WO2015014283A1

WO2015014283A1 - Protein tyrosine kinase inhibitor and application thereof

Info

Publication number: WO2015014283A1
Application number: PCT/CN2014/083284
Authority: WO
Inventors: 王勇; 赵立文; 陈宏雁; 王德忠; 刘阳; 毕胜; 高毅平; 张迪; 张仓
Original assignee: 南京圣和药业股份有限公司
Priority date: 2013-07-31
Filing date: 2014-07-30
Publication date: 2015-02-05
Also published as: TWI546304B; CN104341416A; CN104341416B; TW201504239A

Abstract

The present invention relates to the chemical and medical fields, and provides a compound with protein tyrosine kinase inhibitory activity and pharmaceutically acceptable salt, isomers, solvates, crystals, or prodrugs thereof. The present invention further provides a method for preparing the compound in the present invention, a pharmaceutical composition having the compound in the present invention or pharmaceutically acceptable salt, isomers, solvates, crystals, or prodrugs thereof, and an application of the compound and the composition in the present invention in drugs for treating or preventing tumors.

Description

蛋白酪氨酸激酶抑制剂及其应用 Protein tyrosine kinase inhibitor and its application

技术领域 Technical field

本发明属于化学医药领域，具体涉及一类具有蛋白酪氨酸激酶抑制活性的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。背景技术 The present invention belongs to the field of chemical medicine, and particularly relates to a compound having a protein tyrosine kinase inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition containing the same And the use of these compounds or compositions in the preparation of a medicament. Background technique

蛋白酪氨酸激酶（PTKs)是一类能够催化 ATP上 γ-磷酸转移到蛋白酪氨酸残基上的激酶，通过催化多种蛋白酪氨酸残基上的酚羟基发生磷酸化，进而激活功能蛋白作用的蛋白质酶系。蛋白酪氨酸激酶（PTKs)在细胞内的信号传导通路中占据着十分重要的地位，调节细胞生长、分化、死亡等一系列生理生化过程。蛋白酪氨酸激酶的异常表达可以导致细胞增殖调节发生紊乱，进而导致肿瘤的发生。此外，蛋白酪氨酸激酶的异常表达还与肿瘤的侵袭和转移，肿瘤新生血管的生成，肿瘤的化疗抗药性密切相关。酪氨酸激酶抑制剂可作为三磷酸腺苷（ATP) 与酪氨酸激酶结合的竞争性抑制剂，竞争性结合酪氨酸激酶，阻断酪氨酸激酶的活性，抑制细胞增殖，已经有数种酪氨酸蛋白激酶抑制剂成功地得到了开发。 Protein tyrosine kinases (PTKs) are a class of kinases that catalyze the transfer of γ-phosphates on ATP to protein tyrosine residues, which are activated by catalyzing the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues. A proteinase system that functions as a functional protein. Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Abnormal expression of a protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis. In addition, the abnormal expression of protein tyrosine kinase is also closely related to tumor invasion and metastasis, tumor neovascularization, and tumor chemotherapy resistance. Tyrosine kinase inhibitors act as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, competitively bind to tyrosine kinases, block tyrosine kinase activity, and inhibit cell proliferation. Several tyrosines have been developed. Acid protein kinase inhibitors have been successfully developed.

慢性粒细胞白血病（CML)患者中染色体易位形成 BCR-ABL融合基因，表达的 BCR-ABL 蛋白酪氨酸激酶在细胞信号转导和转化中发挥着重要作用，通过磷酸化等作用，促使 CML成熟粒细胞无限增生。 BCR-ABL在正常细胞中并不表达，已经成为了治疗 CML的理想药物靶标。 The chromosomal translocation in chronic myeloid leukemia (CML) patients forms a BCR-ABL fusion gene, and the expressed BCR-ABL protein tyrosine kinase plays an important role in cell signal transduction and transformation, and promotes CML through phosphorylation and the like. Mature granulocytes infinite proliferation. BCR-ABL is not expressed in normal cells and has become an ideal drug target for the treatment of CML.

伊马替尼是第一个分子靶向治疗的蛋白酪氨酸激酶抑制剂，竞争性抑制三磷酸腺苷 (ATP) 与胸苷激酶（TK) 受体（如 KIT) 的结合位点，阻滞 TK磷酸化，从而抑制信号传导，并可抑制与激酶有关的 KIT突变和野生型的 KIT, 对各种类型的癌症具有治疗效果。伊马替尼在体内外均可在细胞水平上抑制 BCR-ABL酪氨酸激酶，选择性抑制 BCR-ABL阳性细胞系细胞以及费城染色体阳性（Ph+) 的慢性髓性白血病（CML) 和急性淋巴细胞白血病病人的新鲜白血病细胞的增殖，诱导其凋亡。此外，伊马替尼还可以抑制血小板衍生生长因子（PDGF) 的受体酪氨酸激酶以及干细胞因子 (SCF)的受体酪氨酸激酶 c-Kit，从而抑制由 PDGF和干细胞因子介导的细胞行为。临床上主要用于治疗慢性粒细胞白血病 (CML)急变期、加速期或 α-干扰素治疗失败后的慢性期患者、不能手术切除或发生转移的恶性胃肠道间质肿瘤（GIST) 患者；也用于治疗 CD117阳性的胃肠道***瘤 (GIST)。 Imatinib is the first protein-targeted therapeutic protein tyrosine kinase inhibitor that competitively inhibits the binding site of adenosine triphosphate (ATP) to thymidine kinase (TK) receptors (such as KIT) and blocks TK phosphorylation. It inhibits signal transduction and inhibits kinase-related KIT mutations and wild-type KIT, and has therapeutic effects on various types of cancer. Imatinib inhibits BCR-ABL tyrosine kinase at the cellular level in vitro and in vivo, selectively inhibits BCR-ABL-positive cell line cells and Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphoid The proliferation of fresh leukemia cells in patients with cell leukemia induces apoptosis. In addition, imatinib also inhibits the receptor tyrosine kinase of platelet-derived growth factor (PDGF) and the receptor tyrosine kinase c-Kit of stem cell factor (SCF), thereby inhibiting mediated by PDGF and stem cell factors. Cell behavior. Clinically, it is mainly used for the treatment of chronic myeloid leukemia (CML) blast crisis, accelerated phase or chronic phase after failure of α-interferon therapy, and patients with malignant gastrointestinal stromal tumor (GIST) who cannot undergo surgical resection or metastasis; Also used to treat CD117-positive gastrointestinal stromal tumors (GIST).

伊马替尼的开发及临床使用开启了肿瘤分子靶向的新时代。但是长期服用伊马替尼，会产生耐药性，导致病情复发。随着伊马替尼在临床上的广泛应用，耐药问题日益突出。获得性耐受的主要原因是由于 BCR-ABL的点突变导致伊马替尼不能与 BCR-ABL结合而产生的。并且，已发现上百种 BCR-ABL点突变与伊马替尼耐药相关，其中 15~20%的伊马替尼耐受患者存在 T315I突变。伊马替尼耐药性的出现，激起了新一代酪氨酸激酶抑制剂的研发热潮，以期开发出更优的用于治疗白血病，例如耐药或不耐药的各期 CML、 Ph+ ALL的新的药物。发明内容 The development and clinical use of imatinib has opened a new era of tumor molecular targeting. However, taking imatinib for a long time will cause drug resistance and cause the disease to recur. With the widespread clinical application of imatinib, the problem of drug resistance has become increasingly prominent. The main reason for acquired tolerance is due to point mutations in BCR-ABL that result in the inability of imatinib to bind to BCR-ABL. Moreover, hundreds of BCR-ABL point mutations have been found to be associated with imatinib resistance, with 15 to 20% of imatinib-tolerant patients having a T315I mutation. The emergence of imatinib resistance has ignited a wave of research and development of a new generation of tyrosine kinase inhibitors, with a view to developing better CML, Ph+ ALL for the treatment of leukemia, such as drug resistance or non-resistance. New drugs. Summary of the invention

本发明的目的是提供通式 I的一类具有广谱的 BCR-ABL抑制效果的化合物或其药学可接受的盐、异构体、 It is an object of the present invention to provide a class of compounds of the general formula I having a broad spectrum of BCR-ABL inhibitory effects, or pharmaceutically acceptable salts, isomers thereof,

其中： among them:

« 选自氢、垸基、垸氧基、卤代垸基、卤代垸氧基、 -OH、 -NH₂、卤素和 CN; «Selected from hydrogen, fluorenyl, decyloxy, halodecyl, halodecyloxy, -OH, -NH ₂ , halogen and CN;

R₂选自氢、垸基、垸氧基、卤代垸基、卤代垸氧基、 -OH、 -NH₂、卤素和 CN; R _{2 is} selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH ₂ , halogen, and CN;

R₃选自氢、垸基、卤代垸基、卤素、氨基酰基、单垸基氨基酰基、双垸基氨基酰基和氰基； R _{3 is} selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;

R4选自氢、垸基、 -OH、羟垸基、卤代垸基； R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;

X选自 N和 C(R₅)，其中 R₅选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，或者 R₅与其连接的碳原子形成 C(=0)，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代； X is selected from N and C(R ₅ ), wherein R _{5 is} selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate An acylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, or a carbon atom to which R ₅ is bonded to form C(=0), said amino group, monodecylamino group, bis-indenyl group Amino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino may be halogenated by one or more halogen , thiol, amino, cyano substituted;

Y选自 N、 H和 C(R6)，其中 Re选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代； Y is selected from the group consisting of N, H and C(R6), wherein Re is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate An amide group, a mercaptosulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, the amino group, a monodecylamino group, a bis-decylamino group, an acylamino group, a decylamino group, an aryl amide group, a heteroarylamino group, a sulfonylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano;

"表示单键或双键，当 X为 C(=0)时，表示单键； "Indicating a single key or double key, when X is C (=0), it means a single key;

条件是所述化合物不是以下化合物： The condition is that the compound is not the following compound:

3-((2-氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基）乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基）甲基 )-3—三氟甲基苯基]苯甲酰胺； 3-((2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4- Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide;

3-((2-甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基 )-3—三氟甲基苯基]苯甲酰胺； 3-((2-二甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基) 甲基; )-3-三氟甲基苯基]苯甲酰胺。 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4 -methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide; 3-((2-Dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-(( 4-methylpiperazin-1-yl)methyl; )-3-trifluoromethylphenyl]benzamide.

本发明的另一个目的是提供制备本发明的通式 I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的方法。 Another object of the invention is to provide a process for the preparation of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

本发明的再一个目的是提供包含本发明的通式 I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体的组合物，以及包含本发明的通式 I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和另一种或多种蛋白酪氨酸激酶抑制剂的组合物。 A further object of the present invention is to provide a composition comprising a compound of formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another protein tyrosine kinase inhibitor.

本发明的还一个目的是提供本发明的通式 I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药治疗和 /或预防肿瘤的方法，以及本发明的通式 I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药在制备用于治疗和 /或预防肿瘤的药物中的应用。 A further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, for treating and/or preventing a tumor, and the method of the invention Use of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of a tumor.

针对上述目的，本发明提供以下技术方案： For the above purposes, the present invention provides the following technical solutions:

第一方面，本发明提供通式 I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药， In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

其中： among them:

Y选自 N、 H和 C(R6)，其中 Re选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代； Y is selected from the group consisting of N, H and C(R6), wherein Re is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate An amide group, a mercaptosulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, the amino group, a monodecylamino group, a bis-decylamino group, an acylamino group, a decylamino group, an aryl amide group, miscellaneous An aryl amido group, a sulfonylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano;

3-((2-甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基 )-3—三氟甲基苯基]苯甲酰胺； 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4 -methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide;

3-((2-二甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基) 甲基; )-3-三氟甲基苯基]苯甲酰胺。 3-((2-Dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-(( 4-methylpiperazin-1-yl)methyl; )-3-trifluoromethylphenyl]benzamide.

在一些通式 I化合物的实施方案中， X为 N， Y为 N，表示双键。 In some embodiments of the compounds of formula I, X is N and Y is N, indicating a double bond.

在一些通式 I化合物的实施方案中， X为 N， Y为 CCRe), 表示双键，选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 In some embodiments of the compound of Formula I, X is N, Y is CCRe), represents a double bond, selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl Amido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino group, monodecylamino, bis-decylamino, acylamino, Mercaptoylamino, arylamido, heteroaryl amido, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, sulfhydryl, amino , cyano substitution.

在一些通式 I化合物的实施方案中， X为 C(R₅)， Y为 N，表示双键，所述的选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 In some embodiments of the compounds of Formula I, X is C(R ₅ ), Y is N, represents a double bond, and is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, hydrazine Amino group, aryl amido group, heteroaryl amido group, sulfonylamino group, decylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, said amino group, monodecylamino group, biguanide Alkylamino, amido, decylamido, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino can be one or more Halogen, sulfhydryl, amino, cyano substituted.

在一些通式 I化合物的实施方案中， X为 C(=0)， Y为 NH，表示单键。 In some embodiments of the compounds of formula I, X is C(=0) and Y is NH, representing a single bond.

在一些通式 I化合物的实施方案中， X为 C(R₅)， Y为 C(R6)，表示双键，所述的 R₅、 Re分别独立地选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 In some embodiments of the compound of Formula I, X is C(R ₅ ), Y is C(R6), represents a double bond, and said R ₅ , Re are each independently selected from hydrogen, amino, monodecylamino , bis-decylamino, amido, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino, said Amino, monodecylamino, bis-decylamino, amido, decanoylamino, aryl amido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroaryl The sulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano groups.

在一些优选的通式 I化合物的实施方案中， 1^选自氢、 d_₆垸基、 d_₆垸氧基、卤代 d_₆ 垸基、卤代 d.₆垸氧基、 -OH、 -NH₂、卤素和 CN; R₂选自氢、 d.₆垸基、 d.₆垸氧基、卤代 C^垸基、卤代 d.₆垸氧基、 -OH、 -NH₂、卤素和 CN; R₃选自氢、 d.₆垸基、卤代 d.₆垸基、卤素、氨基酰基、单 d_₆垸基氨基酰基、双 d_₆垸基氨基酰基和氰基；和 R4选自氢、。^垸基、 -OH、羟 C^垸基、卤代 C^垸基。 In some preferred embodiments of the compound of Formula I, 1 is selected from the group consisting of hydrogen, d- ₆ fluorenyl, d- ₆ methoxy, halo d- ₆ fluorenyl, halo d. ₆ decyloxy, -OH, - NH ₂ , halogen and CN; R _{2 is} selected from the group consisting of hydrogen, d. ₆ fluorenyl, d. ₆ decyloxy, halo C fluorenyl, halogenated d. ₆ decyloxy, -OH, -NH ₂ , halogen And CN; R _{3 is} selected from the group consisting of hydrogen, d. ₆ fluorenyl, halogenated d. ₆ fluorenyl, halogen, amino acyl, mono d ₆ fluorenylamino acyl, bis d ₆ decylamino acyl and cyano; Since hydrogen, . ^ fluorenyl, -OH, hydroxy C^ fluorenyl, halogenated C^ fluorenyl.

在一些优选的通式 I化合物的实施方案中， 1^选自氢、 d_₄垸基、 d_₄垸氧基、卤代 C₁₄ 垸基、卤代 d.₄垸氧基、 -OH、 -NH₂、卤素和 CN; R₂选自氢、 d.₄垸基、 d.₄垸氧基、卤代 C₁₄垸基、卤代 CM垸氧基、 -OH、 -NH₂、卤素和 CN; R₃选自氢、 d.₄垸基、卤代 d.₄垸基、卤素、氨基酰基、单 C₁₄垸基氨基酰基、双 C₁₄垸基氨基酰基和氰基；和 R4选自氢、 C₁₄垸基、 -OH、羟。₁₄垸基、卤代 C₁₄垸基。 In some preferred embodiments of the compound of Formula I, 1 is selected from the group consisting of hydrogen, d- ₄ thiol, d- ₄ methoxy, halo C ₁₄ Sulfhydryl, halogenated d. ₄ methoxy, -OH, -NH ₂ , halogen and CN; R _{2 is} selected from hydrogen, d. ₄ fluorenyl, d. ₄ decyloxy, halogenated C ₁₄ fluorenyl, halogen Substituting CM methoxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, d. ₄ fluorenyl, halogenated d. ₄ fluorenyl, halogen, aminoacyl, mono C ₁₄ mercaptoaminoacyl, A double C ₁₄ mercaptoamino acyl group and a cyano group; and R 4 is selected from the group consisting of hydrogen, C ₁₄ fluorenyl, -OH, hydroxy. ₁₄ fluorenyl, halogenated C ₁₄ fluorenyl.

更优选地，在通式 I化合物的实施方案中， 1^选自氢、 d_₃垸基、 d_₃垸氧基、卤代 d_₃ 垸基、卤代 d.₃垸氧基、 -OH、 -NH₂、卤素和 CN; R₂选自氢、 d.₃垸基、 d.₃垸氧基、卤代 Cw垸基、卤代 d.₃垸氧基、 -OH、 -NH₂、卤素和 CN; R₃选自氢、 d.₃垸基、卤代 d.₃垸基、卤素、氨基酰基、单 d_₃垸基氨基酰基、双 d_₃垸基氨基酰基和氰基；和 R4选自氢、 d_₃垸基、 -OH、羟 Cw垸基、卤代 C^垸基。 More preferably, in embodiments of the compounds of formula I, 1 ^ is selected from hydrogen, alkyl with d_ _3, d_ ₃ embankment group, d_ ₃ alkyl with halo, haloalkyl d. ₃ embankment group, -OH, -NH ₂ , halogen and CN; R _{2 is} selected from the group consisting of hydrogen, d. ₃ fluorenyl, d. ₃ decyloxy, halo Cw fluorenyl, halogenated d. ₃ decyloxy, -OH, -NH ₂ , halogen And CN; R _{3 is} selected from the group consisting of hydrogen, d. ₃ fluorenyl, halogenated d. ₃ fluorenyl, halogen, amino acyl, mono d ₃ decylamino acyl, bis d ₃ decylamino acyl and cyano; From hydrogen, d_ ₃ fluorenyl, -OH, hydroxy Cw fluorenyl, halogenated C fluorenyl.

优选地，本发明提供通式 la的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药， Preferably, the present invention provides a compound of the formula la or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

其中： among them:

Y选自 N、 H和 C(R6)，其中 Re选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代； "表示单键或双键，当 X为 C(=0)时，表示单键；当 X为 N， Y为 C(R6)，且含有 X、 Y的环与其所稠合的吡啶环及吡啶环所连接的乙炔基一起构成 [1,2,4]-三氮唑并 [1,5-a]吡啶 -7-乙炔基基团时，选自氢、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 Y is selected from the group consisting of N, H and C(R6), wherein Re is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate An amide group, a mercaptosulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, the amino group, a monodecylamino group, a bis-decylamino group, an acylamino group, a decylamino group, an aryl amide group, a heteroarylamino group, a sulfonylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group may be substituted by one or more halogen, fluorenyl, amino, cyano; "indicating a single bond or Double key, when X is C (=0), it means a single bond; When X is N, Y is C(R6), and the ring containing X, Y together with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached constitutes [1,2,4]-triazo[1] a 5-a]pyridine-7-ethynyl group selected from the group consisting of hydrogen, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl Sulfonylamino, heteroarylsulfonylamino, said acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, hetero The arylsulfonylamino group may be substituted by one or more halogen, sulfhydryl, amino, cyano groups.

在一些通式 la化合物的实施方案中， X为 N， Y为 N，表示双键。 In some embodiments of the compound of formula la, X is N and Y is N, indicating a double bond.

