WO2017084640A1

WO2017084640A1 - Nitrogen-containing heterocyclic compound, preparation method therefor, and application in inhibiting kinase activity

Info

Publication number: WO2017084640A1
Application number: PCT/CN2017/070372
Authority: WO
Inventors: 汪舰; 别建波; 郎明
Original assignee: 清华大学
Priority date: 2015-11-17
Filing date: 2017-01-06
Publication date: 2017-05-26
Also published as: CN106699810A

Abstract

Provided are a nitrogen-containing heterocyclic compound, a preparation method therefor, and an application in inhibiting kinase activity. The formula of the nitrogen-containing heterocyclic compound is as shown in formula I or formula I', wherein: R₁, R₂, R₃ and R₄ are independently selected from any one of hydrogen, a halogen, a cyano group, a hydroxy group, an amino group and a substituted or unsubstituted C1-C6 alkyl group, and any two groups within R₁, R₂, R₃ and R₄ may form a 3-10 membered ring system; M₁, M₂ and M₃ are independently selected from CRa or N, and at least one of M₁, M₂ and M₃ is N; W is selected from a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 chain alkenyl group, an unsubstituted or halogenated 4-8 membered chain alkynyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocyclyl group, a 5-10 membered aryl group or heteroaryl group, a substituted carbonyl group, a substituted sulfonyl group and a substituted or unsubstituted amino group. The heterocyclic compound may inhibit EGFR mutant kinase activity or ALK kinase activity, and is multi-target tumour treatment drug having an all-new mechanism of action.

Description

一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用Nitrogen-containing heterocyclic compound, preparation method thereof and application thereof in inhibiting kinase activity

技术领域Technical field

本发明涉及一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用，属于药物化学技术领域。The invention relates to a nitrogen-containing heterocyclic compound, a preparation method thereof and application thereof in inhibiting kinase activity, and belongs to the technical field of medicinal chemistry.

背景技术Background technique

肿瘤分子靶向治疗是基于对肿瘤发生、发展密切相关的关键蛋白，通过化学手段选择性作用于信号蛋白，杀伤肿瘤细胞的一种治疗方法。靶向治疗的特点为：特异性高，选择性强，毒副作用相对于传统化疗药物低；联合用药时，可加强传统化疗的疗效；靶向抑制剂药物临床上容易产生耐药而使治疗药物失效。Tumor molecular targeted therapy is a therapeutic method based on the key protein related to tumorigenesis and development, which selectively acts on signal proteins by chemical means to kill tumor cells. The characteristics of targeted therapy are: high specificity, strong selectivity, and low toxic side effects compared with traditional chemotherapeutic drugs; when combined, it can enhance the efficacy of traditional chemotherapy; targeted inhibitor drugs are clinically prone to drug resistance and therapeutic drugs Invalid.

肺癌是全世界发病率和病死率最高的恶性肿瘤，5年生存率仅为16.8％，2010年肺癌的发病率和病死率居我国所有恶性肿瘤之首。非小细胞肺癌(NSCLC)约占所有肺癌病理类型中的85％，非小细胞肺癌病因复杂，多基因、多靶点调控且易突变产生耐药。非小细胞肺癌治疗药物主要有传统化疗药物铂类、紫杉醇类，抗体类，新生血管抑制剂和靶向抑制剂等，但是随着临床上还是有大量的突变引起的耐药病人出现，因此发现和寻找抗耐药的非小细胞肺癌治疗药物仍是目前工业界的一个热门领域。Lung cancer is the most common malignant tumor with the highest morbidity and mortality in the world. The 5-year survival rate is only 16.8%. In 2010, the incidence and mortality of lung cancer ranked first among all malignant tumors in China. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer pathological types. The cause of non-small cell lung cancer is complex, multi-gene, multi-target regulation and easy mutation to produce resistance. Non-small cell lung cancer treatments mainly include traditional chemotherapeutic drugs such as platinum, paclitaxel, antibodies, neovascular inhibitors and targeted inhibitors, but with the emergence of drug-resistant patients caused by a large number of mutations in the clinic, it was found And looking for anti-drug resistant non-small cell lung cancer treatment drugs is still a hot area of the industry.

近年来，美国FAD相继批准了多个ALK抑制剂，如克唑替尼、色瑞替尼等，以及目前正处于临床后期阶段的第三代EGFR抑制剂，如AZD9219，CO1686等，但是目前这类药物仍然存在疗效不佳，或者选择性不高等问题，因此迫切需要发现和寻找一类具有较高突变耐药选择性，或者具有多重靶点抑制活性的新型治疗药物。In recent years, the United States FAD has successively approved a number of ALK inhibitors, such as crizotinib, ceritinib, etc., and third-generation EGFR inhibitors currently in the late clinical stage, such as AZD9219, CO1686, etc., but currently There are still problems with poor efficacy or low selectivity, so it is urgent to find and find a new type of therapeutic drug with high mutation resistance selectivity or multiple target inhibition activity.

发明公开Invention disclosure

本发明的目的是提供一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用，该含氮杂化化合物可以作为多种肿瘤细胞的增殖抑制剂，是一类全新作用机制的多靶点肿瘤治疗药物。The object of the present invention is to provide a nitrogen-containing heterocyclic compound, a preparation method thereof and the use thereof for inhibiting kinase activity, and the nitrogen-containing hybrid compound can be used as a proliferation inhibitor of various tumor cells, and is a novel mechanism of action. Multi-target tumor treatment drugs.

本发明提供的含氮杂环化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药，其中，含氮杂环化合物的通式如式Ⅰ或式Ⅰ’所示： The present invention provides a nitrogen-containing heterocyclic compound, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a solvate, a polymorph or a prodrug thereof, wherein The general formula of the nitrogen-containing heterocyclic compound is as shown in Formula I or Formula I':

式Ⅰ或式Ⅰ’中：In formula I or formula I':

R₁、R₂、R₃、R₄独立地选自氢、卤素、氰基、羟基、氨基和取代或未取代的C1-C6烷基中的任一种，且R₁、R₂、R₃、R₄中的任意两个基团可以形成3-10元的环系；R ₁ , R ₂ , R ₃ , R _{4 are} independently selected from any of hydrogen, halogen, cyano, hydroxy, amino and substituted or unsubstituted C1-C6 alkyl, and R ₁ , R ₂ , R ₃ , any two groups of R ₄ can form a 3-10 yuan ring system;

M₁、M₂、M₃独立地选自CRa或N，且M₁、M₂和M₃中至少有一个为N；Ra为氢、卤素、氰基、取代或未取代的C1-C6烷基和取代或未取代的C3-C8环烷基中的一种；M ₁ , M ₂ , M _{3 are} independently selected from CRa or N, and at least one of M ₁ , M ₂ and M ₃ is N; Ra is hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkane a group and one of a substituted or unsubstituted C3-C8 cycloalkyl group;

W选自下述基团的任一种：取代或未取代的C1-C6烷基、取代或未取代的C2-C6链烯基、未取代或卤代的4～8元的链炔基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、5-10元的芳香基或杂芳基、取代羰基、取代磺酰基、取代或未取代的氨基，其中，所述杂环基包含1-3个选自N、O、S、P和B中的杂原子；W is selected from any of the following groups: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, an unsubstituted or halogenated 4-8 membered alkynyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocyclic group, a 5-10 membered aryl or heteroaryl group, a substituted carbonyl group, a substituted sulfonyl group, a substituted or unsubstituted amino group Wherein the heterocyclic group contains 1-3 heteroatoms selected from the group consisting of N, O, S, P and B;

所述取代为基团中的一个或多个基团被选自下组的至少一种取代基所取代：卤素、羟基、氨基、氰基、未取代或卤代的C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的5～8元芳基、未取代或卤代的5～8元杂芳基、未取代或卤代的4～8元饱和杂环、未取代或卤代的4～8元碳环；其中，所述杂芳基包含1-3个选自N、O和S中的杂原子，所述杂环包含1-3个选自N、O和S的杂原子；The substituent is one or more groups in the group substituted with at least one substituent selected from the group consisting of halogen, hydroxy, amino, cyano, unsubstituted or halogenated C1-C8 alkyl, unsubstituted Substituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted Substituted or halogenated C2-C6 acyl group, unsubstituted or halogenated 5- to 8-membered aryl group, unsubstituted or halogenated 5- to 8-membered heteroaryl group, unsubstituted or halogenated 4-8 membered saturated heterocyclic ring a 4- to 8-membered carbocyclic ring which is unsubstituted or halogenated; wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O and S, the heterocyclic ring comprising 1-3 selected from N , O and S heteroatoms;

式Ⅰ’中，L选自下述基团的任一种：-CR’R”-、-O-、-NR’-、和－CR’＝，其中R’和R”各自独立地为氢、氟、氘、C1-C6烷基和C1-C6杂环烷基中的任一种，或者其中相邻的R’和R”形成环状基团。In Formula I', L is selected from any of the following groups: -CR'R"-, -O-, -NR'-, and -CR'=, wherein R' and R" are each independently hydrogen. Any one of fluorine, hydrazine, C1-C6 alkyl and C1-C6 heterocycloalkyl, or wherein adjacent R' and R" form a cyclic group.

上述式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或 a compound of the above formula I; or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof;

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐中：R₁、R₂、R₃、R₄具体可为氢。a compound of the formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof: R ₁ , R ₂ , R ₃ , R ₄ may specifically be hydrogen.

上述式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或a compound of the above formula I; or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof;

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐中：式Ⅰ所示化合物或式Ⅰ’所示化合物满足下述1)和/或2)：a compound of formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof: Formula I The compound or the compound of formula I' satisfies the following 1) and/or 2):

1)式Ⅰ或式Ⅰ’中，M₁、M₂独立地选自CH或N，且M₁和M₂中至少有一个为N；M₃选自C-F、C-CF₃、C-Cl、CH和N中的任一种；1) In Formula I or Formula I', M ₁ , M _{2 are} independently selected from CH or N, and at least one of M ₁ and M ₂ is N; M _{3 is} selected from CF, C-CF ₃ , C-Cl Any of CH, N and N;

2)式Ⅰ或式Ⅰ’中，W选自下述基团中的任一种：取代或未取代的C1-C6烷基或环烷基、取代或未取代的4-10元杂环、取代或未取代的4-10元环烷基和取代或未取代的4-10元杂环烷基形成的螺环或桥环；W具体为取代或未取代的下述基团中的任一种：环戊烷、环己烷、四氢吡咯环、四氢呋喃环、哌啶环、四氢哌啶环、哌嗪环、***啉环，吡唑环、吲唑环、苯环或吡啶环；2) In Formula I or Formula I', W is selected from any of the following groups: a substituted or unsubstituted C1-C6 alkyl or cycloalkyl group, a substituted or unsubstituted 4-10 membered heterocyclic ring, a spiro or bridged ring formed by a substituted or unsubstituted 4-10 membered cycloalkyl group and a substituted or unsubstituted 4-10 membered heterocycloalkyl group; W is specifically a substituted or unsubstituted one of the following groups Species: cyclopentane, cyclohexane, tetrahydropyrrole ring, tetrahydrofuran ring, piperidine ring, tetrahydropiperidine ring, piperazine ring, morpholine ring, pyrazole ring, indazole ring, benzene ring or pyridine ring;

所述取代是指取代基独立地选自下述基团的至少一种：卤素、羟基、氰基、氨基、烷基、单烷基氨基、二烷基氨基)、环烷基、杂环基、烷氧基、羟基烷基、烷氧基烷基、羟基烷氧基烷基、氨基烷基、二烷基氨基烷基、烷氧基羰基氨基烷基、环烷基烷基、杂环基烷基、芳烷基、烷基环烷基、环烷基羰基、烷氧基羰基、烷氧基羰基杂环基、(烷氧羰基)(烷基)氨基、(烷氧基烷基)(烷基)氨基。The substitution means that the substituent is independently selected from at least one of the following groups: halogen, hydroxy, cyano, amino, alkyl, monoalkylamino, dialkylamino), cycloalkyl, heterocyclic Alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, cycloalkylalkyl, heterocyclyl Alkyl, aralkyl, alkylcycloalkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (alkoxyalkyl) ( Alkyl) amino group.

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐中：A compound of the formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof:

式Ⅰ所示化合物具体可为下述式I-a所示化合物至式I-j1所示化合物中的任一种： The compound of the formula I may specifically be any one of the compounds of the following formula I-a to the compound of the formula I-j1:

式Ⅰ’所示化合物具体可为下述式Ⅰ’-a至式Ⅰ’-f中的任一种：The compound of the formula I' may specifically be any of the following formulas I'-a to I'-f:

本发明进一步提供了一种制备式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或The invention further provides a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable thereof. Salt; or

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐的方法，包括如下步骤：A method of the compound of Formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof, comprising the steps :

(1)将式Ⅳ所示化合物与式Ⅴ所示化合物，在过渡金属催化剂和/或酸/碱(酸/碱表示酸或碱)存在的条件下进行偶联，得到式Ⅲ所示化合物；(1) a compound of the formula IV and a compound of the formula V, in a transition metal catalyst and/or Coupling in the presence of an acid/base (acid/base representing an acid or a base) provides a compound of formula III;

式Ⅳ中，X和LG各自独立地为离去基团，且选自卤素、磺酸酯、硼酸和硼酸酯中的任一种；In Formula IV, X and LG are each independently a leaving group, and are selected from any of halogen, sulfonate, boric acid, and boric acid ester;

式Ⅲ中，X的定义同式Ⅳ；M₁、M₂和M₃的定义同式Ⅰ或式I’；In Formula III, X is as defined in Formula IV; M ₁ , M ₂ and M ₃ are the same as Formula I or Formula I';

(2)式Ⅲ所示化合物与式Ⅱ所示化合物或式Ⅱ’所示化合物在过渡金属催化剂和/或酸/碱(酸/碱表示酸或碱)存在的条件下进行偶联，得到式I所示化合物或式I’所示化合物；(2) A compound of the formula III is coupled with a compound of the formula II or a compound of the formula II' in the presence of a transition metal catalyst and/or an acid/base (acid/base represents an acid or a base). a compound represented by I or a compound of formula I';

式Ⅱ中，R1、R2、R3、R4、L和W的定义同式Ⅰ；式Ⅱ’中，R₁、R₂、R₃、R₄、L和W的定义同式Ⅰ’。In Formula II, R1, R2, R3, R4, L and W are as defined in Formula I; in Formula II', R ₁ , R ₂ , R ₃ , R ₄ , L and W are as defined in Formula I′.

