N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-cyc lohexylpiperazin-1-yl)-4-methoxyphenyl)acrylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-cyc lohexylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
• 英文别名: N-[5-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-(4-cyclohexylpiperazin-1-yl)-4-methoxyphenyl]prop-2-enamide
• 化学式: C₃₃H₄₂ClN₇O₄S
• 分子量: 668.26
• InChiKey: QMJDDWPSSMHPSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  46
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  137
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-(异丙基磺酰基)苯胺 在 铁粉 、 sodium hydride 、 potassium carbonate 、 氯化铵 、 对甲苯磺酸 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 戊醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-cyc lohexylpiperazin-1-yl)-4-methoxyphenyl)acrylamide
  参考文献：
  名称：

  Discovery of N -(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC

  摘要：

  Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy, Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.08.035

文献信息

• [EN] NOVEL EGFR AND ALK DUAL INHIBITOR<br/>[FR] NOUVEAU DOUBLE INHIBITEUR DE EGFR ET DE ALK<br/>[ZH] 一种新型EGFR和ALK激酶的双重抑制剂
  申请人：PRECEDO PHARMACEUTICALS CO LTD

  公开号：WO2017101803A1

  公开（公告）日：2017-06-22

  本申请提供式I化合物，其是EGFR和ALK的双重抑制剂，可以通过单独使用或者与其它治疗剂联合使用的方式用于治疗非小细胞肺癌等疾病。本申请化合物用于治疗携带EGFR野生型基因、或携带EGFR T790M突变基因和/或EGFR L858R突变型基因和/或EGFR delE746_A750突变型基因的疾病，或用于治疗携带ALK野生型基因、或携带ALK F1174L突变型基因和/或ALK F1196M型基因和/或EML4-ALK突变型基因和/或NPM-ALK突变型基因的疾病，并且可用于一线治疗间变性淋巴瘤激酶(ALK)阳性晚期非小细胞肺癌。
• NOVEL EGFR AND ALK DUAL INHIBITOR
  申请人：Precedo Pharmaceuticals Co., Ltd.

  公开号：EP3392245A1

  公开（公告）日：2018-10-24

  The present application provides a compound of formula I, which is a EGFR and ALK dual inhibitor and can be used alone or in combination with other therapeutic agents to treat diseases such as non-small cell lung cancer. The compounds of the present application are useful in the treatment of diseases carrying the EGFR wild-type gene, or carrying the EGFR T790M mutant gene and/or the EGFR L858R mutant gene and/or the EGFR delE746_A750 mutant gene, or in the treatment of diseases carrying the ALK wild-type gene, ALK F1174L mutant gene and/or ALK F1196M gene and/or EML4-ALK mutant gene and/or NPM-ALK mutant gene, and can be used in the first-line treatment of anaplastic lymphoma kinase (ALK) positive late-stage non-small cell Lung cancer.

  本申请提供了一种式I化合物，它是表皮生长因子受体和ALK双重抑制剂，可单独使用或与其他治疗剂联合使用，治疗非小细胞肺癌等疾病。本申请的化合物可用于治疗携带表皮生长因子受体（EGFR）野生型基因的疾病，或携带表皮生长因子受体（EGFR）T790M 突变基因和/或表皮生长因子受体（EGFR）L858R 突变基因和/或表皮生长因子受体（EGFR）delE746_A750 突变基因的疾病，或携带 ALK 野生型基因的疾病、ALK F1174L 突变基因和/或 ALK F1196M 基因和/或 EML4-ALK 突变基因和/或 NPM-ALK 突变基因，并可用于无性淋巴瘤激酶（ALK）阳性晚期非小细胞肺癌的一线治疗。
• EGFR and ALK dual inhibitor
  申请人：PRECEDO PHARMACEUTICALS CO., LTD

  公开号：US10350210B2

  公开（公告）日：2019-07-16

  The present application provides a compound of formula I, which is a EGFR and ALK dual inhibitor and can be used alone or in combination with other therapeutic agents to treat diseases such as non-small cell lung cancer. The compounds of the present application are useful in the treatment of diseases carrying the EGFR wild-type gene, or carrying the EGFR T790M mutant gene and/or the EGFR L858R mutant gene and/or the EGFR delE746_A750 mutant gene, or in the treatment of diseases carrying the ALK wild-type gene, ALK F1174L mutant gene and/or ALK F1196M gene and/or EML4-ALK mutant gene and/or NPM-ALK mutant gene, and can be used in the first-line treatment of anaplastic lymphoma kinase (ALK) positive late-stage non-small cell Lung cancer.

  本申请提供了一种式I化合物，它是表皮生长因子受体和ALK双重抑制剂，可单独使用或与其他治疗剂联合使用，治疗非小细胞肺癌等疾病。本申请的化合物可用于治疗携带表皮生长因子受体（EGFR）野生型基因的疾病，或携带表皮生长因子受体（EGFR）T790M 突变基因和/或表皮生长因子受体（EGFR）L858R 突变基因和/或表皮生长因子受体（EGFR）delE746_A750 突变基因的疾病，或携带 ALK 野生型基因的疾病、ALK F1174L 突变基因和/或 ALK F1196M 基因和/或 EML4-ALK 突变基因和/或 NPM-ALK 突变基因，并可用于无性淋巴瘤激酶（ALK）阳性晚期非小细胞肺癌的一线治疗。
• Discovery of N -(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC
  作者：Yongfei Chen、Jiaxin Wu、Aoli Wang、Ziping Qi、Taoshan Jiang、Cheng Chen、Fengming Zou、Chen Hu、Wei Wang、Hong Wu、Zhenquan Hu、Wenchao Wang、Beilei Wang、Li Wang、Tao Ren、Shanchun Zhang、Qingsong Liu、Jing Liu

  DOI：10.1016/j.ejmech.2017.08.035

  日期：2017.10

  Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy, Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC. (C) 2017 Elsevier Masson SAS. All rights reserved.