WO2023143344A1

WO2023143344A1 - Novel egfr inhibitor

Info

Publication number: WO2023143344A1
Application number: PCT/CN2023/073042
Authority: WO
Inventors: 谢雨礼; 吴应鸣; 钱立晖
Original assignee: 微境生物医药科技(上海)有限公司
Priority date: 2022-01-30
Filing date: 2023-01-19
Publication date: 2023-08-03

Abstract

Disclosed is a novel EGFR inhibitor. Specifically, the present invention relates to a compound represented by general formula (1) and a preparation method therefor, as well as a use of the compound represented by general formula (1) and isomers, crystal forms, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof as an EGFR inhibitor in the preparation of a drug to fight tumors and other EGFR-related diseases.

Description

新型EGFR抑制剂Novel EGFR Inhibitors

本申请要求申请日为2022年1月30日的中国专利申请202210114690.8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 the Chinese patent application 202210114690.8 with a filing date of January 30, 2022. This application cites the full text of the above-mentioned Chinese patent application.

技术领域technical field

本发明属于药物化学领域，涉及新型EGFR抑制剂，更具体而言，涉及一类吡嗪化合物，及其制备方法和该类化合物作为EGFR抑制剂在制备抗肿瘤药物中的用途。The invention belongs to the field of medicinal chemistry, and relates to novel EGFR inhibitors, more specifically, to a class of pyrazine compounds, a preparation method thereof and the use of the compounds as EGFR inhibitors in the preparation of antitumor drugs.

背景技术Background technique

肺癌是常见的恶性肿瘤之一，每年全球新发肺癌病例数约在160万，因肺癌导致的死亡患者每年约在140万。而其中，非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌总数的80％-85％左右(Nature,2018,553,446–454)。Lung cancer is one of the most common malignant tumors. There are approximately 1.6 million new lung cancer cases worldwide each year, and approximately 1.4 million deaths due to lung cancer each year. Among them, non-small cell lung cancer (NSCLC) accounts for about 80%-85% of the total number of lung cancers (Nature, 2018, 553, 446–454).

EGFR蛋白家族是一类蛋白激酶，负责传导促有丝***信号，在生长发育中发挥了重要的作用。大量的体外肿瘤细胞，动物模型以及人类肿瘤样本的分析和研究表明EGFR家族蛋白的突变导致人类肿瘤发展，是多种癌症发生和发展的重要诱因之一。因此靶向和抑制EGFR突变蛋白的活性是治疗相关肿瘤的重要手段。The EGFR protein family is a class of protein kinases that are responsible for transmitting mitogenic signals and play an important role in growth and development. Analysis and research on a large number of tumor cells in vitro, animal models and human tumor samples have shown that mutations in EGFR family proteins lead to the development of human tumors and are one of the important causes of the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of EGFR mutant proteins is an important means of treating related tumors.

研究显示EGFR基因突变在大约12到47％的非小细胞肺癌中能够被发现。在非小细胞肺癌中，两类最常见的EGFR基因突变为外显子19缺失(del19)和在外显子21中的L858R错译(L858 missense mutation)突变。这两类突变会导致EGFR蛋白不依赖配体而持续激活。虽然具有EGFR蛋白Del19或L858R突变的NSCLC患者对于EGFR蛋白激酶抑制剂(EGFR TKI)例如erlotinib、gefitinib、afatinib或osimertinib的靶向治疗更为敏感，能够在临床上获得较高的(60-85％左右)的客观缓解率(objective response rate,ORR)，但是这一响应通常不会持续太久，大多数使用第一代或第二代EGFR TKIs的患者会在约11个月时发生疾病进展。耐药分析显示在大约50-70％耐药患者中，耐药分子机制是EGFR基因获得第二种突变，称为T790M突变(T790M+)(CancerDiscov.2012,2,872-5)。这一二次突变使第一代和第二代EGFR TKIs对于突变肿瘤细胞失去抑制活性。Studies have shown that EGFR gene mutations can be found in approximately 12 to 47% of non-small cell lung cancers. In NSCLC, the two most common types of EGFR gene mutations are exon 19 deletion (del19) and L858 missense mutation in exon 21. These two types of mutations lead to the continuous activation of EGFR protein independent of ligand. Although NSCLC patients with EGFR protein Del19 or L858R mutations are more sensitive to targeted therapy with EGFR protein kinase inhibitors (EGFR TKIs) such as erlotinib, gefitinib, afatinib, or osimertinib, they can achieve a higher (60-85% However, this response usually does not last long, and most patients treated with first- or second-generation EGFR TKIs develop disease progression at about 11 months. Drug resistance analysis shows that in about 50-70% of drug-resistant patients, the molecular mechanism of drug resistance is the acquisition of a second mutation in the EGFR gene, called T790M mutation (T790M+) (Cancer Discov. 2012, 2, 872-5). This secondary mutation makes the first-generation and second-generation EGFR TKIs lose their inhibitory activity against mutant tumor cells.

Osimertinib作为第三代共价EGFR TKI，被开发用来治疗具有EGFR del19和L858R突变并伴随或不伴随T790M突变的肿瘤。虽然osimertinib针对T790M突变导致的耐药具有较高的响应率，然而，大约70％的患者最终也会发生耐药，疾病会在大约10个月后再次进展(Lung Cancer.2017,108,228-231)。对第三代EGFR TKI耐药的分子机制研究显示，在大约20-40％经历osimertinib治疗并复发的病人中，一个主要的耐药机制是EGFR基因获得第三重突变，即C797S突变。而且，在经过第三代EGFR TKI治疗后，具有EGFR del19/L858R T790M C797S突变体的患者已不能再对第一代、第二代或第三代EGFR TKIs响应。2015年Thress等人首次报道了基于15例患者对于osimertinib的耐药分析，发现其中约有40％的耐药由C797S突变而来(Nature Medicine,2015,21,560-562)。2017年ASCO，Piotrowska和周彩存各报道了23例和99例患者耐药分析，两者的分析结果都显示大约有22％左右的耐药由C797S突变引起。所以靶向抑制EGFR del19/L858R T790M C797S突变能够克服osimertinib耐药，但目前还未有上市的EGFR TKI能够抑制EGFR del19/L858R T790M C797S突变体，所以研究和发现***EGFR TKI来满足这一尚未被满足的临床需求非常迫切。Osimertinib, as a third-generation covalent EGFR TKI, was developed to treat tumors with EGFR del19 and L858R mutations with or without T790M mutations. Although osimertinib has a high response rate for drug resistance caused by the T790M mutation, about 70% of patients will eventually develop drug resistance, and the disease will re-progress after about 10 months (Lung Cancer.2017,108,228-231) . Studies on the molecular mechanism of resistance to third-generation EGFR TKIs have shown that in approximately 20-40% of patients who undergo osimertinib treatment and relapse, a major resistance mechanism is the acquisition of the third mutation in the EGFR gene, namely the C797S mutation. Moreover, after treatment with third-generation EGFR TKIs, patients with the EGFR del19/L858R T790M C797S mutation could no longer respond to first-, second-, or third-generation EGFR TKIs. In 2015, Thress et al first reported the drug resistance analysis of osimertinib based on 15 patients, and found that about 40% of the drug resistance came from the C797S mutation (Nature Medicine, 2015, 21, 560-562). In 2017, ASCO, Piotrowska and Zhou Caicun reported drug resistance analysis of 23 and 99 patients respectively, and the analysis results of both showed that about 22% of the drug resistance was caused by the C797S mutation. Therefore, targeted inhibition of the EGFR del19/L858R T790M C797S mutation can overcome osimertinib resistance, but there is no EGFR TKI on the market that can inhibit the EGFR del19/L858R T790M C797S mutant, so research and discovery of the fourth-generation EGFR TKI to meet this requirement The unmet clinical needs are very urgent.

