WO2016050201A1 - High selectivity substituted pyrimidine pi3k inhibitor - Google Patents

Abstract

The present invention relates to a substituted pyrimidine PI3K inhibitor as represented by formula (I), a stereoisomer of same or a pharmaceutically acceptable salt thereof, where R¹, R², R³, R⁴, R⁵ or R⁶ is as defined in the description. The present invention also relates to a preparation method for these compounds, a pharmaceutical composition, and uses of these compounds in preparing a medicament for treatment and/or prevention of proliferative diseases.

Description

高选择性取代嘧啶类PI3K抑制剂Highly selective substitution of pyrimidine PI3K inhibitors 技术领域Technical field

本发明涉及一种新的高选择性磷脂酰肌醇-3-激酶(PI3K)抑制剂化合物、其立体异构体或其药学上可接受的盐，这些化合物的制备方法，含有这些化合物的药物组合物、以及这些化合物在制备治疗和/或预防细胞增殖性疾病药物中的用途。The present invention relates to a novel highly selective phosphatidylinositol-3-kinase (PI3K) inhibitor compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a process for preparing the same, a drug containing the same Compositions, and the use of these compounds in the manufacture of a medicament for the treatment and/or prevention of cell proliferative disorders.

背景技术Background technique

PI3K-AKt-mTOR信号通路在生物体内众多细胞信号通路中占据相当重要的地位，参与细胞调控如增殖、代谢、生长、分化、凋亡等多种生命活动，在炎症、肿瘤、代谢类疾病和心血管疾病的发病机制中起着重要作用。该信号传导通路可以通过参与细胞自噬以及抑制细胞凋亡等机制诱导肿瘤发生(Amin等，Role of the PI3K/Akt，mTOR，and STK11/LKB1pathways in the tumorigenesis of sclerosing hemangioma of the lung.，2008，38-44.)。PI3K-AKt-mTOR信号通路中比较热门的三个蛋白是PI3K、AKt和mTOR，以这三个蛋白作为抗肿瘤靶点的肿瘤治疗方案逐渐成为研究热点。The PI3K-AKt-mTOR signaling pathway plays an important role in many cellular signaling pathways in vivo, and is involved in various life activities such as proliferation, metabolism, growth, differentiation, apoptosis, etc. in inflammation, tumor, metabolic diseases and It plays an important role in the pathogenesis of cardiovascular disease. This signaling pathway can induce tumorigenesis by participating in mechanisms such as autophagy and inhibition of apoptosis (Amin et al, Role of the PI3K/Akt, mTOR, and STK11/LKB1 pathways in the tumorigenesis of sclerosing hemangioma of the lung., 2008, 38-44.). The three most popular proteins in the PI3K-AKt-mTOR signaling pathway are PI3K, AKt and mTOR, and the tumor treatment schemes with these three proteins as anti-tumor targets have gradually become research hotspots.

PI3K是细胞内重要的信号转导分子，根据PI3K的P110亚基结构特点和底物分子不同可将其分为三大类，其中第I类PI3K功能最为重要(下面所述PI3K指的都是第I类PI3K)。PI3K主要由催化亚基P110和调节亚基P85组成。PI3K可被细胞因子、激素等细胞外信号刺激激活。PI3K的激活可使膜磷酸肌醇磷酸化，催化肌醇环上3位羟基生成3，4-二磷酸磷脂酰肌醇(phosphatidylinositol-3，4-biphosphate，PI-3，4P2)及3，4，5-三磷酸磷脂酰肌醇(phosphatidylinositol 3，4，5-trisphosphate，PI-3，4，5P3)，它们均可作为第二信使在细胞中传递信号，介导PI3K的多种细胞功能，如这些脂质产物可通过与Akt的PH(pleckstrin homology)区结合来激活Akt。肿瘤抑制基因PTEN(phosphatase and tensin homologue)表达产物可诱导3-磷酸肌醇去磷酸化，从而可对PI3K途径进行负调节。PI3K is an important signal transduction molecule in cells. According to the structural characteristics of P3 subunit of PI3K and different substrate molecules, it can be divided into three categories, among which the first type of PI3K function is the most important (PI3K refers to all of the following) Class I PI3K). PI3K consists mainly of a catalytic subunit P110 and a regulatory subunit P85. PI3K can be activated by extracellular signal stimulation such as cytokines and hormones. Activation of PI3K phosphorylates membrane phosphoinositides, catalyzing the 3 hydroxy groups on the inositol ring to produce 3,4-diphosphate phosphatidylinositol-3,4-biphosphate, PI-3,4P2 and 3,4 , phosphatidylinositol 3,4,5-trisphosphate (PI-3,4,5P3), which can act as a second messenger to transmit signals in cells, mediating multiple cellular functions of PI3K, Such lipid products can activate Akt by binding to the pleckstrin homology region of Akt. The expression product of the tumor suppressor gene PTEN (phosphatase and tensin homologue) can induce the dephosphorylation of inositol 3-phosphate, which can negatively regulate the PI3K pathway.

通过抑制PI3K-AKt-mTOR信号通路发挥抗肿瘤作用的药物比较多，包括PI3K/mTOR双重抑制，例如Dactolisib、VS-5584、PI-103、GSK1059615、SAR245409等，这些药物大多处在临床实验阶段；也有单独的mTOR抑制剂，比如Rapamycin、Everolimus、AZD8055等；然而，因mTOR抑制剂本身是一种免疫抑制剂，该抑制剂 易带来真菌或其他微生物的感染等副作用；除此之外，服用mTOR抑制剂后，部分患者还会产生一种非特异性的肺部炎症一间质性肺炎。最近研究表示Rapamycin也易对mTORC2的活性产生干扰，产生类似的症状，如糖耐量下降及胰岛素不敏感等。PI3K-AKt-mTOR信号通路抑制剂中更优选药物是PI3K抑制剂，PI3K存在不同的亚型，不同亚型具有不同的功能，而抑制肿瘤细胞生长的最佳方案是有选择的对突变亚型进行抑制，PI3K众多亚型有基因突变发生，突变率最高的是PI3Kα，有研究报道，PI3Kα抑制剂也可以降低其他亚型抑制剂带来的血小板降低、贫血、转氨酶增高等副作用(Brana&Siu，BMC Medicine，Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment，2012，10-161)。但也有研究报道，只抑制PI3Kα会导致胰岛素抵抗，带来高血糖等副反应(jia S，Liu Z，Zhang S，et al，Nature，Essential roles of PI(3)K-P110βin cell growth，metabolism and tumorigenesis，2008，454：776-779.)，另有研究发现抑制PI3Kβ的突变有利于抑制由PTEN缺失引发的肿瘤(Kevin D.Courtney，Ryan B.Corcoran，and Jeffrey A.Engelman，journal of clinical oncology，2010，28，1075-1083.)，如果可以对PI3K的多种亚型同时产生抑制作用，则可以产生多重治疗效果，对于针对该领域内的药物研发产生显著影响，并为临床多重疾病，特别是肿瘤的治疗提供更多的选择。There are many anti-tumor drugs that inhibit the PI3K-AKt-mTOR signaling pathway, including PI3K/mTOR dual inhibition, such as Dactolisib, VS-5584, PI-103, GSK1059615, SAR245409, etc. Most of these drugs are in clinical trials; There are also mTOR inhibitors alone, such as Rapamycin, Everolimus, AZD8055, etc.; however, since the mTOR inhibitor itself is an immunosuppressant, the inhibitor It is easy to cause side effects such as infection by fungi or other microorganisms; in addition, after taking mTOR inhibitor, some patients also produce a non-specific lung inflammation-interstitial pneumonia. Recent studies have shown that Rapamycin also interferes with the activity of mTORC2, producing similar symptoms such as impaired glucose tolerance and insulin insensitivity. More preferred PI3K-AKt-mTOR signaling pathway inhibitors are PI3K inhibitors. PI3K has different subtypes, different subtypes have different functions, and the best solution for inhibiting tumor cell growth is selective pair subtypes. Inhibition, many subtypes of PI3K have gene mutations, and the highest mutation rate is PI3Kα. It has been reported that PI3Kα inhibitors can also reduce side effects such as thrombocytopenia, anemia, and elevated transaminase caused by other subtype inhibitors (Brana&Siu, BMC). Medicine, Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment, 2012, 10-161). However, studies have also reported that inhibition of PI3Kα alone leads to insulin resistance and side effects such as hyperglycemia (Jia, Liu Z, Zhang S, et al, Nature, Essential roles of PI(3)K-P110βin cell growth, metabolism and Tumorigenesis, 2008, 454: 776-779.), another study found that mutations that inhibit PI3Kβ are beneficial in suppressing tumors caused by PTEN deletion (Kevin D. Courtney, Ryan B. Corcoran, and Jeffrey A. Engelman, journal of clinical oncology , 2010, 28, 1075-1083.), if multiple subtypes of PI3K can be simultaneously inhibited, multiple therapeutic effects can be produced, which have a significant impact on drug development in the field and are multiple clinical diseases. In particular, the treatment of tumors offers more options.

目前已有多个处在开发和临床实验阶段的单独抑制PI3K的化合物，比如Novartis公司的处于临床III期阶段的BKM-120，用于治疗乳腺癌、***癌、黑色素瘤等肿瘤，但BKM-120对PI3Kα的体外活性最高，对其他亚型，如PI3Kβ/δ/γ的体外活性偏低。其他化合物，如XL-499、SF-2626、HS-173和A66等，都还处在临床前研究，其临床效果未知。There are several PI3K-inhibiting compounds in development and clinical trials, such as Novartis's clinical phase III BKM-120, which is used to treat breast cancer, prostate cancer, melanoma and other tumors, but BKM- 120 pairs of PI3Kα have the highest in vitro activity and low activity against other subtypes such as PI3Kβ/δ/γ. Other compounds, such as XL-499, SF-2626, HS-173, and A66, are still in preclinical studies, and their clinical effects are unknown.

因此，寻找一种新的对PI3K激酶具有高选择性，且对所有亚型都具有良好的抑制活性的抗肿瘤药物尤为重要。Therefore, it is particularly important to find a new antitumor drug that has high selectivity for PI3K kinase and has good inhibitory activity against all subtypes.

发明内容 Summary of the invention

本发明提供了一种高选择性PI3K激酶抑制剂、其药物组合物及在制备用于治疗和/或预防增殖性疾病的药物中的用途。The present invention provides a highly selective PI3K kinase inhibitor, a pharmaceutical composition thereof and use thereof in the manufacture of a medicament for the treatment and/or prevention of a proliferative disorder.

本发明的一个实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐：One embodiment of the invention relates to a compound of the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

其中，R¹选自氢原子，卤素，氰基，硝基，羧基，任选被1-3个Q¹取代的3-14元环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、6-10元螺环基或6-10元桥环基，且所述螺环基或桥环基中的碳原子可以被1-3个O、S(O)_m、N(H)_m、NCH₃或C(O)替换；Wherein R ^{1 is} selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a carboxyl group, a 3-14 membered cycloalkyl group optionally substituted by 1 to 3 Q ¹ , a 3-14 membered heterocyclic group, and 6 to 14 members. An aryl group, a 5-14 membered heteroaryl group, a 6-10 membered spirocyclic group or a 6-10 membered bridged ring group, and the carbon atom in the spirocyclic or bridged ring group may be 1-3 O, S (O) _m , N(H) _m , NCH ₃ or C(O) substitution;

R²和R⁴分别独立的选自氢原子，卤素，硝基，羟基，羧基，氨基，氰基，C_1-6烷基，卤代C_1-6烷基，C_1-6烷氧基，卤代C_1-6烷氧基，C_1-6烷基氨基，二C_1-6烷基氨基或C_1-6烷氧基；R ² and R ⁴ are each independently selected from the group consisting of a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a carboxyl group, an amino group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a C _1-6 alkoxy group. , halogenated C _1-6 alkoxy, C _1-6 alkylamino, di C _1-6 alkylamino or C _1-6 alkoxy;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子，卤素，氰基，硝基，羧基，氨基，C_1-6烷基，C_1-6烷基氨基，二C_1-6烷基氨基，C_1-6烷氧基，C_1-6烷基磺酰基，卤代C_1-6烷基或卤代C_1-6烷氧基；R ^{3 is} selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a carboxyl group, an amino group, a C _1-6 alkyl group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group, a C _1-6 alkoxy group. a C _1-6 alkylsulfonyl group, a halogenated C _1-6 alkyl group or a halogenated C _1-6 alkoxy group;

R⁵选自氢原子，氰基，C_1-6烷基，C_1-6烷氧基或NR⁷R⁸，R ⁵ is selected from a hydrogen atom, a cyano group, C _1-6 alkyl, C _1-6 alkoxy or NR ⁷ R ^8,

R⁷、R⁸分别独立的选自氢原子，C_1-6烷基磺酰基，任选被1-3个Q³取代的C_1-6烷基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，或N与R⁷、R⁸连接组成任选被1-3个Q²取代的3-14元杂环基、5-14元杂芳基、6-10元螺环基或6-10元桥环基，所述螺环基或桥环基中的碳原子可以被1-3个O、S(O)_m、N(H)_m、NCH₃或C(O)替换；R ^7, R ⁸ are each independently selected from hydrogen, C _1-6 alkylsulfonyl group, optionally substituted with 1-3 Q ³ substituted C _1-6 alkyl, 3-14 membered cycloalkyl, 3- a 14-membered heterocyclic group, a 6-14 membered aryl group or a 5-14 membered heteroaryl group, or N is bonded to R ⁷ and R ⁸ to form a 3-14 membered heterocyclic group optionally substituted by 1 to 3 Q ² groups, a 5-14 membered heteroaryl group, a 6-10 membered spirocyclic group or a 6-10 membered bridged ring group, wherein the carbon atom in the spiro or bridged ring group may be 1-3 O, S(O) _m , N(H) _m , NCH ₃ or C(O) replacement;

Q¹、Q²、Q³分别独立的选自氨基，卤素，氰基，硝基，羟基，羧基，C_1-6烷基，C_1-6烷氧基，C_1-6烷基磺酰基，C_1-6烷基磺酰基氨基，3-14元环烷基，3-14元杂环基，6-14元芳基或5-14元杂芳基；Q ¹ , Q ² and Q ³ are each independently selected from the group consisting of amino, halogen, cyano, nitro, hydroxy, carboxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl a C _1-6 alkylsulfonylamino group, a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group or a 5-14 membered heteroaryl group;

m选自0、1或2。m is selected from 0, 1, or 2.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自氢原子，卤素，氰基，硝基，羧基，或任选被1-3个Q¹取代的3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基； Wherein R ^{1 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a carboxyl group, or a 3-10 membered cycloalkyl group optionally substituted by 1 to 3 Q ¹ , a 3-10 membered heterocyclic group, 6-10 a aryl group or a 5-10 membered heteroaryl group;

R²和R⁴分别独立的选自氢原子，卤素，硝基，羟基，羧基，氨基，氰基，C_1-4烷基，卤代C_1-4烷基，C_1-4烷氧基，卤代C_1-4烷氧基，C_1-4烷基氨基，二C_1-4烷基氨基或C_1-4烷氧基；R ² and R ⁴ are each independently selected from the group consisting of a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a carboxyl group, an amino group, a cyano group, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group, and a C _1-4 alkoxy group. , halogenated C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino or C _1-4 alkoxy;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子，卤素，氰基，氨基，C_1-4烷基，C_1-4烷基氨基，二C_1-4烷基氨基，C_1-4烷氧基，C_1-4烷基磺酰基，卤代C_1-4烷基或卤代C_1-4烷氧基；R ^{3 is} selected from the group consisting of a hydrogen atom, a halogen, a cyano group, an amino group, a C _1-4 alkyl group, a C _1-4 alkylamino group, a di C _1-4 alkylamino group, a C _1-4 alkoxy group, and a C _1-4 An alkylsulfonyl group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group;

R⁵选自氢原子或NR⁷R⁹，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁹ ,

R⁷、R⁸分别独立的选自氢原子，C_1-4烷基磺酰基，任选被1-3个Q³取代的C_1-4烷基、3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基，或N与R⁷、R⁸连接组成任选被1-3个Q²取代的3-10元杂环基或5-10元杂芳基；R ^7, R ⁸ are each independently selected from hydrogen, C _1-4 alkylsulfonyl, optionally substituted with 1-3 Q ³ substituted C _1-4 alkyl, 3-10 membered cycloalkyl, 3- a 10-membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group, or N is bonded to R ⁷ and R ⁸ to form a 3-10 membered heterocyclic group optionally substituted by 1 to 3 Q ² or 5-10 yuan heteroaryl;

Q¹、Q²、Q³分别独立的选自氨基，卤素，氰基，硝基，羟基，羧基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基，C_1-4烷基磺酰基氨基，3-10元环烷基，3-10元杂环基，6-10元芳基或5-10元杂芳基。Q ¹ , Q ² and Q ³ are each independently selected from the group consisting of amino, halogen, cyano, nitro, hydroxy, carboxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl. , C _1-4 alkylsulfonylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自任选被1-2个Q¹取代的5-8元环烷基、5-8元杂环基、6-8元芳基或5-6元杂芳基；Wherein R ^{1 is} selected from a 5-8 membered cycloalkyl group, a 5-8 membered heterocyclic group, a 6-8 membered aryl group or a 5-6 membered heteroaryl group optionally substituted by 1-2 Q ¹ ;

R²和R⁴分别独立的选自氢原子，卤素，氨基，氰基，C_1-4烷基，氟代C_1-4烷基，C_1-4烷基氨基，二C_1-4烷基氨基或C_1-4烷氧基；R ² and R ⁴ are each independently selected from the group consisting of a hydrogen atom, a halogen, an amino group, a cyano group, a C _1-4 alkyl group, a fluoro C _1-4 alkyl group, a C _1-4 alkylamino group, and a di C _1-4 alkane. Alkylamino or C _1-4 alkoxy;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或卤代C_1-4烷基；R ³ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl C _1-4 alkyl or haloalkyl;

R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

R⁷、R⁸分别独立的选自氢原子，C_1-4烷基磺酰基，任选被1-2个Q³取代的C_1-4烷基，或N与R⁷、R⁸连接组成任选被1-2个Q²取代的5-8元杂环基或5-6元杂芳基；R ^7, R ⁸ are each independently selected from hydrogen, C _1-4 alkyl sulfonyl, optionally substituted with 1-2 Q ³ substituted C _1-4 alkyl, or N and R ^7, R ⁸ connected to form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group optionally substituted by 1-2 Q ² ;

Q¹、Q²、Q³分别独立的选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基。Q ¹ , Q ² and Q ³ are each independently selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自任选被1-2个Q¹取代的5-6元杂环基或5-6元杂芳基，Wherein R ^{1 is} selected from a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group optionally substituted by 1-2 Q ¹ groups,

Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

R²和R⁴分别独立的选自氢原子，卤素，氰基，甲基或三氟甲基；R ² and R ⁴ are each independently selected from a hydrogen atom, a halogen, a cyano group, a methyl group or a trifluoromethyl group;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或氟代C_1-4 烷基；R ^{3 is} selected from a hydrogen atom, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl or fluoro C _1-4 alkyl;

R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

R⁷、R⁸分别独立的选自氢原子，C_1-4烷基，或N与R⁷、R⁸连接组成任选被1-2个Q²取代的5-6元杂环基或5-6元杂芳基；R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a C _1-4 alkyl group, or N is bonded to R ⁷ and R ⁸ to form a 5-6 membered heterocyclic group optionally substituted by 1-2 Q ² or 5 -6 membered heteroaryl;

Q²选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基。Q ^{2 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自任选被1-2个Q¹取代的5-6元杂环基，Wherein R ^{1 is} selected from a 5-6 membered heterocyclic group optionally substituted by 1-2 Q ¹ groups,

Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

R²和R⁴分别选自氢原子；R ² and R ⁴ are each selected from a hydrogen atom;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或氟代C_1-4烷基；R ^{3 is} selected from a hydrogen atom, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl or fluoro C _1-4 alkyl;

R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

R⁷、R⁸分别独立的选自氢原子，C_1-4烷基，或N与R⁷、R⁸连接组成任选被1-2个Q²取代的5-6元杂环基，R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a C _1-4 alkyl group, or N is bonded to R ⁷ and R ⁸ to form a 5-6 membered heterocyclic group optionally substituted by 1-2 Q ² groups.

Q²选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基。Q ^{2 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自任选被1-2个Q¹取代的5-6元饱和杂环基，所述杂环基含有1-2个选自N和/或O杂的原子，Wherein R ^{1 is} selected from a 5-6 membered saturated heterocyclic group optionally substituted by 1 to 2 Q ¹ , the heterocyclic group having 1 to 2 atoms selected from N and/or O,

Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

R²和R⁴分别选自氢原子；R ² and R ⁴ are each selected from a hydrogen atom;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或氟代C_1-4烷基；R ^{3 is} selected from a hydrogen atom, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl or fluoro C _1-4 alkyl;

R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

R⁷、R⁸分别独立的选自氢原子或C_1-4烷基。R ⁷ and R ⁸ are each independently selected from a hydrogen atom or a C _1-4 alkyl group.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自任选被1-2个Q¹取代的下列基团：Wherein R ^{1 is} selected from the group consisting of the following groups optionally substituted by 1-2 Q ¹ :

吡咯烷基、咪唑烷基、吡唑烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、四氢呋喃基、四氢噻吩基、哌啶基、哌嗪基、四氢嘧啶基、吗啉基、1，3-噁嗪烷基、 吡喃基或噻喃基，Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, tetra Hydropyrimidinyl, morpholinyl, 1,3-oxazinyl, Pyranyl or thiopyranyl,

Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

R²、R⁴和R⁶分别选自氢原子；R ² , R ⁴ and R ⁶ are each selected from a hydrogen atom;

R³选自氢原子、卤素、氰基、甲基、甲氧基、甲基磺酰基或三氟甲基；R ^{3 is} selected from a hydrogen atom, a halogen, a cyano group, a methyl group, a methoxy group, a methylsulfonyl group or a trifluoromethyl group;

R⁵选自氢原子、氨基、甲基氨基、乙基氨基、二甲氨基、二乙氨基、吡咯烷基、咪唑烷基、吡唑烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、哌啶基、哌嗪基、四氢嘧啶基、吗啉基或1，3-噁嗪烷基。R ^{5 is} selected from the group consisting of a hydrogen atom, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, an isoxazolidinyl group, an oxazolidine group, and a different Thiazolyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyrimidinyl, morpholinyl or 1,3-oxazinyl.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自氟代吡咯烷基、哌啶基、吗啉基、哌嗪基或1，3-噁嗪烷基；Wherein R ^{1 is} selected from the group consisting of fluoropyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or 1,3-oxazinyl;

R²、R⁴和R⁶分别选自氢原子；R ² , R ⁴ and R ⁶ are each selected from a hydrogen atom;

R³选自氢原子、卤素、氰基、甲基、甲基磺酰基或三氟甲基；R ^{3 is} selected from a hydrogen atom, a halogen, a cyano group, a methyl group, a methylsulfonyl group or a trifluoromethyl group;

R⁵选自氢原子、氨基、甲基氨基、乙基氨基、二甲氨基、二乙氨基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基或异噁唑烷基。R ^{5 is} selected from a hydrogen atom, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a pyrrolidinyl group, a pyrazolidinyl group, an imidazolidinyl group, an oxazolidinyl group or an isoxazolidinyl group.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自任选被1-2个Q¹取代的6元饱和杂环基，所述杂环基含有1-2个选自N和/或O的杂原子；Wherein R ^{1 is} selected from a 6-membered saturated heterocyclic group optionally substituted by 1 to 2 Q ¹ , the heterocyclic group having 1 to 2 hetero atoms selected from N and/or O;

Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

R²和R⁴分别选自氢原子；R ² and R ⁴ are each selected from a hydrogen atom;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或氟代C_1-4烷基；R ^{3 is} selected from a hydrogen atom, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl or fluoro C _1-4 alkyl;

R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

R⁷和R⁸分别独立的选自氢原子，C_1-4烷基，或N与R⁷、R⁸连接组成任选被1-2个Q²取代的5元饱和杂环基，所述的杂原子分别独立的选自1-2个N和/或O；R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a C _1-4 alkyl group, or N is bonded to R ⁷ and R ⁸ to form a 5-membered saturated heterocyclic group optionally substituted by 1-2 Q ² . The heteroatoms are independently selected from 1-2 N and/or O;

Q²选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基。Q ^{2 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.

