases caused by drug resistance due to EGFR C797S mutation (such as EGFR C797S single mutation or L858R/C797S double mutation).

本发明还提供一种预防和/或治疗与EGFR相关的疾病的方法，包括对患者施加治疗有效量的如式(I)所示的化合物或其药学上可接受的盐，或上述药物组合物；较佳地，所述的与EGFR相关的疾病为与EGFR C797S(例如EGFR C797S单突变或L858R/C797S双突变)相关的疾病，例如非小细胞肺癌或非小细胞肺癌脑转移。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 shown in 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.

本发明还提供一种预防和/或治疗由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)导致耐药的疾病的方法，包括对患者施加治疗有效量的如式(I)所示的化合物或其药学上可接受的盐，或上述药物组合物。The present invention also provides a method for preventing and/or treating a drug-resistant disease caused by 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 shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

本发明还提供一种预防和/或治疗对奥希替尼耐药的疾病的方法，包括对患者施加治疗有效量的如式(I)所示的化合物或其药学上可接受的盐，或上述药物组合物；较佳地，所述的对奥希替尼耐药为由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)所导致的耐药；和/或，较佳地，所述对奥希替尼耐药的疾病为对奥希替尼耐药的肿瘤，例如非小细胞肺癌或非小细胞肺癌脑转移；更佳地，所述对奥希替尼耐药的疾病为由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)所导致的耐药的肿瘤，例如非小细胞肺癌或非小细胞肺癌脑转移。The present invention also provides a method for preventing and/or treating a disease resistant to osimertinib, comprising administering to a patient a therapeutically effective amount of a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; preferably, the osimertinib resistance is resistance caused by EGFR C797S mutation (e.g. EGFR C797S single mutation or 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 EGFR C797S mutation (e.g. EGFR C797S single mutation or L858R/C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer.

本发明还提供一种上述任一方案所述的如式(I)所示的化合物的制备方法，其为以下方法1或方法2：The present invention also provides a method for preparing the compound as shown in formula (I) described in any of the above schemes, which is the following method 1 or method 2:

方法1包含以下步骤：在溶剂中，在碱的作用下，如式(I-A)所示的化合物进行脱保护反应，制备得到如式(I)所示的化合物，即可；
Method 1 comprises the following steps: in a solvent, under the action of a base, a compound as represented by formula (IA) is subjected to a deprotection reaction to prepare a compound as represented by formula (I);

其中，“*”、R1、R2、R3、R4和R5的定义如本发明任一方案所述，Ra为炔基保护基；Wherein, "*", R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention, Ra is an alkynyl protecting group;

方法2包含以下步骤：在溶剂中，在酸的作用下，如式(I-B)所示的化合物与如式(I-C)所示的化合物进行缩合反应，制备得到如式(I)所示的化合物，即可；
Method 2 comprises the following steps: in a solvent, under the action of an acid, a compound represented by formula (IB) and a compound represented by formula (IC) undergo a condensation reaction to prepare a compound represented by formula (I);

其中，“*”、R1、R2、R3、R4和R5的定义如本发明任一方案所述。Wherein, "*", R 1 , R 2 , R 3 , R 4 and R 5 are defined as described in any embodiment of the present invention.

在本发明某一方案中，所述的方法1中，所述的溶剂为醚类溶剂，例如环醚类溶剂，进一步例如四氢呋喃。In one embodiment of the present invention, in method 1, the solvent is an ether solvent, such as a cyclic ether solvent, and further such as tetrahydrofuran.

在本发明某一方案中，所述的方法1中，所述的碱为季铵碱，例如四烷基卤化铵，进一步例如四丁基氟化铵。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.

在本发明某一方案中，所述的方法1中，所述的Ra为TMS(即三甲基硅烷基)。In one embodiment of the present invention, in the method 1, the Ra is TMS (i.e., trimethylsilyl).

在本发明某一方案中，所述的方法1中，所述的碱与所述的如式(I-A)所示的化合物的当量比为(1～1.5):1。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.

在本发明某一方案中，所述的方法1中，所述的脱保护反应的反应温度为25～35℃，例如30℃。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.

在本发明某一方案中，所述的方法2中，所述的溶剂为烷基苯类溶剂，例如甲苯。In one embodiment of the present invention, in method 2, the solvent is an alkylbenzene solvent, such as toluene.

在本发明某一方案中，所述的方法2中，所述的酸为有机酸，例如醋酸。In one embodiment of the present invention, in method 2, the acid is an organic acid, such as acetic acid.

在本发明某一方案中，所述的方法2中，所述的如式(I-C)所示的化合物与如式(I-B)所示的化合物的当量比为(2～3):1，例如2.5:1。In one 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 (2-3):1, for example, 2.5:1.

在本发明某一方案中，所述的方法2中，所述的酸与所述的如式(I-B)所示的化合物的当量比为(4～6):1，例如5:1。In one embodiment of the present invention, in method 2, the equivalent ratio of the acid to the compound represented by formula (I-B) is (4-6):1, for example, 5:1.

在本发明某一方案中，所述的方法2中，所述的缩合反应的反应温度为15～25℃，例如20℃。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.

本发明还提供一种如式(I-A)或式(I-B)所示的化合物：
The present invention also provides a compound as shown in formula (IA) or formula (IB):

其中，“*”、R1、R2、R3、R4、R5和Ra的定义如上述任一方案所述。wherein, "*", R 1 , R 2 , R 3 , R 4 , R 5 and Ra are as defined in any of the above schemes.

在本发明某一方案中，所述的如式(I-A)所示的化合物为：
In one embodiment of the present invention, the compound represented by formula (IA) is:

在本发明某一方案中，所述的如式(I-B)所示的化合物为以下化合物中的任一种：
In one embodiment of the present invention, the compound represented by formula (IB) is any one of the following compounds:

表示立体中心的相对构型。 Indicates the relative configuration of a stereocenter.

除非另外说明，本申请中所使用的术语具有如下定义，下文中未涉及的术语的定义如本发明所属领域技术人员的通常理解。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.

本申请中，术语“药学上可接受的盐”是指化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。当化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。In the present application, 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 a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such 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, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

术语“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

术语“烷基”是指具有指定的碳原子数的直链或支链的饱和烃基。在一些实施方案中，所述烷基为C1-6烷基(C1、C2、C3、C4、C5、C6)，例如C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基等。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。The term "alkyl" refers to a straight or branched saturated hydrocarbon group having a specified number of carbon atoms. In some embodiments, the alkyl is a C 1-6 alkyl (C 1 , C 2 , C 3 , C 4 , C 5 , C 6 ), 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 the like.

术语“烷氧基”是指基团-O-RX，其中，RX为如上文所定义的烷基。The term "alkoxy" refers to a group -ORX , wherein RX is alkyl as defined above.

