CN117658982A - 一类新型cdk12/13共价抑制剂或其药物组合物和应用 - Google Patents
一类新型cdk12/13共价抑制剂或其药物组合物和应用 Download PDFInfo
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- CN117658982A CN117658982A CN202211007556.4A CN202211007556A CN117658982A CN 117658982 A CN117658982 A CN 117658982A CN 202211007556 A CN202211007556 A CN 202211007556A CN 117658982 A CN117658982 A CN 117658982A
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- amino
- cyclohexyl
- cyanopyridin
- phenyl
- acrylamide
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Abstract
本发明涉及一类新型CDK12/13共价抑制剂或其药物组合物的制备方法及应用。本发明的一类新型CDK12/13共价抑制剂具有式(I)所示结构，该类化合物可作为蛋白激酶抑制剂，能够有效地、高选择性地抑制CDK12/13蛋白激酶的活性并且能抑制多种肿瘤细胞的增殖、迁移和侵袭。
Description
技术领域
本发明属于化学医药领域，特别是涉及一类新型CDK12/13共价抑制剂或其药物组合物和应用。
背景技术
细胞周期蛋白依赖性激酶(Cyclin dependent kinases，CDKs)，是一类丝氨酸/苏氨酸激酶，CDKs在细胞分裂的控制中起着重要作用，并响应于多种细胞内外信号而调节转录。哺乳动物中已经鉴定和报道的有20种CDK和29种细胞周期蛋白(Cyclin)。CDKs需要与其对应的细胞周期蛋白结合(一个或几个)才能稳定、激活和对下游进行磷酸化。在哺乳动物中CDK分为三个与细胞周期相关的亚家族和六个转录亚家族。
CDK12/13(Cyclin-dependent kinase 12/13)属于丝氨酸/苏氨酸蛋白激酶的细胞周期蛋白依赖性激酶家族(CDKs)的成员，与Cyclin K形成复合物发挥生物学功能。CDK12/13分别含有1490、1512个氨基酸，且享有46％的同源性，激酶区域由300个氨基酸组成其同源性高达92％。与其他转录CDKs相比CDK12/13的N末端含有额外的精氨酸/富含丝氨酸(RS)基序，RS基序常见于参与前mRNA剪接的蛋白质中。Proline-rich motifs(PRIM)的基序也见于N-和C-末端，可能作为SH3，WW或含有肌动蛋白结合蛋白(profilin)结构域的蛋白质的结合位点。CDK12/13与细胞周期蛋白K形成复合物通过磷酸化RNA聚合酶II(RNA PolII)C端结构域(CTD)，CTD由YSPTSPS七个氨基酸组成的高度重复序列，在人类中，CTD包括一个52重复单元。CDK12/13主要对2位的丝氨酸进行磷酸化从而调节转录，及转录后的mRNA的加工。遗传研究表明，CDK12通过抑制内含子聚腺苷酸化位点的切割，促进转录出全长基因的产物，许多同源重组修复基因(如：BRCA1/2、ATM、ATR、FANCD2、FANCI等)包含更多的内含子多腺苷化位点，因此，这些基因的表达对CDK12的丢失或抑制更为敏感。DNA双链断裂具有极强的毒性，同源重组又是修复双链断裂的最准确的无错误途径，在DNA损伤修复过程中至关重要。因此，抑制CDK12/CDK13，能诱导细胞产生同源重组修复缺陷(HRD)引起的DNA损伤，从而杀伤细胞。CDK12/13的抑制剂其他药物联用，具有协同作用促进对癌症细胞杀伤力，克服耐药，减少耐药株的出现。且CDK12与MYC、EWS/FLI融合和PARPi具有合成致死相互作用。CDK12在去势耐药前列腺癌、高级浆液性卵巢癌等有不同比例的突变报道，其中大多数为无义突变或失活突变。CDK12突变不是其作为癌症治疗的潜在靶点的必要条件，调节DNA损伤修复相关蛋白的表达及合成致死相互作用为其作为抗癌靶点提供了机会。由于CDK12在疾病治疗当中具有巨大的潜力，且可以作为癌症发生的生物标志物，近年来引起了科学家越来越大的兴趣。
发明内容
基于此，本发明提供了一类新型CDK12/13共价抑制剂或其药物组合物作为CDK12/13抑制剂的应用，该类化合物能够有效地、高选择性地抑制CDK12/13蛋白激酶，且能抑制多种肿瘤细胞的增殖、迁移和侵袭。
本发明的第一方面，提供了一种具有式(I)结构的CDK12/13共价抑制剂，或其药学上可接受的盐，或其药物组合物或其前药分子：
X、Y、Z分别独立地选自下组：N或CR5；
R5选自下组：氢、卤素、氰基、羟基、氨基、卤代甲基、卤代甲氧基、卤代乙基、卤代乙氧基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、C3-C8环烷氧基、C1-C6烷基取代的氨基；
R1选自下组：H、氰基、卤素、卤代甲基、卤代甲氧基、卤代乙氧基、卤代乙基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基；
W选自下组：化学键、
R2选自下组：H、-NHR6、 -OR6、-CH(R8)R6；
R6选自下组：-(C(R8)R7)R9、-(CH2)nR9；其中，n选自：0、1或2；
R7、R8各自独立地选自下组：氢、卤素、氰基、甲基、卤代甲基、甲氧基、卤代甲氧基、乙基、卤代乙基、乙氧基、卤代乙氧基、羟基、氨基、含有m个杂原子的3-8元杂环，所述的m为1、2或3，且所述的杂原子选自O、S或N；或R7、R8通过相连的C原子一同形成含n个杂原子的3-7杂环，n选自：1、2或3，所述的杂原子选自：O、N、S；
R9选自下组：
1)氰基、C1-C5烷基、卤代C1-C4烷基、C1-C4烷氧基、C3～C10环烷基、取代或未取代的含O、S或N的3-8元芳环或饱和环、含n个杂原子的8-12元稠环、螺环或桥环，n选自：1、2或3，杂原子选自：O、N、S；
2)
其中A、B、C、D、E分别独立地选自：CH、N或CR10；
R10选自下组：卤素、氰基、羟基、氨基、硝基、C1-C3烷基、卤代C1-C3烷基、C1-C4烷氧基、卤代C1-C4烷氧基、C3-C8环烷基；
V为N或CR3；
各个R3各自独立地选自下组：H、卤素、氰基、羟基、氨基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C3-C8环烷基、-(CH2)mR11、-NH(CH2)mR11、-NR14(CH2)mR11、-O(CH2)mR11；取代或未取代的有m个杂原子的3-8元杂环，所述的m为1、2或3，且所述的杂原子选自O、S或N；、含n个杂原子的8-12元稠环、螺环或桥环，n选自：1、2或3，杂原子选自：O、N、S；且至少一个R3不为H；
R11选自下组：C1～C6烷基或NR12R13；其中，R12、R13分别独立地选自：H、C1～C8烷基、-(CH2)mNR14R15、-(CH2)nCR14R15R16，或R12、R13与它们所连接的氮原子一起形成取代或未被取代的含有杂原子的单环、稠环、螺环或桥环；
R14、R15、R16各自独立地选自下组：H、C1～C8烷基、或R14、R15与它们所连接的氮原子或碳原子一起形成被取代或未被取代的含有0-3个杂原子的单环、稠环、螺环或桥环；
m、n独立地选自：0-8的整数。
R4选自下组：H、
R17选自下组：氢、三氟甲基、
R18选自下组：氢或氟；
除非特别说明，所述的“取代”指基团上的一个或多个氢原子被选自下组的取代基替换：卤素、氧代、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6酰基、未取代或卤代的C1-C6酰胺基、未取代或卤代的C1-C6烷胺基、未取代或卤代的C1-C6烷基-羟基、未取代或卤代的C3-C6烷基、未取代或卤代的4-8元杂环基。
在另一优选例中，X、Y、Z分别独立地选自：N或CR5；
R5选自下组：氢、卤素、氰基、卤代甲基、卤代甲氧基。
在另一优选例中，R1选自下组：H、氰基、卤素、卤代甲基、卤代甲氧基、卤代乙氧基、卤代乙基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基。
在另一优选例中，R1选自下组：H、氰基、卤素、卤代甲基。
在另一优选例中，W选自：
在另一优选例中，R2选自下组：-NHR6；
R6选自下组：-(C(R8)R7)R9；
R7、R8各自独立地选自下组：氢、卤素、氰基、甲基、卤代甲基、甲氧基、卤代甲氧基；
R9各自独立地选自下组：苯基、卤代苯基、吡啶基、嘧啶基、异丙基、叔丁基、三氟甲基、二氟甲基、氰基、吡咯基、N-甲基吡咯基、N-甲基咪唑基、N-甲基吡唑基、咪唑基、呋喃基、噻吩基、吡唑基、异恶唑基、恶唑基、卤代C1-C4烷基、C1-C4烷氧基、C1-C4烷基、C3～C7环烷基、C3～C7环氧烷基。
在另一优选例中，所述的R3选自下组：H、卤素、氰基、羟基、氨基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C3-C8环烷基、C3-C8环烷氧基、或4-8元杂环基(包括单环、并环或桥环)。
在另一优选例中，各个R3各自独立地选自下组：H、卤素、氰基、羟基、氨基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C3-C8环烷基、C3-C8环烷氧基、
在另一优选例中，R4选自：H、
在另一优选例中，具有式(II)和(III)所示结构：
在另一优选例中，所述化合物选自实施例1-53的化合物。
本发明的第二方面，提供了一种本发明第一方面所述的CDK12/13共价抑制剂或其药物组合物在制备CDK12/13抑制剂中的应用。
本发明的第三方面，提供了一种本发明第一方面所述的CDK12/13共价抑制剂或其药物组合物，或者其药学上可接受的盐，或者其立体异构体或者其前药分子在制备预防和/或治疗由CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病的药物中的应用。
在另一优选例中，所述由CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病选自下组：前列腺癌、乳腺癌、子宫癌、卵巢癌、非小细胞肺癌、小细胞肺癌、尤文肉瘤、肺腺癌、肺鳞癌、胰腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤。
本发明的第四方面，提供了一种预防和/或治疗肿瘤的药用组合物，其包括活性成分和药学上可接受的辅料，且所述活性成分包括本发明第一方面所述的一类新型CDK12/13共价抑制剂或其药物组合物，或者其药学上可接受的盐，或者其立体异构体或者其前药分子。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
在其中一些实施例中，提供了一类新型CDK12/13共价抑制剂或其药物组合物在制备CDK12/13抑制剂中的应用。
本发明的另一目的是提供一种上述的CDK12/13共价抑制剂或其药物组合物在制备预防和/或治疗由CDK12/13抑制剂中的应用。
在其中一些实施例中，所述的CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病优选为：前列腺癌、乳腺癌、子宫癌、卵巢癌、非小细胞肺癌、小细胞肺癌、尤文肉瘤、肺腺癌、肺鳞癌、胰腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤中的任一种。
本发明的再一目的是提供一种预防和/或治疗肿瘤的药用组合物，包括活性成分和药学上可接受的辅料，所述活性成分包括上述的反式-1,4-环己二胺类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
术语
本发明下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂，均为市售产品。
除非另有定义，本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不用于限制本发明。
本发明的术语“包括”和“具有”以及它们任何变形，意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块，而是可选地还包括没有列出的步骤，或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤。
在本发明中提及的“多个”是指两个或两个以上。“和/或”，描述关联对象的关联关系，表示可以存在三种关系，例如，A和/或B，可以表示：单独存在A，同时存在A和B，单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本发明所述化合物中，当任何变量(例如R10、R11等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C8烷基”中“C1-C8”的定义包括以直链或支链排列的具有1、2、3、4、5、、或8个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
本文所用术语“烷氧基”代表烷基-氧基基团，其中烷基的定义如上所示。
正如本领域技术人员所理解的，本文中所用“卤素”意指包括氯、氟、溴和碘。
本发明包括式(I)化合物的游离形式，也包括其药学上可接受的盐、其立体异构体及其前药分子。术语“游离形式”指以非盐形式的化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式(I)化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
化合物和药学上可接受的盐
本文公开了式(I)化合物，包括式(II)和(III)化合物(其结构在本文中公开)，以及其药学上可接受的盐。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等制备的盐，也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、苯磺酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等，“Pharmaceutical Salts”J.Pharm.Sci.’1977：66：1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