上述的制备方法中，步骤(1)或步骤(2)中，In the above preparation method, in the step (1) or the step (2),

所述偶联反应在溶剂中进行，且所述溶剂选自水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二氧六环中的至少一种；The coupling reaction is carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, At least one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dioxane;

所述过渡金属催化剂选自三(二亚苄基丙酮)二钯、四(三苯基膦)钯、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯和 1,2-二(二苯基膦基)乙烷二氯化钯中的至少一种；所述催化剂配体选自三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦和三邻苯甲基膦中的至少一种；The transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, Palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-o-phenylmethylphosphine)palladium dichloride and At least one of 1,2-bis(diphenylphosphino)ethanedichloropalladium; the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphonium tetrafluoroborate, and tri-n-butyl At least one of phosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, and tri-o-phenylmethylphosphine;

所述碱为无机碱或有机碱；所述无机碱选自氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠和碳酸氢钠中的至少一种；所述有机碱选自吡啶、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、六甲基二硅基锂、六甲基二硅基钠和二甲基吡啶中的至少一种；The base is an inorganic base or an organic base; the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, At least one of potassium carbonate, potassium hydrogencarbonate, sodium carbonate, and sodium hydrogencarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diaza At least one of cyclo[5.4.0]undec-7-ene, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and lutidine;

所述酸选自盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸和乙酸中的至少一种。The acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid.

本发明还提供了式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或The invention further provides a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof;

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；a compound of the formula I'; or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof;

在下述1)或2)中的应用：Application in 1) or 2) below:

1)制备具有抑制EGFR突变激酶活性和/或ALK激酶活性的功能的抑制剂；1) preparing an inhibitor having a function of inhibiting EGFR mutant kinase activity and/or ALK kinase activity;

2)抑制EGFR突变激酶活性和/或ALK激酶活性。2) Inhibition of EGFR mutant kinase activity and/or ALK kinase activity.

本发明进一步提供了一种激酶抑制剂，它包括式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或The invention further provides a kinase inhibitor comprising a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug thereof or a pharmaceutically acceptable salt; or

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐。A compound of the formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof.

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐，a compound of the formula I'; or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof,

在下述1)或2)中的应用：Application in 1) or 2) below:

1)制备预防和/或***产品；1) preparing a preventive and/or therapeutic tumor product;

2)预防和/或***。 2) Prevention and/or treatment of tumors.

上述的应用中，所述肿瘤可为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、淋巴癌和鼻咽癌中的任一种。In the above application, the tumor may be non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal interstitial Any of tumor, leukemia, lymphoma, and nasopharyngeal cancer.

本发明还进一步提供了一种药物组合物，它包括：The invention still further provides a pharmaceutical composition comprising:

1)有效量的式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或1) an effective amount of a compound of formula I or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof;

2)药学上可接受的载体。2) A pharmaceutically acceptable carrier.

本发明还提供了抑制EGFR突变激酶活性和/或ALK激酶活性的方法，它包括如下步骤：给受体动物(例如哺乳动物、人)施用上述任一项所述的式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或The present invention also provides a method of inhibiting EGFR mutant kinase activity and/or ALK kinase activity, which comprises the step of administering to a recipient animal (e.g., a mammal, a human) a compound of formula I as described in any one of the above, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof;

式Ⅰ’所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或a compound of formula I', a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph thereof or prodrug thereof;

所述的药物组合物。Said pharmaceutical composition.

本发明还提供了预防和/或***的方法，它包括如下步骤：给受体动物(例如哺乳动物、人)施用上述任一项所述的式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或The invention also provides a method of preventing and/or treating a tumor comprising the steps of administering to a recipient animal (e.g., a mammal, a human) a compound of formula I as described in any one of the above, which is pharmaceutically acceptable a salt, enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof; or

所述的药物组合物。Said pharmaceutical composition.

上述的方法中，所述肿瘤可为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、淋巴癌和鼻咽癌中的任一种。In the above method, the tumor may be non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal interstitial Any of tumor, leukemia, lymphoma, and nasopharyngeal cancer.

本发明具有如下有益效果：The invention has the following beneficial effects:

本发明提供的具有式I所示结构通式或式Ⅰ’所示结构通式的化合物，可以抑制多种肿瘤细胞，尤其是能选择性作用于EGFR T790M突变和ALK阳性的肺癌细胞，是一类全新作用机制的多靶点肺癌治疗药物。 The compound having the structural formula represented by Formula I or the structural formula represented by Formula I' provided by the present invention can inhibit various tumor cells, especially lung cancer cells which can selectively act on EGFR T790M mutation and ALK positive, A multi-target lung cancer treatment drug with a novel mechanism of action.

本发明中的术语：Terms in the present invention:

除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein

应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。The above description and the following detailed description are to be considered as illustrative and not restrictive. In addition, the terms "comprises" and "comprising", "include", "include", and "include" are not limiting.

可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH₂O-等同于-OCH₂-。When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。The section headings used herein are for the purpose of organizing articles only and are not to be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.

在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms. The total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.

除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of this application, unless otherwise specified Indicates otherwise the following terms have the meanings indicated below.

在本申请中，术语“卤素”是指氟、氯、溴或碘。In the present application, the term "halogen" means fluoro, chloro, bromo or iodo.

“羟基”是指-OH基团。"Hydroxy" means an -OH group.

“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。"Hydroxyalkyl" means an alkyl group as defined below which is substituted by a hydroxy group (-OH).

“羰基”是指-C(＝O)-基团。"Carbonyl" means a -C(=O)- group.

“硝基”是指-NO₂。"Nitro" means -NO ₂ .

“氰基”是指-CN。"Cyano" means -CN.

“氨基”是指-NH₂。"Amino" means -NH ₂ .

“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基、(烷氧羰基)(烷基)氨基、(烷氧基烷基)(烷基)氨基。"Substituted amino" means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino, (alkoxycarbonyl)(alkyl)amino, (alkoxyalkyl)(alkyl)amino.

“羧基”是指-COOH。"Carboxyl" means -COOH.

在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。In the present application, as a group or a part of other groups (for example, in a group such as a halogen-substituted alkyl group), the term "alkyl group" means consisting only of carbon atoms and hydrogen atoms, and is not unsaturated. A bond, a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and attached to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.

在本申请中，作为基团或是其它基团的一部分，术语“烯基”(即“链烯基”)意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。In the present application, the term "alkenyl" (ie "alkenyl") as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propylene Alkyl group, allyl group, but-1-enyl group, but-2-enyl group, penten-1-alkenyl group, pentane-1,4-dienyl group and the like.

在本申请中，作为基团或是其它基团的一部分，术语“炔基”(即“链炔基”)意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。 In the present application, the term "alkynyl" (ie "alkynyl") as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one. a linear or branched hydrocarbon chain having one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and attached to the remainder of the molecule by a single bond Groups such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.

在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed The carbon atom is connected to the rest of the molecule by a single bond. Unless otherwise specifically indicated in the specification, a carbon atom in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] Octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [3.2.1] octenyl, adamantyl, VIII Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.

在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、四氢哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。In the present application, the term "heterocyclyl" as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. A stable 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond. In the heterocyclic group containing a fused ring, one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropiperidinyl, thiomorpholinyl, 2,7-diaza - Spiro[3.5]decane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane- 2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinoline Base, imidazolinyl, imidazolidinyl, quinazorazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, VIII Hydroquinone, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

在本申请中，作为基团或是其它基团的一部分，术语“芳基”(即“芳香基”)意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。In the present application, the term "aryl" (ie "aryl") as a group or part of another group means a conjugate having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. Hydrocarbon ring system group. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.

在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至10元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。 In the present application, the term "heteroaryl" as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected A stable 5- to 10-membered aromatic group derived from a hetero atom of nitrogen, oxygen, and sulfur or a 5- to 10-membered aromatic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole, porphyrin, quinazolinyl, phenylthio, guanidinium, phenanthroline, Isoxazolyl, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 , 3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.

在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.

在本申请中，术语“杂环烷基”是指被上文所定义的杂环基所取代的上文所定义的烷基。In the present application, the term "heterocycloalkyl" refers to an alkyl group as defined above which is substituted by a heterocyclic group as defined above.

在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In the present application, "optional" or "optionally" means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.

本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。The terms "part," "structural moiety," "chemical moiety," "group," and "chemical group", as used herein, refer to a particular fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.

“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。"Stereoisomer" refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure. The invention will cover various stereoisomers and mixtures thereof.

当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。When the compound of the present invention contains an olefinic double bond, the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.

“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.

本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。The compounds of the invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof. The preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.

制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63, 2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemic form of a salt or derivative) using, for example, chiral high performance liquid chromatography. For example, see Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu. Rev. Anal. :341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 23,128.

在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable acid addition salt" means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. These salts can be prepared by methods known in the art.

“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。 "Polymorph" refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.

通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。Generally, crystallization will result in a solvate of the compound of the invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules. The solvent may be water, and the solvate in this case is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases, it is also possible to retain only a defined amount of water or a mixture of water plus a portion of the indefinite solvent. The compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood. Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms. Prodrugs include known amino protecting groups and carboxy protecting groups. Specific prodrug preparation methods can be found in Saulnier, M. G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R. B., et al., J. Med. Chem. 2000, 43, 475.

在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In the present application, "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.

本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。The term "pharmaceutically acceptable" as used herein, refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.

在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。 In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。The "tumor", "cell proliferation-related diseases" and the like according to the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.

本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。The terms "preventing", "preventing" and "preventing" as used herein include the possibility of reducing the occurrence or progression of a disease or condition by a patient.

本文所用的术语“治疗”和其它类似的同义词包括以下含义：The term "treatment" and other similar synonyms as used herein includes the following meanings:

(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing a disease or condition from occurring in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;

(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, ie, curbing its development;

(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) alleviating the disease or condition, ie, causing the condition of the disease or condition to subside; or

(iv)减轻该疾病或病症所造成的症状。(iv) alleviating the symptoms caused by the disease or condition.

本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.

本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。The terms "administering," "administering," "administering," and the like, as used herein, refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. The techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。The terms "pharmaceutical combination", "drug combination", "combination", "administering other treatments", "administering other therapeutic agents" and the like as used herein mean by mixing or combining more than one active ingredient. The medical treatment obtained includes both fixed and unfixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "unfixed combination" refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.

本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。It will also be understood by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by a suitable protecting group. Such functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.

附图说明DRAWINGS

图1为合成式Ⅱ所示化合物或式Ⅱ’所示化合物的路线图。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a scheme for the synthesis of a compound of formula II or a compound of formula II'.

图2为合成式Ⅲ所示化合物的路线图。Figure 2 is a road map for the synthesis of the compound of formula III.

图3为合成式Ⅰ所示化合物或式Ⅰ’所示化合物的路线图。Figure 3 is a scheme for the synthesis of a compound of formula I or a compound of formula I'.

实施发明的最佳方式The best way to implement the invention

下述实施例中所使用的实验方法如无特殊说明，均为常规方法。The experimental methods used in the following examples are conventional methods unless otherwise specified.

下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。The materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

下述实施例中的的中间体按照如下步骤制备得到，其中，式Ⅱ所示化合物或式Ⅱ’所示化合物按照图1的路线图合成；式Ⅲ所示化合物按照图2的路线图合成；式Ⅰ所示化合物或式Ⅰ’所示化合物按照图3的路线图合成。 The intermediates in the following examples were prepared as follows, wherein the compound of formula II or the compound of formula II' was synthesized according to the scheme of Figure 1; the compound of formula III was synthesized according to the scheme of Figure 2; The compound of formula I or the compound of formula I' is synthesized according to the scheme of Figure 3.

中间体1：

Intermediate 1:

将化合物4-溴-2,3-二氢苯并呋喃-7-胺(2.05g，9.58mmol)溶于1,2-二氯乙烷(20mL)中，搅拌均匀后，缓慢滴入(～30min)到预先加热至回流状态的mCPBA(7.80g，38.2mmol)的1,2-二氯乙烷(60mL)中，继续回流反应2h，原料消失。蒸除溶剂，加入EA(50mL)，饱和Na₂S₂O₃(aq)洗(30mL×3)，0.5M NaOH(aq)洗(30mL×3)，柱层析(P/E＝5:1)分离得淡黄色固体1.60g，产率为68％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.84(d,J＝8.8Hz,1H),7.11(d,J＝8.8Hz,1H),4.92(t,J＝8.8Hz,2H),3.35(t,J＝8.8Hz,2H).The compound 4-bromo-2,3-dihydrobenzofuran-7-amine (2.05 g, 9.58 mmol) was dissolved in 1,2-dichloroethane (20 mL), stirred well and then slowly dropped (~ After 30 min), mCPBA (7.80 g, 38.2 mmol) of 1,2-dichloroethane (60 mL), which was previously heated to reflux, was refluxed for 2 h and the material disappeared. The solvent was evaporated, EA (50 mL) was added, and then Na ₂ S ₂ O ₃ (aq) (30 mL×3), 0.5M NaOH (aq) (30mL×3), column chromatography (P/E=5: 1) 1.60 g of a pale yellow solid was isolated, yield 68%. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.84 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.92 (t, J = 8.8 Hz, 2H), 3.35 (t, J = 8.8 Hz, 2H).