除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型。用直形实线键和直形虚线键表示立体中心的相对构型，例如在如式(I-2)所示的化合物，R1连接的为直形实线键，而R2连接的为直形虚线键，此表示R1和R2分别位于哌啶环的异侧；又例如在如式(I-1)所示的化合物，R1连接的为直形实线键，而R2连接的亦为直形实线键，此表示R1和R2分别位于哌啶环的同侧，其中的直形实线键和直形虚线键并不表示R1和R2连接的碳原子的绝对构型。Unless otherwise specified, the key is a solid wedge. and dotted wedge key Indicates the absolute configuration of a stereocenter. Use a straight solid bond and straight dashed key Indicates the relative configuration of the stereocenter. For example, in the compound shown in formula (I-2), R1 is connected by a straight solid bond, while R2 is connected by a straight dotted bond, which means that R1 and R2 are located on the different sides of the piperidine ring. For another example, in the compound shown in formula (I-1), R1 is connected by a straight solid bond, while R2 is also connected by a straight solid bond, which means that R1 and R2 are located on the same side of the piperidine ring, wherein the straight solid bond and the straight dotted bond do not indicate the absolute configuration of the carbon atoms to which R1 and R2 are connected.

在所述的应用中，所述的抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为EGFR C797S抑制效果提供快速检测。In the application, the inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of EGFR C797S inhibitory effects.

术语“药学上可接受的辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2020年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009Sixth Edition)。The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing 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.

术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.

本发明的积极进步效果在于：本发明的苯并嘧啶类化合物对EGFR C797S突变具有良好的抑制活性和EGFR C797S突变选择性，并具有以下一个或多个优点：良好的入脑能力和口服药代动力学性质。The positive and progressive effects of the present invention are 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.

具体实施方式DETAILED DESCRIPTION

下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

实施例1化合物I-1的合成
Example 1 Synthesis of Compound I-1

步骤1中间体1-2的合成Step 1 Synthesis of intermediate 1-2

将化合物1-1(100mg,474.80μmol,1eq)和化合物1-1a(65.62mg,569.76μmol,66.62μL,1.2eq)用3mL的四氢呋喃溶解，并加入三苯基膦(149.44mg,569.76μmol,1.2eq)和偶氮二甲酸二异丙酯(124.81mg,617.23μmol,119.66μL,1.3eq)。反应体系在20℃下搅拌1小时。LCMS监测原料消耗完全，并有主产物生成。反应液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:20gSilica Flash Column；流动相梯度:0～15％甲醇/二氯甲烷；流速:30mL/分钟)制备得中间体1-2(120mg,收率:82.12％)。LCMS(ESI):m/z计算值C15H19ClN3O2 +.[M+H]+＝308.12,实测值[M+H]+＝308.0。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 monitored 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 for C 15 H 19 ClN 3 O 2 + .[M+H] + ＝308.12, found [M+H] + ＝308.0.

步骤2中间体1-4的合成Step 2 Synthesis of Intermediate 1-4

将化合物1-3(3g,15.79mmol,1eq)和化合物1-3a(2.32g,23.64mmol,3.28mL,1.50eq)用30mL的甲苯溶解，并依次加入碘化亚铜(300.69mg,1.58mmol,0.1eq)，双(三苯基膦)二氯化钯(1.11g,1.58mmol,0.1eq)，三苯基膦(414.11mg,1.58mmol,0.1eq)和二异丙基乙胺(10.20g,78.94mmol,13.75mL,5eq)。体系抽真空后，氮气置换三次，在110℃下搅拌反应1小时。反应液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:20gSilica Flash Column；流动相梯度:0～20％乙酸乙酯/石油醚；流速:30mL/分钟)制备得中间体1-4(2.8g,收率:85.54％)。LCMS(ESI):m/z计算值C11H15FNSi+.[M+H]+＝208.10,实测值[M+H]+＝208.1。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 cuprous 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. After the system was evacuated, nitrogen was replaced 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 chromatographed on a silica gel column (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 for C 11 H 15 FNSi + .[M+H] + ＝208.10, found [M+H] + ＝208.1.

..

步骤3中间体1-5的合成Step 3 Synthesis of Intermediate 1-5

将中间体1-2(100mg,324.91μmol,1eq)和中间体1-4(202.08mg,974.74μmol,3eq)用9mL的异丙醇溶解。体系中滴加37％的盐酸溶液(160.09mg,1.62mmol,156.95μL,5eq)。反应体系在100℃下搅拌2小时。LCMS监测原料消耗完全，并有产物生成。反应液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:12gSilica Flash Column；流动相梯度:0～30％(丙酮:甲醇＝8:1)/石油醚；流速:30mL/分钟)制备得中间体1-5(120mg,收率:77.17％)。LCMS(ESI):m/z计算值C26H32FN4O2Si+.[M+H]+＝479.23,实测值[M+H]+＝479.2。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 monitored that the raw material was completely consumed and the 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: 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 for C 26 H 32 FN 4 O 2 Si + .[M+H] + ＝479.23, found [M+H] + ＝479.2.

步骤4化合物I-1的合成Step 4 Synthesis of Compound I-1

将中间体1-5(210mg,438.75μmol,1eq)用2mL的四氢呋喃溶解，并加入TBAF(1M,438.75μL,1eq)。反应体系在30℃下搅拌1小时。LCMS监测原料消耗完全，并有产物生成。反应液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:12gSilica Flash Column；流动相梯度:0～15％甲醇/二氯甲烷；流速:30mL/分钟)制备得化合物I-1(70mg,收率:37.68％,纯度:96％)。LCMS(ESI):m/z计算值C23H24FN4O2 +.[M+H]+＝407.19,实测值[M+H]+＝407.1.1H 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)。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 material was completely consumed and the 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: 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 for C 23 H 24 FN 4 O 2 + .[M+H] + =407.19, found [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＝10.7Hz,2H),1.84-1.71(m,2H).

实施例2化合物I-2的合成：

Example 2 Synthesis of Compound I-2:

步骤1中间体2-2的合成Step 1 Synthesis of intermediate 2-2

将化合物2-1(15g,58.30mmol,1eq)用50mL的四氢呋喃溶解，并在0℃下加入氢化钠(2.47g,61.80mmol,60％纯度,1.06eq)。反应体系在0℃下搅拌30分钟，随后缓慢升至20℃，并继续搅拌30分钟。向上述混合物中缓慢加入N-氟代双苯磺酰胺(NFSI)(18.38g,58.30mmol,1eq)的四氢呋喃溶液(200mL)。反应体系在20℃下搅拌2小时。TLC(石油醚:乙酸乙酯＝10:1)监测原料消耗完全，有产物生成。反应液用100mL的饱和氯化钠水溶液稀释，混合物用乙酸乙酯萃取(100mL*2)。有机相合并后，无水硫酸钠干燥，过滤，滤液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:60gSilica Flash Column；流动相梯度:0～30％乙酸乙酯/石油醚；流速:60mL/分钟)制备得中间体2-2，为无色油状物(6.5g,收率:40.5％)。LCMS(ESI):m/z计算值C12H19FNO5 +.[M+H]+＝276.12,实测值[M-t-Bu+H]+＝220.0。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 heated to 20°C and continued to stir for 30 minutes. A tetrahydrofuran solution (200 mL) of N-fluorobisbenzenesulfonamide (NFSI) (18.38 g, 58.30 mmol, 1 eq) 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) monitored that the raw material was completely consumed and the product was generated. 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, and then chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 60 g 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 for C 12 H 19 FNO 5 + .[M+H] + ＝276.12, found [Mt-Bu+H] + ＝220.0.