在一些通式 la化合物的实施方案中， X为 N， Y为 C(R6)，表示双键，且含有 X、 Y 的环与其所稠合的吡啶环及吡啶环所连接的乙炔基一起构成 [1,2,4]-三氮唑并 [1,5-a]吡啶 -7- 乙炔基基团时， R6选自氢、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 In some embodiments of the compound of formula la, X is N, Y is C(R6), represents a double bond, and the ring containing X, Y is formed with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached. In the case of a [1,2,4]-triazolo[1,5-a]pyridine-7-ethynyl group, R6 is selected from the group consisting of hydrogen, acylamino, decylamido, arylamido, heteroaryl Amido, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said acylamino, decylamido, aryl amide, heteroaryl amide, sulfonyl The amino group, mercaptosulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, sulfhydryl, amino, cyano groups.

在一些通式 la化合物的实施方案中， X为 N， Y为 C(R6)，表示双键，且含有 X、 Y 的环与其所稠合的吡啶环及吡啶环所连接的乙炔基一起构成 [1,2,4]-三氮唑并 [1,5-a]吡啶 -6- 乙炔基基团时， R6选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 In some embodiments of the compound of formula la, X is N, Y is C(R6), represents a double bond, and the ring containing X, Y is formed with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached. [1,2,4]-triazolo[1,5-a]pyridine-6-ethynyl group, R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, hydrazine Amino group, aryl amido group, heteroaryl amido group, sulfonylamino group, decylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, said amino group, monodecylamino group, biguanide Alkylamino, amido, decylamido, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino can be one or more Halogen, sulfhydryl, amino, cyano substituted.

在一些通式 la化合物的实施方案中， X为 C(R₅)， Y为 N，表示双键，所述的 R₅ 选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 In some embodiments of the compound of formula la, X is C(R ₅ ), Y is N, represents a double bond, and said R _{5 is} selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido , mercaptoamido, aryl amido, heteroaryl amido, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino group, monodecylamino group, Bis-nonylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino can be one or Multiple halogen, sulfhydryl, amino, cyano substituted.

在一些通式 la化合物的实施方案中， X为 C(=0)， Y为 NH，表示单键。 In some embodiments of the compound of formula la, X is C(=0) and Y is NH, representing a single bond.

在一些通式 la化合物的实施方案中， X为 C(R₅)， Y为 C(R6)，表示双键，所述的 R₅、 Re分别独立地选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 In some embodiments of the compound of formula la, X is C(R ₅ ), Y is C(R6), represents a double bond, and said R ₅ , Re are each independently selected from hydrogen, amino, monodecylamino , bis-decylamino, amido, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino, said Amino, monodecylamino, bis-decylamino, amido, decanoylamino, aryl amido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroaryl The sulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano groups.

在一些优选的通式 la化合物的实施方案中， 1^选自氢、 d_₆垸基、 d_₆垸氧基、卤代 d_₆ 垸基、卤代 d.₆垸氧基、 -OH、 -NH₂、卤素和 CN; R₂选自氢、 d.₆垸基、 d.₆垸氧基、卤代 C^垸基、卤代 d.₆垸氧基、 -OH、 -NH₂、卤素和 CN; R₃选自氢、 d.₆垸基、卤代 d.₆垸基、卤素、氨基酰基、单 d_₆垸基氨基酰基、双 d_₆垸基氨基酰基和氰基；和 R4选自氢、。^垸基、 -OH、羟 C^垸基、卤代 C^垸基。 In some preferred embodiments of the compound of formula la, 1 is selected from the group consisting of hydrogen, d- ₆ fluorenyl, d- ₆ methoxy, halo d- ₆ fluorenyl, halo d. ₆ decyloxy, -OH, - NH ₂ , halogen and CN; R _{2 is} selected from the group consisting of hydrogen, d. ₆ fluorenyl, d. ₆ decyloxy, halo C fluorenyl, halogenated d. ₆ decyloxy, -OH, -NH ₂ , halogen And CN; R _{3 is} selected from the group consisting of hydrogen, d. ₆ fluorenyl, halogenated d. ₆ fluorenyl, Halogen, aminoacyl, mono-d- _6- ylaminoacyl, bis-d- _6- ylaminoacyl and cyano; and R4 is selected from hydrogen. ^ fluorenyl, -OH, hydroxy C^ fluorenyl, halogenated C^ fluorenyl.

在一些优选的通式 la化合物的实施方案中， 1^选自氢、 d_₃垸基、 d_₃垸氧基、卤代 d_₃ 垸基、卤代 d.₃垸氧基、 -OH、 -NH₂、卤素和 CN; R₂选自氢、 d.₃垸基、 d.₃垸氧基、卤代 Cw垸基、卤代 d.₃垸氧基、 -OH、 -NH₂、卤素和 CN; R₃选自氢、 d.₃垸基、卤代 d.₃垸基、卤素、氨基酰基、单 d_₃垸基氨基酰基、双 d_₃垸基氨基酰基和氰基；和 R4选自氢、 d_₃垸基、 -OH、羟 Cw垸基、卤代 C^垸基。 In some preferred embodiments of the compounds of formula la, 1 ^ is selected from hydrogen, alkyl with d_ _3, d_ ₃ embankment group, d_ ₃ alkyl with halo, haloalkyl group embankment d _3, -OH,. - NH ₂ , halogen and CN; R _{2 is} selected from the group consisting of hydrogen, d. ₃ fluorenyl, d. ₃ decyloxy, halo Cw fluorenyl, halogenated d. ₃ decyloxy, -OH, -NH ₂ , halogen and CN; R _{3 is} selected from the group consisting of hydrogen, d. ₃ fluorenyl, halogenated d. ₃ fluorenyl, halogen, aminoacyl, mono d ₃ decylamino acyl, bis d ₃ decylamino acyl and cyano; and R 4 is selected from hydrogen, d_ ₃ alkyl with, -OH, Cw alkyl with hydroxyl, C ^ alkyl with halo.

进一步优选地，本发明提供通式 I-a的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药， Further preferably, the present invention provides a compound of the formula I-a or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

其中： among them:

R6选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代; 条件是所述化合物不是以下化合物： R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido, decylamino, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonyl Amino, heteroarylsulfonylamino, said amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonate The acylamino, arylsulfonylamino, heteroarylsulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano; provided that the compound is not the following:

进一步优选地，本发提供通式 I-b 的化合物或其药学可接受的盐、异构体、溶剂合物、 Further preferably, the present invention provides a compound of the formula Ib or a pharmaceutically acceptable salt, isomer, solvate thereof,

其中： among them:

Y选自 N和 H; Y is selected from N and H;

R₅选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，或者 R₅与所连接的碳原子形成 C(=0)，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代； R _{5 is} selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonate An acylamino group, a heteroarylsulfonylamino group, or R ₅ forms a C(=0) with the attached carbon atom, said amino group, monodecylamino group, bis-decylamino group, amido group, decyl amido group, aryl group Alkylamino, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, thiol, amino, cyano;

"表示单键或双键，当 R₅与其连接的碳原子形成 C(O)时， "表示单键， Y为 NH。进一步优选地，本发明提供通式 Ia-a的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药， "Indicating a single bond or a double bond, when R ₅ forms a C(O) with the carbon atom to which it is attached, " represents a single bond and Y is NH. Further preferably, the present invention provides a compound of the formula Ia-a or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

其中： among them:

R₃选自氢、垸基、卤代垸基、卤素、氨基酰基、单垸基氨基酰基、双垸基氨基酰基和氰基； R _{3 is} selected from the group consisting of hydrogen, fluorenyl, halodecyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyanide Base

R6选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido, decylamino, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonyl Amino, heteroarylsulfonylamino, said amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonate The acylamino, arylsulfonylamino, heteroarylsulfonylamino group may be substituted by one or more halogen, sulfhydryl, amino, cyano groups.

当 [1,2,4]-三氮唑与所稠合的吡啶环及吡啶环所连接乙炔基一起构成 [1,2,4]-三氮唑并 When [1,2,4]-triazole is combined with the fused pyridine ring and the acetylene-linked ethynyl group to form [1,2,4]-triazole

[1,5-a]吡啶 -7-乙炔基基团时，所述的选自氢、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 When the [1,5-a]pyridine-7-ethynyl group is selected from the group consisting of hydrogen, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonate An amide group, an arylsulfonylamino group, a heteroarylsulfonylamino group, said acylamino group, decyl amido group, aryl amide group, heteroaryl amide group, sulfonylamino group, decyl sulfonylamino group, aryl group The sulfonylamino, heteroarylsulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano groups.

更进一步优选地，本发明提供通式 I-a'的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前 Still more preferably, the present invention provides a compound of the formula I-a' or a pharmaceutically acceptable salt, isomer, solvate, crystal or former thereof

其中： among them:

更进一步优选地，本发明提供通式 I-a"的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，

Still more preferably, the present invention provides a compound of Formula Ia" or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

(I-a") 其中： (I-a") where:

R₃选自氢、垸基、卤代垸基、卤素、氨基酰基、单垸基氨基酰基、双垸基氨基酰基和氰 R _{3 is} selected from the group consisting of hydrogen, fluorenyl, halodecyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyanide

R6选自氢、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代； R6 is selected from the group consisting of hydrogen, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, Heteroarylsulfonylamino, said amido, decylamido, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonyl The amino group may be substituted by one or more halogen, thiol, amino, cyano;

3-((2-二甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基) 甲基; )-3-三氟甲基苯基]苯甲酰胺。。 3-((2-Dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-(( 4-methylpiperazin-1-yl)methyl; )-3-trifluoromethylphenyl]benzamide. .

更进一步优选地，本发明提供通式 I-b'的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前 Still more preferably, the present invention provides a compound of the formula I-b' or a pharmaceutically acceptable salt, isomer, solvate, crystal or former thereof

其中： among them:

« 选自氢、垸基、垸氧基、卤代垸基、卤代垸氧基、 -OH、 - H₂ 卤素和 CN; «Selected from hydrogen, fluorenyl, decyloxy, halodecyl, halodecyloxy, -OH, -H ₂ halogen and CN;

R₂选自氢、垸基、垸氧基、卤代垸基、卤代垸氧基、 -OH、 - H₂ 卤素和 CN; R _{2 is} selected from the group consisting of hydrogen, fluorenyl, decyloxy, halodecyl, halodecyloxy, -OH, -H ₂ halogen, and CN;

R₃选自氢、垸基、卤代垸基、卤素、氨基酰基、单垸基氨基酰基、双垸基氨基酰基和氰 R4选自氢、垸基、 -OH、羟垸基、卤代垸基； R _{3 is} selected from the group consisting of hydrogen, fluorenyl, halodecyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyanide R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;

Y选自 N和 H; Y is selected from N and H;

R₅选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，或者 R₅与其所连接的碳原子形成 C(=0)，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代； R _{5 is} selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonate An acylamino group, a heteroarylsulfonylamino group, or a carbon atom to which R ₅ forms a C(=0), said amino group, monodecylamino group, bis-decylamino group, amido group, decylamino group, aromatic Alkylamino, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, thiol, amino, cyano;

"表示单键或双键，当 R₅与其所连接的碳原子形成 C(=0)时，表示单键， γ为 "Indicating a single bond or a double bond, when R ₅ forms a C (=0) with the carbon atom to which it is attached, it represents a single bond, γ is

更进一步优选地，本发明提供通式 I-b"的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或 Still more preferably, the present invention provides a compound of formula I-b" or a pharmaceutically acceptable salt, isomer, solvate, crystal or

其中： among them:

R4选自氢、垸基、 -OH、羟垸基、卤代垸基; R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;

Y选自 N和 H; Y is selected from N and H;

更进一步优选地，本发明提供通式 Ia-a'的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，

Even more preferably, the present invention provides a compound of the formula Ia-a', or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

其中： among them:

R6选自氢、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 R6 is selected from the group consisting of hydrogen, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino, said Amido, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino can be one or more halogen, hydrazine Substituted, amino, cyano substituted.

在本发明优选的实施方案中， 1^选自氢、垸基、卤代垸基、卤素和 CN。 In a preferred embodiment of the invention, 1 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen and CN.

在本发明更优选的实施方案中，《选自甲基和三氟甲基。 In a more preferred embodiment of the invention, "selected from methyl and trifluoromethyl.

在本发明优选的实施方案中， R₂选自氢、垸基、卤代垸基、卤素和 CN。 In a preferred embodiment of the invention, R _{2 is} selected from the group consisting of hydrogen, fluorenyl, halo fluorenyl, halogen and CN.

在本发明更优选的实施方案中， R₂选自甲基、乙基、丙基和异丙基。 In a more preferred embodiment of the invention, R _{2 is} selected from the group consisting of methyl, ethyl, propyl and isopropyl.

在本发明优选的实施方案中， R₃选自氢、 d_₆垸基、卤代 d_₆垸基、卤素、氨基酰基、单 d_₆垸基氨基酰基、双 d_₆垸基氨基酰基和氰基。 In a preferred embodiment of the invention, R _{3 is} selected from the group consisting of hydrogen, d- ₆ fluorenyl, halo d- ₆ fluorenyl, halogen, aminoacyl, mono d- ₆ fluorenylamino, di d ₆ decylamino acyl and cyano .

在本发明更优选的实施方案中， R₃选自氢、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、卤素和甲氨基酰基。 In a more preferred embodiment of the invention, R _{3 is} selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, halogen and methylamino.

在本发明优选的实施方案中， R4选自氢、 d_₆垸基、 -OH、羟 d_₆垸基、卤代 d_₆垸基。在本发明更优选的实施方案中， R4选自氢、甲基、乙基、丙基、异丙基、 -OH、羟甲基、羟乙基、羟丙基、三氟甲基、三氟乙基。 In a preferred embodiment of the invention, R4 is selected from the group consisting of hydrogen, d- ₆ fluorenyl, -OH, hydroxy d- ₆ fluorenyl, halo d- ₆ fluorenyl. In a more preferred embodiment of the invention, R4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, -OH, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, trifluoro Ethyl.

在本发明优选的实施方案中， R₅选自氨基、单 d_₆垸基氨基、双 d_₆垸基氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙基酰氨基、环丁基酰氨基、苯酰氨基、三氟乙酰氨基、甲磺酰氨基、乙磺酰氨基、苯磺酰氨基，或者 R₅与所连接的碳原子形成 C(=0)。 In a preferred embodiment of the invention, R _{5 is} selected from the group consisting of amino, mono d- ₆ fluorenylamino, bis-d- ₆ ylamino, formylamino, acetylamino, propionylamino, cyclopropylamido, cyclobutyl hydrazide amino, amido phenyl group, a trifluoroacetyl group, a methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl amino group, or R ₅ and the carbon atoms are attached form C (= 0).

在本发明更优选的实施方案中， R₅选自氨基、甲氨基、乙氨基、丙氨基、异丙氨基、二甲氨基、二乙氨基、二丙氨基、甲基乙基氨基、甲基丙基氨基、乙基丙基氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙基酰氨基、环丁基酰氨基、三氟乙酰氨基、甲磺酰氨基、乙磺酰氨基，或者 R₅与所连接的碳原子形成 C(=0)。 In a more preferred embodiment of the invention, R _{5 is} selected from the group consisting of amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropyl Amino, ethylpropylamino, formylamino, acetylamino, propionylamino, cyclopropylamido, cyclobutylamido, trifluoroacetamido, methanesulfonylamino, ethanesulfonyl The amino group, or R ₅ , forms a C (=0) with the attached carbon atom.

在本发明优选的实施方案中， Re选自氨基、单 d_₆垸基氨基、双 d_₆垸基氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙基酰氨基、环丁基酰氨基、苯酰氨基、三氟乙酰氨基、甲磺酰氨基、乙磺酰氨基、苯磺酰氨基。 In a preferred embodiment of the invention, Re is selected from amino, mono d_ ₆ alkyl with an amino group, bis d_ ₆ alkyl with an amino group, formylamino, acetylamino, propionylamino, amido cyclopropyl, cyclobutyl amido , benzoylamino, trifluoroacetamido, methanesulfonylamino, ethanesulfonylamino, benzenesulfonylamino.

在本发明更优选的实施方案中， Re选自氨基、甲氨基、乙氨基、丙氨基、异丙氨基、二甲氨基、二乙氨基、二丙氨基、甲基乙基氨基、甲基丙基氨基、乙基丙基氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙基酰氨基、环丁基酰氨基、三氟乙酰氨基、甲磺酰氨基、乙磺酰氨基。 In a more preferred embodiment of the invention, Re is selected from the group consisting of amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropyl Amino, ethylpropylamino, formylamino, acetylamino, propionylamino, cyclopropylamido, cyclobutylamido, trifluoroacetamido, methanesulfonylamino, ethanesulfonylamino.

本发明提供了以下具体化合物： The present invention provides the following specific compounds:

另一万面，本发明提供本发明的通式化合物的制备方法。通式 I的化合物的制备方法包括如下步骤： In another aspect, the invention provides a process for the preparation of a compound of the formula of the invention. The preparation of the compound of formula I comprises the following steps:

(1 式 5的中间体的制备： (1) Preparation of intermediates of formula 5:

a) 式 1的化合物与式 2的化合物反应得到式 3的中间体;

a) a compound of formula 1 is reacted with a compound of formula 2 to provide an intermediate of formula 3;

b) 式 3的中间体与三甲基硅乙炔反应得到式 4的中间体; c) 式 4的中间体脱去三甲基硅垸基得到式 5的中间体; b) an intermediate of formula 3 is reacted with trimethylsilylacetylene to give an intermediate of formula 4; c) removing the trimethylsilyl group from the intermediate of formula 4 to give an intermediate of formula 5;

5 5

d) 式 5的中间体与式 6的中间体反应得到通式 I的化合物。

d) An intermediate of formula 5 is reacted with an intermediate of formula 6 to give a compound of formula I.

其中， Ri、 R₂、 R₃、、 R6、 X、 Y具有通式 I中的含义， M选自氯、溴、碘。 Wherein, Ri, R ₂ , R ₃ , R6, X, Y have the meanings in the formula I, and M is selected from the group consisting of chlorine, bromine and iodine.

相似地，本领域技术人员可参照本发明通式 I的化合物的制备方法，制备本发明通式 I、通式 Ia、通式 I-a、通式 I-b、通式 Ia-a、通式 I-a'、通式 I-a"、通式 I-b'、通式 I-b"禾口通式 Ia-a' 的化合物。 Similarly, those skilled in the art can prepare the formula I, formula Ia, formula Ia, formula Ib, formula Ia-a, formula I-a of the present invention by referring to the preparation method of the compound of formula I of the present invention. A compound of the formula Ia", the formula I-b', the formula Ib" and the formula Ia-a'.

具体地，通式 I-a的化合物的制备方法包括如下步骤： Specifically, the method for preparing the compound of the formula I-a comprises the following steps:

( 1 ) 式 9的中间体的制备： (1) Preparation of the intermediate of formula 9:

e) 式 7的化合物与异硫氰酰甲酸乙酯反应得到式 8的中间体； e) reacting a compound of formula 7 with ethyl isothiocyanate to give an intermediate of formula 8;

f) 式 8的中间体与盐酸羟胺反应得到式 9的中间体； f) an intermediate of formula 8 is reacted with hydroxylamine hydrochloride to provide an intermediate of formula 9;

(2) 式 10的中间体的合成

(2) Synthesis of intermediates of formula 10

9 0 9 0

g ) 式 9的中间体经过常规的垸基化反应、酰基化反应或磺酰基化反应制得式 10的中间 g) an intermediate of formula 9 is prepared by conventional thiolation, acylation or sulfonylation to give the intermediate of formula 10

(3 ) 通式 I-a的化合物的制备：

(3) Preparation of a compound of formula Ia:

5 1 0 l-a 5 1 0 l-a

h) 式 9的中间体或式 10的中间体与式 5的中间体反应得到通式 I-a化合物；其中， Ri R₂ R₃ R4和 Re具有通式 I-a中的含义， M选自氯、溴、碘。 h) an intermediate of formula 9 or an intermediate of formula 10 is reacted with an intermediate of formula 5 to give a compound of formula Ia; wherein Ri R ₂ R ₃ R4 and Re have the meaning of formula Ia, M is selected from the group consisting of chlorine and bromine , iodine.