中间体2：

Intermediate 2:

将化合物4-溴7-硝基-2,3-二氢苯并呋喃(500mg，2.05mmol)溶于toluene(30mL)中，依次加入Pd(OAc)₂(50mg，0.21mmol)，DavePhos(161mg，0.41mmol)和K₃PO₄(1.31g，6.15mmol,6mL H₂O)，搅拌均匀后，加入4-二甲氨基哌啶(789mg，6.15mmol)，氩气保护下，回流反应20h，原料消失。冷却至室温，蒸除溶剂，EA(30mL)溶解残留物，饱和食盐水洗(20mL×3)，水洗(20mL×2)，柱层析(D/M＝20:1)分离纯化得黄色固体500mg，产率为84％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.92(d,J＝8.8Hz,1H),6.42(d,J＝8.8Hz,1H),4.81(t,J＝8.4Hz,2H),3.71(d,J＝12.0Hz,2H),3.20(t,J＝8.4Hz,2H),3.04(m,1H),2.90(t,J＝11.6Hz,2H),2.71(s,6H),2.25(d,J＝10.4Hz,2H),1.88-1.86(m,2H).The compound 4-bromo 7-nitro-2,3-dihydrobenzofuran (500 mg, 2.05 mmol) was dissolved in toluene (30 mL), then Pd(OAc) ₂ (50 mg, 0.21 mmol), DavePhos (161 mg) , 0.41 mmol) and K ₃ PO ₄ (1.31 g, 6.15 mmol, 6 mL H ₂ O). After stirring, 4-dimethylaminopiperidine (789 mg, 6.15 mmol) was added, and the reaction was refluxed for 20 h under argon. The raw materials disappeared. The mixture was cooled to room temperature, and the solvent was evaporated. EtOAc (30 mL) was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield was 84%. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.92 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 4.81 (t, J = 8.4 Hz, 2H), 3.71 (d, J = 12.0 Hz, 2H), 3.20 (t, J = 8.4 Hz, 2H), 3.04 (m, 1H), 2.90 (t, J = 11.6 Hz, 2H), 2.71 (s, 6H), 2.25 (d, J = 10.4 Hz, 2H), 1.88-1.86 (m, 2H).

中间体3：

Intermediate 3:

采用中间体2相同的合成方法，用N，N-二甲基吡咯替换4-二甲氨基哌啶，制备得到中间体3黄色固体130mg，产率为76％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.87(d,J＝9.2Hz,1H),6.09(d,J＝9.6Hz,1H),4.77-4.67(m,2H),3.77-3.40(m,6H),2.81-2.77(m,1H),2.31(s,6H),2.23-2.17 (m,1H),1.92-1.87(m,1H).Using the same synthetic procedure as Intermediate 2, 4-dimethylaminopiperidine was replaced with N,N-dimethylpyrrole to give Intermediate 3 as a yellow solid (yield: 76%). The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.87 (d, J = 9.2 Hz, 1H), 6.09 (d, J = 9.6 Hz, 1H), 4.77 - 4.67 (m, 2H), 3.77-3.40 (m, 6H), 2.81-2.77 (m, 1H), 2.31 (s, 6H), 2.23-2.17 (m, 1H), 1.92-1.87 (m, 1H).

中间体4：

Intermediate 4:

采用中间体2相同的合成方法，用N-Boc哌嗪替换4-二甲氨基哌啶，制备得到中间体4黄色固体163mg，产率为76％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.93(d,J＝9.2Hz,1H),6.42(d,J＝9.2Hz,1H),4.81(t,J＝8.4Hz,2H),3.57(t,J＝4.8Hz,4H),3.24-3.17(m,6H),1.49(s,6H).Using the same synthetic procedure as Intermediate 2, substituting N-Boc piperazine for 4-dimethylaminopiperidine, 163 mg of Intermediate 4 as a yellow solid was obtained. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.93 (d, J = 9.2 Hz, 1H), 6.42 (d, J = 9.2 Hz, 1H), 4.81 (t, J = 8.4 Hz, 2H), 3.57 (t, J = 4.8 Hz, 4H), 3.24 - 3.17 (m, 6H), 1.49 (s, 6H).

中间体5：

Intermediate 5:

采用中间体2相同的合成方法，用N-甲基哌嗪替换4-二甲氨基哌啶，制备得到中间体5黄色固体84mg，产率为52％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.92(d,J＝9.2Hz,1H),6.43(d,J＝9.2Hz,1H),4.80(t,J＝8.8Hz,2H),3.27(t,J＝4.8Hz,4H),3.21(t,J＝8.8Hz,2H),2.55(t,J＝4.8Hz,4H),2.36(s,3H).Using the same synthetic procedure as Intermediate 2, substituting N-methylpiperazine for 4-dimethylaminopiperidine gave Intermediate 5 as a yellow solid (yield: 52%). The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.92 (d, J = 9.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 4.80 (t, J = 8.8 Hz, 2H), 3.27 (t, J = 4.8 Hz, 4H), 3.21 (t, J = 8.8 Hz, 2H), 2.55 (t, J = 4.8 Hz, 4H), 2.36 (s, 3H).

中间体6：

Intermediate 6:

采用中间体2相同的合成方法，用1-methyl-4-(piperidin-4-yl)piperazine替换4-二甲氨基哌啶，制备得到中间体6黄色粉末状固体148mg，产率为69％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.90(d,J＝9.2Hz,1H),6.41(d,J＝9.2Hz,1H),4.79(t,J＝8.4Hz,2H),3.67(d,J＝12.8Hz,2H),3.20(t,J＝8.8Hz,2H),2.88(t,J＝12.0Hz,2H),2.69(brs,4H),2.56(brs,4H),2.49-2.43(m,1H),2.35(s,3H),1.98(d,J＝11.6Hz,2H),1.68-1.58(m,2H).Using the same synthetic procedure as Intermediate 2, 4-methylaminopiperidine was replaced with 1-methyl-4-(piperidin-4-yl)piperazine to give 148 mg of Intermediate 6 as a yellow powdery solid, yield 69%. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.90 (d, J = 9.2 Hz, 1H), 6.41 (d, J = 9.2 Hz, 1H), 4.79 (t, J = 8.4 Hz, 2H), 3.67 (d, J = 12.8 Hz, 2H), 3.20 (t, J = 8.8 Hz, 2H), 2.88 (t, J = 12.0 Hz, 2H), 2.69 (brs, 4H), 2.56 (brs, 4H), 2.49-2.43 (m, 1H), 2.35 (s, 3H), 1.98 (d, J = 11.6 Hz, 2H), 1.68-1.58 (m, 2H).

中间体7：

Intermediate 7:

将中间体1(200mg，0.82mmol)溶于toluene(10mL)中，依次加入Pd(OAc)₂(20mg，0.08mmol)，DavePhos(65mg，0.16mmol)和K₃PO₄(520mg，2.46mmol,2mL H₂O)，搅拌均匀后，加入tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (760mg，2.46mmol)，氩气保护下，95℃反应4h，原料消失。冷却至室温，蒸除溶剂，EA(30mL)溶解残留物，饱和食盐水洗(20mL×3)，水洗(20mL×2)，柱层析(D/M＝10:1)，得中间体7黄色粉末状固体250mg，产率为88％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.91(d,J＝8.8Hz,1H),6.82(d,J＝8.8Hz,1H),5.91(s,1H),4.83(t,J＝8.8Hz,2H),4.09(m,2H),3.63(t,J＝8.8Hz,2H),3.32(t,J＝8.8Hz,2H),2.45(m,2H),1.50(s,9H).Intermediate 1 (200 mg, 0.82 mmol) was dissolved in toluene (10 mL). Pd(OAc) ₂ (20 mg, 0.08 mmol), DavePhos (65 mg, 0.16 mmol) and K ₃ PO ₄ (520 mg, 2.46 mmol, 2mL H ₂ O), after stirring evenly, add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H) -carboxylate (760 mg, 2.46 mmol), reacted at 95 ° C for 4 h under argon atmosphere, and the starting material disappeared. The mixture was cooled to room temperature, and the solvent was evaporated. EtOAc (30 mL) was evaporated. EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The powdery solid was 250 mg in a yield of 88%. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.91 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.91 (s, 1H), 4.83 ( t, J = 8.8 Hz, 2H), 4.09 (m, 2H), 3.63 (t, J = 8.8 Hz, 2H), 3.32 (t, J = 8.8 Hz, 2H), 2.45 (m, 2H), 1.50 ( s, 9H).

中间体8：

Intermediate 8:

将中间体7(190mg，0.55mmol)溶于DCM(15mL)中，加入TFA(625mg，5.50mmol)，室温反应3h，原料消失。浓缩，得中间体8淡黄色粉末状固体188mg，产率为100％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):9.07(brs,1H),7.94(d,J＝8.4Hz,1H),6.80(d,J＝8.8Hz,1H),6.63(s,1H),5.89(s,1H),4.84(t,J＝8.8Hz,2H),3.94(brs,2H),3.53(brs,2H),3.31(t,J＝8.8Hz,2H),2.76(brs,2H).Intermediate 7 (190 mg, 0.55 mmol) was dissolved in DCM (15 mL). Concentration gave 188 mg of Intermediate 8 as a pale yellow powdery solid. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 9.07 (brs, 1H), 7.94 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.63 ( s, 1H), 5.89 (s, 1H), 4.84 (t, J = 8.8 Hz, 2H), 3.94 (brs, 2H), 3.53 (brs, 2H), 3.31 (t, J = 8.8 Hz, 2H), 2.76 (brs, 2H).

中间体9：

Intermediate 9:

将中间体8(170mg，0.50mmol)溶于THF(10mL)和MeOH(10mL)中，加入甲醛水溶液(120mg，37％，1.50mmol)和三乙酰氧基硼氢化钠(555mg，2.50mmol)，室温反应2h，原料消失。浓缩，加入EA(30mL)，水洗(20mL×3)，柱层析(D/M＝20:1)，得中间体9淡黄色粉末状固体120mg，产率为92％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.90(d,J＝8.8Hz,1H),6.83(d,J＝8.8Hz,1H),5.91(m,1H),4.81(t,J＝8.8Hz,2H),3.33(t,J＝8.8Hz,2H),3.16-3.15(m,2H),2.69(t,J＝5.6Hz,2H),2.53(m,2H),2.44(s,3H).Intermediate 8 (170 mg, 0.50 mmol) was dissolved in THF (10 mL) MeOH (10 mL), EtOAc (EtOAc, EtOAc After reacting for 2 h at room temperature, the starting materials disappeared. Concentration, EA (30 mL), EtOAc (EtOAc (EtOAc) The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.90 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.91 (m, 1H), 4.81 ( t, J = 8.8 Hz, 2H), 3.33 (t, J = 8.8 Hz, 2H), 3.16-3.15 (m, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.53 (m, 2H), 2.44 (s, 3H).

中间体10：

Intermediate 10:

采用中间体2相同的合成方法，用1-Boc-4-(piperidin-4-yl)piperazine替换4-二甲氨基哌啶，制备得到中间体10黄色粉末状固体156mg，产率为 58%。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):7.90(d,J=9.2Hz,1H),6.41(d,J=9.6Hz,1H),4.79(t,J=8.8Hz,2H),3.67(d,J=12.4Hz,2H),3.45(m,4H),3.20(t,J=8.8Hz,2H),2.87(t,J=12.0Hz,2H),2.53(m,4H),2.46(m,2H),1.94(d,J=12.0Hz,2H),1.66-1.59(m,2H).Using the same synthetic procedure as Intermediate 2, 4-dimethylaminopiperidine was replaced with 1-Boc-4-(piperidin-4-yl)piperazine to give 156 mg of Intermediate 10 as a yellow powdery solid. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 7.90 (d, J = 9.2 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 4.79 (t, J = 8.8 Hz, 2H), 3.67 (d, J = 12.4 Hz, 2H), 3.45 (m, 4H), 3.20 (t, J = 8.8 Hz, 2H), 2.87 (t, J = 12.0 Hz, 2H), 2.53 (m, 4H), 2.46 (m, 2H), 1.94 (d, J = 12.0 Hz, 2H), 1.66-1.59 (m, 2H).

中间体11：

Intermediate 11:

将中间体2（463mg，1.59mmol）溶于methanol（20mL）中，加入Pd/C（60mg），催化氢化3h，原料消失。滤除Pd/C，浓缩，得中间体11类白色固体410mg，产率为99%。结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):6.38(d,J=8.0Hz,1H),6.24(d,J=8.4Hz,1H),4.45(t,J=8.4Hz,2H),4.23(brs,2H),3.16(d,J=12.0Hz,2H),3.04(t,J=8.4Hz,2H),2.45-2.50(m,2H),2.31(m,7H),1.85(d,J=11.6Hz,2H),1.55-1.47(m,2H).Intermediate 2 (463 mg, 1.59 mmol) was dissolved in methanol (20 mL). Pd / C (60 mg) The Pd/C was filtered off and concentrated to give a white solid (yel. The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 6.38 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 4.45 (t, J = 8.4) Hz, 2H), 4.23 (brs, 2H), 3.16 (d, J = 12.0 Hz, 2H), 3.04 (t, J = 8.4 Hz, 2H), 2.45 - 2.50 (m, 2H), 2.31 (m, 7H) ), 1.85 (d, J = 11.6 Hz, 2H), 1.55-1.47 (m, 2H).