本发明的另一实施方案涉及通式(I)所示的化合物、立体异构体或其药学上可接受的盐，Another embodiment of the present invention relates to a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

其中，R¹选自任选被1-2个Q¹取代的6元饱和杂环基，所述杂环基含有1-2个选自N和/或O的杂原子；Wherein R ^{1 is} selected from a 6-membered saturated heterocyclic group optionally substituted by 1 to 2 Q ¹ , the heterocyclic group having 1 to 2 hetero atoms selected from N and/or O;

Q¹选自氨基、氟原子、氯原子、溴原子、氰基、羟基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基或叔丁氧基； Q ^{1 is} selected from the group consisting of amino, fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, Butoxy or tert-butoxy;

R²和R⁴分别选自氢原子；R ² and R ⁴ are each selected from a hydrogen atom;

R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

R³选自氢原子、氟原子、氯原子、溴原子、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、甲基磺酰基、乙基磺酰基、丙基磺酰基、异丙基磺酰基或三氟甲基；R ^{3 is} selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butyl group. Oxyl, tert-butoxy, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or trifluoromethyl;

R⁵选自氢原子、氨基、甲基氨基、乙基氨基、二甲氨基或二乙氨基。R ^{5 is} selected from a hydrogen atom, an amino group, a methylamino group, an ethylamino group, a dimethylamino group or a diethylamino group.

发明详述Detailed description of the invention

本发明所述“卤素”是指氟、氯、溴、碘等。The "halogen" as used in the present invention means fluorine, chlorine, bromine, iodine or the like.

本发明所述“C_1-6烷基”指含有1-6个碳原子的烷烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、1，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、2-乙基丁基和1-甲基-2-甲基丙基等。所述“C_1-4烷基”指含有1-4个碳原子的上述实施例。The "C _1-6 alkyl group" of the present invention means a linear or branched alkyl group derived from a part of an alkane having 1 to 6 carbon atoms, which is removed by a hydrogen atom, such as a methyl group, an ethyl group, a n-propyl group or a different group. Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl -2-methylpropyl and the like. The "C _1-4 alkyl group" means the above examples containing from 1 to 4 carbon atoms.

本发明所述的“C_1-6烷氧基”是指前文所定义的C_1-6烷基通过氧原子与母体分子部分连接的基团，即“C_1-6烷基-O-”基团，如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基和正己氧基等。所述的“C_1-4烷氧基”指含有1-4个碳原子的上述实施例，即“C_1-4烷基-O-”基团。The "C _1-6 alkoxy group" as used in the present invention means a group in which a C _1-6 alkyl group as defined above is bonded to a parent molecular moiety through an oxygen atom, that is, "C _1-6 alkyl-O-" A group such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy and n-hexyloxy. The "C _1-4 alkoxy group" refers to the above embodiment having 1 to 4 carbon atoms, that is, a "C _1-4 alkyl-O-" group.

本发明所述的“甲基氨基”、“二甲氨基”、“C_1-6烷基磺酰基”、“C_1-6烷基磺酰基氨基”是指CH₃NH-、(CH₃)₂N-、C_1-6烷基-SO₂-、C_1-6烷基-SO₂-NH-。“C_1-6烷基”如前文所定义。The "methylamino", "dimethylamino", "C _1-6 alkylsulfonyl" and "C _1-6 alkylsulfonylamino" as used in the present invention mean CH ₃ NH-, (CH ₃ ). ₂ N-, C _1-6 alkyl-SO ₂ -, C _1-6 alkyl-SO ₂ -NH-. "C _1-6 alkyl" is as defined above.

本发明所示的“3-14元环烷基”指3-14个碳原子的环烷烃部分去除一个氢原子衍生的环状烷基，包括3-8元环烷基、6-14元并环环烷基。The "3-14 membered cycloalkyl group" shown in the present invention means a cycloalkane moiety of 3 to 14 carbon atoms which is removed by a hydrogen atom-derived cyclic alkyl group, including a 3-8 membered cycloalkyl group, 6-14 members. Cyclocycloalkyl.

“3-8元环烷基”，是指3-8个碳原子的环烷烃部分去除一个氢原子衍生的饱和或部分饱和的环状烷基，3-8元饱和环烷基其实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、甲基环丙烷基、二甲基环丙烷基、甲基环丁烷基、二甲基环丁烷基、甲基环戊烷基、二甲基环戊烷基、甲基环己烷基、二甲基环己烷基；3-8元部分饱和环烷基，是指至少含有一个双键且不具有芳香性的环状基团，其具体实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、1，4-环己二烯基、环庚烯基、1，4-环庚二烯基、环辛烯基、1，5-环辛二烯基等。"3-8 membered cycloalkyl" means a saturated or partially saturated cyclic alkyl group derived by removing a hydrogen atom from a cycloalkane moiety of 3 to 8 carbon atoms, and examples of a 3-8 membered saturated cycloalkyl group include Not limited to: cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, methylcyclopropane, dimethylcyclopropane, methylcyclobutane a group, a dimethylcyclobutane group, a methylcyclopentyl group, a dimethylcyclopentyl group, a methylcyclohexane group, a dimethylcyclohexane group; a 3-8 membered partially saturated cycloalkyl group; It means a cyclic group having at least one double bond and having no aromaticity, and specific examples thereof include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and 1,4-cyclohexane. Dienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl and the like.

“6-14元并环环烷基”，是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的6-14元饱和或部分饱和环状基团，6-14元饱和并环环烷基其实例包括但不 限于：二环[3.1.0]己烷基、二环[4.1.0]庚烷基、二环[2.2.0]己烷基、二环[3.2.0]庚烷基、二环[4.2.0]辛烷基、八氢并环戊二烯基、八氢-1H-茚基、十氢化萘基、十四氢菲基；6-14元部分饱和并环环烷基，是指至少含有一个双键且整个环系不具有芳香性的环状基团，其具体实例包括但不限于：双环[3.1.0]己-2-烯基、双环[4.1.0]庚-3-烯基、双环[3.2.0]庚-3-烯基、双环[4.2.0]辛-3-烯基、1，2，3，3a-四氢并环戊二烯基、2，3，3a，4，7，7a-六氢-1H-茚基、1，2，3，4，4a，5，6，Sa-八氢化萘基、1，2，4a，5，6，8a-六氢化萘基、1，2，3，4，5，6，7，8，9，10-十氢菲基、2，3-二氢-1H-茚基、1H-茚基、1，2，3，4-四氢萘基、1，4-二氢萘基等。"6-14 membered cyclocycloalkyl" means a 6-14 membered saturated or partially saturated cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms, 6 -14-membered saturated cyclo-cycloalkyl examples of which include but not Limited to: bicyclo [3.1.0] hexane, bicyclo [4.1.0] heptyl, bicyclo [2.2.0] hexane, bicyclo [3.2.0] heptyl, bicyclo [4.2 .0] octyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecafluorophenanthyl; 6-14 membered partially saturated cyclocycloalkyl, meaning at least A cyclic group containing one double bond and the entire ring system is not aromatic, and specific examples thereof include, but are not limited to, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-ene , bicyclo[3.2.0]hept-3-enyl, bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydrocyclopentadienyl, 2,3,3a ,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,Sa-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydrogenation Naphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthrenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3 , 4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.

本发明所述的“3-10元环烷基”、“5-8元环烷基”、“5-6元环烷基”指的是上述实例中含有3-10个、5-8个、5-6个碳原子的具体实例。The "3-10 membered cycloalkyl group", "5-8 membered cycloalkyl group", and "5-6 membered cycloalkyl group" as used in the present invention means that the above examples contain 3-10, 5-8 Specific examples of 5-6 carbon atoms.

本发明所述“3-14元杂环基”是指含有一至多个杂原子的3-14元饱和或部分饱和环状基团，所述“杂原子”选自N、S、O、CO、SO和/或SO₂等，优选1-3个N、S和/或O原子，更优选1-2个选自N和/或O的杂原子。包括3-8元杂环基和6-14元稠杂环基。The "3-14 membered heterocyclic group" of the present invention means a 3-14 membered saturated or partially saturated cyclic group containing one to a plurality of hetero atoms selected from N, S, O, CO. And SO and/or SO ₂ and the like, preferably 1 to 3 N, S and/or O atoms, more preferably 1 to 2 hetero atoms selected from N and/or O. It includes a 3-8 membered heterocyclic group and a 6-14 membered fused heterocyclic group.

“3-8元杂环基”，是指含有3-8个环原子(其中至少含有一个杂原子)的饱和或部分饱和环状基团。3-8元饱和杂环基其具体实例包括但不仅限于：氧杂环丙烷基、氮杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、四氢噻吩基、吡咯烷基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、1，4-二氧杂环己烷基、1，3-二氧杂环己烷基、1，3-二硫杂环己烷基、哌啶基、吗啉基、哌嗪基、四氢吡喃基、四氢噻喃基等；3-8元部分饱和杂环基，是指至少含有一个双键且不具有芳香性的杂环基团，其具体实例包括但不仅限于：二氢吡咯基、二氢呋喃基、二氢噻吩基、2，3-二氢咪唑基、4，5-二氢咪唑基、2，3-二氢吡唑基、4，5-二氢吡唑基、2，3-二氢噁唑基、4，5-二氢噁唑基、2，3-二氢异噁唑基、4，5-二氢异噁唑基、1，2-二氢吡啶、3，4-二氢吡啶、1，2，3，6-四氢吡啶、2，3，4，5-四氢吡啶、1，2，-二氢嘧啶、4，5-二氢嘧啶、1，2，5，6-四氢嘧啶、1，2，3，4-四氢嘧啶、2H-吡喃基、3，4-二氢-2H-吡喃基、2H-噻喃基、3，4-二氢-2H-噻喃基、5，6-二氢-4H-1，3-噁嗪基、3，4-二氢-2H-1，4-噁嗪基、2H-1，2-噁嗪基、4H-1，2-噁嗪基、6H-1，2-噁嗪基、2H-1，3-噁嗪基、4H-1，3-噁嗪基、6H-1，3-噁嗪基、2H-1，4-噁嗪基、4H-1，4-噁嗪基、异噁嗪基等；优选5-8元杂环基，更优选5-6元杂环基，进一步优选5-6元饱和杂环基。The "3-8 membered heterocyclic group" means a saturated or partially saturated cyclic group having 3 to 8 ring atoms (having at least one hetero atom). Specific examples of the 3-8-membered saturated heterocyclic group include, but are not limited to, an oxacyclopropane group, an aziridine group, an azetidinyl group, an oxetanyl group, a thietane group, a tetrahydrofuran. Base, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,4-dioxane , 1,3-dioxanyl, 1,3-dithiacyclohexane, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, etc. A 3-8 membered partially saturated heterocyclic group means a heterocyclic group having at least one double bond and having no aromaticity, and specific examples thereof include, but are not limited to, dihydropyrrolyl, dihydrofuranyl, dihydrothiophene. , 2,3-dihydroimidazolyl, 4,5-dihydroimidazolyl, 2,3-dihydropyrazolyl, 4,5-dihydropyrazolyl, 2,3-dihydrooxazolyl, 4,5-dihydrooxazolyl, 2,3-dihydroisoxazolyl, 4,5-dihydroisoxazolyl, 1,2-dihydropyridine, 3,4-dihydropyridine, 1, 2,3,6-tetrahydropyridine, 2,3,4,5-tetrahydropyridine, 1,2,-dihydropyrimidine, 4,5-di Hydropyrimidine, 1,2,5,6-tetrahydropyrimidine, 1,2,3,4-tetrahydropyrimidine, 2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2H-thiopyran , 3,4-dihydro-2H-thiopyranyl, 5,6-dihydro-4H-1,3-oxazinyl, 3,4-dihydro-2H-1,4-oxazinyl, 2H -1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H -1,3-oxazinyl, 2H-1,4-oxazinyl, 4H-1,4-oxazinyl, isoxazinyl, etc.; preferably a 5-8 membered heterocyclic group, more preferably 5-6 members The heterocyclic group is further preferably a 5-6 membered saturated heterocyclic group.

“6-14元稠杂环基”，是指含有6-14个环原子(其中至少含有一个杂原子)由两个或两个以上环状结构彼此共用两个相邻的原子连接起来形成的饱和或部分饱和稠环结构，优选6-10元稠杂环基，如苯并3-8元杂环基形成的结构，3-8元杂环基并3-8元杂环基形成的结构等，具体实例包括但不限于：1，3-二氢苯并呋喃基、苯并[d][1.3]二氧 杂环戊烯基、异吲哚啉基、色满基、1，2，3，4-四氢吡咯并[3，4-c]吡咯、

环丁烷并四氢吡咯基、环戊烷并四氢吡咯基、氮杂环丁烷并咪唑烷基、

等。"6-14 membered fused heterocyclic group" means that 6-14 ring atoms (having at least one hetero atom) are bonded by two or more ring structures sharing two adjacent atoms with each other. a structure formed by a saturated or partially saturated fused ring structure, preferably a 6-10 membered fused heterocyclic group, such as a benzo-3-8 membered heterocyclic group, and a 3-8 membered heterocyclic group and a 3-8 membered heterocyclic group. Etc. Specific examples include, but are not limited to, 1,3-dihydrobenzofuranyl, benzo[d][1.3]dioxolyl, isoindolyl, chromanyl, 1,2, 3,4-tetrahydropyrrolo[3,4-c]pyrrole,

Cyclobutane tetrahydropyrrolyl, cyclopentahydrotetrahydropyrrolyl, azetidinazolidinyl,

Wait.

本发明所述“3-10元杂环基”、“5-8元杂环基”和“5-6元杂环基”分别指上述“3-14元杂环基”中环原子数为3-10元、5-8元和5-6元的具体实例。The "3-10 membered heterocyclic group", "5-8 membered heterocyclic group" and "5-6 membered heterocyclic group" of the present invention mean that the number of ring atoms in the above "3-14 membered heterocyclic group" is 3, respectively. Specific examples of -10 yuan, 5-8 yuan, and 5-6 yuan.

本发明所述的“6-14元芳基”是指环原子为6-14元碳原子的环状芳香族化合物除去氢原子得到基团，包括6-8元芳基和8-14元稠环芳基。6-8元芳基包括苯基、环辛四烯基等。8-14元稠环芳基是指由两个或两个以上芳环彼此共用两个相邻的碳原子所形成的稠环基团，包括萘基、蒽基和菲基等；The "6-14 membered aryl group" as used in the present invention means a cyclic aromatic compound having a ring atom of 6 to 14 carbon atoms, and a hydrogen atom is removed to obtain a group, including a 6-8 membered aryl group and an 8-14 membered fused ring. Aryl. The 6-8 membered aryl group includes a phenyl group, a cyclooctadecenyl group, and the like. The 8-14 membered fused ring aryl group refers to a fused ring group formed by two or more aromatic rings sharing two adjacent carbon atoms, including a naphthyl group, an anthracenyl group, a phenanthryl group and the like;

本发明所述“6-10元芳基”和“6-8元芳基”分别是指上述“6-14元芳基”中环原子数为6-10元和6-8元的具体实例。The "6-10 membered aryl group" and "6-8 membered aryl group" of the present invention mean a specific example of the above-mentioned "6-14 membered aryl group" having 6 to 10 members and 6 to 8 members.

本发明所述的“5-14元杂芳基”，是指包含一个或多个杂原子的环原子数为5-14元的环状芳香族基团，所述“杂原子”选自N、S、O、CO、SO和/或SO₂等，优选1-3个选自N、S和/或O的杂原子，更优选1-2个选自N和/或O的杂原子。杂芳基可通过碳或杂环原子与母体键合。包括5-8元杂芳基和8-14元稠杂芳基。The "5-14 membered heteroaryl group" as used in the present invention means a cyclic aromatic group having 5 to 14 members of a ring atom containing one or more hetero atoms, and the "hetero atom" is selected from N. And S, O, CO, SO and/or SO ₂ and the like, preferably 1 to 3 hetero atoms selected from N, S and/or O, more preferably 1 to 2 hetero atoms selected from N and/or O. The heteroaryl group can be bonded to the parent through a carbon or heterocyclic atom. It includes a 5-8 membered heteroaryl group and a 8-14 membered heteroaryl group.

5-8元杂芳基，包括但不限于吡咯基、咪唑基、吡唑基、1，2，3-***基、1，2，4-***基、吡啶基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、1，2，3-噻二唑基、1，2，4-噻二唑基、1，3，4-噻二唑基、1，2，3-噁二唑基、1，2，4-噁二唑基、1，2，5-噁二唑基、1，2，3-三嗪基、1，2，4-三嗪基、四唑基、噁***基、哒嗪基、嘧啶基、吡嗪基、1，2，4-三嗪基、1，3，5-三嗪基、1，2，4，5-四嗪基等；优选5-6元杂芳基。5-8 membered heteroaryl, including but not limited to pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, furyl, thienyl , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazinyl, 1,2,4-tri Zinyl, tetrazolyl, oxatriazole, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5 a tetrazinyl group or the like; preferably a 5-6 membered heteroaryl group.

8-14元稠杂芳基，是指含有8-14个环原子(其中至少含有一个杂原子)由两个或两个以上芳环(至少有一个为杂芳环)彼此共用两个相邻的原子连接起来形成的稠环结构，包括但不限于苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、喹啉基、异喹啉基、吲嗪基、吲唑基、酞嗪基、喹喔啉基、喹唑啉基、苯并二嗪基、苯并异噁唑基、苯并噁嗪基、苯并咪唑基、吡啶并吡啶基、吡唑并[3，4-b]吡啶基、嘌呤基、吖啶基和呫吨基等；The 8-14 membered heteroaryl group means that 8 to 14 ring atoms (having at least one hetero atom) are shared by two adjacent two or more aromatic rings (at least one of which is a heteroaromatic ring) A fused ring structure formed by the joining of atoms, including but not limited to benzofuranyl, isobenzofuranyl, benzothienyl, fluorenyl, isodecyl, quinolinyl, isoquinolinyl, pyridazine , carbazolyl, pyridazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzisoxazolyl, benzoxazinyl, benzimidazolyl, pyridopyridinyl, pyridyl Zizo[3,4-b]pyridyl, indenyl, acridinyl and xanthenyl;

本发明所述“5-10元杂芳基”和“5-6元杂芳基”分别是指上述“5-14元杂芳基”中环原子数为5-10元和5-6元的具体实例。The "5-10 membered heteroaryl group" and "5-6 membered heteroaryl group" in the present invention mean that the above-mentioned "5-14 membered heteroaryl group" has a ring number of 5-10 yuan and 5-6 yuan, respectively. Specific examples.

本发明所述“6-10元螺环基”指至少有两个环共享一个原子形成的环原子数为 6-10个的环状结构，包括6-10元饱和或不饱和的螺环结构。6-10元饱和螺环基的实例包括但不限于螺[2.4]庚烷、螺[3.4]辛烷、螺[4.4]壬烷、螺[2.5]辛烷、螺[3.5]壬烷、螺[4.5]癸烷、1-氧-2，7-二氮杂螺[4.4]壬-2-烯、螺[3.4]辛-5，7-二酮等；6-10元部分饱和螺环基的实例包括但不限于螺[3.4]辛-6-烯基、螺[3.5]壬-6-烯基、螺[4.4]壬-2，7-二烯基、螺[4.5]癸-6，8-二烯基等。The "6-10 membered spiro group" as used in the present invention means that the number of ring atoms formed by at least two rings sharing one atom is 6-10 ring structures, including 6-10 yuan saturated or unsaturated spiro ring structures. Examples of 6-10 membered saturated spirocyclic groups include, but are not limited to, spiro[2.4]heptane, spiro[3.4]octane, spiro[4.4]decane, spiro[2.5]octane, spiro[3.5]decane, spiro [4.5] decane, 1-oxo-2,7-diazaspiro[4.4]non-2-ene, spiro[3.4]oct-5,7-dione, etc.; 6-10 member partially saturated spiro group Examples include, but are not limited to, spiro[3.4]oct-6-alkenyl, spiro[3.5]non-6-alkenyl, spiro[4.4]indole-2,7-dienyl, spiro[4.5]癸-6, 8-dienyl and the like.

本发明所述“6-10元桥环基”指任意两个环共用两不直接相连的原子形成的环原子数为6-10个的环状结构，包括6-10元饱和或不饱和的桥环结构。6-10元饱和桥环基的实例包括但不限于双环[3.1.1]庚烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.1]壬烷基、金刚烷基等；6-10元部分饱和桥环基的实例包括但不限于双环[2.2.1]庚-5-烯基、双环[3.2.1]辛-6-烯基、双环戊二烯基等；The "6-10 membered bridged ring group" as used in the present invention means a ring structure in which any two rings share two atoms which are not directly connected, and the number of ring atoms is 6-10, including 6-10 yuan saturated or unsaturated. Bridge ring structure. Examples of 6-10 membered saturated bridged ring groups include, but are not limited to, bicyclo [3.1.1] heptyl, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] Octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonanyl, adamantyl, and the like; examples of 6-10 membered partially saturated bridged ring groups include, but are not limited to, bicyclo [2.2.1] Hg-5-alkenyl, bicyclo[3.2.1]oct-6-alkenyl, biscyclopentadienyl, etc.;

本发明所述的“6-10元螺环基”和“6-10元桥环基”中的任一环原子可被一个或多个杂原子替换，所述的杂原子选自N、S、O、NH、NH₂、NCH₃、C(O)、SO和/或SO₂等。Any of the "6-10 membered spiro group" and "6-10 membered bridged ring group" of the present invention may be replaced by one or more hetero atoms selected from N, S. , O, NH, NH ₂ , NCH ₃ , C(O), SO and/or SO ₂ and the like.

特别优选的化合物或其立体异构体或其药学上可接受的盐包括：Particularly preferred compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof include:

本发明还提供了上述化合物的制备方法：The invention also provides a preparation method of the above compound:

反应步骤Reaction step

步骤1：中间体1的制备Step 1: Preparation of Intermediate 1

将吗啉和/或R¹-H溶于适合的溶剂中，加入原料1的溶液，升温搅拌，分液，洗涤，干燥，纯化得中间体1。The morpholine and/or R ¹ -H are dissolved in a suitable solvent, and the solution of the raw material 1 is added, stirred at a temperature, separated, washed, dried, and purified to obtain Intermediate 1.