步骤2中间体2-3的合成Step 2 Synthesis of intermediate 2-3

将中间体2-2(3.8g,13.80mmol,1eq)用35mL的DMF溶解，并加入三乙胺(4.19g,41.41mmol,5.76mL,3eq)和三乙基氯硅烷(4.58g,30.37mmol,5.17mL,2.2eq)。反应体系在60℃下搅拌30分钟。TLC(石油醚:乙酸乙酯＝8:1)监测原料消耗完全，有产物点生成。反应降至20℃后，用饱和碳酸氢钠水溶液(100mL)淬灭。混合物用环己烷萃取(50mL*2)。有机相合并后，无水硫酸钠干燥，过滤，滤液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:120gSilica Flash Column；流动相梯度:0～30％乙酸乙酯/石油醚；流速:90mL/分钟)制备得中间体2-3，为无色油状物(3.1g,收率:57.65％)。1H 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)。The 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 raw materials and the formation of product spots. 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 and chromatographed on a silica gel column (ISCO fast liquid preparative chromatograph; column model: 120g Silica Flash Column; mobile phase gradient: 0-30% ethyl acetate/petroleum ether; flow rate: 90 mL/min) to prepare intermediate 2-3 as a colorless oil (3.1 g, yield: 57.65%). 1 H NMR (400 MHz, CD 3 Cl) 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).

步骤3中间体2-4的合成Step 3 Synthesis of intermediate 2-4

将中间体2-3(3.3g,8.47mmol,1eq)用60mL的乙腈溶解，并加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(Selectfluor)(4.50g,12.71mmol,1.5eq)。反应体系在20℃下搅拌17小时。TLC(石油醚:乙酸乙酯＝7:1)监测原料消耗完全，有产物点生成。反应液减压蒸干得残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:80gSilica Flash Column；流动相梯度:0～100％乙酸乙酯/石油醚；流速:80mL/分钟)制备得中间体2-4，为无色油状物(2.2g,收率:88.55％)。LCMS(ESI):m/z计算值C12H18F2NO5 +.[M+H]+＝294.11,实测值[M-t-Bu+H]+＝238.0。The 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 raw materials 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 for C 12 H 18 F 2 NO 5 + .[M+H] + ＝294.11, found [Mt-Bu+H] + ＝238.0.

步骤4中间体2-5的合成Step 4 Synthesis of Intermediate 2-5

将中间体2-4(2.2g,7.50mmol,1eq)用30mL的乙醇溶解，并滴加入氢氧化钾溶液(1M,8.25mL,1.1eq)。反应体系在80℃下搅拌3小时。TLC(石油醚:乙酸乙酯＝4:1)监测原料消耗完全，有产物生成。反应液用80mL的乙酸乙酯和80mL的水稀释。有机相分离，水相用乙酸乙酯萃取(80mL*2)。有机相合并后，饱和食盐水洗涤(30mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:50gSilica Flash Column；流动相梯度:0～90％乙酸乙酯/石油醚；流速:40mL/分钟)制备得中间体2-5，为无色油状物(1.4g,收率:79.34％)。LCMS(ESI):m/z计算值C10H16F2NO3 +.[M+H]+＝236.11,实测值[M-t-Bu+H]+＝180.0。The 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 generation 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 fast liquid preparative chromatograph; column model: 50g 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 for C 10 H 16 F 2 NO 3 + .[M+H] + ＝236.11, found [Mt-Bu+H] + ＝180.0.

步骤5中间体2-6，2-7和2-8的合成Step 5 Synthesis of intermediates 2-6, 2-7 and 2-8

将中间体2-5(1.4g,5.95mmol,1eq)用20mL的四氢呋喃溶解，并在0℃下，缓慢滴加二异丁基氢化铝的甲苯溶液(1M,5.95mL,1eq)。反应体系在0℃下搅拌1小时。TLC监测原料反应完全，展开剂为(石油醚(含有0.2％甲酸)/乙酸乙酯(含有10％甲醇)＝3:1。生成的产物中间体为三个异构体，中间体2-6的Rf值约为0.31，中间体2-7的Rf值约为0.30，中间体2-8的Rf值约为0.18。反应液浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:60gSilica Flash Column；流动相梯度:0～30％乙酸乙酯/石油醚；流速:40mL/分钟)制备得中间体2-6，为无色油状物(120mg,收率:8.5％)。1H 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).19F NMR(376MHz,DMSO-d6)δppm-192.21(d,J＝59.0Hz)。制备得中间体2-7，为无色油状物(510mg,收率:36.12％).1HNMR(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).19F NMR(376MHz,CD3Cl)δppm-198.00(br d,J＝215.0Hz),-204.46(br d,J＝211.5Hz)。同时，制备得中间体2-8，为无色油状物(505mg,收率:35.76％).1H 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)。The 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 generated product intermediates were three isomers, the Rf value of intermediate 2-6 was about 0.31, the Rf value of intermediate 2-7 was about 0.30, and the Rf value of intermediate 2-8 was about 0.18. The reaction solution was concentrated to a residue and chromatographed on a silica gel column (ISCO fast 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 (400 MHz, 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) δppm -192.21 (d, J = 59.0 Hz). Intermediate 2-7 was prepared as a colorless oil (510 mg, yield: 36.12%). 1 H NMR (400 MHz, CD 3 Cl) 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). 19 F NMR (376 MHz, CD 3 Cl) 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 H NMR (400 MHz, CD 3 Cl) 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 F NMR (376 MHz, CD 3 Cl) δ ppm -202.45 (br d, J=69.4 Hz).

步骤6中间体2-10的合成Step 6 Synthesis of Intermediate 2-10

将中间体2-8(250.00mg,1.05mmol,1eq)和中间体2-9(206.68mg,1.05mmol,1eq)(制备方法参考专利CN110343090A,2019)用5mL的四氢呋喃溶解，并加入叔丁醇钾(153.72mg,1.37mmol,1.3eq)。反应体系在20℃下搅拌1小时。TLC(石油醚:乙酸乙酯＝1:1)监测原料反应完全，有主产物生成。反应液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:12gSilica Flash Column；流动相梯度:0～90％乙酸乙酯/石油醚；流速:30mL/分钟)制备得中间体2-10，为黄色固体(308mg,收率:70.71％)。LCMS(ESI):m/z计算值C18H22F2N3O6 +.[M+H]+＝414.15,实测值[M-t-Bu+H]+＝358.1。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 that the raw material reaction was complete 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: 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 for C 18 H 22 F 2 N 3 O 6 + .[M+H] + ＝414.15, found [Mt-Bu+H] + ＝358.1.