本发明所公开的化合物包括至少一个不对称或手性中心，因此可以立体异构体的形式存在。各个手性中心为“R”或“S”，具体取决于手性碳原子周围的取代基构型。此处使用的术语“R”和“S”如IUPAC 1974Recommendations for Section E,FundamentalStereochemistry,in Pure Appl.Chem.1976,45:13-30中定义。各种立体异构体及其混合物具体包括在本公开的范围内，立体异构体包括对映异构体和非对映异构体，以及对映异构体或非对映异构体的混合物。化合物的单一立体异构体可以由含有不对称或手性中心的市售起始材料合成制备，或通过制备外消旋混合物，然后按照本领域普通技术人员熟知的拆分方法制备。这些拆分方法的示例如下：(1)将对映异构体混合物连接到手性助剂上，通过重结晶或色谱法分离所得非对映异构体混合物，以及任选地从助剂中释放光学纯产物，如Furniss,Hannaford,Smith,and Tatchell,“Vogel's Textbook of Practical OrganicChemistry,”5th edition(1989),Longman Scientific&Technical,Essex CM202JE,England中所述；(2)在手性色谱柱上直接分离光学对映体混合物；(3)分级重结晶法。
本发明所公开的化合物可以以不同的互变异构形式存在，并且所有这些形式都包括在本公开的范围内。
本公开的化合物也可以是前药形式。如本文所用，术语“前药”是指在代谢时(例如，在体内或体外)产生活性化合物的化合物。在一些实施方案中，前药可以是无活性的，或具有比游离药物低的活性，但可以提供有利的处理、给药或代谢特性。本发明的示例性前药部分可以通过核苷酸的羟基、氨基、磷酸酯或硫代磷酸酯主链与游离药物连接，并且可以包含酯、氨基甲酸酯、羰基、硫酯、酰胺、异氰酸酯、脲、硫脲或其他生理上可接受的代谢不稳定部分。在一些实施方案中，前药通过酶水解被激活。
本公开还包括同位素标记的化合物，其与式(I)、式(II)或式(III)中列举的那些相同，但一个或多个原子被具有质量或质量数不同于自然界中通常发现的原子质量或质量数的原子取代。适合包含在本公开的化合物中的同位素的实例是氢、碳、氮、氧、磷、硫、氟和氯，例如但不限于2H、3H、13C、14C、15N、18O、31P、35S、18F和36Cl分别。用较重的同位素(例如氘，即2H)进行取代可以提供某些治疗优势，这些优势源于更高的代谢稳定性，例如体内半衰期增加或剂量要求降低，因此在某些情况下可能是优选的。该化合物可以结合用于医学成像的正电子发射同位素和用于确定受体分布的正电子发射断层扫描(PET)研究。可掺入式(I)、(II)或(III)化合物中的合适的正电子发射同位素是11C、13N、15O和18F。同位素标记的式(I)、(II)或(III)化合物通常可以通过本领域技术人员已知的常规技术或通过类似于本文描述的那些的方法使用合适的同位素标记的试剂代替一种非同位素标记的试剂。
本文公开的化合物可以与药学上可接受的溶剂如水、乙醇等以溶剂化和非溶剂化形式存在，并且本公开旨在涵盖溶剂化和非溶剂化形式。在一个实施方案中，该化合物是无定形的。在一个实施方案中，该化合物是单一的多晶型物。在另一个实施方案中，该化合物是多晶型物的混合物。在另一个实施方案中，该化合物是结晶形式。
药物组合物和给药方法
由于本公开的化合物是CDK12/13抑制剂，因此本公开的化合物及其药学上可接受的盐以及本文公开的其他化合物形式可以包含在可用于治疗、预防和减轻疾病的药物组合物中与CDK12/13的活性有关。
本发明的药物组合物包含有效量，例如安全有效量的本发明化合物或其药学上可接受的盐和药学上可接受的赋形剂或载体。“有效量”是指足以引发所需生物反应(例如，治疗病症)的量。“安全有效量”是指：该化合物的用量足以显着改善病情而不引起严重的副作用。通常，药物组合物包含1至3000(活性剂量范围为3至30mg/kg)mg的本发明化合物/剂，更优选地包含10至2000mg的本发明化合物/剂。优选地，“一剂”是胶囊剂或片剂。
“药学上可接受的载体”是指：一种或多种适合人类使用的相容性固体或液体填充剂或凝胶物质，必须具有足够的纯度和足够低的毒性。本文中的“相容性”是指组合物的组分可以与本发明的化合物混合并相互混合，而不会显着降低化合物的功效。药学上可接受的载体部分的实例包括纤维素及其衍生物(例如羧甲基纤维素钠、乙基纤维素钠和醋酸纤维素)、明胶、滑石粉、固体润滑剂(例如硬脂酸和硬脂酸镁)、硫酸钙、植物油(例如大豆油、芝麻油、花生油和橄榄油)、多元醇(如丙二醇、甘油、甘露醇和山梨糖醇)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂和无热原水。
本发明的化合物或药物组合物的给药方式没有特别限制，代表性的给药方式包括(但不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌内或皮下)、或局部给药。
用于口服给药的固体制剂包括胶囊、片剂、丸剂、散剂和颗粒剂。在这些固体制剂中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，例如柠檬酸钠或磷酸二钙，或与以下成分混合：(a)填充剂或填充剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如羟甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如甘油；(d)崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、海藻酸、一些复合硅酸盐和碳酸钠；(e)缓凝溶剂，例如石蜡；(f)吸收促进剂，例如季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如高岭土；(i)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠或其混合物。在胶囊剂、片剂和丸剂中，所述的制剂还可以包括缓冲剂。
固体剂型，例如片剂、糖衣丸、胶囊、丸剂和颗粒剂，可以由包衣和壳材料制备，例如肠溶衣和本领域熟知的其他材料。它们可以包含遮光剂，并且活性化合物或这种组合物中的化合物可以以延迟方式在消化道的一部分中释放。可用的嵌入成分的例子是聚合物和蜡。必要时，活性化合物还可与上述赋形剂中的一种或多种形成微囊形式。
用于口服给药的液体剂型包括药学上可接受的乳剂、溶液、悬浮液、糖浆或酏剂。除活性化合物外，液体剂型可包含本领域常用的惰性稀释剂，例如水或其他溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺和油，特别是棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油和芝麻油，或它们的混合物。
除了这些惰性稀释剂之外，该组合物还可包含助剂，例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除活性化合物外，悬浮液还可包含悬浮剂，例如乙氧基化异十八醇、聚氧乙烯山梨糖醇和山梨糖醇酯、微晶纤维素、甲醇铝和琼脂，或其混合物。
用于肠胃外注射的组合物可以包含生理上可接受的无菌水溶液或无水溶液、分散体、悬浮液或乳液，以及用于重新溶解成无菌可注射溶液或分散体的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其合适的混合物。
用于局部施用本公开化合物的剂型包括软膏剂、散剂、贴剂、喷雾剂和吸入剂。在无菌条件下将活性成分与生理上可接受的载体和任何防腐剂、缓冲剂或抛射剂(如果需要)混合。
本公开的化合物可以单独施用或可以与其他药学上可接受的化合物组合施用。
当使用药物组合物时，安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，给药时剂量为药学上认为的有效剂量，对于体重为60kg的人，每日给药剂量通常为1-2000mg，优选6-600mg。当然，具体剂量也应综合考虑给药途径、患者健康状况等因素来确定，这些都在熟练医师的技能范围内。
治疗用途和方法
如上所述，本公开的化合物是CDK12/13抑制剂，因此所述化合物或包含所述化合物的组合物可用于治疗、预防和减轻与CDK12/13的活性或异常表达相关的疾病。在一些实施方案中，本文公开的是本文公开的化合物在制备用于预防和/或治疗由CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病的药物中的用途。在一些实施方案中，本文公开的是本文公开的化合物，其用于预防和/或治疗由CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病。在一些实施方案中，本文公开了一种在有需要的受试者中治疗由CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病的方法，包括向受试者施用有效量的本文公开的化合物。在一些实施方案中，CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病包括：前列腺癌、乳腺癌、子宫癌、卵巢癌、非小细胞肺癌、小细胞肺癌、尤文肉瘤、肺腺癌、鳞状细胞癌细胞肺癌、胰腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠道间质瘤、白血病、组织细胞淋巴瘤、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌和神经胶质瘤。
当用于本文所公开的用途和方法时，所公开的化合物和组合物可以与其他已知疗法组合使用。如本文所用，“联合”施用是指在受试者患有疾病的过程中向受试者给予两种(或多种)不同的治疗，例如，在受试者被诊断出之后、疾病被治愈或消除，或因其他原因停止治疗之前给予两种或多种治疗。在一些实施方案中，当第二种治疗开始进行时，一种治疗仍在进行，因此在进行治疗方面存在重叠。这在一些情况下，在本文中被称为“同时”或“同时进行”。在其他实施方案中，一种治疗在另一种治疗开始之前结束。在任一情况的一些实施方案中，联合治疗更有效。
例如，第二次治疗表现出更好的效果，比如与在没有第二次治疗的情况下施用第二次治疗相比，进行较少的第二次治疗可以看到相同的效果，或者第二次治疗在更大程度上减轻了症状，或者在第一次治疗中发现了类似的的情况。在一些实施方案中，这样的联合治疗使得与病症相关的症状或其他参数的改善大于在不存在另一种治疗的情况下进行一种治疗所观察到的改善。两种处理的效果可以是部分累计的、完全累计的或大于累计的。所述的治疗可以使得进行第一种治疗的效果在进行第二种治疗时仍然可检测到。
本文公开的化合物或组合物和至少一种另外的治疗剂可以同时、在同一或不同的组合物中给药，或顺序给药。对于顺序给药，可以首先给药本文所述的化合物，然后给药另外的药剂，或者可以颠倒给药顺序。
在一些实施方案中，本文所述的化合物与其他治疗性治疗方式组合施用，包括手术、放射、移植(例如，干细胞移植、骨髓移植)、化学疗法、免疫疗法、冷冻疗法和/或热疗法。这样的联合疗法可以允许施用的药剂和/或其他药剂的较低剂量，从而避免与各种疗法相关的可能的毒性或并发症。
在一些实施方案中，本文所述的化合物与至少一种另外的治疗剂如化疗剂一起施用。在某些实施方案中，本文所述的化合物与一种或多种另外的化学治疗剂组合施用。化疗剂可以是在美国国家癌症研究所公布的“癌症药物A到Z清单”中确定的化疗剂。
与现有技术相比，本发明具有以下有益效果：
本发明提供的新型CDK12/13共价抑制剂或其药物组合物，可以有效地抑制CDK12蛋白激酶，可以用于制备预防或者治疗由CDK12蛋白激酶介导的疾病的药物，比如前列腺癌、乳腺癌、子宫癌、卵巢癌、非小细胞肺癌、小细胞肺癌、尤文肉瘤、肺腺癌、肺鳞癌、胰腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤等，同时具有较强的抑制活性、激酶选择性和较好的药代动力学特点。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-(二甲基氨基)哌啶-1-yl)苯基)丙烯酰胺(YJZ5118)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide
步骤1：1-(4-溴-2-硝基苯基)-N，N-二甲基哌啶-4-胺(2)
1-(4-bromo-2-nitrophenyl)-N,N-dimethylpiperidin-4-amine(2)
将4-溴-1-氟-2-硝基苯(1.72g,7.8mmol)、溶于50ml乙腈溶剂中，缓慢加入N，N-二甲基哌啶-4-胺(1g,7.8mmol)，室温反应3h。TLC检测，待原料1消耗完全，减压旋干溶剂，得到橙黄色油状液体，未经任何纯化直接进行下一步反应。
步骤2：6-6-(((((1r，4r)-4-氨基环己基)氨基)烟腈(4)
6-(((1r,4r)-4-aminocyclohexyl)amino)nicotinonitrile(4)
1H NMR(400MHz,Chloroform-d)δ8.35(d,J＝2.2Hz,1H),7.55(dd,J＝8.8,2.3Hz,1H),6.35(d,J＝8.9Hz,1H),5.05–4.84(m,1H),3.64(s,1H),2.73(dq,J＝7.0,4.2,3.6Hz,1H),2.12(dq,J＝7.6,3.5,2.9Hz,2H),1.94(tt,J＝5.6,2.4Hz,2H),1.34(d,J＝6.3Hz,2H),1.32–1.21(m,4H).
将反式-1,4-环己二胺(10g,87.6mol)，CsCO3(34g,105.1mol)溶于100ml DMSO中，间隔10min分五批次缓慢加入6-氟烟碱(3g,25mol)，室温搅拌1h，升至60℃继续反应1h，TLC检测至7消耗完全，真空旋干DMSO，将浓缩之后的产物溶于DCM和适量甲醇中，用硅藻土过滤，二氯洗涤滤饼几次后收集滤液浓缩，硅胶柱层析得白色固体产物(3.4g，产率63％)。
步骤3：6-((((1r，4r)-4-((4-(4-(二甲基氨基)哌啶-1-基)-3-硝基苯基)氨基)环己基)氨基)烟腈(5)
6-(((1r,4r)-4-((4-(4-(dimethylamino)piperidin-1-yl)-3-nitrophenyl)amino)cyclohexyl)amino)nicotinonitrile(5)
将化合物2(2.5g，7.6mol)，化合物4(2g，9.1mol)，Xantphos(439.3mg，0.76mol)，Pd2(dba)3(348mg，0.38mol)，tert-BuONa(1.46g，15.2mol)溶于100ml甲苯中，氩气保护，置换三次，95℃搅拌反应过夜。冷却至室温用后硅藻土过滤，旋干溶剂，柱层析分离得深红色固体1.9g(产率54％)。
1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝2.3Hz,1H),7.64(dd,J＝8.8,2.4Hz,1H),7.54(d,J＝7.5Hz,1H),7.17(d,J＝8.9Hz,1H),6.87(d,J＝2.7Hz,1H),6.80(dd,J＝8.9,2.8Hz,1H),6.53(d,J＝8.9Hz,1H),5.83(d,J＝8.0Hz,1H),3.77(s,1H),3.28–3.13(m,1H),2.97(d,J＝10.8Hz,2H),2.64(td,J＝11.7,2.3Hz,2H),2.17(s,6H),2.11(dq,J＝6.1,3.5Hz,1H),1.98(q,J＝9.3,8.1Hz,4H),1.79–1.70(m,2H),1.47–1.30(m,4H),1.29–1.18(m,2H).