EGFR del19/L858R T790M C797S突变体作为经第三代EGFR TKI治疗后新浮现的EGFR突变体，目前的研究还不是很多。目前只有少数***EGFR TKI被报道能够抑制EGFR del19/L858R T790M C797S突变体。比如Boehringer Ingelheim报道了一类大环化合物BI-4020具有抗EGFR del19/L858R T790M C797S突变体活性以及体内抗肿瘤活性(J Med Chem.2019,62,10272-10293)。而专利WO2019/015655中，报道了一类芳基磷氧化合物具有抗EGFR del19/L858R T790M C797S突变体活性以及体内抗肿瘤活性。其通式A及代表化合物B(专利中实施例41)结构如下(式中各符号的定义请参照该专利)：
The EGFR del19/L858R T790M C797S mutant is a newly emerged EGFR mutant after the third-generation EGFR TKI treatment, and there are not many studies at present. Only a few fourth-generation EGFR TKIs have been reported to be able to inhibit the EGFR del19/L858R T790M C797S mutant. For example, Boehringer Ingelheim reported that a class of macrocyclic compounds BI-4020 has anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity (J Med Chem.2019, 62, 10272-10293). In the patent WO2019/015655, a class of aryl phosphine oxides was reported to have anti-EGFR del19/L858R T790M C797S mutant activity and in vivo anti-tumor activity. Its general formula A and representative compound B (Example 41 in the patent) have the following structure (please refer to the patent for the definition of each symbol in the formula):

目前，研究和发现具有针对EGFR del19/L858R T790M C797S突变活性好的化合物存在迫切的需求。At present, there is an urgent need to research and discover compounds with good activity against EGFR del19/L858R T790M C797S mutation.

发明内容Contents of the invention

本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
The present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

通式(1)中：In general formula (1):

Y为(C1-C6)烷基、(C3-C11)环烷基、(3-11元)杂环烷基、(C6-C14)芳基或(5-10元)杂芳基，其中所述(C1-C6)烷基、(C3-C11)环烷基、(3-11元)杂环烷基、(C6-C14)芳基或(5-10元)杂芳基可任选被1个或多个下列基团取代：-H、卤素、-R⁴、-OR⁴、-(CH₂)_nOR⁴、-(CH₂)_nNR⁴R⁵、-NR⁴R⁵、-CN、-C(O)NR⁴R⁵、-NR⁵C(O)R⁴、-NR⁵S(O)₂R⁴、-S(O)_pR⁴、-S(O)₂NR⁴R⁵和-O-CH₂-O-；Y is (C1-C6) alkyl, (C3-C11) cycloalkyl, (3-11) heterocycloalkyl, (C6-C14) aryl or (5-10) heteroaryl, wherein The (C1-C6) alkyl, (C3-C11) cycloalkyl, (3-11) heterocycloalkyl, (C6-C14) aryl or (5-10) heteroaryl can optionally be Substituted by one or more of the following groups: -H, halogen, -R ⁴ , -OR ⁴ , -(CH ₂ ) _n OR ⁴ , -(CH ₂ ) _n NR ⁴ R ⁵ , -NR ⁴ R ⁵ , - CN, -C(O)NR ⁴ R ⁵ , -NR ⁵ C(O)R ⁴ , -NR ⁵ S(O) ₂ R ⁴ , -S(O) _p R ⁴ , -S(O) ₂ NR ⁴ ^R5 and -O-CH2 _- O-;

X¹为N或CH； ^X1 is N or CH;

X²为N或CH； ^X2 is N or CH;

X³为N或CH； ^X3 is N or CH;

X为(C6-C14)亚芳基或(5-11元)亚杂芳基，其中所述(C6-C14)亚芳基或(5-11元)亚杂芳基可任选被1个或多个下列基团取代：-H、卤素、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)烷氧基和(C1-C6)卤代烷氧基；X is (C6-C14) arylene group or (5-11 yuan) heteroarylene group, wherein said (C6-C14) arylene group or (5-11 yuan) heteroarylene group can be optionally replaced by 1 Or more of the following groups are substituted: -H, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy and (C1-C6) haloalkoxy;

R¹为-H、卤素、-(CH₂)_nNR⁶R⁷、-NR⁶R⁷、-O(CH₂)_mNR⁶R⁷、-N(R⁵)(CH₂)_mNR⁶R⁷、(C1-C6)烷氧基、-CH₂-(3-15元)杂环烷基或(3-15元)杂环烷基，其中所述(C1-C6)烷氧基、-CH₂-(3-15元)杂环烷基或(3-15元)杂环烷基可任选被1个或多个下列基团取代：-H、-R⁴、-(CH₂)_nNR⁶R⁷、-NR⁶R⁷、-O(CH₂)_mNR⁶R⁷、-N(R⁵)(CH₂)_mNR⁶R⁷和-R³；R ¹ is -H, halogen, -(CH ₂ ) _n NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -O(CH ₂ ) _m NR ⁶ R ⁷ , -N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ , (C1-C6) alkoxy, -CH ₂ -(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl, wherein the (C1-C6) alkoxy, -CH ₂ -(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl may be optionally substituted by one or more of the following groups: -H, -R ⁴ , -(CH ₂ ) _n NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -O(CH ₂ ) _m NR ⁶ R ⁷ , -N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ and -R ³ ;

L¹为-O-、-NH-或者化学键；L ¹ is -O-, -NH- or a chemical bond;