中间体12：

Intermediate 12:

采用中间体11相同的合成方法，用中间体3替换中间体2，得到中间体12类白色固体68mg，产率为96%。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):6.51(d,J=8.4Hz,1H),6.06(d,J=8.4Hz,1H),4.58-4.50(m,2H),3.41-3.18(m,6H),2.82(t,J=7.2Hz,1H),2.29(s,6H),2.12-2.11(m,1H),1.88-1.83(m,1H).Intermediate 2 was replaced with Intermediate 3 using the same synthetic procedure as Intermediate 11 to afford Intermediate <RTIgt; The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 6.51 (d, J = 8.4 Hz, 1H), 6.06 (d, J = 8.4 Hz, 1H), 4.58-4.50 (m, 2H), 3.41-3.18(m,6H), 2.82 (t, J=7.2Hz, 1H), 2.29(s,6H), 2.12-2.11(m,1H), 1.88-1.83(m,1H).

中间体13：

Intermediate 13:

采用中间体11相同的合成方法，用中间体4替换中间体2，得到中间体13类白色固体87mg，产率为92%。结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):6.41(d,J=8.4Hz,1H),6.25(d,J=8.0Hz,1H),4.55(brs,2H),4.46(t,J=8.4Hz,2H),3.40(m,4H),3.07(t,J=8.4Hz,2H),2.75(t,J=4.8Hz,4H),1.41(s,9H).Intermediate 2 was replaced with Intermediate 4 using the same synthetic procedure as Intermediate 11 to afford 87% of Intermediate 13 White solid. The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 6.41 (d, J = 8.4 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 4.55 (brs, 2H), 4.46 (t, J = 8.4 Hz, 2H), 3.40 (m, 4H), 3.07 (t, J = 8.4 Hz, 2H), 2.75 (t, J = 4.8 Hz, 4H), 1.41 (s, 9H).

中间体14：

Intermediate 14:

采用中间体11相同的合成方法，用中间体5替换中间体2，得到中间体14类白色固体58mg，产率为100％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):6.55(d,J＝8.4Hz,1H),6.43(d,J＝8.4Hz,1H),4.61(t,J＝8.4Hz,2H),3.32(m,6H),3.16(t,J＝8.4Hz,2H),2.79(s,3H),1.28(m,4H).Intermediate 2 was replaced with Intermediate 5 using the same synthetic procedure as Intermediate 11 to afford Intermediate &lt The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 6.55 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 4.61 (t, J = 8.4 Hz, 2H), 3.32 (m, 6H), 3.16 (t, J = 8.4 Hz, 2H), 2.79 (s, 3H), 1.28 (m, 4H).

中间体15：

Intermediate 15:

采用中间体11相同的合成方法，用中间体6替换中间体2，得到中间体15类白色固体64mg，产率为78％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):6.51(d,J＝8.4Hz,1H),6.33(d,J＝8.4Hz,1H),4.57(t,J＝8.4Hz,2H),3.28(d,J＝12.0Hz,2H),3.14(t,J＝8.4Hz,2H),2.67-2.52(m,10H),2.37-2.34(m,1H),2.32(s,3H),1.92(d,J＝12.4Hz,2H),1.71-1.61(m,2H).Intermediate 2 was replaced with Intermediate 6 using the same synthetic procedure as Intermediate 11 to afford Intermediate &lt The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 6.51 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 4.57 (t, J = 8.4 Hz, 2H), 3.28 (d, J = 12.0 Hz, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.67-2.52 (m, 10H), 2.37-2.34 (m, 1H), 2.32 (s, 3H) ), 1.92 (d, J = 12.4 Hz, 2H), 1.71-1.61 (m, 2H).

中间体16：

Intermediate 16:

采用中间体11相同的合成方法，用中间体7替换中间体2，得到中间体16微黄色色固体48mg，产率为77％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):6.85(d,J＝8.4Hz,1H),6.54(d,J＝8.0Hz,1H),5.71(s,1H),4.55(t,J＝8.8Hz,2H),3.55(brs,2H),3.26(t,J＝8.8Hz,2H),3.09-3.07(m,2H),2.63(t,J＝5.6Hz,2H),2.51(m,2H),2.40(s,3H).Intermediate 2 was replaced with Intermediate 7 using the same synthetic procedure as Intermediate 11 to afford Intermediate <RTIgt; The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 6.85 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.71 (s, 1H), 4.55 ( t, J = 8.8 Hz, 2H), 3.55 (brs, 2H), 3.26 (t, J = 8.8 Hz, 2H), 3.09 - 3.07 (m, 2H), 2.63 (t, J = 5.6 Hz, 2H), 2.51 (m, 2H), 2.40 (s, 3H).

中间体17：

Intermediate 17:

将中间体16(70mg，0.27mmol)溶于methanol(10mL)中，加入Pd/C(15mg)，催化氢化3h，原料消失。滤除Pd/C，浓缩，得微黄色色固体49mg，产率为79％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):6.59(d,J＝8.4Hz,1H),6.54(d,J＝8.0Hz,1H),5.71(s,1H),4.58(t,J＝8.8Hz,2H),3.46(brs,2H),3.18(t,J＝8.8Hz,2H),2.98-2.95(m,2H),2.38-2.33(m,1H),2.31(s,3H),2.05-1.98(m,2H),1.81-1.68(m,4H).Intermediate 16 (70 mg, 0.27 mmol) was dissolved in methanol (10 mL). Pd / C (15 mg). The Pd/C was filtered off and concentrated to give a pale yellow solid (yield: 49). The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 6.59 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.71 (s, 1H), 4.58 ( t, J = 8.8 Hz, 2H), 3.46 (brs, 2H), 3.18 (t, J = 8.8 Hz, 2H), 2.98-2.95 (m, 2H), 2.38-2.33 (m, 1H), 2.31 (s) , 3H), 2.05-1.98 (m, 2H), 1.81-1.68 (m, 4H).

中间体18：

Intermediate 18:

采用中间体11相同的合成方法，用中间体9替换中间体2，得到微黄色色固体90mg，产率为90％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):6.56-6.54(m,2H),4.59(t,J＝8.8Hz,2H),4.23(m,2H),3.48(ts,2H),3.18(t,J＝8.8Hz,2H),2.76(m,2H),2.52-2.49(m,1H),1.74(d,J＝12.4Hz,2H),1.64-1.55(m,2H).Intermediate 2 was replaced with Intermediate 9 using the same synthetic procedure as Intermediate 11 to give a pale yellow solid (yield: 90%). The structure verification data are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 6.56-6.54 (m, 2H), 4.59 (t, J = 8.8 Hz, 2H), 4.23 (m, 2H), 3.48 (ts, 2H) ), 3.18 (t, J = 8.8 Hz, 2H), 2.76 (m, 2H), 2.52 - 2.49 (m, 1H), 1.74 (d, J = 12.4 Hz, 2H), 1.64-1.55 (m, 2H) .

中间体19：

Intermediate 19:

采用中间体11相同的合成方法，用中间体10替换中间体2，得到类白色固体55mg，产率为74％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):6.51(d,J＝8.4Hz,1H),6.33(d,J＝8.4Hz,1H),4.57(t,J＝8.4Hz,2H),3.55(brs,4H),3.30(d,J＝11.6Hz,2H),3.14(t,J＝8.4Hz,2H),2.64-2.58(m,7H),1.90(m,2H),1.71(m,2H),1.47(s,9H).Intermediate 2 was replaced with Intermediate 10 using the same synthetic procedure as Intermediate 11 to afford 55 mg of white solid. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 6.51 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 4.57 (t, J = 8.4 Hz, 2H), 3.55 (brs, 4H), 3.30 (d, J = 11.6 Hz, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.64 - 2.58 (m, 7H), 1.90 (m, 2H), 1.71 (m, 2H), 1.47 (s, 9H).

中间体20：

Intermediate 20:

将化合物4,6-二氯嘧啶(100mg，0.60mmol)和2-(氨基苯基)二甲基氧膦(51mg，0.30mmol)溶于正丁醇(5mL)中，加入DIEA(116mg，0.90mmol)，回流反应12h，原料基本消失。柱层析(P/E＝1:6)，得白色固体50mg，产率为56％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):11.02(s,1H),6.62(dd,J₁＝8.4Hz,J₂＝4.4Hz,1H),8.54(s,1H),7.57-7.52(m,1H),7.29-7.23(m,1H),7.14-7.09(m,1H),6.74(s,1H),1.85(s,3H),1.82(s,3H).The compound 4,6-dichloropyrimidine (100 mg, 0.60 mmol) and 2-(aminophenyl)dimethyl phosphine oxide (51 mg, 0.30 mmol) were dissolved in n-butanol (5 mL) and DIEA (116 mg, 0.90) Methyl), reflux reaction for 12 h, the raw materials basically disappeared. Column chromatography (P/E = 1:6) gave 50 mg of white solid. The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 11.02 (s, 1H), 6.62 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.54 (s, 1H), 7.57-7.52 (m, 1H), 7.29-7.23 (m, 1H), 7.14-7.09 (m, 1H), 6.74 (s, 1H), 1.85 (s, 3H), 1.82 (s, 3H).

中间体21：

Intermediate 21:

采用中间体20相同的合成方法，用2,4-二氯-5-氟嘧啶(100mg，0.60mmol)替换4,6-二氯嘧啶，得中间体21白色固体50mg，产率为56％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):11.84(s,1H),8.80(dd,J₁＝8.4Hz,J₂＝4.4Hz,1H),8.08(d,J＝2.8Hz,1H),7.62-7.58(m,1H),7.29-7.24(m,1H), 7.19-7.14(m,1H),1.87(s,3H),1.84(s,3H).The same synthesis method as Intermediate 20 was used, and 4,6-dichloropyrimidine was replaced with 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.60 mmol) to give Intermediate 21 as a white solid (yield: 50%). The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 11.84 (s, 1H), 8.80 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.08 (d, J = 2.8) Hz, 1H), 7.62-7.58 (m, 1H), 7.29-7.24 (m, 1H), 7.19-7.14 (m, 1H), 1.87 (s, 3H), 1.84 (s, 3H).

中间体22：

Intermediate 22:

采用中间体20相同的合成方法，用2,4-二氯嘧啶(352mg，2.36mmol)替换4,6-二氯嘧啶，得中间体22得白色固体120mg，产率为36％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):11.22(s,1H),8.69(dd,J₁＝8.4Hz,J₂＝4.4Hz,1H),8.14(d,J＝5.6Hz,1H),7.59-7.55(m,1H),7.27-7.25(m,1H),7.14-7.10(m,1H),6.58(d,J＝5.6Hz,1H),1.85(s,3H),1.82(s,3H).Using 4,6-dichloropyrimidine, 2,4-dichloropyrimidine (352 mg, 2.36 mmol), the intermediate 22 was obtained as a white solid (yield: 36%). The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 11.22 (s, 1H), 8.69 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.14 (d, J = 5.6) Hz, 1H), 7.59-7.55 (m, 1H), 7.27-7.25 (m, 1H), 7.14-7.10 (m, 1H), 6.58 (d, J = 5.6 Hz, 1H), 1.85 (s, 3H) , 1.82 (s, 3H).

中间体23和24：

Intermediates 23 and 24:

采用中间体20相同的合成方法，用2,4-二氯-5-三氟甲基嘧啶(386mg，1.78mmol)替换4,6-二氯嘧啶，得中间体23和24的混合物：白色固体210mg，产率为68％。结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):11.67(s,1H),11.28(s,0.5H),8.65-8.62(m,1H),8.59(s,1H),8.49-8.46(m,1H),7.61-7.54(m,1.5H),7.34-7.22(m,2H),7.15-7.12(m,1H),1.86(s,3H),1.85(s,1.5H),1.83(s,3H),1.81(s,1.5H).Using 4,6-dichloropyrimidine, 2,4-dichloro-5-trifluoromethylpyrimidine (386 mg, 1.78 mmol), a mixture of intermediates 23 and 24: white solid 210 mg, yield 68%. The structure verification data are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 11.67 (s, 1H), 11.28 (s, 0.5H), 8.65-8.62 (m, 1H), 8.59 (s, 1H), 8.49- 8.46 (m, 1H), 7.61 - 7.54 (m, 1.5H), 7.34 - 7.22 (m, 2H), 7.15-7.12 (m, 1H), 1.86 (s, 3H), 1.85 (s, 1.5H), 1.83 (s, 3H), 1.81 (s, 1.5H).

中间体25：

Intermediate 25:

采用中间体20相同的合成方法，用2,4-二氯-1,3,5-三嗪(267mg，1.78mmol)替换4,6-二氯嘧啶，得中间体25：白色固体150mg，产率为60％。结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):11.81(brs,1H),8.63(dd,J₁＝8.4Hz,J₂＝4.4Hz,1H),8.57(s,1H),7.60(t,J＝8.0Hz,1H),7.33-7.27(m,1H),7.22-7.18(m,1H),1.88(s,3H),1.85(s,3H). The same synthesis method as the intermediate 20 was carried out, and 4,6-dichloropyrimidine was replaced with 2,4-dichloro-1,3,5-triazine (267 mg, 1.78 mmol) to obtain Intermediate 25: 150 mg of white solid. The rate is 60%. The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.81 (brs, 1H), 8.63 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.57 (s, 1H) ), 7.60 (t, J = 8.0 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.22 - 7.18 (m, 1H), 1.88 (s, 3H), 1.85 (s, 3H).