步骤4：3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)-1-(4-(4-(二甲基氨基)哌啶-1-基)-3-硝基苯基)脲(6)
3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-(4-(4-(dimethylamino)piperidin-1-yl)-3-nitrophenyl)urea(6)
将化合物5(1.9g，4.1mol)溶于10ml DMF中，加入苄基异氰酸酯(1.64g，12.3mol)，DIEA(1.59g，12.3mol)，95℃反应5h。旋干溶剂，柱层析得黄色固体2g(产率83％)。
1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝2.3Hz,1H),7.61(dd,J＝8.9,2.3Hz,1H),7.58(d,J＝2.4Hz,1H),7.49(d,J＝7.8Hz,1H),7.35(dd,J＝8.8,2.5Hz,1H),7.32–7.25(m,3H),7.18(td,J＝5.5,3.0Hz,3H),6.48(d,J＝9.0Hz,1H),6.24(t,J＝6.1Hz,1H),4.33–4.21(m,1H),4.16(d,J＝6.1Hz,2H),3.51(s,1H),3.28(d,J＝12.4Hz,2H),2.86(td,J＝12.2,2.3Hz,2H),2.24(s,1H),2.21(s,6H),1.92(d,J＝12.0Hz,2H),1.82(t,J＝12.7Hz,4H),1.49(qd,J＝11.9,3.8Hz,2H),1.31(q,J＝14.8,13.7Hz,2H),1.18–1.04(m,2H).
步骤5：N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-(二甲基氨基)哌啶-1-yl)苯基)丙烯酰胺(YJZ5118)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide(YJZ5118)
将化合物6(2g，3.35mol)，10％Pd/C(200mg)，溶于70ml甲醇，在氢气氛围下室温反应3小时。待反应完全，硅藻土抽滤，旋干溶剂，得初产品未经纯化直接用于下一步。将该步的初产品溶于50ml无水DCM中，加入DIEA(518.8mg，4mol)，在0℃下搅拌15min后，缓慢加入丙烯酰氯(364mg，4mol)，反应10min后升至室温继续反应15min。TLC监测，反应结束后旋干DCM，用乙酸乙酯，饱和碳酸氢钠萃取，收集有机相浓缩，柱层析得410mg(两步总产率20％)。
1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.31(d,J＝2.4Hz,1H),7.92(s,1H),7.60(dd,J＝9.0,2.4Hz,1H),7.49(d,J＝7.5Hz,1H),7.30–7.23(m,2H),7.22–7.13(m,4H),6.90(dd,J＝8.3,2.5Hz,1H),6.73(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.28(dd,J＝17.0,2.0Hz,1H),5.84–5.72(m,2H),4.32–4.22(m,1H),4.17(d,J＝6.0Hz,2H),3.50(s,1H),3.07(d,J＝11.4Hz,2H),2.65(t,J＝11.2Hz,2H),2.23(s,6H),2.17(d,J＝11.1Hz,1H),1.92(d,J＝11.9Hz,2H),1.85(d,J＝11.4Hz,2H),1.78(d,J＝12.9Hz,2H),1.74–1.68(m,2H),1.32(q,J＝12.2Hz,2H),1.22–1.09(m,2H).
HRMS(ESI)calcd for C36H44N8O2[M+H]+,621.3660；found,621.3666。
实施例2：N-(2-(4-乙酰基哌嗪-1-基)-5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)苯基)丙烯酰胺(YJZ5111)
N-(2-(4-acetylpiperazin-1-yl)-5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)acrylamide(YJZ5111)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.31(dd,J＝2.4,0.7Hz,1H),8.02–7.95(m,1H),7.61(dd,J＝8.8,2.4Hz,1H),7.50(d,J＝7.6Hz,1H),7.30–7.24(m,2H),7.22(d,J＝8.4Hz,1H),7.18(ddd,J＝7.0,4.5,2.7Hz,3H),6.92(dd,J＝8.4,2.5Hz,1H),6.75(dd,J＝16.9,10.2Hz,1H),6.48(d,J＝8.9Hz,1H),6.30(dd,J＝17.0,1.9Hz,1H),5.85–5.78(m,2H),4.26(d,J＝11.9Hz,1H),4.17(d,J＝6.0Hz,2H),3.72–3.63(m,4H),3.51(s,1H),2.86(t,J＝5.0Hz,2H),2.81(t,J＝5.1Hz,2H),2.06(s,3H),1.93(d,J＝9.7Hz,2H),1.79(d,J＝11.4Hz,2H),1.32(q,J＝12.4,12.0Hz,2H),1.18(q,J＝12.4,12.0Hz,2H).
HRMS(ESI)calcd for C35H40N8O3[M+H]+,621.3296；found,621.3295。
实施例3：N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ5114)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(4-methylpiperazin-1-yl)phenyl)acrylamide(YJZ5114)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.31(d,J＝2.3Hz,1H),8.05(s,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.52(d,J＝7.6Hz,1H),7.31–7.24(m,3H),7.18(dt,J＝6.4,1.6Hz,3H),6.95(dd,J＝8.4,2.4Hz,1H),6.75(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.32(dd,J＝17.0,1.9Hz,1H),5.89–5.79(m,2H),4.34–4.22(m,1H),4.18(d,J＝6.0Hz,2H),3.51(s,5H),3.18(s,2H)3.07(d,J＝19.4Hz,2H),2.88(s,3H),1.92(d,J＝11.8Hz,2H),1.80(d,J＝11.5Hz,2H),1.39–1.27(m,2H),1.21–1.09(m,2H).
HRMS(ESI)calcd for C34H40N8O2[M+H]+,593.3347；found,593.3365。
实施例4：N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-吗啉代苯基)丙烯酰胺(YJZ5127)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-morpholinophenyl)acrylamide(YJZ5127)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.31(dd,J＝2.4,0.7Hz,1H),7.95(s,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.50(d,J＝7.6Hz,1H),7.30–7.22(m,3H),7.22–7.15(m,3H),6.94(dd,J＝8.4,2.5Hz,1H),6.73(dd,J＝16.9,10.2Hz,1H),6.48(d,J＝8.9Hz,1H),6.28(dd,J＝16.9,1.9Hz,1H),5.80(dt,J＝10.2,3.3Hz,2H),4.35–4.22(m,1H),4.17(d,J＝6.0Hz,2H),3.83(t,J＝4.5Hz,4H),3.50(s,H),2.86(t,J＝4.6Hz,4H),1.93(d,J＝11.9Hz,2H),1.79(d,J＝11.6Hz,2H),1.32(q,J＝12.2Hz,2H),1.18(q,J＝12.2Hz,2H).
HRMS(ESI)calcd for C33H37N7O3[M+H]+,580.3031；found,5890.3024。
实施例5：N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)丙烯酰胺(YJZ5125)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide(YJZ5125)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.31(d,J＝2.3Hz,1H),8.24(d,J＝2.5Hz,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.50(d,J＝7.6Hz,1H),7.33(d,J＝8.4Hz,1H),7.30–7.24(m,2H),7.21–7.14(m,3H),6.89(dd,J＝8.4,2.5Hz,1H),6.48(d,J＝8.7Hz,1H),6.45–6.39(m,1H),6.30(dd,J＝17.0,2.2Hz,1H),5.82(dd,J＝9.9,2.2Hz,1H),5.76(t,J＝6.0Hz,1H),4.33–4.23(m,1H),4.18(d,J＝6.0Hz,2H),3.52(s,H),2.83(t,J＝5.7Hz,2H),2.72(s,3H),2.40(t,J＝5.6Hz,2H),2.23(s,6H),1.93(d,J＝12.1Hz,2H),1.79(d,J＝11.9Hz,2H),1.32(q,J＝12.3Hz,2H),1.18(dd,J＝28.1,15.7Hz,2H).
HRMS(ESI)calcd for C34H42N8O2[M+H]+,595.3503；found,595.3508。
实施例6：N-(5-(3-苄基-1-(((1r，4R)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((1R，4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-(基)苯基)丙烯酰胺(YJZ6096)
N-(5-(3-benzyl-1-((1r,4R)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)acrylamide(YJZ6096)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.33(d,J＝2.4Hz,1H),7.61(dd,J＝8.8,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.30–7.23(m,2H),7.17(dt,J＝9.0,3.0Hz,3H),7.13(d,J＝2.1Hz,1H),6.90–6.79(m,2H),6.54(dd,J＝17.0,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.23(dd,J＝17.1,2.1Hz,1H),5.73(dd,J＝10.1,2.1Hz,1H),5.59(d,J＝6.2Hz,1H),4.31–4.20(m,1H),4.17(d,J＝6.1Hz,2H),4.09(s,1H),3.51(s,1H),3.39(dd,J＝8.9,2.4Hz,2H),3.07(d,J＝9.0Hz,1H),2.81(d,J＝9.6Hz,1H),2.65(dd,J＝9.7,2.3Hz,1H),2.26(s,3H),1.92(d,J＝11.2Hz,2H),1.85–1.71(m,3H),1.68(d,J＝9.2Hz,1H),1.31(dt,J＝15.5,11.6Hz,3H),1.14(t,J＝13.5Hz,3H).
HRMS(ESI)calcd for C35H40N8O2[M+H]+,605.3347；found,605.3329。
实施例7：N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-(氧杂环丁-3-基)哌嗪-1-基)苯基)丙烯酰胺(YJZ6028)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)acrylamide(YJZ6028)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.31(dd,J＝2.3,0.7Hz,1H),7.96–7.87(m,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.31–7.21(m,3H),7.21–7.13(m,3H),6.93(dd,J＝8.4,2.4Hz,1H),6.68(dd,J＝17.0,10.2Hz,1H),6.47(d,J＝8.8Hz,1H),6.27(dd,J＝17.0,1.8Hz,1H),5.78(dd,J＝8.8,3.0Hz,2H),4.58(t,J＝6.5Hz,2H),4.49(t,J＝6.1Hz,2H),4.32–4.22(m,1H),4.17(d,J＝6.0Hz,2H),3.53(p,J＝6.3Hz,2H),3.51(s,H)2.90(t,J＝4.6Hz,4H),1.99(s,1H),1.92(d,J＝12.0Hz,2H),1.78(d,J＝11.8Hz,2H),1.32(d,J＝12.6Hz,2H),1.24(s,2H),1.19–1.11(m,2H).
HRMS(ESI)calcd for C36H42N8O3[M+H]+,635.3453；found,635.3431。
实施例8：N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)苯基)丙烯酰胺(YJZ6085)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)phenyl)acrylamide(YJZ6085)
合成方法与实施例1方法类似。
1H NMR(400MHz,Acetone-d6)δ8.89(s,1H),8.37(d,J＝2.4Hz,1H),8.29(d,J＝2.3Hz,1H),7.56(dd,J＝8.8,2.4Hz,1H),7.34(d,J＝8.3Hz,1H),7.30–7.22(m,4H),7.18(td,J＝6.5,5.9,2.6Hz,1H),7.01(dd,J＝8.4,2.5Hz,1H),6.73(d,J＝7.9Hz,1H),6.60–6.49(m,2H),6.36(dd,J＝16.9,1.7Hz,1H),5.79(dd,J＝10.2,1.7Hz,1H),5.28(t,J＝6.1Hz,1H),4.54–4.44(m,1H),4.32(d,J＝6.1Hz,2H),3.70(s,1H),3.39(d,J＝2.5Hz,2H),3.12(q,J＝7.3Hz,2H),2.96(t,J＝4.8Hz,3H),2.78(p,J＝3.2,2.7Hz,4H),2.13–2.08(m,2H),1.97–1.90(m,2H),1.52–1.41(m,2H),1.36(m,2H).
HRMS(ESI)calcd for C36H40N8O2[M+H]+,617.3347；found,617.3326。
实施例9：N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(3-(二甲基氨基)吡咯烷-1-yl)苯基)丙烯酰胺(YJZ6082)
N-N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)acrylamide(YJZ6082)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.32(d,J＝2.4Hz,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.50(d,J＝7.6Hz,1H),7.31–7.23(m,2H),7.21–7.13(m,4H),6.89(s,2H),6.56(dd,J＝17.0,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.24(dd,J＝17.0,2.1Hz,1H),5.74(dd,J＝10.0,2.1Hz,1H),5.57(d,J＝6.2Hz,1H),4.26(t,J＝3.5Hz,1H),4.17(d,J＝6.2Hz,2H),3.50(s,1H),3.21(t,J＝8.9Hz,4H),2.66(t,J＝8.0Hz,1H),2.16(s,6H),2.13–2.05(m,1H),1.92(s,2H),1.81–1.68(m,3H),1.30(t,J＝12.6Hz,2H),1.19–1.05(m,2H).