步骤2：中间体2的制备Step 2: Preparation of intermediate 2

将中间体1、原料2和醋酸钾加入到适合的溶剂中，氮气保护下加入合适的催化剂，升温搅拌，抽滤，旋蒸，洗涤得中间2。The intermediate 1, the raw material 2 and the potassium acetate are added to a suitable solvent, and a suitable catalyst is added under a nitrogen atmosphere, and the mixture is stirred at a temperature, suction-filtered, and steamed, and washed to obtain a middle portion 2.

步骤3：中间体3的制备Step 3: Preparation of intermediate 3

将中间体2和原料3溶于适合的溶剂中，加入碳酸铯，氮气保护下加入合适的催 化剂，升温搅拌，旋蒸，加入乙酸乙酯和水，分液，浓缩，纯化得中间体3。Dissolve intermediate 2 and starting material 3 in a suitable solvent, add cesium carbonate, and add appropriate nucleus under the protection of nitrogen. The agent is heated at a temperature and stirred, and then steamed, and ethyl acetate and water are added thereto, and the mixture is separated, and concentrated to obtain Intermediate 3.

步骤4：式(I)化合物的制备Step 4: Preparation of a compound of formula (I)

将中间体3溶于吡啶中，加入原料4，升温搅拌，浓缩，纯化得式(I)化合物。The intermediate 3 is dissolved in pyridine, and the starting material 4 is added, stirred at elevated temperature, concentrated, and purified to give the compound of the formula (I).

反应流程图中的R¹、R²、R³、R⁴、R⁵、R⁶如前文所述。R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ in the reaction scheme are as described above.

原料3来源于市购或制备。Starting material 3 is derived from commercially available or prepared.

以上步骤所述的溶剂选自有机溶剂、无机溶剂或其混合溶剂，具体包括但不限于苯、甲苯、二氯甲烷、氯仿、四氢呋喃、N，N-二甲基亚砜、丙酮、乙腈、吡啶、水等。所述的催化剂包括但不限于三环己基膦、正丁基二(1-金刚烷基)膦、三(二亚苄基丙酮)二钯、醋酸钯、碳酸铯、1，1-双(二苯基膦)二茂铁二氯化钯、1，1-双(二叔丁基膦基)二茂铁二氯化钯等。The solvent described in the above step is selected from an organic solvent, an inorganic solvent or a mixed solvent thereof, and specifically includes but is not limited to benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethyl sulfoxide, acetone, acetonitrile, pyridine. , water, etc. The catalyst includes, but is not limited to, tricyclohexylphosphine, n-butylbis(1-adamantyl)phosphine, tris(dibenzylideneacetone)dipalladium, palladium acetate, cesium carbonate, 1,1-double (two Phenylphosphine) ferrocene palladium dichloride, 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride, and the like.

本发明上述通式(I)任一化合物药学上可接受的盐是指由药学上可接受的、非毒性碱或酸制备的盐，包括有机酸盐、无机酸盐、有机碱盐、无机碱盐。有机酸盐包括甲酸、乙酸、苯磺酸、苯甲酸、对甲苯磺酸、樟脑磺酸、柠檬酸、甲磺酸、乙磺酸、丙磺酸、富马酸、葡糖酸、谷氨酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘酸、双羟萘酸、泛酸、琥珀酸、酒石酸、天冬氨酸、甘油磷酸、樟脑磺酸、环戊烷丙酸、新戊酸、酸性天然氨基酸(如天冬氨酸、谷氨酸等)等的盐。无机酸盐包括氢溴酸、氢氯酸、硝酸、硫酸、磷酸、硝酸等的盐。The pharmaceutically acceptable salt of the compound of the above formula (I) of the present invention means a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including an organic acid salt, a mineral acid salt, an organic alkali salt, an inorganic base. salt. Organic acid salts include formic acid, acetic acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid , isethionethane, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, aspartic acid, glycerophosphoric acid, camphorsulfonic acid, cyclopentane propionic acid , a salt of pivalic acid, an acidic natural amino acid (such as aspartic acid, glutamic acid, etc.). The inorganic acid salt includes a salt of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, nitric acid or the like.

有机碱盐包括伯、仲和叔胺，被取代胺包括天然存在的取代胺、环胺和碱离子交换树脂，选自甜菜碱、咖啡因、胆碱、N，N’-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡甲胺、氨基葡萄糖、海巴明、异丙基胺、甲基葡糖胺、吗啉、哌嗪、哌啶、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇、碱性天然氨基酸(如赖氨酸、精氨酸、组氨酸等)等的盐。无机碱盐包括铵以及锂、钠、钾、钙、镁、锌、钡、铝、铁、酮、亚铁、锰、二价锰等的盐。The organic base salts include primary, secondary and tertiary amines, and the substituted amines include naturally occurring substituted amines, cyclic amines and alkali ion exchange resins selected from the group consisting of betaines, caffeine, choline, N,N'-dibenzylethylene. Amine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, meglumine, glucosamine, sea Bamin, isopropylamine, methyl glucosamine, morpholine, piperazine, piperidine, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, alkaline A salt of a natural amino acid (such as lysine, arginine, histidine, etc.). The inorganic base salts include ammonium and salts of lithium, sodium, potassium, calcium, magnesium, zinc, cesium, aluminum, iron, ketone, ferrous iron, manganese, divalent manganese, and the like.

本发明式(I)化合物的“立体异构体”是指当式(I)化合物存在不对称碳原子时，会产生对映异构体，当化合物存在碳碳双键或环状结构时，会产生顺反异构体，当化合物存在酮或肟时，会产生互变异构体，所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。The "stereoisomer" of the compound of the formula (I) of the present invention means that when an asymmetric carbon atom is present in the compound of the formula (I), an enantiomer is produced, and when the compound has a carbon-carbon double bond or a cyclic structure, The cis-trans isomer is produced. When the compound is present in the ketone or oxime, a tautomer is produced, and all enantiomers, diastereomers, racemic isomers of the compound of formula (I), Cis trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of the invention.

本发明还包括通式(I)所述任一化合物或其立体异构体或药学上可接受的盐与一种或多种药学上可接受的载体组成的药物组合物。所述的药物组合物可通过常规的方法，添加药用载体如赋形剂、粘合剂、增湿剂、崩解剂、增稠剂等任何种类的制剂助剂制备成临床上或药学上可接受的任一剂型，可经过口服、肠胃外、雾化、直肠、阴 道、腹膜或局部给药等方式施用于需要这种治疗的患者，如片剂、颗粒、胶囊、粉末、注射剂、吸入剂、舌下给药制剂、糖浆、凝胶、油膏、栓剂、洗剂、鼻腔滴剂、喷雾剂、透皮制剂等。所述的肠胃外包括皮下注射、静脉注射、肌肉注射、胸骨内注射或其他输液技术。每一单位制剂中含有生理有效量的式(I)所示的化合物0.01g～10g，可以为但不限于0.01g、0.05g、0.1g、0.125g、0.15g、0.2g、0.25g、0.3g、0.4g、0.5g、0.6g、0.75g、1g、1.25g、1.5g、1.75g、2g、2.5g、3g、4g、5g、10g等。The invention also includes pharmaceutical compositions of any of the compounds of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers. The pharmaceutical composition can be prepared into a clinical or pharmaceutical form by a conventional method by adding a pharmaceutical carrier such as an excipient, a binder, a moisturizing agent, a disintegrating agent, a thickening agent and the like to any kind of formulation auxiliary. Acceptable in any dosage form, oral, parenteral, aerosolized, rectal, vaginal Oral, peritoneal or topical administration to patients in need of such treatment, such as tablets, granules, capsules, powders, injections, inhalants, sublingual formulations, syrups, gels, ointments, suppositories, washes Agents, nasal drops, sprays, transdermal preparations, and the like. The parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection or other infusion techniques. Each unit of the preparation contains a physiologically effective amount of 0.01 g to 10 g of the compound represented by the formula (I), which may be, but not limited to, 0.01 g, 0.05 g, 0.1 g, 0.125 g, 0.15 g, 0.2 g, 0.25 g, 0.3. g, 0.4 g, 0.5 g, 0.6 g, 0.75 g, 1 g, 1.25 g, 1.5 g, 1.75 g, 2 g, 2.5 g, 3 g, 4 g, 5 g, 10 g, and the like.

本发明的上述药物组合物还可以包含一种或多种第二治疗活性剂，所述治疗活性剂为抗代谢物，选自卡培他滨、吉西他滨或培美曲塞二钠；为生长因子抑制剂，选自帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼或凡德他尼；为抗体，选自赫赛汀或贝伐单抗；为有丝***抑制剂，选自紫杉醇、长春瑞滨、多西他赛或多柔比星；为抗肿瘤激素类，选自来曲唑、他莫西芬、氟维司群、氟他胺或曲普瑞林；为烷化剂类，选自环磷酰胺、氮芥、马法兰、瘤可宁或卡莫司汀；为金属类，选自卡铂、顺铂或奥沙利铂；为拓扑异构酶抑制剂，选自拓扑特肯喜树碱、拓扑替康或依立替康；为嘌呤类似物，选自6-巯基嘌呤、6-硫鸟嘌呤或硫唑嘌呤；为生物药，选自免疫调节蛋白、抗肿瘤抗原的单克隆抗体、肿瘤抑制基因或癌疫苗；或为HDAC抑制剂，选自SAHA、西达本胺或恩替诺特。The above pharmaceutical composition of the present invention may further comprise one or more second therapeutically active agents which are antimetabolites selected from the group consisting of capecitabine, gemcitabine or pemetrexed disodium; Inhibitor, selected from the group consisting of pazopanib, imatinib, erlotinib, lapatinib, gefitinib or vandetanib; an antibody selected from Herceptin or bevacizumab; a mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel or doxorubicin; an antitumor hormone selected from the group consisting of letrozole, tamoxifen, fulvestrant, flutamide or tropa Ruilin; is an alkylating agent selected from the group consisting of cyclophosphamide, nitrogen mustard, melphalan, cyclamate or carmustine; is a metal selected from carboplatin, cisplatin or oxaliplatin; An enzyme inhibitor selected from the group consisting of topotecan camptothecin, topotecan or irinotecan; a purine analog selected from the group consisting of 6-mercaptopurine, 6-thioguanine or azathioprine; a regulatory protein, a monoclonal antibody against a tumor antigen, a tumor suppressor gene or a cancer vaccine; or an HDAC inhibitor selected from the group consisting of SAHA, Sida Knott amine or Entecavir.

本发明还包括通式(I)所述任一化合物或其立体异构体或其药学上可接受的盐在制备用于预防和/或治疗增殖性疾病药物中的用途，所述的增殖性疾病为癌症或非癌性增殖性疾病，所述的癌症选自肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、乳腺导管瘤、头颈癌、子***、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤；所述非癌性增殖性疾病选自皮肤或***的良性增生。The present invention also includes the use of any of the compounds of the formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prophylaxis and/or treatment of a proliferative disease, said proliferative The disease is cancer or a non-cancerous proliferative disease selected from the group consisting of lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, breast ductal tumor, head and neck cancer, and a child. Cervical cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female genital cancer, carcinoma in situ, lymphoma, Neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villus Tumor, melanoma, cell tumor, and sarcoma; the non-cancerous proliferative disease is selected from benign hyperplasia of the skin or prostate.

本发明的通式(I)化合物或其立体立体异构体或其药学上可接受的盐具有优良的PI3K抑制活性，它们除了可用于预防和/或治疗增殖性疾病之外，也用于预防和/或治疗其它由PI3K信号通路紊乱引起的疾病，例如炎性、疾病阻塞性呼吸道疾病、白细胞(特别是嗜中性粒细胞)以及B和T囊依赖性淋巴细胞功能异常的疾病、心血管疾病、动脉粥样硬化、高血压、深层静脉血栓形成、中风、心肌梗塞、不稳定性心绞痛、血栓栓塞、肺栓塞、血栓溶解性疾病、急性动脉局部缺血、外周血栓性阻塞和冠状动脉疾病、再灌注损伤、视网膜病变等疾病。The compound of the formula (I) of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt thereof has excellent PI3K inhibitory activity, and is useful for prevention in addition to being useful for preventing and/or treating proliferative diseases. And/or treatment of other diseases caused by disorders of the PI3K signaling pathway, such as inflammatory, disease-obstructing respiratory diseases, white blood cells (especially neutrophils), and B and T-sac-dependent lymphocyte dysfunction, cardiovascular Disease, atherosclerosis, hypertension, deep vein thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombotic disease, acute arterial ischemia, peripheral thrombotic obstruction, and coronary artery disease , reperfusion injury, retinopathy and other diseases.

本发明通过体外药理学实验进一步阐述本发明的有益效果但不应将此理解为本发明化合物仅具有以下有益效果： The present invention further illustrates the beneficial effects of the present invention by in vitro pharmacological experiments, but it should not be understood that the compounds of the present invention have only the following beneficial effects:

下述实验中缩写所代表的含义如下：The meanings of the abbreviations in the following experiments are as follows:

HEPES：羟乙基哌嗪乙硫磺酸；HEPES: hydroxyethylpiperazine ethanesulfuric acid;

EGTA：乙二醇二***二胺四乙酸；EGTA: ethylene glycol diethyl ether diamine tetraacetic acid;

EDTA：乙二胺四乙酸EDTA: ethylenediaminetetraacetic acid

CHAPS：3-[3-(胆酰胺丙基)二甲氨基]丙磺酸内盐；CHAPS: 3-[3-(cholamidopropyl)dimethylamino]propanesulfonic acid inner salt;

DTT：二硫苏糖醇；DTT: dithiothreitol;

PIP2：4，5-二磷酸磷脂酰肌醇；PIP2: 4,5-diphosphophosphatidylinositol;

ATP：三磷酸腺苷；ATP: adenosine triphosphate;

DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;

Tween-20：吐温20；Tween-20: Tween 20;

HPC：羟丙基纤维素；HPC: hydroxypropyl cellulose;

HP-β-CD：羟丙基倍他环糊精。HP-β-CD: hydroxypropyl beta-cyclodextrin.

实验例1 化合物的体外酶学抑制活性测定Experimental Example 1 Determination of in vitro enzymatic inhibitory activity of a compound

测试物 化合物1、2、3、4、5，其化学名称和结构见制备实施例；Test compound 1, 2, 3, 4, 5, the chemical name and structure of which are shown in the preparation examples;

对照药 BKM120，结构式见背景技术。The reference drug BKM120, the structural formula see the background art.

mTOR酶学实验方法mTOR enzymatic experimental method

1.试剂配制1. Reagent preparation

1.1 1倍激酶缓冲液：50mM HEPES，pH 7.5，10mM MgCl₂，1mM EGTA，3mM MnCl₂，0.01％Tween-20，2mM DTT；1.1 1X kinase buffer: 50mM HEPES, pH 7.5, 10mM MgCl ₂ , 1mM EGTA, 3mM MnCl ₂ , 0.01% Tween-20, 2mM DTT;

1.2 4倍激酶溶液：1倍激酶缓冲液中加入mTOR激酶，配制4倍激酶溶液，终浓度为2.5nM或4nM；1.2 4 times kinase solution: 1 time kinase buffer was added to mTOR kinase to prepare 4 times kinase solution, the final concentration was 2.5nM or 4nM;

1.3 2倍底物和ATP溶液：1倍激酶缓冲液中加入底物4EBP1和ATP，配制2倍底物溶液，4EBP1终浓度为50nM，ATP终浓度为10.8μM或6μM；1.3 2 times substrate and ATP solution: 1 substrate kinase buffer was added to the substrate 4EBP1 and ATP, 2 times the substrate solution was prepared, the final concentration of 4EBP1 was 50nM, and the final concentration of ATP was 10.8μM or 6μM;

1.4 4倍测试物溶液：采用100％DMSO配制最高浓度100倍的测试物溶液，终浓度10μM，用100％DMSO 4倍梯度稀释10个浓度，再用1倍激酶缓冲液稀释25倍，得到4倍的测试物溶液；1.4 4 times test solution: 100% DMSO was used to prepare a test solution with a maximum concentration of 100 times, a final concentration of 10 μM, diluted with 10% concentration in 100% DMSO, and then diluted 25 times with 1× kinase buffer to obtain 4 Times test solution;

1.5 检测液的配制：配制含2倍终浓度EDTA和4EBP1磷酸化抗体的检测液，EDTA终浓度为8mM，4EBP磷酸化抗体终浓度为2nM。1.5 Preparation of test solution: A test solution containing 2 times the final concentration of EDTA and 4EBP1 phosphorylated antibody was prepared, the final concentration of EDTA was 8 mM, and the final concentration of 4EBP phosphorylated antibody was 2 nM.

2.实验步骤2. Experimental steps

2.1 往384孔板中每孔加入2.5μL系列稀释的4倍测试物溶液，复孔；2.1 Add 2.5 μL of serially diluted 4 times test solution to each well of a 384-well plate, and repeat the well;

2.2 每孔加入2.5μL4倍激酶溶液，震动混匀；2.2 Add 2.5 μL of 4× kinase solution to each well and mix by shaking;

2.3 每孔加入5μL 2倍底物和ATP溶液，室温孵育1小时； 2.3 Add 5 μL of 2 times substrate and ATP solution to each well and incubate for 1 hour at room temperature;

2.4 最后加入10μL检测液终止反应，60分钟后，Envision读取数据Lance signal(665nM)。2.4 Finally, 10 μL of the test solution was added to terminate the reaction. After 60 minutes, Envision read the data Lance signal (665 nM).

3.数据处理3. Data processing

抑制率％＝(最大值-样本值)/(最大值-最小值)×100Inhibition rate % = (maximum - sample value) / (maximum - minimum value) × 100

其中“最大值”为DMSO对照孔读数，“最小值”为不加激酶的对照孔读数。The "maximum" is the DMSO control well reading and the "minimum" is the control well reading without kinase.

输入GraphPad Prism 5.0作图，得到曲线及IC₅₀。The GraphPad Prism 5.0 was input and the curve and IC ₅₀ were obtained.

PI3Kα酶学实验方法PI3Kα enzymatic experimental method

1.试剂配制1. Reagent preparation

1.1 1倍激酶缓冲液：50mM HEPES，pH 7.5，3mM MgCl₂，1mM EGTA，100mM NaCl，0.03％CHAPS，2mM DTT；1.1 1X kinase buffer: 50 mM HEPES, pH 7.5, 3 mM MgCl ₂ , 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, 2 mM DTT;

1.2 4倍激酶溶液：1倍激酶缓冲液中加入PI3Kα激酶，配制4倍激酶溶液，终浓度为1.65nM；1.2 4 times kinase solution: 1 time kinase buffer was added PI3Kα kinase to prepare a 4 times kinase solution, the final concentration was 1.65 nM;

1.3 2倍底物和ATP溶液：1倍激酶缓冲液中加入底物PIP2和ATP，配制2倍底物溶液，PIP2终浓度为50μM，ATP终浓度为25μM；1.3 2 times substrate and ATP solution: 1 time kinase buffer was added to the substrate PIP2 and ATP, 2 times the substrate solution was prepared, the final concentration of PIP2 was 50 μM, and the final concentration of ATP was 25 μM;

1.4 4倍测试物溶液：采用100％DMSO配制最高浓度100倍的测试物溶液，终浓度10μM，用100％DMSO 4倍梯度稀释10个浓度，再用1倍激酶缓冲液稀释25倍，得到4倍的测试物溶液；1.4 4 times test solution: 100% DMSO was used to prepare a test solution with a maximum concentration of 100 times, a final concentration of 10 μM, diluted with 10% concentration in 100% DMSO, and then diluted 25 times with 1× kinase buffer to obtain 4 Times test solution;

1.5 Kinase-Glo reagent试剂，将其放置升温到室温，用来终止反应并产生检测信号。1.5 Kinase-Glo reagent, which is allowed to warm to room temperature to terminate the reaction and generate a detection signal.

2.实验步骤2. Experimental steps

2.1 往384孔板中每孔加入2.5μL系列稀释的4倍测试物溶液；2.1 Add 2.5 μL of serially diluted 4 times test solution to each well of a 384-well plate;

2.2 每孔加入2.5μL 4倍激酶溶液，震动混匀；2.2 Add 2.5 μL of 4× kinase solution to each well and mix by shaking;

2.3 每孔加入5μL 2倍底物和ATP溶液，室温孵育1小时；2.3 Add 5 μL of 2 times substrate and ATP solution to each well and incubate for 1 hour at room temperature;

2.4 最后加入10μL检测溶液终止反应，缓慢震摇15分钟后，Flexstation读取数据RLU。2.4 Finally, add 10 μL of detection solution to terminate the reaction. After shaking for 15 minutes, Flexstation reads the data RLU.

3.数据处理3. Data processing

抑制率％＝100-(最大值-样本值)/(最大值-最小值)×100Inhibition rate %=100-(maximum-sample value)/(maximum-minimum value)×100

其中“最大值”为不加激酶的对照孔读数，“最小值”为DMSO对照孔读数。The "maximum" is the control well reading without kinase, and the "minimum" is the DMSO control well reading.

输入GraphPad Prism 5.0作图，得到曲线及IC₅₀。The GraphPad Prism 5.0 was input and the curve and IC ₅₀ were obtained.

PI3Kδ酶学实验方法PI3Kδ enzymatic experimental method

1.试剂配制 1. Reagent preparation

1.1 1倍激酶缓冲液：50mM HEPES，pH 7.5，3mM MgCl₂，1mM EGTA，100mM NaCl，0.03％CHAPS，2mM DTT；1.1 1X kinase buffer: 50 mM HEPES, pH 7.5, 3 mM MgCl ₂ , 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, 2 mM DTT;

1.2 4倍激酶溶液：1倍激酶缓冲液中加入PI3Kδ激酶，配制4倍激酶溶液，终浓度为5.7nM；1.2 4 times kinase solution: 1 time kinase buffer was added PI3Kδ kinase to prepare 4 times kinase solution, the final concentration was 5.7nM;

1.3 2倍底物和ATP溶液：1倍激酶缓冲液中加入底物PIP2和ATP，配制2倍底物溶液，PIP2终浓度为50μM，ATP终浓度为25μM；1.3 2 times substrate and ATP solution: 1 time kinase buffer was added to the substrate PIP2 and ATP, 2 times the substrate solution was prepared, the final concentration of PIP2 was 50 μM, and the final concentration of ATP was 25 μM;

1.4 4倍测试物溶液：采用100％DMSO配制最高浓度100倍的测试物溶液，终浓度10μM，用100％DMSO 4倍梯度稀释10个浓度，再用1倍激酶缓冲液稀释25倍，得到4倍的测试物溶液；1.4 4 times test solution: 100% DMSO was used to prepare a test solution with a maximum concentration of 100 times, a final concentration of 10 μM, diluted with 10% concentration in 100% DMSO, and then diluted 25 times with 1× kinase buffer to obtain 4 Times test solution;

1.5 Kinase-Glo reagent试剂，将其放置升温到室温，用来终止反应并产生检测信号。1.5 Kinase-Glo reagent, which is allowed to warm to room temperature to terminate the reaction and generate a detection signal.