具体地，其中 R₅与其连接的碳原子形成 C(=0)， Y为 NH的通式 I-b的化合物的制备方法包括如下步骤： Specifically, a method for preparing a compound of the formula Ib wherein R ₅ and its attached carbon atom form C (=0) and Y is NH comprises the following steps:

( 1 ) 式 13的中 (1) in the middle of formula 13

1 1 12 13 1 1 12 13

i) 式 11的中间体与水合肼反应得到式 12的中间体; i) an intermediate of formula 11 is reacted with hydrazine hydrate to give an intermediate of formula 12;

j) 式 12的中间体与三光气反应得到式 13的中间体; j) an intermediate of formula 12 is reacted with triphosgene to give an intermediate of formula 13;

(2) 式 I-b的目标化合物的制备 (2) Preparation of the target compound of formula I-b

⁵ 1 3 '-^b k) 式 13的中间体与式 5的中间体反应得到其中 R₅与其连接的碳原子形成 C(=0)、 Y为 NH的通式 I-b的化合物； ⁵ 1 3 '- ^b k) an intermediate of formula 13 is reacted with an intermediate of formula 5 to give a compound of formula Ib wherein R ₅ and its attached carbon atom form C (=0), Y is NH;

其中， Ri R₂ R₃和 R4具有通式 I-b中的含义， M选自氯、溴、碘。 Wherein Ri R ₂ R ₃ and R 4 have the meanings in the formula Ib, and M is selected from the group consisting of chlorine, bromine and iodine.

第三方面，本发明提供药物组合物，其包含本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药。 In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.

在一些实施方案中，本发明提供本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药及包含本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的药物组合物，所述化合物或药物组合物用于治疗或预防癌症，所述癌症包括实体瘤以及各种形式的白血病，包括对其他治疗抵抗的白血病。 In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a compound comprising the same, or a pharmaceutically acceptable salt, isomer thereof , solvate, crystal or former A pharmaceutical composition of the medicament for use in the treatment or prevention of cancer, including solid tumors and various forms of leukemia, including leukemia resistant to other therapies.

在一些实施方案中，本发明提供药物组合物，其包含本发明的化合物、异构体、溶剂合物、结晶或前药，还包含选自下列组成的一种或多种：酪氨酸蛋白酶抑制剂、 EGFR抑制剂、 VEGFR抑制剂、 BCR-ABL抑制剂、 c-kit抑制剂、 c-Met抑制剂、 Raf抑制剂、 MEK抑制剂、组蛋白去乙酰酶抑制剂、 VEGF抗体、 EGF抗体、 HIV蛋白激酶抑制剂、 HMG-CoA还原酶抑制剂等。 In some embodiments, the invention provides a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the invention, further comprising one or more selected from the group consisting of: tyrosine protease Inhibitors, EGFR inhibitors, VEGFR inhibitors, BCR-ABL inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies , HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.

可以将本发明的化合物、异构体、溶剂合物、结晶或前药与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜 (例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。 The compound, isomer, solvate, crystal or prodrug of the present invention may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. . Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The preparation may be administered by any route, for example, by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.

第四方面，本发明提供本发明的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和 /或预防肿瘤的方法和在制备预防和 /或***药物中的应用，包括向肿瘤易发人群或肿瘤患者施用本发明的化合物、异构体、溶剂合物、结晶或前药或者包含本发明的化合物、异构体、溶剂合物、结晶或前药的药物组合物，以有效降低肿瘤发生率、延长肿瘤患者生命。 In a fourth aspect, the present invention provides a method for treating and/or preventing a tumor of a compound, an isomer, a solvate, a crystal or a prodrug of the present invention or a pharmaceutical composition of the present invention and in the preparation of a medicament for preventing and/or treating cancer Use of a compound, isomer, solvate, crystal or prodrug of the invention or a compound, isomer, solvate, crystal or prodrug of the invention, to a tumor-prone population or tumor patient The pharmaceutical composition is effective for reducing the incidence of tumors and prolonging the life of tumor patients.

在一些实施方案中，本发明提供用于治疗和 /或预防肿瘤的方法，包括向有此需要的个体给予治疗和 /或预防有效量的本发明的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物。可以向有需要的哺乳动物给予本发明的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物以抑制肿瘤的生长、发展和 /或转移，所述肿瘤包括实体瘤，例如乳腺癌、结肠癌、胃癌、胰腺癌、中枢神经***肿瘤和头颈癌以及各种形式的白血病，包括对其他治疗抵抗如对伊马替尼或其他激酶抑制剂抵抗的白血病和其他癌症，所述激酶被本发明的化合物或组合物所抑制。术语说明 In some embodiments, the invention provides a method for treating and/or preventing a tumor comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound, isomer, solvate, crystallization of the invention Or a prodrug or a pharmaceutical composition of the invention. The compounds, isomers, solvates, crystals or prodrugs of the invention or pharmaceutical compositions of the invention may be administered to a mammal in need thereof to inhibit tumor growth, progression and/or metastasis, including solid tumors For example, breast cancer, colon cancer, gastric cancer, pancreatic cancer, central nervous system tumors and head and neck cancer, and various forms of leukemia, including leukemia and other cancers that are resistant to other treatments such as imatinib or other kinase inhibitors, The kinase is inhibited by a compound or composition of the invention. Terminology

本发明的"垸基"是指直链、支链或环状的饱和烃基，优选为 d_₆垸基，例如，合适的 d_₆ 垸基基团包括但不限于甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、环戊基、环己基、正己基。在本文中，所述垸基进一步优选为 d_₃ 垸基，合适的 d_₃垸基为甲基、乙基、丙基、异丙基、环丙基。如本文所用，本发明中的垸基包括取代或未取代的垸基，所述垸基可任选被一个或多个选自以下的基团取代：垸基、垸氧基、芳氧基、垸氨基、芳基氨基、卤素、羟基、氨基、硝基、氰基、垸基酰基、氨基酰基、垸氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基。 The "mercapto" of the present invention means a linear, branched or cyclic saturated hydrocarbon group, preferably a d- ₆ fluorenyl group. For example, a suitable d- ₆ fluorenyl group includes, but is not limited to, a methyl group, an ethyl group, a n-propyl group. Base, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl. Herein, the embankment group more preferably d_ ₃ alkyl with a suitable d_ ₃ alkyl with methyl, ethyl, propyl, isopropyl, cyclopropyl. As used herein, a fluorenyl group in the present invention includes a substituted or unsubstituted fluorenyl group which may be optionally substituted with one or more groups selected from the group consisting of an anthracenyl group, a decyloxy group, an aryloxy group, Anthracene amino, arylamino, halogen, hydroxy, amino, nitro, cyano, decyl acyl, amino acyl, Amidinoyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl.

本发明的"焼氧基 "是指垸基 -0-，优选为 d_₆垸基 -0-，进一步优选为 d_₃垸基 -0-，合适的 d_₃垸基 -0-为甲氧基、乙氧基、丙氧基、异丙氧基。 "Firing group" of the present invention means alkyl with -0-, preferably d_ ₆ alkyl with -0-, more preferably alkyl with -0- d_ _3, d_ ₃ alkyl with a suitable -0- methoxy , ethoxy, propoxy, isopropoxy.

本发明的"卤素"是指氟、氯、溴、碘，优选为氟、氯。 The "halogen" of the present invention means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

本发明的"卤代垸基"是指至少被一个卤素取代的垸基，优选为卤代 d_₆垸基，进一步优选为卤代 Cw垸基，合适的卤代 d_₃垸基为氯甲基、氟甲基、二氯甲基、二氟甲基、三氯甲基、三氟甲基、氯乙基、氟乙基、二氯乙基、二氟乙基、三氯乙基、三氟乙基。 The "halogenated fluorenyl group" of the present invention means a fluorenyl group substituted with at least one halogen, preferably a halogenated d- ₆ fluorenyl group, further preferably a halogenated Cw fluorenyl group, and a suitable halogenated d ₃ fluorenyl group is a chloromethyl group. , fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, chloroethyl, fluoroethyl, dichloroethyl, difluoroethyl, trichloroethyl, trifluoro Ethyl.

本发明的"卤代垸氧基"是指至少被一个卤素取代的垸氧基，优选为至少被一个卤素取代的 d_₆垸氧基，进一步优选为卤代 d_₃垸氧基，合适的卤代 d_₃垸氧基为氯甲氧基、氟甲氧基、二氯甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基；二氯乙氧基、二氟乙氧基、三氯乙氧基、三氟乙氧基。 "Embankment haloalkoxy group" of the present invention means at least one halogen substituted embankment group, preferably at least one halogen substituted embankment d_ ₆ group, more preferably a halogeno group d_ ₃ embankment, a suitable halide Generation d_ ₃ methoxy is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; dichloroethoxy, difluoroethyl Oxy, trichloroethoxy, trifluoroethoxy.

本发明的"酰氨基 "是指 HC(0)- H -。 The "amido" of the present invention means HC(0)-H-.

本发明的"垸基酰氨基"是指垸基 -C(0)- H -，优选为 d_₆垸基 -C(0)- H -，进一步优选为 Ci_-3垸基 -C(0)- H -。 The "mercaptoamido" of the present invention means fluorenyl-C(0)-H-, preferably d- ₆ fluorenyl-C(0)-H-, and more preferably Ci _-3 fluorenyl-C(0) - H -.

本发明的"芳基酰氨基"是指芳基 -C(0)- H -。 The "arylamino group" of the present invention means aryl-C(0)-H-.

本发明的"杂芳基酰氨基 "是指杂芳基 -C(0)- H -。 The "heteroarylamino group" of the present invention means a heteroaryl group -C(0)-H-.

本发明的"磺酰氨基"是指 HS(0)₂-NH -。 The "sulfonylamino group" of the present invention means HS(0) ₂ -NH -.

本发明的"垸基磺酰氨基 "是指垸基 -S(0)₂- H -，优选为 d_₆垸基 -S(0)₂- H -，进一步优选为 .₃垸基 -S(0)₂-NH -。 The "mercaptosulfonylamino group" of the present invention means fluorenyl-S(0) ₂ - H -, preferably d_ ₆ fluorenyl-S(0) ₂ - H - , more preferably . ₃ fluorenyl-S ( 0) ₂ -NH -.

本发明的"芳基磺酰氨基 "是指芳基 -S(0)₂- H -。 The "arylsulfonylamino group" of the present invention means aryl-S(0) ₂ - H -.

本发明的"杂芳基磺酰氨基"是指杂芳基- S(0)₂- H -。 The "heteroarylsulfonylamino" of the present invention means heteroaryl-S(0) ₂ -H-.

本发明的"芳基"是指含有一个或多个苯环的芳烃基团。合适的芳基包括苯基、萘基。本发明的"杂芳基 "是指芳基中至少有一个碳原子被杂原子替代的芳香性基团。所述的杂原子为 0、 S、 N。 The "aryl group" of the present invention means an aromatic hydrocarbon group containing one or more benzene rings. Suitable aryl groups include phenyl, naphthyl. The "heteroaryl" of the present invention means an aromatic group in which at least one carbon atom of the aryl group is replaced by a hetero atom. The heteroatoms are 0, S, N.

本发明的"溶剂合物"在常规意义上是指溶质（如活性化合物、活性化合物的盐）和溶剂 The "solvate" of the present invention means, in a conventional sense, a solute (e.g., an active compound, a salt of an active compound) and a solvent.

(如水）组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂合物通常被称作水合物，例如一水合物、二水合物、三水合物等。 (such as water) a composite formed by a combination. Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.

本发明的 "结晶"是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。本发明的"异构体"是指化合物的顺式或反式构型的异构体。因此，本发明包括每种顺式异构体或反式异构体而基本不含其它异构体以及这些异构体的混合物。 "Crystalline" of the present invention means various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms. The "isomer" of the present invention refers to an isomer of the cis or trans configuration of the compound. Accordingly, the invention includes each cis isomer or trans isomer substantially free of other isomers and mixtures of such isomers.

本发明的"前药"是指在生物体的生理条件下，由于与酶、胃酸等反应而转化成本发明的化合物的化合物，即通过酶的氧化、还原、水解等转化成本发明的化合物的化合物和 /或通过胃酸等的水解反应等转化成本发明的化合物的化合物。 The "prodrug" of the present invention refers to a compound which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into a compound of the invention by oxidation, reduction, hydrolysis or the like of the enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.

本发明的"药学可接受的盐"是指本发明的化合物与酸形成的药学上可接受的盐，所述的酸包括但不限于磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸等等。 The "pharmaceutically acceptable salt" of the present invention means a pharmaceutically acceptable salt formed by the compound of the present invention and an acid, Acids include, but are not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, and the like.

本发明的"药物组合物"是指包含任何一种本文所述的化合物，包括异构体、前药、溶剂合物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。 The "pharmaceutical composition" of the present invention is intended to include any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.

本发明的"药学上可接受的载体"是指对有机体不引起明显剌激性和不干扰所给予化合物的生物活性和性质的载体，包含溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、以及纤维素和乙酸纤维素；麦芽、明胶等。 The "pharmaceutically acceptable carrier" of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes a solvent, a diluent or other excipients, a dispersing agent, a surface. Active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention. Some examples which may be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin, and the like.

本发明的"赋形剂 "指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。 "Excipient" as used in the present invention refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol.

本发明的"在制备用于治疗和 /或预防肿瘤的药物中的应用"是指可以抑制肿瘤的生长、发展和 /或转移，主要向所需要的人或动物给治予治疗有效剂量的本发明的化合物以抑制、减慢或逆转受治疗者肿瘤的生长、发展或扩撒。 The "application in the preparation of a medicament for treating and/or preventing a tumor" of the present invention means that the growth, development and/or metastasis of the tumor can be inhibited, and the therapeutically effective dose is mainly administered to a human or animal in need thereof. The compounds of the invention inhibit, slow or reverse the growth, progression or spread of a tumor in a subject.

本发明的化合物是指本发明所有的通式化合物，包括通式 I、通式 Ia、通式 I-a、通式 I-b、通式 Ia-a、通式 I-a'、通式 I-a"、通式 I-b'、通式 I-b"和通式 Ia-a'任一通式所述的化合物及具体化合物。具体实施方式 The compound of the present invention refers to all the compounds of the formula of the present invention, including the formula I, the formula Ia, the formula Ia, the formula Ib, the formula Ia-a, the formula I-a', the formula Ia", A compound of the formula I-b', formula Ib" and formula Ia-a' and specific compounds. detailed description

下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。 The following representative examples are intended to better illustrate the invention and are not intended to limit the scope of the invention.

实施例 1 3-((2-甲氨基 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 Example 1 3-((2-Methylamino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

于 50mL圆底烧瓶中，在冰浴条件下，加入 2-氨基 -4-甲基 -5-溴吡啶（1.87g lOmmol), 再加入二氯甲垸 (DCM, 20mL)，再加入异硫氰酰甲酸乙酯（EtOC(O)NCS, 1.4g 10.6mmol), 5 °C反应 15min，常温下，再反应 2h 40°C浓缩，加入 50ml石油醚（PE) ，有大量的固体析出，过滤，滤饼用 PE洗涤 3次，干燥，得到标题化合物。 In a 50 mL round bottom flask, 2-amino-4-methyl-5-bromopyridine (1.87 g lOmmol) was added in an ice bath, then dichloromethane (DCM, 20 mL) was added, then isothiocyanate was added. Ethyl acylate (EtOC(O)NCS, 1.4g 10.6mmol), reacted at 5 °C for 15min, concentrated at room temperature, then reacted for 2h at 40 °C, added 50ml petroleum ether (PE), a large amount of solid precipitated, filtered, The filter cake was washed 3 times with PE and dried to give the title compound.

ESI-MS m/z: [M+H]⁺ = 317.9 ESI-MS m/z: [M+H] ⁺ = 317.9

步骤 2 2-氨基 -6- -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 2 Preparation of 2-amino-6--7-methyl-[1,2,4]triazolo[1,5-a]pyridine

于 lOOmL茄形瓶中，加入 1-(4-甲基 -5-溴吡啶 -2-基) -3-乙氧基羰基硫脲（1.21mg 4mmol)、盐酸羟胺 (1.38g 20 mmol)及 Ν,Ν-二异丙基乙胺（DIEA, 1.65mL), 再加入 40ml甲醇和乙醇的混合溶液（V:V=1 : 1 ) ，室温搅拌 lh，升温至 70°C反应 4h。反应 4h后，停止加热，旋干，加入 20ml冰水，过滤，干燥，得到标题化合物。 In a 100 mL eggplant-shaped flask, 1-(4-methyl-5-bromopyridin-2-yl)-3-ethoxycarbonylthiourea (1.21 mg 4 mmol), hydroxylamine hydrochloride (1.38 g 20 mmol) and hydrazine were added. , Ν-diisopropylethylamine (DIEA, 1.65 mL), and a mixture of 40 ml of methanol and ethanol (V: V = 1 : 1 ) was added, stirred at room temperature for 1 h, and heated to 70 ° C for 4 h. After 4 h of reaction, the reaction was quenched with EtOAc.

1H MR (300 MHz, DMSO-d6) δ: 8.88 (s, 1H), 7.36 (s, 1H), 6.04 (s, 2H), 2.37 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 8.88 (s, 1H), 7.36 (s, 1H), 6.04 (s, 2H), 2.37 (s, 3H).

ESI-MS m/z: [M+H]+ = 227.1 ESI-MS m/z: [M+H]+ = 227.1

步骤 3 2-甲氨基 -6溴 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备

Step 3 Preparation of 2-methylamino-6bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine

在干燥的 100 ml两口烧瓶中，加入化合物 2-氨基 -6-溴 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 (200 mg, 0.88 mmol), 多聚甲醛 (264 mg, 8.8 mmol)，甲醇钠（190 mg 3.52 mmol)和甲醇（5 ml) ，氮气保护下 80°C反应 2h，冷却到室温，将硼氢化钠（167.2 mg, 4.4 mmol) 分批小心加入到反应体系中，加热到 80°C搅拌 2h后冰浴条件下，加入丙酮淬灭过量的硼氢化钠，浓缩。加入水（20 ml) ，乙酸乙酯（EA 50 ml ) 萃取三次，合并有机相浓缩，干燥，过滤，柱层析纯化得到标题化合物。 In a dry 100 ml two-necked flask, the compound 2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 0.88 mmol) was added. , paraformaldehyde (264 mg, 8.8 mmol), sodium methoxide (190 mg 3.52 mmol) and methanol (5 ml), reacted at 80 ° C for 2 h under nitrogen, cooled to room temperature, sodium borohydride (167.2 mg, 4.4 mmol) The mixture was carefully added to the reaction system in portions, heated to 80 ° C and stirred for 2 h. After ice bath, excess sodium borohydride was quenched with acetone and concentrated. After addition of water (20 ml), EtOAc (EtOAc m.

ESI-MS m/z: [M+H]⁺ = 241.1 ESI-MS m/z: [M+H] ⁺ = 241.1

步骤 4: 3-碘 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺的制备

Step 4: Preparation of 3-iodo-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide

在反应器中加入 4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯胺（2.27g， 8.3mmol)、 3-碘 -4-甲基苯甲酰氯（10mmol)、 15ml四氢呋喃、 10ml三乙胺，室温搅拌 4小时。反应结束，用饱和 NaHC0₃溶液洗涤，乙酸乙酯 /水萃取，饱和 NaCl溶液洗涤，无水 Na₂S0₄干燥，减压蒸熘除去溶剂，硅胶柱纯化得标题化合物。 4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline (2.27 g, 8.3 mmol), 3-iodo-4-methylbenzoyl chloride (10 mmol) was added to the reactor. ), 15 ml of tetrahydrofuran, 10 ml of triethylamine, and stirred at room temperature for 4 hours. End of the reaction, and extracted with saturated NaHC0 ₃ solution, washed with ethyl acetate / water, washed with saturated NaCl solution and dried over anhydrous Na ₂ S0 _4, the solvent was removed under reduced pressure leavened distilled off, silica gel column chromatography to give the title compound.

