2-(4-(6-((5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-ol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 2-(4-(6-((5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-ol
• 英文别名: 2-(4-(6-((5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethanol；2-[4-[6-[[5-Fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanol；2-[4-[6-[[5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanol
• 化学式: C₂₈H₃₁F₂N₇O
• 分子量: 519.597
• InChiKey: IIJWYFPAKYPUIM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  89.8
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  环戊基乙酮 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 四(三苯基膦)钯 、 potassium acetate 、 caesium carbonate 、 溶剂黄146 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.0h， 生成 2-(4-(6-((5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethan-1-ol
  参考文献：
  名称：

  经过合理设计的高效CDK4 / 6抑制剂可克服胶质母细胞瘤治疗中的血脑屏障

  摘要：

  多形胶质母细胞瘤（GBM）是成人中最常见和最致命的恶性脑肿瘤。疾病的发展与细胞周期蛋白D-CDK4 / 6-INK4-Rb通路的失调有关，导致增殖增加。因此，CDK4 / 6激酶抑制剂有望成为GBM治疗的候选药物。最近开发的CDK4 / 6抑制剂palbociclib，ribociclib和abemaciclib在皮下神经胶质瘤模型中有效，但它们的血脑屏障（BBB）通透性差，限制了药物向中枢神经系统的传递。在这里，我们设计和合成了一系列具有良好BBB通透性的新型CDK4 / 6抑制剂，用于治疗GBM。化合物11表现出良好的药理特性，并且BBB随K p显着渗透口服剂量为10 mg / kg时，小鼠的Mp值为4.10，K p，uu值为0.23。CDK4 /细胞周期蛋白D1和CDK6 /细胞周期蛋白D3的IC 50值分别为3 nM和1 nM。使用GBM的原位异种移植小鼠模型进行的体内研究表明，对于3

  DOI：

  10.1016/j.ejmech.2017.12.003

文献信息

• [EN] PROTEIN KINASE INHIBITOR, PREPARATION METHOD AND MEDICAL USE THEREOF<br/>[FR] INHIBITEUR DE PROTÉINE KINASE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION MÉDICALE<br/>[ZH] 一种蛋白激酶抑制剂及其制备方法和医药用途
  申请人：GAN&LEE PHARMACEUTICALS

  公开号：WO2017092635A1

  公开（公告）日：2017-06-08

  本发明提供一种结构式I所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，氘代化合物，前药或其混合物形式，或结构式I所示的化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，氘代化合物，前药或其混合物的药学上可以接受的盐或溶剂化物，其中R1～R7如文中定义。本发明还提供所述化合物的制备方法和医药用途。本发明所述的化合物活性优于或与目前处于III期临床试验的候选药物LY2835219相当，部分化合物表现出更好的选择性。而且优选的化合物口服吸收良好、血脑分布好，预示着本发明的化合物有希望被开发成新的治疗细胞增殖相关疾病的药物，尤其是脑瘤，为临床医生和患者提供新的选择。
• PROTEIN KINASE INHIBITOR, PREPARATION METHOD AND MEDICAL USE THEREOF
  申请人：Gan & Lee Pharmaceuticals

  公开号：EP3385262A1

  公开（公告）日：2018-10-10

  The present invention provides compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutically acceptable salt or solvate of the compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, wherein R1 to R7 are as defined in the description. The present invention also provides a preparation method and a medical use of the compounds, The compounds of the present invention have an activity superior or equivalent to the candidate drug LY283521 9 currently under phase III clinical trial, and some of the compounds exhibit better selectivity. Moreover, the preferred compounds exhibit good absorption and good blood-brain distribution when administered orally. The compounds of the present invention thus show promise for development into novel drugs for the treatment of diseases associated with cell proliferation, particularly brain tumors, providing new options for clinicians and patients.

  本发明提供了式I所示化合物或其同系物、中间体、外消旋体、对映体、非对映异构体、氘代化合物、原药或其混合物，或式I所示化合物或其同系物、中间体、外消旋体、对映体、非对映异构体、氘代化合物、原药或其混合物的药学上可接受的盐或溶液，其中R1至R7如描述中所定义。本发明还提供了化合物的制备方法和医疗用途。本发明化合物的活性优于或等同于目前正在进行 III 期临床试验的候选药物 LY283521 9，其中一些化合物表现出更好的选择性。此外，优选化合物在口服时具有良好的吸收性和血脑分布性。因此，本发明的化合物有望开发成新型药物，用于治疗与细胞增殖有关的疾病，特别是脑肿瘤，为临床医生和患者提供了新的选择。
• Protein kinase inhibitors, preparation method and medical use thereof
  申请人：Gan & Lee Pharmaceuticals

  公开号：US11091476B2

  公开（公告）日：2021-08-17

  The embodiments disclosed herein provide compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutically acceptable salt or solvate of the compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, wherein R1 to R7 are as defined in the description. This application also provides a preparation method and a medical use of the compounds. The compounds of this disclosure have an activity superior or equivalent to the candidate drug LY2835219 currently under phase III clinical trial, and some of the compounds exhibit better selectivity. Moreover, the preferred compounds exhibit good absorption and good blood-brain distribution when administered orally. The compounds of this disclosure thus show promise for development into novel drugs for the treatment of diseases associated with cell proliferation, particularly brain tumors, providing new options for clinicians and patients.

  本文公开的实施方案提供了如式 I 所示的化合物或其同分异构体、中间体、外消旋体、对映体、非对映异构体、氘代化合物、原药或其混合物，或如式 I 所示的化合物或其同分异构体、中间体、外消旋体、对映体、非对映异构体、氘代化合物、原药或其混合物的药学上可接受的盐或溶液，其中 R1 至 R7 如描述中所定义。本申请还提供了化合物的制备方法和医疗用途。本公开的化合物具有优于或等同于目前正在进行 III 期临床试验的候选药物 LY2835219 的活性，其中一些化合物具有更好的选择性。此外，优选化合物在口服时具有良好的吸收性和血脑分布性。因此，本公开的化合物有望开发成新型药物，用于治疗与细胞增殖相关的疾病，尤其是脑肿瘤，为临床医生和患者提供了新的选择。
• 4-(3H-INDOL-5-YL)-N-(PYRIDIN-2-YL)PYRIMIDIN-2-AMINE DERIVATIVES AS PROTEIN KINASE INHIBITORS, PREPARATION METHOD AND MEDICAL USE THEREOF
  申请人：Gan & Lee Pharmaceuticals

  公开号：EP3385262B1

  公开（公告）日：2022-07-13
• PROTEIN KINASE INHIBITORS, PREPARATION METHOD AND MEDICAL USE THEREOF
  申请人：Gan & Lee Pharmaceuticals

  公开号：US20200165239A1

  公开（公告）日：2020-05-28

  The embodiments disclosed herein provide compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, or a pharmaceutically acceptable salt or solvate of the compounds as shown in formula I or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, a deuterated compound, a prodrug or a mixture thereof, wherein R 1 to R 7 are as defined in the description. This application also provides a preparation method and a medical use of the compounds. The compounds of this disclosure have an activity superior or equivalent to the candidate drug LY2835219 currently under phase III clinical trial, and some of the compounds exhibit better selectivity. Moreover, the preferred compounds exhibit good absorption and good blood-brain distribution when administered orally. The compounds of this disclosure thus show promise for development into novel drugs for the treatment of diseases associated with cell proliferation, particularly brain tumors, providing new options for clinicians and patients.