R²为(C1-C6)烷基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基，其中所述(C1-C6)烷基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基可任选被1个或多个下列基团取代：-H、卤素、-R⁴、-(CH₂)_nOR⁴-、-(CH₂)_nNR⁴R⁵-、-OR⁴、-NR⁴R⁵、-CN、-C(O)NR⁴R⁵、-NR⁵C(O)R⁴、-NR⁵S(O)₂R⁴、-S(O)_pR⁴和-S(O)₂NR⁴R⁵；R ² is (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 yuan) heterocycloalkyl, wherein said (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl can be optionally substituted by one or more of the following groups: -H, halogen, -R ⁴ , -(CH ₂ ) _n OR ⁴ -, -(CH ₂ ) _n NR ⁴ R ⁵ -, -OR ⁴ , -NR ⁴ R ⁵ , -CN, -C(O)NR ⁴ R ⁵ , -NR ⁵ C( O)R ⁴ , -NR ⁵ S(O) ₂ R ⁴ , -S(O) _p R ⁴ and -S(O) ₂ NR ⁴ R ⁵ ;

R³为(3-11元)杂环烷基，其中所述(3-11元)杂环烷基可任选被1个或多个下列基团取代：-H、-CD₃、-R⁴、-OR⁴和-NR⁴R⁵； R ³ is a (3-11 membered) heterocycloalkyl group, wherein the (3-11 membered) heterocycloalkyl group can be optionally substituted by one or more of the following groups: -H, -CD ₃ , -R ⁴ , -OR ⁴ and -NR ⁴ R ⁵ ;

R⁴和R⁵各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基；R ⁴ and R ⁵ are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl;

R⁶和R⁷各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基，或R⁶和R⁷与其连接的N原子能够共同组成一个(3-11元)杂环烷基，其中所述(3-11元)杂环烷基可任选被1个或多个下列基团取代：-H、-CD₃、卤素、-R⁴和-OR⁴；R ⁶ and R ⁷ are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R ⁶ and R ⁷ can jointly form a (3-11 member) Heterocycloalkyl, wherein the (3-11 membered) heterocycloalkyl can be optionally substituted by one or more of the following groups: -H, -CD ₃ , halogen, -R ⁴ and -OR ⁴ ;

和and

p为0、1或2的整数，n为0、1、2或3的整数，m为1、2或3的整数。p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.

在另一优选例中，其中所述通式(1)中，Y为(C1-C3)烷基、(C3-C6)环烷基、(5-6元)杂环烷基、苯基或(5-9元)杂芳基，其中所述(C1-C3)烷基、(C3-C6)环烷基、(5-6元)杂环烷基、苯基或(5-9元)杂芳基可任选被1个或多个下列基团取代：-H、-F、-Cl、-Br、-CN、-OH、-OCH₃、-NH₂、-N(CH₃)₂、-NHCOCH₃、-NHSO₂CH₃、-SO₂CH₃、-CH₃、-CONH₂、-CH₂OH和-O-CH₂-O-。In another preferred example, in the general formula (1), Y is (C1-C3) alkyl, (C3-C6) cycloalkyl, (5-6 membered) heterocycloalkyl, phenyl or (5-9 membered) heteroaryl, wherein said (C1-C3) alkyl, (C3-C6) cycloalkyl, (5-6 membered) heterocycloalkyl, phenyl or (5-9 membered) Heteroaryl can be optionally substituted with one or more of the following groups: -H, -F, -Cl, -Br, -CN, -OH, -OCH ₃ , -NH ₂ , -N(CH ₃ ) ₂ , _-NHCOCH3 , _-NHSO2CH3 , _-SO2CH3 _{, -CH3, -CONH2, -CH2OH} _, _and _-O _- _CH2- O-.

在另一优选例中，其中所述通式(1)中，Y为：-CH₃、-CH₂CH₃、 In another preferred example, in the general formula (1), Y is: -CH ₃ , -CH ₂ CH ₃ ,

在另一优选例中，其中所述通式(1)中，X为亚苯基或6元亚杂芳基，其中所述亚苯基或6元亚杂芳基可任选被1个或多个下列基团取代：-H、-F、-CH₃、-CH₂CH₃、-CH(CH₃)₂、-OCH₃、-OCF₂H和-OCF₃。In another preferred example, in the general formula (1), X is phenylene or 6-membered heteroarylene, wherein the phenylene or 6-membered heteroarylene can be optionally replaced by 1 or Substitution of multiples of the following groups: -H, -F, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -OCF ₂ H and -OCF ₃ .

在另一优选例中，其中所述通式(1)中，X为：
In another preferred example, in the general formula (1), X is:

在另一优选例中，其中所述通式(1)中，R¹为：-H、-N(CH₃)₂、-CH₂-(6-11元)杂环烷基或(6-11元)杂环烷基，其中所述(6-11元)杂环烷基为：所述(6-11元)杂环烷基可任选被1个或多个下列基团取代：-H、-CH₃、-N(CH₃)₂、和-CD₃。In another preferred example, in the general formula (1), R ¹ is: -H, -N(CH ₃ ) ₂ , -CH ₂ -(6-11 membered) heterocycloalkyl or (6- 11 yuan) heterocycloalkyl, wherein the (6-11 yuan) heterocycloalkyl is: The (6-11 membered) heterocycloalkyl group can be optionally substituted by one or more of the following groups: -H, -CH ₃ , -N(CH ₃ ) ₂ , and - CD ₃ .

在另一优选例中，其中所述通式(1)中，R¹为： -H、-N(CH₃)₂、 In another preference, wherein in the general formula (1), R ¹ is: -H, -N(CH ₃ ) ₂ ,

在另一优选例中，其中所述通式(1)中，当L²为：-NH-时，R²为：
In another preferred example, in the general formula (1), when L ² is: -NH-, R ² is:

在另一优选例中，其中所述通式(1)中，当L²为：-O-时，R²为：
In another preferred example, in the general formula (1), when L ² is: -O-, R ² is:

在另一优选例中，其中所述通式(1)中，当L²为：化学键时，R²为：
In another preferred example, in the general formula (1), when L ² is: a chemical bond, R ² is:

在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：

In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:

本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.

本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与EGFR突变相关疾病的药物中的用途。其中，所述的疾病优选癌症，所述癌症为血液癌和实体瘤。Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Use for preparing medicines for treating, regulating or preventing diseases related to EGFR mutations. Wherein, said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.

本发明的再一个目的还提供治疗、调节或预防与EGFR突变蛋白相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。Another object of the present invention is also to provide a method for treating, regulating or preventing diseases related to EGFR mutant protein, comprising administering to the subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or its various Constructs, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.

