2-氨基-4-氯-6-(1-哌啶)嘧啶 | 104637-64-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 2-氨基-4-氯-6-(1-哌啶)嘧啶
• 英文名称: 2-amino-4-chloro-6-piperidinopyrimidine
• 英文别名: 4-chloro-6-(piperidin-1-yl)pyrimidin-2-amine；4-chloro-6-(1-piperidinyl)-2-pyrimidinamine；4-Chloro-6-piperidin-1-yl-pyrimidin-2-ylamine；4-chloro-6-piperidin-1-ylpyrimidin-2-amine
• CAS: 104637-64-1
• 化学式: C₉H₁₃ClN₄
• 分子量: 212.682
• InChiKey: XXWWICKWOHZSQJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  55
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi

反应信息

• 作为反应物：
  描述：

  2-氨基-4-氯-6-(1-哌啶)嘧啶 在 四(三苯基膦)钯 、 碳酸氢钠 、 一水合肼 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 6.0h， 生成 6-[2-amino-6-(1-piperidinyl)-4-pyrimidinyl]-1H-indazol-3-amine
  参考文献：
  名称：

  Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

  摘要：

  Phosphoinositide-dependent protein kinase-1 (PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDKI might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDKI inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OC1-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDKI and the potential pharmacological uses of a PDK1 inhibitor.

  DOI：

  10.1021/jm101527u
• 作为产物：
  描述：

  哌啶 、 2-氨基-4,6-二氯嘧啶 在 N,N-二异丙基乙胺 作用下， 以 正丁醇 为溶剂， 生成 2-氨基-4-氯-6-(1-哌啶)嘧啶
  参考文献：
  名称：

  探索氨基甲酰胺衍生的嘧啶-硫代吲哚偶联物作为潜在的具有抑制血管生成作用的VEGFR-2抑制剂。

  摘要：

  通过分子杂交从已知结构基序开发新的小分子是药物发现的趋势之一。在这方面，我们通过分子杂交策略将两个药效基团（嘧啶和硫代吲哚）结合在一个实体中，并在嘧啶的C2位置引入尿素官能团以提高H键相互作用的效率。在合成的缀合物12a-aa中，发现化合物12k对MDA-MB-231（乳腺癌），HepG2（肝），A549（肺）和PC-3（前列腺）的IC50值分别为5.85、7.87、6.41和10.43μM。 ）癌细胞系。进一步评估所有这些化合物对VEGFR-2蛋白的抑制活性。结果表明，在测试化合物中，12d，12e，12k，12l，12p，12q，12t和12u显着抑制了VEGFR-2，IC50值为310-920 nM，与阳性对照（210 nM）相关。HUVECs中的管形成分析显着抑制了血管生成，transwell分析则显着抑制了细胞侵袭。通过线粒体膜电位去极化，ROS产生增加和随后的DNA损伤导致凋亡

  DOI：

  10.1016/j.ejmech.2020.112457

文献信息

• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSÉS CHIMIQUES
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2010120854A1

  公开（公告）日：2010-10-21

  The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及取代吲唑衍生物。具体而言，本发明涉及根据公式I的化合物：其中R1-R6和X在此定义。本发明的化合物是PDK1的抑制剂，可用于治疗由组成性激活的ACG激酶（如癌症，特别是白血病、乳腺癌、结肠癌和肺癌）引起的疾病。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还进一步涉及使用本发明化合物或包含本发明化合物的药物组合物来抑制PDK1活性和治疗相关疾病的方法。
• Hit-to-Lead Optimization of Benzoxazepinoindazoles As Human African Trypanosomiasis Therapeutics
  作者：Dana M. Klug、Laura Tschiegg、Rosario Diaz、Domingo Rojas-Barros、Guiomar Perez-Moreno、Gloria Ceballos、Raquel García-Hernández、Maria Santos Martinez-Martinez、Pilar Manzano、Luis Miguel Ruiz、Conor R. Caffrey、Francisco Gamarro、Dolores Gonzalez Pacanowska、Lori Ferrins、Miguel Navarro、Michael P. Pollastri

  DOI：10.1021/acs.jmedchem.9b01506

  日期：2020.3.12

  Human African trypanosomiasis (HAT) is a neglected tropical disease caused by infection with either of two subspecies of the parasite Trypanosoma brucei. Due to a lack of economic incentive to develop new drugs, current treatments have severe limitations in terms of safety, efficacy, and ease of administration. In an effort to develop new HAT therapeutics, we report the structure–activity relationships