步骤7中间体2-11的合成Step 7 Synthesis of Intermediate 2-11

将中间体2-10(308mg,745.09μmol,1eq)用4mL的二氯甲烷溶解，并滴加4mL的三氟乙酸。反应体系在25℃下搅拌1小时。LCMS监测原料消耗完全，有产物生成。反应液减压浓缩得中间体2-11，浅黄色油状物(305mg,粗品，三氟乙酸盐)。LCMS(ESI):m/z计算值C13H14F2N3O4 +.[M+H]+＝314.09,实测值[M+H]+＝314.1。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 starting material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to obtain the intermediate 2-11 as a light yellow oil (305 mg, crude product, trifluoroacetate). LCMS (ESI): m/z calculated value C 13 H 14 F 2 N 3 O 4 + .[M+H] + ＝314.09, found value [M+H] + ＝314.1.

步骤8中间体2-12的合成Step 8 Synthesis of Intermediate 2-12

将中间体2-11(305mg,713.81μmol,1eq)用2mL的甲醇溶解，并依次加入37％的甲醛水溶液(116.06mg,1.43mmol,2eq)和氰基硼氢化钠(93.63mg,1.49mmol,2eq)。反应体系在20℃下搅拌2小时。TLC(乙酸乙酯:甲醇＝20:1)监测原料反应完全，有主产物生成。反应液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:12gSilica Flash Column；流动相梯度:0～100％(丙酮:甲醇＝10:1)/石油醚；流速:30mL/分钟)制备得中间体2-12，为黄色固体(192mg,收率:82.18％)。LCMS(ESI):m/z计算值C14H16F2N3O4 +.[M+H]+＝328.11,实测值[M+H]+＝328.1。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 in sequence. 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 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: 12g 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 for C 14 H 16 F 2 N 3 O 4 + .[M+H] + ＝328.11, found [M+H] + ＝328.1.

步骤9中间体2-13的合成Step 9 Synthesis of Intermediate 2-13

将中间体2-12(192mg,586.65μmol,1eq)用5mL的乙醇溶解，并加入连二亚硫酸钠(612.84mg,3.52mmol,6eq)。反应体系在20℃下搅拌16小时。TLC(石油醚:乙酸乙酯＝3:1)监测原料反应完全，有主产物生成。反应体系用10mL的乙酸乙酯和10mL的水稀释。有机相分离，水相用乙酸乙酯萃取(10mL*2)。有机相合并后，饱和食盐水洗涤(10mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩至残余物，并经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:12gSilica Flash Column；流动相梯度:0～100％(乙酸乙酯:甲醇＝20:1)/石油醚；流速:30mL/分钟)制备得中间体2-13，为无色油状物(72mg,收率:41.28％)。LCMS(ESI):m/z计算值C14H18F2N3O2 +.[M+H]+＝298.14,实测值[M+H]+＝298.1。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 generated. 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 fast liquid preparative chromatograph; column model: 12g 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 F 2 N 3 O 2 + .[M+H] + ＝298.14, found [M+H] + ＝298.1.

步骤10化合物I-2的合成Step 10 Synthesis of Compound I-2

将中间体2-13(72mg,242.18μmol,1eq)用2mL的甲苯溶解，并依次加入醋酸(72.71mg,1.21mmol,69.32μL,5eq)和中间体2-13a(169.69mg,605.45μmol,2.5eq)(CN115260153A,2022)。反应体系在20℃下搅拌2小时。LCMS监测原料消耗完全，有产物生成。反应液浓缩得残余物，经硅胶柱层析(ISCO快速液相制备色谱仪；柱型号:12gSilica Flash Column；流动相梯度:0～100％(乙酸乙酯:甲醇＝10:1)/石油醚；流速:30mL/分钟)制备得化合物I-2，为白色固体(23mg,收率:21.04％,纯度:98％)。LCMS(ESI):m/z计算值C23H22F3N4O2 +.[M+H]+＝443.17,实测值[M+H]+＝443.2.1HNMR(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)。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) were added in sequence. The reaction system was stirred at 20 ° C for 2 hours. LCMS monitored 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 for C23H22F3N4O2 + . [ M+H] + = 443.17 , found [M+H] + = 443.2. 1H NMR (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).

实施例3化合物I-3和化合物I-4的合成：
Example 3 Synthesis of Compound I-3 and Compound I-4:

步骤1化合物3-6的合成Step 1 Synthesis of Compound 3-6

参照实施例2的合成方法，替换相应的原料，以中间体2-7和中间体2-9为原料，制备合成化合物3-6，为白色固体。LCMS(ESI):m/z计算值C23H22F3N4O2 +.[M+H]+＝443.17,实测值[M+H]+＝443.2。Referring to the synthesis method of Example 2, corresponding raw materials were substituted 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 for C 23 H 22 F 3 N 4 O 2 + .[M+H] + ＝443.17, found [M+H] + ＝443.2.

步骤2化合物I-3和化合物I-4的手性制备Step 2 Chiral preparation of compound I-3 and compound I-4

将化合物3-6(70mg)，进一步用手性SFC分离，手性制备条件：手性柱DAICEL CHIRALPAK AS(规格：250mm*30mm,粒径10μm)，洗脱相为CO2(A)：含0.1％氨水的乙醇(B)，等梯度(A/B＝70/30)。分得化合物I-3,前峰，为白色固体(30mg，收率：42.85％，ee％值:98％)。LCMS(ESI):m/z计算值C23H22F3N4O2 +.[M+H]+＝443.17,实测值[M+H]+＝443.2.1H NMR(400MHz,DMSO-d6)δppm9.47(s,1H),8.39(s,1H),7.97(s,1H),7.61(t,J＝7.5Hz,1H),7.47(t,J＝6.9Hz,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)。分得化合物I-4，后峰，为白色固体(29mg，收率：41.42％，ee％值:98％)。LCMS(ESI):m/z计算值C23H22F3N4O2 +.[M+H]+＝443.17,实测值[M+H]+＝443.2.1H 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)。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 CO 2 (A): ethanol containing 0.1% ammonia (B), isocratic (A/B=70/30). Compound I-3 was isolated as a front peak, a white solid (30 mg, yield: 42.85%, ee% value: 98%). LCMS (ESI): m/z calculated value C 23 H 22 F 3 N 4 O 2 + .[M+H] + ＝443.17, found value [M+H] + ＝443.2. 1 H NMR (400MHz, DMSO-d6) δppm9.47(s,1H),8.39(s,1H),7.97(s,1H),7.61(t,J＝7.5Hz,1H),7.47(t,J＝6.9Hz,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 (29mg, yield: 41.42%, ee% value: 98%). LCMS (ESI): m/z calculated for C 23 H 22 F 3 N 4 O 2 + .[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),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).