2.实验步骤2. Experimental steps

2.1 往384孔板中每孔加入2.5μL系列稀释的4倍测试物溶液；2.1 Add 2.5 μL of serially diluted 4 times test solution to each well of a 384-well plate;

2.2 每孔加入2.5μL 4倍激酶溶液，震动混匀；2.2 Add 2.5 μL of 4× kinase solution to each well and mix by shaking;

2.3 每孔加入5μL2倍底物和ATP溶液，室温孵育2小时；2.3 Add 5 μL of 2 times substrate and ATP solution to each well and incubate for 2 hours at room temperature;

2.4 最后加入10μL检测溶液终止反应，缓慢震摇15分钟后，Flexstation读取数据RLU。2.4 Finally, add 10 μL of detection solution to terminate the reaction. After shaking for 15 minutes, Flexstation reads the data RLU.

3.数据处理3. Data processing

抑制率％＝100-(最大值-样本值)/(最大值-最小值)×100Inhibition rate %=100-(maximum-sample value)/(maximum-minimum value)×100

其中“最大值”为不加激酶的对照孔读数，“最小值”为DMSO对照孔读数。The "maximum" is the control well reading without kinase, and the "minimum" is the DMSO control well reading.

输入GraphPad Prism 5.0作图，得到曲线及IC₅₀。The GraphPad Prism 5.0 was input and the curve and IC ₅₀ were obtained.

PI3Kβ，PI3Kγ酶学实验方法PI3Kβ, PI3Kγ enzymatic experimental method

1.试剂配制1. Reagent preparation

1.1 1倍激酶缓冲液：50mM HEPES，pH 7.5，3mM MgCl₂，1mM EGTA，100mM NaCl，0.03％CHAPS，2mM DTT；1.1 1X kinase buffer: 50 mM HEPES, pH 7.5, 3 mM MgCl ₂ , 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, 2 mM DTT;

1.2 4倍激酶溶液：1倍激酶缓冲液中分别加入PI3Kβ或PI3Kγ激酶，配制4倍激酶溶液，终浓度为PI3Kβ4.8nM，PI3Kγ7.6nM；1.2 4 times kinase solution: PI3Kβ or PI3Kγ kinase was added to 1× kinase buffer to prepare 4 times kinase solution, the final concentration was PI3Kβ4.8nM, PI3Kγ7.6nM;

1.3 2倍底物和ATP溶液：1倍激酶缓冲液中加入底物PIP2和ATP，配制2倍底物溶液，PIP2终浓度为50μM，ATP终浓度为25μM；1.3 2 times substrate and ATP solution: 1 time kinase buffer was added to the substrate PIP2 and ATP, 2 times the substrate solution was prepared, the final concentration of PIP2 was 50 μM, and the final concentration of ATP was 25 μM;

1.4 4倍测试物溶液：采用100％DMSO配制最高浓度100倍的测试物溶液，终浓度10μM，用100％DMSO 4倍梯度稀释10个浓度，再用1倍激酶缓冲液稀释25倍，得到4倍的测试物溶液； 1.4 4 times test solution: 100% DMSO was used to prepare a test solution with a maximum concentration of 100 times, a final concentration of 10 μM, diluted with 10% concentration in 100% DMSO, and then diluted 25 times with 1× kinase buffer to obtain 4 Times test solution;

1.5 ADP-Glo reagent试剂，将其放置升温到室温，用来终止反应并产生检测信号。1.5 ADP-Glo reagent, which is allowed to warm to room temperature to terminate the reaction and generate a detection signal.

2.实验步骤2. Experimental steps

2.1 往384孔板中每孔加入2.5μL系列稀释的4倍测试物溶液；2.1 Add 2.5 μL of serially diluted 4 times test solution to each well of a 384-well plate;

2.2 每孔加入2.5μL4倍激酶溶液，震动混匀；2.2 Add 2.5 μL of 4× kinase solution to each well and mix by shaking;

2.3 每孔加入5μL2倍底物和ATP溶液，室温孵育1小时；2.3 Add 5 μL of 2 times substrate and ATP solution to each well and incubate for 1 hour at room temperature;

2.4 384孔板中每孔取出5μL反应液转移至新的384孔板，新加入反应液的的384孔板中每孔加入5μL ADP-Glo reagent，缓慢震摇混匀，然后平衡40分钟。2.4 Remove 5 μL of the reaction solution from each well in a 384-well plate and transfer to a new 384-well plate. Add 5 μL of ADP-Glo reagent to each well of the 384-well plate to which the reaction solution was added, slowly shake and mix, and then equilibrate for 40 minutes.

2.5 每孔加入10μL检测溶液终止反应，震摇1分钟，平衡60分钟后，synergy读取数据RLU。2.5 Add 10 μL of detection solution to each well to stop the reaction, shake for 1 minute, and after 60 minutes of equilibration, synergy reads the data RLU.

3.数据处理3. Data processing

抑制率％＝(最大值-样本值)/(最大值-最小值)×100Inhibition rate % = (maximum - sample value) / (maximum - minimum value) × 100

其中“最小值”为不加激酶的对照孔读数，“最大值”为DMSO对照孔读数。The "minimum" is the control well reading without kinase and the "maximum" is the DMSO control well reading.

输入GraphPad Prism 5.0作图，得到曲线及IC₅₀。The GraphPad Prism 5.0 was input and the curve and IC ₅₀ were obtained.

表1.化合物的体外酶学活性(IC₅₀，nM)Table 1. In vitro enzymatic activity of compounds (IC ₅₀ , nM)

由表1可知，本发明化合物对于PI3K激酶的众多亚型均具有很好的抑制活性，与mTOR激酶的抑制活性相比，本发明化合物对于PI3K激酶具有较高的选择性。As is apparent from Table 1, the compounds of the present invention have excellent inhibitory activity against numerous subtypes of PI3K kinase, and the compounds of the present invention have higher selectivity for PI3K kinase than the inhibitory activity of mTOR kinase.

实验例2 本发明化合物的体外细胞学抑制活性Experimental Example 2 In vitro cytological inhibitory activity of the compound of the present invention

测试物 本发明化合物1、3、5，其化学名称和结构见制备实施例。Test Articles Compounds 1, 3, and 5 of the present invention, the chemical names and structures thereof, are shown in the Preparation Examples.

对照药 BKM120，结构式见背景技术。The reference drug BKM120, the structural formula see the background art.

下述实验中所用细胞株代表的含义如下：The meaning of the cell lines used in the following experiments is as follows:

U87MG：人脑星形胶质母细胞瘤细胞株；U87MG: human brain astrocyte cell line;

BT474：人乳腺导管瘤细胞株；BT474: human breast ductal tumor cell line;

NCI-N87：人胃癌细胞株；NCI-N87: human gastric cancer cell line;

HCT116：人结肠癌细胞株；HCT116: human colon cancer cell line;

PC-3：人***癌细胞株； PC-3: human prostate cancer cell line;

实验方法(CelltiterGlo assay)Experimental method (CelltiterGlo assay)

1.准备细胞Prepare cells

1.1细胞培养：1.1 Cell culture:

所有细胞根据ATCC(美国模式培养物集存库)推荐的条件进行培养，细胞在对数生长期进行试验。All cells were cultured according to the conditions recommended by the ATCC (American Model Culture Collection), and the cells were tested in the logarithmic growth phase.

1.2细胞悬液制备：1.2 Cell suspension preparation:

移除细胞培养瓶中的培养基，磷酸缓冲液(PBS)润洗细胞，加入胰酶替代物(TrypLE)溶液离心分离，用含10％胎牛血清(FBS)的培养基重悬，计数并调整到合适浓度，只有细胞活力大于90％的细胞用于进一步实验。The medium in the cell culture flask was removed, the cells were washed with phosphate buffered saline (PBS), centrifuged with trypsin substitute (TrypLE) solution, resuspended in medium containing 10% fetal bovine serum (FBS), and counted. Adjusted to the appropriate concentration, only cells with cell viability greater than 90% were used for further experiments.

表2.细胞接种数目Table 2. Number of cell inoculations

2.配制测试化合物2. Formulating test compounds

2.1配制测试化合物DMSO储备液，浓度见表3。2.1 Preparation of test compound DMSO stock solution, the concentration is shown in Table 3.

表3.测试化合物储备液浓度(mM)Table 3. Test compound stock concentration (mM)

2.2配制测试化合物工作储备液2.2 Preparation of test compound working stock solution

测试化合物储备液10mM(或5mM)稀释至4mM，然后用DMSO 4倍连续梯度稀释，共10个浓度。然后分别取2μL的DMSO梯度稀释的化合物加到198μL的培养液中，为测试化合物工作储备液(化合物浓度为终浓度的100倍，DMSO浓度为1％，最高浓度为40μM)The test compound stock solution was diluted to 4 mM at 10 mM (or 5 mM) and then diluted 4 times in DMSO with a total of 10 concentrations. Then, 2 μL of DMSO gradient diluted compound was added to 198 μL of the culture solution to prepare a test compound working stock solution (the compound concentration was 100 times the final concentration, the DMSO concentration was 1%, and the highest concentration was 40 μM).

最大值为DMSO溶剂对照，空白孔只加培养基，不接种细胞。The maximum value is the DMSO solvent control, the blank wells are only added to the medium, and the cells are not seeded.

2.3药物处理(细胞接种24小时后) 2.3 drug treatment (24 hours after cell inoculation)

每孔加入50μL培养基，每孔培养基的总体积为150μL。每孔加入50μL工作储备液(4倍稀释，DMSO终浓度为0.25％)。50 μL of medium was added to each well, and the total volume of the medium per well was 150 μL. 50 μL of working stock (4 fold dilution, DMSO final concentration of 0.25%) was added to each well.

需加入化合物3的孔，培养基体积加至199μL，然后加入1μL，2mM的化合物3的储备液(200倍稀释，DMSO终浓度0.5％)。The wells of Compound 3 were added, the medium volume was added to 199 μL, and then 1 μL of a 2 mM stock solution of Compound 3 (200-fold dilution, DMSO final concentration 0.5%) was added.

测试化合物的终浓度为：10000nM，2500nM，625nM，156.25nM，39.06nM，9.76nM，2.44nM，0.61nM，0.15nM，0.04nM。The final concentrations of the test compounds were: 10000 nM, 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.76 nM, 2.44 nM, 0.61 nM, 0.15 nM, 0.04 nM.

NCI-N87细胞，5％CO₂细胞培养箱中培养96小时；NCI-N87 cells were cultured for 96 hours in a 5% CO ₂ cell incubator;

其他细胞，5％CO₂细胞培养箱中培养72小时。Other cells were cultured for 72 hours in a 5% CO ₂ cell incubator.

3.检测3. Detection

每孔移除80μL培养基，培养板在室温放置30分钟，每孔加入60μL试剂(Celltiter Glo assay kit)，振荡器震摇2min混匀(避光)，室温孵育10分钟(避光)。多功能酶标仪读取光信号值。80 μL of the medium was removed from each well, and the plate was allowed to stand at room temperature for 30 minutes, 60 μL of reagent (Celltiter Glo assay kit) was added to each well, and the shaker was shaken for 2 min to mix (protected from light), and incubated at room temperature for 10 minutes (protected from light). The multi-function microplate reader reads the optical signal value.

4.数据处理4. Data processing

1)抑制率(％)＝(DMSO溶剂对照孔读数-测试物孔读数)/(DMSO溶剂对照孔读数-空白对照孔读数)×100％；1) Inhibition rate (%) = (DMSO solvent control well reading - test substance well reading) / (DMSO solvent control well reading - blank control well reading) x 100%;

2)输入GraphPad Prism5.0作图，得到曲线及IC₅₀。2) Input GraphPad Prism 5.0 to obtain a curve and IC ₅₀ .

实验结果及结论Experimental results and conclusions

表4.本发明化合物的体外细胞学活性(IC₅₀，nM)Table 4. In vitro cytological activity of compounds of the invention (IC ₅₀ , nM)

由表4可知道，本发明化合物对BT474、U87-MG、NCI-N87、PC-3、HCT116的抗增殖活性均优于对照药。As can be seen from Table 4, the anti-proliferative activity of the compounds of the present invention against BT474, U87-MG, NCI-N87, PC-3, and HCT116 was superior to that of the control drug.

实验例3 本发明化合物的小鼠药代动力学实验Experimental Example 3 Mouse pharmacokinetic experiment of the compound of the present invention

供试品：本发明化合物1、化合物3，自制，其化学名称和制备方法见各化合物的制备实施例。Test article: Compound 1 of the present invention, Compound 3, self-made, and the chemical name and preparation method thereof are shown in the preparation examples of the respective compounds.

对照药BKM-120，自制，其结构式如背景技术所述。The control drug BKM-120 was prepared and its structural formula was as described in the background art.

(1)口服给药供试品溶液制备(1) Oral administration for preparation of test solution

对照药口服给药(po)处方均0.1％吐温80+2％HPC，配制方法如下： The oral administration (po) prescription of the control drug was 0.1% Tween 80+2% HPC, and the preparation method was as follows:

2％HPC+0.1％吐温80的配制方法：称取HPC 20g缓慢加入1000mL搅拌着的水中，待HPC搅拌均匀后，加入1mL吐温80，搅拌均匀即得。2%HPC+0.1% Tween 80 preparation method: Weigh 20g of HPC and slowly add 1000mL of stirred water. After the HPC is evenly stirred, add 1mL Tween 80 and stir evenly.

称取2.90mg对照药，加入配制好的上述溶媒并置于组织研磨器中，以1000转速/分钟的转速分散均匀，即得理论浓度为1.0mg/mL灌胃给药混悬液，实测浓度见表5。Weigh 2.90mg of the reference drug, add the prepared solvent and place it in the tissue grinder, and disperse evenly at 1000 rpm, that is, the theoretical concentration of 1.0mg/mL can be administered by intragastric administration. See Table 5.

化合物1、化合物3口服给药(po)处方为pH1.2 10％Captisol，配制方法如下：Compound 1 and Compound 3 were administered orally (po) to a pH of 1.2% Captisol. The preparation method was as follows:

pH1.2 10％captisol的配制：称取captisol 2g，加入少量pH1.2盐酸超声溶解，再用pH1.2盐酸定容至20mL，涡旋混匀，即得。Preparation of pH 1.2 10% captisol: Weigh 2 g of captisol, add a small amount of pH 1.2 hydrochloric acid to dissolve ultrasonically, then dilute to 20 mL with pH 1.2 hydrochloric acid, vortex and mix, that is.

将6.78mg化合物1加入6.201mL 10％Captisol(pH1.2)，配成理论浓度为1mg/mL灌胃给药混悬液，实测浓度见表5。6.78 mg of Compound 1 was added to 6.201 mL of 10% Captisol (pH 1.2) to prepare a suspension of the theoretical concentration of 1 mg/mL, and the measured concentrations are shown in Table 5.

取3.94mg化合物3，置于组织研磨器底部，加入1.897mL上述溶媒，1000rpm/min的转速研磨均匀，将研磨液转移入离心管，再用剩余1mL的上述溶媒清洗组织研磨器，将清洗液转入离心管中，涡旋混匀，即得理论浓度为1.0mg/mL灌胃给药混悬液，实测浓度见表5。Take 3.94mg of compound 3, place it on the bottom of the tissue grinder, add 1.897mL of the above solvent, grind it evenly at 1000rpm/min, transfer the slurry into the centrifuge tube, and then wash the tissue grinder with the remaining 1mL of the above solvent. Transfer into the centrifuge tube, vortex and mix, that is, the theoretical concentration of 1.0mg / mL oral administration suspension, the measured concentration is shown in Table 5.

(2)静脉注射给药供试品溶液制备(2) Preparation of test solution by intravenous injection

对照药静脉注射(iv)给药处方为5％DMSO+20％(40％HP-β-CD)+75％灭菌注射用水，配制方法如下：The control drug is administered intravenously (iv) with 5% DMSO + 20% (40% HP-β-CD) + 75% sterile water for injection. The preparation method is as follows:

40％HP-β-CD配制：称取HP-β-CD 2g，加入少量纯化水超声溶解，再用纯化水定容至5mL，涡旋混匀即得。40% HP-β-CD preparation: Weigh HP-β-CD 2g, add a small amount of purified water to dissolve ultrasonically, then dilute to 5mL with purified water, vortex and mix.

取1.98mg对照药加入DMSO 99μL，超声溶解，再加入40％HP-β-CD 395μL，涡旋混匀，置于50℃水浴中保温20min，再加入1.478mL灭菌注射用水，涡旋混匀，即得澄清透明理论浓度为1.0mg/mL的静脉注射给药溶液，实测浓度见表5。Take 1.98mg of the reference drug into the DMSO 99μL, sonicate, add 40% HP-β-CD 395μL, vortex and mix, put in a 50 ° C water bath for 20min, then add 1.478mL sterile water for injection, vortex and mix That is, the intravenous administration solution having a transparent theoretical concentration of 1.0 mg/mL can be clarified, and the measured concentrations are shown in Table 5.

化合物1静脉注射(iv)给药处方为10％DMSO+10％PEG400+80％(28％Captisol)，配制方法如下：Compound 1 was administered intravenously (iv) with 10% DMSO + 10% PEG 400 + 80% (28% Captisol). The preparation method was as follows:

28％captisol溶液的配制：称取captisol 1.4g，加入少量纯化水超声溶解，再用纯化水定容至5mL，涡旋混匀即得。Preparation of 28% captisol solution: Weigh capgsol 1.4g, add a small amount of purified water to dissolve ultrasonically, then dilute to 5mL with purified water, vortex and mix.

取2.24mg化合物1加入205μL DMSO，加热超声溶解，再加入205μL PEG400，涡旋混匀，再加入1.639mL 28％captisol，涡旋混匀，置于50℃恒温水浴锅中保温20min，溶解，涡旋，混匀，即得澄清透明理论浓度为1.0mg/mL的静脉注射给药溶液，实测浓度见表5。Take 2.24mg of compound 1 into 205μL DMSO, heat and dissolve, add 205μL PEG400, vortex and mix, then add 1.639mL 28% captisol, vortex and mix, put in a constant temperature water bath at 50 °C for 20min, dissolve, vortex Spin and mix, that is, to clarify the intravenous administration solution with a theoretical concentration of 1.0 mg/mL. The measured concentrations are shown in Table 5.

化合物3静脉注射(iv)给药处方为5％DMSO+10％PEG400+85％(28％HP-β-CD)，配制方法如下：Compound 3 was administered intravenously (iv) with 5% DMSO + 10% PEG 400 + 85% (28% HP-β-CD). The preparation method was as follows:

28％HP-β-CD配制：称取HP-β-CD 9.8g，加入少量纯化水，加热超声溶解，再加入纯化水定容至35mL，涡旋混匀即得。 Preparation of 28% HP-β-CD: Weigh 9.8g of HP-β-CD, add a small amount of purified water, heat and dissolve, add purified water to 35mL, vortex and mix.

将5.58mg的化合物3分别加入525.5μL的DMSO、1.051mL的PEG400和8.934mL的28％HP-β-CD，配成终浓度为0.5mg/mL澄清透明溶液。5.58 mg of Compound 3 was added to 525.5 μL of DMSO, 1.051 mL of PEG400, and 8.934 mL of 28% HP-β-CD, respectively, to a final clear concentration of 0.5 mg/mL clear clear solution.

实验方法experimental method

表5.供试品药液的给药信息Table 5. Drug administration information of the test article

采血时间点设置如下：The blood collection time point is set as follows:

iv/po：药后0.083h，0.25h，0.5h，1h，2h，4h，6h，8h，24h.Iv/po: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h.

每个时间点通过尾静脉采取30-60μL全血，加入到K2EDTA抗凝管里，低温离心机中8000转/分钟离心6min分离血浆，血浆于-80℃冰箱冻存。At each time point, 30-60 μL of whole blood was taken through the tail vein, added to the K2EDTA anticoagulant tube, and plasma was separated by centrifugation at 8000 rpm for 6 min in a low temperature centrifuge, and the plasma was frozen in a refrigerator at -80 °C.

血浆样品分析：Plasma sample analysis:

对照药(iv/po)、化合物1(iv)、化合物3(po)的血浆样品分析均采用蛋白沉淀法：取10μL血浆，加入200μL含内标的乙腈溶液，1000转/分钟涡旋5min，然后12000转/分钟离心5min，取上清液150μL，再加入50μL水，涡旋混匀，LC-MS/MS分析。The plasma samples of the reference drug (iv/po), compound 1 (iv), and compound 3 (po) were analyzed by protein precipitation: 10 μL of plasma was added, 200 μL of an internal standard acetonitrile solution was added, and vortexed at 1000 rpm for 5 min, then Centrifuge at 12,000 rpm for 5 min, take 150 μL of the supernatant, add 50 μL of water, vortex and mix, and analyze by LC-MS/MS.

化合物1(po)、化合物3(iv)的血浆样品分析均采用蛋白沉淀法：10μL血浆加入10μL空白工作溶液，100μL含内标的乙腈沉淀蛋白，取出50μL上清加入100μL纯水。超出定量上限的样品用空白裸鼠血浆稀释1倍测定，LC-MS/MS分析。 Plasma samples of Compound 1 (po) and Compound 3 (iv) were analyzed by protein precipitation: 10 μL of plasma was added to 10 μL of a blank working solution, 100 μL of an internal standard acetonitrile precipitated protein, and 50 μL of the supernatant was taken out and 100 μL of pure water was added. Samples that exceeded the upper limit of quantitation were diluted 1 time with blank nude mouse plasma and analyzed by LC-MS/MS.

表6.小鼠PK评价结果(iv)Table 6. Results of mouse PK evaluation (iv)

表7.小鼠PK评价结果(po)Table 7. Mouse PK evaluation results (po)

AUC_last代表药时曲线下面积0→t；CL代表清除率；V_ss表示稳态表观分布容积；AUC _last represents the area under the curve of the drug time 0→t; CL represents the clearance rate; V _ss represents the apparent apparent volume of distribution;

T_max代表血药浓度达峰时间；C_max代表血药浓度达峰浓度；F％代表绝对生物利用度；T _max represents the peak time of blood concentration; C _max represents the peak concentration of blood concentration; F% represents absolute bioavailability;

由表1和表2的实验结果可知，在同等剂量下，与对照药相比，本发明化合物在小鼠体内具有较高的暴露量(AUC_last)、较低的清除率(CL)，且口服生物利用度(F)高，具备良好的药代动力学性质。From the experimental results of Tables 1 and 2, it is known that the compound of the present invention has a higher exposure (AUC _last ) and a lower clearance (CL) in mice than the control drug at the same dose, and Oral bioavailability (F) is high and has good pharmacokinetic properties.

实验例4 本发明化合物在U87MG人源胶质母细胞瘤异种移植模型中的药效实验Experimental Example 4 Pharmacodynamic experiment of the compound of the present invention in U87MG human glioblastoma xenograft model

测试物 化合物1，其化学名称和结构见制备实施例；Test compound Compound 1, whose chemical name and structure are shown in the preparation examples;

对照药 BKM120，结构式见背景技术。The reference drug BKM120, the structural formula see the background art.