通过合成和仔细研究了多类涉及具有EGFR抑制作用的新化合物，发明人发现在通式(1)化合物中，当Y为芳基或杂芳基时，化合物意外地具有很强的EGFR^{del19/T790M/C797S}和EGFR^{L858R/T790M/C797S}抑制活性，并且对于野生型EGFRWT有较高的选择性。By synthesizing and carefully studying many types of new compounds related to EGFR inhibitory effect, the inventors found that in the compound of general formula (1), when Y is aryl or heteroaryl, the compound unexpectedly has a strong EGFR ^{del19/ T790M/C797S} and EGFR ^{L858R/T790M/C797S} inhibit activity, and have higher selectivity for wild-type EGFRWT.

应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

化合物的合成compound synthesis

下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。The preparation method of the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.

以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4^thEd.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4^thEd.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^rdEd.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). General methods for the preparation of compounds can be obtained by using appropriate reagents and The conditions under which different groups are introduced in the formulas provided herein vary.

一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列一般反应流程1制备：In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared using the following general reaction scheme 1:

一般反应流程1
General reaction scheme 1

通式(1)化合物的实施方式可根据一般反应流程1制备，其中R¹、R²、X、Y、X¹和L¹如上文中所定义，H表示氢，当L¹为-O-或-NH-时，B¹表示氢，当L¹为化学键时，B¹表示硼酸、硼酸酯或三氟硼酸盐，B²表示硼酸、硼酸酯或三氟硼酸盐。如一般反应流程1所示,化合物1-1和化合物1-2反应生成化合物1-3，化合物1-3经过氯代反应生成化合物1-4，化合物1-4和R²-L¹-B¹反应生成化合物1-5，化合物1-5与R¹-X-B²发生偶联反应生成化合物1-6，化合物1-6与化合物1-7繁盛取代反应生成化合物1-8，化合物1-8脱去保护基得到目标化合物1-9。The embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1, wherein R ¹ , R ² , X, Y, X ¹ and L ¹ are as defined above, H represents hydrogen, when L ¹ is -O- or When -NH-, B ¹ represents hydrogen, when L ¹ is a chemical bond, B ¹ represents boric acid, boric acid ester or trifluoroborate, and B ² represents boric acid, boric acid ester or trifluoroborate. As shown in general reaction scheme 1, compound 1-1 reacts with compound 1-2 to generate compound 1-3, compound 1-3 undergoes chlorination reaction to generate compound 1-4, compound 1-4 and R ² -L ¹ -B ¹ reaction to generate compound 1-5, compound 1-5 undergoes coupling reaction with R ¹ -XB ² to generate compound 1-6, compound 1-6 and compound 1-7 flourish substitution reaction to generate compound 1-8, compound 1-8 The protecting group is removed to obtain the target compound 1-9.

化合物的进一步形式Further forms of compounds

“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。"Pharmaceutically acceptable" here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.

术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式化合物与酸或碱反应获得，其中所述的酸或碱包括，但不限于发现于Stahl和Wermuth，Handbook of Pharmaceutical Salts:Properties,Selection,and Use 1^stEd.，(Wiley,2002)中的酸和碱。The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and that does not abolish the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of formula with an acid or base including, but not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection , and Use ^1st Ed., Acids and Bases in (Wiley, 2002).

应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。References to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selected during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. selectively formed. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.

在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。In other embodiments, compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.

在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。In another aspect, the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur. Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(³H)、碘-125(¹²⁵I)和C-14(¹⁴C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

术语the term

如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.

除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH₃、CH₃CH₂、CF₃、CHF₂、CF₃CH₂、CF₃(CH₃)CH、ⁱPr、ⁿPr、ⁱBu、ⁿBu或^tBu。Unless otherwise specified, "alkyl" means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl ^groups are selected from _CH3 , _CH3CH2 , _CF3 , _CHF2 , _CF3CH2 _, _CF3 ( _CH3 )CH, _iPr , ^nPr , ^iBu , ^nBu or ^tBu .

除非另有规定，“亚烷基”指二价的如上所定义的烷基。亚烷基的例子包括但不限于，亚甲基和亚乙基。Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, are preferred.

除非另有规定，“亚烯基”指二价的如上所定义的烯基。Unless otherwise specified, "alkenylene" means a divalent alkenyl group as defined above.

除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。 Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. A lower alkynyl group having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, is preferred.

除非另有规定，“亚炔基”指二价的如上所定义的炔基。Unless otherwise specified, "alkynylene" means a divalent alkynyl group as defined above.

除非另有规定，“环烷基”是指非芳香族烃环***(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫代基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。Unless otherwise specified, "cycloalkyl" means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl". Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form oxo or thioxo. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarcinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.

除非另有规定，“亚环烷基”指二价的如上所定义的环烷基。Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH₃、OCF₃、CHF₂O、CF₃CH₂O、^i-PrO、^n-PrO、^i-BuO、^n-BuO或^t-BuO。Unless otherwise specified, "alkoxy" means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from OCH ₃ , OCF ₃ , CHF ₂ O, CF ₃ CH ₂ O, ^i- PrO, ^n- PrO, ^i- BuO, ^n- BuO or ^t- BuO.

除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

除非另有规定，“芳氧基”指通过醚氧原子键合到分子其余部分的芳基。芳氧基的例子包括但不限于苯氧基和萘氧基。Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ether oxygen atom. Examples of aryloxy include, but are not limited to, phenoxy and naphthyloxy.

除非另有规定，“亚芳基”指二价的如上所定义的芳基。亚芳基的例子包括但不限于，亚苯基、亚萘基和亚菲基。Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的。例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3,2-b]吡啶基、1H-吡咯[2,3-c]吡啶基、1H-吡咯[3,2-c]吡啶基、1H-吡咯[2,3-b]吡啶基、 Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic. For example a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,

除非另有规定，“亚杂芳基”指二价的如上所定义的杂芳基。Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

除非另有规定，“杂环烷基”指非芳香族环或环***，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和磷的杂原子环成员。如果杂环烷基含有至少一个双键，那么部分不饱和杂环烷基可被称为“杂环烯基”，或如果杂环烷基含有至少一个三键，那么部分不饱和杂环烷基可被称为“杂环炔基”。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环***。在一些实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫代基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。在一些实施例中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分(也称为部分不饱和杂环)，例如哌啶、吗啉、氮杂环庚三烯或噻吩基等的苯并衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括但不限于氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1,2,3,4-四氢喹啉基、莨菪烷基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2,4(1H,3H)-二酮基、1,4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S,S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、 Unless otherwise specified, "heterocycloalkyl" means a non-aromatic ring or ring system which may optionally contain one or more alkenylene groups as rings A portion of a structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or thioxo or other oxidized linkages (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties (also known as partially unsaturated heterocycles) having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, Benzo derivatives of morpholine, azepine or thienyl, etc. A heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuryl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butane Amide group, valerolactam group, imidazolinone group, hydantoin group, dioxolanyl group, phthalimide group, pyrimidine-2,4(1H,3H)-dione group, 1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , pyridonyl, 3-pyrrolinyl, thiopyranyl, pyroneyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,

除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substitution") appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.

