5-(6-(1-(ethylsulfonyl)cyclopropyl)-2-morpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 5-(6-(1-(ethylsulfonyl)cyclopropyl)-2-morpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine
• 英文别名: 5-[6-(1-Ethylsulfonylcyclopropyl)-2-morpholin-4-ylpyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine；5-[6-(1-ethylsulfonylcyclopropyl)-2-morpholin-4-ylpyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine
• 化学式: C₁₉H₂₂F₃N₅O₃S
• 分子量: 457.477
• InChiKey: BFOJWDLBRDOUDA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  2,6-二氯嘧啶-4-甲酸甲酯 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium tetrahydroborate 、 四丁基碘化铵 、 sodium hydride 、 sodium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 5-(6-(1-(ethylsulfonyl)cyclopropyl)-2-morpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine
  参考文献：
  名称：

  Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines

  摘要：

  The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C-4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3K alpha/beta/gamma/delta (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50= 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C-4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

  DOI：

  10.1021/acsmedchemlett.8b00167

文献信息

• 2-morpholin-4,6-disubstituted pyrimidine derivative, and preparation method and pharmaceutical use thereof
  申请人：Shanghai Haiyan Pharmaceutical Technology Co., Ltd.

  公开号：US10227324B2

  公开（公告）日：2019-03-12

  Disclosed is a 2-morpholin-4,6-disubstituted pyrimidine derivative as shown in formula (1) below, and a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutical composition thereof and a use thereof, wherein the definition of each group is as shown in the description. The compound has a PI3K kinase inhibition activity, and has a relatively high inhibitive ability and a low cytotoxicity against PIK3CA mutant breast cancer cell strains T47D and MCF-7.

  公开了一种如下式（1）所示的2-吗啉-4,6-二取代嘧啶衍生物及其药学上可接受的盐、溶液剂、立体异构体或原药，以及其药物组合物及其用途，其中各基团的定义如说明书所示。该化合物具有 PI3K 激酶抑制活性，对 PIK3CA 突变乳腺癌细胞株 T47D 和 MCF-7 具有相对较高的抑制能力和较低的细胞毒性。
• [EN] 2-MORPHOLIN-4,6-DISUBSTITUTED PYRIMIDINE DERIVATIVE, AND PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF<br/>[FR] DÉRIVÉ DE PYRIMIDINE DISUBSTITUÉ EN 2-MORPHOLIN-4,6 ET PROCÉDÉ DE PRÉPARATION ET UTILISATION PHARMACEUTIQUE ASSOCIÉS<br/>[ZH] 2-吗啉-4,6-二取代的嘧啶衍生物、其制法与医药上的用途
  申请人：SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY CO LTD

  公开号：WO2016095833A1

  公开（公告）日：2016-06-23

  一种如下式(I)所示的2-吗啉-4,6-二取代的嘧啶衍生物、其药学上可接受的盐、溶剂化物、立体异构体或其前药，其药物组合物及其应用，其中各基团定义如说明书中所示。所述化合物具有PI3K激酶抑制活性，对PIK3CA突变型乳腺癌细胞株T47D和MCF-7具有较高的抑制性和低细胞毒性。
• 2-MORPHOLIN-4,6-DISUBSTITUTED PYRIMIDINE DERIVATIVE, AND PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF
  申请人：Shanghai Haiyan Pharmaceutical Technology Co., Ltd.

  公开号：EP3235816B1

  公开（公告）日：2020-02-12
• Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines
  作者：Sida Shen、Xiangyu He、Zheng Yang、Liang Zhang、Yingtao Liu、Zhiyuan Zhang、Weiwei Wang、Wei Liu、Yufeng Li、Dong Huang、Kai Sun、Xiaojing Ni、Xu Yang、Xinxin Chu、Yumin Cui、Qiang Lv、Jiong Lan、Fusheng Zhou

  DOI：10.1021/acsmedchemlett.8b00167

  日期：2018.7.12

  The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C-4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3K alpha/beta/gamma/delta (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50= 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C-4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.