HRMS(ESI)calcd for C35H42N8O2[M+H]+,607.3503；found,607.3480。
实施例10：N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(3-(二甲基氨基)氮杂环丁烷-1-yl)苯基)丙烯酰胺(YJZ6077)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(3-(dimethylamino)azetidin-1-yl)phenyl)acrylamide(YJZ6077)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.33(d,J＝2.3Hz,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.30–7.23(m,2H),7.20–7.14(m,3H),7.11(d,J＝2.4Hz,1H),6.90(dd,J＝8.6,2.4Hz,1H),6.61(d,J＝8.5Hz,1H),6.55(dd,J＝17.0,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.24(dd,J＝17.0,2.1Hz,1H),5.74(dd,J＝10.2,2.1Hz,1H),5.59(t,J＝6.1Hz,1H),4.31–4.20(m,1H),4.17(d,J＝6.0Hz,2H),3.98(t,J＝7.2Hz,2H),3.60(t,J＝6.7Hz,2H),3.50(s,1H),3.12(d,J＝14.5Hz,H),2.11(s,6H),1.96–1.85(m,2H),1.76(d,J＝12.0Hz,2H),1.39–1.23(m,2H),1.14(ddd,J＝25.5,13.6,8.9Hz,2H).
HRMS(ESI)calcd for C34H40N8O2[M+H]+,593.3347；found,593.3329。
实施例11：N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-溴苯基)丙烯酰胺(YJZ6048)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-bromophenyl)acrylamide(YJZ6048)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.32(d,J＝2.4Hz,1H),7.73(d,J＝8.4Hz,1H),7.61(dd,J＝9.0,2.4Hz,2H),7.48(d,J＝7.6Hz,1H),7.30–7.24(m,2H),7.23–7.14(m,3H),6.96(dd,J＝8.5,2.5Hz,1H),6.68(dd,J＝17.0,10.2Hz,1H),6.48(d,J＝8.9Hz,1H),6.31(dd,J＝17.0,2.0Hz,1H),6.11(t,J＝5.9Hz,1H),5.82(dd,J＝10.2,2.0Hz,1H),4.34–4.22(m,1H),4.16(d,J＝6.0Hz,2H),3.52(s,1H),1.93(d,J＝12.1Hz,2H),1.79(d,J＝12.1Hz,2H),1.32(q,J＝12.3Hz,2H),1.24–1.10(m,2H).
HRMS(ESI)calcd for C29H29BrN6O2[M+H]+,573.1608；found,573.1618。
实施例12：N-(5-(3-苄基-1-(((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ6093)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide(YJZ6093)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.31(d,J＝2.3Hz,1H),7.91(s,1H),7.60(dd,J＝8.9,2.3Hz,1H),7.49(d,J＝7.6Hz,1H),7.30–7.24(m,2H),7.21(d,J＝8.4Hz,1H),7.20–7.15(m,3H),6.92(dd,J＝8.4,2.4Hz,1H),6.65(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.27(dd,J＝17.0,1.9Hz,1H),5.78(td,J＝9.6,3.9Hz,2H),4.33–4.22(m,1H),4.17(d,J＝6.0Hz,2H),3.51(s,1H),2.95–2.75(m,4H),2.45(d,J＝10.6Hz,2H),2.37(d,J＝9.4Hz,1H),2.25(s,3H),1.92(d,J＝12.0Hz,2H),1.78(d,J＝12.0Hz,2H),1.32(q,J＝12.5Hz,2H),1.16(t,J＝12.8Hz,2H),1.01(d,J＝6.1Hz,3H).
HRMS(ESI)calcd for C35H42N8O2[M+H]+,607.3503；found,607.3521。
实施例13：N-(5-(3-苄基-1-(((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3-甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ8027)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3-methylpiperazin-1-yl)phenyl)acrylamide(YJZ8027)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.31(d,J＝2.3Hz,1H),7.93(s,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.26(q,J＝6.8,6.0Hz,2H),7.22–7.12(m,4H),6.91(dd,J＝8.4,2.5Hz,1H),6.66(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.27(dd,J＝17.0,1.9Hz,1H),5.82–5.72(m,2H),4.27(s,1H),4.17(d,J＝6.0Hz,2H),3.47(d,J＝7.1Hz,1H),3.03–2.81(m,4H),2.68–2.57(m,2H),2.28(t,J＝10.3Hz,1H),1.92(d,J＝12.0Hz,2H),1.78(d,J＝11.9Hz,2H),1.38–1.25(m,2H),1.20–1.08(m,2H),0.97(d,J＝6.4Hz,3H).
HRMS(ESI)calcd for C34H40N8O2[M+H]+,593.3347；found,593.3333。
实施例14：N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(1-甲基-6-氧代-1，6-二氢吡啶-3-基)苯基)丙烯酰胺(YJZ5028)
N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)acrylamide(YJZ5028)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.32(d,J＝2.3Hz,1H),7.88(d,J＝2.6Hz,1H),7.60(q,J＝9.6,7.4Hz,3H),7.45(dd,J＝9.3,2.6Hz,1H),7.39(d,J＝8.1Hz,1H),7.28(t,J＝7.5Hz,2H),7.24–7.14(m,3H),7.06(dd,J＝8.1,2.2Hz,1H),6.47(dd,J＝13.9,9.2Hz,3H),6.24(dd,J＝17.0,2.2Hz,1H),5.98(s,1H),5.74(d,J＝10.2Hz,1H),4.30(t,J＝11.9Hz,1H),4.19(d,J＝6.0Hz,2H),3.65–3.55(m,1H),3.48(s,3H),1.93(d,J＝12.0Hz,2H),1.82(d,J＝11.7Hz,2H),1.31(td,J＝15.4,14.6,7.1Hz,4H).
HRMS(ESI)calcd for C35H35N7O3[M+H]+,602.2874；found,602.2853。
实施例15：N-(3-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)苯基)丙烯酰胺(YJZ4156)
N-(3-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)acrylamide(YJZ4156)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.31(d,J＝2.3Hz,1H),7.79–7.69(m,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.56(t,J＝2.0Hz,1H),7.55–7.48(m,1H),7.41(t,J＝8.0Hz,1H),7.31–7.23(m,2H),7.23–7.13(m,3H),6.90(dt,J＝7.8,1.3Hz,1H),6.51–6.39(m,2H),6.29(dd,J＝17.0,2.1Hz,1H),5.89(t,J＝6.0Hz,1H),5.79(dd,J＝10.0,2.1Hz,1H),4.29(td,J＝9.9,8.2,5.7Hz,1H),4.16(d,J＝6.0Hz,2H),3.51(s,1H),1.93(d,J＝12.0Hz,2H),1.79(d,J＝11.9Hz,2H),1.32(q,J＝12.3Hz,2H),1.16(td,J＝15.6,14.5,7.2Hz,2H).
HRMS(ESI)calcd for C29H30N6O2[M+H]+,495.2503；found,495.2485。
实施例16：(E)-N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯基)-4-(二甲基氨基)丁-2-烯酰胺(YJZ5078)
(E)-N-(5-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4-(dimethylamino)but-2-enamide(YJZ5078)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.32(d,J＝2.4Hz,1H),7.86(d,J＝2.7Hz,1H),7.67–7.58(m,2H),7.53(d,J＝7.6Hz,1H),7.44(dd,J＝9.4,2.7Hz,1H),7.38(dd,J＝8.0,2.9Hz,1H),7.33–7.25(m,2H),7.25–7.15(m,3H),7.11–7.01(m,1H),6.72(d,J＝15.3Hz,1H),6.51–6.43(m,2H),6.40(d,J＝15.4Hz,1H),5.95(s,1H),4.35–4.25(m,1H),4.19(d,J＝6.0Hz,2H),3.48(d,J＝2.4Hz,4H),1.93(d,J＝12.9Hz,2H),1.82(d,J＝12.4Hz,2H),1.40–1.28(m,2H),1.19(m,2H).
HRMS(ESI)calcd for C38H42N8O3[M+H]+,659.3453；found,659.3456。
实施例17：N-(5-(3-苄基-1-(((1r，4S)-4-((5-氰基嘧啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ7007)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-cyanopyrimidin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide(YJZ7007)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.62(q,J＝3.0Hz,2H),8.28(d,J＝8.0Hz,1H),7.94–7.84(m,1H),7.31–7.24(m,2H),7.23–7.13(m,4H),6.92(dd,J＝8.4,2.4Hz,1H),6.66(dd,J＝16.9,10.2Hz,1H),6.27(dd,J＝16.9,1.9Hz,1H),5.88–5.75(m,2H),4.31–4.20(m,1H),4.17(d,J＝6.0Hz,2H),3.57–3.45(m,1H),2.97–2.75(m,4H),2.49–2.41(m,2H),2.36(td,J＝6.4,2.9Hz,1H),2.25(s,3H),1.91–1.83(m,2H),1.82–1.72(m,2H),1.50–1.35(m,2H),1.12(dt,J＝12.6,3.8Hz,2H),1.00(d,J＝6.1Hz,3H).
HRMS(ESI)calcd for C34H41N9O2[M+H]+,608.3456；found,608.3463。
实施例18：N-(5-(((((1r，4r)-4-)((5-氰基吡啶-2-基)氨基)环己基)氨基)-2-(4-(二甲基氨基)哌啶-1-基)苯基)丙烯酰胺(YJZ6109)
N-(5-(((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)amino)-2-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide(YJZ6109)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.38(d,J＝2.3Hz,1H),7.70–7.59(m,1H),7.53(d,J＝7.6Hz,2H),6.94(d,J＝8.6Hz,1H),6.60(dd,J＝16.9,10.2Hz,1H),6.53(d,J＝8.9Hz,1H),6.29(dd,J＝8.7,2.7Hz,1H),6.21(dd,J＝16.9,1.9Hz,1H),5.80–5.70(m,1H),5.31(d,J＝8.1Hz,1H),3.77(s,1H),3.11(d,J＝7.6Hz,1H),2.82(d,J＝11.3Hz,2H),2.61–2.52(m,2H),2.20(s,6H),2.13(tt,J＝10.7,3.6Hz,1H),2.05–1.92(m,4H),1.80(d,J＝12.2Hz,2H),1.63(tt,J＝12.9,6.5Hz,2H),1.37–1.27(m,2H),1.23(dd,J＝9.8,3.7Hz,2H).
HRMS(ESI)calcd for C28H37N7O[M+H]+,488.3132；found,488.3134。
实施例19：N-(5-(1-((1r,4S)-4-((5-氰基吡啶-2-基)氨基)环己基-3-(环丙基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1025)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(cyclopropylmethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.31(d,J＝2.3Hz,1H),7.88–7.78(m,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.20(d,J＝8.4Hz,1H),6.88(dd,J＝8.4,2.5Hz,1H),6.64(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.26(dd,J＝16.9,1.9Hz,1H),5.79(dd,J＝10.2,1.9Hz,1H),5.09(t,J＝5.7Hz,1H),4.26(tt,J＝11.2,3.0Hz,2H),3.48(s,1H),2.97–2.74(m,6H),2.45(d,J＝10.7Hz,2H),2.39–2.32(m,1H),2.25(s,3H),1.91(d,J＝12.2Hz,2H),1.76(d,J＝12.0Hz,2H),1.32(q,J＝12.5Hz,2H),1.12(q,J＝11.9,11.5Hz,3H),1.01(d,J＝6.1Hz,3H),0.88–0.81(m,1H),0.31–0.24(m,2H),0.08–0.01(m,2H).
HRMS(ESI)calcd for C32H42N8O2[M+H]+,571.3503；found,571.3491
实施例20：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(氧杂环丁基-3-基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1031)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(oxetan-3-ylmethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.30(d,J＝2.3Hz,1H),7.80(s,1H),7.60(dd,J＝8.8,2.4Hz,1H),7.48(d,J＝7.6Hz,1H),7.19(d,J＝8.4Hz,1H),6.85(dd,J＝8.4,2.4Hz,1H),6.64(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝9.0Hz,1H),6.25(dd,J＝17.0,1.8Hz,1H),5.79(dd,J＝10.2,1.9Hz,1H),5.44(t,J＝5.9Hz,1H),4.50(ddd,J＝7.7,5.9,1.7Hz,2H),4.22(q,J＝6.1Hz,3H),3.47(s,1H),3.22(t,J＝6.3Hz,2H),3.01–2.76(m,5H),2.49–2.42(m,2H),2.40–2.30(m,1H),2.25(s,3H),1.91(d,J＝12.9Hz,2H),1.75(d,J＝12.9Hz,2H),1.31(q,J＝13.4,12.7Hz,2H),1.11(q,J＝10.2,7.9Hz,2H),1.01(d,J＝6.1Hz,3H).
HRMS(ESI)calcd for C32H42N8O3[M+H]+,587.3453；found,571.3440
实施例21：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-((1-甲基-1H-吡唑-4-基)甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1033)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.30(d,J＝2.4Hz,1H),7.82(s,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.44(s,1H),7.23–7.13(m,2H),6.87(dd,J＝8.4,2.5Hz,1H),6.64(dd,J＝16.9,10.3Hz,1H),6.47(d,J＝8.8Hz,1H),6.26(dd,J＝17.0,1.9Hz,1H),5.79(dd,J＝10.2,1.9Hz,1H),5.40(t,J＝5.7Hz,1H),4.25(d,J＝11.5Hz,1H),3.97(d,J＝5.8Hz,2H),3.75(s,3H),3.49(s,1H),2.95–2.76(m,4H),2.47–2.41(m,2H),2.38–2.31(m,1H),2.25(s,3H),1.91(d,J＝12.4Hz,2H),1.76(d,J＝12.0Hz,2H),1.31(q,J＝12.5Hz,2H),1.12(q,J＝12.7Hz,2H),1.01(d,J＝6.1Hz,3H).
