N2-(6-chloro-2-methyl-4-pyrimidinyl)-5-(4-aminophenyl)-1,3-thiazol-2-amine | 1395052-25-1

• 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: N2-(6-chloro-2-methyl-4-pyrimidinyl)-5-(4-aminophenyl)-1,3-thiazol-2-amine
• 英文别名: N-[5-(4-aminophenyl)-1,3-thiazol-2-yl]-6-chloro-2-methylpyrimidin-4-amine；5-(4-aminophenyl)-N-(6-chloro-2-methylpyrimidin-4-yl)-1,3-thiazol-2-amine
• CAS: 1395052-25-1
• 化学式: C₁₄H₁₂ClN₅S
• 分子量: 317.802
• InChiKey: MCIHXRYFLDYLIE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N2-(6-chloro-2-methyl-4-pyrimidinyl)-5-(4-aminophenyl)-1,3-thiazol-2-amine 在 吡啶 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.5h， 生成 N-[4-(2-[6-(3-aminotetrahydro-1H-1-pyrrolyl)-2-methyl-4-pyrimidinyl]amino-1,3-thiazol-5-yl)phenyl]-N′-(5-ethyl-3-isoxazolyl)urea dihydrochloride
  参考文献：
  名称：

  Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations

  摘要：

  Numerous FLT3 inhibitors have been explored as a viable therapy for the treatment of acute myeloid leukemia (AML). However, clinical data have been underwhelming due to incomplete inhibition of FLT3 or the emergence of resistant mutations treated with these older agents. We previously developed a series of 3-phenyl-1H-5-pyrazolylamine derivatives as highly potent and selective FLT3 inhibitors with good in vivo efficacy using an intravenous (IV) route. However, the poor bioavailability of these pyrazole compounds limits the development of these promising antileukemic compounds for clinical use. Herein, we describe a novel class of 5-phenyl-thiazol-2-ylamine compounds that are multi-targeted FLT3 inhibitors. From this class of compounds, compound 7h was very potent against AML cell lines and exhibited excellent oral efficacy in AML xenograft models. In addition, further studies demonstrated that compound 7h exhibited potent in vitro and in vivo activities against clinically relevant AC220 (3)-resistant kinase domain mutants of FLT3-ITD. (C) 2015 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2015.05.008
• 作为产物：
  描述：

  4,6-二氯-2-甲基嘧啶 、 5-(4-aminophenyl)-1,3-thiazol-2-amine 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 1.5h， 生成 N2-(6-chloro-2-methyl-4-pyrimidinyl)-5-(4-aminophenyl)-1,3-thiazol-2-amine
  参考文献：
  名称：

  PYRAZOLE COMPOUNDS AND THIAZOLE COMPOUNDS AS PROTEIN KINASES INHIBITORS

  摘要：

  其中A、B、D、X、Y、R1、R2、R3、m、p和q的化合物的化学式（I）： 还公开了一种抑制FMS样酪氨酸激酶3、极光激酶或血管内皮生长因子受体的方法。

  公开号：

  US20120225880A1

文献信息

• PYRAZOLE COMPOUNDS AND THIAZOLE COMPOUNDS AS PROTEIN KINASES INHIBITORS
  申请人：Jiaang Weir-Torn

  公开号：US20120225880A1

  公开（公告）日：2012-09-06

  A compound of formula (I): wherein A, B, D, X, Y, R 1 , R 2 , R 3 , m, p, and q are defined herein. Also disclosed is a method for inhibiting FMS-like tyrosine kinase 3, aurora kinase, or vascular endothelial growth factor receptor.

  其中A、B、D、X、Y、R1、R2、R3、m、p和q的化合物的化学式（I）： 还公开了一种抑制FMS样酪氨酸激酶3、极光激酶或血管内皮生长因子受体的方法。
• US9255072B2
  申请人：——

  公开号：US9255072B2

  公开（公告）日：2016-02-09
• Identification of a potent 5-phenyl-thiazol-2-ylamine-based inhibitor of FLT3 with activity against drug resistance-conferring point mutations
  作者：Chiung-Tong Chen、John T.-A. Hsu、Wen-Hsing Lin、Cheng-Tai Lu、Shih-Chieh Yen、Tsu Hsu、Yu-Ling Huang、Jen-Shin Song、Chun-Hwa Chen、Ling-Hui Chou、Kuei-Jung Yen、Ching-Ping Chen、Po-Chu Kuo、Chen-Lung Huang、H. Eugene Liu、Yu-Sheng Chao、Teng-Kuang Yeh、Weir-Torn Jiaang

  DOI：10.1016/j.ejmech.2015.05.008

  日期：2015.7

  Numerous FLT3 inhibitors have been explored as a viable therapy for the treatment of acute myeloid leukemia (AML). However, clinical data have been underwhelming due to incomplete inhibition of FLT3 or the emergence of resistant mutations treated with these older agents. We previously developed a series of 3-phenyl-1H-5-pyrazolylamine derivatives as highly potent and selective FLT3 inhibitors with good in vivo efficacy using an intravenous (IV) route. However, the poor bioavailability of these pyrazole compounds limits the development of these promising antileukemic compounds for clinical use. Herein, we describe a novel class of 5-phenyl-thiazol-2-ylamine compounds that are multi-targeted FLT3 inhibitors. From this class of compounds, compound 7h was very potent against AML cell lines and exhibited excellent oral efficacy in AML xenograft models. In addition, further studies demonstrated that compound 7h exhibited potent in vitro and in vivo activities against clinically relevant AC220 (3)-resistant kinase domain mutants of FLT3-ITD. (C) 2015 Published by Elsevier Masson SAS.
• Discovery of Conformational Control Inhibitors Switching off the Activated c-KIT and Targeting a Broad Range of Clinically Relevant c-KIT Mutants
  作者：Tsung-Sheng Wu、Wen-Hsing Lin、Hui-Jen Tsai、Ching-Cheng Hsueh、Tsu Hsu、Pei-Chen Wang、Hui-You Lin、Yi-Hui Peng、Cheng-Tai Lu、Lung-Chun Lee、Chih-Hsiang Tu、Fang-Chun Kung、Hui-Yi Shiao、Teng-Kuang Yeh、Jen-Shin Song、Jia-Yu Chang、Yu-Chieh Su、Li-Tzong Chen、Chiung-Tong Chen、Weir-Torn Jiaang、Su-Ying Wu

  DOI：10.1021/acs.jmedchem.8b01845

  日期：2019.4.25

  Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, alpha C-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.