“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

除非另有规定，可以理解词语“包含”，或其变体如“包括”或“含有”是指包括所述的元素或整数，或者元素或整数的组，但不排除任意其他的元素或整数，或者元素或整数的组。Unless otherwise specified, it is to be understood that the word "comprising", or variations thereof such as "includes" or "containing", means the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer , or a group of elements or integers.

取代基“-O-CH₂-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如： The substituent "-O-CH ₂ -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:

当一个连接基团的数量为0时，比如-(CH₂)₀-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a single bond.

当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。 When one of the variables is selected from a chemical bond, it means that the two groups connected are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。The term "membered ring" includes any ring structure. The term "member" is meant to indicate the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.

术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.

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，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键 Unless otherwise noted, keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key

除非另有说明，用表示单键或双键。Unless otherwise specified, use Indicates a single or double bond.

特定药学及医学术语Certain pharmaceutical and medical terms

术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.

术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。The term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom. As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.

“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers. The asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.

“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to In animals), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。The term "administered, administering, or administration" as used herein means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.

虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。 Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein should be understood (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and other similar Those) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood as the number of significant digits indicated plus the usual rounding method.

除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.

治疗用途therapeutic use

本发明提供了使用本发明通式(1)化合物或药物组合物治疗疾病的方法，包括但不限于涉及EGFR突变病况(例如癌症)。The present invention provides methods for treating diseases, including but not limited to conditions involving EGFR mutations (such as cancer), using compounds of general formula (1) or pharmaceutical compositions of the present invention.

在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)化合物的药物组合物。在一些实施例中，癌症由EGFR突变介导。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、***癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。In some embodiments, there is provided a method for treating cancer, the method comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof. In some embodiments, the cancer is mediated by EGFR mutations. In other embodiments, the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, stomach cancer, mesothelioma or all cancer metastases.

给药途径Route of administration

本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。The compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts . Wherein "safe and effective amount" refers to: the amount of the compound is sufficient to obviously improve the condition without producing serious side effects. The safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.

“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity . "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.

用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. When necessary, the active compound It can also be in microencapsulated form with one or more of the above-mentioned excipients.

用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.

本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

具体实施方式Detailed ways

在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail, so that the content of the present invention becomes very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined in the present application.

所有实施例中，¹H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。In all the examples, ¹ H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.

本发明采用下述缩略词：CDCl₃代表氘代氯仿；CD₃OD代表氘代甲醇；DMSO-d6代表氘代二甲亚砜；EtOAc代表乙酸乙酯；Hexane代表正己烷；MeCN代表乙腈；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；NMP代表1-甲基吡咯烷-2-酮；Dioxane代表1,4-二氧六环；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；h代表小时；K₃PO₄代表磷酸钾；min代表分钟；MS代表质谱；NaH代表氢化钠；NMR代表核磁共振；Pd₂(dba)₃代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl₂代表1,1'-双(二苯基膦基)二茂铁]二氯化钯；TFA(CF₃COOH)代表三氟乙酸；TLC代表薄层色谱；THF代表四氢呋喃；Xantphos代表4,5-双(二苯基膦)-9,9-二甲基氧杂蒽。The present invention adopts the following abbreviations: CDCl ₃ represents deuterated chloroform; CD ₃ OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; EtOAc represents ethyl acetate; Hexane represents n-hexane; MeCN represents acetonitrile; DCM stands for dichloromethane; DIPEA stands for diisopropylethylamine; NMP stands for 1-methylpyrrolidin-2-one; Dioxane stands for 1,4-dioxane; DMF stands for N,N-dimethylformazan amide; DMSO stands for dimethyl sulfoxide; h stands for hour; K ₃ PO ₄ stands for potassium phosphate _; min stands for minute; MS stands for mass spectrum; _NaH stands for sodium hydride; NMR stands for nuclear magnetic resonance; benzylacetone)dipalladium; Pd(dppf)Cl ₂ represents 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; TFA(CF ₃ COOH) represents trifluoroacetic acid; TLC represents thin layer chromatography; THF represents four Hydrofuran; Xantphos stands for 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

实施例1化合物511的合成
The synthesis of embodiment 1 compound 511

步骤1：化合物511-2的合成:
Step 1: Synthesis of compound 511-2:

将1-1(22.25g,100mmol)，511-1(21.7g,100mmol)和醋酸(1mL)溶于乙醇(500mL)中，混合液在90℃搅拌36h，LC-MS监测反应有产物，将反应液温度降至50℃，过滤，滤饼用乙醇洗涤，滤液减压浓缩得到粗产物(20g,收率:53％)，粗产物可直接用于下一步反应。 1-1 (22.25g, 100mmol), 511-1 (21.7g, 100mmol) and acetic acid (1mL) were dissolved in ethanol (500mL), and the mixture was stirred at 90°C for 36h. LC-MS monitored the reaction for products. The temperature of the reaction solution was lowered to 50° C., filtered, the filter cake was washed with ethanol, and the filtrate was concentrated under reduced pressure to obtain a crude product (20 g, yield: 53%), which could be directly used in the next reaction.

MS(ESI):375[M+H]⁺。MS (ESI): 375 [M+H] ⁺ .

步骤2：化合物511-3的合成:
Step 2: Synthesis of compound 511-3:

将511-2(3.75g,10mmol)溶于二氯甲烷(100mL)中，在0℃慢慢加入草酰氯(3.8g,30mmol)和DMF(5滴),混合液氩气置换后搅拌升温至40℃反应12h。LC-MS监测反应完成后，混合液浓缩，将粗产物溶于二氯甲烷(100mL)和水(100mL)中，加入饱和碳酸氢钠溶液(10mL)，用二氯甲烷萃取(100mLX3)，有机相合并，并用无水硫酸钠干燥，将有机相过滤，减压浓缩得到粗产物，粗产物柱层析纯化得产物(3.5g,收率:88.8％)。Dissolve 511-2 (3.75g, 10mmol) in dichloromethane (100mL), slowly add oxalyl chloride (3.8g, 30mmol) and DMF (5 drops) at 0°C, replace the mixture with argon and heat up to React at 40°C for 12h. After the LC-MS monitoring reaction was completed, the mixed solution was concentrated, and the crude product was dissolved in dichloromethane (100mL) and water (100mL), and saturated sodium bicarbonate solution (10mL) was added, extracted with dichloromethane (100mL×3), organic The phases were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product (3.5 g, yield: 88.8%).