HRMS(ESI)calcd for C33H42N10O2[M+H]+,611.3565；found,611.3550
实施例22：N-(5-(1-((1r,4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-环丙基脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ9173)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-cyclopropylureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.30(d,J＝2.3Hz,1H),7.78(s,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.47(d,J＝7.8Hz,1H),7.17(d,J＝8.4Hz,1H),6.83(dd,J＝8.4,2.4Hz,1H),6.63(dd,J＝16.9,10.3Hz,1H),6.48(d,J＝8.9Hz,1H),6.25(dd,J＝16.9,1.9Hz,1H),5.79(dd,J＝10.2,1.9Hz,1H),5.14(d,J＝2.9Hz,1H),4.24(tt,J＝12.0,3.7Hz,1H),3.48(s,1H),2.96–2.75(m,4H),2.49–2.41(m,3H),2.35(ddd,J＝9.2,6.0,2.7Hz,1H),2.25(s,3H),1.91(d,J＝11.9Hz,2H),1.76(d,J＝11.9Hz,2H),1.32(q,J＝13.1,12.5Hz,2H),1.12(q,J＝13.1,12.5Hz,2H,2H),1.01(d,J＝6.1Hz,3H),0.51–0.44(m,2H),0.32–0.24(m,2H).
实施例23：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(2-氟苄基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ9179)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(2-fluorobenzyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.31(d,J＝2.9Hz,1H),7.93(s,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.47(d,J＝7.6Hz,1H),7.28–7.20(m,3H),7.15(td,J＝7.3,1.3Hz,1H),7.09(ddd,J＝9.9,8.6,1.3Hz,1H),6.94(dd,J＝8.4,2.5Hz,1H),6.66(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.27(dd,J＝17.0,1.8Hz,1H),5.84–5.73(m,2H),4.31–4.24(m,1H),4.22(d,J＝6.0Hz,2H),3.50(s,1H),2.96–2.77(m,4H),2.48–2.43(m,2H),2.41–2.32(m,1H),1.92(d,J＝11.6Hz,2H),1.78(d,J＝11.3Hz,2H),1.32(q,J＝12.2Hz,2H),1.15(q,J＝12.6Hz,2H),1.01(d,J＝6.1Hz,3H).
实施例24：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(3-氟苄基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ9177)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(3-fluorobenzyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.31(d,J＝2.4Hz,1H),7.91(s,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.47(d,J＝7.6Hz,1H),7.31(td,J＝7.9,6.1Hz,1H),7.22(d,J＝8.4Hz,1H),7.06–7.01(m,1H),7.01–6.94(m,2H),6.92(dd,J＝8.4,2.5Hz,1H),6.65(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.27(dd,J＝16.9,1.9Hz,1H),5.87(t,J＝6.1Hz,1H),5.79(dd,J＝10.1,1.9Hz,1H),4.27(ddd,J＝11.9,8.2,3.7Hz,1H),4.17(d,J＝6.0Hz,2H),3.50(s,1H),2.97–2.75(m,4H),2.48–2.43(m,2H),2.41–2.32(m,1H),2.25(s,3H),1.97–1.87(m,2H),1.78(d,J＝12.0Hz,2H),1.32(q,J＝12.3,11.8Hz,2H),1.15(q,J＝15.4,14.3Hz,2H),1.01(d,J＝6.1Hz,3H).
实施例25：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(4-氟苄基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ9166)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-fluorobenzyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.30(d,J＝2.3Hz,1H),7.89(s,1H),7.60(dd,J＝8.9,2.3Hz,1H),7.48(d,J＝7.6Hz,1H),7.22(dd,J＝8.3,6.3Hz,3H),7.08(t,J＝8.8Hz,2H),6.90(dd,J＝8.4,2.5Hz,1H),6.65(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.27(dd,J＝17.0,1.8Hz,1H),5.90–5.73(m,2H),4.26(td,J＝10.1,8.3,5.9Hz,1H),4.14(d,J＝5.9Hz,2H),3.49(s,1H),2.96–2.76(m,4H),2.49–2.42(m,2H),2.40–2.32(m,1H),2.25(s,3H),1.92(d,J＝10.1Hz,2H),1.77(d,J＝10.9Hz,2H),1.32(q,J＝13.5,11.7Hz,2H),1.14(q,J＝12.2Hz,2H),1.01(d,J＝6.1Hz,3H).
实施例26：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-((S)-1-苯乙基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ9170)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-((S)-1-phenylethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.30(s,1H),7.86(s,1H),7.60(d,J＝8.9Hz,1H),7.45(d,J＝7.5Hz,1H),7.34–7.14(m,6H),6.92(d,J＝8.4Hz,1H),6.64(dd,J＝17.0,10.3Hz,1H),6.47(d,J＝8.9Hz,1H),6.28(d,J＝17.0Hz,1H),5.80(d,J＝10.3Hz,1H),5.17(d,J＝7.9Hz,1H),4.88–4.76(m,1H),4.23(t,J＝12.0Hz,1H),3.49(s,1H),3.01–2.72(m,4H),2.48–2.41(m,2H),2.36(s,1H),2.25(s,3H),1.91(t,J＝11.2Hz,2H),1.80(d,J＝11.7Hz,1H),1.71(d,J＝11.8Hz,1H),1.30(s,2H),1.24(d,J＝6.7Hz,3H),1.19–1.07(m,2H),1.02(d,J＝6.1Hz,3H).
实施例27：N-(5-(1-((1r，4R)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-((R)-1-苯乙基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ9176)
N-(5-(1-((1r,4R)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-((R)-1-phenylethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.30(d,J＝2.4Hz,1H),7.86(s,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.46(d,J＝7.6Hz,1H),7.30–7.15(m,6H),6.92(dd,J＝8.4,2.5Hz,1H),6.65(dd,J＝17.0,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.28(dd,J＝16.9,1.9Hz,1H),5.80(dd,J＝10.2,1.9Hz,1H),5.18(d,J＝8.0Hz,1H),4.82(p,J＝7.1Hz,1H),4.29–4.18(m,1H),3.49(s,1H),2.99–2.74(m,4H),2.49–2.42(m,2H),2.41–2.31(m,1H),2.26(s,3H),1.91(t,J＝10.7Hz,2H),1.80(d,J＝11.9Hz,1H),1.71(d,J＝12.4Hz,1H),1.36–1.27(m,2H),1.24(d,J＝7.0Hz,3H),1.17–1.07(m,2H),1.01(d,J＝6.1Hz,3H).
实施例28：N-(5-(N-((1r,4r)-4-((5-氰基吡啶-2-基)氨基)环己基)甲基磺酰氨基)-2-(4-(二甲氨基)哌啶-1-基)苯基)丙烯酰胺(YJZ6131)
N-(5-(N-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)methylsulfonamido)-2-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide(YJZ6131)
合成方法与实施例1方法类似。
1H NMR(400MHz,Chloroform-d)δ8.51(s,1H),8.40(d,J＝2.3Hz,1H),8.29(d,J＝2.3Hz,1H),7.50(dd,J＝8.8,2.2Hz,1H),7.16(d,J＝8.4Hz,1H),7.04(dd,J＝8.4,2.5Hz,1H),6.51–6.46(m,2H),6.34(d,J＝8.8Hz,1H),5.87(dd,J＝7.1,4.3Hz,1H),4.99(d,J＝7.7Hz,1H),4.22–4.10(m,1H),3.61–3.50(m,1H),3.24(d,J＝12.4Hz,2H),3.03(s,3H),2.94(d,J＝4.7Hz,1H),2.90(d,J＝4.3Hz,6H),2.83(t,J＝11.9Hz,2H),2.43–2.27(m,4H),2.14(d,J＝12.1Hz,2H),2.07(d,J＝12.3Hz,2H),1.43(t,J＝7.3Hz,4H).
HRMS(ESI)calcd for C29H39N7O3S[M+H]+,566.2908；found,566.2901。
实施例29：N-(5-((N-((1r,4r)-4-((5-氰基吡啶-2-基)氨基)环己基)-1-苯基甲基)磺酰胺)-2-(4-(二甲氨基)哌啶-1-基)苯基)丙烯酰胺(YJZ6136)
N-(5-((N-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-phenylmethyl)sulfonamido)-2-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide(YJZ6136)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.33(d,J＝2.3Hz,1H),7.80(s,1H),7.63(dd,J＝8.9,2.4Hz,1H),7.59(d,J＝7.3Hz,1H),7.30–7.09(m,5H),6.97(d,J＝8.4Hz,1H),6.83(d,J＝8.4Hz,1H),6.67(dd,J＝16.9,10.2Hz,1H),6.51(d,J＝8.9Hz,1H),6.28(dd,J＝16.9,1.9Hz,1H),5.79(dd,J＝10.4,2.0Hz,1H),4.58(s,1H),3.69–3.51(m,1H),3.45–3.38(m,2H),3.02(d,J＝10.2Hz,2H),2.90(s,1H),2.57(s,8H),1.97(p,J＝10.4,8.3Hz,6H),1.89–1.75(m,2H),1.52–1.19(m,4H).
HRMS(ESI)calcd for C35H43N7O3S[M+H]+,509.0701；found,509.0698。
实施例30：N-(5-(N-((1r,4r)-4-((5-氰基吡啶-2-基)氨基)环己基)乙酰胺)-2-(4-(二甲氨基)哌啶-1-基)苯基)丙烯酰胺(YJZ6115)
N-(5-(N-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)acetamido)-2-(4-(dimethylamino)piperidin-1-yl)phenyl)acrylamide(YJZ6115)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.39–8.28(m,1H),7.84(d,J＝2.3Hz,1H),7.66–7.56(m,2H),7.21(d,J＝8.4Hz,1H),6.96(dd,J＝8.3,2.5Hz,1H),6.88–6.71(m,1H),6.50(d,J＝8.9Hz,1H),6.29(dd,J＝17.0,1.9Hz,1H),5.81(dd,J＝10.1,1.9Hz,1H),4.44(s,1H),3.49(d,J＝16.7Hz,1H),3.34–3.24(m,1H),3.18(d,J＝11.4Hz,2H),2.75(s,8H),2.11(d,J＝11.3Hz,2H),2.05–1.98(m,2H),1.94(t,J＝9.8Hz,2H),1.77(d,J＝11.9Hz,2H),1.65(s,3H),1.40–1.27(m,2H),1.20(t,J＝7.3Hz,2H).
HRMS(ESI)calcd for C30H39N7O2[M+H]+,530.3238；found,530.3228。
实施例31：N-(5-(3-苄基-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)-3-氟苯基)丙烯酰胺(YJZ8070)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)-3-fluorophenyl)acrylamide(YJZ8070)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.07–8.99(m,2H),8.33(d,J＝2.3Hz,1H),7.98–7.87(m,1H),7.63(dd,J＝8.9,2.4Hz,1H),7.56(d,J＝7.5Hz,1H),7.23(td,J＝8.0,6.1Hz,1H),7.06(d,J＝8.4Hz,1H),7.03–6.93(m,2H),6.76–6.59(m,3H),6.50(d,J＝8.9Hz,1H),6.26(dd,J＝17.0,1.9Hz,1H),5.80(dd,J＝10.2,1.9Hz,1H),4.38(t,J＝3.6Hz,1H),4.10(d,J＝6.0Hz,2H),3.55(s,1H),2.96–2.73(m,4H),2.49–2.42(m,1H),2.40–2.31(m,2H),2.25(s,3H),1.98(d,J＝11.4Hz,2H),1.89–1.78(m,2H),1.43–1.22(m,4H),1.01(d,J＝6.4Hz,3H).
实施例32：N-(5-(3-苄基-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲)-2-((S)-3,4-二甲基哌嗪-1-基)吡啶-3-基)丙烯酰胺(YJZ9171)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)pyridin-3-yl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.32(d,J＝2.3Hz,1H),7.93(s,1H),7.87(d,J＝2.4Hz,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.31–7.24(m,2H),7.22–7.14(m,3H),6.69(dd,J＝17.0,10.2Hz,1H),6.48(d,J＝8.9Hz,1H),6.29(dd,J＝17.0,2.0Hz,1H),6.22(t,J＝6.0Hz,1H),5.80(dd,J＝10.1,1.9Hz,1H),4.27(tt,J＝12,3.6Hz,1H),4.17(d,J＝5.9Hz,2H),3.52(s,1H),3.41–3.35(m,1H),3.32–3.27(s,1H),2.95(td,J＝11.9,2.6Hz,1H),2.76(d,J＝11.6Hz,1H),2.57(dd,J＝12.2,10.0Hz,1H),2.45–2.37(m,1H),2.33(t,J＝4.2Hz,1H),2.23(s,3H),1.93(d,J＝12.2Hz,2H),1.79(d,J＝11.8Hz,2H),1.33(q,J＝12.4Hz,2H),1.11(q,J＝12.5Hz,2H),1.00(d,J＝6.2Hz,3H).
