N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide | 1578246-27-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide
• 英文别名: N-[2-methoxy-4-(1-methylpyrazol-4-yl)phenyl]formamide
• CAS: 1578246-27-1
• 化学式: C₁₂H₁₃N₃O₂
• 分子量: 231.254
• InChiKey: ZDTXZDIMSKHFOO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  56.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide 在 sodium hydride 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 为溶剂， 反应 22.33h， 生成 N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(oxetan-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine
  参考文献：
  名称：

  [EN] INHIBITOR COMPOUNDS
  [FR] COMPOSÉS INHIBITEURS

  摘要：

  本发明涉及式(I)的化合物，其中R、R、Ar、W、X和Z均如本文所定义。本发明的化合物已知可以通过直接或间接地与Mps1激酶本身相互作用来抑制单丝粒体1（Mps1，也称为TTK）激酶的纺锤体检查点功能。具体而言，本发明涉及将这些化合物用作治疗和/或预防增殖性疾病，如癌症的治疗剂。本发明还涉及制备这些化合物的方法，以及包含它们的药物组合物。

  公开号：

  WO2014037750A1
• 作为产物：
  描述：

  甲酸 、 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline 反应 2.0h， 以65%的产率得到N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide
  参考文献：
  名称：

  扩大融合嘧啶作为激酶抑制剂支架的范围：吡啶并[3,4-d]嘧啶的合成和修饰†

  摘要：

  融合的嘧啶核心是特殊的激酶支架，但在激酶抑制剂计划的背景下，很少有 2-氨基-吡啶并[3,4- d ]嘧啶化学型的例子被披露。此外，尚未报道获得 2-氨基-吡啶并[3,4- d ]嘧啶衍生物的通用合成路线。在这里，我们报告了一种针对此类分子的通用且有效的化学方法。我们的策略涉及8-氯-2-（甲硫基）吡啶并[3,4- d ]嘧啶中间体的简明制备及其有效衍生化，以得到具有激酶抑制剂潜力的新型化合物。

  DOI：

  10.1039/c4ob02238f

文献信息

• Rapid Discovery of Pyrido[3,4-<i>d</i>]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach
  作者：Paolo Innocenti、Hannah L. Woodward、Savade Solanki、Sébastien Naud、Isaac M. Westwood、Nora Cronin、Angela Hayes、Jennie Roberts、Alan T. Henley、Ross Baker、Amir Faisal、Grace Wing-Yan Mak、Gary Box、Melanie Valenti、Alexis De Haven Brandon、Lisa O’Fee、Harry Saville、Jessica Schmitt、Berry Matijssen、Rosemary Burke、Rob L. M. van Montfort、Florence I. Raynaud、Suzanne A. Eccles、Spiros Linardopoulos、Julian Blagg、Swen Hoelder

  DOI：10.1021/acs.jmedchem.5b01811

  日期：2016.4.28

  chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which

  单极纺锤体 1 (MPS1) 在细胞从中期到后期的转变中起核心作用，是纺锤体装配检查点的主要组成部分之一。染色体不稳定的癌细胞严重依赖 MPS1 来应对由异常数量的染色体和中心体引起的压力，因此比正常细胞对 MPS1 抑制更敏感。我们报告了一系列新的基于吡啶并[3,4- d ]嘧啶的抑制剂的发现和优化，通过我们先前报道的抑制剂 CCT251455 的基于结构的杂交方法和适度有效的筛选命中。这个新系列中的化合物对 MPS1 显示出优异的效力和选择性，在体内人类肿瘤异种移植模型中转化为生物标志物调节。
• INHIBITOR COMPOUNDS
  申请人：CANCER RESEARCH TECHNOLOGY

  公开号：US20150239884A1

  公开（公告）日：2015-08-27

  The present invention relates to compounds of formula I wherein R 1 , R 4 , Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

  本发明涉及式I的化合物，其中R1、R4、Ar、W、X和Z均如本文所定义。本发明的化合物已知能够直接或间接地通过与Mps1激酶本身的相互作用来抑制单纺锤体1（Mps1，也称为TTK）激酶的纺锤体检查点功能。特别地，本发明涉及使用这些化合物作为治疗和/或预防增生性疾病，如癌症的治疗剂。本发明还涉及制备这些化合物的过程，以及包含它们的药物组合物。
• Inhibitor compounds
  申请人：Cancer Research Technology Limited

  公开号：US09409907B2

  公开（公告）日：2016-08-09

  The present invention relates to compounds of formula I wherein R1, R4, Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

  本发明涉及式I的化合物，其中R1、R4、Ar、W、X和Z的定义如本文所述。本发明的化合物已知可以直接或间接地通过与Mps1激酶本身的相互作用来抑制单纺锤体1（Mps1 - 也称为TTK）激酶的纺锤体检查点功能。特别地，本发明涉及使用这些化合物作为治疗和/或预防增生性疾病，如癌症的治疗剂。本发明还涉及制备这些化合物的过程，以及包含它们的药物组合物。
• Compounds that inhibit MPS1 kinase
  申请人：Cancer Research Technology Limited

  公开号：US10479788B2

  公开（公告）日：2019-11-19

  The present invention relates to compounds of formula I wherein R1, R4, Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

  本发明涉及式 I 的化合物 其中 R1、R4、Ar、W、X 和 Z 均如本文所定义。已知本发明的化合物可直接或间接通过与 Mps1 激酶本身的相互作用抑制 Monospindle 1（Mps1--又称 TTK）激酶的纺锤体检查点功能。特别是，本发明涉及将这些化合物用作治疗和/或预防癌症等增殖性疾病的治疗剂。本发明还涉及这些化合物的制备工艺以及包含这些化合物的药物组合物。
• Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4-<i>d</i>]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate <i>N</i>²-(2-Ethoxy-4-(4-methyl-4<i>H</i>-1,2,4-triazol-3-yl)phenyl)-6-methyl-<i>N</i>⁸-neopentylpyrido[3,4-<i>d</i>]pyrimidine-2,8-diamine (BOS172722)
  作者：Hannah L. Woodward、Paolo Innocenti、Kwai-Ming J. Cheung、Angela Hayes、Jennie Roberts、Alan T. Henley、Amir Faisal、Grace Wing-Yan Mak、Gary Box、Isaac M. Westwood、Nora Cronin、Michael Carter、Melanie Valenti、Alexis De Haven Brandon、Lisa O’Fee、Harry Saville、Jessica Schmitt、Rosemary Burke、Fabio Broccatelli、Rob L. M. van Montfort、Florence I. Raynaud、Suzanne A. Eccles、Spiros Linardopoulos、Julian Blagg、Swen Hoelder

  DOI：10.1021/acs.jmedchem.8b00690

  日期：2018.9.27

  Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4-d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4-d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.