MS(ESI):393[M+H]⁺。MS (ESI): 393 [M+H] ⁺ .

步骤3：化合物511-5的合成：
Step 3: Synthesis of compound 511-5:

将511-3(2g,5mmol)，511-4(606.9mg,6mmol)和DIPEA(1.29g,10mmol)，溶于乙醇(50mL)，混合液氩气置换后室温搅拌15min，然后搅拌升温至70℃反应12h。LC-MS监测反应完成，混合液降温后，减压浓缩得到粗产物，粗产物经柱层析纯化得产物(2.1g,收率:91.7％)。Dissolve 511-3 (2g, 5mmol), 511-4 (606.9mg, 6mmol) and DIPEA (1.29g, 10mmol) in ethanol (50mL), replace the mixture with argon and stir at room temperature for 15min, then heat up to 70 ℃ reaction 12h. The completion of the reaction was monitored by LC-MS. After cooling down, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product (2.1 g, yield: 91.7%).

MS(ESI):458[M+H]⁺。MS (ESI): 458 [M+H] ⁺ .

步骤4：化合物511-7的合成:
Step 4: Synthesis of compound 511-7:

将511-5(1.5g,3.3mmol)，511-6(518.6mg,3.63mmol)，无水磷酸钾(1.4g,6.6mmol)，溶于Dioxane/H₂O(10mL/2mL)，加入Pd(dppf)₂Cl₂(241mg,0.33mmol)，混合液氩气置换后快速升温至105℃反应30min。LC-MS监测反应完成，混合液降温后，减压浓缩得到粗产物，粗产物经过柱层析纯化得产物(1.95g,收率:81.9％)。511-5 (1.5g, 3.3mmol), 511-6 (518.6mg, 3.63mmol), anhydrous potassium phosphate (1.4g, 6.6mmol), dissolved in Dioxane/H ₂ O (10mL/2mL), added Pd (dppf) ₂ Cl ₂ (241mg, 0.33mmol), the mixture was replaced with argon gas and then heated rapidly to 105°C for 30min. The completion of the reaction was monitored by LC-MS. After cooling down, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product (1.95 g, yield: 81.9%).

MS(ESI):723[M+H]⁺。MS (ESI): 723 [M+H] ⁺ .

步骤5：化合物511-9的合成：
Step 5: Synthesis of compound 511-9:

将511-7(723mg,1mmol)，511-8(250.8mg,1.5mmol)，叔丁醇钠(288.3mg,3mmol)，溶于甲苯(20mL)，加入Pd₂(dba)₃(45.7mg,0.05mmol)，混合液氩气置换后快速升温至110℃反应3小时。LC-MS监测反应完成，混合液降温后，减压浓缩得到粗产物，粗产物经过柱层析纯化得产物(630g,收率: 73.7％)。Dissolve 511-7 (723mg, 1mmol), 511-8 (250.8mg, 1.5mmol), sodium tert-butoxide (288.3mg, 3mmol) in toluene (20mL), add Pd ₂ (dba) ₃ (45.7mg, 0.05mmol), the mixture was replaced with argon and then rapidly heated to 110°C for 3 hours. LC-MS monitors that the reaction is complete. After the mixed solution is cooled, it is concentrated under reduced pressure to obtain the crude product. The crude product is purified by column chromatography to obtain the product (630g, yield: 73.7%).

MS(ESI):854[M+H]⁺。MS (ESI): 854 [M+H] ⁺ .

步骤6：化合物511-10的合成：
Step 6: Synthesis of compound 511-10:

将511-9(500mg,0.58mmol)和三氟乙酸(2mL)溶于二氯甲烷(5mL)，混合液氩气置换后室温搅拌2小时。LC-MS监测反应完成，混合液减压浓缩，将粗产物溶于二氯甲烷(20mL)和水(20mL)中，加入饱和碳酸氢钠溶液(5mL)，用二氯甲烷萃取(20mLX3)，有机相合并，并用无水硫酸钠干燥，将有机相过滤，减压浓缩得到粗产物，粗产物柱层析纯化得产物(310mg,收率:88.5％)。511-9 (500 mg, 0.58 mmol) and trifluoroacetic acid (2 mL) were dissolved in dichloromethane (5 mL), and the mixture was replaced with argon and stirred at room temperature for 2 hours. LC-MS monitored the completion of the reaction, the mixture was concentrated under reduced pressure, the crude product was dissolved in dichloromethane (20mL) and water (20mL), saturated sodium bicarbonate solution (5mL) was added, extracted with dichloromethane (20mL×3), The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product (310 mg, yield: 88.5%).

MS(ESI):604[M+H]⁺。MS (ESI): 604 [M+H] ⁺ .

步骤7：化合物511的合成：
Step 7: Synthesis of Compound 511:

将511-10(300mg,0.49mmol)和37％甲醛水溶液(1mL)溶于甲醇(2mL)中，混合液氩气置换后室温搅拌2小时。室温下向混合液中加入三乙酰氧基硼氢化钠(212mg,1mmol)，反应液继续在室温反应12小时，LC-MS监测反应完成，混合液减压浓缩得到粗产物，粗产物经过柱层析纯化得产物(280mg,收率:92.5％)。Dissolve 511-10 (300mg, 0.49mmol) and 37% aqueous formaldehyde (1mL) in methanol (2mL), and replace the mixture with argon at room temperature Stir for 2 hours. Sodium triacetoxyborohydride (212 mg, 1 mmol) was added to the mixture at room temperature, and the reaction solution continued to react at room temperature for 12 hours. LC-MS monitored the completion of the reaction. The mixture was concentrated under reduced pressure to obtain a crude product, which was passed through a column layer The product was purified by analysis (280 mg, yield: 92.5%).

¹H NMR(400MHz,DMSO-d₆)δ7.75(s,1H),7.60-7.60(m,3H),7.38-7.29(m,3H),7.00-6.98(m,2H),6.20-6.10(m,1H),5.70-5.69(m,1H),5.65-5.50(m,1H),5.50-5.35(m,1H),3.95-3.85(m,2H),3.80-3.70(m,2H),3.50-3.55(m,2H),2.80-2.50(m,9H),2.48-2.37(m,1H),2.36(s,3H),2.10-2.00(m,2H),2.00-1.90(m,2H),1.70-1.55(m,2H),1.55-1.40(m,2H)。 ¹ H NMR (400MHz,DMSO-d ₆ )δ7.75(s,1H),7.60-7.60(m,3H),7.38-7.29(m,3H),7.00-6.98(m,2H),6.20-6.10 (m,1H),5.70-5.69(m,1H),5.65-5.50(m,1H),5.50-5.35(m,1H),3.95-3.85(m,2H),3.80-3.70(m,2H) ,3.50-3.55(m,2H),2.80-2.50(m,9H),2.48-2.37(m,1H),2.36(s,3H),2.10-2.00(m,2H),2.00-1.90(m, 2H), 1.70-1.55(m, 2H), 1.55-1.40(m, 2H).