1H MR (500 MHz, CDC1₃) δ: 8.39(s,lH,N-H), 8.29(s,lH,Ar-H), 7.88(d,lH,Ar-H), 1H MR (500 MHz, CDC1 ₃ ) δ: 8.39 (s, lH, NH), 8.29 (s, lH, Ar-H), 7.88 (d, lH, Ar-H),

7.86(s,lH,Ar-H), 7.75(d,lH,Ar-H), 7.73(d,lH,Ar-H), 7.28(d,lH,Ar-H), 3.62(s,2H,PhCH₂), 7.86(s,lH,Ar-H), 7.75(d,lH,Ar-H), 7.73(d,lH,Ar-H), 7.28(d,lH,Ar-H), 3.62(s,2H, PhCH ₂ ),

2.60(b,8H, 4 -CH₂), 2.47(s,3H,-CH₃), 2.31(s,3H,-CH₃)。 2.60(b,8H,4 -CH ₂ ), 2.47(s,3H,-CH ₃ ), 2.31(s,3H, -CH ₃ ).

步骤 5: 3-三甲基硅垸基乙炔基 -4-甲基 -N-[4-((4-甲基哌嗪 -1-基；)甲基; )-3-三氟甲基苯基]苯甲酰胺的制备 Step 5: 3-Trimethylsilylethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl);-3-trifluoromethylbenzene Preparation of benzamide

将 3-碘 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺（3.1g， 6.1mmol)、 Pd(PPh₃)₂Cl₂ (426mg, 0.61mmol)、 Cul (231mg, 1.21mmol) 置于反应器中，加入甲苯 30ml 作溶剂，三乙胺 lml维持碱性环境。惰性气体保护下，向该混合物中加入三甲基硅垸基乙炔 (3.0g， 30.3mmol), 58°C搅拌 24小时。反应结束，向反应混合物中加入乙酸乙酯和水进行萃取，合并有机层，用饱和 NaCl溶液洗涤，加入无水 Na₂S0₄干燥。减压浓缩，残留物经硅胶柱纯化得标题化合物。 3-iodo-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide (3.1 g, 6.1 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (426 mg, 0.61 mmol), Cul (231 mg, 1.21 mmol) was placed in a reactor, 30 ml of toluene was added as a solvent, and 1 ml of triethylamine was maintained in an alkaline environment. To the mixture was added trimethylsilylacetylene (3.0 g, 30.3 mmol) under an inert gas atmosphere, and stirred at 58 ° C for 24 hours. End of the reaction, ethyl acetate and water were added to the reaction mixture was extracted, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous added Na ₂ S0 _4. The residue was purified by EtOAcqqqqqq

1H MR (500 MHz, CDCI3) δ: 8.30(s,lH,N-H), 7.86(s,lH,Ar-H), 7.83(d,lH,Ar-H), 1H MR (500 MHz, CDCI3) δ: 8.30 (s, lH, N-H), 7.86 (s, lH, Ar-H), 7.83 (d, lH, Ar-H),

7.72(s,lH,Ar-H), 7.55(d,lH,Ar-H), 7.41(d,lH,Ar-H), 7.24(d,lH,Ar-H), 3.60(s,2H,PhCH₂), 7.72(s,lH,Ar-H), 7.55(d,lH,Ar-H), 7.41(d,lH,Ar-H), 7.24(d,lH,Ar-H), 3.60(s,2H, PhCH ₂ ),

2.48(b,8H, 4 -CH₂), 2.45(s,3H,-CH₃), 2.28(s,3H,-CH₃), 0.26(s,9H, 3x-CH₃)₀ 2.48(b,8H, 4 -CH ₂ ), 2.45(s,3H,-CH ₃ ), 2.28(s,3H,-CH ₃ ), 0.26(s,9H, 3x-CH ₃ ) ₀

步骤 6: 3-乙炔基 -4-甲基 -N-[4-《4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 Step 6: Preparation of 3-ethynyl-4-methyl-N-[4-"4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

将步骤 5反应所得物 (1.59g， 3.3mmol) 碳酸钾 (1.82g， 13.2mmol) 20ml甲醇混合于反应器中，惰性气体保护下，室温搅拌 3小时。反应结束，旋转蒸发仪上除去甲醇，加入乙酸乙酯和水进行萃取，合并有机层，用饱和 NaCl溶液洗涤，加入无水 Na₂S0₄干燥。然后将该有机溶液在旋转蒸发仪上浓缩，残留物经硅胶柱纯化得标题化合物。

The reaction product of the reaction of the step 5 (1.59 g, 3.3 mmol), potassium carbonate (1.82 g, 13.2 mmol), 20 ml of methanol was mixed in the reactor, and the mixture was stirred at room temperature for 3 hours under an inert gas atmosphere. The reaction completed, the methanol was removed on a rotary evaporator, ethyl acetate and the organic layer was extracted with water, combined, washed with saturated NaCl solution, dried over anhydrous added Na ₂ S0 _4. The organic solution was then concentrated on a rotary evaporator.

1H MR (500 MHz, CDC1₃) δ: 10.47(s,lH,N-H), 8.19(s,lH,Ar-H), 8.08(s,lH,Ar-H), 1H MR (500 MHz, CDC1 ₃ ) δ: 10.47 (s, lH, NH), 8.19 (s, lH, Ar-H), 8.08 (s, lH, Ar-H),

8.04(d,lH,Ar-H), 7.91(d,lH,Ar-H), 7.70(d,lH,Ar-H), 7.47(d,lH,Ar-H), 4.50(s,lH≡CH) , 8.04(d,lH,Ar-H), 7.91(d,lH,Ar-H), 7.70(d,lH,Ar-H), 7.47(d,lH,Ar-H), 4.50(s,lH≡ CH),

3.56(s,2H,PhCH₂), 2.50(s,3H,-CH₃), 2.36(b,8H,- 4><CH₂), 2.15(s,3H,-CH₃)。 3.56 (s, 2H, PhCH ₂ ), 2.50 (s, 3H, -CH ₃ ), 2.36 (b, 8H, - 4 >< CH ₂ ), 2.15 (s, 3H, -CH ₃ ).

步骤 7 3-((2-甲氨基 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 7 3-((2-Methylamino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpiperazine)

- -基;)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 -based;) Preparation of methyl)-3-trifluoromethylphenyl]benzamide

称取 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺（126mg， 0.3mmol)， 2-甲氨基 -6-溴 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶（60mg， 0.3mmol)， Pd(Pph₃)₂Cl₂ (22mg, 0.03mmol), 三环己膦 (Pcy3, 16mg, 0.06 mmol), Cul (6mg， 0.03 mmol), 碳酸铯 ( lOOmg, 0.3 mmol), 加入封管中。然后在封管中加入 6滴二异丙基乙基胺（DIPEA) 以及 6mL DMF。通氩气排氧 5分钟后密封， 80°C搅拌过夜。各反应物加入 10 mL封管中，加 DMF 至一半体积，通氩气排氧 5分钟，密封， 80°C搅拌过夜。次日反应液用氨水洗涤 2次，乙酸乙酯萃取 3次，合并有机层后用饱和食盐水洗涤若干次，加入无水硫酸钠干燥，纯化得到目标化合物。 3-Ethynyl-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide (126 mg, 0.3 mmol) , 2-Methylamino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine (60 mg, 0.3 mmol), Pd(Pph ₃ ) ₂ Cl ₂ ( 22 mg, 0.03 mmol), tricyclohexylphosphine (Pcy3, 16 mg, 0.06 mmol), Cul (6 mg, 0.03 mmol), cesium carbonate (100 mg, 0.3 mmol). Then 6 drops of diisopropylethylamine (DIPEA) and 6 mL of DMF were added to the sealed tube. After argon gas was purged for 5 minutes, it was sealed and stirred at 80 ° C overnight. The reactants were placed in a 10 mL sealed tube, DMF was added to half volume, and argon gas was purged for 5 minutes, sealed, and stirred at 80 ° C overnight. The next day, the reaction mixture was washed twice with aqueous ammonia, and the mixture was combined with ethyl acetate.

1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.92 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 8.05 (d, 1H), 7.92 (d, 1H), 7.70( d, 1H), 7.52 (d, 1H), 7.34 (s, 1H), 6.58 (q, 1H), 3.57 (s, 2H), 2.82 (s, 3H), 2.57 (s, 3H), 2.53 (s, 3H), 2.38 (m, 8H), 2.16 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.92 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 8.05 (d, 1H), 7.92 (d , 1H), 7.70( d, 1H), 7.52 (d, 1H), 7.34 (s, 1H), 6.58 (q, 1H), 3.57 (s, 2H), 2.82 (s, 3H), 2.57 (s, 3H), 2.53 (s, 3H), 2.38 (m, 8H), 2.16 (s, 3H).

ESI-MS m/z: [M+H]+ = 576.3。实施例 2 3-((2-氨基 -5-三氟甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 576.3. Example 2 3-((2-Amino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl -N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-氨基 -5-三氟甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备

Step 1 Preparation of 2-amino-5-trifluoromethyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -5-溴 -6-三氟甲基吡啶为原料，按实施例 1步骤 1和步骤 2制备标题化合物。 1H MR (300 MHz, DMSO-d6) δ: 7.77 (d, IH), 7.59 (d, IH), 6.48 (s, 2H)。 The title compound was prepared in the same manner as in Example 1 Step 1 and Step 2 from 2-amino-5-bromo-6-trifluoromethylpyridine. 1H MR (300 MHz, DMSO-d6) δ: 7.77 (d, IH), 7.59 (d, IH), 6.48 (s, 2H).

步骤 2 3-((2-氨基 -5-三氟甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Amino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- Preparation of N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

以 2-氨基 -5-三氟甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制得目标化合物。 2-amino-5-trifluoromethyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4 -(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material to give the title compound.

1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.20 (s, IH), 8.16 (s, IH), 8.07 (d, IH), 8.04 (d, IH), 7.76 (d, IH), 7.74 (d, IH), 7.71 (d, IH), 7.54 (d, IH), 6.61 (s, 2H), 3.57 (s, 2H), 2.73 (s, 3H), 2.40 (m, 8H), 2.18 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.20 (s, IH), 8.16 (s, IH), 8.07 (d, IH), 8.04 (d, IH), 7.76 (d , IH), 7.74 (d, IH), 7.71 (d, IH), 7.54 (d, IH), 6.61 (s, 2H), 3.57 (s, 2H), 2.73 (s, 3H), 2.40 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H]⁺ = 616.4。实施例 3 3-((2-氨基 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H] ⁺ = 616.4. Example 3 3-((2-Amino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-氨基 -6-溴 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备以 2-氨基 -4-甲基 -5-溴吡啶为原料，按实施例 1步骤 1和步骤 2制得标题化合物。 Step 1 Preparation of 2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine Starting from 2-amino-4-methyl-5-bromopyridine, the title compound was obtained according to Step 1 and Step 2 of Example 1.

1H MR (300 MHz, DMSO-d6) δ: 8.88 (s, IH), 7.36 (s, IH), 6.04 (s, 2H), 2.37 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 8.88 (s, IH), 7.36 (s, IH), 6.04 (s, 2H), 2.37 (s, 3H).

ESI-MS m/z: [M+H]+ = 227.1。 ESI-MS m/z: [M+H]+ = 227.1.

步骤 2 3-((2-氨基 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基;)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Amino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- Preparation of [4-((4-methylpiperazin-1-yl;)methyl)-3-trifluoromethylphenyl]benzamide

以 2-氨基 -6-溴 -7-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制得目标化合物。 2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( Starting from 4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure of Step 7 of Example 1.

1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.86 (s, IH), 8.21 (s, IH), 8.15 (s, IH), 8.06 (d, IH), 7.92 (d, IH), 7.71 (d, IH), 7.52 (d, IH), 7.33 (s, IH), 6.13 (s, 2H), 3.58 (s, 2H), 2.58 (s, 6H), 2.40 (m, 8H), 2.19 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.86 (s, IH), 8.21 (s, IH), 8.15 (s, IH), 8.06 (d, IH), 7.92 (d , IH), 7.71 (d, IH), 7.52 (d, IH), 7.33 (s, IH), 6.13 (s, 2H), 3.58 (s, 2H), 2.58 (s, 6H), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H]+ = 562.4。实施例 4 3-((2-氨基 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 562.4. Example 4 3-((2-Amino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-氨基 -6-溴 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-amino-6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -3-甲基 -5-溴吡啶为原料，按实施例 1步骤 1和步骤 2制得标题化合物。 The title compound was obtained according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-3-methyl-5-bromopyridine as the starting material.

步骤 2 3-((2-氨基 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((2-Amino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-methylpiperazine)

-1-基;)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 Preparation of -1-yl;)methyl)-3-trifluoromethylphenyl]benzamide

以 2-氨基 -6-溴 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。

2-amino-6-bromo-8-methyl-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( Starting from 4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure

Ή MR (300 MHz, OMSO-d₆) δ: 10.52 (s, IH), 8.76 (s, IH), 8.21 (s, IH), 8.15 (s, IH), 8.06 (d, IH), 7.91 (d, IH), 7.70 (d, IH), 7.51 (d, IH), 7.42 (s, IH), 6.16 (s, 2H), 3.58 (s, 2H), 3.26 (s, 6H), 2.42 (m, 8H), 2.20 (s, 3H；)。 Ή MR (300 MHz, OMSO-d ₆ ) δ: 10.52 (s, IH), 8.76 (s, IH), 8.21 (s, IH), 8.15 (s, IH), 8.06 (d, IH), 7.91 ( d, IH), 7.70 (d, IH), 7.51 (d, IH), 7.42 (s, IH), 6.16 (s, 2H), 3.58 (s, 2H), 3.26 (s, 6H), 2.42 (m , 8H), 2.20 (s, 3H;).

ESI-MS m/z: [M+H]+ = 562.3。实施例 5 3-((2-氨基 -5-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 562.3. Example 5 3-((2-Amino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-氨基 -5-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-amino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -6-甲基 -5-溴吡啶为原料，按实施例 1步骤 1和步骤 2制得标题化合物。 The title compound was obtained according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-6-methyl-5-bromopyridine as the starting material.

步骤 2 3-((2-氨基 -5-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((2-Amino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-methylpiperazine)

以 2-氨基 -5-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-amino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( Starting from 4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure

1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.21 (s, IH), 8.17 (s, IH), 8.06 (d, IH), 7.91 (d, lH), 7.71 (d, IH), 7.58 (d, IH), 7.52 (s, IH), 7.29 (s, IH), 6.21 (s, 2H), 3.58 (s, 2H), 2.85 (s, 3H), 2.58 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.21 (s, IH), 8.17 (s, IH), 8.06 (d, IH), 7.91 (d, lH), 7.71 (d , IH), 7.58 (d, IH), 7.52 (s, IH), 7.29 (s, IH), 6.21 (s, 2H), 3.58 (s, 2H), 2.85 (s, 3H), 2.58 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H]+ = 562.5。实施例 6 3-((2-二甲氨基 -5-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲 ESI-MS m/z: [M+H]+ = 562.5. Example 6 3-((2-Dimethylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl -N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethyl

以 2-氨基 -6-甲基 -5-溴吡啶为原料，按实施例 1步骤 1和步骤 2的方法制得标题化合物步骤 2 2-二甲氨基 -5-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备

Starting from 2-amino-6-methyl-5-bromopyridine as the starting material, the title compound was obtained according to the procedure of Step 1 and Step 2 of Example 1 Step 2 2-Dimethylamino-5-methyl-6-bromo-[ Preparation of 1,2,4]triazo[1,5-a]pyridine

于 50mL茄形瓶中，在冰浴条件下，加入 2-氨基 -5-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶 (1.06mg， 5mmol)、干燥的 THF 20ml，再加入氢化钠（240mg， lOmmol), 搅拌 15min，再加入 2ml碘甲垸，常温反应 4h。旋干，加入 50ml水，乙酸乙酯萃取（30ml*3 )，柱层析纯化得到标题化合物。 In a 50 mL eggplant-shaped flask, 2-amino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine (1.06 mg, was added under ice bath). 5 mmol), 20 ml of dry THF, sodium hydride (240 mg, 10 mmol) was added, stirred for 15 min, then 2 ml of iodomethyl hydrazide was added and reacted at room temperature for 4 h. The mixture was evaporated to dryness.

步骤 3 3-((2-二甲氨基 -5-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基;)甲基; )-3-三氟甲基苯基]苯甲酰胺的制备 Step 3 3-((2-Dimethylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- Preparation of N-[4-((4-methylpiperazin-1-yl))methyl;)-3-trifluoromethylphenyl]benzamide

以 2-二甲氨基 -5-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-Dimethylamino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4 -(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material.

1H MR (300 MHz, DMS0-d6) δ: 10.53 (s, IH), 8.21 (s, IH), 8.17 (s, IH), 8.06 (d, IH), 7.92 (d, IH), 7.71 (d, IH), 7.64 (d, IH), 7.53 (d, IH), 7.37 (s, IH), 3.57 (s, 2H), 3.31 (s, 3H), 3.08 (s, 3H), 2.88 (s, 3H), 2.58 (s, 3H), 2.39 (m, 8H), 2.18 (s, 3H)。 1H MR (300 MHz, DMS0-d6) δ: 10.53 (s, IH), 8.21 (s, IH), 8.17 (s, IH), 8.06 (d, IH), 7.92 (d, IH), 7.71 (d , IH), 7.64 (d, IH), 7.53 (d, IH), 7.37 (s, IH), 3.57 (s, 2H), 3.31 (s, 3H), 3.08 (s, 3H), 2.88 (s, 3H), 2.58 (s, 3H), 2.39 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H]+ = 590.3。实施例 7 3-((2-二甲氨基 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基 ESI-MS m/z: [M+H]+ = 590.3. Example 7 3-((2-Dimethylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl -N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethyl

步骤 1 2-二甲氨基 -8-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-dimethylamino-8-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -3-甲基 -5-溴吡啶为原料，按照实施例 6步骤 1和步骤 2的方法制备标题化合物。步骤 2 3-((2-二甲氨基 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌 The title compound was prepared according to the procedure of Example 6 Step 1 and Step 2 from 2-amino-3-methyl-5-bromopyridine. Step 2 3-((2-Dimethylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-methylperidine)

以 2-二甲氨基 -8-甲基 -6溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-Dimethylamino-8-methyl-6bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material.

IH MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.87 (s, IH), 8.22 (s, IH), 8.16 (s, IH), 8.07 (d, IH), 7.92 (d, IH), 7.72 (d, IH), 7.53 (d, IH), 7.48 (s, IH), 3.58 (s, 2H), 3.31 (s, 3H), 3.08 (s, 3H), 2.88 (s, 3H), 2.58 (s, 3H), 2.37 (m, 8H), 2.18 (s, 3H)。 IH MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.87 (s, IH), 8.22 (s, IH), 8.16 (s, IH), 8.07 (d, IH), 7.92 (d , IH), 7.72 (d, IH), 7.53 (d, IH), 7.48 (s, IH), 3.58 (s, 2H), 3.31 (s, 3H), 3.08 (s, 3H), 2.88 (s, 3H), 2.58 (s, 3H), 2.37 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H]+ = 590.3。实施例 8 3-((2-甲氨基 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯 ESI-MS m/z: [M+H]+ = 590.3. Example 8 3-((2-Methylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylbenzene

步骤 1 2-甲氨基 -8-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备以 2-氨基 -3-甲基 -5-溴吡啶为原料，按照实施例 1步骤 1-3的方法制备出标题化合物。 1H MR (300 MHz, OMSO-d₆) δ: 8.83-8.79 (m, IH), 7.43 (s, IH), 6.53-6.52 (m, IH), 3.32 (s,

Step 1 Preparation of 2-methylamino-8-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine Starting from 2-amino-3-methyl-5-bromopyridine, the title compound was obtained according to the procedure 1H MR (300 MHz, OMSO-d ₆ ) δ: 8.83-8.79 (m, IH), 7.43 (s, IH), 6.53-6.52 (m, IH), 3.32 (s,

3H), 2.39 (s, 3H)。 3H), 2.39 (s, 3H).

