3-氨基-6,6-二甲基-4,6-二氢吡咯并[3,4-C]吡唑-5(2H)-羧酸叔丁酯 | 718632-44-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡唑类
• 中文名称: 3-氨基-6,6-二甲基-4,6-二氢吡咯并[3,4-C]吡唑-5(2H)-羧酸叔丁酯
• 英文名称: tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
• 英文别名: tert-butyl 3-amino-6,6-dimethyl-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate
• CAS: 718632-44-1
• 化学式: C₁₂H₂₀N₄O₂
• 分子量: 252.316
• InChiKey: XOQXOJPUZGHMLL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  84.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-氨基-6,6-二甲基-4,6-二氢吡咯并[3,4-C]吡唑-5(2H)-羧酸叔丁酯 在 盐酸 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 20.0h， 以98%的产率得到6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-aminedihydrochloride
  参考文献：
  名称：

  2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships

  摘要：

  Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.03.021
• 作为产物：
  描述：

  二碳酸二叔丁酯 在 potassium tert-butylate 、 四甲基氢氧化铵 、 potassium hydrogencarbonate 、 溶剂黄146 、 肼 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 64.0h， 生成 3-氨基-6,6-二甲基-4,6-二氢吡咯并[3,4-C]吡唑-5(2H)-羧酸叔丁酯
  参考文献：
  名称：

  2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships

  摘要：

  Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10-100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.03.021

文献信息

• Design, synthesis, biological evaluation and pharmacophore model analysis of novel tetrahydropyrrolo[3,4-c]pyrazol derivatives as potential TRKs inhibitors
  作者：Tianxiao Wu、Chu Zhang、Ruicheng Lv、Qiaohua Qin、Nian Liu、Wenbo Yin、Ruifeng Wang、Yin Sun、Xiaoyan Wang、Yixiang Sun、Dongmei Zhao、Maosheng Cheng

  DOI：10.1016/j.ejmech.2021.113627

  日期：2021.11

  indicate that compound 19m has a good drug safety. Partial ADME properties were evaluated in vitro and in vivo. Compound 19m exhibited a good AUC values and volume of distribution and low clearance in the pharmacokinetics experiment of rats. Finally, a pharmacophore model guided by experimental results is proposed. We hope this theoretical model can help researchers find type I TRK inhibitors more efficiently

  原肌球蛋白受体激酶 TRK 负责由NTRK基因融合引起的不同肿瘤类型，并已被确定为抗癌治疗的成功靶点。在此，我们通过合理的药物设计策略，从微摩尔效力的17a中报道了一种有效的选择性 TRKs 抑制剂19m 。化合物19m显着抑制TRK依赖性细胞系(Km-12)的增殖，而对TRK非依赖性细胞系(A549和THLE-2)没有抑制作用。此外，激酶选择性分析表明，除了TRK之外，化合物19m仅对ALK表现出较强的抑制活性。这些数据可能表明化合物19m具有良好的用药安全性。部分 ADME 特性在体外和体内进行了评估。化合物19m在大鼠药代动力学实验中表现出良好的AUC值和分布容积以及较低的清除率。最后，提出了以实验结果为指导的药效团模型。我们希望这个理论模型能够帮助研究人员更有效地寻找I型TRK抑制剂。
• [EN] TETRAAZA-CYCLOPENTA[A]INDENYL AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS<br/>[FR] TÉTRAAZA-CYCLOPENTA[A]INDÉNYLE ET LEUR UTILISATION EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS
  申请人：MERCK PATENT GMBH

  公开号：WO2013091773A1

  公开（公告）日：2013-06-27

  The present invention provides compounds of Formula (I) as M1 receptor positive allosteric modulators for the treatment of diseases mediated by the muscarinic M1 mediator.

  本发明提供了式(I)化合物，作为M1受体阳性异构调节剂，用于治疗由毒蕈碱M1介质介导的疾病。
• Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
  申请人：——

  公开号：US20030171357A1

  公开（公告）日：2003-09-11

  Bicyclo-pyrazole compounds of formula (I), as herein defined, are useful for treating diseases linked to disregulated protein kinases.

  Bicyclo-pyrazole化合物的化学式（I），如本文所定义，可用于治疗与失调蛋白激酶相关的疾病。
• Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype
  作者：Calla M. Olson、Yanke Liang、Alan Leggett、Woojun D. Park、Lianbo Li、Caitlin E. Mills、Selma Z. Elsarrag、Scott B. Ficarro、Tinghu Zhang、Robert Düster、Matthias Geyer、Taebo Sim、Jarrod A. Marto、Peter K. Sorger、Ken D. Westover、Charles Y. Lin、Nicholas Kwiatkowski、Nathanael S. Gray

  DOI：10.1016/j.chembiol.2019.02.012

  日期：2019.6

  but its precise role remains elusive. We previously described THZ1, a CDK7 inhibitor, which dramatically inhibits superenhancer-associated gene expression. However, potent CDK12/13 off-target activity obscured CDK7s contribution to this phenotype. Here, we describe the discovery of a highly selective covalent CDK7 inhibitor. YKL-5-124 causes arrest at the G1/S transition and inhibition of E2F-driven

  细胞周期蛋白依赖性激酶7（CDK7）调节细胞周期和转录，但其确切作用仍然难以捉摸。我们先前描述了THZ1，一种CDK7抑制剂，可显着抑制与超增强子相关的基因表达。但是，有效的CDK12 / 13脱靶活性掩盖了CDK7对这种表型的贡献。在这里，我们描述了一种高度选择性的共价CDK7抑制剂的发现。YKL-5-124导致G1 / S转变停滞并抑制E2F驱动的基因表达；这些作用由无法共价参与YKL-5-124的CDK7突变体挽救，证明了靶标特异性。与THZ1不同，用YKL-5-124处理不会导致RNA聚合酶II C末端域磷酸化的改变；但是，可以通过将YKL-5-124和选择性CDK12 / 13抑制剂THZ531结合来重建抑制作用，揭示了CDK控制基因转录中的潜在冗余。这些发现凸显了CDK7 / 12/13多种药理学对THZ1的抗癌活性的重要性，并认为选择性抑制CDK7可能对治疗E2F失调标记的癌症有用。
• Bicyclo-Pyrazoles and Pharmaceutical Compositions Comprising Them
  申请人：Fancelli Daniele

  公开号：US20090221632A1

  公开（公告）日：2009-09-03

  Bicyclo-pyrazole compounds of formula (I), as herein defined, are useful for treating diseases linked to disregulated protein kinases.

  公式（I）所定义的双环吡唑化合物可用于治疗与失调的蛋白激酶相关的疾病。