实验方法experimental method

将U87MG肿瘤细胞5×10⁶+Matrigel/0.1mL(MEM∶Matrigel＝70∶30)接种于雌性裸鼠右侧前胁肋部皮下，共接种67只。待肿瘤生长到约170mm³时进行分组给药，每组8只，共6组，分别为：溶剂对照组；对照药剂量30mg/kg给药组；对照药剂量60mg/kg给药组；化合物1剂量10mg/kg给药组；化合物1剂量30mg/kg给药组；化合物1剂量90mg/kg给药组。U87MG tumor cells 5×10 ⁶ + Matrigel/0.1 mL (MEM: Matrigel=70:30) were inoculated subcutaneously into the right anterior flank of female nude mice, and a total of 67 were inoculated. When the tumors were grown to about 170 mm ³ , group administration was performed, 8 rats in each group, a total of 6 groups, respectively: solvent control group; control dose 30 mg/kg administration group; control dose 60 mg/kg administration group; compound 1 dose 10 mg/kg administration group; Compound 1 dose 30 mg/kg administration group; Compound 1 dose 90 mg/kg administration group.

每周使用游标卡尺对肿瘤体积进行2次测量，测量肿瘤的长径和短径，其体积计算公式为：体积＝0.5×长径×短径²。根据测量结果计算相对肿瘤体积(relative tumor volume，RTV)和相对肿瘤体积增比值(T/C)。RTV＝V_t/V₀，其中Vt为分组给药后第t天的肿瘤体积均值，V₀为分组当天的肿瘤体积均值。T/C＝TRTV/CRTV x 100％，其中TRTV为治疗组RTV，CRTV为溶剂对照组RTV。肿瘤生长抑制率(％，TGI)按 如下公式计算：(1-T/C)×100％。The tumor volume was measured twice a week using a vernier caliper, and the long and short diameters of the tumor were measured. The volume was calculated as: volume = 0.5 × long diameter × short diameter ² . Relative tumor volume (RTV) and relative tumor volume increase ratio (T/C) were calculated based on the measurement results. RTV = V _t / V _0, where Vt is the mean tumor volume on days after grouping administration t, V ₀ is the mean tumor volume of day packet. T/C = TRTV/CRTV x 100%, wherein TRTV is the treatment group RTV and CRTV is the solvent control group RTV. The tumor growth inhibition rate (%, TGI) was calculated according to the following formula: (1-T/C) × 100%.

应用SPSS17.0统计学软件进行One-Way ANOVA检验，对肿瘤体积进行组间统计学分析。P＜0.05认为有显著性差异。The One-Way ANOVA test was performed using SPSS 17.0 statistical software, and the tumor volume was statistically analyzed between groups. P < 0.05 was considered to have a significant difference.

给药方案Dosing regimen

表8.供试品的给药信息Table 8. Drug administration information of the test sample

实验结果Experimental result

U87MG肿瘤细胞接种34天后，对照组(组1)肿瘤体积均值为1394mm³。After 34 days of U87MG tumor cell inoculation, the control group (group 1) had a mean tumor volume of 1394 mm ³ .

对照药剂量为30mg/kg给药组(组2)肿瘤体积均值为283mm³(T/C＝19.7％，肿瘤生长抑制率为80.3％，与溶剂对照组比较P＜0.001)；The dose of the control drug was 30 mg/kg (group 2). The mean tumor volume was 283 mm ³ (T/C = 19.7%, the tumor growth inhibition rate was 80.3%, compared with the solvent control group, P < 0.001).

对照药剂量为60mg/kg给药组(组3)肿瘤体积均值为64mm³(T/C＝4.6％，肿瘤生长抑制率为95.4％，P＜0.001)，有三只动物死亡。The control dose was 60 mg/kg (group 3). The mean tumor volume was 64 mm ³ (T/C = 4.6%, tumor growth inhibition rate was 95.4%, P < 0.001), and three animals died.

化合物1剂量为10mg/kg给药组(组4)肿瘤体积均值为110mm³(T/C＝7.9％，肿瘤生长抑制率为92.1％，与溶剂对照组比较P＜0.001)；The dose of Compound 1 was 10 mg/kg (group 4). The mean tumor volume was 110 mm ³ (T/C = 7.9%, tumor growth inhibition rate was 92.1%, P < 0.001 compared with the solvent control group);

化合物1剂量为30mg/kg给药组(组5)肿瘤体积均值为59mm³(T/C＝4.2％，肿瘤生长抑制率为95.8％，与溶剂对照组比较P＜0.001)；The dose of Compound 1 was 30 mg/kg (group 5). The mean tumor volume was 59 mm ³ (T/C = 4.2%, the tumor growth inhibition rate was 95.8%, compared with the solvent control group, P <0.001);

化合物1剂量为90mg/kg给药组(组6)肿瘤体积均值为39mm3(T/C＝2.7％，肿瘤生长抑制率为97.3％，与溶剂对照组比较P＜0.001)。详见表9。 The dose of Compound 1 was 90 mg/kg (group 6). The mean tumor volume was 39 mm3 (T/C = 2.7%, tumor growth inhibition rate was 97.3%, P < 0.001 compared with the solvent control group). See Table 9 for details.

表9.本发明化合物对U87MG人源胶质母细胞瘤异种移植荷瘤裸鼠的抑瘤作用Table 9. Antitumor effect of the compound of the present invention on U87MG human glioblastoma xenograft tumor-bearing nude mice

(肿瘤接种后第34天)(day 34 after tumor inoculation)

注：^a.均数±标准误；^b.与对照组比较(Dunnett T3)；P^TV：肿瘤体积P值，P^TW：肿瘤重量P值。Note: ^a . Mean ± standard error; ^b . Comparison with control group (Dunnett T3); P ^TV : tumor volume P value, P ^TW : tumor weight P value.

实验结论Experimental results

对于U87MG人源胶质母细胞瘤异种移植肿瘤模型实验，本发明化合物组在肿瘤细胞接种34天后，相对于溶剂对照组统计学均有显著的抑制肿瘤作用(各组P＜0.001)。For the U87MG human glioblastoma xenograft tumor model experiment, the compound group of the present invention significantly inhibited the tumor effect after 34 days of tumor cell inoculation with respect to the solvent control group (P < 0.001 for each group).

本发明化合物在剂量为10mg/kg和30mg/kg条件下，其肿瘤抑制率(TGI)分别明显高于同剂量对照药(剂量30mg/kg)。The tumor inhibition rate (TGI) of the compound of the present invention was significantly higher than that of the same dose of the control drug (dose 30 mg/kg) at the doses of 10 mg/kg and 30 mg/kg, respectively.

对照药在剂量60mg/kg时，出现动物死亡，说明该药达到耐受剂量，而本发明化合物在剂量为90mg/kg条件下，仍然具有良好的抑制活性，且无动物死亡情况，说明本发明化合物相对于对照药具有较好的耐受性及较低的毒性。At the dose of 60 mg/kg, the animal died, indicating that the drug reached the tolerated dose, while the compound of the present invention still had good inhibitory activity at the dose of 90 mg/kg, and there was no animal death, indicating the present invention. The compound has better tolerance and lower toxicity than the control drug.

实验例5 本发明化合物激酶谱实验Experimental Example 5 Compound kinase spectrum experiment of the present invention

本实验例提供了本发明化合物1在10μM和1μM浓度下，对人体内60种激酶的体外抑制活性。This experimental example provides the in vitro inhibitory activity of Compound 1 of the present invention against 60 kinases in humans at concentrations of 10 μM and 1 μM.

试验方法experiment method

化合物1在CHK1和MARK1激酶的筛选用ADP-Glo Luminescent的方法；Compound 1 was screened for CHK1 and MARK1 kinase using the ADP-Glo Luminescent method;

化合物1在FAK，cRAF，BRAF(V600E)的检测用Lantha Screen的方法。Compound 1 was tested at FAK, cRAF, BRAF (V600E) using the method of Lantha Screen.

化合物1在其他55种激酶的筛选用迁移率检测技术(mobility shift assay)；Compound 1 was screened for mobility shift assay in the other 55 kinases;

实验结果表明，化合物1在10μM、1μM的浓度下，对ABL、ALK、AXL、AKT1、AURA、AURB、AMPKa1、BRAF V600E、cRAF、CDK2、CK1d、CHK1、DYRK1a、DYRK1b、CAMK2a、EGFR、ERK2、EPHA1、FGFR1、FLT3、FAK、FES、GSK3b、 IRAK4、IGF1R、JNK2、JNK3、JAK2、JAK3、cKit、KDR、LYNa、LCK、MET、MAPKAPK2、MAPKAPK5、MARK1、MSK1、MST2、P38a、PAK4、PDK1、PKD1、P70S6K、PIM1、P1M2、PAK2、PDGFRb、PKACa、PKCa、NEK2、TAKO2、ROCK1、ROCK2、RSK1、RSK2、SGK、SRC、SYK、TIE2等以上60种测试激酶无抑制活性或抑制活性非常弱，而在实验例1中，化合物1在较低浓度下即对PI3K酶产生较好的抑制活性，说明本发明化合物对PI3K激酶具有高度的选择性。The results showed that Compound 1 was at a concentration of 10 μM and 1 μM for ABL, ALK, AXL, AKT1, AURA, AURB, AMPKa1, BRAF V600E, cRAF, CDK2, CK1d, CHK1, DYRK1a, DYRK1b, CAMK2a, EGFR, ERK2. EPHA1, FGFR1, FLT3, FAK, FES, GSK3b, IRAK4, IGF1R, JNK2, JNK3, JAK2, JAK3, cKit, KDR, LYNa, LCK, MET, MAPKAPK2, MAPKAPK5, MARK1, MSK1, MST2, P38a, PAK4, PDK1, PKD1, P70S6K, PIM1, P1M2, PAK2, PDGFRb, 60 kinds of test kinases such as PKACa, PKCa, NEK2, TAKO2, ROCK1, ROCK2, RSK1, RSK2, SGK, SRC, SYK, TIE2, etc. have no inhibitory activity or inhibitory activity, and in Experimental Example 1, Compound 1 is lower. At the concentration, the PI3K enzyme produced a good inhibitory activity, indicating that the compound of the present invention is highly selective for PI3K kinase.

具体实施方式Detailed ways

下述实验中缩写所代表的含义：The meaning of the abbreviation in the following experiments:

PE：石油醚；PE: petroleum ether;

EA：乙酸乙酯；EA: ethyl acetate;

DMSO-d₆：氘代二氯亚砜DMSO-d ₆ : deuterated thionyl chloride

实施例1 1-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)脲(化合物1)的制备Example 1 Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)urea (Compound 1)

1)4，4′-(6-氯嘧啶-2，4-二基)二吗啉的制备1) Preparation of 4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine

将吗啉(12.6mL，144mmol)溶于甲苯(22mL)和水(8.8mL)的混合溶剂中，称取2，4，6-三氯嘧啶(4.4g，24mmol)溶于甲苯(22mL)中，室温下缓慢滴加到上述混合液中，加料完毕后升温至83℃，搅拌反应3小时，降温，分液，有机相用盐酸(10mol/L)洗涤，无水硫酸钠干燥，粗品经硅胶柱层析(石油醚∶乙酸乙酯＝1∶1)纯化得标题化合物(6.3g，产率92.4％)。The morpholine (12.6 mL, 144 mmol) was dissolved in a mixed solvent of toluene (22 mL) and water (8.8 mL), and 2,4,6-trichloropyrimidine (4.4 g, 24 mmol) was dissolved in toluene (22 mL) The mixture was slowly added dropwise to the above mixture at room temperature. After the addition was completed, the temperature was raised to 83 ° C, and the reaction was stirred for 3 hours. The temperature was lowered and the mixture was separated. The organic phase was washed with hydrochloric acid (10 mol/L), dried over anhydrous sodium sulfate The title compound (6.3 g, yield: 92.4%)

2)4，4′-(6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)嘧啶-2，4-二基)二吗啉的制备 2) 4,4'-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl) Preparation of dimorpholine

将4，4′-(6-氯嘧啶-2，4-二基)二吗啉(5.0g，17.6mmol)、联硼酸频哪醇酯(5.8g，22.8mmol)和醋酸钾(2.59g，26.4mmol)加入到乙腈(100mL)中，氮气保护下加入三环己基膦(395mg，1.4mmol)和三(二亚苄基丙酮)二钯(645mg，0.7mmol)，升温至84℃反应3小时，趁热抽滤，滤液浓缩后加入甲苯(30mL)和石油醚(100mL)，搅拌，析出沉淀，抽滤，滤饼用石油醚洗涤得标题化合物(5.3g，产率80.1％)。4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine (5.0 g, 17.6 mmol), boronic acid pinacol ester (5.8 g, 22.8 mmol) and potassium acetate (2.59 g, 26.4 mmol) was added to acetonitrile (100 mL), and tricyclohexylphosphine (395 mg, 1.4 mmol) and tris(dibenzylideneacetone) dipalladium (645 mg, 0.7 mmol) were added under nitrogen atmosphere, and the mixture was heated to 84 ° C for 3 hours. After suction filtration, the filtrate was concentrated. EtOAc (EtOAc) (EtOAc).

3)5-溴-4-(三氟甲基)吡啶-2-胺的制备3) Preparation of 5-bromo-4-(trifluoromethyl)pyridin-2-amine

称取N-溴代丁二酰亚胺(11.2g，63mmol)加入到四氢呋喃(72.5mL)中，降温至0℃，将5-溴-4-(三氟甲基)吡啶-2-胺(9.7g，60mmol)溶于四氢呋喃(57.5mL)中，缓慢滴加到上述溶液中，保持温度在0℃，滴加完毕后缓慢升至室温，搅拌0.5小时，加入硫代硫酸钠(2.5g)的水溶液(47.5mL)淬灭，浓缩，粗品硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得标题化合物(12.5g，产率86.8％)。N-bromosuccinimide (11.2 g, 63 mmol) was weighed into tetrahydrofuran (72.5 mL), and the temperature was lowered to 0 ° C to give 5-bromo-4-(trifluoromethyl)pyridin-2-amine ( 9.7 g, 60 mmol) was dissolved in tetrahydrofuran (57.5 mL), slowly added dropwise to the above solution, keeping the temperature at 0 ° C, slowly increasing to room temperature after the completion of the addition, stirring for 0.5 hours, adding sodium thiosulfate (2.5 g) The title compound (12.5 g, yield 86.8%) was obtained.

4)5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺的制备(BKM120)4) Preparation of 5-(2,6-dimorpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (BKM120)

将4，4′-(6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)嘧啶-2，4-二基)二吗啉(4.4g，11.7mmol)和5-溴-4-(三氟甲基)吡啶-2-胺(1.13g，4.7mmol)溶于四氢呋喃(25mL)，搅拌下加入碳酸铯(4.59g，14.1mmol)，氮气保护下加入1，1’-双(二叔丁基膦)二茂铁二氯化钯(308mg，0.47mmol)，缓慢升温至45℃，搅拌反应1小时，减压蒸除四氢呋喃后，加入乙酸乙酯(80mL)和水(80mL)，分液，有机相用无水硫酸钠干燥，浓缩，硅胶柱层析(石油醚∶乙酸乙酯∶三乙胺＝1∶1∶0.01)纯化得标题化合物(1.5g，产率77.8％)。4,4'-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl) Morpholine (4.4 g, 11.7 mmol) and 5-bromo-4-(trifluoromethyl)pyridin-2-amine (1.13 g, 4.7 mmol) were dissolved in tetrahydrofuran (25 mL). 14.1 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (308 mg, 0.47 mmol) was added under nitrogen atmosphere, and the temperature was slowly raised to 45 ° C, and the reaction was stirred for 1 hour, and distilled under reduced pressure. After the tetrahydrofuran, ethyl acetate (80 mL) and water (80 mL) were evaporated. The title compound (1.5 g, yield 77.8%) was obtained.

5)N-((5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)氨基甲酰基)苯甲酰胺的制备 5) Preparation of N-((5-(2,6-dimorpholinium-4-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)benzamide

将5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺(300mg，0.73mmol)溶于二氯甲烷(8mL)中，缓慢加入苯甲酰异氰酸酯(215mg，1.46mmol)，50℃封管搅拌反应16小时，抽滤，滤饼用二氯甲烷洗涤得标题化合物(300mg，产率73.6％)。5-(2,6-Dimorpholinimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (300 mg, 0.73 mmol) was dissolved in dichloromethane (8 mL) and benzene was slowly charged. The formyl compound (300 mg, yield 73.6%) was obtained by the title compound (300 mg, yield: 73.6%).

6)1-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)脲的制备6) Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)urea

将N-((5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)氨基甲酰基)苯甲酰胺(300mg，0.54mmol)加入到乙醇(8mL)中，加入碳酸钾(74.5mg，0.54mmol)，85℃反应2小时，抽滤，滤饼分别用甲醇、二氯甲烷和乙酸乙酯洗涤，真空干燥得标题化合物(200mg，产率81.7％)。Add N-((5-(2,6-dimorpholinium-4-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)benzamide (300 mg, 0.54 mmol) To a solution of ethanol (8 mL), EtOAc (EtOAc (EtOAc,EtOAc. The yield was 81.7%).

分子式：C₁₉H₂₂F₃N₇O₃ 分子量：453.2 LC-MS(m/z)：454.2(M+H⁺)Molecular formula: C ₁₉ H ₂₂ F ₃ N ₇ O ₃ Molecular weight: 453.2 LC-MS (m/z): 454.2 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.67(s，1H)，8.43(s，1H)，8.10(s，1H)，6.82(s，2H)，6.30(s，1H)，3.64-3.61(m，16H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.67 (s, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 6.82 (s, 2H), 6.30 (s, 1H), 3.64 -3.61 (m, 16H).

实施例2 N-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)吡咯烷-1-甲酰胺(化合物2)的制备Example 2 Preparation of N-(5-(2,6-dimorpholinium-4-yl)-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-1-carboxamide (Compound 2)

1)N-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)吡咯烷-1-甲酰胺的制备 1) Preparation of N-(5-(2,6-dimorpholinium-4-yl)-4-(trifluoromethyl)pyridin-2-yl)pyrrolidine-1-carboxamide

将5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺(具体制备方法见实施例1第(1)-(4)步，100mg，0.24mmol)溶于DMF(5mL)中，冷却至0℃，加入氢化钠(25mg，0.62mmol，含量60％)，搅拌10分钟，滴加1-吡咯烷羰酰氯(39mg，0.29mmol)，室温下搅拌2小时。反应混合物倒入水(5mL)中，乙酸乙酯(10mL×3)萃取，浓缩，粗品经硅胶柱层析(石油醚∶乙酸乙酯＝1∶1)纯化得到白色固体标题化合物(32mg，产率26％)。5-(2,6-Dimorpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (for the specific preparation method, see step (1)-(4) of Example 1, 100 mg , 0.24 mmol) was dissolved in DMF (5 mL), cooled to 0 ° C, sodium hydride (25 mg, 0.62 mmol, content 60%) was added, and stirred for 10 min, and 1-pyrrolidinecarbonyl chloride (39 mg, 0.29 mmol) was added dropwise. Stir at room temperature for 2 hours. The reaction mixture was poured into water (5 mL), EtOAc (EtOAc) Rate 26%).

分子式：C₂₃H₂₈F₃N₇O₃ 分子量：507.5 LC-MS(m/z)：508(M+H⁺)Molecular formula: C ₂₃ H ₂₈ F ₃ N ₇ O ₃ Molecular weight: 507.5 LC-MS (m/z): 508 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.36(s，1H)，8.45(s，1H)，8.36(s，1H)，6.32(s，1H)，3.58-3.64(m，16H)，3.37-3.42(m，4H)，1.80-1.85(m，4H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.36 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 6.32 (s, 1H), 3.58-3.64 (m, 16H) , 3.37-3.42 (m, 4H), 1.80-1.85 (m, 4H).

实施例3 1-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)-3-甲基脲(化合物3)的制备Example 3 Preparation of 1-(5-(2,6-dimorpholinium-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-3-methylurea (Compound 3)

(1)1-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)-3-甲基脲的制备(1) Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-3-methylurea

将5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺(90mg，0.22mmol)溶于吡啶(5mL)中，滴加甲氨基甲酰氯(104mg，1.1mmol)，室温下搅拌48小时，浓缩，粗品经硅胶柱层析(石油醚∶乙酸乙酯＝1∶1)纯化得到白色固体状标题化合物(20mg，产率19％)。5-(2,6-Dimorpholinimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (90 mg, 0.22 mmol) was dissolved in pyridine (5 mL). The title compound (20 mg, yield 19%) was obtained.

分子式：C₂₀H₂₄F₃N₇O₃ 分子量：467.4 LC-MS(m/z)：468(M+H⁺)Molecular formula: C ₂₀ H ₂₄ F ₃ N ₇ O ₃ Molecular weight: 467.4 LC-MS (m/z): 468 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.69(s，1H)，8.42(s，1H)，8.03(s，1H)，7.33(s，1H)，6.30(s，1H)，3.57-3.63(m，16H)，2.71(d，J＝4.0，3H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.69 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.33 (s, 1H), 6.30 (s, 1H), 3.57 -3.63 (m, 16H), 2.71 (d, J = 4.0, 3H).

实施例4 3-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)-1，1-二甲基脲(化合物4)制备Example 4 3-(5-(2,6-Dimorpholinimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-1,1-dimethylurea (Compound 4) preparation

(1)3-(5-溴-4-(三氟甲基)吡啶-2-基-1，1-二甲基脲的制备(1) Preparation of 3-(5-bromo-4-(trifluoromethyl)pyridin-2-yl-1,1-dimethylurea

将5-溴-4-(三氟甲基)吡啶-2-胺(482mg，2.0mmol)溶于干燥的四氢呋喃中，冰浴冷却，加入氢化钠(96mg，4mmol)，升至室温搅拌30分钟，向体系缓慢滴加二甲氨基甲酰氯(236mg，2.2mmol)，滴加完毕后继续反应2h，加入少量水淬灭，用乙酸乙酯(20mL)萃取，分液，有机相用无水硫酸钠干燥，浓缩，粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯＝5∶1)，得标题化合物(71mg，产率11％)。5-Bromo-4-(trifluoromethyl)pyridin-2-amine (482 mg, 2.0 mmol) was dissolved in dry EtOAc (EtOAc m. Dimethylcarbamoyl chloride (236mg, 2.2mmol) was slowly added dropwise to the system. After the addition was completed, the reaction was continued for 2 h, quenched with a small amount of water, extracted with ethyl acetate (20 mL), and then evaporated. The sodium was dried, and then evaporated. mjjjjjjjj

(2)4，4′-(6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)嘧啶-2，4-二基)二吗啉的制备(2) 4,4'-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl Preparation of dimorpholine

将4，4′-(6-氯嘧啶-2，4-二基)二吗啉(1.43g，5.0mmol)、联硼酸频那醇酯(1.27g，5mmol)、Pd(dppf)Cl₂(143mg，0.19mmol)和碳酸铯(1.95g，6.0mmol)溶于1，4-二氧六环(50mL)中，80℃反应4h，浓缩反应液，加入饱和食盐水溶液(100mL)，用乙酸乙酯(200mL)萃取，分液，有机相用无水硫酸钠干燥，浓缩，粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇＝20∶1)，得标题化合物(0.62g，产率33％)。4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine (1.43 g, 5.0 mmol), pinacol borate (1.27 g, 5 mmol), Pd(dppf)Cl ₂ ( 143 mg, 0.19 mmol) and cesium carbonate (1.95 g, 6.0 mmol) were dissolved in 1,4-dioxane (50 mL), and reacted at 80 ° C for 4 h. The reaction mixture was concentrated, and then brine (100 mL) The title compound (0.62 g, yield 33) was obtained eluted eluted eluted eluted %).