ESI-MS m/z: [M+H]⁺ = 241.0。 ESI-MS m/z: [M+H] ⁺ = 241.0.

步骤 2 3-((2-甲氨基 -8-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((2-Methylamino-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpiperazine)

-1- -1-

以 2-甲氨基 -8-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-Methylamino-8-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.82 (s, IH), 8.21 (s, IH), 8.14 (s, IH), 8.06 (d, IH), 7.91 (d, IH), 7.70( d, IH), 7.51 (d, IH), 7.44 (s, IH), 6.62 (q, IH), 3.57 (s, 2H), 3.26 (s, 3H), 2.84 (d, 3H), 2.56 (d, 3H), 2.41 (m, 8H), 2.18 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, IH), 8.82 (s, IH), 8.21 (s, IH), 8.14 (s, IH), 8.06 (d, IH), 7.91 (d , IH), 7.70( d, IH), 7.51 (d, IH), 7.44 (s, IH), 6.62 (q, IH), 3.57 (s, 2H), 3.26 (s, 3H), 2.84 (d, 3H), 2.56 (d, 3H), 2.41 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H]+ = 576.3。实施例 9 3-((2-氨基 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯 ESI-MS m/z: [M+H]+ = 576.3. Example 9 3-((2-Amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzene

步骤 1 2-氨基 -6-溴 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-amino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -3-氟 -5-溴吡啶为原料，按照实施例 1步骤 1和步骤 2的方法制备出标题化合物。 1H MR (300 MHz, OMSO-d₆) δ: 8.30 (s, IH), 7.27 (dd, IH), 4.58 (m, 2H)。 The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-3-fluoro-5-bromopyridine as the starting material. 1H MR (300 MHz, OMSO-d ₆ ) δ: 8.30 (s, IH), 7.27 (dd, IH), 4.58 (m, 2H).

步骤 2 3-((2-氨基 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1- 基;)甲基; )-3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[ Preparation of 4-((4-methylpiperazin-1-yl;)methyl; )-3-trifluoromethylphenyl]benzamide

以 2-氨基 -6-溴 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-amino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4 The title compound was prepared according to the procedure of Step 7 of Example 1 using m.p.p.

1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.88 (s, IH), 8.19 (s, IH), 8.14 (s, IH), 8.05 (d, IH), 7.91 (d, IH), 7.69 (d, IH), 7.64 (d, IH), 7.51 (d, IH), 6.44 (s, 2H), 3.57 (s, 2H), 2.73 (s, 3H), 2.40 (m, 8H), 2.25 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.88 (s, IH), 8.19 (s, IH), 8.14 (s, IH), 8.05 (d, IH), 7.91 (d , IH), 7.69 (d, IH), 7.64 (d, IH), 7.51 (d, IH), 6.44 (s, 2H), 3.57 (s, 2H), 2.73 (s, 3H), 2.40 (m, 8H), 2.25 (s, 3H).

ESI-MS m/z: [M+H]+ = 566.4。实施例 10 3-((2-甲氨基 -5-三氟甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4- 甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基苯甲酰胺 ESI-MS m/z: [M+H]+ = 566.4. Example 10 3-((2-Methylamino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-A --N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenylbenzamide

步骤 1 2-甲氨基 -5-三氟甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-methylamino-5-trifluoromethyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -5-溴 -6-三氟甲基吡啶为原料，按照实施例 1步骤 1-3的方法制备出标题产物。 1H MR (500 MHz, DMSO-^) δ ： 7.79-7.77(m, IH), 7.63-7.61 (m, IH), 6.91 (s, IH), 2.85 (s_: Starting from 2-amino-5-bromo-6-trifluoromethylpyridine, the title product was obtained according to the procedure of Step 1-3 of Example 1. 1H MR (500 MHz, DMSO-^) δ : 7.79-7.77 (m, IH), 7.63-7.61 (m, IH), 6.91 (s, IH), 2.85 (s _:

3H 3H

ESI-MS m/z: [M+H]⁺ = 296.0。 ESI-MS m/z: [M+H] ⁺ = 296.0.

步骤 2 3-((2-甲氨基 -5-三氟甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基;)甲基; )-3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Methylamino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl Preparation of -N-[4-((4-methylpiperazin-1-yl;)methyl;)-3-trifluoromethylphenyl]benzamide

以 2-甲氨基 -5-三氟甲基 -6-溴 [1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。

2-methylamino-5-trifluoromethyl-6-bromo[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4 -(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material.

1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.20 (d, IH), 8.16 (d, IH), 8.05 (d, IH), 7.96 (dd, IH), 7.77 (dd, 2H), 7.71 (d, IH), 7.54 (d, IH), 7.02 (q, IH), 3.58 (s, 2H), 2.87 (d, 3H), 2.55 (s, 3H), 2.41 (m, 8H), 2.21 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.20 (d, IH), 8.16 (d, IH), 8.05 (d, IH), 7.96 (dd, IH), 7.77 (dd , 2H), 7.71 (d, IH), 7.54 (d, IH), 7.02 (q, IH), 3.58 (s, 2H), 2.87 (d, 3H), 2.55 (s, 3H), 2.41 (m, 8H), 2.21 (s, 3H).

ESI-MS m/z: [M+H]+ = 630.3。实施例 11 3-((2-氨基 -8-甲氨基甲酰基 [1,2,4]三氮唑并 [1,5-a]吡啶 -6-基）乙炔基 )-4-甲基 __N_[₄_((4_甲基哌噪基)甲 _₃_三氟甲基苯基〗苯甲醜胺 ESI-MS m/z: [M+H]+ = 630.3. Example 11 3-((2-Amino-8-methylcarbamoyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl_ _N _[ ₄ _((4_methylpipeno)-methyl- ₃ _trifluoromethylphenyl benzyl amide

步骤 1 2-氨基 -6-溴 -8-甲氨基甲酰基 [1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-amino-6-bromo-8-methylcarbamoyl [1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -5-溴 -N-甲基烟酰胺为原料，按照实施例 1步骤 1和步骤 2的方法制备出标题化合物。 The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-5-bromo-N-methylnicotinamide as the starting material.

步骤 2 3-((2-氨基 -8-甲氨基甲酰基 [1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4- 甲基哌嗪 -1-基;)甲基; )-3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Amino-8-carbamoyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl;)methyl;)-3-trifluoromethylphenyl]benzamide

以 2-氨基 -6-溴 -8-甲氨基甲酰基 [1,2,4]三氮唑并 [1,5-a]吡啶]吡啶和 3-乙炔基 -4-甲基 -_N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-amino-6-bromo-8-carbamoyl[1,2,4]triazolo[1,5-a]pyridine]pyridine and 3-ethynyl-4-methyl- _N- [ Starting from 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure

1H MR (300 MHz, DMSO-d6) δ: 10.51 (s, IH), 9.17 (d, 2H), 8.20 (s, 2H), 8.14 (s, IH), 8.06 (d, IH), 7.93 (d, IH), 7.71 (d, IH), 7.52 (d, IH), 6.63 (s, 2H), 3.57 (s, 2H), 2.95 (d, 3H), 2.58 (s, 3H), 2.40 (m, 8H), 2.17 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.51 (s, IH), 9.17 (d, 2H), 8.20 (s, 2H), 8.14 (s, IH), 8.06 (d, IH), 7.93 (d , IH), 7.71 (d, IH), 7.52 (d, IH), 6.63 (s, 2H), 3.57 (s, 2H), 2.95 (d, 3H), 2.58 (s, 3H), 2.40 (m, 8H), 2.17 (s, 3H).

ESI-MS m/z: [M+H]+ = 605.5。实施例 12 3-((2-氨基 -7-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 605.5. Example 12 3-((2-Amino-7-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-氨基 -6-溴 -7-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-amino-6-bromo-7-chloro-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -4-氯 -5-溴为原料，按照实施例 1步骤 1和步骤 2的方法制备出标题化合物。 The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-4-chloro-5-br.

1H MR (300 MHz, DMSO-d6) δ: 7.25 (t, 2H), 7.17 (d, 2H)。 1H MR (300 MHz, DMSO-d6) δ: 7.25 (t, 2H), 7.17 (d, 2H).

步骤 2 3-((2-氨基 -7-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1- 基;)甲基; )-3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Amino-7-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[ Preparation of 4-((4-methylpiperazin-1-yl;)methyl; )-3-trifluoromethylphenyl]benzamide

以 2-氨基 -6-溴 -7-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-amino-6-bromo-7-chloro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4 The target compound was prepared by the method of Step 7 of Example 1 using m-methylpiperazin-1-ylmethyl-3-trifluoromethylphenyl]benzamide as a starting material.

1H MR (300 MHz, DMSO-d6) δ: 10.55 (s, IH), 9.09 (s, IH), 8.20 (d, IH), 8.16 (s, IH), 8.06 (d, IH), 7.94 (d, IH), 7.72 (s, IH), 7.71 (s, IH), 7.53 (d, IH), 6.36 (s, 2H), 3.57 (s, 2H), 2.58 (s, 3H) 2.35 (s, 3H), 2.31 (m, 8H)。 1H MR (300 MHz, DMSO-d6) δ: 10.55 (s, IH), 9.09 (s, IH), 8.20 (d, IH), 8.16 (s, IH), 8.06 (d, IH), 7.94 (d , IH), 7.72 (s, IH), 7.71 (s, IH), 7.53 (d, IH), 6.36 (s, 2H), 3.57 (s, 2H), 2.58 (s, 3H) 2.35 (s, 3H) ), 2.31 (m, 8H).

ESI-MS m/z: [M+H]+ = 582.2。实施例 13 3-((2-甲氨基 -5-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺

ESI-MS m/z: [M+H]+ = 582.2. Example 13 3-((2-Methylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-甲氨基 -5-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-methylamino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -5-溴 -6-甲基为原料，按照实施例 1步骤 1-3的方法合成标题产物。 The title product was synthesized according to the procedure of Step 1-3 of Example 1 using 2-amino-5-bromo-6-methyl as the starting material.

ESI-MS m/z: [M+H]⁺ = 241.6。 ESI-MS m/z: [M+H] ⁺ = 241.6.

步骤 2 3-((2-甲氨基 -5-甲基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((2-Methylamino-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpiperazine)

以 2-甲氨基 -5-甲基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-methylamino-5-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.21 (s, IH), 8.18 (s, IH), 8.07 (d, IH), 7.92 (d, IH), 7.71 (d, IH), 7.61 (d, IH), 7.53 (d, IH), 7.33 (d, IH), 6.69 (m, IH), 3.58 (s, 2H), 2.87 (m, 6H), 2.58 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.21 (s, IH), 8.18 (s, IH), 8.07 (d, IH), 7.92 (d, IH), 7.71 (d , IH), 7.61 (d, IH), 7.53 (d, IH), 7.33 (d, IH), 6.69 (m, IH), 3.58 (s, 2H), 2.87 (m, 6H), 2.58 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H]+ = 576.3。实施例 14 3-((2-氨基 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 576.3. Example 14 3-((2-Amino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-氨基 -6-溴 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-amino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -3-氯 -5-溴吡啶为原料，按照实施例 1步骤 1和步骤 2的方法制备出标题化合物。 1H MR (300 MHz, DMSO-d6) δ: 8.38 (s, IH), 7.59 (s, IH), 4.67 (m, 2H)。 The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 using 2-amino-3-chloro-5-bromopyridine as the starting material. 1H MR (300 MHz, DMSO-d6) δ: 8.38 (s, IH), 7.59 (s, IH), 4.67 (m, 2H).

步骤 2 3-((2-氨基 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1- Step 2 3-((2-Amino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[ 4-((4-methylpiperazin-1-

以 2-氨基 -6-溴 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-amino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4 The title compound was prepared according to the procedure of Step 7 of Example 1 using m.p.p.

1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.96 (s, IH), 8.21 (s, IH), 8.16 (d, IH), 8.08 (d, IH), 7.93 (d, IH), 7.84 (d, IH), 7.71 (d, IH), 7.52 (d, IH), 6.45 (s, 2H), 3.62 (s, 2H), 2.57 (s, 3H), 2.45 (m, 8H), 1.75 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.96 (s, IH), 8.21 (s, IH), 8.16 (d, IH), 8.08 (d, IH), 7.93 (d , IH), 7.84 (d, IH), 7.71 (d, IH), 7.52 (d, IH), 6.45 (s, 2H), 3.62 (s, 2H), 2.57 (s, 3H), 2.45 (m, 8H), 1.75 (s, 3H).

ESI-MS m/z: [M+H]+ = 582.1。实施例 15 3-((2-二甲氨基 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基 ESI-MS m/z: [M+H]+ = 5821. Example 15 3-((2-Dimethylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl- N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethyl

以 2-氨基 -3-氟 -5-溴吡啶为原料，按照实施例 1的步骤 1-2的方法制备出标题化合物。步骤 2 2-二甲氨基 - -溴 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备

Starting from 2-amino-3-fluoro-5-bromopyridine, the title compound was obtained according to the procedure Step 2 Preparation of 2-dimethylamino-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

在干燥的 100 ml两口烧瓶中，加入化合物 2-氨基 -6-溴 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶 (160 mg, 0.69 mmol), 氢化钠（ 138 mg, 3.47 mmol ) 和四氢呋喃（10 mL) 。反应体系在氮气保护条件下 0°C，反应 30分钟。然后，碘甲垸（199 mg, 1.38 mmol) 溶在四氢呋喃（10 mL) 分批滴加到上述反应液中，室温搅拌 12h。 TLC检测。冰浴条件下，加入甲醇淬灭过量的氢化钠，浓缩。加入水（20 ml ) ，用 IN稀盐酸调节 pH到 7，乙酸乙酯（50 ml )三次，浓缩，干燥，过滤，柱层析纯化得到标题化合物。 In a dry 100 ml two-necked flask, the compound 2-amino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine (160 mg, 0.69 mmol) was added. Sodium hydride (138 mg, 3.47 mmol) and tetrahydrofuran (10 mL). The reaction system was reacted at 0 ° C under nitrogen for 30 minutes. Then, iodoformamidine (199 mg, 1.38 mmol) was dissolved in tetrahydrofuran (10 mL), and the mixture was added dropwise to the mixture, and stirred at room temperature for 12 h. TLC detection. Excessive hydrogenation was quenched by adding methanol under ice bath Sodium, concentrated. Water (20 ml) was added, EtOAc (EtOAc m.

1H MR (500 MHz, OMSO-d₆) δ 8.95 ( s, IH), 7.78 (d, IH), 3.04 (s, 6H)。 1H MR (500 MHz, OMSO-d ₆ ) δ 8.95 ( s, IH), 7.78 (d, IH), 3.04 (s, 6H).

步骤 3 3-((2-二甲氨基 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基;)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 Step 3 3-((2-Dimethylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl;)methyl)-3-trifluoromethylphenyl]benzamide

以 2-二甲氨基 -6-溴 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-Dimethylamino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4- (4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide was used as a starting material, and the title compound was obtained according to the procedure of Step 7 of Example 1.

1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, lH), 8.97 (s, IH), 8.20 (s, IH), 8.15 (d, IH), 8.05 (d, IH), 7.93 (d, IH), 7.70 (d, IH), 7.68 (d, IH), 7.52 (d, IH), 3.57 (s, 2H), 3.25 (s, 3H), 3.08 (s, 3H), 2.56 (s, 3H), 2.40 (m, 8H), 2.18 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.52 (s, lH), 8.97 (s, IH), 8.20 (s, IH), 8.15 (d, IH), 8.05 (d, IH), 7.93 (d , IH), 7.70 (d, IH), 7.68 (d, IH), 7.52 (d, IH), 3.57 (s, 2H), 3.25 (s, 3H), 3.08 (s, 3H), 2.56 (s, 3H), 2.40 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H]+ = 594.3。实施例 16 3-((2-甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1- 基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 594.3. Example 16 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[4- ((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-甲氨基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-methylamino-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -5-溴吡啶为原料，按照实施例 1步骤 1-3的方法制备出标题化合物。 The title compound was prepared according to the procedure of Step 1-3 of Example 1 from 2-amino-5-bromopyridine.

1H MR (300 MHz, DMSO-d6) δ: 8.95 (d, IH), 7.56 (dd, IH), 7.34 (d, IH), 6.54 (d, IH), 2.81 1H MR (300 MHz, DMSO-d6) δ: 8.95 (d, IH), 7.56 (dd, IH), 7.34 (d, IH), 6.54 (d, IH), 2.81

(d, 3H) ₀ (d, 3H) ₀

ESI-MS m/z: [M+H]⁺ = 227.2。 ESI-MS m/z: [M+H] ⁺ = 227.2.

步骤 2 3-((2-甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基) 甲基; )-3-三氟甲基苯基]苯甲酰胺的制备

Step 2 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpiperazin-1-yl)methyl; )-3-trifluoromethylphenyl]benzamide

以 2-甲氨基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-methylamino-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methyl The title compound was prepared according to the method of Step 7 of Example 1 using piazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H MR (300 MHz, DMSO-d6) δ: 10.52( s, IH), 8.99 (s, IH), 8.21 (s, IH), 8.16 (d, IH), 8.06 (d, IH), 7.92 (d, IH), 7.71 (d, IH), 7.60 (d, IH), 7.52 (d, IH), 7.42 (d, IH), 6.64 (m, IH), 3.57 (s, 2H), 2.86 (dd, 3H), 2.56 (s, 3H), 2.37 (m, 8H), 2.16 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.52 ( s, IH), 8.99 (s, IH), 8.21 (s, IH), 8.16 (d, IH), 8.06 (d, IH), 7.92 (d , IH), 7.71 (d, IH), 7.60 (d, IH), 7.52 (d, IH), 7.42 (d, IH), 6.64 (m, IH), 3.57 (s, 2H), 2.86 (dd, 3H), 2.56 (s, 3H), 2.37 (m, 8H), 2.16 (s, 3H).

ESI-MS m/z: [M+H]+ = 562.2。实施例 17 3-((2-甲氨基 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 562.2. Example 17 3-((2-Methylamino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-甲氨基 -6-溴 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-methylamino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -3-氯 -5-溴吡啶为原料，按照实施例 1步骤 3的方法制备出标题化合物。 The title compound was prepared according to the procedure of Example 1 Step 3 using 2-amino-3-chloro-5-bromopyridine.

1H MR (300 MHz, DMSO-d6) δ: 9.00 (s, IH), 7.88 (s, IH), 6.81 (s, IH), 2.82 (d, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 9.00 (s, IH), 7.88 (s, IH), 6.81 (s, IH), 2.82 (d, 3H).

ESI-MS m/z: [M+H]⁺ = 260.9。 ESI-MS m/z: [M+H] ⁺ = 260.9.

步骤 2 3-((2-甲氨基 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((2-Methylamino-8-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-methylpiperazine)

以 2-甲氨基 -6-溴 -8-氯 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-methylamino-6-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( Starting from 4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure

1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.20 (s, IH), 8.15 (s, IH), 8.06 (d, IH), 7.93 (d, IH), 7.73 (d, IH), 7.68 (d, IH), 7.62 (d, IH), 7.52 (d, IH), 6.94 (m, IH), 3.57 (s, 2H), 2.86 (s, 3H), 2.73 (s, 3H), 2.37 (m, 8H), 2.18 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.20 (s, IH), 8.15 (s, IH), 8.06 (d, IH), 7.93 (d, IH), 7.73 (d , IH), 7.68 (d, IH), 7.62 (d, IH), 7.52 (d, IH), 6.94 (m, IH), 3.57 (s, 2H), 2.86 (s, 3H), 2.73 (s, 3H), 2.37 (m, 8H), 2.18 (s, 3H).

ESI-MS m/z: [M+H]+ = 596.2。实施例 18 3-((2-甲氨基 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基 ESI-MS m/z: [M+H]+ = 596.2. Example 18 3-((2-Methylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethyl

步骤 1 2-甲氨基 -6-溴 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-methylamino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -3-氟 -5-溴吡啶为原料，按照实施 1步骤 1-3的方法制备出标题化合物。 Starting from 2-amino-3-fluoro-5-bromopyridine, the title compound was obtained according to the procedure of 1 to 1-3.