中间体26：

Intermediate 26:

采用中间体20相同的合成方法，用2,4,5-三氯嘧啶（866mg，4.72mmol）替换4,6-二氯嘧啶，得中间体26：类白色固体483mg，产率为65%。结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):11.55(brs,1H),8.67(dd,J₁=8.4Hz,J₂=4.4Hz,1H),8.22(s,1H),7.60(t,J=8.4Hz,1H),7.32-7.28(m,1H),7.20-7.18(m,1H),1.86(s,3H),1.83(s,3H).Using the same synthetic procedure as Intermediate 20, 4,6-dichloropyrimidine was replaced with 2,4,5-trichloropyrimidine (866 mg, 4.72 mmol) to give Intermediate 26: mp. The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.55 (brs, 1H), 8.67 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.22 (s, 1H) ), 7.60 (t, J = 8.4 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.20-7.18 (m, 1H), 1.86 (s, 3H), 1.83 (s, 3H).

实施例1：

Example 1:

将中间体11（25mg，0.10mmol）和中间体20（35mg，0.12mmol）溶于iPrOH（1mL）中，加入浓盐酸（24mg，0.25mmol），微波反应（250w，130℃，120min，300psi）。冷却至室温，加入EA（20mL），饱和碳酸氢钠（aq）洗（20mL×3），饱和食盐水洗（20mL×3），柱层析（D/M/Et₃N=10:1:0.02），得实施例1：类白色固体48mg，产率为71%。Intermediate 11 (25 mg, 0.10 mmol) and Intermediate 20 (35 mg, 0.12 mmol) eluted eluted elute . Cool to room temperature, add EA (20 mL), wash with saturated sodium hydrogen carbonate (aq) (20 mL×3), wash with saturated brine (20 mL×3), column chromatography (D/M/Et ₃ N=10:1:0.02 Example 1 was obtained as an off-white solid, 48 mg, yield 71%.

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.01(s,1H),8.46(dd,J₁=8.4Hz,J₂=4.4Hz,1H),8.35(s,1H),7.47(t,J=7.6Hz,1H),7.23-7.15(m,2H),7.02-6.98(m,1H),6.45(d,J=8.8Hz,1H),6.35(s,1H),5.87(s,1H),4.60(t,J=8.8Hz,2H),3.40(d,J=12.0Hz,2H),3.20(t,J=8.8Hz,2H),2.67(t,J=12.0Hz,2H),2.33(s,6H),2.29-2.23(m,1H),1.93(d,J=12.0Hz,2H),1.80(s,3H),1.74(s,3H),1.68-1.58(m,2H).HRMS(ESI):m/z,calcd for C₂₇H₃₆N₆O₂P[M+H⁺]:507.2637,found 507.2646.The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.01 (s, 1H), 8.46 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.35 (s, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.02-6.98 (m, 1H), 6.45 (d, J = 8.8 Hz, 1H), 6.35 (s, 1H), 5.87 (s, 1H), 4.60 (t, J = 8.8 Hz, 2H), 3.40 (d, J = 12.0 Hz, 2H), 3.20 (t, J = 8.8 Hz, 2H), 2.67 (t, J = 12.0 Hz) , 2H), 2.33 (s, 6H), 2.29-2.23 (m, 1H), 1.93 (d, J = 12.0 Hz, 2H), 1.80 (s, 3H), 1.74 (s, 3H), 1.68-1.58 ( m, 2H). HRMS (ESI): m/z, calcd for C ₂₇ H ₃₆ N ₆ O ₂ P [M+H ⁺ ]: 507.2637, found 507.2646.

实施例2：

Example 2:

以中间体11(50mg，0.19mmol)和中间体21(71mg，0.24mmol)为原料，采用实施例1相同的方法合成，制备得到实施例2：类白色固体84mg，产率为84％。Intermediate 11 (50 mg, 0.19 mmol) and Intermediate 21 (71 mg, 0.24 mmol) were used as the starting material, and the same procedure as in Example 1 was used to give Example 2: 84 mg as a white solid.

结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):11.51(s,1H),8.66(m,1H),8.24(s,1H),8.02(d,J＝3.2Hz,1H),7.54(dd,J₁＝13.6Hz,J₂＝7.6Hz,1H),7.32(t,J＝7.6Hz,1H),7.21(d,J＝8.4Hz,1H),7.08(t,J＝7.2Hz,1H),6.44(d,J＝8.8Hz,1H),4.49(t,J＝8.4Hz,2H),3.41-3.39(m,2H),3.16(t,J＝8.0Hz,2H),3.01(m,1H),2.64(t,J＝12.0Hz,2H),2.53(s,6H),2.01(d,J＝10.0Hz,2H),1.80(s,3H),1.77(s,3H),1.80-1.65(m,2H).HRMS(ESI):m/z,calcd for C₂₇H₃₅N₆O₂PF[M+H⁺]:525.2543,found525.2557.The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.51 (s, 1H), 8.66 (m, 1H), 8.24 (s, 1H), 8.02 (d, J = 3.2 Hz, 1H) ), 7.54 (dd, J ₁ = 13.6 Hz, J ₂ = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.08 (t, J) = 7.2 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 4.49 (t, J = 8.4 Hz, 2H), 3.41-3.39 (m, 2H), 3.16 (t, J = 8.0 Hz, 2H) ), 3.01 (m, 1H), 2.64 (t, J = 12.0 Hz, 2H), 2.53 (s, 6H), 2.01 (d, J = 10.0 Hz, 2H), 1.80 (s, 3H), 1.77 (s) , 3H), 1.80-1.65 (m, 2H). HRMS (ESI): m/z, calcd for C ₂₇ H ₃₅ N ₆ O ₂ PF [M+H ⁺ ]: 525.2543, found525.2557.

实施例3：

Example 3:

以中间体11(40mg，0.15mmol)和中间体22(54mg，0.19mmol)为原料，采用实施例1相同的方法合成，制备得到实施例3：类白色固体35mg，产率为45％。Intermediate 11 (40 mg, 0.15 mmol) and Intermediate 22 (54 mg, 0.19 mmol) were used as the starting material, and the same procedure as in Example 1 was used to give Example 3: 35 mg of white solid, yield 45%.

结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):10.95(s,1H),8.51-8.50(m,1H),8.11(s,1H),7.95(d,J＝5.6Hz,1H),7.52(d,J₁＝12.8Hz,J₂＝6.4Hz,1H),7.31(t,J＝7.6Hz,1H),7.25(d,J＝8.4Hz,1H),7.04(d,J＝7.6Hz,1H),6.43(d,J＝8.8Hz,1H),5.96(d,J＝5.6Hz,1H),4.49(t,J＝8.4Hz,2H),3.39(m,2H),3.17-3.13(m,3H),2.63(t,J＝12.0Hz,2H),2.43(s,6H),1.97-1.94(m,2H),1.78(s,3H),1.75(s,3H),1.62-1.59(m,2H).HRMS(ESI):m/z,calcd for C₂₇H₃₆N₆O₂P[M+H⁺]:507.2637,found 507.2634.The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 10.95 (s, 1H), 8.51-8.50 (m, 1H), 8.11 (s, 1H), 7.95 (d, J = 5.6 Hz) , 1H), 7.52 (d, J ₁ = 12.8 Hz, J ₂ = 6.4 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.04 (d , J = 7.6 Hz, 1H), 6.43 (d, J = 8.8 Hz, 1H), 5.96 (d, J = 5.6 Hz, 1H), 4.49 (t, J = 8.4 Hz, 2H), 3.39 (m, 2H) ), 3.17-3.13 (m, 3H), 2.63 (t, J = 12.0 Hz, 2H), 2.43 (s, 6H), 1.97-1.94 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.62-1.59 (m, 2H). HRMS (ESI): m/z, calcd for C ₂₇ H ₃₆ N ₆ O ₂ P [M+H ⁺ ]: 507.2637, found 507.2634.

实施例4和实施例5：

Example 4 and Example 5:

以中间体11(65mg，0.25mmol)和中间体23,24(108mg，0.31mmol)为原料，采用实施例1相同的方法合成，制备得到实施例化合物4和5：类白色固体60mg。Starting from Intermediate 11 (65 mg, 0.25 mmol) and Intermediate 23, 24 (108 mg, 0.31 mmol),

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.81(s,1H),10.36(s,0.5H),8.49-8.48(m,1H),8.35-8.32(m,2H),7.90(d,J＝7.6Hz,1H),7.79(d,J＝7.6Hz,0.5H),7.46-7.34(m,1.5H),7.27-7.17(m,1.5H),7.06-7.05(m,1.5H),6.95(s,1.5H),6.49(d,J＝8.4Hz,1H),6.37(brs,0.5H),4.65-4.61(m,3H),3.49-3.43(m,3H),3.21-3.17(m,3H),3.00(m,1.5H),2.77-2.72(m,12H),2.25(d,J＝10.8Hz,3H),1.91-1.89(m,3H),1.84(s,4.5H),1.81(s,4.5H).HRMS(ESI):m/z,calcd for C₂₈H₃₅N₆O₂PF₃[M+H⁺]:575.2511,found 575.2527.The structure verification data are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.81 (s, 1H), 10.36 (s, 0.5H), 8.49-8.48 (m, 1H), 8.35-8.32 (m, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 0.5H), 7.46-7.34 (m, 1.5H), 7.27-7.17 (m, 1.5H), 7.06-7.05 (m) , 1.5H), 6.95 (s, 1.5H), 6.49 (d, J = 8.4 Hz, 1H), 6.37 (brs, 0.5H), 4.65 - 4.61 (m, 3H), 3.49 - 3.43 (m, 3H) , 3.21-3.17 (m, 3H), 3.00 (m, 1.5H), 2.77-2.72 (m, 12H), 2.25 (d, J = 10.8 Hz, 3H), 1.91-1.89 (m, 3H), 1.84 ( s, 4.5H), 1.81 (s, 4.5H). HRMS (ESI): m/z, calcd for C ₂₈ H ₃₅ N ₆ O ₂ PF ₃ [M+H ⁺ ]: 575.2511, found 575.2527.

实施例6：

Example 6

以中间体11(40mg，0.15mmol)和25(54mg，0.19mmol)为原料，采用实施例1相同的方法合成，制备得到实施例化合物6：类白色固体13mg，产率为17％。Intermediate 11 (40 mg, 0.15 mmol) and 25 (54 mg, 0.19 mmol) were used as a starting material to give the compound of Example 1 as a white solid (yield: 17%).

结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):11.17(s,1H),9.14(brs,1H),8.41(brs,1H),8.23(s,1H),7.53(m,1H),7.24(m,1H),7.09-7.07(m,2H),6.46(m,1H),4.50(t,J＝8.4Hz,2H),3.33(m,2H),3.17(m,3H),3.05(m,1H),2.65(t,J＝11.2Hz,2H),2.50(s,6H),1.97(m,2H),1.78(s,3H),1.75(s,3H),1.64-1.61(m,2H).HRMS(ESI):m/z,calcd for C₂₆H₃₅N₇O₂P[M+H⁺]:508.2590,found 508.2596.The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.17 (s, 1H), 9.14 (brs, 1H), 8.41 (brs, 1H), 8.23 (s, 1H), 7.53 (m) , 1H), 7.24 (m, 1H), 7.09-7.07 (m, 2H), 6.46 (m, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.33 (m, 2H), 3.17 (m, 3H), 3.05 (m, 1H), 2.65 (t, J = 11.2 Hz, 2H), 2.50 (s, 6H), 1.97 (m, 2H), 1.78 (s, 3H), 1.75 (s, 3H), 1.64-1.61(m,2H).HRMS(ESI): m/z,calcd for C ₂₆ H ₃₅ N ₇ O ₂ P[M+H ⁺ ]:508.2590,found 508.2596.

实施例7：

Example 7

以中间体11(50mg，0.19mmol)和26(75mg，0.24mmol)为原料，采用实施例1相同的方法合成，制备得到实施例化合物7：类白色固体74mg，产率为72％。The compound of Example 7 was obtained by the same procedure as in Example 1 using Intermediate 11 (50 mg, 0.19 mmol) and 26 (75 mg, 0.24 mmol) as the starting material. The body was 74 mg and the yield was 72%.

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.84(s,1H),8.63(dd,J₁＝8.4Hz,J₂＝4.4Hz,1H),8.08(s,1H),7.80(d,J＝8.4Hz,1H),7.46(t,J＝8.0Hz,1H),7.29-7.24(m,1H),7.11(d,J＝6.8Hz,1H),6.81(s,1H),6.43(d,J＝8.4Hz,1H),4.60(t,J＝8.8Hz,2H),3.38(d,J＝12.0Hz,2H),3.21(t,J＝8.4Hz,2H),2.66(t,J＝12.0Hz,2H),2.33(s,6H),2.30-2.23(m,1H),1.93(d,J＝11.6Hz,2H),1.85(s,3H),1.81(s,3H),1.69-1.60(m,2H).HRMS(ESI):m/z,calcd for C₂₇H₃₅N₆O₂PCl[M+H⁺]:541.2248,found541.2257.The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.84 (s, 1H), 8.63 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.08 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.29-7.24 (m, 1H), 7.11 (d, J = 6.8 Hz, 1H), 6.81 (s, 1H) ), 6.43 (d, J = 8.4 Hz, 1H), 4.60 (t, J = 8.8 Hz, 2H), 3.38 (d, J = 12.0 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H), 2.66 (t, J = 12.0 Hz, 2H), 2.33 (s, 6H), 2.30-2.23 (m, 1H), 1.93 (d, J = 11.6 Hz, 2H), 1.85 (s, 3H), 1.81 (s) , 3H), 1.69-1.60 (m, 2H). HRMS (ESI): m/z, calcd for C ₂₇ H ₃₅ N ₆ O ₂ PCl [M+H ⁺ ]: 541.2248, found541.2257.