(3)3-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)-1，1-二甲基脲制备 (3) Preparation of 3-(5-(2,6-dimorpholinium-4-yl)-4-(trifluoromethyl)pyridin-2-yl)-1,1-dimethylurea

将4，4′-(6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)嘧啶-2，4-二基)二吗啉(87mg，0.23mmol)、3-(5-溴-4-(三氟甲基)吡啶-2-基-1，1-二甲基脲(71mg，0.23mmol)、Pd(dppf)Cl₂(8mg，0.01mmol)和碳酸铯(114mg，0.35mmol)溶于1，4-二氧六环中，70℃反应5小时，加入乙酸乙酯(20mL)，用饱和食盐水洗涤，反相色谱分离纯化(水∶乙腈＝5∶1-2∶3)，得标题化合物(40mg，产率36％)。4,4'-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl) Morpholine (87 mg, 0.23 mmol), 3-(5-bromo-4-(trifluoromethyl)pyridin-2-yl-1,1-dimethylurea (71 mg, 0.23 mmol), Pd(dppf)Cl ₂ (8 mg, 0.01 mmol) and cesium carbonate (114 mg, 0.35 mmol) were dissolved in 1,4-dioxane, and reacted at 70 ° C for 5 hours, ethyl acetate (20 mL) was added, and washed with saturated brine. The title compound (40 mg, yield 36%) was obtained.

分子式：C₂₁H₂₆F₃N₇O₃ 分子量：481.5 LC-MS(m/z)：482(M+H⁺)Molecular formula: C ₂₁ H ₂₆ F ₃ N ₇ O ₃ Molecular weight: 481.5 LC-MS (m/z): 482 (M+H ⁺ )

¹H-NMR(400MHz，CDCl₃)δ：8.51(s，1H)，8.38(s，1H)，7.38(s，1H)，5.99(s，1H)，7.74-7.80(m，12H)，3.59-3.62(m，4H)，3.09(s，6H). ¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.51 (s, 1H), 8.38 (s, 1H), 7.38 (s, 1H), 5.99 (s, 1H), 7.74-7.80 (m, 12H), 3.59 -3.62 (m, 4H), 3.09 (s, 6H).

实施例5 N-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)甲酰胺(化合物5)的制备Example 5 Preparation of N-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)carboxamide (Compound 5)

1)4，4′-(6-氯嘧啶-2，4-2-基)二吗啉的制备1) Preparation of 4,4'-(6-chloropyrimidin-2,4-2-yl)dimorpholine

将吗啉(2.8g，32.1mmol)溶于甲苯(11mL)和水(4.4mL)的混合溶剂中，室温搅拌，然后向其缓慢滴加2，4，6-三氯嘧啶(1.0g，5.4mmol)的甲苯(11mL)溶液。加毕，升温至85℃反应2小时。反应完毕后，浓缩反应液，粗品经硅胶柱层析(PE∶EA＝10∶1)分离纯化，得标题化合物(1.2g，产率78.1％)。The morpholine (2.8 g, 32.1 mmol) was dissolved in a mixed solvent of toluene (11 mL) and water (4.4 mL), stirred at room temperature, and then 2,4,6-trichloropyrimidine (1.0 g, 5.4) was slowly added dropwise thereto. A solution of mmol) in toluene (11 mL). After the addition, the temperature was raised to 85 ° C for 2 hours. After the reaction was completed, the reaction mixture was evaporated. mjjjjjjjjj

2)5-溴-4-(三氟甲基)吡啶-2-胺的制备 2) Preparation of 5-bromo-4-(trifluoromethyl)pyridin-2-amine

将N-溴代琥珀酰亚胺(5.7g，32.0mmol)溶于四氢呋喃(40mL)中，体系降至0℃下，然后向其缓慢滴加4-(三氟甲基)吡啶-2-胺(5.0g，30.9mmol)的四氢呋喃(30mL)溶液，加毕，升温至25℃下反应2小时。反应完毕后，浓缩反应液，粗品经硅胶柱层析(PE∶EA＝5∶1)分离纯化，得标题化合物(5.0g，产率67.1％)。N-bromosuccinimide (5.7 g, 32.0 mmol) was dissolved in tetrahydrofuran (40 mL), the system was dropped to 0 ° C, and then 4-(trifluoromethyl)pyridin-2-amine was slowly added dropwise thereto. (5.0 g, 30.9 mmol) in tetrahydrofuran (30 mL) was added and the mixture was warmed to 25 ° C for 2 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjj

3)5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺的制备3) Preparation of 5-(2,6-dimorpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine

将4，4′-(6-氯嘧啶-2，4-二基)二吗啉(1.2g，4.2mmol)、5-溴-4-(三氟甲基)吡啶-2-胺(1.1g，4.6mmol)、双联频哪醇硼酸酯(1.6g，6.3mmol)、碳酸铯(2.7g，8.3mmol)、醋酸钯(94mg，0.42mmol)和正丁基二(1-金刚烷基)膦(301mg，0.84mmol)，依次加入到甲苯(10mL)和甲醇(10mL)混合溶剂中，氮气保护下，70℃油浴反应1小时。反应完毕，浓缩反应液，粗品经硅胶柱层析(PE∶EA＝1∶1)分离纯化，得到标题化合物(985mg，产率57.2％)。4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine (1.2 g, 4.2 mmol), 5-bromo-4-(trifluoromethyl)pyridin-2-amine (1.1 g , 4.6 mmol), bis-pinacol borate (1.6 g, 6.3 mmol), cesium carbonate (2.7 g, 8.3 mmol), palladium acetate (94 mg, 0.42 mmol) and n-butylbis(1-adamantyl) Phosphine (301 mg, 0.84 mmol) was added to a mixed solvent of toluene (10 mL) and methanol (10 mL), and the mixture was reacted under a nitrogen atmosphere at 70 ° C for 1 hour. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjjj

4)N-(5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)甲酰胺的制备4) Preparation of N-(5-(2,6-dimorpholinium-4-yl)-4-(trifluoromethyl)pyridin-2-yl)carboxamide

在0℃下将5-(2，6-二吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺(300mg，0.73mmol)溶于甲酸(2mL)中，然后向其缓慢滴加醋酸酐(3mL)，加毕，升温至25℃下反应4小时。反应完毕后，加入水(20mL)和乙酸乙酯(50mL)，分液，有机相分别用碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，加入氨水(5mL)洗涤，再次浓缩，粗品经硅胶柱层析(PE∶EA＝1∶1)分离纯化，得标题化合物(102mg，产率31.9％)。5-(2,6-Dimorpholinium pyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (300 mg, 0.73 mmol) was dissolved in formic acid (2 mL) at 0 ° C then Acetic anhydride (3 mL) was slowly added dropwise thereto, and the mixture was heated to a temperature of 25 ° C for 4 hours. After completion of the reaction, water (20 mL) and ethyl acetate (50 mL) were added, and the organic layer was washed with sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, filtered, concentrated, The residue was concentrated again, and the title compound was obtained from mjjjjjjj

分子式：C₁₉H₂₁F₃N₆O₃ 分子量：438.4 LC-MS(m/z)：439.0(M+H⁺)Molecular formula: C ₁₉ H ₂₁ F ₃ N ₆ O ₃ Molecular weight: 438.4 LC-MS (m/z): 439.0 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：11.19(s，0.5H)，10.91(s，0.5H)，9.35(s，0.5H)，8.42-8.57(m，2H)，7.30(s，0.5H)，6.33(s，1H)，3.58-3.64(m，16H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 11.19 (s, 0.5H), 10.91 (s, 0.5H), 9.35 (s, 0.5H), 8.42-8.57 (m, 2H), 7.30 (s , 0.5H), 6.33 (s, 1H), 3.58-3.64 (m, 16H).

实施例6 1-(5-(2，6-二吗啉嘧啶-4-基)-4-(甲基磺酰基)吡啶-2-基)脲(化合物6)的制备Example 6 Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-(methylsulfonyl)pyridin-2-yl)urea (Compound 6)

1)4，4′-(6-氯嘧啶-2，4-二基)二吗啉的制备1) Preparation of 4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine

将吗啉(6.3g，72.33mmol)溶于甲苯(11mL)和水(4.4mL)的混合溶剂中，25℃下向其中滴加2，4，6-三氯嘧啶(2.2g。12mmol)的甲苯(11mL)溶液。加毕，加热至85℃搅拌反应2小时。将反应液浓缩，所得粗品用硅胶柱层析(石油醚∶乙酸乙酯＝10∶1)纯化即得白色固体状标题化合物(2.5g，产率73.5％)。The morpholine (6.3 g, 72.33 mmol) was dissolved in a mixed solvent of toluene (11 mL) and water (4.4 mL), and 2,4,6-trichloropyrimidine (2.2 g, 12 mmol) was added dropwise thereto at 25 °C. Toluene (11 mL) solution. After the addition was completed, the reaction was stirred for 2 hours while heating to 85 °C. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal

2)4，4′-(6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)嘧啶-2，4-二基)二吗啉的制备2) 4,4'-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl) Preparation of dimorpholine

将4，4′-(6-氯嘧啶-2，4-二基)二吗啉(2.4g，8.4mmol)和双联硼酸频那醇酯(2.7g，10.6mmol)溶于乙腈(20mL)中，加入乙酸钾(1.2g，12.2mmol)、三环己基膦(0.16g，0.57mmol)和三(二亚苄基丙酮)二钯(0.3g，0.33mmol)，加毕，氮气保护下加热至85℃搅拌反应2小时。将反应液过滤，滤液浓缩，所得粗品用硅胶柱层析(石油醚∶乙酸乙酯＝10∶1)纯化即得白色固体状标题化合物(1.2g，产率37.5％)。4,4'-(6-Chloropyridin-2,4-diyl)dimorpholine (2.4 g, 8.4 mmol) and bis-boronic acid pinacol ester (2.7 g, 10.6 mmol) were dissolved in acetonitrile (20 mL) Add potassium acetate (1.2g, 12.2mmol), tricyclohexylphosphine (0.16g, 0.57mmol) and tris(dibenzylideneacetone) dipalladium (0.3g, 0.33mmol), add, heat under nitrogen The reaction was stirred at 85 ° C for 2 hours. The reaction mixture was filtered, and then evaporated tolulululululululululululululululululululululu

3)4-(甲硫基)吡啶-2-胺的制备3) Preparation of 4-(methylthio)pyridin-2-amine

将4-氯吡啶-2-胺(2.5g，19.44mmol)溶于乙醇(20mL)中，加入甲硫醇钠水溶液(20mL，40mmol，2M)，密封加热至140℃搅拌反应16小时。将反应液浓缩后，加入水(20 mL)和***(20mL)，搅拌5分钟后过滤，滤饼干燥即得白色固体状标题化合物(2.3g，产率85.2％)。4-Chloropyridin-2-amine (2.5 g, 19.44 mmol) was dissolved in ethanol (20 mL), aqueous sodium thioacetate (20 mL, 40 mmol, 2M) was added and the mixture was heated to 140 ° C and stirred for 16 hours. After concentrating the reaction solution, water was added (20 The title compound (2.3 g, yield 85.2%) was obtained.

4)5-溴-4-(甲硫基)吡啶-2-胺的制备4) Preparation of 5-bromo-4-(methylthio)pyridin-2-amine

将4-(甲硫基)吡啶-2-胺(0.6g，4.28mmol)溶于N，N-二甲基甲酰胺(5mL)中，冰水浴冷却至0℃，加入N-溴代丁二酰亚胺(0.8g，4.49mmol)，25℃搅拌反应3小时。将反应液浓缩，所得粗品用硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化即得白色固体状标题化合物(0.67g，产率71.3％)。4-(Methylthio)pyridin-2-amine (0.6 g, 4.28 mmol) was dissolved in N,N-dimethylformamide (5 mL), cooled to 0 ° C in ice water, and N-bromobutane The imide (0.8 g, 4.49 mmol) was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated to give crystal crystal crystal crystal crystal crystal crystal crystal

5)5-溴-4-(甲磺酰基)吡啶-2-胺的制备5) Preparation of 5-bromo-4-(methylsulfonyl)pyridin-2-amine

将5-溴-4-(甲硫基)吡啶-2-胺(0.5g，2.28mmol)溶于乙酸(5mL)和丙酮(5mL)的混合溶剂中，0℃下加入高锰酸钾(0.75g，4.75mmol)的水(3mL)溶液，加毕25℃搅拌反应1小时。将反应液用氨水中和至pH＝7，加入乙酸乙酯(10mL×2)萃取，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，所得粗品用硅胶柱层析(石油醚∶乙酸乙酯＝2∶1)纯化即得白色固体状标题化合物(0.38g，产率66.7％)。5-Bromo-4-(methylthio)pyridin-2-amine (0.5 g, 2.28 mmol) was dissolved in a mixed solvent of acetic acid (5 mL) and acetone (5 mL), and potassium permanganate (0.75) was added at 0 °C. A solution of g, 4.75 mmol) in water (3 mL) was stirred and stirred at 25 ° C for 1 hour. The reaction solution was neutralized with aqueous ammonia to pH = 7 and ethyl acetate (10 mL × 2) was evaporated. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The title compound (0.38 g, yield: 66.7%)

6)叔丁基(5-溴-4-(甲磺酰基)吡啶-2-基)氨基甲酸酯的制备6) Preparation of tert-butyl (5-bromo-4-(methylsulfonyl)pyridin-2-yl)carbamate

将5-溴-4-(甲磺酰基)吡啶-2-胺(0.38g，1.51mmol)溶于二氯甲烷(10mL)中，加入三乙胺(0.35g，3.46mmol)和二碳酸二叔丁酯(0.35g，1.6mmol)，25℃搅拌反应3小时。将反应液浓缩，所得粗品用硅胶柱层析(石油醚∶乙酸乙酯＝5∶1)纯化即得白色固体状标题化合物(0.43g，产率81.1％)。5-Bromo-4-(methylsulfonyl)pyridin-2-amine (0.38 g, 1.51 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.35 g, 3.46 mmol) and di-dicarbonate Butyl ester (0.35 g, 1.6 mmol) was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal

7)叔丁基(5-(2，6-二吗啉嘧啶-4-基)-4-(甲磺酰基)吡啶-2-基)氨基甲酸酯的制备 7) Preparation of tert-butyl (5-(2,6-dimorpholinium-4-yl)-4-(methylsulfonyl)pyridin-2-yl)carbamate

将叔丁基(5-溴-4-(甲磺酰基)吡啶-2-基)氨基甲酸酯(0.32g，0.91mmol)和4，4′-(6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)嘧啶-2，4-二基)二吗啉(0.35g，0.93mmol)溶于四氢呋喃(10mL)中，加入1，1′-双(二叔丁基膦)二茂铁二氯合钯(50mg，0.077)和碳酸铯(0.6g，1.84mmol)水溶液(3mL)，加热至45℃搅拌反应1小时，将反应液过滤，滤液浓缩，所得粗品用硅胶柱层析(二氯甲烷∶甲醇＝20∶1)纯化即得白色固体状标题化合物(0.22g，产率46.8％)。tert-Butyl (5-bromo-4-(methylsulfonyl)pyridin-2-yl)carbamate (0.32 g, 0.91 mmol) and 4,4'-(6-(4,4,5,5) -Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl)dimorpholine (0.35 g, 0.93 mmol) was dissolved in tetrahydrofuran (10 mL). 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium (50 mg, 0.077) and cesium carbonate (0.6 g, 1.84 mmol) in water (3 mL) were added, and the mixture was stirred at 45 ° C for 1 hour. The reaction mixture was filtered, and then evaporated tolululululululululululululululululululu

8)5-(2，6-二吗啉嘧啶-4-基)-4-(甲磺酰基)吡啶-2-胺的制备8) Preparation of 5-(2,6-dimorpholinpyrimidin-4-yl)-4-(methylsulfonyl)pyridin-2-amine

将叔丁基(5-(2，6-二吗啉嘧啶-4-基)-4-(甲磺酰基)吡啶-2-基)氨基甲酸酯(0.22g，0.42mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(3mL)，20℃搅拌反应2小时。将反应液浓缩，加入乙酸乙酯(30mL)，用饱和碳酸氢钠水溶液洗涤(10mL×2)，有机相用无水硫酸钠干燥，过滤，将滤液浓缩，所得粗品用硅胶柱层析(二氯甲烷∶甲醇＝10∶1)纯化即得白色固体状标题化合物(0.11g，产率61.1％)。tert-Butyl (5-(2,6-dimorpholinium-4-yl)-4-(methylsulfonyl)pyridin-2-yl)carbamate (0.22 g, 0.42 mmol) was dissolved in dichloro Trifluoroacetic acid (3 mL) was added to methane (5 mL), and the mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated, EtOAc EtOAc (EtOAc m. Purification of the title compound (0.11 g, yield: 61.1%)

9)N-((5-(2，6-二吗啉嘧啶-4-基)-4-(甲磺酰基)吡啶-2-基)氨基甲酰)苯甲酰胺的制备9) Preparation of N-((5-(2,6-dimorpholinium-4-yl)-4-(methylsulfonyl)pyridin-2-yl)carbamoyl)benzamide

将5-(2，6-二吗啉嘧啶-4-基)-4-(甲磺酰基)吡啶-2-胺(65mg，0.15mmol)溶于二氯甲烷(2mL)中，加入苯甲酰异氰酸酯(25mg，0.17mmol)，密封加热至50℃搅拌反应16小时。将反应液浓缩，加入甲醇(2mL)，搅拌5分钟后过滤，滤饼干燥即得白色固体状标题化合物(58mg，产率65.9％)。5-(2,6-Dimorpholinimidin-4-yl)-4-(methylsulfonyl)pyridin-2-amine (65 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). The isocyanate (25 mg, 0.17 mmol) was heated to 50 ° C and stirred for 16 hours. The reaction mixture was concentrated, EtOAc EtOAcjjjjjjjjjj

10)1-(5-(2，6-二吗啉嘧啶-4-基)-4-(甲基磺酰基)吡啶-2-基)脲的制备 10) Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-(methylsulfonyl)pyridin-2-yl)urea

将5-((2，6-二吗啉嘧啶-4-基)-4-(甲磺酰基)吡啶-2-基)氨基甲酰苯甲酰胺(58mg，0.1mmol)溶于乙醇(1mL)中，加入碳酸钾(15mg，0.1mmol)，加热至85℃搅拌反应1小时。将反应液浓缩，所得粗品用硅胶柱层析(二氯甲烷∶甲醇＝10∶1)纯化，即得白色固体状标题化合物(30mg，产率63.8％)。5-((2,6-Dimorpholin-4-yl)-4-(methylsulfonyl)pyridin-2-yl)carbamoylbenzamide (58 mg, 0.1 mmol) was dissolved in ethanol (1 mL) Potassium carbonate (15 mg, 0.1 mmol) was added, and the mixture was heated to 85 ° C and stirred for 1 hour. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal crystal

分子式：C₁₉H₂₅N₇O₅S 分子量：463.5 LC-MS(m/z)：464.2(M+H⁺)Molecular formula: C ₁₉ H ₂₅ N ₇ O ₅ S Molecular weight: 463.5 LC-MS (m/z): 464.2 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.64(s，1H)，8.30(d，J＝10Hz，2H)，6.82(s，2H)，6.26(s，1H)，3.58-3.71(m，16H)，3.49(s，3H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.64 (s, 1H), 8.30 (d, J = 10Hz, 2H), 6.82 (s, 2H), 6.26 (s, 1H), 3.58-3.71 ( m, 16H), 3.49 (s, 3H).

实施例7 1-(5-(2，6-二吗啉嘧啶-4-基)-4-甲基吡啶-2-基)脲(化合物7)的制备Example 7 Preparation of 1-(5-(2,6-dimorpholinimidin-4-yl)-4-methylpyridin-2-yl)urea (Compound 7)

1)5-溴-4-甲基吡啶-2-胺的制备1) Preparation of 5-bromo-4-methylpyridin-2-amine

称取4-甲基吡啶-2-胺(2.16g，20.0mmol)加入到冰醋酸(20mL)中，降温至0℃，缓慢滴加溴素(3.84g，24.0mmol)，保持温度在0℃左右，滴加完毕，继续搅拌0.5小时，析出大量固体，加入水(100mL)，乙酸乙酯(150mL×2)萃取，合并有机相，依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得标题化合物(2.65g，产率71.0％)。4-Methylpyridin-2-amine (2.16 g, 20.0 mmol) was weighed into glacial acetic acid (20 mL), cooled to 0 ° C, bromine (3.84 g, 24.0 mmol) was slowly added dropwise, maintaining the temperature at 0 ° C After the addition was completed, stirring was continued for 0.5 hour, and a large amount of solid was precipitated. Water (100 mL), ethyl acetate (150 mL×2) was added and the organic phase was combined and washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The residue was dried over EtOAcjjjjjjjjjjj

2)4-甲基-5-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)吡啶-2-胺的制备2) Preparation of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

称取5-溴-4-甲基吡啶-2-胺(400mg，2.1mmol)、联硼酸频哪醇酯(815mg，3.2 mmol)、(1，1-双(二苯基磷)二茂铁)二氯化钯(315mg，0.43mmol)和醋酸钾(839mg，8.6mmol)加入到1，4-二氧六环(15mL)中，氮气保护下升温至90℃反应16小时。冷却至室温，抽滤，滤液真空浓缩，粗品直接用于下一步。Weigh out 5-bromo-4-methylpyridin-2-amine (400 mg, 2.1 mmol), boronic acid pinacol ester (815 mg, 3.2 Methyl), (1,1-bis(diphenylphosphino)ferrocene)palladium dichloride (315 mg, 0.43 mmol) and potassium acetate (839 mg, 8.6 mmol) were added to 1,4-dioxane (15 mL) In the reaction, the temperature was raised to 90 ° C under nitrogen for 16 hours. It was cooled to room temperature, suction filtered, and the filtrate was concentrated in vacuo.