MS(ESI):618[M+H]⁺。MS (ESI): 618 [M+H] ⁺ .

实施例2-658化合物1-510及512-658的合成The synthesis of embodiment 2-658 compound 1-510 and 512-658

使用类似的合成方法，可以得到表2中目标化合物1-510和化合物512-658。Using similar synthetic methods, the target compounds 1-510 and compounds 512-658 in Table 2 can be obtained.

表2

Table 2

实施例659本发明化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)酶的抑制活性的检测Example 659 Detection of the inhibitory activity of the compounds of the present invention on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzymes

运用HTRF方法测定化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)酶活的抑制作用。具体如下。The inhibitory effect of compounds on EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT) enzyme activity was determined by HTRF method. details as follows.

将WT或者突变型EGFR蛋白与梯度稀释的化合物在28℃孵育10分钟后加入biotin-标记的通用酪氨酸激酶底物(TK)和ATP，在室温反应40分钟。终止反应后加入针对TK的Eu3+-Cryptate标记抗体和streptavidin-XL665，在室温孵育60分钟。通过检测615nm和665nm的发光，计算665/615的比值，定量TK底物磷酸化的水平。与对照组相比，计算化合物抑制百分比。结果见下列表3。WT or mutant EGFR protein was incubated with serially diluted compounds at 28°C for 10 minutes, then biotin-labeled universal tyrosine kinase substrate (TK) and ATP were added, and reacted at room temperature for 40 minutes. After terminating the reaction, Eu3+-Cryptate labeled antibody against TK and streptavidin-XL665 were added and incubated at room temperature for 60 minutes. The level of TK substrate phosphorylation was quantified by detecting the luminescence at 615 nm and 665 nm and calculating the ratio 665/615. The percent inhibition of the compound was calculated compared to the control group. The results are shown in Table 3 below.

表3.本发明化合物对EGFR(del19/T790M/C797S)、EGFR(L858R/T790M/C797S)或EGFR(WT)的抑制活性

+表示抑制率小于或等于20％
++表示抑制率为20％至50％
+++表示抑制率大于50％。
N.D表示活性未测Table 3. The inhibitory activity of the compounds of the present invention to EGFR (del19/T790M/C797S), EGFR (L858R/T790M/C797S) or EGFR (WT)

+ indicates that the inhibition rate is less than or equal to 20%
++ means 20% to 50% inhibition
+++ indicates an inhibition rate greater than 50%.
ND means activity not determined

从表3数据可知，本发明中Y基团为芳基或杂芳基的化合物对EGFR(del19/T790M/C797S)和EGFR(L858R/T790M/C797S)的酶活性有意想不到的较好的抑制活性。From the data in Table 3, it can be seen that the compounds whose Y group is aryl or heteroaryl in the present invention have unexpected better inhibitory activity on the enzyme activity of EGFR (del19/T790M/C797S) and EGFR (L858R/T790M/C797S) .

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 implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or changes can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims

一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

通式(1)中：In general formula (1):

Y为(C1-C6)烷基、(C3-C11)环烷基、(3-11元)杂环烷基、(C6-C14)芳基或(5-10元)杂芳基，其中所述(C1-C6)烷基、(C3-C11)环烷基、(3-11元)杂环烷基、(C6-C14)芳基或(5-10元)杂芳基可任选被1个或多个下列基团取代：-H、卤素、-R⁴、-OR⁴、-(CH₂)_nOR⁴、-(CH₂)_nNR⁴R⁵、-NR⁴R⁵、-CN、-C(O)NR⁴R⁵、-NR⁵C(O)R⁴、-NR⁵S(O)₂R⁴、-S(O)_pR⁴、-S(O)₂NR⁴R⁵和-O-CH₂-O-；Y is (C1-C6) alkyl, (C3-C11) cycloalkyl, (3-11) heterocycloalkyl, (C6-C14) aryl or (5-10) heteroaryl, wherein The (C1-C6) alkyl, (C3-C11) cycloalkyl, (3-11) heterocycloalkyl, (C6-C14) aryl or (5-10) heteroaryl can optionally be Substituted by one or more of the following groups: -H, halogen, -R ⁴ , -OR ⁴ , -(CH ₂ ) _n OR ⁴ , -(CH ₂ ) _n NR ⁴ R ⁵ , -NR ⁴ R ⁵ , - CN, -C(O)NR ⁴ R ⁵ , -NR ⁵ C(O)R ⁴ , -NR ⁵ S(O) ₂ R ⁴ , -S(O) _p R ⁴ , -S(O) ₂ NR ⁴ ^R5 and -O-CH2 _- O-;

X¹为N或CH； ^X1 is N or CH;

X²为N或CH； ^X2 is N or CH;

X³为N或CH； ^X3 is N or CH;

X为(C6-C14)亚芳基或(5-11元)亚杂芳基，其中所述(C6-C14)亚芳基或(5-11元)亚杂芳基可任选被1个或多个下列基团取代：-H、卤素、(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)烷氧基和(C1-C6)卤代烷氧基；X is (C6-C14) arylene group or (5-11 yuan) heteroarylene group, wherein said (C6-C14) arylene group or (5-11 yuan) heteroarylene group can be optionally replaced by 1 Or more of the following groups are substituted: -H, halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy and (C1-C6) haloalkoxy;

R¹为-H、卤素、-(CH₂)_nNR⁶R⁷、-NR⁶R⁷、-O(CH₂)_mNR⁶R⁷、-N(R⁵)(CH₂)_mNR⁶R⁷、(C1-C6)烷氧基、-CH₂-(3-15元)杂环烷基或(3-15元)杂环烷基，其中所述(C1-C6)烷氧基、-CH₂-(3-15元)杂环烷基或(3-15元)杂环烷基可任选被1个或多个下列基团取代：-H、-R⁴、-(CH₂)_nNR⁶R⁷、-NR⁶R⁷、-O(CH₂)_mNR⁶R⁷、-N(R⁵)(CH₂)_mNR⁶R⁷和-R³；R ¹ is -H, halogen, -(CH ₂ ) _n NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -O(CH ₂ ) _m NR ⁶ R ⁷ , -N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ , (C1-C6) alkoxy, -CH ₂ -(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl, wherein the (C1-C6) alkoxy, -CH ₂ -(3-15 membered) heterocycloalkyl or (3-15 membered) heterocycloalkyl may be optionally substituted by one or more of the following groups: -H, -R ⁴ , -(CH ₂ ) _n NR ⁶ R ⁷ , -NR ⁶ R ⁷ , -O(CH ₂ ) _m NR ⁶ R ⁷ , -N(R ⁵ )(CH ₂ ) _m NR ⁶ R ⁷ and -R ³ ;