手性分析条件:仪器Waters UPCC配PDA检测器，手性柱Chiralpak AS-3(规格：150mm*4.6mm,粒径3μm)，洗脱相为CO2(A)：含0.05％乙二胺的乙醇(B)，梯度:5％ B至40％ B 4分钟，40％B至5％ B 0.2分钟，保持5％ B 1.8分钟)；流速2.5mL每分钟，柱温度35℃；化合物I-3，保留时间：3.71分钟；化合物I-4，保留时间：4.24分钟。Chiral analysis conditions: instrument Waters UPCC with PDA detector, chiral column Chiralpak AS-3 (specification: 150 mm*4.6 mm, particle size 3 μm), elution phase CO 2 (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 per minute, column temperature 35°C; compound I-3, retention time: 3.71 minutes; compound I-4, retention time: 4.24 minutes.

实施例4化合物I-5的合成：
Example 4 Synthesis of Compound I-5:

参照实施例2的合成方法，替换相应的原料，以中间体2-6和中间体2-9为原料，制备合成化合物I-5，为白色固体。LCMS(ESI):m/z计算值C23H22F3N4O2 +.[M+H]+＝443.17,实测值[M+H]+＝443.2.1H 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)。Referring to the synthesis method of Example 2, the corresponding raw materials were replaced, and intermediate 2-6 and intermediate 2-9 were used as raw materials to prepare compound I-5 as a white solid. LCMS (ESI): m/z calculated for C23H22F3N4O2 + . [M+H] + = 443.17 , found [M+H] + = 443.2. 1H 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).

化合物结构

Compound structure

生物测试例1：细胞增殖抑制数据Biological test example 1: Cell proliferation inhibition data

分别利用稳转EGFR-C797S突变的Ba/F3细胞系和EGFR野生型A431细胞系，评价化合物对EGFR-C797S驱动的细胞增殖抑制活性和对野生型EGFR细胞的增殖抑制活性。The Ba/F3 cell line stably expressing EGFR-C797S mutation and the A431 cell line expressing 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.

试验步骤：将A431重悬细胞或悬浮培养的Ba/F3-TEL-EGFR-C797S细胞离心，在生长培养基中重悬，用细胞计数器计数。将细胞悬浮液在生长培养基中稀释至所需密度，取细胞悬液至96孔板。在96孔板中加入不同浓度的待测化合物，于37℃，5％ CO2条件下孵育72小时。Experimental steps: A431 resuspended cells or Ba/F3-TEL-EGFR-C797S cells in suspension culture were centrifuged, resuspended in growth medium, and counted using a cell counter. The cell suspension was diluted to the desired density in growth medium and the cell suspension was transferred to a 96-well plate. Different concentrations of the test compound were added to the 96-well plate and incubated at 37°C, 5% CO 2 for 72 hours.

72小时后，取出细胞培养板，每孔加入试剂，将内容物在振动器上混合2分钟以使细胞裂解。室温孵育10分钟，使发光信号稳定并在SpectraMax Paradigm多功能荧光酶标仪上记录发光。抗细胞增殖活性抑制率计算公式为：抑制率(％)＝100-(RLU化合物-RLU空白)/(RLU对照-RLU空白)*100％(其中RLU对照孔为细胞加DMSO孔，RLU空白孔为培养基加DMSO孔)，通过化合物浓度和抑制率拟合曲线并计算IC50(半数抑制浓度)。After 72 hours, remove the cell culture plate and add 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 multifunctional fluorescence microplate reader. The anti-cell proliferation activity inhibition rate calculation formula is: inhibition rate (%) = 100-(RLU compound-RLU blank)/(RLU control-RLU blank)*100% (where RLU control wells are cell plus DMSO wells, and RLU blank wells are culture medium plus DMSO wells), and the curve is fitted by compound concentration and inhibition rate and IC 50 (half-maximal inhibition concentration) is calculated.

化合物测试结果如下表1：The compound test results are shown in Table 1 below:

表1.化合物对EGFR野生型A431细胞和EGFR-C797S突变型Ba/F3细胞增殖的抑制作用
Table 1. Inhibitory effects of compounds on proliferation of EGFR wild-type A431 cells and EGFR-C797S mutant Ba/F3 cells

本发明化合物对稳转EGFR-C797S的Ba/F3细胞具有强效增殖抑制活性，效果显著优于WSD-0922、第三代EGFR抑制剂AZD9291和第四代抑制剂BLU-945；具有更佳的EGFR C797S突变选择性。The compounds of the present invention have potent proliferation inhibitory activity against 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 have better EGFR C797S mutation selectivity.

生物测试例2：激酶抑制数据Biological Test Example 2: Kinase Inhibition Data

利用HTRF技术评价化合物对野生型，C797S单突变，L858R/C797S双突变的EGFR激酶活性抑制作用。HTRF technology was used to evaluate the inhibitory effects of compounds on the EGFR kinase activity of wild-type, C797S single mutation, and L858R/C797S double mutation.

将待测化合物加到384分析板上，加入激酶与Metal混合溶液。在孔中加入底物和ATP溶液，25℃孵育40分钟。加入激酶检测试剂5μL,25℃孵育60分钟。用微滴板读取620nm(Cryptate)和665nm(XL665)的荧光信号。Add the compound to be tested to the 384 assay plate and add the kinase and metal mixed solution. 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. Use a microtiter plate to read the fluorescence signal at 620nm (Cryptate) and 665nm (XL665).

％抑制作用计算如下：％抑制率＝100％-(化合物-阳性对照)/(阴性对照-阳性对照)*100％The % inhibition was calculated as follows: % inhibition rate = 100% - (compound - positive control) / (negative control - positive control) * 100%

用GraphPad 7.0将％抑制率和化合物浓度对数拟合到非线性回归(剂量响应-变斜率)中，计算IC50。 IC50 was calculated by fitting the logarithm of % inhibition and compound concentration to a non-linear regression (dose response - variable slope) using GraphPad 7.0.

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*hillslope))Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*hillslope))

X：抑制剂浓度的对数；Y：％抑制率。X: logarithm of inhibitor concentration; Y: % inhibition rate.

化合物对EGFR-WT、EGFR-C797S、EGFR-L858R/C797S激酶抑制活性如下表2：The inhibitory activity of the compounds on EGFR-WT, EGFR-C797S, and EGFR-L858R/C797S kinases is shown in Table 2:

表2.化合物对EGFR-WT、EGFR-C797S、EGFR-L858R/C797S激酶抑制IC50(nM)值
Table 2. IC 50 (nM) values of compounds against EGFR-WT, EGFR-C797S, and EGFR-L858R/C797S kinases

/：未检测/: Not detected

本发明化合物对EGFR-C797S、EGFR-L858R/C797S双突变具有强效抑制活性。The compound of the present invention has a strong inhibitory activity against EGFR-C797S and EGFR-L858R/C797S double mutations.