实施例33：N-(3-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-5-溴苯基)丙烯酰胺(YJZ8053)
N-(3-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-5-bromophenyl)acrylamide(YJZ8053)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.35–8.28(m,1H),8.10(t,J＝1.9Hz,1H),7.61(dd,J＝9.0,2.4Hz,1H),7.48(d,J＝7.6Hz,1H),7.42(t,J＝1.9Hz,1H),7.32–7.24(m,2H),7.23–7.15(m,3H),7.08(t,J＝1.8Hz,1H),6.48(d,J＝8.9Hz,1H),6.41(dd,J＝17.0,9.9Hz,1H),6.31(dd,J＝16.9,2.2Hz,1H),6.21(t,J＝6.0Hz,1H),5.83(dd,J＝9.9,2.2Hz,1H),4.25(d,J＝12.0Hz,1H),4.16(d,J＝5.9Hz,2H),3.54(s,1H),1.94(d,J＝11.5Hz,2H),1.80(d,J＝11.8Hz,2H),1.31(t,J＝12.2Hz,2H),1.26–1.11(m,2H).
HRMS(ESI)calcd for C29H29BrN6O2[M+H]+,573.1608；found,573.1601。
实施例34：N-(3-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-5-甲氧基苯基)丙烯酰胺(YJZ8058)
N-(3-(3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-5-methoxyphenyl)acrylamide(YJZ8058)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.31(dd,J＝2.3,0.7Hz,1H),7.61(dd,J＝8.9,2.4Hz,1H),7.48(q,J＝3.8,2.1Hz,2H),7.31–7.24(m,2H),7.23–7.15(m,3H),7.08(t,J＝1.8Hz,1H),6.51–6.37(m,3H),6.28(dd,J＝17.0,2.1Hz,1H),5.93(t,J＝6.1Hz,1H),5.82–5.75(m,1H),4.25(d,J＝11.6Hz,1H),4.16(d,J＝6.0Hz,2H),3.76(s,3H),3.54(s,1H),1.98–1.88(m,2H),1.80(d,J＝11.7Hz,2H),1.32(d,J＝12.3Hz,2H),1.27–1.19(m,2H).
HRMS(ESI)calcd for C30H32N6O3[M+H]+,525.2609；found,525.2590。
HPLC purity＝96.44％,Rt 10.63min。
实施例35：N-(3-(3-苄基-1-(((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-5-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ8062)
(3-(3-benzyl-1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-5-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide(YJZ8062)
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.31(d,J＝2.3Hz,1H),7.61(dd,J＝9.0,2.3Hz,1H),7.48(d,J＝7.6Hz,1H),7.37(s,1H),7.26(dd,J＝8.6,6.2Hz,2H),7.19(d,J＝7.1Hz,3H),6.97(s,1H),6.52–6.43(m,2H),6.43–6.36(m,1H),6.26(dd,J＝16.9,2.1Hz,1H),5.82–5.72(m,2H),4.25(t,J＝11.9Hz,1H),4.17(d,J＝6.0Hz,2H),3.47(t,J＝13.0Hz,3H),2.87–2.71(m,2H),2.40(t,J＝10.9Hz,2H),2.22(s,3H),2.12(t,J＝6.4Hz,1H),1.94(d,J＝11.8Hz,2H),1.80(d,J＝11.7Hz,2H),1.25(q,J＝12.8Hz,4H),1.06(d,J＝6.1Hz,3H).
HRMS(ESI)calcd for C35H42N8O2[M+H]+,607.3503；found,607.3477。
实施例36：3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)-1-(4-(哌嗪-1-基)苯基)尿素(YJZ7037)
3-benzyl-1-((1r,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-(4-(piperazin-1-yl)phenyl)urea
合成方法与实施例1方法类似。
1H NMR(600MHz,DMSO-d6)δ8.30(d,J＝2.3Hz,1H),7.60(d,J＝6.7Hz,1H),7.53(s,1H),7.27(t,J＝7.5Hz,2H),7.17(dd,J＝12.7,7.3Hz,3H),7.03–6.93(m,4H),6.49(d,J＝8.9Hz,1H),5.58(t,J＝6.2Hz,1H),4.26(tt,J＝12.0,3.0Hz,1H),4.15(d,J＝6.0Hz,2H),3.51(s,1H),3.10(t,J＝5.0Hz,4H),2.83(t,J＝5.0Hz,4H),1.91(d,J＝12.2Hz,2H),1.77(d,J＝10.5Hz,2H),1.31(q,J＝13.8,12.9Hz,2H),1.24(s,1H),1.10(q,J＝11.4Hz,2H).13CNMR(151MHz,DMSO-d6)δ159.71,157.27,153.55,151.202,141.80,131.92,128.47(5C),127.14(4C),126.68,119.59,115.74,94.41,53.36,49.16(2C),46.07(2C),43.93,40.52,31.77(2C),30.66(2C).
HRMS(ESI)for C30H35N7O[M+H]+,calcd:510.2976,found:510.2956.
实施例37：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3,4-二氟苄基)草酰胺(YJZ8101)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(3,4-difluorobenzyl)oxalamide(YJZ8101)
步骤1：N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3,4-二氟苄基)-N1-(4-((S)-3,4-二甲基哌嗪-1-基)-3-硝基苯基)草酰胺
N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(3,4-difluorobenzyl)-N1-(4-((S)-3,4-dimethylpiperazin-1-yl)-3-nitrophenyl)oxalamide
将(3,4-二氟苯基)甲胺(239mg，1.67mol)，草酰氯(317.8mg，2.5mol)溶于20ml无水THF中，氩气保护条件下75℃回流3h，旋干THF及过量的草酰氯，未经纯化，粗产品直接用于下一步反应。将化合物7(250mg，0.56)(化合物7合成方法如实施例1；步骤3)，DIEA(72mg，0.56mol)溶于10ml无水DMF中备用。将上述与草酰氯反应后的粗产品溶于10mlTHF，在0℃条件下缓慢将该THF溶液加入化合物7的DMF中，升至室温反应30min。TLC检测，反应结束后旋干溶剂，用乙酸乙酯，饱和碳酸氢钠萃取，收集有机相浓缩，柱层析得270mg(产率75％)。
1H NMR(400MHz,DMSO-d6)δ9.22(t,J＝6.1Hz,1H),8.32–8.29(m,1H),7.72(s,1H),7.63(t,J＝8.7Hz,2H),7.44–7.38(m,2H),7.20(dt,J＝10.8,8.5Hz,2H),6.94(ddd,J＝11.7,7.9,2.2Hz,1H),6.71(d,J＝6.6Hz,1H),6.52(d,J＝8.9Hz,1H),4.40–4.29(m,1H),4.08(d,J＝5.9Hz,2H),3.59(dt,J＝14.1,6.5Hz,1H),3.19–2.90(m,5H),2.79(s,2H),2.24(s,5H),1.95(q,J＝9.0,8.5Hz,3H),1.84(d,J＝13.2Hz,2H),1.42–1.32(m,3H),1.32–1.18(m,10H),1.05(dd,J＝13.6,6.6Hz,4H).
步骤2：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3,4-二氟苄基)草酰胺(YJZ8101)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(3,4-difluorobenzyl)oxalamide(YJZ8101)
合成方法与实施例1步骤5方法类似。
1H NMR(400MHz,DMSO-d6)δ9.05–8.98(m,2H),8.32(d,J＝2.3Hz,1H),7.92(s,1H),7.62(dd,J＝8.8,2.3Hz,1H),7.51(d,J＝7.4Hz,1H),7.22(dt,J＝10.8,8.4Hz,1H),7.03(d,J＝8.4Hz,1H),6.98–6.90(m,2H),6.69–6.59(m,2H),6.49(d,J＝8.9Hz,1H),6.26(dd,J＝16.9,1.9Hz,1H),5.83–5.76(m,1H),4.37(d,J＝6.2Hz,2H),4.06(d,J＝6.1Hz,2H),3.55(s,1H),2.84(d,J＝46.3Hz,4H),2.45(d,J＝11.2Hz,1H),2.39(d,J＝20.5Hz,2H),2.25(s,3H),1.97(d,J＝11.6Hz,2H),1.86(s,2H),1.35(t,J＝12.0Hz,3H),1.24(s,2H),1.00(t,J＝6.4Hz,3H).
HRMS(ESI)calcd for C36H40F2N8O3[M+H]+,；found,509.0698。
实施例38：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3-氟苄基)草酰胺(YJZ8087)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(3-fluorobenzyl)oxalamide(YJZ8087)
合成方法与实施例37方法类似。
1H NMR(400MHz,DMSO-d6)δ9.07–8.99(m,2H),8.33(d,J＝2.3Hz,1H),7.98–7.87(m,1H),7.63(dd,J＝8.9,2.4Hz,1H),7.56(d,J＝7.5Hz,1H),7.23(td,J＝8.0,6.1Hz,1H),7.06(d,J＝8.4Hz,1H),7.03–6.93(m,2H),6.76–6.59(m,3H),6.50(d,J＝8.9Hz,1H),6.26(dd,J＝17.0,1.9Hz,1H),5.80(dd,J＝10.2,1.9Hz,1H),4.38(t,J＝3.6Hz,1H),4.10(d,J＝6.0Hz,2H),3.55(s,1H),2.96–2.73(m,4H),2.48–2.30(m,3H),2.25(s,3H),1.98(d,J＝11.4Hz,2H),1.89–1.78(m,2H),1.43–1.22(m,4H),1.01(d,J＝6.4Hz,3H).
HRMS(ESI)calcd for C36H41FN8O3[M+H]+,653.3358；found,653.3340。
实施例39：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(4-氟苄基)草酰胺(YJZ8093)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(4-fluorobenzyl)oxalamide(YJZ8093)
合成方法与实施例37方法类似。
1H NMR(400MHz,DMSO-d6)δ9.08(d,J＝11.4Hz,1H),8.96(t,J＝6.1Hz,1H),8.33(d,J＝2.3Hz,1H),7.90(s,1H),7.62(dd,J＝8.9,2.4Hz,1H),7.52(d,J＝7.6Hz,1H),7.00(td,J＝8.6,6.1Hz,2H),6.92(dd,J＝8.4,2.5Hz,1H),6.84(dd,J＝8.5,5.6Hz,2H),6.68(dd,J＝17.0,10.2Hz,1H),6.50(d,J＝8.9Hz,1H),6.27(dt,J＝17.8,4.1Hz,1H),5.80(dd,J＝10.0,2.0Hz,1H),4.45–4.31(m,1H),4.05(d,J＝6.2Hz,2H),3.55(s,1H),2.98–2.70(m,4H),2.47–4.46(m,1H)2.38(s,2H),2.26(s,3H),1.98(d,J＝11.7Hz,2H),1.88–1.78(m,2H),1.45–1.30(m,2H),1.24(s,2H),1.01(d,J＝5.7Hz,3H).
HRMS(ESI)calcd for C36H41FN8O3[M+H]+,653.3358；found,653.3337。
实施例40：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(2,3-二氟苄基)草酰胺(YJZ8107)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(2,3-difluorobenzyl)oxalamide(YJZ8107)
合成方法与实施例37方法类似。
1H NMR(400MHz,DMSO-d6)δ9.05(dd,J＝11.4,5.3Hz,2H),8.35–8.32(m,1H),7.94–7.86(m,1H),7.63(dd,J＝8.9,2.4Hz,1H),7.55(d,J＝7.5Hz,1H),7.31–7.24(m,1H),7.03(d,J＝8.5Hz,1H),7.01–6.96(m,1H),6.93(dd,J＝8.4,2.5Hz,1H),6.64(d,J＝10.4Hz,1H),6.50(d,J＝8.9Hz,2H),6.27(dd,J＝17.0,1.9Hz,1H),5.84–5.76(m,1H),4.43–4.30(m,1H),4.15(d,J＝5.8Hz,2H),3.53(d,J＝15.5Hz,1H),2.98–2.70(m,4H),2.49–2.44(m,1H),2.37(s,2H),2.25(d,J＝3.1Hz,3H),1.96(s,2H),1.84(d,J＝11.1Hz,2H),1.42–1.21(m,4H),1.01(dd,J＝5.8,2.8Hz,3H).
HRMS(ESI)calcd for C36H40F2N8O3[M+H]+,671.3264；found,671.3246。
实施例41：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3,5-二氟苄基)草酰胺(YJZ8102)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(3,5-difluorobenzyl)oxalamide(YJZ8102)
合成方法与实施例37方法类似。
1H NMR(400MHz,DMSO-d6)δ9.05(t,J＝6.1Hz,1H),8.95(s,1H),8.33(d,J＝2.3Hz,1H),7.95(s,1H),7.62(dd,J＝8.8,2.4Hz,1H),7.52(d,J＝7.5Hz,1H),7.11–7.00(m,2H),6.96(dd,J＝8.3,2.5Hz,1H),6.62(d,J＝7.5Hz,3H),6.50(d,J＝8.9Hz,1H),6.25(dd,J＝16.9,1.9Hz,1H),5.84–5.76(m,1H),4.37(s,1H),4.11(d,J＝6.0Hz,2H),3.55(s,1H),2.93–2.72(m,4H),2.39(d,J＝44.0Hz,3H),2.25(s,3H),1.96(s,3H),1.84(d,J＝10.8Hz,2H),1.35(t,J＝12.0Hz,2H),1.24(s,2H),1.00(d,J＝5.4Hz,3H).
