4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde oxime

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde oxime
• 英文别名: N-[(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)methylidene]hydroxylamine
• 化学式: C₉H₁₂N₆O
• 分子量: 220.234
• InChiKey: JAHRWOGKTCQYGO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde oxime 在 cesium fluoride 、 [双(三氟乙酰氧基)碘]苯 作用下， 以 甲醇 、 乙醇 、 水 、 乙腈 为溶剂， 反应 6.5h， 生成 1-isopropyl-3-(isoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants

  摘要：

  Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.

  DOI：

  10.1021/acs.jmedchem.5b01522
• 作为产物：
  描述：

  3-溴-1H-吡唑并[3,4-D]嘧啶-4-胺 在 sodium periodate 、 四氧化锇 、 四(三苯基膦)钯 、 盐酸羟胺 、 sodium acetate 、 potassium carbonate 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 27.0h， 生成 4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde oxime
  参考文献：
  名称：

  A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants

  摘要：

  Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.

  DOI：

  10.1021/acs.jmedchem.5b01522

文献信息

• Synthesis and structure–activity relationship study of pyrazolo[3,4- d ]pyrimidines as tyrosine kinase RET inhibitors
  作者：Chengyan Wang、Hongchun Liu、Zilan Song、Yinchun Ji、Li Xing、Xia Peng、Xisheng Wang、Jing Ai、Meiyu Geng、Ao Zhang

  DOI：10.1016/j.bmcl.2017.03.088

  日期：2017.6

  Three series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized and evaluated as RET kinase inhibitors. Compounds 23a and 23c were identified to show significant activity both in the biochemical and the BaF3/CCDC6-RET cell assays. Compound 23c was found to significantly inhibit RET phosphorylation and down-stream signaling in BaF3/CCDC6-RET cells, confirming its potent cellular RET-targeting

  合成了三个系列的吡唑并[3,4-d]嘧啶衍生物，并作为RET激酶抑制剂进行了评估。化合物23a和23c在生化和BaF3 / CCDC6-RET细胞分析中均显示出显着活性。发现化合物23c在BaF3 / CCDC6-RET细胞中显着抑制RET磷酸化和下游信号传导，从而证实了其有效的细胞RET靶向特性。与具有严重毒性相关的对KDR具有相同效力的其他RET抑制剂不同，23c即使在1μM的浓度下也没有显示出显着的KDR抑制作用。这些结果证明23c是有效且选择性的RET抑制剂。
• [EN] SUBSTITUTED PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS AS RET KINASE INHIBITORS<br/>[FR] COMPOSÉS DE PYRAZOLO[3,4-D]PYRIMIDINE SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA KINASE RET
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2019143991A1

  公开（公告）日：2019-07-25

  Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R1 and R2 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.

  本文提供的是Formula I的化合物，以及其互变异构体和药学上可接受的盐和溶剂化合物，其中R1和R2具有规范中给定的含义，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，包括与RET相关的疾病和疾病。
• Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
  申请人：Array Biopharma Inc.

  公开号：US11524963B2

  公开（公告）日：2022-12-13

  Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R 1 and R 2 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.

  本文提供了式 I 的化合物：及其同系物和药学上可接受的盐和溶剂，其中 R 1 和 R 2 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用 RET 激酶抑制剂治疗的疾病，包括 RET 相关疾病和紊乱。
• SUBSTITUTED PYRAZOLO[3,4-D]PYRIMIDINE COMPOUNDS AS RET KINASE INHIBITORS
  申请人：Array Biopharma, Inc.

  公开号：EP3740490A1

  公开（公告）日：2020-11-25
• SUBSTITUTED PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS AS RET KINASE INHIBITORS
  申请人：Array Biopharma Inc.

  公开号：US20200399279A1

  公开（公告）日：2020-12-24

  Provided herein are compounds of the Formula I: and tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R 1 and R 2 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.