5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-amine | 501902-76-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并二恶烷
• 英文名称: 5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-amine
• CAS: 501902-76-7
• 化学式: C₁₁H₁₁N₃O₂
• mdl: MFCD02664129
• 分子量: 217.227
• InChiKey: UYDKYVDCSQWKNF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.181
• 拓扑面积：
  73.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-amine 、 苯基(3-(叔-丁基)-1-(P-甲苯基)-1H-吡唑-5-基)氨基甲酯 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 生成 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]urea
  参考文献：
  名称：

  Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors

  摘要：

  Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.039
• 作为产物：
  描述：

  苯并二氧六环-6-甲酸甲酯 在 sodium hydride 、 一水合肼 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 11.0h， 生成 5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-amine
  参考文献：
  名称：

  Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model

  摘要：

  FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV411 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.05.021

文献信息

• Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model
  作者：Hao Heng、Zhijie Wang、Hongmei Li、Yatian Huang、Qingyuan Lan、Xiaoxing Guo、Liang Zhang、Yanle Zhi、Jiongheng Cai、Tianren Qin、Li Xiang、Shuxian Wang、Yadong Chen、Tao Lu、Shuai Lu

  DOI：10.1016/j.ejmech.2019.05.021

  日期：2019.8

  FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV411 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML (C) 2019 Elsevier Masson SAS. All rights reserved.
• Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors
  作者：Samit K. Bhattacharya、Gary E. Aspnes、Scott W. Bagley、Markus Boehm、Arthur D. Brosius、Leonard Buckbinder、Jeanne S. Chang、Joseph Dibrino、Heather Eng、Kosea S. Frederick、David A. Griffith、Matthew C. Griffor、Cristiano R.W. Guimarães、Angel Guzman-Perez、Seungil Han、Amit S. Kalgutkar、Jacquelyn Klug-McLeod、Carmen Garcia-Irizarry、Jianke Li、Blaise Lippa、David A. Price、James A. Southers、Daniel P. Walker、Liuqing Wei、Jun Xiao、Michael P. Zawistoski、Xumiao Zhao

  DOI：10.1016/j.bmcl.2012.10.039

  日期：2012.12

  Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.