HRMS(ESI)calcd for C36H40F2N8O3[M+H]+,671.3264；found,671.3242。
实施例42：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4R)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-((R)-1-苯乙基)草酰胺(YJZ8105)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4R)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-((R)-1-phenylethyl)oxalamide(YJZ8105)
合成方法与实施例37方法类似。
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.82(d,J＝8.1Hz,1H),8.33(d,J＝2.4Hz,1H),7.93(s,1H),7.62(dd,J＝8.9,2.5Hz,1H),7.52(d,J＝7.5Hz,1H),7.22(t,J＝7.4Hz,2H),7.17(d,J＝7.0Hz,1H),7.03(d,J＝8.0Hz,3H),6.95(dd,J＝8.4,2.5Hz,1H),6.73–6.61(m,1H),6.50(d,J＝8.9Hz,1H),6.32–6.22(m,1H),5.79(d,J＝10.3Hz,1H),4.62(t,J＝7.3Hz,1H),4.36(s,1H),3.54(s,3H),2.79(d,J＝11.1Hz,4H),2.47(m,1H),2.36(s,2H),2.25(s,3H),1.98(s,2H),1.85(s,2H),1.35(t,J＝12.0Hz,2H),1.24(s,2H),1.11(d,J＝7.0Hz,3H),1.00(dd,J＝5.9,2.9Hz,3H).
HRMS(ESI)calcd for C37H44N8O3[M+H]+,671.3264；found,671.3261。
实施例43：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-((S)-1-苯乙基)草酰胺(YJZ8106)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-((S)-1-phenylethyl)oxalamide(YJZ8106)
合成方法与实施例37方法类似。
1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.86(d,J＝8.1Hz,1H),8.33(d,J＝2.3Hz,1H),7.92(s,1H),7.63(dd,J＝8.8,2.4Hz,1H),7.56(d,J＝7.5Hz,1H),7.40(d,J＝4.3Hz,1H),7.23(dd,J＝9.5,5.3Hz,2H),7.17(d,J＝7.1Hz,1H),7.07–6.98(m,2H),6.95(dd,J＝8.4,2.4Hz,1H),6.67(dt,J＝17.6,9.4Hz,1H),6.50(d,J＝9.0Hz,1H),6.33–6.23(m,1H),5.79(d,J＝9.9Hz,1H),4.66–4.57(m,1H),4.37(s,1H),3.64–3.52(m,1H),2.96–2.70(m,4H),2.48–2.42(m,1H),2.40–2.30(m,2H),2.25(s,3H),2.04–1.94(m,2H),1.85(s,2H),1.42–1.25(m,4H),1.12(d,J＝7.0Hz,3H),1.01(dd,J＝6.9,3.2Hz,4H).
HRMS(ESI)calcd for C37H44N8O3[M+H]+,649.3609；found,649.3615。
实施例44：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(环丙基甲基)草酰胺(YJZ8103)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(cyclopropylmethyl)oxalamide(YJZ8103)
合成方法与实施例37方法类似。
1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),8.29(dd,J＝8.0,2.3Hz,2H),7.50(dd,J＝8.8,2.3Hz,1H),7.17(dd,J＝7.2,5.0Hz,2H),6.89(dd,J＝8.4,2.5Hz,1H),6.41(dd,J＝16.9,1.3Hz,1H),6.34–6.23(m,2H),5.82(dd,J＝10.1,1.3Hz,1H),5.03(d,J＝7.8Hz,1H),4.58(s,1H),3.53(d,J＝22.4Hz,1H),3.01–2.95(m,4H),2.89(dd,J＝11.6,2.8Hz,1H),2.51–2.43(m,1H),2.40(s,3H),2.30(s,1H),2.14(d,J＝11.0Hz,2H),1.98(s,2H),1.83(s,2H),1.55–1.34(m,4H),1.15(d,J＝6.2Hz,3H),0.94–0.80(m,1H),0.50–0.39(m,2H),0.15–0.07(m,2H).
HRMS(ESI)calcd for C33H42N8O3[M+H]+,599.3453；found,599.3435。
实施例45：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-环丙基草酰胺(YJZ8095)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-cyclopropyloxalamide(YJZ8095)
合成方法与实施例37方法类似。
1H NMR(400MHz,Chloroform-d)δ8.61(s,1H),8.30(dd,J＝2.3,0.7Hz,1H),8.25(d,J＝2.4Hz,1H),7.51(dd,J＝8.8,2.3Hz,1H),7.20–7.12(m,2H),6.89(dd,J＝8.4,2.5Hz,1H),6.42(dd,J＝16.9,1.3Hz,1H),6.34–6.24(m,2H),5.83(dd,J＝10.1,1.3Hz,1H),5.08(s,1H),4.55(d,J＝3.6Hz,1H),3.51(s,1H),3.03–2.94(m,2H),2.93–2.87(m,1H),2.55(dq,J＝7.2,3.6Hz,1H),2.52–2.44(m,1H),2.41(s,3H),2.33(s,1H),2.14(d,J＝10.8Hz,2H),2.06–1.88(m,4H),1.42(h,J＝12.8,10.3Hz,4H),1.16(d,J＝6.2Hz,3H),0.69(dq,J＝7.1,2.2Hz,2H),0.43(s,2H).
HRMS(ESI)calcd for C32H40N8O3[M+H]+,585.3296；found,585.3294。
实施例46：N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(2,2,2-三氟乙基)草酰胺(YJZ8104)
N1-(3-acrylamido-4-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-N1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-N2-(2,2,2-trifluoroethyl)oxalamide(YJZ8104)
合成方法与实施例37方法类似。
1H NMR(400MHz,Chloroform-d)δ8.62(s,1H),8.30(t,J＝2.8Hz,2H),7.63–7.44(m,2H),7.17(d,J＝8.4Hz,1H),6.88(dd,J＝8.4,2.5Hz,1H),6.43(dd,J＝16.8,1.3Hz,1H),6.35–6.24(m,2H),5.84(dd,J＝10.1,1.2Hz,1H),5.03(s,1H),4.58(t,J＝11.8Hz,1H),3.82–3.70(m,2H),3.51(s,1H),3.03–2.93(m,2H),2.92–2.85(m,1H),2.53–2.44(m,1H),2.41(s,3H),2.33(s,1H),2.16(d,J＝11.0Hz,2H),1.79(s,4H),1.43(t,J＝11.5Hz,4H),1.16(d,J＝6.3Hz,3H).
HRMS(ESI)calcd for C31H37F3N8O3[M+H]+,627.3013；found,627.2994。
实施例47：N-(5-(3-苄基-1-((1r，4S)-4-((5-氯吡啶-2-基)氨基)环己基)脲)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1070)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-chloropyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.91(s,1H),7.87(d,J＝2.8Hz,1H),7.34(dd,J＝9.0,2.8Hz,1H),7.26(q,J＝11.1,9.4Hz,3H),7.19(t,J＝6.8Hz,4H),6.91(d,J＝8.3Hz,1H),6.70–6.57(m,2H),6.42(d,J＝8.9Hz,1H),6.27(d,J＝16.9Hz,1H),5.86–5.69(m,2H),4.27(t,J＝11.9Hz,1H),4.17(d,J＝6.0Hz,2H),3.01–2.72(m,4H),2.49–2.41(m,2H),2.40–2.31(m,1H),2.25(s,3H),1.93(d,J＝12.1Hz,2H),1.77(d,J＝11.9Hz,2H),1.26(q,J＝11.4Hz,2H),1.16(q,J＝11.5Hz,2H),1.00(d,J＝6.3Hz,3H).
实施例48：N-(5-(3-(2-氯苄基)-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1060)
N-(5-(3-(2-chlorobenzyl)-1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.31(d,J＝2.3Hz,1H),7.97(s,1H),7.60(dd,J＝8.8,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.39–7.34(m,1H),7.34–7.29(m,1H),7.28–7.20(m,3H),6.98(dd,J＝8.4,2.4Hz,1H),6.67(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.28(dd,J＝16.9,1.9Hz,1H),5.87–5.77(m,2H),4.28(dt,J＝7.5,3.6Hz,1H),4.23(d,J＝6.0Hz,2H),3.51(s,1H),2.97–2.76(m,4H),2.49–2.42(m,2H),2.40–2.32(m,1H),2.25(s,3H),1.93(d,J＝11.9Hz,2H),1.80(d,J＝11.9Hz,2H),1.32(q,J＝12.2Hz,2H),1.23–1.10(m,2H),1.01(d,J＝6.1Hz,3H).
实施例49：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(吡啶-3-基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1061)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(pyridin-3-ylmethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.39(t,J＝2.2Hz,2H),8.30(d,J＝2.4Hz,1H),7.89(s,1H),7.60(ddt,J＝8.1,5.6,2.2Hz,2H),7.48(d,J＝7.6Hz,1H),7.30(dd,J＝7.9,4.8Hz,1H),7.21(d,J＝8.3Hz,1H),6.91(dd,J＝8.4,2.6Hz,1H),6.66(dd,J＝16.8,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.27(dd,J＝16.9,1.9Hz,1H),5.94(t,J＝6.1Hz,1H),5.79(dd,J＝10.2,1.9Hz,1H),4.25(t,J＝11.8Hz,1H),4.17(d,J＝5.9Hz,2H),3.49(s,1H),2.96–2.76(m,4H),2.49–2.41(m,2H),2.40–2.29(m,1H),2.25(s,3H),1.91(d,J＝12.2Hz,2H),1.77(d,J＝11.6Hz,2H),1.31(q,J＝12.7Hz,2H),1.13(q,J＝13.5,13.1Hz,2H),1.01(d,J＝6.1Hz,3H).
实施例50：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(恶唑-4-基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1063)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(oxazol-4-ylmethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.31(d,J＝2.4Hz,1H),8.23(s,1H),7.85(s,1H),7.75(s,1H),7.60(dd,J＝8.9,2.4Hz,1H),7.49(d,J＝7.5Hz,1H),7.20(d,J＝8.4Hz,1H),6.92(dd,J＝8.4,2.5Hz,1H),6.65(dd,J＝16.9,10.2Hz,1H),6.47(d,J＝8.8Hz,1H),6.26(dd,J＝16.9,1.8Hz,1H),5.85–5.72(m,1H),5.56(t,J＝5.8Hz,1H),4.26(t,J＝12.2Hz,1H),4.17(d,J＝6.0Hz,2H),3.48(s,1H),2.99–2.75(m,4H),2.49–2.40(m,2H),2.40–2.31(m,1H),2.25(s,3H),1.92(d,J＝12.1Hz,2H),1.79(d,J＝12.1Hz,2H),1.31(q,J＝12.7Hz,2H),1.13(q,J＝12.1,11.6Hz,2H),1.01(d,J＝6.1Hz,3H).
实施例51：N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(2,2,2-三氟乙基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1065)
N-(5-(1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(2,2,2-trifluoroethyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.31(d,J＝2.3Hz,1H),7.91–7.79(m,1H),7.61(dd,J＝8.8,2.4Hz,1H),7.49(d,J＝7.6Hz,1H),7.22(d,J＝8.4Hz,1H),6.87(dd,J＝8.3,2.4Hz,1H),6.66(dd,J＝17.0,10.2Hz,1H),6.47(d,J＝8.9Hz,1H),6.26(dd,J＝17.0,1.9Hz,1H),5.83(t,J＝6.3Hz,1H),5.79(dd,J＝10.2,1.8Hz,1H),4.26(t,J＝12.2Hz,1H),3.79–3.66(m,2H),3.50(s,1H),2.97–2.76(m,4H),2.49–2.43(m,2H),2.40–2.31(m,1H),2.25(s,3H),1.92(d,J＝12.1Hz,2H),1.83–1.71(m,2H),1.32(q,J＝12.3Hz,2H),1.16(q,J＝12.3Hz,2H),1.01(d,J＝6.1Hz,3H).
实施例52：N-(5-(3-苄基-1-((1r，4S)-4-((5-(三氟甲基)吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺(YJZ1066)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)acrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.21(d,J＝2.5Hz,1H),7.92(s,1H),7.55(dd,J＝8.9,2.6Hz,1H),7.31–7.24(m,2H),7.24–7.13(m,5H),6.92(dd,J＝8.3,2.5Hz,1H),6.66(dd,J＝16.9,10.2Hz,1H),6.50(d,J＝8.9Hz,1H),6.27(dd,J＝16.9,1.9Hz,1H),5.85–5.72(m,2H),4.27(t,J＝12.2Hz,1H),4.17(d,J＝6.0Hz,2H),3.49(s,1H),2.98–2.75(m,4H),2.49–2.41(m,2H),2.41–2.31(m,1H),2.25(s,3H),1.94(d,J＝11.6Hz,2H),1.85–1.72(m,2H),1.30(q,J＝12.4Hz,2H),1.17(q,J＝12.5Hz,2H)1.01(d,J＝6.1Hz,3H).
实施例53：N-(5-(3-苄基-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-2-氟丙烯酰胺(YJZ1072)
N-(5-(3-benzyl-1-((1r,4S)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-2-fluoroacrylamide
合成方法与实施例1方法类似。
1H NMR(400MHz,DMSO-d6)δ9.42(t,J＝2.8Hz,1H),8.30(s,1H),8.08(s,1H),7.60(d,J＝8.9Hz,1H),7.49(d,J＝7.6Hz,1H),7.34(d,J＝8.3Hz,1H),7.30–7.23(m,2H),7.22–7.13(m,3H),6.97(d,J＝8.3Hz,1H),6.47(d,J＝8.9Hz,1H),5.90–5.80(m,1.48H),5.71(s,0.52H),5.53(d,J＝15.0Hz 1H),4.28(t,J＝12.2Hz,1H),4.17(d,J＝5.9Hz,2H),3.49(s,1H),2.97–2.81(m,4H),2.56–2.53(m,1H),2.30(t,J＝10.6Hz,1H),2.24(s,3H),2.23–2.15(m,1H),1.92(d,J＝12.1Hz,2H),1.79(d,J＝12.1Hz,2H),1.32(q,J＝12.4Hz,2H),1.16(q,J＝12.5Hz,2H),1.03(d,J＝6.2Hz,3H).