L¹为-O-、-NH-或者化学键；L ¹ is -O-, -NH- or a chemical bond;

R²为(C1-C6)烷基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基，其中所述(C1-C6)烷基、(C3-C14)环烷基、(C6-C14)芳基、(3-11元)杂环烷基可任选被1个或多个下列基团取代：-H、卤素、-R⁴、-(CH₂)_nOR⁴-、-(CH₂)_nNR⁴R⁵-、-OR⁴、-NR⁴R⁵、-CN、-C(O)NR⁴R⁵、-NR⁵C(O)R⁴、-NR⁵S(O)₂R⁴、-S(O)_pR⁴和-S(O)₂NR⁴R⁵；R ² is (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 yuan) heterocycloalkyl, wherein said (C1-C6) alkyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl can be optionally substituted by one or more of the following groups: -H, halogen, -R ⁴ , -(CH ₂ ) _n OR ⁴ -, -(CH ₂ ) _n NR ⁴ R ⁵ -, -OR ⁴ , -NR ⁴ R ⁵ , -CN, -C(O)NR ⁴ R ⁵ , -NR ⁵ C( O)R ⁴ , -NR ⁵ S(O) ₂ R ⁴ , -S(O) _p R ⁴ and -S(O) ₂ NR ⁴ R ⁵ ;

R³为(3-11元)杂环烷基，其中所述(3-11元)杂环烷基可任选被1个或多个下列基团取代：-H、-CD₃、-R⁴、-OR⁴和-NR⁴R⁵；R ³ is a (3-11 membered) heterocycloalkyl group, wherein the (3-11 membered) heterocycloalkyl group can be optionally substituted by one or more of the following groups: -H, -CD ₃ , -R ⁴ , -OR ⁴ and -NR ⁴ R ⁵ ;

R⁴和R⁵各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基；R ⁴ and R ⁵ are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl;

R⁶和R⁷各自独立地为-H、(C1-C6)烷基或(C3-C14)环烷基，或R⁶和R⁷与其连接的N原子能够共同组成一个(3-11元)杂环烷基，其中所述(3-11元)杂环烷基可任选被1个或多个下列基团取代：-H、-CD₃、卤素、-R⁴和-OR⁴；R ⁶ and R ⁷ are each independently -H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R ⁶ and R ⁷ can jointly form a (3-11 member) Heterocycloalkyl, wherein the (3-11 membered) heterocycloalkyl can be optionally substituted by one or more of the following groups: -H, -CD ₃ , halogen, -R ⁴ and -OR ⁴ ;

和and

p为0、1或2的整数，n为0、1、2或3的整数，m为1、2或3的整数。p is an integer of 0, 1 or 2, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.
如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Y为(C1-C3)烷基、(C3-C6)环烷基、(5-6元)杂环烷基、苯基或(5-9元)杂芳基，其中所述(C1-C3)烷基、(C3-C6)环烷基、(5-6元)杂环烷基、苯基或(5-9元)杂芳基可任选被1个或多个下列基团取代：-H、-F、-Cl、-Br、-CN、-OH、-OCH₃、-NH₂、-N(CH₃)₂、-NHCOCH₃、-NHSO₂CH₃、-SO₂CH₃、-CH₃、-CONH₂、-CH₂OH和-O-CH₂-O-。The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Y is (C1-C3) Alkyl, (C3-C6) cycloalkyl, (5-6 member) heterocycloalkyl, phenyl or (5-9 member) heteroaryl, wherein said (C1-C3) alkyl, (C3- C6) Cycloalkyl, (5-6 membered) heterocycloalkyl, phenyl or (5-9 membered) heteroaryl can be optionally substituted by one or more of the following groups: -H, -F, - Cl, -Br, -CN, -OH, -OCH ₃ , -NH ₂ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -NHSO ₂ CH ₃ , -SO ₂ CH ₃ , -CH ₃ , -CONH ₂ , _-CH2OH and -O-CH2 _- O-.
如权利要求2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Y为：-CH₃、-CH₂CH₃、
The compound as claimed in claim 2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein In the general formula (1), Y is: -CH ₃ , -CH ₂ CH ₃ ,
如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X为亚苯基或6元亚杂芳基，其中所述亚苯基或6元亚杂芳基可任选被1个或多个下列基团取代：-H、-F、-CH₃、-CH₂CH₃、-CH(CH₃)₂、-OCH₃、-OCF₂H和-OCF₃。The compound according to any one of claims 1-3 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), X is phenylene or 6-membered heteroarylene, wherein the phenylene or 6-membered heteroarylene can be optionally substituted by one or more of the following groups: -H, -F, -CH ₃ , - CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -OCF ₂ H and -OCF ₃ .
如权利要求4所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X为：

The compound as claimed in claim 4 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), X is:
如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R¹为：-H、-N(CH₃)₂、-CH₂-(6-11元)杂环烷基或(6-11元)杂环烷基，其中所述(6-11元)杂环烷基为：所述(6-11元)杂环烷基可任选被1个或多个下列基团取代：-H、-CH₃、-N(CH₃)₂、和-CD₃。The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ¹ is: -H, -N(CH ₃ ) ₂ , -CH ₂ -(6-11 membered) heterocycloalkyl or (6-11 membered) heterocycloalkyl, wherein the (6-11 membered) heterocycloalkyl Cycloalkyl is: The (6-11 membered) heterocycloalkyl group can be optionally substituted by one or more of the following groups: -H, -CH ₃ , -N(CH ₃ ) ₂ , and - CD ₃ .
如权利要求6所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R¹为：-H、-N(CH₃)₂、 The compound as claimed in claim 6 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ¹ is: -H, -N(CH ₃ ) ₂ ,
如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当L¹为-NH-时，R²为：
The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when When L ¹ is -NH-, R ² is:
如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当L¹为-O-时，R²为：
The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when When L ¹ is -O-, R ² is:
如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，当L¹为化学键时，R²为：
The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when When L ¹ is a chemical bond, R ² is:
如权利要求1-10中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：

The compound according to any one of claims 1-10 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:
一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-11中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-11, or its isomers, crystal forms, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
一种如权利要求1-11中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求12所述的药物组合物在制备治疗EGFR突变相关疾病药物中的用途。 A compound as described in any one of claims 1-11, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the drug as claimed in claim 12 Use of the composition in preparing medicines for treating EGFR mutation-related diseases.