IH MR (300 MHz, DMSO-d6) δ: 8.34 (s, IH), 7.37-7.35 (m, IH), 3.49 (s, 1H)， 3.06 (s, 3H)₀ IH MR (300 MHz, DMSO-d6) δ: 8.34 (s, IH), 7.37-7.35 (m, IH), 3.49 (s, 1H), 3.06 (s, 3H) ₀

ESI-MS m/z: [M+H]+ = 245.0。 ESI-MS m/z: [M+H]+ = 245.0.

步骤 2 3-((2-甲氨基 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((2-Methylamino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- [4-((4-methylpiperazine)

-1-基；)甲基; )-3-三氟甲基苯基]苯甲酰胺

-1-yl;)methyl; )-3-trifluoromethylphenyl]benzamide

以 2-甲氨基 -6-溴 -8-氟 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-methylamino-6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-( Starting from 4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure

1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.94 (s, 1H), 8.20 (s, 1H), 8.16 (d, 1H), 8.06 (d, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.66 (d, 1H), 7.52 (d, 1H), 6.87 (m, 1H), 3.57 (s, 2H), 2.85 (d, 3H), 2.56 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.94 (s, 1H), 8.20 (s, 1H), 8.16 (d, 1H), 8.06 (d, 1H), 7.93 (d , 1H), 7.71 (d, 1H), 7.66 (d, 1H), 7.52 (d, 1H), 6.87 (m, 1H), 3.57 (s, 2H), 2.85 (d, 3H), 2.56 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H]+ = 580.2。实施例 19 3-((2-异丙基氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟 ESI-MS m/z: [M+H]+ = 580.2. Example 19 3-((2-Isopropylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[ 4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoro

步骤 1 2-氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -4-溴吡啶为原料，按照实施 1步骤 1和步骤 2的方法制备出标题化合物。 The title compound was prepared by the procedure of Step 1 and Step 2 using 2-amino-4-bromopyridine as the starting material.

步骤 2 2-异丙基氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备

Step 2 Preparation of 2-isopropylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

在干燥的 50 ml 两口烧瓶中，加入 2-氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶 (300 mg, 1.4 mmol), 钠氢（280 mg, 7.0 mmol, 质量分数 60% ) 禾 P DMF ( 5 ml ) 。反应体系在氮气保护条件下 10°C，反应 1小时。然后，异丙基溴（512 mg, 4.2 mmol )分批滴加到上述反应液中，室温搅拌 2h。 TLC检测。反应液倒入到冰水中，乙酸乙酯萃取（50 ml )三次，浓缩，干燥，过滤，柱层析纯化得到标题化合物。 In a dry 50 ml two-necked flask, 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (300 mg, 1.4 mmol), sodium hydrogen (280 mg) , 7.0 mmol, mass fraction 60%) Wo P DMF (5 ml). The reaction system was reacted at 10 ° C under nitrogen gas for 1 hour. Then, isopropyl bromide (512 mg, 4.2 mmol) was added dropwise to the above reaction mixture in portions and stirred at room temperature for 2 h. TLC detection. The reaction mixture was poured into EtOAc (EtOAc)EtOAc.

1H MR (300 MHz, OMSO-d₆) δ: 8.53 (d, 1H), 7.67 (d, 1H), 7.01 (dd, 1H), 6.53 (d, 1H), 3.82-3.73 (m, 1H), 1.16 (d, 6H)。 1H MR (300 MHz, OMSO-d ₆ ) δ: 8.53 (d, 1H), 7.67 (d, 1H), 7.01 (dd, 1H), 6.53 (d, 1H), 3.82-3.73 (m, 1H), 1.16 (d, 6H).

ESI-MS m/z: [M+H]+ = 255.0。 ESI-MS m/z: [M+H]+ = 255.0.

步骤 3 3-((2-异丙基氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1- 基;)甲基; )-3-三氟甲基苯基]苯甲酰胺的制备

Step 3 3-((2-Isopropylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4 -((4-Methylpiperazin-1-yl;)methyl;)-3-trifluoromethylphenyl]benzamide

以 2-异丙基氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-isopropylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4- The title compound was prepared according to the method of Step 7 of Example 1 using methylpiperazine-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.63 (d, IH), 8.20 (s, 2H), 8.06 (d, IH), 7.94 (d, IH), 7.71 (d, IH), 7.62 (s, IH), 7.53 (d, IH), 7.01 (d, IH), 6.57 (d, IH), 3.85 (m, IH), 3.57 (s, 2H), 2.57 (s, 3H), 2.39 (m, 8H), 2.17 (s, 3H), 1.18 (s, 6H)。 1H MR (300 MHz, DMSO-d6) δ: 10.54 (s, IH), 8.63 (d, IH), 8.20 (s, 2H), 8.06 (d, IH), 7.94 (d, IH), 7.71 (d , IH), 7.62 (s, IH), 7.53 (d, IH), 7.01 (d, IH), 6.57 (d, IH), 3.85 (m, IH), 3.57 (s, 2H), 2.57 (s, 3H), 2.39 (m, 8H), 2.17 (s, 3H), 1.18 (s, 6H).

ESI-MS m/z: [M+H]+ = 590.2。 ESI-MS m/z: [M+H]+ = 590.2.

实施例 20 3-((2-甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -5-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 Example 20 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethynyl)-4-methyl-N-[4- ((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 2-甲氨基 -5-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-methylamino-5-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -6-溴吡啶为原料，按照实施 1步骤 1-3的方法制备出标题化合物。 Starting from 2-amino-6-bromopyridine, the title compound was obtained according to the procedure of 1 to 1-3.

ESI-MS m/z: [M+H]⁺ = 227.0。 ESI-MS m/z: [M+H] ⁺ = 227.0.

步骤 2 3-((2-甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -5-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基) 甲基; )-3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpiperazin-1-yl)methyl; )-3-trifluoromethylphenyl]benzamide

以 2-甲氨基 -5-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三。 2-methylamino-5-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methyl Piperazin-1-ylmethyl)-3-tri.

1H MR (300 MHz, DMSO-d6) δ: 10.58 (s, IH), 8.25 (s, IH), 8.21 (d, IH), 8.06 (d, IH), 8.02 (d, IH), 7.72 (d, IH), 7.58 (d, IH), 7.48 (d, 2H), 7.27 (d, IH), 6.61 (m, IH), 3.58 (s, 2H), 2.88 (dd, 3H), 2.68 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.58 (s, IH), 8.25 (s, IH), 8.21 (d, IH), 8.06 (d, IH), 8.02 (d, IH), 7.72 (d , IH), 7.58 (d, IH), 7.48 (d, 2H), 7.27 (d, IH), 6.61 (m, IH), 3.58 (s, 2H), 2.88 (dd, 3H), 2.68 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H]+ = 562.3。 ESI-MS m/z: [M+H]+ = 562.3.

实施例 21 3-((2-甲氨基- [1,2,4]三氮唑并 [1,5-a]吡啶 -8-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1- 基)甲基) -3-三氟甲基苯基]

Example 21 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethynyl)-4-methyl-N-[4- ((4-methylpiperazine-1- Methyl)-3-trifluoromethylphenyl]

步骤 1 2-甲氨基 -8-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-methylamino-8-bromo-[1,2,4]triazolo[1,5-a]pyridine

以 2-氨基 -3-溴吡啶为原料，按照实施 1步骤 1至步骤 3的方法制备出标题化合物。 The title compound was prepared by the procedure of Step 1 to Step 3 using 2-amino-3-bromopyridine as a starting material.

1H MR (300 MHz, OMSO-d₆) δ: 8.62 (d, IH), 7.73 (d, IH), 6.82-6.77 (m, IH), 6.69-6.67 (m, IH), 2.82 (d, 3H)。 1H MR (300 MHz, OMSO-d ₆ ) δ: 8.62 (d, IH), 7.73 (d, IH), 6.82-6.77 (m, IH), 6.69-6.67 (m, IH), 2.82 (d, 3H ).

ESI-MS m/z: [M+H]⁺ = 227.0。 ESI-MS m/z: [M+H] ⁺ = 227.0.

步骤 2 3-((2-甲氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -8-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基) 甲基; )- -三氟甲基苯基]苯甲酰胺的制备

Step 2 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpiperazin-1-yl)methyl; )--trifluoromethylphenyl]benzamide

以 2-甲氨基 -8-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-methylamino-8-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methyl The title compound was prepared according to the method of Step 7 of Example 1 using the the the the

1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.68 (d, IH), 8.21 (s, IH), 8.18 (d, IH), 8.06 (d, IH), 7.94 (d, IH), 7.73 (s, IH), 7.70 (s, IH), 7.54 (d, IH), 6.93 (d, IH), 6.68 (m, IH), 3.57 (s, 2H), 2.85 (d, 3H), 2.61 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.68 (d, IH), 8.21 (s, IH), 8.18 (d, IH), 8.06 (d, IH), 7.94 (d , IH), 7.73 (s, IH), 7.70 (s, IH), 7.54 (d, IH), 6.93 (d, IH), 6.68 (m, IH), 3.57 (s, 2H), 2.85 (d, 3H), 2.61 (s, 3H), 2.40 (m, 8H), 2.19 (s, 3H).

ESI-MS m/z: [M+H]+ = 562.3。实施例 22 3-((2-(2,2,2-三氟乙酰氨基)咪唑并 [1,2-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 562.3. Example 22 3-((2-(2,2,2-Trifluoroacetamido)imidazo[1,2-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4- ((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

在一个 50 mL圆底烧瓶中加入 2-氨基 -4-溴吡啶 (1.72 g， lO mmol), 吡啶（5 mL), 冰浴下缓慢滴加对甲苯磺酰氯（2.29 g, 12 mmol ) ，升温至 90°C，反应 6h, 加入水，乙酸乙酯萃取，硅胶柱层析得到标题化合物。 2-Amino-4-bromopyridine (1.72 g, 10 mmol), pyridine (5 mL) was added to a 50 mL round bottom flask, and p-toluenesulfonyl chloride (2.29 g, 12 mmol) was slowly added dropwise in an ice bath. The mixture was reacted to EtOAc (EtOAc).

步骤 2 2-(4-溴 -2对甲苯磺酰亚胺基吡啶 -1(2H)-基)乙酰胺的制备

Step 2 Preparation of 2-(4-bromo-2p-toluenesulfonimidopyridine-1(2H)-yl)acetamide

在 25 mL圆底烧瓶中加入 2-对甲苯磺酰氨基 -4-溴吡啶 (327 mg, 1.0 mmol), DMF (5 Ml), 2- 溴乙酰胺（152 mg, 1.1 mmol) 以及二异丙基乙基胺（ 142 mg, 1.1 mmol), 室温反应 24h。加入水，乙酸乙酯萃取，无水硫酸钠干燥，硅胶柱层析得到标题化合物。 Add 2-p-toluenesulfonylamino-4-bromopyridine (327 mg, 1.0 mmol), DMF (5 Ml), 2-bromoacetamide (152 mg, 1.1 mmol) and diisopropyl in a 25 mL round bottom flask. Base ethylamine (142 mg, 1.1 mmol), reacted at room temperature for 24 h. Water was added, and the mixture was evaporated.

步骤 3 2-(2,2,2-三氟乙酰氨基 )-7-溴-咪唑并 [1,2-a]吡啶 Step 3 2-(2,2,2-Trifluoroacetamido)-7-bromo-imidazo[1,2-a]pyridine

在 25 mL圆底烧瓶中加入 2-(4-溴 -2对甲苯磺酰亚胺基吡啶 -1(2H)-基）乙酰胺 (385 mg, 1.0 mmol), 三氟乙酸酐 (2.10 g, 10 mmol), 以及二氯甲垸（5 mL)，回流 2h, TLC监控反应完毕，冰浴下加入水，二氯甲垸萃取 3次，合并有机相，饱和碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，硅胶柱层析得到标题化合物。 In a 25 mL round bottom flask was added 2-(4-bromo-2p-toluenesulfonimidopyridine-1(2H)-yl)acetamide (385 mg, 1.0 mmol), trifluoroacetic acid anhydride (2.10 g, 10 mmol), and dichloromethane (5 mL), reflux for 2 h, TLC monitoring reaction was completed, water was added to the ice bath, and the mixture was extracted three times with chloroform, and the organic phase was combined, washed with saturated sodium hydrogen carbonate and saturated brine. Drying over anhydrous sodium sulfate and silica gel column chromatography

1H MR (300 MHz, DMSO-d6) δ: 12.51 (s, IH), 8.57 (d, IH), 8.28 (s, IH), 7.85 (s, IH), 7.14 (dd, 1H)₀ 1H MR (300 MHz, DMSO-d6) δ: 12.51 (s, IH), 8.57 (d, IH), 8.28 (s, IH), 7.85 (s, IH), 7.14 (dd, 1H) ₀

ESI-MS m/z: [M+H]⁺ = 329.9。 ESI-MS m/z: [M+H] ⁺ = 329.9.

步骤 4 3-((2-(2,2,2-三氟乙酰胺氨基)咪唑并 [1,2-a]吡嗪 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基；)甲基; )-3-三氟甲基苯基]苯甲酰胺 Step 4 3-((2-(2,2,2-Trifluoroacetamideamino)imidazo[1,2-a]pyrazin-7-yl)ethynyl)-4-methyl-N-[4 -((4-methylpiperazin-1-yl;)methyl; )-3-trifluoromethylphenyl]benzamide

以 2-(2,2,2-三氟乙酰氨基 )-7-溴-咪唑并 [1,2-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-(2,2,2-Trifluoroacetamido)-7-bromo-imidazo[1,2-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-A The target compound was prepared according to the method of Step 7 of Example 1, using pipiperazine-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

1H MR (300 MHz, DMSO-d6) δ: 10.50 (s, IH), 8.63 (d, IH), 8.31 (s, IH), 8.17 (s, 2H), 8.03 (d, IH), 7.91 (d, IH), 7.78 (d, IH), 7.69 (s, IH), 7.67 (s, IH), 7.50 (d, IH), 7.07 (d, IH), 3.54 (s, 2H), 2.55 (s, 3H), 2.36 (m, 8H), 2.16 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.50 (s, IH), 8.63 (d, IH), 8.31 (s, IH), 8.17 (s, 2H), 8.03 (d, IH), 7.91 (d , IH), 7.78 (d, IH), 7.69 (s, IH), 7.67 (s, IH), 7.50 (d, IH), 7.07 (d, IH), 3.54 (s, 2H), 2.55 (s, 3H), 2.36 (m, 8H), 2.16 (s, 3H).

ESI-MS m/z: [M+H]+ =643.3。 ESI-MS m/z: [M+H]+ = 643.3.

实施例 23 3-((2-乙酰氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟 Example 23 3-((2-Acetylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4- ((4-methylperidazole) Pyrazin-1-yl)methyl)-3-trifluoro

以 2-氨基 -4-溴吡啶为原料，按照实施例 1步骤 1和步骤 2的方法制备出标题化合物。步骤 2 2-乙酰氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 from 2-amino-4-bromopyridine. Step 2 Preparation of 2-Acetylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

在干燥的 50 ml两口烧瓶中，加入化合物 2-氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶 (213 mg, lmmol)和乙酸酐（10 ml) ，接着加入吡啶 (118mg， 1.5mmol)。反应体系 85 °C回流，反应过夜。 TLC检测，反应液浓缩，乙酸乙酯 /水萃取，有机层干燥，柱层析纯化得到标题化合物。 In a dry 50 ml two-necked flask, the compound 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (213 mg, 1 mmol) and acetic anhydride (10 ml) were added. Then, pyridine (118 mg, 1.5 mmol) was added. The reaction system was refluxed at 85 ° C and the reaction was carried out overnight. The title compound was obtained by EtOAc (EtOAc).

ESI-MS m/z: [M+H]+ = 255.0。 ESI-MS m/z: [M+H]+ = 255.0.

步骤 3 3-((2-乙酰氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1- 基 -3-三氟甲基苯基]苯甲酰胺的制备

Step 3 3-((2-Acetylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpiperazin-1-yl-3-trifluoromethylphenyl)benzamide

以 2-乙酰氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-Acetylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methyl The title compound was prepared according to the method of Step 7 of Example 1 using the the the the

IH MR (300 MHz, DMS0-d6) δ: 10.84 (s, IH), 10.54 (s, IH), 8.90 (d, IH), 8.22 (d, IH), 8.21 (d, IH), 8.07 (d, IH), 7.98 (d, IH), 7.97 (s, IH), 7.71 (d, IH), 7.55 (s, IH), 7.27 (dd, IH), 3.58 (s, 2H), 2.60 (s, 3H), 2.41 (m, 8H), 2.19 (s, 3H), 2.16 (s, 3H)。 IH MR (300 MHz, DMS0-d6) δ: 10.84 (s, IH), 10.54 (s, IH), 8.90 (d, IH), 8.22 (d, IH), 8.21 (d, IH), 8.07 (d , IH), 7.98 (d, IH), 7.97 (s, IH), 7.71 (d, IH), 7.55 (s, IH), 7.27 (dd, IH), 3.58 (s, 2H), 2.60 (s, 3H), 2.41 (m, 8H), 2.19 (s, 3H), 2.16 (s, 3H).

ESI-MS m/z: [M+H]+ = 590.3。实施例 24 3-((2-甲磺酰氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲

ESI-MS m/z: [M+H]+ = 590.3. Example 24 3-((2-Methanesulfonylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)ethynyl)-4-methyl-N-[ 4-((4-Methylpiperazin-1-yl)methyl)-3-trifluoromethyl

以 2-氨基 -4-溴吡啶为原料，按照实施例 1步骤 1和步骤 2的方法制备出标题化合物。步骤 2 2-甲磺酰氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 The title compound was prepared according to the procedure of Step 1 and Step 2 of Example 1 from 2-amino-4-bromopyridine. Step 2 Preparation of 2-methanesulfonylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine

在干燥的 100 mL两口烧瓶中，先加入 THF(5 mL), 然后加入化合物 2-氨基 -7-溴 -[1,2,4] 三氮唑并 [1,5-a]吡啶 (213 mg, 100 mmol), 甲磺酰氯（3 ml), 吡啶（5 mL)。室温反应 24小时。 TLC检测原料消失。加入水（10 ml)，二氯甲垸（20 ml) 萃取三次，浓缩，干燥，过滤，柱层析纯化得标题化合物。 In a dry 100 mL two-necked flask, THF (5 mL) was added first, followed by the addition of the compound 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine (213 mg , 100 mmol), methanesulfonyl chloride (3 ml), pyridine (5 mL). The reaction was carried out at room temperature for 24 hours. The TLC detected the disappearance of the raw materials. Add water (10 ml), dichloromethane (20 ml), extract three times, concentrate, dry, filter, column Chromatography to give the title compound.

1H MR (300 MHz, DMSO-d6) δ: 9.01 (d, IH), 8.35 (s, IH), 7.58 (dd, IH), 3.68 (s, 3H)。步骤 3 3-((2-甲磺酰氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -7-基；)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基;)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 1H MR (300 MHz, DMSO-d6) δ: 9.01 (d, IH), 8.35 (s, IH), 7.58 (dd, IH), 3.68 (s, 3H). Step 3 3-((2-Methanesulfonylamino-[1,2,4]triazolo[1,5-a]pyridin-7-yl;)ethynyl)-4-methyl-N-[ Preparation of 4-((4-methylpiperazin-1-yl;)methyl)-3-trifluoromethylphenyl]benzamide

以 2-甲磺酰氨基 -7-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1- 物。

2-Methanesulfonylamino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4- Methyl piperazine-1.