生物测试例3：大鼠入脑测试Biological test example 3: rat brain test

SD大鼠给药前12h禁食，不禁水。灌胃给予供试品，溶剂为Solutol Hs15:20％ Hp-β-CD＝6:94(v:v)。给药后两小时恢复食物。给药后4小时麻醉处死，采集静脉血和脑。全血分离血浆。脑组织用冰生理盐水清洗内容物和残留血液，滤纸吸干，用生理盐水匀浆。样品于-80℃保存至分析。SD rats were fasted for 12 hours before administration, but not water. The test sample was administered by gavage, and the solvent was Solutol Hs15:20% Hp-β-CD=6:94 (v:v). Food was resumed two hours after administration. The rats were anesthetized and killed 4 hours after administration, and venous blood and brain were collected. Plasma was separated from whole blood. The brain tissue was washed with ice saline to remove the contents and residual blood, dried with filter paper, and homogenized with saline. The samples were stored at -80℃ until analysis.

采用HPLC-MS/MS对血浆和脑组织匀浆样品中化合物的浓度进行分析。The concentrations of the compounds in plasma and brain homogenate samples were analyzed by HPLC-MS/MS.

大鼠口服化合物4小时后血浆和脑内浓度及脑血浓度比见下表3：The plasma and brain concentrations and the brain-blood concentration ratio of the compound 4 hours after oral administration are shown in Table 3 below:

表3：大鼠口服化合物4小时后血浆和脑组织及脑血浓度比

Table 3: Ratio of plasma, brain tissue and brain-blood concentrations in rats 4 hours after oral administration of the compound

本发明化合物拥有良好的入脑能力。The compound of the present invention has good brain-penetrating ability.

生物测试例4：大鼠PK测试Biological test example 4: rat PK test

SD大鼠给药前12h禁食，不禁水。灌胃给予供试品，剂量5mg/kg，溶剂为Solutol Hs15:20％ Hp-β-CD＝6:94(v:v)。给药后两小时恢复食物。动物于给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0和24小时经颈静脉或合适部位取血。全血分离血浆后于-80℃保存至分析。SD rats were fasted for 12 hours before administration, but not water. The test sample 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 resumed two hours after administration. Blood was collected from the animals 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. After plasma was separated from whole blood, it was stored at -80°C until analysis.

采用HPLC-MS/MS对血浆样品中化合物的浓度进行分析。The concentrations of compounds in plasma samples were analyzed by HPLC-MS/MS.

大鼠口服供试品后药动参数见下表4：The pharmacokinetic parameters of the test product after oral administration to rats are shown in Table 4 below:

表4大鼠口服供试品后药动参数
Table 4 Pharmacokinetic parameters of the test products after oral administration in rats

本发明化合物具有良好的口服PK性质。The compounds of the present invention have good oral PK properties.

虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims (14)

