1-(1-甲基乙基)-3-(2-苯基乙炔基)-1H-吡唑并[3,4-d]嘧啶-4-胺 | 1357349-91-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 中文名称: 1-(1-甲基乙基)-3-(2-苯基乙炔基)-1H-吡唑并[3,4-d]嘧啶-4-胺
• 英文名称: 1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: 1-(1-Methylethyl)-3-(2-phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine；3-(2-phenylethynyl)-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 1357349-91-7
• 化学式: C₁₆H₁₅N₅
• 分子量: 277.329
• InChiKey: JQOIRTDBHMDWMT-UHFFFAOYSA-N

物化性质

• 沸点：
  495.3±40.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  69.6
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P264,P270,P301+P312,P330,P501
• 危险性描述：
  H302

制备方法与用途

生物活性

SPP-86 是一种选择性的 RET 酪氨酸激酶的有效抑制剂，其 IC50 值为 8 nM。SPP-86 抑制 MCF7 细胞中 RET 诱导激活的 PI3K/Akt 和 MAPK 信号通路，并能抑制 RET 诱导的 ERα 磷酸化。

靶点

• IC50: 8 nM (RET)

体外研究

SPP-86 在不同细胞系中的表现如下：

1. 在表达 RET/PTC1 的 TPC1 细胞中，SPP86（0-10 μM）抑制了 MAPK 信号通路和增殖，但未对 8505C 或 C643 细胞产生相同效果。
2. 在 MCF7 细胞中（人乳腺癌细胞），SPP86（0-10 μM）在 30 分钟内抑制了 RET 诱导的 ERα 磷酸化和细胞增殖。

Western Blot 分析

• 甲状腺癌衍生细胞系 (TPC1, BRAF V600E (8505C), RAS G13R (C643))：

  • 浓度：0-10 μM
  • 孵育时间：90 分钟
  • 结果：抑制了甲状腺癌细胞系中 RET 诱导的 ERK1/2 磷酸化。

• MCF7 细胞（人乳腺癌细胞）：

  • 浓度：0-10 μM
  • 孵育时间：30 分钟
  • 结果：抑制了 RET 诱导的 ERα 磷酸化和 MCF7 细胞增殖。

反应信息

• 作为反应物：
  描述：

  1-(1-甲基乙基)-3-(2-苯基乙炔基)-1H-吡唑并[3,4-d]嘧啶-4-胺 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 反应 48.0h， 以78%的产率得到1-isopropyl-3-phenethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Preparation of 3-Substituted-1-Isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines as RET Kinase Inhibitors

  摘要：

  A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.

  DOI：

  10.1021/jm3003944
• 作为产物：
  描述：

  3-碘-4-氨基吡唑并[3,4-d]嘧啶 在 copper(l) iodide 、 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.33h， 生成 1-(1-甲基乙基)-3-(2-苯基乙炔基)-1H-吡唑并[3,4-d]嘧啶-4-胺
  参考文献：
  名称：

  Preparation of 3-Substituted-1-Isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines as RET Kinase Inhibitors

  摘要：

  A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.

  DOI：

  10.1021/jm3003944

文献信息

• Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors
  申请人：Array BioPharma, Inc.

  公开号：US10137124B2

  公开（公告）日：2018-11-27

  Provided herein are compounds of the Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X1, X2, X3, X4, Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

  本文提供了公式I的化合物，其立体异构体和药学上可接受的盐或溶剂，其中A、B、X1、X2、X3、X4、环D和E在规范中给出的含义，它们是RET激酶的抑制剂，并可用于治疗和预防可通过RET激酶抑制剂治疗的疾病，包括RET相关的疾病和障碍。
• Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors
  申请人：Array BioPharma, Inc.

  公开号：US10023570B2

  公开（公告）日：2018-07-17

  Provided herein are compounds of the General Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, D, E, X1, X2, X3 and X4 have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including diseases or disorders mediated by a RET kinase.

  本文提供的是通式 I 的化合物： 及其立体异构体和药学上可接受的盐或溶液，其中 A、B、D、E、X1、X2、X3 和 X4 具有说明书中给出的含义，它们是 RET 激酶的抑制剂，可用于治疗和预防可以用 RET 激酶抑制剂治疗的疾病，包括由 RET 激酶介导的疾病或紊乱。
• [EN] SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUND, COMPOSITION CONTAINING THE SAME AND USE THEREOF<br/>[FR] COMPOSÉ PYRAZOLO[1,5-A]PYRIDINE SUBSTITUÉ, COMPOSITION LE CONTENANT ET UTILISATION ASSOCIÉE<br/>[ZH] 取代的吡唑并[1,5-a]吡啶化合物及包含该化合物的组合物及其用途
  申请人：SHENZHEN TARGETRX INC

  公开号：WO2020114388A1

  公开（公告）日：2020-06-11

  本发明提供了一种取代的吡唑并[1,5-a]吡啶化合物及包含该化合物的组合物及其用途，所述的取代的吡唑并[1,5-a]吡啶化合物如式(I)所示化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物。本发明化合物及其组合物可用于治疗RET激酶介导的疾病或病症且具有更优良的药代动力学性质。
• Development of Alkyne-Containing Pyrazolopyrimidines To Overcome Drug Resistance of Bcr-Abl Kinase
  作者：Xu Liu、Alvin Kung、Brock Malinoski、G. K. Surya Prakash、Chao Zhang

  DOI：10.1021/acs.jmedchem.5b01125

  日期：2015.12.10

  Despite the success of imatinib at inhibiting Bcr-Abl and treating chronic myelogenous leukemia (CML), resistance to the therapy occurs over time in patients. In particular, the resistance to imatinib caused by the gatekeeper mutation T315I in Bcr-Abl remains a challenge in the clinic. Inspired by the successful development of ponatinib to curb drug resistance, we hypothesize that the incorporation of an alkyne linker in other heterocyclic scaffolds can also achieve potent inhibition of Bcr-Abl(T315I) by allowing for simultaneous occupancy of both the active site and the allosteric pocket in the Abl kinase domain. Herein, we describe the design, synthesis, and characterization of a series of alkyne-containing pyrazolopyrimidines as Bcr-Abl inhibitors. Our results demonstrate that some alkyne-containing pyrazolopyrimidines potently inhibit not only Abl(T315I) in vitro but also Bcr-Abl(T315I) in cells. These pyrazolopyrimidines can serve as lead compounds for future development of novel targeted therapy to overcome drug resistance of CML.
• SUBSTITUTED PYRAZOLO[1,5-A]PYRIDINE COMPOUNDS AS RET KINASE INHIBITORS
  申请人：Array Biopharma Inc.

  公开号：EP3523301B1

  公开（公告）日：2020-05-27