实施例8：

Example 8

以中间体14(40mg，0.17mmol)和26(67mg，0.21mmol)为原料，采用实施例1相同的方法合成，制备得到实施例8：类白色固体40mg，产率为46％。The intermediate 14 (40 mg, 0.17 mmol) and 26 (67 mg, 0.21 mmol) were used as the starting materials, and the same procedure as in Example 1 was used to obtain the compound of Example 8 as a white solid (yield: 46%).

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.86(s,1H),8.62(dd,J₁＝8.0Hz,J₂＝4.4Hz,1H),8.08(s,1H),7.84(d,J＝8.4Hz,1H),7.46(t,J＝8.0Hz,1H),7.30-7.27(m,1H),7.11(d,J＝6.4Hz,1H),6.83(s,1H),6.46(d,J＝8.8Hz,1H),4.61(t,J＝8.8Hz,2H),3.20(d,J＝8.4Hz,2H),3.12-3.07(m,4H),2.45(s,3H),1.85(s,3H),1.82(s,3H),1.41(t,J＝7.2Hz,2H).HRMS(ESI):m/z,calcd for C₂₅H₃₁N₆O₂PCl[M+H⁺]:513.1935,found513.1924.The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.86 (s, 1H), 8.62 (dd, J ₁ = 8.0 Hz, J ₂ = 4.4 Hz, 1H), 8.08 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.30-7.27 (m, 1H), 7.11 (d, J = 6.4 Hz, 1H), 6.83 (s, 1H) ), 6.46 (d, J = 8.8 Hz, 1H), 4.61 (t, J = 8.8 Hz, 2H), 3.20 (d, J = 8.4 Hz, 2H), 3.12-3.07 (m, 4H), 2.45 (s) ,3H),1.85(s,3H),1.82(s,3H),1.41(t,J=7.2Hz,2H).HRMS(ESI):m/z,calcd for C ₂₅ H ₃₁ N ₆ O ₂ PCl [M+H ⁺ ]: 513.1935, found513.1924.

实施例9：

Example 9

以中间体13(40mg，0.12mmol)和26(47mg，0.15mmol)为原料，采用实施例1相同的方法合成，制备得到实施例9：白色固体14 mg，产率为22％。Intermediate 13 (40 mg, 0.12 mmol) and 26 (47 mg, 0.15 mmol) were used as the starting materials, which were synthesized in the same manner as in Example 1 to give Example 9: White solid 14 Mg, the yield was 22%.

结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):11.21(s,1H),8.53(brs,1H),8.47(s,1H),8.07(s,1H),7.53(dd,J₁＝14.0Hz,J₂＝8.4Hz,1H),7.29(m,1H),7.17(d,J＝8.8Hz,1H),7.10-7.08(m,1H),6.45(d,J＝8.4Hz,1H),5.76(s,1H),4.49(t,J＝8.0Hz,2H),3.30(m,4H),3.19-3.12(m,6H),1.78(s,3H),1.75(s,3H).HRMS(ESI):m/z,calcd for C₂₄H₂₉N₆O₂PCl[M+H⁺]:499.1778,found 499.1779.The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.21 (s, 1H), 8.53 (brs, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.53 (dd , J ₁ = 14.0 Hz, J ₂ = 8.4 Hz, 1H), 7.29 (m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.10-7.08 (m, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.76 (s, 1H), 4.49 (t, J = 8.0 Hz, 2H), 3.30 (m, 4H), 3.19-3.12 (m, 6H), 1.78 (s, 3H), 1.75 ( s, 3H). HRMS (ESI): m/z, calcd for C ₂₄ H ₂₉ N ₆ O ₂ PCl [M+H ⁺ ]: 499.1778, found 499.1779.

实施例10：

Example 10:

以中间体12(35mg，0.14mmol)和26(55mg，0.18mmol)为原料，采用实施例1相同的方法合成，制备得到实施例10：白色固体60mg，产率为81％。The intermediate 12 (35 mg, 0.14 mmol) and 26 (55 mg, 0.18 mmol) were used as the starting materials, and the same procedure as in Example 1 was used to give Example 10: 60 mg of white solid.

结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):11.19(s,1H),8.56(brs,1H),8.31(s,1H),8.03(s,1H),7.51(dd,J₁＝14.0Hz,J₂＝7.2Hz,1H),7.28(m,1H),7.77(t,J＝6.8Hz,1H),6.98(d,J＝8.4Hz,1H),6.09(d,J＝8.4Hz,1H),4.46-4.35(m,2H),3.52-3.24(m,6H),2.90(m,1H),2.29(s,6H),2.13-2.09(m,1H),1.78(m,1H),1.75(s,3H),1.74(s,3H).HRMS(ESI):m/z,calcd for C₂₆H₃₃N₆O₂PCl[M+H⁺]:527.2091,found 527.2104.The structure verification data is as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.19 (s, 1H), 8.56 (brs, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.51 (dd , J ₁ = 14.0 Hz, J ₂ = 7.2 Hz, 1H), 7.28 (m, 1H), 7.77 (t, J = 6.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.09 (d , J=8.4 Hz, 1H), 4.46-4.35 (m, 2H), 3.52-3.24 (m, 6H), 2.90 (m, 1H), 2.29 (s, 6H), 2.13-2.09 (m, 1H), 1.78(m,1H), 1.75(s,3H), 1.74(s,3H).HRMS(ESI): m/z,calcd for C ₂₆ H ₃₃ N ₆ O ₂ PCl[M+H ⁺ ]:527.2091, Found 527.2104.

实施例11：

Example 11

以中间体15(40mg，0.13mmol)和26(50mg，0.16mmol)为原料，采用实施例1相同的方法合成，制备得到实施例11：类白色固体35mg，产率为46％。The intermediates 15 (40 mg, 0.13 mmol) and 26 (50 mg, 0.16 mmol) were used as the starting materials, and the same procedure as in Example 1 was used to obtain the compound of Example 11 as a white solid (yield: 46%).

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.85(s,1H),8.63(dd,J₁＝8.0Hz,J₂＝4.0Hz,1H),8.08(s,1H),7.81(d,J＝8.8Hz,1H),7.46(t,J ＝7.2Hz,1H),7.30-7.25(m,1H),7.11(d,J＝7.6Hz,1H),6.81(s,1H),6.42(d,J＝8.8Hz,1H),4.61(t,J＝8.4Hz,2H),3.40(d,J＝13.6Hz,2H),3.19(t,J＝8.0Hz,2H),2.92-2.51(m,13H),2.01(m,2H),1.85(s,3H),1.81(s,3H),1.79-1.75(m,2H).HRMS(ESI):m/z,calcd for C₃₀H₄₀N₇O₂PCl[M+H⁺]:596.2670,found 596.2673.The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.85 (s, 1H), 8.63 (dd, J ₁ = 8.0 Hz, J ₂ = 4.0 Hz, 1H), 8.08 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H) ), 6.42 (d, J = 8.8 Hz, 1H), 4.61 (t, J = 8.4 Hz, 2H), 3.40 (d, J = 13.6 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H), 2.92-2.51 (m, 13H), 2.01 (m, 2H), 1.85 (s, 3H), 1.81 (s, 3H), 1.79-1.75 (m, 2H). HRMS (ESI): m/z, calcd for C ₃₀ H ₄₀ N ₇ O ₂ PCl[M+H ⁺ ]: 596.2670, found 596.2673.

实施例12：

Example 12

以中间体16(30mg，0.13mmol)和26(50mg，0.16mmol)为原料，采用实施例1相同的方法合成，制备得到实施例12：类白色固体25mg，产率为38％。The intermediate 16 (30 mg, 0.13 mmol) and 26 (50 mg, 0.16 mmol) were used as the starting materials, and the same procedure as in Example 1 was used to obtain the compound of Example 12: 25 mg of white solid, yield 38%.

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.85(s,1H),8.61(m,1H),8.10(s,1H),7.97(m,1H),7.48(m,1H),7.26(m,1H),7.13(m,1H),7.00(s,1H),6.74(m,1H),5.79(s,1H),4.59(m,2H),3.32-3.11(m,4H),2.66-2.34(m,7H),1.85(s,3H),1.82(s,3H).HRMS(ESI):m/z,calcd for C₂₆H₃₀N₅O₂PCl[M+H⁺]:510.1826,found 510.1830.The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.85 (s, 1H), 8.61 (m, 1H), 8.10 (s, 1H), 7.97 (m, 1H), 7.48 (m, 1H) ), 7.26 (m, 1H), 7.13 (m, 1H), 7.00 (s, 1H), 6.74 (m, 1H), 5.79 (s, 1H), 4.59 (m, 2H), 3.32-3.11 (m, 4H), 2.66-2.34 (m, 7H), 1.85 (s, 3H), 1.82 (s, 3H). HRMS (ESI): m/z, calcd for C ₂₆ H ₃₀ N ₅ O ₂ PCl [M+H ⁺ ]: 510.1826, found 510.1830.

实施例13：

Example 13

以中间体17(40mg，0.17mmol)和26(67mg，0.21mmol)为原料，采用实施例1相同的方法合成，制备得到实施例13：类白色固体28mg，产率为38％。The intermediate 17 (40 mg, 0.17 mmol) and 26 (67 mg, 0.21 mmol) were used as the starting material, and the same procedure as in Example 1 was used to give Example 13: 28 mg as a white solid.

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.84(s,1H),8.61-8.60(m,1H),8.09(s,1H),7.94(d,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,1H),7.30-7.26(m,1H),7.14(t,J＝6.4Hz,1H),6.93(s,1H),6.72(t,J＝7.2Hz,1H),4.62(t,J＝8.4Hz,2H),3.24(t,J＝8.4Hz,2H),3.02(d,J＝10.0Hz,2H),2.44-2.36(m,4H),2.08-2.05(m,2H),1.89-1.82(m,10H).HRMS(ESI): m/z,calcd for C₂₆H₃₂N₅O₂PCl[M+H⁺]:512.1982,found 512.1970.The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.84 (s, 1H), 8.61-8.60 (m, 1H), 8.09 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H) ), 7.46 (t, J = 8.0 Hz, 1H), 7.30-7.26 (m, 1H), 7.14 (t, J = 6.4 Hz, 1H), 6.93 (s, 1H), 6.72 (t, J = 7.2 Hz) , 1H), 4.62 (t, J = 8.4 Hz, 2H), 3.24 (t, J = 8.4 Hz, 2H), 3.02 (d, J = 10.0 Hz, 2H), 2.44-2.36 (m, 4H), 2.08 -2.05 (m, 2H), 1.89-1.82 (m, 10H). HRMS (ESI): m/z, calcd for C ₂₆ H ₃₂ N ₅ O ₂ PCl [M+H ⁺ ]: 512.1982, found 512.1970.

实施例14：

Example 14

将中间体18(30mg，0.09mmol)溶于toluene(4mL)中，依次加入Pd₂(dba)₃(8mg，0.009mmol)，DavePhos(8mg，0.018mmol)和K₃PO₄(40mg，0.018mmol,0.4mL H₂O)，搅拌均匀后，加入中间体26(34mg，0.11mmol)，氩气保护下，90℃反应1h，原料消失。冷却至室温，蒸除溶剂，EA(30mL)溶解残留物，饱和食盐水洗(20mL×3)，水洗(20mL×2)，柱层析(D/M＝10:1)，得实施例14：白色粉末状固体36mg，产率为64％。Intermediate 18 (30 mg, 0.09 mmol) was dissolved in toluene (4 mL). Pd ₂ (dba) ₃ (8 mg, 0.009 mmol), DavePhos (8 mg, 0.018 mmol) and K ₃ PO ₄ (40 mg, 0.018 mmol) , 0.4 mL of H ₂ O), after stirring uniformly, Intermediate 26 (34 mg, 0.11 mmol) was added, and the reaction was carried out at 90 ° C for 1 h under argon atmosphere, and the starting material disappeared. The mixture was cooled to room temperature, and the solvent was evaporated. EtOAc (30 mL························· White powdery solid 36 mg, yield 64%.

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.86(s,1H),8.61(dd,J₁＝8.4Hz,J₂＝4.4Hz,1H),8.10(s,1H),7.94(d,J＝8.0Hz,1H),7.48(t,J＝8.0Hz,1H),7.31-7.26(m,1H),7.16-7.12(m,1H),6.93(s,1H),6.65(d,J＝8.8Hz,1H),4.63(t,J＝8.4Hz,2H),4.27(m,2H),3.25(t,J＝8.4Hz,2H),2.79(t,J＝12.4Hz,2H),2.62-2.56(m,1H),1.85(s,3H),1.82(s,3H),1.79-1.63(m,4H),1.50(s,9H).The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.86 (s, 1H), 8.61 (dd, J ₁ = 8.4 Hz, J ₂ = 4.4 Hz, 1H), 8.10 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.16-7.12 (m, 1H), 6.93 (s, 1H), 6.65 (d, J = 8.8 Hz, 1H), 4.63 (t, J = 8.4 Hz, 2H), 4.27 (m, 2H), 3.25 (t, J = 8.4 Hz, 2H), 2.79 (t, J = 12.4 Hz) , 2H), 2.62-2.56 (m, 1H), 1.85 (s, 3H), 1.82 (s, 3H), 1.79-1.63 (m, 4H), 1.50 (s, 9H).

