4-amino-N-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxamide | 1308400-45-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-amino-N-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxamide
• 英文别名: 4-amino-N-[4-(morpholin-4-ylmethyl)phenyl]-1H-pyrazole-5-carboxamide
• CAS: 1308400-45-4
• 化学式: C₁₅H₁₉N₅O₂
• 分子量: 301.348
• InChiKey: DJQUHVQRGHPWHU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  96.3
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-amino-N-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxamide 、 4-氯噻吩并[3,2-d]嘧啶 生成 4-(4-thieno[3,2-d]pyrimidinylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide
  参考文献：
  名称：

  Polycyclic Substituted Pyrazole Kinase Activity Inhibitors and Use Thereof

  摘要：

  本发明涉及药物化学领域，特别涉及4-（五元杂环嘧啶/吡啶取代）氨基-1H-3-吡唑羧酰胺衍生物，其制备方法，含有这些化合物的制药组合物以及它们的药用，特别是作为蛋白激酶抑制剂用于抗肿瘤。

  公开号：

  US20150368259A1
• 作为产物：
  描述：

  4-吗啉甲基苯胺 在 FeO(OH)/C 、 1-羟基苯并三唑 、 一水合肼 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 4-amino-N-(4-(morpholinomethyl)phenyl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  Novel 1<i>H</i>-Pyrazole-3-carboxamide Derivatives: Synthesis, Anticancer Evaluation and Identification of Their DNA-Binding Interaction

  摘要：

  合成了四种新型 1H-吡唑-3-甲酰胺衍生物，并研究了它们对癌细胞的抗增殖作用、激酶抑制作用，特别是 DNA 结合相互作用，以解释抗肿瘤机制。开发了 DNA 小沟结合模型，并预测了化合物的结合能。与预测一致，在生理条件下通过电子吸收光谱测定了化合物的结合能力，并通过粘度测量进一步验证。一种化合物 5-(3-环丙基脲基)-N-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-1-H-吡唑-3-甲酰胺 (pym-5) 具有最高的 DNA 结合能力亲和力（Kpym-5=1.06×105 M−1）。结果表明，荧光光谱中溴化乙锭-小牛胸腺 DNA (EB-CT-DNA) 复合物的发射强度降低了 50% 以上，表明 pym-5 可以强烈影响 DNA 构象。此外，在 pBR322 DNA 切割测定中，pym-5 对超螺旋质粒 pBR322 DNA 显示出切割活性。我们的研究表明 DNA 可能作为这些吡唑衍生物的潜在靶标。

  DOI：

  10.1248/cpb.c13-00676

文献信息

• 4-(脂肪环并嘧啶/吡啶取代)氨基-1H-3-吡唑甲酰胺类FLT3抑制剂及其用途
  申请人：中国药科大学

  公开号：CN109970717B

  公开（公告）日：2022-10-18

  本发明涉及一种4‑(饱和脂肪环并嘧啶/吡啶取代)氨基‑1H‑3‑吡唑甲酰胺类FLT3抑制剂及其用途或其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物或前药，他们的制备方法，包括含此类化合物的药用组合物、以及它们的医疗用途。
• [EN] POLYCYCLIC SUBSTITUTED PYRAZOLE KINASE ACTIVITY INHIBITORS AND USE THEREOF<br/>[FR] INHIBITEURS DE L'ACTIVITÉ DE LA PYRAZOLE KINASE POLYCYCLIQUE SUBSTITUÉE ET LEUR UTILISATION
  申请人：UNIV CHINA PHARMA

  公开号：WO2014108053A1

  公开（公告）日：2014-07-17

  本发明涉及药物化学领域，具体涉及4-（五元杂环并嘧啶/吡啶取代）氨基-1H-3-吡唑甲酰胺类衍生物、它们的制备方法、含有这些化合物的药用组合物以及它们的医疗用途，特别是作为蛋白激酶抑制剂的抗肿瘤用途。
• Discovery of the selective and efficacious inhibitors of FLT3 mutations
  作者：Yanle Zhi、Baoquan Li、Chao Yao、Hongmei Li、Puzhou Chen、Jiyin Bao、Tianren Qin、Yue Wang、Tao Lu、Shuai Lu

  DOI：10.1016/j.ejmech.2018.06.010

  日期：2018.7

  Fms-like tyrosine kinase 3 (FLT3) is among the most frequently mutated protein in acute myeloid leukemia (AML), which has been confirmed as an important drug target for AML chemotherapy. Starting from the lead compound LT-106-175, a series of 1-H-pyrazole-3-carboxamide derivatives were synthesized to improve the FLT3 inhibitory potency and selectivity. Among them, compound 50 was identified as a highly potent and selective FLT3 inhibitor (IC50 = 0.213 nM), which showed equal activities against various mutants of FLT3 including FLT3 (ITD)-D835V and FLT3 (ITD)-F691L that is resistant to quizartinib. Compound 50 also exhibited efficacy against the human AML cell line MV4-11 (IC50 = 16.1 nM) harboring FLT3-ITD mutants. Inversely, compound 50 displayed no cytotoxicity to FLT3-independent cells, and the biochemical analyses showed that its effects were related to the inhibition of FLT3 signal pathways. Additionally, compound 50 induced apoptosis in MV4-11 cell as demonstrated by flow cytometry. Moreover, compound 50 showed enhanced metabolic stability. Altogether, it was concluded that compound 50 could be a promising FLT3 inhibitor for further developing therapeutic remedy of AML (C) 2018 Elsevier Masson SAS. All rights reserved.
• Discovery of 4-((7<i>H</i>-Pyrrolo[2,3-<i>d</i>]pyrimidin-4-yl)amino)-<i>N</i>-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1<i>H</i>-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia
  作者：Yue Wang、Yanle Zhi、Qiaomei Jin、Shuai Lu、Guowu Lin、Haoliang Yuan、Taotao Yang、Zhanwei Wang、Chao Yao、Jun Ling、Hao Guo、Tonghui Li、Jianlin Jin、Baoquan Li、Li Zhang、Yadong Chen、Tao Lu

  DOI：10.1021/acs.jmedchem.7b01261

  日期：2018.2.22

  A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC50 values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC50: 0.008 mu M), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD50: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.
• POLYCYCLIC SUBSTITUTED PYRAZOLE KINASE ACTIVITY INHIBITORS AND USE THEREOF
  申请人：Shanghai Fosun Pharmaceutical Development Co., Ltd.

  公开号：EP2955185B1

  公开（公告）日：2021-01-06