3)5-(2，6-二吗啉嘧啶-4-基)-4-甲基吡啶-2-胺的制备3) Preparation of 5-(2,6-dimorpholinpyrimidin-4-yl)-4-methylpyridin-2-amine

将上一步所得粗品(2.1mmol)溶于1，4-二氧六环(15mL)中，依次加入4，4′-(6-氯嘧啶-2，4-二基)二吗啉(340mg，1.2mmol)、四(三苯基膦)钯(43mg，0.04mmol)和碳酸铯(1.95g，6.0mmol)，氮气保护下升温至120℃反应18小时。反应液冷却至室温，加入水(60mL)，乙酸乙酯(100mL)萃取，有机相用饱和食盐水(100mL)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(二氯甲烷∶甲醇＝20∶1)纯化得标题化合物(87mg，产率20.3％)。The crude product obtained in the previous step (2.1 mmol) was dissolved in 1,4-dioxane (15 mL), and then 4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine (340 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium (43 mg, 0.04 mmol) and cesium carbonate (1.95 g, 6.0 mmol) were heated to 120 ° C under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. Purification of the title compound (87 mg, yield: 20.3%)

4)N-((5-(2，6-二吗啉嘧啶-4-基)-4-甲基吡啶-2-基)氨基甲酰基)苯甲酰胺的制备4) Preparation of N-((5-(2,6-dimorpholinium-4-yl)-4-methylpyridin-2-yl)carbamoyl)benzamide

称取5-(2，6-二吗啉嘧啶-4-基)-4-甲基吡啶-2-胺(60mg，0.17mmol)和苯甲酰异氰酸酯(30mg，0.2mmol)溶于二氯甲烷(5mL)中，60℃封管反应两小时。冷却至室温，析出白色固体，抽滤，滤饼用二氯甲烷(2mL)洗，真空干燥得标题化合物(48mg，产率56.6％)。5-(2,6-Dimorpholinpyrimidin-4-yl)-4-methylpyridin-2-amine (60 mg, 0.17 mmol) and benzoyl isocyanate (30 mg, 0.2 mmol) were weighed in dichloromethane In a (5 mL), the tube was sealed at 60 ° C for two hours. After cooling to room temperature, a white solid was evaporated,jjjjjjjjjjjj

6)1-(5-(2，6-二吗啉嘧啶-4-基)-4-甲基吡啶-2-基)脲的制备6) Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-methylpyridin-2-yl)urea

将N-((5-(2，6-二吗啉嘧啶-4-基)-4-甲基吡啶-2-基)氨基甲酰基)苯甲酰胺(46mg，0.09mmol)溶于无水乙醇(3mL)中，加入碳酸钾(15mg，0.11mmol)，升温至80℃反应2小时。冷却至室温，抽滤，所得固体依次用水洗(1mL)，甲醇洗(0.5mL)，真空干燥得标 题化合物(13mg，产率36.2％)。Dissolving N-((5-(2,6-dimorpholinimidin-4-yl)-4-methylpyridin-2-yl)carbamoyl)benzamide (46 mg, 0.09 mmol) in absolute ethanol Potassium carbonate (15 mg, 0.11 mmol) was added to (3 mL), and the mixture was heated to 80 ° C for 2 hours. After cooling to room temperature and suction filtration, the obtained solid was washed with water (1 mL), methanol (0.5 mL) and dried in vacuo. Compound (13 mg, yield 36.2%).

分子式：C₁₉H₂₅N₇O₃ 分子量：399.45 LC-MS(m/z)：400.2(M+H⁺)Molecular formula: C ₁₉ H ₂₅ N ₇ O ₃ Molecular weight: 399.45 LC-MS (m/z): 400.2 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.14(s，1H)，8.21(s，1H)，7.30(s，1H)，7.23-6.70(brs，1H)，6.26(s，1H)，3.68-3.60(m，12H)，3.60-3.53(m，4H)，2.36(s，3H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.14 (s, 1H), 8.21 (s, 1H), 7.30 (s, 1H), 7.23-6.70 (brs, 1H), 6.26 (s, 1H) , 3.68-3.60 (m, 12H), 3.60-3.53 (m, 4H), 2.36 (s, 3H).

实施例8 1-(4-氰基-5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)脲(化合物8)的制备Example 8 Preparation of 1-(4-cyano-5-(2,6-dimorpholinpyrimidin-4-yl)pyridin-2-yl)urea (Compound 8)

1)2-氨基-4-氰基-5-溴吡啶的制备1) Preparation of 2-amino-4-cyano-5-bromopyridine

称取N-溴代丁二酰亚胺(11.2g，63mmol)加入到四氢呋喃(72.5mL)中，降温至0℃，称取2-氨基-4-氰基吡啶(7.15g，60mmol)溶于四氢呋喃(57.5mL)中，缓慢滴加到上述溶液中，保持温度在0℃左右，滴加完毕后缓慢升至室温，搅拌0.5h，加入硫代硫酸钠(2.5g)水溶液(47.5mL)淬灭，真空浓缩，粗品经硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得标题化合物(5.1g，产率42.9％)。N-bromosuccinimide (11.2 g, 63 mmol) was weighed into tetrahydrofuran (72.5 mL), cooled to 0 ° C, and 2-amino-4-cyanopyridine (7.15 g, 60 mmol) was dissolved. In tetrahydrofuran (57.5 mL), slowly add dropwise to the above solution, keep the temperature at about 0 ° C, slowly increase to room temperature after the addition, stir for 0.5 h, add sodium thiosulfate (2.5 g) aqueous solution (47.5 mL) and quench The title compound (5.1 g, yield 42.9%) was obtained.

2)2-氨基-4-氰基-5-(2，6-二吗啉嘧啶-4-基)吡啶的制备2) Preparation of 2-amino-4-cyano-5-(2,6-dimorpholinpyrimidin-4-yl)pyridine

将4，4′-(6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)嘧啶-2，4-二基)二吗啉(1.77g，4.7mmol)和2-氨基-4-氰基-5-溴吡啶(0.93g，4.7mmol)溶于四氢呋喃(25mL)中，搅拌条件下加入碳酸铯(4.59g，14.1mmol)，氮气保护下加入1，1’-双(二叔丁基膦)二茂铁二氯化钯(308mg，0.47mmol)，缓慢升温至45℃，反应1小时。减压蒸除四氢呋喃，加入乙酸乙酯(80mL)和水(80mL)，分液，有机相用无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(石油醚∶乙酸乙酯∶三乙胺＝1∶1∶0.01)纯化得标题化合物(0.7g，产率40.5％)。4,4'-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2,4-diyl) Morpholine (1.77 g, 4.7 mmol) and 2-amino-4-cyano-5-bromopyridine (0.93 g, 4.7 mmol) were dissolved in tetrahydrofuran (25 mL) and EtOAc (4.59 g, 14.1 mmol) 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (308 mg, 0.47 mmol) was added under nitrogen, and the temperature was slowly raised to 45 ° C for 1 hour. Ethyl acetate (80 mL) and water (80 mL) were evaporated, evaporated, evaporated, evaporated, evaporated Purification of the title compound (0.7 g, yield 40.5%).

3)N-((4-氰基-5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)氨基甲酰基)苯甲酰胺的制备 3) Preparation of N-((4-cyano-5-(2,6-dimorpholinium-4-yl)pyridin-2-yl)carbamoyl)benzamide

将2-氨基-4-氰基-5-(2，6-二吗啉嘧啶-4-基)吡啶(500mg，1.36mmol)溶于二氯甲烷(8mL)中，缓慢加入苯甲酰异氰酸酯(400mg，2.72mmol)，50℃封管反应16小时，抽滤，滤饼用二氯甲烷洗涤得标题化合物(510mg，产率72.9％)。2-Amino-4-cyano-5-(2,6-dimorpholinium pyrimidin-4-yl)pyridine (500 mg, 1.36 mmol) was dissolved in dichloromethane (8 mL) and benzoyl isocyanate was slowly added. The title compound (510 mg, yield 72.9%) was obtained.

4)1-(4-氰基-5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)脲的制备4) Preparation of 1-(4-cyano-5-(2,6-dimorpholinpyrimidin-4-yl)pyridin-2-yl)urea

将N-((4-氰基-5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)氨基甲酰基)苯甲酰胺(400mg，0.78mmol)加入到乙醇(8mL)中，加入碳酸钾(107.6mg，0.78mmol)，85℃反应2小时，抽滤，滤饼分别用甲醇、二氯甲烷和乙酸乙酯洗涤，真空干燥得标题化合物(290mg，产率90.6％)。Add N-((4-cyano-5-(2,6-dimorpholinimidin-4-yl)pyridin-2-yl)carbamoyl)benzamide (400 mg, 0.78 mmol) to ethanol (8 mL) The potassium carbonate (107.6 mg, 0.78 mmol) was added, and the mixture was reacted at 85 ° C for 2 hours, and filtered with suction. ).

分子式：C₁₉H₂₂N₈O₃ 分子量：410.4 LC-MS(m/z)：411.2(M+H⁺)Molecular formula: C ₁₉ H ₂₂ N ₈ O ₃ Molecular weight: 410.4 LC-MS (m/z): 411.2 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.65(s，1H)，8.92(s，1H)，8.10(s，1H)，6.75(s，2H)，6.65(s，1H)，3.74-3.62(m，16H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.65 (s, 1H), 8.92 (s, 1H), 8.10 (s, 1H), 6.75 (s, 2H), 6.65 (s, 1H), 3.74 -3.62 (m, 16H).

实施例9 1-(5-(2，6-二吗啉嘧啶-4-基)-4-氟吡啶-2-基)脲(化合物9)的制备Example 9 Preparation of 1-(5-(2,6-dimorpholinimidin-4-yl)-4-fluoropyridin-2-yl)urea (Compound 9)

1)5-溴-4-氟吡啶-2-胺的制备1) Preparation of 5-bromo-4-fluoropyridin-2-amine

将N-溴代丁二酰亚胺(1.78g，10.0mmol)溶于四氢呋喃(10mL)，降温至0℃，称取4-氟吡啶-2-胺(1.12g，10.0mmol)溶于四氢呋喃(10mL)，缓慢滴加至上述溶液中，保持 温度在0℃左右，滴加完毕，缓慢升至室温继续搅拌1小时。反应液直接浓缩，粗品经硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化得标题化合物(1.59g，产率83.2％)。N-bromosuccinimide (1.78 g, 10.0 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ° C, and 4-fluoropyridin-2-amine (1.12 g, 10.0 mmol) was dissolved in tetrahydrofuran. 10mL), slowly added to the above solution, keep The temperature was around 0 ° C, the addition was completed, and the temperature was slowly raised to room temperature and stirring was continued for 1 hour. The reaction mixture was concentrated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal

2)4-氟-5-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)吡啶-2-胺的制备2) Preparation of 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

称取5-溴-4-氟吡啶-2-胺(389mg，2.0mmol)、联硼酸频哪醇酯(787mg，3.1mmol)，(1，1-双(二苯基膦)二茂铁)二氯化钯(293mg，0.4mmol)和醋酸钾(785mg，8.0mmol)加入到1，4-二氧六环(10mL)中，氮气保护下升温至90℃反应16小时。冷却至室温，抽滤，滤液真空浓缩，粗品直接用于下一步。5-Bromo-4-fluoropyridin-2-amine (389 mg, 2.0 mmol), boranoic acid pinacol ester (787 mg, 3.1 mmol), (1,1-bis(diphenylphosphino)ferrocene) Palladium dichloride (293 mg, 0.4 mmol) and potassium acetate (785 mg, 8.0 mmol) were added to 1,4-dioxane (10 mL), and the mixture was heated to 90 ° C under nitrogen for 16 hours. It was cooled to room temperature, suction filtered, and the filtrate was concentrated in vacuo.

3)5-(2，6-二吗啉嘧啶-4-基)-4-氟吡啶-2-胺的制备3) Preparation of 5-(2,6-dimorpholinpyrimidin-4-yl)-4-fluoropyridin-2-amine

将上一步所得粗品(2.0mmol)溶于1，4-二氧六环(15mL)中，依次加入4，4′-(6-氯嘧啶-2，4-二基)二吗啉(285mg，1.0mmol)、四(三苯基膦)钯(58mg，0.05mmol)和碳酸铯(2.61g，8.0mmol)，氮气保护下升温至120℃反应18小时。反应液冷却至室温，加入水(60mL)，乙酸乙酯(100mL)萃取，有机相用饱和食盐水(100mL)洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(二氯甲烷∶甲醇＝20∶1)纯化得标题化合物(239mg，产率66.4％)。The crude product obtained in the previous step (2.0 mmol) was dissolved in 1,4-dioxane (15 mL), and then 4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine (285 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) and cesium carbonate (2.61 g, 8.0 mmol) were heated to 120 ° C under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. Purification of the title compound (239 mg, yield: 66.4%)

4)N-((5-(2，6-二吗啉嘧啶-4-基)-4-氟吡啶-2-基)氨基甲酰基)苯甲酰胺的制备4) Preparation of N-((5-(2,6-dimorpholinium-4-yl)-4-fluoropyridin-2-yl)carbamoyl)benzamide

称取5-(2，6-二吗啉嘧啶-4-基)-4-氟吡啶-2-胺(227mg，0.63mmol)和苯甲酰异氰酸酯(101mg，0.69mmol)溶于二氯甲烷(10mL)中，60℃封管反应两小时。冷却至室温，析出白色固体，抽滤，滤饼用二氯甲烷(2mL)洗，真空干燥得标题化合物(210mg，产率65.1％)。5-(2,6-Dimorpholinpyrimidin-4-yl)-4-fluoropyridin-2-amine (227 mg, 0.63 mmol) and benzoyl isocyanate (101 mg, 0.69 mmol) were weighed in dichloromethane. In 10 mL), the tube was sealed at 60 ° C for two hours. After cooling to room temperature, a white solid was obtained,jjjjjjjjjjjj

5)1-(5-(2，6-二吗啉嘧啶-4-基)-4-氟吡啶-2-基)脲的制备 5) Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)-4-fluoropyridin-2-yl)urea

将N-((5-(2，6-二吗啉嘧啶-4-基)-4-氟吡啶-2-基)氨基甲酰基)苯甲酰胺(210mg，0.41mmol)溶于叔丁醇(8mL)中，加入叔丁醇钾(70mg，0.22mmol)，升温至80℃反应7小时。冷却至室温，抽滤，所得固体依次用水洗(5mL)，甲醇洗(3mL)，真空干燥得标题化合物(28mg，产率16.9％)。N-((5-(2,6-Dimorpholinium-4-yl)-4-fluoropyridin-2-yl)carbamoyl)benzamide (210 mg, 0.41 mmol) was dissolved in tert-butanol ( To 8 mL), potassium t-butoxide (70 mg, 0.22 mmol) was added, and the mixture was heated to 80 ° C for 7 hours. The mixture was cooled to room temperature, EtOAc (EtOAc m.

分子式：C₁₈H₂₂FN₇O₃ 分子量：403.4 LC-MS(m/z)：404.2(M+H⁺)Molecular formula: C ₁₈ H ₂₂ FN ₇ O ₃ Molecular weight: 403.4 LC-MS (m/z): 404.2 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.48(s，1H)，8.79(d，J＝10.8Hz，1H)，7.50(d，J＝10.8Hz，1H)，6.78(s，2H)，6.43(s，1H)，3.72-3.60(m，12H)，3.60-3.53(m，4H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.48 (s, 1H), 8.79 (d, J = 10.8Hz, 1H), 7.50 (d, J = 10.8Hz, 1H), 6.78 (s, 2H ), 6.43 (s, 1H), 3.72-3.60 (m, 12H), 3.60-3.53 (m, 4H).

实施例10 1-(5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)脲(化合物10)的制备Example 10 Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)pyridin-2-yl)urea (Compound 10)

1)5-(2，6-二吗啉嘧啶-4-基)吡啶-2-胺的制备1) Preparation of 5-(2,6-dimorpholinpyrimidin-4-yl)pyridin-2-amine

将4，4′-(6-氯嘧啶-2，4-二基)二吗啉(1.0g，3.5mmol)和5-溴吡啶-2-胺(605mg，3.5mmol)溶于甲苯(10mL)中，加入联硼酸频那醇酯(889mg，3.5mmol)、碳酸铯(2.28g，7.0mmol)和甲醇(10mL)，氮气保护下加入醋酸钯(157mg，0.7mmol)和正丁基二(1-金刚烷基)膦(501mg，1.4mmol)，升温至70℃反应1小时。冷却至室温，浓缩，加水(80mL)和乙酸乙酯(80mL)，分液，有机相用无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(二氯甲烷∶甲醇＝50∶1)纯化得标题化合物(800mg，产率66.7％)。4,4'-(6-chloropyrimidin-2,4-diyl)dimorpholine (1.0 g, 3.5 mmol) and 5-bromopyridin-2-amine (605 mg, 3.5 mmol) were dissolved in toluene (10 mL) Add boranoic acid pinacol ester (889 mg, 3.5 mmol), cesium carbonate (2.28 g, 7.0 mmol) and methanol (10 mL), and add palladium acetate (157 mg, 0.7 mmol) and n-butyl di(1-) under nitrogen. Adamantyl)phosphine (501 mg, 1.4 mmol) was heated to 70 ° C for 1 hour. The mixture was cooled to room temperature, EtOAc (EtOAc m. The title compound (800 mg, yield 66.7%) was obtained.

2)N-((5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)氨基甲酰基)苯甲酰胺的制备 2) Preparation of N-((5-(2,6-dimorpholinpyrimidin-4-yl)pyridin-2-yl)carbamoyl)benzamide

将5-(2，6-二吗啉嘧啶-4-基)吡啶-2-胺(250mg，0.73mmol)溶于二氯甲烷(8mL)中，缓慢加入苯甲酰异氰酸酯(215mg，1.46mmol)，50℃封管反应16小时，抽滤，滤饼用二氯甲烷洗涤，得标题化合物(300mg，产率84.0％)。5-(2,6-Dimorpholinium-4-yl)pyridin-2-amine (250 mg, 0.73 mmol) was dissolved in dichloromethane (8 mL) and benzoyl isocyanate (215 mg, 1.46 mmol) was slowly added. The reaction mixture was sealed at 50 ° C for 16 hr.

4)1-(5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)脲的制备4) Preparation of 1-(5-(2,6-dimorpholinpyrimidin-4-yl)pyridin-2-yl)urea

将N-((5-(2，6-二吗啉嘧啶-4-基)吡啶-2-基)氨基甲酰基)苯甲酰胺(300mg，0.61mmol)加入到乙醇(8mL)中，加入碳酸钾(84.2mg，0.61mmol)，85℃反应2小时，抽滤，滤饼分别用甲醇、二氯甲烷和乙酸乙酯洗涤，真空干燥得标题化合物(210mg，产率89.4％)。Add N-((5-(2,6-dimorpholinimidin-4-yl)pyridin-2-yl)carbamoyl)benzamide (300 mg, 0.61 mmol) to ethanol (8 mL). Potassium (84.2 mg, 0.61 mmol), mp.

分子式：C₁₈H₂₃N₇O₃ 分子量：385.4 LC-MS(m/z)：386.2(M+H⁺)Molecular formula: C ₁₈ H ₂₃ N ₇ O ₃ Molecular weight: 385.4 LC-MS (m/z): 386.2 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.33(s，1H)，8.93(d，J＝2.0Hz，1H)，8.34(dd，J₁＝2.0Hz，J₂＝8.8Hz，1H)，7.50(d，J＝8.8Hz，1H)，7.20-6.80(brs，2H)，6.67(s，1H)，3.70-3.62(m，16H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.33 (s, 1H), 8.93 (d, J = 2.0Hz, 1H), 8.34 (dd, J 1 = 2.0Hz, J 2 = 8.8Hz, 1H ), 7.50 (d, J = 8.8 Hz, 1H), 7.20-6.80 (brs, 2H), 6.67 (s, 1H), 3.70-3.62 (m, 16H).

实施例11 (S)-1-(5-(6-(3-氟吡咯烷-1-基)-2-吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)脲(化合物11)的制备Example 11 (S)-1-(5-(6-(3-Fluoropyrrolidin-1-yl)-2-morpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridine-2- Preparation of urea (compound 11)

1)4-(4，6-二氯嘧啶-2-基)吗啉的制备1) Preparation of 4-(4,6-dichloropyrimidin-2-yl)morpholine

将2，4，6-三氯嘧啶(3.0g，16.4mmol)溶解在甲醇(50mL)中，冷却至0℃，加入碳酸氢钠(5.5g，65.5mmol)，将吗啉(1.4g，16.1mmol)的甲醇(10mL)溶液逐滴加入，升至 25℃，继续搅拌16小时。将反应液浓缩，加入乙酸乙酯(100mL)和水(50mL)，分液，水相用乙酸乙酯(50mL)萃取，有机相合并，浓缩，剩余物经硅胶柱层析(石油醚∶乙酸乙酯＝3∶1)纯化，得标题化合物(2.0g，产率54％)。2,4,6-Trichloropyrimidine (3.0 g, 16.4 mmol) was dissolved in methanol (50 mL), cooled to 0 ° C, sodium bicarbonate (5.5 g, 65.5 mmol), morpholine (1.4 g, 16.1) Methanol) (10 mL) solution was added dropwise and raised to Stirring was continued for 16 hours at 25 °C. The reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc)EtOAc. Purification of the title compound (2.0 g, yield 54%).

2)(S)-4-(4-氯-6-(3-氟吡咯烷-1-基)嘧啶-2-基)吗啉的制备2) Preparation of (S)-4-(4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-2-yl)morpholine

将4-(4，6-二氯嘧啶-2-基)吗啉(1.0g，4.3mmol)溶于二氯甲烷(50mL)中，加入(S)-3-氟吡咯烷盐酸盐(0.8g，6.4mmol)，冰水浴下，缓慢加入三乙胺(2.6g，25.7mmol)，升至25℃，继续搅拌5小时。将反应液浓缩，加入乙酸乙酯(50mL)和水(30mL)，分液，水相用乙酸乙酯(30mL)萃取，有机相合并，浓缩，剩余物经硅胶柱层析(石油醚∶乙酸乙酯＝2∶1)纯化，得标题化合物(0.8g，产率66.7％)。4-(4,6-Dichloropyrimidin-2-yl)morpholine (1.0 g, 4.3 mmol) was dissolved in dichloromethane (50 mL) and (S)-3-fluoropyrrolidine hydrochloride (0.8) g, 6.4 mmol), triethylamine (2.6 g, 25.7 mmol) was slowly added in ice-water bath, then warmed to 25 ° C and stirring was continued for 5 hours. The reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc) Purification of the title compound (0.8 g, yield 66.7%).

3)5-溴-4-(三氟甲基)吡啶-2-胺的制备3) Preparation of 5-bromo-4-(trifluoromethyl)pyridin-2-amine

将4-(三氟甲基)吡啶-2-胺(2.0g，12.3mmol)溶于氯仿(50mL)中，然后降至0℃下，再将N-溴代琥珀酰亚胺(2.4g，13.5mmol)缓慢加入到体系中，加毕，升温至25℃反应2小时。反应完毕，浓缩反应液，剩余物经硅胶柱柱层析(石油醚∶乙酸乙酯＝4∶1)纯化，得标题化合物(2.5g，产率84.2％)。4-(Trifluoromethyl)pyridin-2-amine (2.0 g, 12.3 mmol) was dissolved in chloroform (50 mL), then reduced to 0 ° C, then N-bromosuccinimide (2.4 g, 13.5 mmol) was slowly added to the system, and after the addition, the temperature was raised to 25 ° C for 2 hours. After completion of the reaction, the reaction mixture was evaporated. mjjjjjjj

4)5-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-4-(三氟甲基)吡啶-2-胺的制备4) 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine preparation

将5-溴-4-(三氟甲基)吡啶-2-胺(0.5g，2.1mmol)溶于1，4-二氧六环(20mL)中，加入双联频哪醇硼酸酯(0.8g，3.2mmol)、[1，1′-双(二苯基磷)二茂铁]二氯化钯(0.16g，0.22mmol)和乙酸钾(0.6g，6.1mmol)，升温至100℃，反应14小时。过滤，浓缩得标题化合物(0.6g)，直接用于下一步反应。5-Bromo-4-(trifluoromethyl)pyridin-2-amine (0.5 g, 2.1 mmol) was dissolved in 1,4-dioxane (20 mL) and bis-pinacol borate ( 0.8 g, 3.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.16 g, 0.22 mmol) and potassium acetate (0.6 g, 6.1 mmol), heated to 100 ° C , the reaction was 14 hours. Filtration and concentration gave the title compound (0.6 g).