实施例15：

Example 15

将中间体19(40mg，0.13mmol)溶于toluene(6mL)中，依次加入Pd₂(dba)₃(11mg，0.013mmol)，DavePhos(10mg，0.025mmol)和K₃PO₄(53mg，0.25mmol,1mL H₂O)，搅拌均匀后，加入化合物26(58mg，0.15mmol)，氩气保护下，90℃反应4h，原料消失。冷却至室温，蒸除溶剂，EA(30mL)溶解残留物，饱和食盐水洗(20mL×3)，水洗(20mL×2)，柱层析(D/M＝20:1)，得实施例16：白色粉末状固体70mg，产率为81％。Intermediate 19 (40 mg, 0.13 mmol) was dissolved in toluene (6 mL). Pd ₂ (dba) ₃ (11 mg, 0.013 mmol), DavePhos (10 mg, 0.025 mmol) and K ₃ PO ₄ (53 mg, 0.25 mmol) After 1 mL of H ₂ O), the compound 26 (58 mg, 0.15 mmol) was added, and the mixture was reacted under argon atmosphere at 90 ° C for 4 h, and the starting material disappeared. The mixture was cooled to room temperature, and the solvent was evaporated. EtOAc (30 mL························ The white powdery solid was 70 mg in a yield of 81%.

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.83(s,1H),8.62(dd, J₁＝8.0Hz,J₂＝4.4Hz,1H),8.08(s,1H),7.80(d,J＝8.4Hz,1H),7.46(t,J＝7.2Hz,1H),7.26(m,1H),7.13-7.11(m,1H),6.82(s,1H),6.42(d,J＝8.8Hz,1H),4.60(t,J＝8.0Hz,2H),3.53-3.38(m,6H),3.19(t,J＝8.4Hz,2H),2.70-2.64(m,7H),1.97(brs,2H),1.85(s,3H),1.81(s,3H),1.64(m,2H),1.47(s,9H).The structure verification data is as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.83 (s, 1H), 8.62 (dd, J ₁ = 8.0 Hz, J ₂ = 4.4 Hz, 1H), 8.08 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.26 (m, 1H), 7.13 - 7.11 (m, 1H), 6.82 (s, 1H), 6.42 (d) , J = 8.8 Hz, 1H), 4.60 (t, J = 8.0 Hz, 2H), 3.53-3.38 (m, 6H), 3.19 (t, J = 8.4 Hz, 2H), 2.70 - 2.64 (m, 7H) , 1.97 (brs, 2H), 1.85 (s, 3H), 1.81 (s, 3H), 1.64 (m, 2H), 1.47 (s, 9H).

实施例16：

Example 16:

将实施例14(28mg，0.05mmol)溶于DCM(4mL)中，加入TFA(0.5mL)，室温反应3h，原料消失。冷却至室温，蒸除溶剂，得实施例16：白色粉末状固体136mg，产率为57％。Example 14 (28 mg, 0.05 mmol) was dissolved in DCM (4 mL). After cooling to room temperature, the solvent was evaporated to give a white crystallite.

结构验证数据如下：¹H NMR(CDCl₃)δ(ppm):10.02(s,1H),10.73(brs,1H),9.82(s,1H),9.37(s,1H),8.47(s,1H),7.41(d,J＝7.6Hz,1H),7.26-7.21(m,3H),6.74(d,J＝8.0Hz,1H),4.61(t,J＝8.0Hz,2H),3.59(d,J＝9.2Hz,2H),3.24(t,J＝8.0Hz,2H),3.07(m,2H),2.79(m,1H),2.19-2.15(m,2H),2.01(d,J＝12.8Hz,2H),.1.87(s,3H),1.84(s,3H).HRMS(ESI):m/z,calcd for C₂₅H₃₀N₅O₂PCl[M+H⁺]:498.1826,found 498.1826.The structure verification data are as follows: ¹ H NMR (CDCl ₃ ) δ (ppm): 10.02 (s, 1H), 10.73 (brs, 1H), 9.82 (s, 1H), 9.37 (s, 1H), 8.47 (s, 1H) ), 7.41 (d, J = 7.6 Hz, 1H), 7.26 - 7.21 (m, 3H), 6.74 (d, J = 8.0 Hz, 1H), 4.61 (t, J = 8.0 Hz, 2H), 3.59 (d) , J=9.2Hz, 2H), 3.24 (t, J=8.0Hz, 2H), 3.07(m, 2H), 2.79(m, 1H), 2.19-2.15(m, 2H), 2.01(d, J= 12.8 Hz, 2H), .1.87 (s, 3H), 1.84 (s, 3H). HRMS (ESI): m/z, calcd for C ₂₅ H ₃₀ N ₅ O ₂ PCl [M+H ⁺ ]: 498.1826, Found 498.1826.

实施例17：

Example 17

将实施例15(40mg，0.06mmol)溶于DCM(4mL)中，加入TFA(0.5mL)，室温反应3h，原料消失。冷却至室温，蒸除溶剂，得实施例17：白色粉末状固体40mg，产率为78％。Example 15 (40 mg, 0.06 mmol) was dissolved in DCM (4 mL). After cooling to room temperature, the solvent was evaporated to give a white crystal.

结构验证数据如下：¹H NMR(DMSO-d₆)δ(ppm):11.38(s,1H),9.16(brs,2H),8.73(s,1H),8.52(s,1H),8.10(s,1H),7.56-7.52(m,1H),7.30(s,1H),7.16-7.11(m,2H),6.46(d,J＝8.4Hz,2H),4.50(t,J＝8.0Hz,2H),3.75(m,4H),3.49-3.40(m,6H),3.19-3.08(m,3H),2.70(t,J＝11.6Hz,2H),2.12(d,J＝10.0Hz,2H),1.79(s,3H),1.76(m,5H).HRMS(ESI):m/z, calcd for C₂₉H₃₈N₇O₂PCl[M+H⁺]:582.2513,found 582.2516.The structure verification data are as follows: ¹ H NMR (DMSO-d ₆ ) δ (ppm): 11.38 (s, 1H), 9.16 (brs, 2H), 8.73 (s, 1H), 8.52 (s, 1H), 8.10 (s) , 1H), 7.56-7.52 (m, 1H), 7.30 (s, 1H), 7.16-7.11 (m, 2H), 6.46 (d, J = 8.4 Hz, 2H), 4.50 (t, J = 8.0 Hz, 2H), 3.75 (m, 4H), 3.49-3.40 (m, 6H), 3.19-3.08 (m, 3H), 2.70 (t, J = 11.6 Hz, 2H), 2.12 (d, J = 10.0 Hz, 2H) ), 1.79 (s, 3H), 1.76 (m, 5H). HRMS (ESI): m/z, calcd for C ₂₉ H ₃₈ N ₇ O ₂ PCl [M+H ⁺ ]: 582.2513, found 582.2516.

测试例1、本发明化合物对ALK^wt/ALK^L1196M激酶活性的测定Test Example 1. Determination of the activity of ALK ^wt /ALK ^L1196M kinase by the compound of the present invention

实施例化合物12000g离心5min，加入DMSO配制成10^-2M储液，涡旋均匀后超声10min待用，-40℃保存(有特殊储存要求的化合物按照具体情况修改)。测试时将化合物用DMSO从储液稀释到所测试浓度的100倍(体系中DMSO浓度为1％)。Example Compound 12000g centrifugation 5min, added DMSO formulated as 10 ^-2 M stock solution, after 10min ultrasonic vortex uniform stand stored (Compound special storage requirements modifications of the specific conditions) -40 ℃. Compounds were diluted from the stock solution with DMSO to 100 times the concentration tested (DMSO concentration in the system was 1%).

测试方法：testing method:

1、酶反应底物Poly(Glu,Tyr)4：1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl，pH7.2-7.4)稀释成20μg/mL，125μL/孔包被酶标板，置37℃反应12-16小时。弃去孔中液体。洗板，用T-PBS(含0.1％Tween-20的无钾离子的PBS，200μL/孔)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时；1. The enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 μg/mL, 125 μL/well coated with the enzyme label. The plate was reacted at 37 ° C for 12-16 hours. Discard the liquid in the well. The plate was washed, and the plate was washed three times with T-PBS (0.1% Tween-20 in potassium-free PBS, 200 μL/well) for 5 minutes each time. The enzyme plate was dried in an oven at 37 ° C for 1-2 hours;

2、每孔加入以反应缓冲液(50mM HEPES pH 7.4,50mM MgCl₂,0.5mM MnCl₂,0.2mM Na₃VO₄,1mM DTT)稀释的ATP溶液49μL，每孔中加入1μL待测试化合物，再加入50μL以反应缓冲液稀释的ALK^wt/ALK^L1196M激酶域重组蛋白启动反应，每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。弃去孔中液体，T-PBS洗板三次；2. Add 49 μL of ATP solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl ₂ , 0.5 mM MnCl ₂ , 0.2 mM Na ₃ VO ₄ , 1 mM DTT) to each well, and add 1 μL of the compound to be tested to each well. 50 μL of ALK ^wt /ALK ^L1196M kinase domain recombinant protein diluted in reaction buffer was added to initiate the reaction, and two wells without ATP control wells were required for each experiment. The reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). Discard the liquid in the well and wash the plate three times with T-PBS;

3、加入抗体PY99稀释液(抗体用含BSA 5mg/mL的T-PBS 1:500稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次；3. Add the antibody PY99 dilution (antibody diluted 1:500 with BSA 5 mg/mL T-PBS), 100 μL/well, and shake for 37 hours at 37 °C. Discard the liquid in the well and wash the plate three times with T-PBS;

4、加入辣根过氧化物酶标记的羊抗鼠二抗稀释液(抗体用含BSA5mg/ml的T-PBS 1:2000稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次；4. Add horseradish peroxidase-labeled goat anti-mouse secondary antibody dilution (antibody diluted 1:2000 with BSA 5 mg/ml T-PBS), 100 μL/well, and shaken at 37 ° C for 0.5 hour. Discard the liquid in the well and wash the plate three times with T-PBS;

5、加入2mg/ml的OPD显色液100μL/孔【用含有0.03％H₂O₂的0.1M柠檬酸－柠檬酸钠缓冲液(pH＝5.4)稀释】，25℃避光反应1-10分钟；5, add 2mg / ml OPD color solution 100μL / well [diluted with 0.1M citric acid-sodium citrate buffer (pH = 5.4) containing 0.03% H ₂ O ₂ ], 25 ° C protected from light 1-10 minute;

6、加入2M H₂SO₄ 50μL/孔中止反应，用可调波长式微孔板酶标仪VERSAmax读数，波长为490nm；6, adding 2M H ₂ SO ₄ 50μL / well to stop the reaction, using a tunable wavelength microplate microplate reader VERSAmax reading, the wavelength is 490nm;

7、结果分析，IC₅₀值采用酶标仪随机附带软件以四参数法回归求得。0<IC50<100nM，记为“+++”；100nM<IC50<500nM，记为“++”；IC50>500nM，记为“+”。实验结果如表1所示。 7. Analysis of the results. IC ₅₀ values were obtained by four-parameter regression using the software attached to the microplate reader. 0 < IC50 < 100 nM, denoted as "+++"; 100 nM < IC50 < 500 nM, denoted "++"; IC50 > 500 nM, denoted "+". The experimental results are shown in Table 1.

抑制率的计算公式如下：The formula for calculating the inhibition rate is as follows:

表1、实施例1-18化合物对ALK^wt/ALK^L1196M激酶的抑制活性Table 1. Inhibitory activity of the compounds of Examples 1-18 on ALK ^wt /ALK ^L1196M kinase

测试例2：化合物对其它激酶的抑制活性Test Example 2: Inhibitory activity of compounds against other kinases

采用与测试例1类似的激酶筛选方法测试了ALK^L1152，ALK^G1202，ALK^F1245，ALK^C1156，ALK^G1269，ALK^S1206，EGFR ^wt,EGFR ^TT90M,EGFR ^T790M/L858R,ROS等激酶的抑制活性。结果显示部分实施例化合物如实施例7，8，9，12，13，16等对ALK^L1152，ALK^G1202，ALK^F1245，ALK^C1156，ALK^G1269，ALK^S1206，ROS激酶的抑制活性IC50均小于100nM，显示了较好的抑制活性；同时，上述化合物对EGFR ^wt,EGFR ^TT90M,EGFR ^T790M/L858R等激酶的抑制活性IC50小于500nM，同样也显示了较高的活性。The inhibitory activities of kinases such as ALK ^L1152 , ALK ^G1202 , ALK ^F1245 , ALK ^C1156 , ALK ^G1269 , ALK ^S1206 , EGFR ^wt , EGFR ^TT90M , EGFR ^T790M/L858R and ROS were tested by a kinase screening method similar to that of Test Example 1. The results showed that some of the example compounds such as Examples 7, ⁸ , ⁹ , ¹² , ¹³ , 16 and so on ALK ^L1152 , ALK ^G1202 , ALK ^F1245 , ALK ^C1156 , ALK ^G1269 , ALK ^S1206 , ROS kinase inhibitory activity IC50 are less than 100nM, It showed better inhibitory activity; at the same time, the inhibitory activity of the above compounds against EGFR ^wt , EGFR ^TT90M , EGFR ^T790M/L858R and other kinases was less than 500 nM, and also showed higher activity.

测试例3：化合物对细胞增殖抑制活性Test Example 3: Compound inhibiting cell proliferation activity

通过Cell Titer 96单溶液细胞增殖实验测评实施例化合物对细胞增殖抑制的活性。接种24小时后，使用实施例化合物处理细胞，生长72小时。在零时刻(处理时间)校正细胞计数，使用XLfit version 4.2.2进行Microsoft Excel绘制相对于对照组(DMSO)的生长百分数数据，测定抑制50％生长的浓度(GI50值)。结果显示，实施例化合物7，8，9，12，13，16等对NCI-H3122和EML4-ALK ^G1202等细胞株具有较强的增殖抑制活性，IC50小于100nM；同时，上述化合物对H1975，A431，SK-N-SH等细胞株也具有较好的抑制活性，IC50小于500nM。The activity of the example compounds against cell proliferation inhibition was assessed by Cell Titer 96 single solution cell proliferation assay. 24 hours after seeding, cells were treated with the example compounds and grown for 72 hours. The cell count was corrected at time zero (treatment time), and the percent growth data of the Microsoft Excel was plotted against the control group (DMSO) using XLfit version 4.2.2, and the concentration (GI50 value) for inhibiting 50% growth was determined. The results showed that the compounds of Examples 7, 8, 9, 12, 13, 16 had strong proliferation inhibitory activity against cell lines such as NCI-H3122 and EML4-ALK ^G1202 , and the IC50 was less than 100 nM; meanwhile, the above compounds were against H1975, A431. Cell lines such as SK-N-SH also have good inhibitory activity with an IC50 of less than 500 nM.