1H MR (300 MHz, DMSO-d6) δ: 10.53 (s, IH), 8.81 (d, IH), 8.21 (d, 2H), 8.06 (d, IH), 7.95 (d, IH), 7.88 (s, IH), 7.71 (d, IH), 7.54 (d, IH), 7.21 (d, IH), 3.58 (s, 2H),3.26 (s,3H), 2.96 (b, IH), 2.59 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.53 (s, IH), 8.81 (d, IH), 8.21 (d, 2H), 8.06 (d, IH), 7.95 (d, IH), 7.88 (s , IH), 7.71 (d, IH), 7.54 (d, IH), 7.21 (d, IH), 3.58 (s, 2H), 3.26 (s, 3H), 2.96 (b, IH), 2.59 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H]⁺ = 626.2。实施例 25 3-((3-氧代 -2,3-二氢 -[1,2,4]三氮唑并 [4,3-a]吡啶 -8-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三 ESI-MS m/z: [M+H] ⁺ = 626.2. Example 25 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)ethynyl)-4-A ke-N-[4-((4-methylpiperazin-1-yl)methyl)-3-III

步骤 1 2-肼基 -3-溴吡啶的制备

Step 1 Preparation of 2-mercapto-3-bromopyridine

在一个 250 ml圆底烧瓶加入 2-氟 -3-溴吡啶 (3.52 g, 20 mmol),水合肼 (200 mmol)和 THF(25 mL), 室温搅拌 6h. 浓缩至体积为 30%，冰浴下冷却析晶，过滤，收集晶体，真空干燥，得到标题化合物。 In a 250 ml round bottom flask was added 2-fluoro-3-bromopyridine (3.52 g, 20 mmol), hydrazine hydrate (200 mmol) and THF (25 mL), and stirred at room temperature for 6 h. The crystals were crystallized by cooling, filtered, crystals crystals crystals

步骤 2 8-溴 -[1,2,4]三氮唑并 [4,3-a]吡啶 -3(2H)-酮的制备

Step 2 Preparation of 8-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one

在干燥的 100 ml两口烧瓶中，加入三光气（888 mg， 300 mmol), 四氢呋喃溶液 100 mL. 分批加入化合物 2-肼基 -3-溴吡啶（188 mg， 100 mmol) ，反应 3小时， TLC点板原料消失。在冰浴下缓慢加入 100 mL水。减压蒸熘去除 70%溶剂。然后静置慢慢析出固体过滤抽干，鼓风干燥 8小时得到标题化合物。步骤 3 3-((3-氧代 -2,3-二氢 -[1,2,4]三氮唑并 [4,3-a]吡啶 -8-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪In a dry 100 ml two-necked flask, triphosgene (888 mg, 300 mmol) and tetrahydrofuran solution 100 mL were added. The compound 2-mercapto-3-bromopyridine (188 mg, 100 mmol) was added in portions and reacted for 3 hours. The TLC dot plate material disappeared. Slowly add 100 mL of water under an ice bath. The 70% solvent was removed by steam distillation under reduced pressure. Then, it was allowed to stand for precipitation, and the solid was filtered and dried, and dried under air for 8 hours to give the title compound. Step 3 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)ethynyl)-4-methyl -N-[4-((4-methylpiperazine)

-1-基;) -3-三氟甲基苯基]苯甲酰胺的制备

Preparation of -1-yl;)-3-trifluoromethylphenyl]benzamide

以 8-溴 -[1,2,4]三氮唑并 [4,3-a]吡啶 -3(2H)-酮和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 8-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one and 3-ethynyl-4-methyl-N-[4-(4- The title compound was prepared according to the method of Step 7 of Example 1 using methylpiperazine-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

lH MR (300 MHz, DMSO-d6) δ: 12.67 (s, IH), 10.58 (s, IH), 8.21 (s, IH), 8.18 (s, IH), 8.07 (d, IH), 7.95 (d, IH), 7.91 (d, IH), 7.71 (d, IH), 7.55 (d, IH), 7.54 (s, IH), 6.65 (t, IH), 3.58 (s, 2H), 2.59 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H)。 lH MR (300 MHz, DMSO-d6) δ: 12.67 (s, IH), 10.58 (s, IH), 8.21 (s, IH), 8.18 (s, IH), 8.07 (d, IH), 7.95 (d , IH), 7.91 (d, IH), 7.71 (d, IH), 7.55 (d, IH), 7.54 (s, IH), 6.65 (t, IH), 3.58 (s, 2H), 2.59 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H]⁺ = 549.3。实施例 26 3-((3-氧代 -2,3-二氢 -[1,2,4]三氮唑并 [4,3-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三基苯基]苯甲酰胺 ESI-MS m/z: [M+H] ⁺ = 549.3. Example 26 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethynyl)-4-A --N-[4-((4-methylpiperazin-1-yl)methyl)-3-triphenyl)benzamide

步骤 1 7-溴 -[1,2,4]三氮唑并 [4,3-a]吡啶 -3(2H)-酮的制备 Step 1 Preparation of 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one

以 2-氟 -4-溴吡啶为原料，同实施例 25步骤 1和步骤 2的方法制备标题化合物。 The title compound was prepared in the same manner as in Example 25 Step 1 and Step 2 from 2-fluoro-4-bromopyridine.

ESI-MS m/z: [M+H]+ = 214.0。 ESI-MS m/z: [M+H]+ = 214.0.

步骤 2 3-((3-氧代 -2,3-二氢 -[1,2,4]三氮唑并 [4,3-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethynyl)-4-methyl -N-[4-((4-methylpiperazine)

以 7-溴 -[1,2,4]三氮唑并 [4,3-a]吡啶 -3(2H)-酮和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 7-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one and 3-ethynyl-4-methyl-N-[4-(4- The title compound was prepared according to the method of Step 7 of Example 1 using methylpiperazine-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

IH MR (300 MHz, DMSO-d6) δ: 12.66 (s, IH), 10.52 (s, IH), 8.19 (d, 2H), 8.06 (d, IH), 7.95 (d, IH), 7.85 (d, IH), 7.71 (d, IH), 7.54 (t, 2H), 6.62 (d, IH), 3.58 (s, 2H), 2.56 (s, 3H), 2.42 (m, 8H), 2.36 (s, 3H)。 IH MR (300 MHz, DMSO-d6) δ: 12.66 (s, IH), 10.52 (s, IH), 8.19 (d, 2H), 8.06 (d, IH), 7.95 (d, IH), 7.85 (d , IH), 7.71 (d, IH), 7.54 (t, 2H), 6.62 (d, IH), 3.58 (s, 2H), 2.56 (s, 3H), 2.42 (m, 8H), 2.36 (s, 3H).

ESI-MS m/z: [M+H]+ = 549.2。实施例 27 3-((3-氧代 -2,3-二氢 -[1,2,4]三氮唑并 [4,3-a]吡啶 -5-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H]+ = 549.2. Example 27 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)ethynyl)-4-A --N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

步骤 1 5-溴 -[1,2,4]三氮唑并 [4,3-a]吡啶 -3(2H)-酮的制备 Step 1 Preparation of 5-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one

以 2-氟 -6-溴吡啶为原料，同实施例 25步骤 1和步骤 2的方法制备标题化合物。 The title compound was prepared in the same manner as in Example 25 Step 1 and Step 2 from 2-fluoro-6-bromopyridine.

ESI-MS m/z: [M+H]+ = 214.0。 ESI-MS m/z: [M+H]+ = 214.0.

步骤 2 3-((3-氧代 -2,3-二氢 -[1,2,4]三氮唑并 [4,3-a]吡啶 -5-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪Step 2 3-((3-Oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)ethynyl)-4-methyl -N-[4-((4-methylpiperazine)

-1-基)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 Preparation of -1-yl)methyl)-3-trifluoromethylphenyl]benzamide

以 5-溴 -[1,2,4]三氮唑并 [4,3-a]吡啶 -3(2H)-酮和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基) -3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 5-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one and 3-ethynyl-4-methyl-N-[4-(4- The title compound was prepared according to the method of Step 7 of Example 1 using methylpiperazine-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as a starting material.

lH MR (300 MHz, DMSO-d6) δ: 12.68 (s, IH), 10.59 (s, IH), 8.22 (s, IH), 8.18 (s, IH), 8.08 (d, IH), 7.96 (d, IH), 7.91 (d, IH), 7.71 (d, IH), 7.55 (d, IH), 7.54 (d, IH), 6.65 (t, IH), 3.61 (s, 2H), 2.59 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H)。 lH MR (300 MHz, DMSO-d6) δ: 12.68 (s, IH), 10.59 (s, IH), 8.22 (s, IH), 8.18 (s, IH), 8.08 (d, IH), 7.96 (d , IH), 7.91 (d, IH), 7.71 (d, IH), 7.55 (d, IH), 7.54 (d, IH), 6.65 (t, IH), 3.61 (s, 2H), 2.59 (s, 3H), 2.42 (m, 8H), 2.22 (s, 3H).

ESI-MS m/z: [M+H]⁺ = 549.3。实施例 28 3-((2-甲氨基咪唑并 [1,2-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基] ESI-MS m/z: [M+H] ⁺ = 549.3. Example 28 3-((2-Methylaminoimidazo[1,2-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4-methylpiperazine-1) -yl)methyl)-3-trifluoromethylphenyl]

2-甲氨基 -7-溴-咪唑并 [1,2-a]吡啶的制备 Preparation of 2-methylamino-7-bromo-imidazo[1,2-a]pyridine

在 lOOmL 圆底烧瓶中加入 2-(2,2,2-三氟乙酰氨基 )-7-溴-咪唑并 [1,2-a]吡啶 (308 mg, 1.0 mmol),碘甲垸 (170 mg, 1.2 mmol),碳酸钾 (414 mg, 3.0 mmol)以及丙酮 (5 mL)，室温搅拌 14h。向体系中加入水（5 mL), 回流 2h，减压除去溶剂，加入水，用乙酸乙酯萃取，无水硫酸钠干燥，硅胶柱层析得到目标产物。

In a 100 mL round bottom flask was added 2-(2,2,2-trifluoroacetamido)-7-bromo-imidazo[1,2-a]pyridine (308 mg, 1.0 mmol), iodoguanidine (170 mg) , 1.2 mmol), potassium carbonate (414 mg, 3.0 mmol) and acetone (5 mL). Water (5 mL) was added to the mixture, and the residue was evaporated.

1H MR (300 MHz, DMSO-d6) δ: 8.71 (d, IH), 8.34 (s, IH), 8.30 (s, IH), 7.54 (dd, IH), 3.76 (s, 3H), 2.67 (b,l H)。 1H MR (300 MHz, DMSO-d6) δ: 8.71 (d, IH), 8.34 (s, IH), 8.30 (s, IH), 7.54 (dd, IH), 3.76 (s, 3H), 2.67 (b , l H).

ESI-MS m/z: [M+H]⁺ = 226.0。 ESI-MS m/z: [M+H] ⁺ = 226.0.

步骤 2 3-((2-甲氨基咪唑并 [1,2-a]吡啶 -7-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟

Step 2 3-((2-Methylaminoimidazo[1,2-a]pyridin-7-yl)ethynyl)-4-methyl-N-[4-((4-methylpiperazin-1- Methyl)-3-trifluoro

以 2-甲氨基 -7-溴-咪唑并 [1,2-a]吡啶和 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制备出目标化合物。 2-Methylamino-7-bromo-imidazo[1,2-a]pyridine and 3-ethynyl-4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl) Starting from -3-trifluoromethylphenyl]benzamide, the title compound was obtained according to the procedure of Step 7 of Example 1.

1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.82 (d, IH), 8.39 (s, IH), 8.23 (d, 2H), 8.22 (s, IH), 8.07 (d, IH), 7.98 (d, IH), 7.72 (d, IH), 7.57 (d, IH), 7.49 (d, IH), 4.03 (q, IH), 3.83 (s, 3H), 3.58 (s, 2H), 2.62 (s, 3H), 2.40 (m, 8H), 2.17 (s, 3H)。 1H MR (300 MHz, DMSO-d6) δ: 10.56 (s, IH), 8.82 (d, IH), 8.39 (s, IH), 8.23 (d, 2H), 8.22 (s, IH), 8.07 (d , IH), 7.98 (d, IH), 7.72 (d, IH), 7.57 (d, IH), 7.49 (d, IH), 4.03 (q, IH), 3.83 (s, 3H), 3.58 (s, 2H), 2.62 (s, 3H), 2.40 (m, 8H), 2.17 (s, 3H).

ESI-MS m/z: [M+H]⁺ = 561.4。实施例 29 3-((2-环丙基甲酰氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲 -3-三氟甲基苯基]苯甲酰胺 ESI-MS m/z: [M+H] ⁺ = 561.4. Example 29 3-((2-Cyclopropylformamido-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl)methyl-3-trifluoromethylphenyl]benzamide

步骤 1 2-环丙基甲酰氨基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶的制备 Step 1 Preparation of 2-cyclopropylformamido-6-bromo-[1,2,4]triazolo[1,5-a]pyridine

称取 172mg环丙甲酸于反应瓶中，加入 5mL DMA溶解后，滴入 238mg氯化亚砜，室温搅拌 2h，加入 426 mg 2-氨基 -6-溴 -[1,2,4]三氮唑并 [1,5-&]吡¾ 50°C下反应 16h，依次乙酸乙酯萃取、无水硫酸钠干燥，硅胶柱层析得到标题化合物。 Weigh 172 mg of cyclopropanecarboxylic acid in the reaction flask, add 5 mL of DMA to dissolve, add 238 mg of thionyl chloride, stir at room temperature for 2 h, and add 426 mg of 2-amino-6-bromo-[1,2,4]triazole. And [1,5-&]pyridine was reacted at 50 ° C for 16 h.

步骤 2 3-((2-环丙基甲酰氨基 -[1,2,4]三氮唑并 [1,5-a]吡啶 -6-基)乙炔基 )-4-甲基 -N-[4-((4-甲基哌嗪 -1-基)甲基) -3-三氟甲基苯基]苯甲酰胺的制备 Step 2 3-((2-Cyclopropylformylamino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N- Preparation of [4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide

以步骤 1所得物 2-环丙基甲酰氨基 -6-溴 -[1,2,4]三氮唑并 [1,5-a]吡啶和实施例 1步骤 6所得物 3-乙炔基 -4-甲基 -N-[4-(4-甲基哌嗪 -1-基甲基 )-3-三氟甲基苯基]苯甲酰胺为原料，按照实施例 1步骤 7的方法制得目标化合物。 The product obtained in the first step was 2-cyclopropylformylamino-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and the product obtained in Step 6 of Example 1 was 3-ethynyl- 4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as raw material, according to The target compound was obtained by the method of Step 7 of Example 1.

1H MR (500 MHz, OMSO-d₆) δ: 11.13 (s, IH), 11.54(s, IH), 8.89 (d, IH), 8.21 (d, 2H), 8.06(d, IH), 7.96-7.97(m, 2H), 7.71(d, IH), 7.55(d, IH), 7.25-7.27 (m, lH),3.57(s, 2H), 2.60 (s, 3H), 2.38 (m, 8H), 2.16 (s, 3H), 2.01 (m, IH), 0.83-0.85 (m, 4H)。 1H MR (500 MHz, OMSO-d ₆ ) δ: 11.13 (s, IH), 11.54 (s, IH), 8.89 (d, IH), 8.21 (d, 2H), 8.06 (d, IH), 7.96- 7.97(m, 2H), 7.71(d, IH), 7.55(d, IH), 7.25-7.27 (m, lH), 3.57(s, 2H), 2.60 (s, 3H), 2.38 (m, 8H) , 2.16 (s, 3H), 2.01 (m, IH), 0.83-0.85 (m, 4H).

ESI-MS m/z: [M+H]+ = 616。实验例 1 本发明的化合物体外细胞活性评价 ESI-MS m/z: [M+H]+ = 616. Experimental Example 1 Evaluation of in vitro cell viability of the compound of the present invention

1. 试验材料 Test material

1.1 化合物 1.1 Compound

以上实施例制备的本发明的化合物，每个化合物用 DMSO溶解至 10mM后，用完全培养基稀释至 50μΜ，然后用含 0.1% DMSO的完全培养基稀释至 ΙΟμΜ后，依次 10倍稀释，共 10个浓度。 The compound of the present invention prepared in the above examples, each compound was dissolved in DMSO to 10 mM, diluted to 50 μM with complete medium, and then diluted to ΙΟμΜ with complete medium containing 0.1% DMSO, sequentially diluted 10 times, total 10 Concentration.

1.2 细胞 1.2 cells

Κ562白血病细胞：购自美国 ATCC公司 Κ562 leukemia cells: purchased from the United States ATCC company

1.3试剂 1.3 reagent

二甲基亚砜（Dimethyl sulfoxide, DMSO ) , 购于美国 Sigma公司； Dimethyl sulfoxide (DMSO), purchased from Sigma, USA;

发光法细胞活力检测试剂盒（CellTiter-Glo® Luminescent Cell Viability Assay Kit) ，购于美国 Promega公司； CellTiter-Glo® Luminescent Cell Viability Assay Kit, purchased from Promega, USA;

IMEM培养基（IMEM medium) ，购于美国 Gibco公司； IMEM medium (IMEM medium), purchased from Gibco, USA;

青霉素 /链霉素（Pen/Strep ) ，购于美国 Gibco公司； Penicillin/streptomycin (Pen/Strep), purchased from Gibco, USA;

胎牛血清（Fatal bovine serun, FBS ) ，购于美国 Gibco公司； Fetal bovine serun (FBS), purchased from Gibco, USA;

0.25%含 EDTA胰酶（0.25% Trypsin-EDTA) ，购于美国 Gibco公司； 0.25% containing EDTA trypsin (0.25% Trypsin-EDTA), purchased from Gibco, USA;

10 cm细胞培养皿（ 10 cm cell culture dish) ，购于美国 Corning公司； 10 cm cell culture dish, purchased from Corning, USA;

50 mL离心管（50 mL centrifuge tube) ，购于美国 Coming公司； 50 mL centrifuge tube (50 mL centrifuge tube), purchased from Coming, USA;

384孔平底透光白板（384 Well Flat Clear Bottom White) ，购于美国 Coming公司；磷酸盐缓冲液（Phosphate Buffered Saline, PBS ) ，每周配制。 384 Well Flat Clear Bottom White, purchased from Coming, USA; Phosphate Buffered Saline (PBS), prepared weekly.

1.4仪器 1.4 Instrument

自动聚焦荧光多功能酶标仪（PHERAstar Plus ) ，购于德国 BMG Labtech公司。 Autofocus fluorescent multi-function microplate reader (PHERAstar Plus), purchased from BMG Labtech, Germany.

2. 实验方法： 2. Experimental method:

1) 收集对数期细胞，调整细胞悬液浓度至 l x lO⁵个 /ml， 384孔板每孔加入 40μί细胞悬液，每孔细胞数为 4x l0³个 /孔。边缘孔用无菌 PBS填充； 1) Collect log phase cells, adjust the cell suspension concentration to lx lO ⁵ /ml, add 40 μί cell suspension to each well of 384-well plate, and the number of cells per well is 4×10 ³ /well. The edge holes are filled with sterile PBS;

2) 加入 ΙΟμί的以上浓度梯度的本发明的化合物。每个化合物每个浓度重复三次。空白对照加入 ΙΟμί同等浓度的 DMSO; 2) Add the above concentration gradient of the compound of the invention to ΙΟμί. Each compound was repeated three times for each concentration. The blank control was added to the same concentration of DMSO;

3) 细胞在 37°C/5% C0₂培养箱中孵育； 4) 加药 72h后加入 30μί发光法细胞活力检测试剂混合液； 3) The cells were incubated in a 37 ° C / 5% CO ₂ incubator; 4) After adding the drug for 72 hours, add 30 μί luminescence cell viability assay reagent mixture;

5) 37°C/5% C0₂培养箱中孵育 lOmin; 低转速离心后在 PHERAstar酶标仪上测定化学发光值； 5) Incubate for 10 min in a 37 ° C / 5% C0 ₂ incubator; determine the chemiluminescence value on a PHERAstar microplate reader after centrifugation at low speed;

6) 细胞活力（Cell Viability) = (RLU _ffn¾/RLU阴性） χ 100%，其中 RLU样品为加药孔 RLU (相对光单位）值， RLU ,为不加药孔 RLU值（即同等浓度 DMSO处理的细胞对照），采用 Graphpad Prism 4.0数据处理软件四参数逻辑拟合模块进行处理数据计算 IC₅。。 IC₅₀值表示与未加化合物处理组相比，化合物抑制 50%细胞生长对应的化合物浓度。 IC₅。结果见表 1。 6) Cell Viability = (RLU _ffn3⁄4 / RLU negative) χ 100%, where RLU sample is the dosing hole RLU (relative light unit) value, RLU, is the unfilled RLU value (ie the same concentration of DMSO treatment) Cell control), using the Graphpad Prism 4.0 data processing software four-parameter logic fitting module for processing data calculation IC ₅ . . The IC ₅₀ value indicates the concentration of the compound corresponding to 50% cell growth inhibition of the compound compared to the compound-free treated group. IC ₅ . The results are shown in Table 1.