一种如式(I)所示的化合物或其药学上可接受的盐，
A compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,
其中，in, 标注“*”的碳原子表示当为手性碳原子时，其为R构型、S构型或它们的混合物；The carbon atom marked with "*" indicates that when it is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof; R1和R2各自独立地为H或卤素； R1 and R2 are each independently H or halogen; R3为C1-C6烷基；R 3 is C 1 -C 6 alkyl; R4为C1-C6烷氧基；R 4 is C 1 -C 6 alkoxy; R5为卤素。 R5 is halogen. 如权利要求1所述的如式(I)所示的化合物或其药学上可接受的盐，其特征在于，其满足以下条件的一种或多种：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)R1和R2中，所述的卤素各自独立地为F、Cl、Br或I，例如F；(1) In R1 and R2 , the halogen is independently F, Cl, Br or I, for example, F; (2)R3中，所述的C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，例如甲基；(2) In R 3 , the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example, methyl; (3)R4中，所述的C1-C6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基，例如甲氧基；(3) In R 4 , the C 1 -C 6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example, methoxy; (4)R5中，所述的卤素为F、Cl、Br或I，例如F。(4) In R 5 , the halogen is F, Cl, Br or I, for example, F. 如权利要求1所述的如式(I)所示的化合物或其药学上可接受的盐，其特征在于，其满足以下条件的一种或多种：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)R1为H或F，例如F；(1) R1 is H or F, for example F; (2)R2为H或F，例如F；(2) R2 is H or F, for example F; (3)R3为甲基；(3) R 3 is methyl; (4)R4为甲氧基；(4) R 4 is methoxy; (5)R5为F。(5) R5 is F. 如权利要求1所述的如式(I)所示的化合物或其药学上可接受的盐，其特征在于，其为以下情况中的任一种：The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is any one of the following: (1)R1为H或F；(1) R1 is H or F; R2为H或F； R2 is H or F; R3为甲基； R3 is methyl; R4为甲氧基； R4 is methoxy; R5为F；R 5 is F; (2)R1为F；(2) R1 is F; R2为F； R2 is F; R3为甲基； R3 is methyl; R4为甲氧基； R4 is methoxy; R5为F；R 5 is F; (3)R1为H；(3) R1 is H; R2为H； R2 is H; R3为甲基； R3 is methyl; R4为甲氧基； R4 is methoxy; R5为F。 R5 is F. 如权利要求1-4至少一项所述的如式(I)所示的化合物或其药学上可接受的盐，其特征在于，所述的如式(I)所示的化合物为如式(I-1)、式(I-2)、式(I-3)或式(I-4)所示的化合物：
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 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):
其中，上述各式中，R1、R2、R3、R4和R5的定义如权利要求1-4至少一项所述，表示立体中心的相对构型。Wherein, in the above formulae, R 1 , R 2 , R 3 , R 4 and R 5 are defined as in at least one of claims 1 to 4, Indicates the relative configuration of a stereocenter. 如权利要求1-4至少一项所述的如式(I)所示的化合物或其药学上可接受的盐，其特征在于，所述的如式(I)所示的化合物为如式(I-5)、式(I-6)、式(I-7)或式(I-8)所示的化合物：
The compound of formula (I) or a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 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):
其中，上述各式中，R1、R2、R3、R4和R5的定义如权利要求1-4至少一项所述。Wherein, in the above formulae, R 1 , R 2 , R 3 , R 4 and R 5 are defined as in at least one of claims 1-4. 如权利要求1所述的如式(I)所示的化合物或其药学上可接受的盐，其特征在于，所述的如式(I)所示的化合物为以下化合物中的任一种：
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 one of the following compounds:
如权利要求1所述的如式(I)所示的化合物或其药学上可接受的盐，其特征在于，所述的如式(I)所示的化合物为以下化合物中的任一种：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 one of the following compounds: 中在以下手性分析条件下先出峰的化合物：手性色谱柱，洗脱相为CO2(A)：含0.05％乙二胺的乙醇(B)，梯度：5％B至40％B 4分钟，40％B至5％B 0.2分钟，保持5％B 1.8分钟，流速2.5mL/min；较佳地，所述条件中，所述的手性色谱柱为手性柱Chiralpak AS-3，其规格为150mm*4.6mm，填料粒径3μm，仪器Waters UPCC配PDA检测器，柱温度35℃；和/或，较佳地，所述先出峰的化合物的保留时间约为3.71min； The compound that elutes first under the following chiral analysis conditions: chiral chromatographic column, eluting phase is CO 2 (A): ethanol containing 0.05% ethylenediamine (B), gradient: 5% B to 40% B for 4 minutes, 40% B to 5% B for 0.2 minutes, keep 5% B for 1.8 minutes, flow rate 2.5 mL/min; preferably, under the conditions, the chiral chromatographic column is a chiral column Chiralpak AS-3, with a specification of 150 mm*4.6 mm, a filler particle size of 3 μm, an instrument Waters UPCC with a PDA detector, and a column temperature of 35°C; and/or, preferably, the retention time of the compound that elutes first is about 3.71 min; 中在以下手性分析条件下后出峰的化合物：手性色谱柱，洗脱相为CO2(A)：含0.05％乙二胺的乙醇(B)，梯度：5％B至40％B 4分钟，40％B至5％B 0.2分钟，保持5％B 1.8分钟，流速2.5mL/min；较佳地，所述条件中，所述的手性色谱柱为手性柱Chiralpak AS-3，其规格为150mm*4.6mm，填料粒径3μm，仪器Waters UPCC配PDA检测器，柱温度35℃；和/或，较佳地，所述后出峰的化合物的保留时间约为4.24min。 The compound eluting later under the following chiral analysis conditions: chiral chromatographic column, eluting phase is CO2 (A): ethanol containing 0.05% ethylenediamine (B), 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 conditions, the chiral chromatographic column is a chiral column Chiralpak AS-3, with a specification of 150 mm*4.6 mm, a filler particle size of 3 μm, an instrument Waters UPCC with a PDA detector, and a column temperature of 35°C; and/or, preferably, the retention time of the compound eluting later is about 4.24 min. 一种药物组合物，其包含(i)如权利要求1-8至少一项所述的如式(I)所示的化合物或其药学上可接受的盐，和(ii)药学上可接受的辅料。A pharmaceutical composition comprising (i) a compound of formula (I) according to at least one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient. 一种如权利要求1-8至少一项所述的如式(I)所示的化合物或其药学上可接受的盐，或如权利要求9所述的药物组合物在制备EGFR抑制剂中的应用；较佳地，所述的EGFR抑制剂为EGFR C797S抑制剂，例如EGFR C797S单突变抑制剂、L858R/C797S双突变抑制剂。A use of a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in at least one of claims 1 to 8, or a 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 mutation inhibitor or a L858R/C797S double mutation inhibitor. 一种如权利要求1-8至少一项所述的如式(I)所示的化合物或其药学上可接受的盐，或如权利要求9所述的药物组合物在制备预防和/或治疗与EGFR相关的疾病的药物中的应用；较佳地，所述的与EGFR相关的疾病为与EGFR C797S突变相关的疾病，例如肿瘤，进一步例如非小细胞肺癌或非小细胞肺癌脑转移。A use of a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described in at least one of claims 1 to 8, or a pharmaceutical composition as described in claim 9, in the preparation of a medicament for preventing and/or treating an EGFR-related disease; preferably, the EGFR-related disease is a disease associated with the EGFR C797S mutation, such as a tumor, further such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer. 一种如权利要求1-8至少一项所述的如式(I)所示的化合物或其药学上可接受的盐，或如权利要求9所述的药物组合物在制备预防和/或治疗对奥希替尼耐药的疾病的药物中的应用；较佳地，所述的对奥希替尼耐药为由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)所导致的耐药；和/或，较佳地，所述对奥希替尼耐药的疾病为对奥希替尼耐药的肿瘤，例如非小细胞肺癌或非小细胞肺癌脑转移；更佳地，所述对奥希替尼耐药的疾病为由EGFR C797S突变(例如EGFR C797S单突变或L858R/C797S双突变)所导致的耐药的肿瘤，例如非小细胞肺癌或非小细胞肺癌脑转移。A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in at least one of claims 1 to 8, or a pharmaceutical composition as described in claim 9, in the preparation of a medicament for preventing and/or treating a disease resistant to osimertinib; preferably, the osimertinib resistance is resistance caused by EGFR C797S mutation (e.g. EGFR C797S single mutation or 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 EGFR C797S mutation (e.g. EGFR C797S single mutation or L858R/C797S double mutation), such as non-small cell lung cancer or brain metastasis of non-small cell lung cancer. 一种如权利要求1-8至少一项所述的如式(I)所示的化合物的制备方法，其为以下方法1或方法2：A method for preparing a compound of formula (I) as claimed in at least one of claims 1 to 8, which is the following method 1 or method 2: 方法1包含以下步骤：在溶剂中，在碱的作用下，如式(I-A)所示的化合物进行脱保护反应，制备得到如式(I)所示的化合物，即可；
Method 1 comprises the following steps: in a solvent, under the action of a base, a compound represented by formula (IA) is subjected to a deprotection reaction to prepare a compound represented by formula (I);
其中，“*”、R1、R2、R3、R4和R5的定义如权利要求1-8至少一项所述，Ra为炔基保护基；wherein, "*", R 1 , R 2 , R 3 , R 4 and R 5 are as defined in at least one of claims 1 to 8, and Ra is an alkynyl protecting group; 方法2包含以下步骤：在溶剂中，在酸的作用下，如式(I-B)所示的化合物与如式(I-C)所示的化合物进行缩合反应，制备得到如式(I)所示的化合物，即可；
Method 2 comprises the following steps: in a solvent, under the action of an acid, a compound represented by formula (IB) and a compound represented by formula (IC) undergo a condensation reaction to prepare a compound represented by formula (I);
其中，“*”、R1、R2、R3、R4和R5的定义如权利要求1-8至少一项所述；wherein, “*”, R 1 , R 2 , R 3 , R 4 and R 5 are defined as at least one of claims 1 to 8; 较佳地，所述的方法1满足以下条件的一种或多种：Preferably, the method 1 meets one or more of the following conditions: (1)所述的溶剂为醚类溶剂，例如环醚类溶剂，进一步例如四氢呋喃；(1) The solvent is an ether solvent, such as a cyclic ether solvent, and further such as tetrahydrofuran; (2)所述的碱为季铵碱，例如四烷基卤化铵，进一步例如四丁基氟化铵；(2) The base is a quaternary ammonium base, such as a tetraalkylammonium halide, and further such as tetrabutylammonium fluoride; (3)所述的Ra为TMS；(3) Ra is TMS; (4)所述的碱与所述的如式(I-A)所示的化合物的当量比为(1～1.5):1；(4) The equivalent ratio of the base to the compound represented by formula (I-A) is (1 to 1.5):1; (5)所述的方法1中，所述的脱保护反应的反应温度为25～35℃，例如30℃；(5) In method 1, the reaction temperature of the deprotection reaction is 25 to 35° C., for example, 30° C.; 较佳地，所述的方法2满足以下条件的一种或多种：Preferably, the method 2 satisfies one or more of the following conditions: (1)所述的溶剂为烷基苯类溶剂，例如甲苯；(1) The solvent is an alkylbenzene solvent, such as toluene; (2)所述的方法2中，所述的酸为有机酸，例如醋酸；(2) In method 2, the acid is an organic acid, such as acetic acid; (3)所述的方法2中，所述的如式(I-C)所示的化合物与如式(I-B)所示的化合物的当量比为(2～3):1，例如2.5:1；(3) In method 2, the equivalent ratio of the compound represented by formula (I-C) to the compound represented by formula (I-B) is (2-3):1, for example, 2.5:1; (4)所述的方法2中，所述的酸与所述的如式(I-B)所示的化合物的当量比为(4～6):1，例如5:1；(4) In method 2, the equivalent ratio of the acid to the compound represented by formula (I-B) is (4-6):1, for example, 5:1; (5)所述的方法2中，所述的缩合反应的反应温度为15～25℃，例如20℃。(5) In method 2, the reaction temperature of the condensation reaction is 15-25°C, for example, 20°C. 一种如式(I-A)或式(I-B)所示的化合物：
A compound represented by formula (IA) or formula (IB):
其中，“*”、R1、R2、R3、R4和R5的定义如权利要求1-8至少一项所述，wherein, "*", R 1 , R 2 , R 3 , R 4 and R 5 are defined as in at least one of claims 1 to 8, Ra的定义如权利要求13所述；The definition of Ra is as in claim 13; 较佳地，所述的如式(I-A)所示的化合物为：
Preferably, the compound represented by formula (IA) is:
较佳地，所述的如式(I-B)所示的化合物为以下化合物中的任一种：
Preferably, the compound represented by formula (IB) is any one of the following compounds:
表示立体中心的相对构型。 Indicates the relative configuration of a stereocenter.
PCT/CN2025/072438 2024-01-15 2025-01-15 Benzopyrimidine compound, preparation method therefor, pharmaceutical composition and use thereof Pending WO2025152954A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410058994 2024-01-15
CN202410058994.6 2024-01-15