实施例54：部分化合物对CDK12，CDK13及CDK9激酶的IC50测试
测试化合物的激酶抑制活性通过LANCE Ultra测定进行评估，该测定检测ULight-4E-BP1(Thr37/Thr46)底物肽(150nM)的ATP依赖性磷酸化。简而言之，酶反应在反应缓冲液(25mM HEPES(pH 7.5)、10mM MgCl2、0.01％BSA、0.01％Tween 20、1mM DTT)中进行。该测定在384孔板(6μL)中进行。ATP底物的终浓度为10μM，而ULight-4E-BP1(Thr37/Thr46)底物肽的终浓度为150nM。CDK9、CDK12或CDK13的最终浓度分别为0.3、30或30nM。化合物和酶的预温育在室温下进行60分钟。在室温下孵育15、60或90分钟后，通过在LANCE检测缓冲液中添加10mM EDTA和0.15nM Eu标记的抗磷酸eIF4E结合蛋白1(Thr37/46)抗体来终止反应。通过使用EnVision分光光度计(PerkinElmer)监测时间分辨荧光(激发，320nm；发射供体，615nm；发射受体，665nm)。读数计算为(受体计数/供体计数)×1000。IC50值是通过将S形剂量反应曲线拟合到抑制剂浓度的测定读数图上得出的。所有拟合均使用程序Prism5.03(GraphPad Software，San Diego，CA)计算。
激酶活性测试结果如表1所示。
表1部分化合物对激酶抑制活性测试结果(IC50:nM)
IC50:<15nM＝*；15-50nM＝**；50-500nM＝***；>500nM＝****，#：表示未测试。
从表1数据可以看出，本发明的新型CDK12/13共价抑制剂对CDK12/13激酶具有较强的抑制活性，且代表性化合物YJZ5118对CDK9具有很好的激酶选择性好。
实施例55细胞增殖抑制活性研究
采用CellTiter-Glo Luminescent Cell Viability Assay(Promega,Madison,WI)测定VCaP细胞增殖活性。将细胞接种在其各自培养基中的96孔板上，37℃下在5％CO2的培养箱孵育。孵育过夜后，制备化合物的系列稀释液，并将其添加到96孔板中。加入等于每个孔中存在的细胞培养基体积的CellTiter-Glo试剂的体积(例如，向100微升96孔板细胞的培养基中添加100微升试剂)。在轨道振荡器上混合内容物2分钟以诱导细胞裂解。让96孔板在室温下孵育10分钟以稳定发光信号。记录发光：使用Infinite M1000 Pro读板器(Tecan,Zürich,Switzerland)获取每个孔的发光信号，使用GraphPad Prism软件(GraphPad Software Inc,La Jolla,CA)分析数据。
测试结果如表2所示。
表2化合物细胞活性测试结果(IC50:nM)
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IC50:<15nM＝*；15-50nM＝**；50-500nM＝***；>500nM＝****。
从表2数据可以看出，本发明的一类新型CDK12/13共价抑制剂化合物对VCap细胞增殖有很强的抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (13)
1.具有式(I)结构的CDK12/13共价抑制剂，或其药学上可接受的盐，或其药物组合物或其前药分子：
X、Y、Z分别独立地选自下组：N或CR5；
R5选自下组：氢、卤素、氰基、羟基、氨基、卤代甲基、卤代甲氧基、卤代乙基、卤代乙氧基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、C3-C8环烷氧基、C1-C6烷基取代的氨基；
R1选自下组：H、氰基、卤素、卤代甲基、卤代甲氧基、卤代乙氧基、卤代乙基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、C3-C8环烷氧基；
W选自下组：化学键、
R2选自下组：H、-NHR6、-OR6、-CH(R8)R6；
R6选自下组：-(C(R8)R7)R9、-(CH2)nR9；其中，n选自：0、1或2；
R7、R8各自独立地选自下组：氢、卤素、氰基、甲基、卤代甲基、甲氧基、卤代甲氧基、乙基、卤代乙基、乙氧基、卤代乙氧基、羟基、氨基、含有m个杂原子的3-8元杂环，所述的m为1、2或3，且所述的杂原子选自O、S或N；或R7、R8通过相连的C原子一同形成含n个杂原子的3-7杂环，n选自：1、2或3，所述的杂原子选自：O、N、S；
R9选自下组：
1)氰基、C1-C5烷基、卤代C1-C4烷基、C1-C4烷氧基、C3～C10环烷基、取代或未取代的含O、S或N的3-8元芳环或饱和环、含n个杂原子的8-12元稠环、螺环或桥环，n选自：1、2或3，杂原子选自：O、N、S；
2)
其中A、B、C、D、E分别独立地选自：CH、N或CR10；
R10选自下组：卤素、氰基、羟基、氨基、硝基、C1-C3烷基、卤代C1-C3烷基、C1-C4烷氧基、卤代C1-C4烷氧基、C3-C8环烷基；
V为N或CR3；
各个R3各自独立地选自下组：H、卤素、氰基、羟基、氨基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C3-C8环烷基、-(CH2)mR11、-NH(CH2)mR11、-NR14(CH2)mR11、-O(CH2)mR11；取代或未取代的有m个杂原子的3-8元杂环，所述的m为1、2或3，且所述的杂原子选自O、S或N；、含n个杂原子的8-12元稠环、螺环或桥环，n选自：1、2或3，杂原子选自：O、N、S；且至少一个R3不为H；
R11选自下组：C1～C6烷基或NR12R13；其中，R12、R13分别独立地选自：H、C1～C8烷基、-(CH2)mNR14R15、-(CH2)nCR14R15R16，或R12、R13与它们所连接的氮原子一起形成取代或未被取代的含有杂原子的单环、稠环、螺环或桥环；
R14、R15、R16各自独立地选自下组：H、C1～C8烷基、或R14、R15与它们所连接的氮原子或碳原子一起形成被取代或未被取代的含有0-3个杂原子的单环、稠环、螺环或桥环；
m、n独立地选自：0-8的整数；
R4选自下组：H、
R17选自下组：氢、三氟甲基、
R18选自下组：氢或氟；
除非特别说明，所述的“取代”指基团上的一个或多个氢原子被选自下组的取代基替换：卤素、氧代、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6酰基、未取代或卤代的C1-C6酰胺基、未取代或卤代的C1-C6烷胺基、未取代或卤代的C1-C6烷基-羟基、未取代或卤代的C3-C6烷基、未取代或卤代的4-8元杂环基。
2.根据权利要求1所述的CDK12/13共价抑制剂，其特征在于，
X、Y、Z分别独立地选自：N或CR5；
R5选自下组：氢、卤素、氰基、卤代甲基、卤代甲氧基。
3.根据权利要求1所述的一类新型CDK12/13共价抑制剂或其药物组合物，其特征在于，
R1选自下组：H、氰基、卤素、卤代甲基、卤代甲氧基、卤代乙氧基、卤代乙基、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基。
4.根据权利要求1-2任一所述的CDK12/13共价抑制剂，其特征在于，
W选自：
5.根据权利要求1所述的CDK12/13共价抑制剂，其特征在于，
R2选自下组：-NHR6；
R6选自下组：-(C(R8)R7)R9；
R7、R8各自独立地选自下组：氢、卤素、氰基、甲基、卤代甲基、甲氧基、卤代甲氧基；
R9各自独立地选自下组：苯基、卤代苯基、吡啶基、嘧啶基、异丙基、叔丁基、三氟甲基、二氟甲基、氰基、吡咯基、N-甲基吡咯基、N-甲基咪唑基、N-甲基吡唑基、咪唑基、呋喃基、噻吩基、吡唑基、异恶唑基、恶唑基、卤代C1-C4烷基、C1-C4烷氧基、C1-C4烷基、C3～C7环烷基、C3～C7环氧烷基。
6.根据权利要求1-3所述的CDK12/13共价抑制剂，其特征在于，
各个R3各自独立地选自下组：H、卤素、氰基、羟基、氨基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C3-C8环烷基、C3-C8环烷氧基、
7.根据权利要求1所述的CDK12/13共价抑制剂，或者其药学上可接受的盐，或者其立体异构体或者其前药分子，其特征在于，
R4选自：H、
8.根据权利要求1～7任一项所述的CDK12/13共价抑制剂，或者其药学上可接受的盐，或者其立体异构体或者其前药分子，其特征在于，具有式(II)和(III)所示结构：
9.根据权利要求1-8所述的CDK12/13共价抑制剂，其特征在于，所述化合物选自：
N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-(二甲基氨基)哌啶-1-yl)苯基)丙烯酰胺；
N-(2-(4-乙酰基哌嗪-1-基)-5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-吗啉代苯基)丙烯酰胺；
N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-(((1r，4R)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((1R，4R)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-(基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-(氧杂环丁-3-基)哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(3-(二甲基氨基)吡咯烷-1-yl)苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(3-(二甲基氨基)氮杂环丁烷-1-yl)苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-溴苯基)丙烯酰胺；
N-(5-(3-苄基-1-(((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-(((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3-甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(1-甲基-6-氧代-1，6-二氢吡啶-3-基)苯基)丙烯酰胺；
N-(3-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)苯基)丙烯酰胺；
(E)-N-(5-(3-苄基-1-(((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)苯基)-4-(二甲基氨基)丁-2-烯酰胺；
N-(5-(3-苄基-1-(((1r，4S)-4-((5-氰基嘧啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(((((1r，4r)-4-)((5-氰基吡啶-2-基)氨基)环己基)氨基)-2-(4-(二甲基氨基)哌啶-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r,4S)-4-((5-氰基吡啶-2-基)氨基)环己基-3-(环丙基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(氧杂环丁基-3-基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-((1-甲基-1H-吡唑-4-基)甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r,4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-环丙基脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(2-氟苄基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(3-氟苄基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(4-氟苄基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-((S)-1-苯乙基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4R)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-((R)-1-苯乙基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(N-((1r,4r)-4-((5-氰基吡啶-2-基)氨基)环己基)甲基磺酰氨基)-2-(4-(二甲氨基)哌啶-1-基)苯基)丙烯酰胺；
N-(5-((N-((1r,4r)-4-((5-氰基吡啶-2-基)氨基)环己基)-1-苯基甲基)磺酰胺)-2-(4-(二甲氨基)哌啶-1-基)苯基)丙烯酰胺；
N-(5-(N-((1r,4r)-4-((5-氰基吡啶-2-基)氨基)环己基)乙酰胺)-2-(4-(二甲氨基)哌啶-1-基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)-3-氟苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲)-2-((S)-3,4-二甲基哌嗪-1-基)吡啶-3-基)丙烯酰胺；
N-(3-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-5-溴苯基)丙烯酰胺；
N-(3-(3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-5-甲氧基苯基)丙烯酰胺；
N-(3-(3-苄基-1-(((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-5-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
3-苄基-1-((1r，4r)-4-((5-氰基吡啶-2-基)氨基)环己基)-1-(4-(哌嗪-1-基)苯基)尿素；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3,4-二氟苄基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3-氟苄基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(4-氟苄基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(2,3-二氟苄基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(3,5-二氟苄基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4R)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-((R)-1-苯乙基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-((S)-1-苯乙基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(环丙基甲基)草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-环丙基草酰胺；
N1-(3-丙烯酰胺基-4-((S)-3,4-二甲基哌嗪-1-基)苯基)-N1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-N2-(2,2,2-三氟乙基)草酰胺；
N-(5-(3-苄基-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-2-氟丙烯酰胺；
N-(5-(3-苄基-1-((1r，4S)-4-((5-(三氟甲基)吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(2,2,2-三氟乙基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(恶唑-4-基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)-3-(吡啶-3-基甲基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(3-(2-氯苄基)-1-((1r，4S)-4-((5-氰基吡啶-2-基)氨基)环己基)脲基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺；
N-(5-(3-苄基-1-((1r，4S)-4-((5-氯吡啶-2-基)氨基)环己基)脲)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)丙烯酰胺。
10.权利要求1～9任一所述的CDK12/13共价抑制剂或其药物组合物在制备CDK12/13抑制剂中的应用。
11.权利要求1～9任一所述的CDK12/13共价抑制剂或其药物组合物，或者其药学上可接受的盐，或者其立体异构体或者其前药分子在制备预防和/或治疗由CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病的药物中的应用。
12.权利要求10或11任一所述的应用，其特征在于，所述由CDK12/13丝氨酸/苏氨酸蛋白激酶介导的疾病选自下组：前列腺癌、乳腺癌、子宫癌、卵巢癌、非小细胞肺癌、小细胞肺癌、尤文肉瘤、肺腺癌、肺鳞癌、胰腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤。
13.一种预防和/或治疗肿瘤的药用组合物，其特征在于，包括活性成分和药学上可接受的辅料，且所述活性成分包括权利要求1～9任一所述的一类新型CDK12/13共价抑制剂或其药物组合物，或者其药学上可接受的盐，或者其立体异构体或者其前药分子。
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