N-tert-butyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine | 1401345-76-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-tert-butyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine
• 英文别名: N-tert-butyl-5-[3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl]-1,3,4-oxadiazol-2-amine
• CAS: 1401345-76-3
• 化学式: C₂₁H₂₂N₆O
• 分子量: 374.445
• InChiKey: BQKBRLMFCCUJQA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  92.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-iodo-1-tosyl-1H-indole-5-carbohydrazide 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium acetate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.75h， 生成 N-tert-butyl-5-(3-(4-cyclopropylpyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine
  参考文献：
  名称：

  The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors

  摘要：

  High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (K-i values of 0.55 nM and 0.28 nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50 = 150 nM). This compound had moderate clearance and bioavailability in rat (CL = 2.42 L/kg/h; %F = 24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74 mu M (18 mu g/mL) when dosed at 10, 30, 100 and 200 mg/kg po in mice. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.12.067

文献信息

• [EN] AZOLE COMPOUNDS AS PIM INHIBITORS<br/>[FR] COMPOSÉS D'AZOLE UTILISÉS EN TANT QU'INHIBITEURS DES PIM
  申请人：AMGEN INC

  公开号：WO2012129338A1

  公开（公告）日：2012-09-27

  The invention relates to bicyclic compounds of formulas I and Ia, and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.

  该发明涉及公式I和Ia的双环化合物及其盐。在某些实施例中，该发明涉及Pim-1和/或Pim-2和/或Pim-3蛋白激酶活性或酶功能的抑制剂或调节剂。在更进一步的实施例中，该发明涉及包含本文所披露的化合物的药物组合物，以及它们在预防和治疗Pim激酶相关疾病和病症，尤其是癌症中的用途。
• Azole Compounds as PIM Inhibitors
  申请人：Wang Hui-Ling

  公开号：US20140187553A1

  公开（公告）日：2014-07-03

  The invention relates to bicyclic compounds of formulas I and Ia, and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.

  本发明涉及式I和Ia及其盐的双环化合物。在某些实施例中，本发明涉及Pim-1和/或Pim-2以及/或Pim-3蛋白激酶活性或酶功能的抑制剂或调节剂。在更进一步的实施例中，本发明涉及包含本文所披露的化合物的制药组合物及其在预防和治疗Pim激酶相关疾病和条件，优选为癌症中的应用。
• US9321756B2
  申请人：——

  公开号：US9321756B2

  公开（公告）日：2016-04-26
• The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors
  作者：Ryan P. Wurz、Liping H. Pettus、Claire Jackson、Bin Wu、Hui-Ling Wang、Brad Herberich、Victor Cee、Brian A. Lanman、Anthony B. Reed、Frank Chavez、Thomas Nixey、Jimmy Laszlo、Paul Wang、Yen Nguyen、Christine Sastri、Nadia Guerrero、Jeff Winston、J. Russell Lipford、Matthew R. Lee、Kristin L. Andrews、Christopher Mohr、Yang Xu、Yihong Zhou、Darren L. Reid、Andrew S. Tasker

  DOI：10.1016/j.bmcl.2014.12.067

  日期：2015.2

  High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (K-i values of 0.55 nM and 0.28 nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50 = 150 nM). This compound had moderate clearance and bioavailability in rat (CL = 2.42 L/kg/h; %F = 24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74 mu M (18 mu g/mL) when dosed at 10, 30, 100 and 200 mg/kg po in mice. (C) 2015 Elsevier Ltd. All rights reserved.