工业应用Industrial application

Claims

式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或a compound of formula I, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph thereof or prodrug thereof;

式Ⅰ’所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；a compound of formula I', a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph thereof or prodrug thereof;

式Ⅰ或式Ⅰ’中：In formula I or formula I':

R₁、R₂、R₃、R₄独立地选自氢、卤素、氰基、羟基、氨基和取代或未取代的C1-C6烷基中的任一种，且R₁、R₂、R₃、R₄中的任意两个基团可以形成3-10元的环系；R ₁ , R ₂ , R ₃ , R _{4 are} independently selected from any of hydrogen, halogen, cyano, hydroxy, amino and substituted or unsubstituted C1-C6 alkyl, and R ₁ , R ₂ , R ₃ , any two groups of R ₄ can form a 3-10 yuan ring system;

M₁、M₂、M₃独立地选自CRa或N，且M₁、M₂和M₃中至少有一个为N；Ra为氢、卤素、氰基、取代或未取代的C1-C6烷基和取代或未取代的C3-C8环烷基中的一种；M ₁ , M ₂ , M _{3 are} independently selected from CRa or N, and at least one of M ₁ , M ₂ and M ₃ is N; Ra is hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkane a group and one of a substituted or unsubstituted C3-C8 cycloalkyl group;

W选自下述基团的任一种：取代或未取代的C1-C6烷基、取代或未取代的C2-C6链烯基、未取代或卤代的4～8元的链炔基、取代或未取代的C3-C8环烷基、取代或未取代的4-8元杂环基、5-10元的芳香基或杂芳基、取代羰基、取代磺酰基、取代或未取代的氨基，其中，所述杂环基包含1-3个选自N、O、S、P和B中的杂原子；W is selected from any of the following groups: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, an unsubstituted or halogenated 4-8 membered alkynyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocyclic group, a 5-10 membered aryl or heteroaryl group, a substituted carbonyl group, a substituted sulfonyl group, a substituted or unsubstituted amino group Wherein the heterocyclic group contains 1-3 heteroatoms selected from the group consisting of N, O, S, P and B;

所述取代为基团中的一个或多个基团被选自下组的取代基所取代：卤素、羟基、氨基、氰基、未取代或卤代的C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的5～8元芳基、未取代或卤代的5～8元杂芳基、未取代或卤代的4～8元饱和杂环、未取代或卤代的4～8元碳环；其中，所述杂芳基包含1-3个选自N、 O和S中的杂原子，所述杂环包含1-3个选自N、O和S的杂原子；The substitution is such that one or more groups in the group are substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, cyano, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogen. C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted or halogen a C2-C6 acyl group, an unsubstituted or halogenated 5- to 8-membered aryl group, an unsubstituted or halogenated 5- to 8-membered heteroaryl group, an unsubstituted or halogenated 4-8 membered saturated heterocyclic ring, unsubstituted Or a halogenated 4-8 membered carbocyclic ring; wherein the heteroaryl group comprises 1-3 selected from N, a hetero atom in O and S, said heterocyclic ring comprising 1-3 heteroatoms selected from N, O and S;

式Ⅰ’中，L选自下述基团的任一种：-CR’R”-、-O-、-NR’-、和－CR’＝，其中R’和R”各自独立地为氢、氟、氘、C1-C6烷基或杂环烷基，或者相邻的R’和R”形成环状基团。In Formula I', L is selected from any of the following groups: -CR'R"-, -O-, -NR'-, and -CR'=, wherein R' and R" are each independently hydrogen. , fluorine, hydrazine, C1-C6 alkyl or heterocycloalkyl, or adjacent R' and R" form a cyclic group.
根据权利要求1所述的式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或A compound of formula I according to claim 1 or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof ;or

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐，其特征在于：A compound of the formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof, which is characterized by:

式Ⅰ所示化合物或式Ⅰ’所示化合物满足下述1)和/或2)：The compound of formula I or the compound of formula I' satisfies the following 1) and / or 2):

1)式Ⅰ或式Ⅰ’中，M₁、M₂独立地选自CH或N，且M₁和M₂中至少有一个为N；M₃选自C-F、C-CF₃、C-Cl、CH和N中的任一种；1) In Formula I or Formula I', M ₁ , M _{2 are} independently selected from CH or N, and at least one of M ₁ and M ₂ is N; M _{3 is} selected from CF, C-CF ₃ , C-Cl Any of CH, N and N;

2)式Ⅰ或式Ⅰ’中，W选自下述基团中的任一种：取代或未取代的C1-C6烷基或环烷基、取代或未取代的4-6元杂环、取代或未取代的4-10元环烷基和取代或未取代的4-10元杂环烷基形成的螺环或桥环；2) In Formula I or Formula I', W is selected from any of the group consisting of a substituted or unsubstituted C1-C6 alkyl or cycloalkyl group, a substituted or unsubstituted 4-6 membered heterocyclic ring, a spiro or bridged ring formed by a substituted or unsubstituted 4-10 membered cycloalkyl group and a substituted or unsubstituted 4-10 membered heterocycloalkyl group;

所述取代是指取代基独立地选自：卤素、羟基、氰基、氨基、烷基、单烷基氨基、二烷基氨基、环烷基、杂环基、烷氧基、羟基烷基、烷氧基烷基、羟基烷氧基烷基、氨基烷基、二烷基氨基烷基、烷氧基羰基氨基烷基、环烷基烷基、杂环基烷基、芳烷基、烷基环烷基、环烷基羰基、烷氧基羰基、烷氧基羰基杂环基、(烷氧羰基)(烷基)氨基、(烷氧基烷基)(烷基)氨基。The substitution means that the substituent is independently selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, Alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, alkyl Cycloalkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (alkoxyalkyl)(alkyl)amino.
根据权利要求1或2所述的式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或A compound of formula I according to claim 1 or 2, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug thereof or pharmaceutically acceptable thereof Salt; or

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐，其特征在于：A compound of the formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof, which is characterized by:

式Ⅰ所示化合物为下述式I-a所示化合物至式I-j1所示化合物中的任一种：The compound of formula I is any one of the compounds of formula I-a to the compound of formula I-j1:

式Ⅰ’所示化合物为下述式Ⅰ’-a至式Ⅰ’-f中的任一种：The compound of the formula I' is any one of the following formulas I'-a to I'-f:
制备权利要求1-3中任一项所述的式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或A compound of formula I according to any one of claims 1 to 3, or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug thereof or a pharmaceutically acceptable salt; or

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐的方法，包括如下步骤：A method of the compound of Formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof, comprising the steps :

(1)将式Ⅳ所示化合物与式Ⅴ所示化合物，在过渡金属催化剂和/或酸/碱存在的条件下进行偶联，得到式Ⅲ所示化合物；(1) coupling a compound of the formula IV with a compound of the formula V in the presence of a transition metal catalyst and/or an acid/base to obtain a compound of the formula III;

式Ⅳ中，X和LG各自独立地为离去基团，且选自卤素、磺酸酯、硼酸和硼酸酯中的任一种； In Formula IV, X and LG are each independently a leaving group, and are selected from any of halogen, sulfonate, boric acid, and boric acid ester;

式Ⅲ中，X的定义同式Ⅳ；M₁、M₂和M₃的定义同式Ⅰ；In Formula III, X is as defined in Formula IV; M ₁ , M ₂ and M ₃ are as defined in Formula I;

(2)式Ⅲ所示化合物与式Ⅱ所示化合物或式Ⅱ’所示化合物在过渡金属催化剂和/或酸/碱存在的条件下进行偶联，得到式I所示化合物或式I’所示化合物；(2) A compound of the formula III is coupled with a compound of the formula II or a compound of the formula II' in the presence of a transition metal catalyst and/or an acid/base to give a compound of the formula I or a formula I' Compound

式Ⅱ中，R₁、R₂、R₃、R₄和W的定义同式Ⅰ；式Ⅱ’中，R₁、R₂、R₃、R₄、L和W的定义同式Ⅰ’。In Formula II, R ₁ , R ₂ , R ₃ , R ₄ and W are as defined in Formula I; in Formula II′, R ₁ , R ₂ , R ₃ , R ₄ , L and W are as defined in Formula I′.
根据权利要求4所述的方法，其特征在于：步骤(1)或步骤(2)中，The method according to claim 4, wherein in step (1) or step (2),

所述偶联反应在溶剂中进行，且所述溶剂选自水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺和二氧六环中的至少一种；The coupling reaction is carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, At least one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dioxane;

所述过渡金属催化剂选自三(二亚苄基丙酮)二钯、四(三苯基膦)钯、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯和1，2-二(二苯基膦基)乙烷二氯化钯中的至少一种；所述催化剂配体选自三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦和三邻苯甲基膦中的至少一种；The transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, Palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(trio-phenylmethylphosphine)palladium dichloride and 1,2-di ( At least one of diphenylphosphino)ethane palladium dichloride; the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine , three pairs of benzyl phosphine, At least one of tricyclohexylphosphine and tri-o-phenylmethylphosphine;

所述碱为无机碱或有机碱；所述无机碱选自氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠和碳酸氢钠中的至少一种；所述有机碱选自吡啶、三乙胺、N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯、六甲基二硅基锂、六甲基二硅基钠和二甲基吡啶中的至少一种；The base is an inorganic base or an organic base; the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, At least one of potassium carbonate, potassium hydrogencarbonate, sodium carbonate, and sodium hydrogencarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diaza At least one of cyclo[5.4.0]undec-7-ene, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and lutidine;

所述酸选自盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸和乙酸中的至少一种。The acid is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid.
权利要求1-3中任一项所述的式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或A compound of formula I according to any one of claims 1 to 3, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polycrystal thereof Form or its prodrug; or

式Ⅰ’所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；a compound of formula I', a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph thereof or prodrug thereof;

在下述1)或2)中的应用：Application in 1) or 2) below:

1)制备具有抑制EGFR突变激酶活性和/或ALK激酶活性的功能的抑制剂；1) preparing an inhibitor having a function of inhibiting EGFR mutant kinase activity and/or ALK kinase activity;

2)抑制EGFR突变激酶活性和/或ALK激酶活性。2) Inhibition of EGFR mutant kinase activity and/or ALK kinase activity.
一种激酶抑制剂，它包括权利要求1-3中任一项所述的式Ⅰ所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐；或A kinase inhibitor comprising a compound of formula I as claimed in any one of claims 1 to 3, or an enantiomer, diastereomer, tautomer, solvate thereof, or more a crystalline form, prodrug or pharmaceutically acceptable salt; or

式Ⅰ’所示化合物或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物、前药或药学上可接受的盐。A compound of the formula I' or an enantiomer, diastereomer, tautomer, solvate, polymorph, prodrug or pharmaceutically acceptable salt thereof.
权利要求1-3中任一项所述的式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或A compound of formula I according to any one of claims 1 to 3, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polycrystal thereof Form or its prodrug; or

式Ⅰ’所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；a compound of formula I', a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph thereof or prodrug thereof;

在下述1)或2)中的应用：Application in 1) or 2) below:

1)制备预防和/或***产品；1) preparing a preventive and/or therapeutic tumor product;

2)预防和/或***。 2) Prevention and/or treatment of tumors.
根据权利要求8所述的应用，其特征在于：所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、淋巴癌和鼻咽癌中的任一种。The use according to claim 8, wherein the tumor is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cells. Any of cancer, gastrointestinal stromal tumors, leukemia, lymphoma, and nasopharyngeal cancer.
一种药物组合物，其特征在于：它包括：A pharmaceutical composition characterized in that it comprises:

1)有效量的权利要求1-3中任一项所述的式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；和1) An effective amount of a compound of formula I according to any one of claims 1 to 3, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer thereof, a solvate, a polymorph or a prodrug thereof;

2)药学上可接受的载体。2) A pharmaceutically acceptable carrier.
抑制EGFR突变激酶活性和/或ALK激酶活性的方法，它包括如下步骤：给受体动物施用权利要求1-3中任一项所述的式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或A method of inhibiting EGFR mutant kinase activity and/or ALK kinase activity, comprising the steps of: administering to a recipient animal a compound of formula I according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, Enantiomers, diastereomers, tautomers, solvates, polymorphs or prodrugs thereof; or

式Ⅰ’所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或a compound of formula I', a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph thereof or prodrug thereof;

权利要求10所述的药物组合物。The pharmaceutical composition of claim 10.
预防和/或***的方法，它包括如下步骤：给受体动物施用权利要求1-3中任一项所述的式Ⅰ所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或A method of preventing and/or treating a tumor, which comprises the step of administering to a recipient animal a compound of the formula I according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, an enantiomer thereof , diastereomers, tautomers, solvates, polymorphs or prodrugs thereof; or

式Ⅰ’所示化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或其前药；或a compound of formula I', a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, polymorph thereof or prodrug thereof;

权利要求10所述的药物组合物。The pharmaceutical composition of claim 10.
根据权利要求12所述的方法，其特征在于：所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、淋巴癌和鼻咽癌中的任一种。 The method according to claim 12, wherein the tumor is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cells. Any of cancer, gastrointestinal stromal tumors, leukemia, lymphoma, and nasopharyngeal cancer.