5)(S)-5-(6-(3-氟吡咯烷-1-基)-2-吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺的制备 5) Preparation of (S)-5-(6-(3-fluoropyrrolidin-1-yl)-2-morpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine

将5-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-4-(三氟甲基)吡啶-2-胺(0.6g，2.1mmol)和(S)-4-(4-氯-6-(3-氟吡咯烷-1-基)嘧啶-2-基)吗啉(0.6g，2.1mmol)溶于1，4-二氧六环(30mL)中，加入[1，1′-双(二苯基磷)二茂铁]二氯化钯(0.15g，0.20mmol)、碳酸钠(0.7g，6.6mmol)和水(3mL)，加热至100℃，反应12h。过滤，浓缩，剩余物经硅胶柱层析(石油醚∶乙酸乙酯＝1∶1)纯化，得到标题化合物(0.5g，产率58.1％)。5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (0.6 g, 2.1 mmol) and (S)-4-(4-chloro-6-(3-fluoropyrrolidin-1-yl)pyrimidin-2-yl)morpholine (0.6 g, 2.1 mmol) were dissolved in 1,4 In a dioxane (30 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.15 g, 0.20 mmol), sodium carbonate (0.7 g, 6.6 mmol) and Water (3 mL) was heated to 100 ° C for 12 h. Filtration, EtOAc (EtOAc)EtOAc.

6)(S)-N-((5-(6-(3-氟吡咯烷-1-基)-2-吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)氨基甲酰基)苯甲酰胺的制备6) (S)-N-((5-(6-(3-Fluoropyrrolidin-1-yl)-2-morpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridine-2- Preparation of carbamoyl)benzamide

将(S)-5-(6-(3-氟吡咯烷-1-基)-2-吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-胺(0.18g，0.44mmol)悬浮在二氯甲烷(20mL)中，加入苯甲酰异氰酸酯(0.13g，0.88mmol)，加热至50℃，反应3h，过滤，固体用二氯甲烷(20mL)洗涤，干燥，得到目标化合物(160mg，产率64.0％)。(S)-5-(6-(3-Fluoropyrrolidin-1-yl)-2-morpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (0.18 g, 0.44 mmol) was suspended in dichloromethane (20 mL), benzoyl isocyanate (0.13 g, 0.88 mmol) was added, heated to 50 ° C, 3 h, filtered, and the solid was washed with dichloromethane (20 mL) Compound (160 mg, yield 64.0%).

7)(S)-1-(5-(6-(3-氟吡咯烷-1-基)-2-吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)脲的制备7) (S)-1-(5-(6-(3-Fluoropyrrolidin-1-yl)-2-morpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl Preparation of urea

将(S)-N-((5-(6-(3-氟吡咯烷-1-基)-2-吗啉嘧啶-4-基)-4-(三氟甲基)吡啶-2-基)氨基甲酰基)苯甲酰胺(0.16g，0.28mmol)溶解在甲醇(20mL)中，加入碳酸钾(58.0mg，0.42mmol)，25℃下搅拌4h，过滤，固体用水(10mL)和甲醇(20mL)依次洗涤，干燥，得到标题化合物(80mg，产率63.0％)。(S)-N-((5-(6-(3-Fluoropyrrolidin-1-yl)-2-morpholinpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl The carbamoyl)benzamide (0.16 g, 0.28 mmol) was dissolved in MeOH (20 mL), EtOAc (EtOAc (EtOAc) 20 mL) was washed sequentially and dried to give crystall

分子式：C₁₉H₂₁F₄N₇O₂ 分子量：455.4 LC-MS(m/z)：456.2(M+H⁺)Molecular formula: C ₁₉ H ₂₁ F ₄ N ₇ O ₂ Molecular weight: 455.4 LC-MS (m/z): 456.2 (M+H ⁺ )

¹H-NMR(400MHz，DMSO-d₆)δ：9.59(s，1H)，8.45(s，1H)，8.09(s，1H)，6.81(s，2H)，6.03(s，1H)，5.35(s，0.5H)，5.48(s，0.5H)，3.82-3.85(m，1H)，3.59-3.65(m，10H)，3.41-3.43(m，1H)，2.12-2.28(m，2H). ^{1 H-NMR (400MHz, DMSO} -d 6) δ: 9.59 (s, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 6.81 (s, 2H), 6.03 (s, 1H), 5.35 (s, 0.5H), 5.48 (s, 0.5H), 3.82-3.85 (m, 1H), 3.59-3.65 (m, 10H), 3.41-3.43 (m, 1H), 2.12-2.28 (m, 2H) .

Claims (12)

1. 通式(I)所示的化合物、立体异构体或其药学上可接受的盐：a compound represented by the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

   

   

   其中，R¹选自氢原子，卤素，氰基，硝基，羧基，任选被1-3个Q¹取代的3-14元环烷基、3-14元杂环基、6-14元芳基、5-14元杂芳基、6-10元螺环基或6-10元桥环基，且所述螺环基或桥环基中的碳原子可以被1-3个O、S(O)_m、N(H)_m、NCH₃或C(O)替换；Wherein R ^{1 is} selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a carboxyl group, a 3-14 membered cycloalkyl group optionally substituted by 1 to 3 Q ¹ , a 3-14 membered heterocyclic group, and 6 to 14 members. An aryl group, a 5-14 membered heteroaryl group, a 6-10 membered spirocyclic group or a 6-10 membered bridged ring group, and the carbon atom in the spirocyclic or bridged ring group may be 1-3 O, S (O) _m , N(H) _m , NCH ₃ or C(O) substitution;

   R²和R⁴分别独立的选自氢原子，卤素，硝基，羟基，羧基，氨基，氰基，C_1-6烷基，卤代C_1-6烷基，C_1-6烷氧基，卤代C_1-6烷氧基，C_1-6烷基氨基，二C_1-6烷基氨基或C_1-6烷氧基；R ² and R ⁴ are each independently selected from the group consisting of a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a carboxyl group, an amino group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a C _1-6 alkoxy group. , halogenated C _1-6 alkoxy, C _1-6 alkylamino, di C _1-6 alkylamino or C _1-6 alkoxy;

   R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

   R³选自氢原子，卤素，氰基，硝基，羧基，氨基，C_1-6烷基，C_1-6烷基氨基，二C_1-6烷基氨基，C_1-6烷氧基，C_1-6烷基磺酰基，卤代C_1-6烷基或卤代C_1-6烷氧基；R ^{3 is} selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a carboxyl group, an amino group, a C _1-6 alkyl group, a C _1-6 alkylamino group, a di C _1-6 alkylamino group, a C _1-6 alkoxy group. a C _1-6 alkylsulfonyl group, a halogenated C _1-6 alkyl group or a halogenated C _1-6 alkoxy group;

   R⁵选自氢原子，氰基，C_1-6烷基，C_1-6烷氧基或NR⁷R⁸，R ⁵ is selected from a hydrogen atom, a cyano group, C _1-6 alkyl, C _1-6 alkoxy or NR ⁷ R ^8,

   R⁷、R⁸分别独立的选自氢原子，C_1-6烷基磺酰基，任选被1-3个Q³取代的C_1-6烷基、3-14元环烷基、3-14元杂环基、6-14元芳基或5-14元杂芳基，或N与R⁷、R⁸连接组成任选被1-3个Q²取代的3-14元杂环基、5-14元杂芳基、6-10元螺环基或6-10元桥环基，所述螺环基或桥环基中的碳原子可以被1-3个O、S(O)_m、N(H)_m、NCH₃或C(O)替换；R ^7, R ⁸ are each independently selected from hydrogen, C _1-6 alkylsulfonyl group, optionally substituted with 1-3 Q ³ substituted C _1-6 alkyl, 3-14 membered cycloalkyl, 3- a 14-membered heterocyclic group, a 6-14 membered aryl group or a 5-14 membered heteroaryl group, or N is bonded to R ⁷ and R ⁸ to form a 3-14 membered heterocyclic group optionally substituted by 1 to 3 Q ² groups, a 5-14 membered heteroaryl group, a 6-10 membered spirocyclic group or a 6-10 membered bridged ring group, wherein the carbon atom in the spiro or bridged ring group may be 1-3 O, S(O) _m , N(H) _m , NCH ₃ or C(O) replacement;

   Q¹、Q²、Q³分别独立的选自氨基，卤素，氰基，硝基，羟基，羧基，C_1-6烷基，C_1-6烷氧基，C_1-6烷基磺酰基，C_1-6烷基磺酰基氨基，3-14元环烷基，3-14元杂环基，6-14元芳基或5-14元杂芳基；Q ¹ , Q ² and Q ³ are each independently selected from the group consisting of amino, halogen, cyano, nitro, hydroxy, carboxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfonyl a C _1-6 alkylsulfonylamino group, a 3-14 membered cycloalkyl group, a 3-14 membered heterocyclic group, a 6-14 membered aryl group or a 5-14 membered heteroaryl group;

   m选自0、1或2。m is selected from 0, 1, or 2.
2. 如权利要求1所述的化合物、立体异构体或其药学上可接受的盐：The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1:

   其中，R¹选自氢原子，卤素，氰基，硝基，羧基，或任选被1-3个Q¹取代的3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基；Wherein R ^{1 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a carboxyl group, or a 3-10 membered cycloalkyl group optionally substituted by 1 to 3 Q ¹ , a 3-10 membered heterocyclic group, 6-10 a aryl group or a 5-10 membered heteroaryl group;

   R²和R⁴分别独立的选自氢原子，卤素，硝基，羟基，羧基，氨基，氰基，C_1-4烷基，卤代C_1-4烷基，C_1-4烷氧基，卤代C_1-4烷氧基，C_1-4烷基氨基，二C_1-4烷基氨基或 C_1-4烷氧基；R ² and R ⁴ are each independently selected from the group consisting of a hydrogen atom, a halogen, a nitro group, a hydroxyl group, a carboxyl group, an amino group, a cyano group, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group, and a C _1-4 alkoxy group. , halogenated C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino or C _1-4 alkoxy;

   R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

   R³选自氢原子，卤素，氰基，氨基，C_1-4烷基，C_1-4烷基氨基，二C_1-4烷基氨基，C_1-4烷氧基，C_1-4烷基磺酰基，卤代C_1-4烷基或卤代C_1-4烷氧基；R ^{3 is} selected from the group consisting of a hydrogen atom, a halogen, a cyano group, an amino group, a C _1-4 alkyl group, a C _1-4 alkylamino group, a di C _1-4 alkylamino group, a C _1-4 alkoxy group, and a C _1-4 An alkylsulfonyl group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group;

   R⁵选自氢原子或NR⁷R^s，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ^s ,

   R⁷、R⁸分别独立的选自氢原子，C_1-4烷基磺酰基，任选被1-3个Q³取代的C_1-4烷基、3-10元环烷基、3-10元杂环基、6-10元芳基或5-10元杂芳基，或N与R⁷、R⁸连接组成任选被1-3个Q²取代的3-10元杂环基或5-10元杂芳基；R ^7, R ⁸ are each independently selected from hydrogen, C _1-4 alkylsulfonyl, optionally substituted with 1-3 Q ³ substituted C _1-4 alkyl, 3-10 membered cycloalkyl, 3- a 10-membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group, or N is bonded to R ⁷ and R ⁸ to form a 3-10 membered heterocyclic group optionally substituted by 1 to 3 Q ² or 5-10 yuan heteroaryl;

   Q¹、Q²、Q³分别独立的选自氨基，卤素，氰基，硝基，羟基，羧基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基，C_1-4烷基磺酰基氨基，3-10元环烷基，3-10元杂环基，6-10元芳基或5-10元杂芳基。Q ¹ , Q ² and Q ³ are each independently selected from the group consisting of amino, halogen, cyano, nitro, hydroxy, carboxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl. , C _1-4 alkylsulfonylamino, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl.
3. 如权利要求2所述的化合物、立体异构体或其药学上可接受的盐：The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2:

   其中，R¹选自任选被1-2个Q¹取代的5-8元环烷基、5-8元杂环基、6-8元芳基或5-6元杂芳基；Wherein R ^{1 is} selected from a 5-8 membered cycloalkyl group, a 5-8 membered heterocyclic group, a 6-8 membered aryl group or a 5-6 membered heteroaryl group optionally substituted by 1-2 Q ¹ ;

   R²和R⁴分别独立的选自氢原子，卤素，氨基，氰基，C_1-4烷基，氟代C_1-4烷基，C_1-4烷基氨基，二C_1-4烷基氨基或C_1-4烷氧基；R ² and R ⁴ are each independently selected from the group consisting of a hydrogen atom, a halogen, an amino group, a cyano group, a C _1-4 alkyl group, a fluoro C _1-4 alkyl group, a C _1-4 alkylamino group, and a di C _1-4 alkane. Alkylamino or C _1-4 alkoxy;

   R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

   R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或卤代C_1-4烷基；R ³ is selected from hydrogen, halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl C _1-4 alkyl or haloalkyl;

   R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

   R⁷、R⁸分别独立的选自氢原子，C_1-4烷基磺酰基，任选被1-2个Q³取代的C_1-4烷基，或N与R⁷、R⁸连接组成任选被1-2个Q²取代的5-8元杂环基或5-6元杂芳基；R ^7, R ⁸ are each independently selected from hydrogen, C _1-4 alkyl sulfonyl, optionally substituted with 1-2 Q ³ substituted C _1-4 alkyl, or N and R ^7, R ⁸ connected to form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group optionally substituted by 1-2 Q ² ;

   Q¹、Q²、Q³分别独立的选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基。Q ¹ , Q ² and Q ³ are each independently selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.
4. 如权利要求3所述的化合物、立体异构体或其药学上可接受的盐：The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3:

   其中，R¹选自任选被1-2个Q¹取代的5-6元杂环基或5-6元杂芳基，Wherein R ^{1 is} selected from a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group optionally substituted by 1-2 Q ¹ groups,

   Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

   R²和R⁴分别独立的选自氢原子，卤素，氰基，甲基或三氟甲基；R ² and R ⁴ are each independently selected from a hydrogen atom, a halogen, a cyano group, a methyl group or a trifluoromethyl group;

   R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

   R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或氟代C_1-4烷基；R ^{3 is} selected from a hydrogen atom, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl or fluoro C _1-4 alkyl;

   R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

   R⁷、R⁸分别独立的选自氢原子，C_1-4烷基，或N与R⁷、R⁸连接组成任选被1-2个Q²取代的5-6元杂环基或5-6元杂芳基； R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a C _1-4 alkyl group, or N is bonded to R ⁷ and R ⁸ to form a 5-6 membered heterocyclic group optionally substituted by 1-2 Q ² or 5 -6 membered heteroaryl;

   Q²选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基。Q ^{2 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.
5. 如权利要求4所述的化合物、立体异构体或其药学上可接受的盐：The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 4:

   其中，R¹选自任选被1-2个Q¹取代的5-6元杂环基，Wherein R ^{1 is} selected from a 5-6 membered heterocyclic group optionally substituted by 1-2 Q ¹ groups,

   Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

   R²和R⁴分别选自氢原子；R ² and R ⁴ are each selected from a hydrogen atom;

   R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

   R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或氟代C_1-4烷基；R ^{3 is} selected from a hydrogen atom, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl or fluoro C _1-4 alkyl;

   R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

   R⁷、R⁸分别独立的选自氢原子，C_1-4烷基，或N与R⁷、R⁸连接组成任选被1-2个Q²取代的5-6元杂环基，R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a C _1-4 alkyl group, or N is bonded to R ⁷ and R ⁸ to form a 5-6 membered heterocyclic group optionally substituted by 1-2 Q ² groups.

   Q²选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基。Q ^{2 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy.
6. 如权利要求5所述的化合物、立体异构体或其药学上可接受的盐：The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 5:

   其中，R¹选自任选被1-2个Q¹取代的5-6元饱和杂环基，所述杂环基含有1-2个选自N和/或O的杂原子，Wherein R ^{1 is} selected from a 5-6 membered saturated heterocyclic group optionally substituted by 1 to 2 Q ¹ , the heterocyclic group having 1 to 2 hetero atoms selected from N and/or O,

   Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

   R²和R⁴分别选自氢原子；R ² and R ⁴ are each selected from a hydrogen atom;

   R⁶选自氢原子；R ^{6 is} selected from a hydrogen atom;

   R³选自氢原子，卤素，氰基，C_1-4烷基，C_1-4烷氧基，C_1-4烷基磺酰基或氟代C_1-4烷基；R ^{3 is} selected from a hydrogen atom, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylsulfonyl or fluoro C _1-4 alkyl;

   R⁵选自氢原子或NR⁷R⁸，R ^{5 is} selected from a hydrogen atom or NR ⁷ R ⁸ ,

   R⁷、R⁸分别独立的选自氢原子或C_1-4烷基。R ⁷ and R ⁸ are each independently selected from a hydrogen atom or a C _1-4 alkyl group.
7. 如权利要求5所示的化合物、其立体异构体或其药学上可接受的盐：A compound according to claim 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

   其中，R¹选自任选被1-2个Q¹取代的下列基团：Wherein R ^{1 is} selected from the group consisting of the following groups optionally substituted by 1-2 Q ¹ :

   吡咯烷基、咪唑烷基、吡唑烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、四氢呋哺基、四氢噻吩基、哌啶基、哌嗪基、四氢嘧啶基、吗啉基、1，3-噁嗪烷基、吡哺基或噻喃基，Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazine Base, tetrahydropyrimidinyl, morpholinyl, 1,3-oxazinyl, pyridyl or thiopyranyl,

   Q¹选自氨基，卤素，氰基，羟基，C_1-4烷基或C_1-4烷氧基；Q ^{1 is} selected from the group consisting of amino, halogen, cyano, hydroxy, C _1-4 alkyl or C _1-4 alkoxy;

   R²、R⁴和R⁶分别选自氢原子；R ² , R ⁴ and R ⁶ are each selected from a hydrogen atom;

   R³选自氢原子、卤素、氰基、甲基、甲氧基、甲基磺酰基或三氟甲基；R ^{3 is} selected from a hydrogen atom, a halogen, a cyano group, a methyl group, a methoxy group, a methylsulfonyl group or a trifluoromethyl group;

   R⁵选自氢原子、氨基、甲基氨基、乙基氨基、二甲氨基、二乙氨基、吡咯烷基、咪唑烷基、吡唑烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、哌啶基、哌嗪基、四氢嘧啶基、吗啉基或1，3-噁嗪烷基。 R ^{5 is} selected from the group consisting of a hydrogen atom, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, an isoxazolidinyl group, an oxazolidine group, and a different Thiazolyl, thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyrimidinyl, morpholinyl or 1,3-oxazinyl.
8. 如权利要求7所示的化合物、其立体异构体或其药学上可接受的盐：A compound according to claim 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

   其中，R¹选自氟代吡咯烷基、哌啶基、吗啉基、哌嗪基或1，3-噁嗪烷基；Wherein R ^{1 is} selected from the group consisting of fluoropyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or 1,3-oxazinyl;

   R²、R⁴和R⁶分别选自氢原子；R ² , R ⁴ and R ⁶ are each selected from a hydrogen atom;

   R³选自氢原子、卤素、氰基、甲基、甲基磺酰基或三氟甲基；R ^{3 is} selected from a hydrogen atom, a halogen, a cyano group, a methyl group, a methylsulfonyl group or a trifluoromethyl group;

   R⁵选自氢原子、氨基、甲基氨基、乙基氨基、二甲氨基、二乙氨基、吡咯烷基、吡唑烷基、咪唑烷基、噁唑烷基或异噁唑烷基。R ^{5 is} selected from a hydrogen atom, an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a pyrrolidinyl group, a pyrazolidinyl group, an imidazolidinyl group, an oxazolidinyl group or an isoxazolidinyl group.
9. 如权利要求8所示的化合物、其立体异构体或其药学上可接受的盐：A compound according to claim 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

   

   
10. 一种药物组合物，所述药物组合物包含根据权利要求1-9任一项所述的化合物或其立体异构体或其药学上可接受的盐和药用载体。A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. 根据权利要求10的药物组合物，所述药物组合物还包含一种或多种第二治疗活性剂，所述的第二治疗活性剂为抗代谢物，选自卡培他滨、吉西他滨或培美曲塞二钠；为生长因子抑制剂，选自帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼或凡德他尼；为抗体，选自赫赛汀或贝伐单抗；为有丝***抑制剂，选自紫杉醇、长春瑞滨、多西他赛或多柔比星；为抗肿瘤激素类，选自来曲唑、他莫西芬、氟维司群、 氟他胺或曲普瑞林；为烷化剂类，选自环磷酰胺、氮芥、马法兰、瘤可宁或卡莫司汀；为金属类，选自卡铂、顺铂或奥沙利铂；为拓扑异构酶抑制剂：选自拓扑特肯喜树碱、拓扑替康或依立替康；为嘌呤类似物：选自6-巯基嘌呤、6-硫鸟嘌呤或硫唑嘌呤；为生物药，选自免疫调节蛋白、抗肿瘤抗原的单克隆抗体、肿瘤抑制基因或癌疫苗；或为HDAC抑制剂，选自SAHA、西达本胺或恩替诺特。A pharmaceutical composition according to claim 10, further comprising one or more second therapeutically active agents, said second therapeutically active agent being an antimetabolite selected from capecitabine, gemcitabine or culture Metrexate disodium; a growth factor inhibitor selected from pazopanib, imatinib, erlotinib, lapatinib, gefitinib or vandetanib; Cystatin or bevacizumab; a mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel or doxorubicin; an antitumor hormone selected from the group consisting of letrozole, tamoxifen, and fluorovitamin Division, Flutamide or triptorelin; an alkylating agent selected from the group consisting of cyclophosphamide, nitrogen mustard, melphalan, cyclamate or carmustine; metal, selected from carboplatin, cisplatin or oxali Platinum; is a topoisomerase inhibitor: selected from the group consisting of topotecan camptothecin, topotecan or irinotecan; an anthraquinone analog: selected from the group consisting of 6-mercaptopurine, 6-thioguanine or azathioprine; The biopharmaceutical is selected from the group consisting of an immunomodulatory protein, a monoclonal antibody against a tumor antigen, a tumor suppressor gene or a cancer vaccine; or an HDAC inhibitor selected from the group consisting of SAHA, sidaben or entinostat.
12. 权利要求1-9任一项所述化合物或其立体异构体或其药学上可接受的盐在制备用于预防和/或治疗增殖性疾病药物中的用途，所述的增殖性疾病为癌症或非癌性增殖性疾病，所述的癌症选自肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、乳腺导管瘤、头颈癌、子***、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤或肉瘤；所述非癌性增殖性疾病选自皮肤或***的良性增生。 Use of a compound according to any one of claims 1-9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis and/or treatment of a proliferative disorder, said proliferative disorder being cancer Or a non-cancerous proliferative disease selected from the group consisting of lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, breast ductal tumor, head and neck cancer, cervical cancer, Endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female genital cancer, carcinoma in situ, lymphoma, neurofibroma Disease, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colonic villus adenoma, melanin Tumor, cell tumor or sarcoma; said non-cancerous proliferative disease being selected from benign hyperplasia of the skin or prostate.