Publications (1)

Publication Number Publication Date
WO2025152954A1 true WO2025152954A1 (en) 2025-07-24

Family

ID=96333601

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/072438 Pending WO2025152954A1 (en) 2024-01-15 2025-01-15 Benzopyrimidine compound, preparation method therefor, pharmaceutical composition and use thereof

Country Status (2)

Country Link
CN (1) CN120309585A (en)
WO (1) WO2025152954A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1642552A (en) * 2002-03-30 2005-07-20 贝林格尔英格海姆法玛两合公司 4-(N-anilino)-quinazolines/quinolines as tyrosine kinase inhibitors
WO2010026029A1 (en) * 2008-09-03 2010-03-11 Boehringer Ingelheim International Gmbh Use of quinazoline derivatives for the treatment of viral diseases
WO2015154725A1 (en) * 2014-04-11 2015-10-15 四川海思科制药有限公司 Quinazoline derivative and preparation method and use in medicine thereof
CN108069946A (en) * 2016-11-08 2018-05-25 威尚（上海）生物医药有限公司 With the substituted quinazoline compound through blood-brain barrier ability
WO2019196619A1 (en) * 2018-04-08 2019-10-17 威尚（上海）生物医药有限公司 Quinazoline derivative salt-form crystal form, and preparation method therefor and application thereof
CN115260153A (en) * 2022-07-21 2022-11-01 威尚（上海）生物医药有限公司 A kind of 6-substituted chiral pure difluoropiperidine quinazoline derivative and preparation method thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1642552A (en) * 2002-03-30 2005-07-20 贝林格尔英格海姆法玛两合公司 4-(N-anilino)-quinazolines/quinolines as tyrosine kinase inhibitors
WO2010026029A1 (en) * 2008-09-03 2010-03-11 Boehringer Ingelheim International Gmbh Use of quinazoline derivatives for the treatment of viral diseases
WO2015154725A1 (en) * 2014-04-11 2015-10-15 四川海思科制药有限公司 Quinazoline derivative and preparation method and use in medicine thereof
CN108069946A (en) * 2016-11-08 2018-05-25 威尚（上海）生物医药有限公司 With the substituted quinazoline compound through blood-brain barrier ability
WO2019196619A1 (en) * 2018-04-08 2019-10-17 威尚（上海）生物医药有限公司 Quinazoline derivative salt-form crystal form, and preparation method therefor and application thereof
CN115260153A (en) * 2022-07-21 2022-11-01 威尚（上海）生物医药有限公司 A kind of 6-substituted chiral pure difluoropiperidine quinazoline derivative and preparation method thereof

Also Published As

Publication number Publication date
CN120309585A (en) 2025-07-15

Similar Documents

Publication Publication Date Title
TWI811358B (en) Erbb receptor inhibitors
AU2022201058B2 (en) Novel Jak1 selective inhibitors and uses thereof
CN110407856B (en) Macrocyclic compound and composition containing same
CN115836070A (en) Fused ring compound as EGFR inhibitor and its preparation method and application
WO2022007841A1 (en) Egfr inhibitor, preparation method therefor, and pharmaceutical application thereof
WO2021073498A1 (en) Egfr inhibitor, composition, and method for preparation thereof
TW202019935A (en) Selective estrogen receptor degrader
JP6139792B2 (en) Pyrido [2,3-d] pyrimidin-4-one compounds as tankyrase inhibitors
CN110483485A (en) Pyrimidines, preparation method and medical usage
EP3615526B1 (en) Phenoxyquinazoline compounds and their use in treating cancer
CN110903283A (en) Substituted quinazoline compound, pharmaceutical composition containing compound and application of compound
EP4293029B1 (en) Azaheteroaryl compound, preparation method therefor, and application thereof
CN113072550A (en) High-selectivity fibroblast growth factor receptor inhibitor and application thereof
WO2025152954A1 (en) Benzopyrimidine compound, preparation method therefor, pharmaceutical composition and use thereof
WO2025148870A1 (en) Ras inhibitor
TW202428279A (en) A kras g12d inhibitor and its application
CN108419436B (en) A kind of substituted pyrazine carboxamide compound and the composition comprising the compound and use thereof
CN120476112A (en) Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
WO2023134608A1 (en) Fused ring compounds serving as hpk1 inhibitors
CN116670126A (en) Azaaryl derivatives with EGFR inhibitory activity, preparation methods and applications thereof
WO2023116763A1 (en) Pyridazine compound, and pharmaceutical composition and use thereof
AU2022262335A1 (en) Compounds as pd1/pd-l1 inhibitors and methods thereof
WO2025240834A1 (en) Nsd2-targeted chemical degraders and compositions and methods of use thereof
HK40045061A (en) Erbb receptor inhibitors
CN120020131A (en) Aromatic ring thiazine derivatives and their medical uses

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25741515

Country of ref document: EP

Kind code of ref document: A1