  非洲人类锥虫病 (HAT) 是一种被忽视的热带疾病，由感染布氏锥虫的两个亚种中的任何一个引起。由于缺乏开发新药的经济动力，目前的治疗方法在安全性、有效性和易于给药方面存在严重限制。为了开发新的 HAT 疗法，我们报告了先前通过人类激酶抑制剂的高通量筛选以及随后的 HAT体内实验确定的一系列苯并恶氮杂吲唑在布氏木虱周围的构效关系。我们确定了化合物18，它显示出改进的激酶选择性特征和可接受的药代动力学参数，作为一个有希望的先导。尽管在 HAT 全身模型中用18只小鼠治愈了 60% 的小鼠，但该化合物无法清除该疾病的 CNS 模型中的寄生虫血症。我们还报告了针对T. cruzi、L. donovani和S. mansoni交叉筛选这些化合物的结果。
• CHEMICAL COMPOUNDS
  申请人：Axten Jeffrey Michael

  公开号：US20110275611A1

  公开（公告）日：2011-11-10

  The invention is directed to 6-(4-pyrimidinyl)-1H-indazole derivatives. Specifically, the invention is directed to compounds according to Formula (I) wherein R 1 -R 4 are defined herein. The compounds of the invention axe inhibitors of PDK1 and can be useful in the treatment of immune and metabolic diseases and disorders characterized by constitutively activated ACG kinases such as cancer and more specifically cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention

  本发明涉及6-(4-嘧啶基)-1H-吲唑衍生物。具体而言，本发明涉及公式（I）中R1-R4所定义的化合物。本发明的化合物是PDK1的抑制剂，可用于治疗免疫和代谢性疾病和障碍，这些疾病和障碍以恒定激活的ACG激酶为特征，例如乳腺、结肠和肺癌等。因此，本发明还涉及包含本发明化合物的制药组合物。本发明还涉及使用本发明化合物或包含本发明化合物的制药组合物抑制PDK1活性和治疗相关障碍的方法。
• Chemical compounds
  申请人：Axten Jeffrey Michael

  公开号：US08697685B2

  公开（公告）日：2014-04-15

  The invention is directed to 6-(4-pyrimidinyl)-1H-indazole derivatives. Specifically, the invention is directed to compounds according to Formula (I) wherein R1-R4 are defined herein. The compounds of the invention axe inhibitors of PDK1 and can be useful in the treatment of immune and metabolic diseases and disorders characterized by constitutively activated ACG kinases such as cancer and more specifically cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

  本发明涉及6-(4-嘧啶基)-1H-吲唑衍生物。具体而言，本发明涉及公式(I)中R1-R4所定义的化合物。本发明的化合物是PDK1的抑制剂，可用于治疗免疫和代谢性疾病和障碍，这些疾病和障碍以恒定激活的ACG激酶为特征，例如乳腺癌、结肠癌和肺癌等癌症。因此，本发明进一步涉及包括本发明化合物的药物组合物。本发明还涉及使用本发明化合物或包括本发明化合物的药物组合物来抑制PDK1活性和治疗与之相关的疾病的方法。
• Two polymorphs, with<i>Z</i>′ = 1 and 2, of 2-amino-4-chloro-6-morpholinopyrimidine in<i>P</i>2₁/<i>c</i>, and 2-amino-4-chloro-6-piperidinopyrimidine, which is isomorphous and almost isostructural with the<i>Z</i>′ = 2 polymorph
  作者：Katharine F. Bowes、Christopher Glidewell、John N. Low、Manuel Melguizo、Antonio Quesada

  DOI：10.1107/s0108270102020012

  日期：2003.1.15

  Crystallization of 2-amino-4-chloro-6-morpholinopyrimidine, C8H11ClN4O, (I), yields two polymorphs, both with space group P2(1)/c, having Z' = 1 (from diethyl ether solution) and Z' = 2 (from dichloromethane solution), denoted (Ia) and (Ib), respectively. In polymorph (Ia), the molecules are linked by an N-H...O and an N-H...N hydrogen bond into sheets built from alternating R-2(2) (8) and R-6(6) (40) rings. In polymorph (Ib), one molecule acts as a triple acceptor of hydrogen bonds and the other acts as a single acceptor; one N-H...O and three N-H...N hydrogen bonds link the molecules in a complex chain containing two types of R-2(2) (8) and one type of R-4(4) (18) ring. 2-Amino-4-chloro-6-piperidinopyrimidine, C9H13ClN4, (II), which is isomorphous with polymorph (Ib), also has Z' = 2 in P2(1)/c, and the molecules are linked by three N-H...N hydrogen bonds into a centrosymmetric four-molecule aggregate containing three R-2(2) (8) rings.