表 1 Table 1

'― "表不未测试。 '― "The table is not tested.

从以上实验结果可以看出，本发明的化合物对白血病细胞的 IC_5Q值在 nM水平，具有强的抑制活性° Jia H-Y等 (Jia H-Y, et al. ZD 6474 inhibits Src kinase leading to apoptosis of imatinib-resistant K562 cells. Leuk Res (2009), doi: 10.1016/j.leukres.2009.03.033) 研究显示伊马替尼对 K562细胞的 IC₅₀值为 280 nM, H Luo等（H Luo, et al. HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance. Leukemia (2010) 24, 1807—1809; doi: 10.1038/leu.2010.169; Published online 12 August 2010) 实验证明伊马替尼对 K562细胞的 IC₅。值为 296 nM。由此可见，对于不耐药的白血病细胞，本发明的化合物与伊马替尼具有相当，甚至更优异的效果。实验例 2 ABL1 (T315I)酪氨酸激酶活性评价 It can be seen from the above experimental results that the compound of the present invention has a strong inhibitory activity on the IC _5Q value of leukemia cells at the nM level (Jia HY, et al. ZD 6474 inhibits Src kinase leading to apoptosis of imatinib- Resistant K562 cells. Leuk Res (2009), doi: 10.1016/j.leukres.2009.03.033) Studies have shown that the IC ₅₀ value of imatinib for K562 cells is 280 nM, H Luo et al (H Luo, et al. HH -GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance. Leukemia (2010) 24, 1807-1809; doi: 10.1038/leu.2010.169; Published online 12 August 2010) imatinib IC ₅ on K562 cells. The value is 296 nM. Thus, for leukemia cells that are not resistant, the combination of the present invention It has comparable and even better effects to imatinib. Experimental Example 2 Evaluation of ABL1 (T315I) Tyrosine Kinase Activity

本实验测试本发明实施例制备的化合物对 ABL (T3151)激酶活性的抑制，使用伊马替尼作为对照。伊马替尼参照中国专利 CN1043531C中描述的方法制得并通过氢谱和质谱鉴定。 This experiment tested the inhibition of ABL (T3151) kinase activity by the compounds prepared in the examples of the present invention, using imatinib as a control. Imatinib was prepared by the method described in Chinese Patent No. CN1043531C and identified by hydrogen spectroscopy and mass spectrometry.

使用商购的人源 ABL T315I突变酶（Human ABL1 (T315I), active, 目录号 # 14-522， Millipore公司，美国）测试 ABL (T3151)酪氨酸激酶活性。按厂商说明书进行激酶活性测定。肽底物（Peptide substrate) 为 Abltide (EAIYAAPFAKKK；)，购于美国 Millipore公司。离子交换层析滤纸 P81 ( ion exchange filter paper)购于英国 Whatman公司。 [ γ -33Ρ] ATP购于 Perkin Elmer 公司。 ABL (T3151) tyrosine kinase activity was tested using a commercially available human ABL T315I mutant enzyme (Human ABL1 (T315I), active, Cat. No. #14-522, Millipore, USA). Kinase activity assays were performed according to the manufacturer's instructions. The Peptide substrate was Abltide (EAIYAAPFAKKK;), which was purchased from Millipore, USA. Ion exchange chromatography paper P81 (ion exchange filter paper) was purchased from Whatman Company, UK. [ γ -33Ρ] ATP was purchased from Perkin Elmer.

本发明的化合物以及伊马替尼从 Ι μΜ开始分别 3倍连续稀释，共 10个浓度 (50.8 pM, 152.0 pM, 457.0 pM, 1.37 nM, 4.12 nM, 12.3 nM, 37.0 nM, 111.0 nM, 333.0nM和 1.0μΜ)。每孔加入 5.0 μΜ Abltide, 然后加入人源 T315I突变酶。室温下加入 [γ-³³Ρ]ΑΤΡ，终浓度为 Ι .ΟμΜ, 反应 120 分钟。将 20μ1等分试样转移到 P81离子交换层析纸上。然后层析纸用 0.75%磷酸溶液充分洗涤 3 次，再用丙酮洗涤一次。最后，进行 γ-³³Ρ放射性测定。实验结果见表 2。 The compound of the present invention and imatinib were serially diluted 3 times from ΙμΜ, respectively, for a total of 10 concentrations (50.8 pM, 152.0 pM, 457.0 pM, 1.37 nM, 4.12 nM, 12.3 nM, 37.0 nM, 111.0 nM, 333.0 nM). And 1.0μΜ). 5.0 μΜ Abltide was added to each well, followed by human T315I mutant enzyme. [γ- ³³ Ρ]ΑΤΡ was added at room temperature, and the final concentration was Ι.ΟμΜ, and the reaction was carried out for 120 minutes. A 20 μl aliquot was transferred to a P81 ion exchange chromatography paper. The chromatography paper was then washed thoroughly 3 times with a 0.75% phosphoric acid solution and once with acetone. Finally, a gamma- ³³ Ρ radioactivity assay was performed. The experimental results are shown in Table 2.

表 2 Table 2

ICso(nM) ICso(nM) 人源 T315I突变酶受试药人源 T315I突变酶实施例 1 137.90 实施例 2 109.90 实施例 3 13.41 实施例 4 2.50 实施例 5 0.81 实施例 6 351.9 实施例 7 111.30 实施例 8 7.52 实施例 9 18.35 实施例 10 302.50 实施例 11 173.10 实施例 12 170.00 实施例 13 14.12 实施例 14 18.14 实施例 15 808.90 实施例 16 4.19 实施例 17 62.58 实施例 18 48.60 实施例 19 58.63 实施例 20 154.40 实施例 21 836.40 实施例 22 92.64 实施例 23 0.09 实施例 24 269.70 实施例 25 458.90 实施例 26 0.11 实施例 27 532.20 实施例 28 621.50 伊马替尼 >1000 实施例 29 0.1 以上实验结果表明，本发明的化合物对 T315I突变酶的 IC_5Q显著优于伊马替尼，具有强效的抑制 T315I突变酶的能力。 ICso(nM) ICso(nM) human T315I mutant enzyme test human T315I mutant enzyme Example 1 137.90 Example 2 109.90 Example 3 13.41 Example 4 2.50 Example 5 0.81 Example 6 351.9 Example 7 111.30 Implementation Example 8 7.52 Example 9 18.35 Example 10 302.50 Example 11 173.10 Example 12 170.00 Example 13 14.12 Example 14 18.14 Example 15 808.90 Example 16 4.19 Example 17 62.58 Example 18 48.60 Example 19 58.63 Example 20 154.40 Example 21 836.40 Example 22 92.64 Example 23 0.09 Example 24 269.70 Example 25 458.90 Example 26 0.11 Example 27 532.20 Example 28 621.50 Imatinib>1000 Example 29 0.1 The above experimental results show that the compound of the present invention has a superior IC _5Q to the T315I mutant enzyme than imatinib, and has potent ability to inhibit the T315I mutant enzyme.

从本发明的实验结果可以得出，本发明的化合物不仅对没有突变的白血病细胞具有非常好的效果，而且能够显著抑制 T315I突变酶，因此是广谱的 BCR-ABL抑制剂。对于对酪氨酸激酶抑制剂（TKI) 治疗耐药或抵抗的肿瘤病患者，例如慢性粒细胞白血病 (CML)慢性期、急变期、加速期患者以及费城染色体阳性（Ph+)的慢性粒细胞白血病和急性淋巴细胞白血病患者应具有好的前景。 From the experimental results of the present invention, it can be concluded that the compound of the present invention has not only a very good effect on leukemia cells without mutation, but also a significant inhibition of the T315I mutant enzyme, and thus is a broad-spectrum BCR-ABL inhibitor. For patients with cancer disease resistant or resistant to tyrosine kinase inhibitor (TKI) treatment, such as chronic myeloid leukemia (CML) chronic phase, blast phase, accelerated phase, and Philadelphia chromosome positive (Ph+) chronic myeloid leukemia Patients with acute lymphoblastic leukemia should have good prospects.

尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。 While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

Claims

权利要求书 Claim

1. 通式 I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药， A compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

R₂ (I) R ₂ (I)

其中， among them,

Y选自 N、 H和 C(R6)，其中 Re选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基和杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基或杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基或氰基取代；和 Y is selected from the group consisting of N, H and C(R6), wherein Re is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate An amide group, a mercaptosulfonylamino group, an arylsulfonylamino group and a heteroarylsulfonylamino group, said amino group, monodecylamino group, bis-indenylamino group, acylamino group, decylamido group, aryl amide group, a heteroarylamino group, a sulfonylamino group, a decylsulfonylamino group, an arylsulfonylamino group or a heteroarylsulfonylamino group may be substituted by one or more halogen, thiol, amino or cyano groups;

2. 根据权利要求 1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物 2. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein said compound

其中， among them,

R4选自氢、垸基、 -OH、羟垸基、卤代垸基；和 R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halogenated fluorenyl;

R6选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基和杂芳基磺酰氨基，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基或杂芳基磺酰氨基可以被一个或多个 ¾素、垸基、氨基或氰基取代。 R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido, decylamino, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonyl Amino and heteroarylsulfonylamino, said amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, sulfhydryl sulfonate The acylamino, arylsulfonylamino or heteroarylsulfonylamino group may be substituted by one or more 3, 4, decyl, amino or cyano groups.

3. 根据权利要求 1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化 3. A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein said compounding

其中， among them,

« 选自氢、垸基、垸氧基、卤代垸基、卤代垸氧基、 -OH、 -NH₂、卤素、 CN; «Selected from hydrogen, fluorenyl, decyloxy, halodecyl, halodecyloxy, -OH, -NH ₂ , halogen, CN;

R₂选自氢、垸基、垸氧基、卤代垸基、卤代垸氧基、 -OH、 -NH₂、卤素、 CN; R _{2 is} selected from the group consisting of hydrogen, fluorenyl, decyloxy, halodecyl, halodecyloxy, -OH, -NH ₂ , halogen, CN;

R₃选自氢、垸基、 ¾代垸基、 ¾素、氨基酰基、单垸基氨基酰基、双垸基氨基酰基、氰 R _{3 is} selected from the group consisting of hydrogen, fluorenyl, _3⁄4 fluorenyl, _3⁄4 , aminoacyl, monodecylaminoacyl, bis-decylaminoacyl, cyanide

R4选自氢、垸基、 -ΟΗ、羟垸基、卤代垸基； R4 is selected from the group consisting of hydrogen, fluorenyl, -hydrazine, hydroxydecyl, halogenated fluorenyl;

Υ选自 Ν， Η; R₅选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，或者 R₅与所连接的碳原子形成 C(=0)，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代；和 Υ selected from Ν, Η; R _{5 is} selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonate An acylamino group, a heteroarylsulfonylamino group, or R ₅ forms a C(=0) with the attached carbon atom, said amino group, monodecylamino group, bis-decylamino group, amido group, decyl amido group, aryl group Alkylamino, heteroaryl amido, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, sulfhydryl, amino, cyano;

表示单键或双键，当 R₅与其连接的碳原子形成 C(=0)时，表示单键， Y 为肌 Represents a single bond or a double bond. When R ₅ forms a C (=0) with its attached carbon atom, it represents a single bond and Y is a muscle.

4. 根据权利要求 1或 2的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所 ' 所示的化合物， The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound represented by

( I-a， ) 其中，

( Ia, ) where,

R₃选自氢、垸基、 ¾代垸基、 ¾素、氨基酰基、单垸基氨基酰基、双垸基氨基酰基、氰基； R _{3 is} selected from the group consisting of hydrogen, fluorenyl, _3⁄4 fluorenyl, _3⁄4 , aminoacyl, monodecylaminoacyl, bis-decylaminoacyl, cyano;

R4选自氢、垸基、 -ΟΗ、羟垸基、卤代垸基；和 R4 is selected from the group consisting of hydrogen, fluorenyl, hydrazine, hydroxy fluorenyl, halogenated fluorenyl;

5. 根据权利要求 1或 2的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物为通式 I-a"所示的化合物， The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound is a compound represented by the formula I-a"

( I-a" ) 其中， ( Ia" ) among them,

R6选自氢、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，所述的酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代。 R6 is selected from the group consisting of hydrogen, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, Heteroarylsulfonylamino, said amido, decylamido, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonyl The amino group may be substituted by one or more halogen, sulfhydryl, amino, cyano groups.

6. 根据权利要求 1或 3的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所 ' 所示的化合物， The compound according to claim 1 or 3, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound represented by

其中， among them,

Υ选自 Ν， Η; Υ selected from Ν, Η;

R₅选自氢、氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基，或者 R₅与所连接的碳原子形成 C(=0)，所述的氨基、单垸基氨基、双垸基氨基、酰氨基、垸基酰氨基、芳基酰氨基、杂芳基酰氨基、磺酰氨基、垸基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基可以被一个或多个卤素、垸基、氨基、氰基取代；和 R _{5 is} selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonate An acylamino group, a heteroarylsulfonylamino group, or R ₅ forms a C(=0) with the attached carbon atom, said amino group, monodecylamino group, bis-decylamino group, amido group, decyl amido group, aryl group Alkylamino, heteroaryl amido, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, sulfhydryl, amino, cyano;

"表示单键或双键，当 R₅与其所连接的碳原子形成 C(=0)时，表示单键，"Indicating a single bond or a double bond, when R ₅ forms a C (=0) with the carbon atom to which it is attached, it means a single bond,

Y为顺。 Y is shun.

7. 根据权利要求 1或 3的化合物或其药学可接受的盐、异构体、溶剂合物、结The compound according to claim 1 or 3, or a pharmaceutically acceptable salt, isomer, solvate or knot thereof

"所示的化合物， "The compound shown,

其中， among them,

Υ选自 Ν和 Η; Υ selected from Ν and Η;

Y为 H。 Y is H.

8. 根据权利要求 1至 7之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein

« 选自氢、 d_₆垸基、卤代 d_₆垸基、卤素、 CN，优选选自甲基和三氟甲基； «selected from hydrogen, d- ₆ fluorenyl, halo d- ₆ fluorenyl, halogen, CN, preferably selected from methyl and trifluoromethyl;

R₂选自氢、 d_₆垸基、卤代 d_₆垸基、卤素、 CN，优选选自甲基、乙基、丙基和异丙基;R _{2 is} selected from the group consisting of hydrogen, d ₆ fluorenyl, halogenated d ₆ fluorenyl, halogen, CN, preferably selected from the group consisting of methyl, ethyl, propyl and isopropyl;

R₃选自氢、 d_₆垸基、卤代 d_₆垸基、卤素、氨基酰基、单 d_₆垸基氨基酰基、双 d_₆ 垸基氨基酰基、氰基，优选选自氢、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、卤素和甲氨基酰基；和 R _{3 is} selected from the group consisting of hydrogen, d ₆ fluorenyl, halogenated d ₆ fluorenyl, halogen, amino acyl, mono d ₆ fluorenylamino acyl, bis d ₆ decylamino acyl, cyano, preferably selected from hydrogen, methyl, Ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, halogen and methylamino; and

R4选自氢、 d.₆垸基、 -OH、羟 .₆垸基、卤代 d.₆垸基，优选选自氢、甲基、乙基、丙基、异丙基、 -OH、羟甲基、羟乙基、羟丙基、三氟甲基、三氟乙基。 R4 is selected from the group consisting of hydrogen, d. ₆ fluorenyl, -OH, hydroxy. ₆ fluorenyl, halogenated d. ₆ fluorenyl, preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, -OH, hydroxy Methyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, trifluoroethyl.

9. 根据权利要求 1至 8之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中 The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein

R₅选自氢、氨基、单 d_₆垸基氨基、双 d_₆垸基氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙基酰氨基、环丁基酰氨基、苯酰氨基、三氟乙酰氨基、甲磺酰氨基、乙磺酰氨基，或者R _{5 is} selected from the group consisting of hydrogen, amino, mono d ₆垸 ylamino, bis d ₆ ylamino, formylamino, acetylamino, propionylamino, Cyclopropylamido, cyclobutylamido, benzoylamino, trifluoroacetamido, methanesulfonylamino, ethanesulfonylamino, or

R₅与所其连接的碳原子形成 C(=0); 和 R ₅ forms a C (=0) with the carbon atom to which it is attached;

R6选自氢、氨基、单 d_₆垸基氨基、双 d_₆垸基氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙基酰氨基、环丁基酰氨基、苯酰氨基、三氟乙酰氨基、甲磺酰氨基、乙磺酰氨基。 R6 is selected from the group consisting of hydrogen, amino, mono-d- ₆ -ylamino, bis-d- ₆ -ylamino, formylamino, acetylamino, propionylamino, cyclopropylamido, cyclobutylamido, phenylamido, trifluoro Acetylamino, methanesulfonylamino, ethanesulfonylamino.

10. 根据权利要求 1至 9之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合 The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isomer or solvent thereof

11. 一种药物组合物，其包含权利要求 1至 10之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和可药用载体。 11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.

12. 用于治疗和 /或预防肿瘤的方法，包括向需要其的个体给予治疗或预防有效量的权利要求 1至 10之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或权利要求 11的药物组合物。 12. A method for the treatment and/or prevention of a tumor comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or isomer thereof A solvate, crystallization or prodrug or a pharmaceutical composition of claim 11.

13. 权利要求 1-10之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或权利要求 11所述的药物组合物在制备用于治疗和 /或预防肿瘤的药物中的应用。 13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or the pharmaceutical composition of claim 11 in the preparation for treatment And/or use in drugs that prevent tumors.

International application No. International application No.

INTERNATIONAL SEARCH REPORT PCT/CN2014/083284 INTERNATIONAL SEARCH REPORT PCT/CN2014/083284

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons:This international search report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons:

1. Kl Claims Nos.: 12 1. Kl Claims Nos.: 12

because they relate to subject matter not required to be searched by this Authority, namely: Because they relate to subject matter not required to be searched by this Authority, ie:

Claim 12 is directed to a method of treatment of the human/animal body (PCT Rule 39.1 (iv)). Claim 12 is directed to a method of treatment of the human/animal body (PCT Rule 39.1 (iv)).

Claims Nos.: Claims Nos.:

because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: Because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no express international search can be carried out, specifically:

3. □ Claims Nos.: 3. □ Claims Nos.:

because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Because they are belongs claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet) Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows: This International Searching Authority found multiple inventions in this international application, as follows:

1.口 As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 1. all the additional search fees were timely paid by the applicant, this international search report covers all searchable claims.

2.口 As all searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment of additional fees. 2. All searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment of additional fees.

3. □ As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 3. □ As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:

4. □ No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: 4. □ No required additional search fees were timely paid by the applicant. results, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

Remark on protest 口 The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. Remark on protest The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee.

ΓΊ The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation. Additional The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation.

ΓΊ No protest accompanied the payment of additional search fees. ΓΊ No protest accompanied the payment of additional search fees.

Form PCT/ISA/210 (continuation of first sheet (2)) (July 2009) Form PCT/ISA/210 (continuation of first sheet (2)) (July 2009)