N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide | 1578247-90-1

• 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-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide
• 英文别名: N-(2-Methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide；N-[2-methoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]formamide
• CAS: 1578247-90-1
• 化学式: C₁₁H₁₂N₄O₂
• 分子量: 232.242
• InChiKey: RDFPGSPEKDHYFL-UHFFFAOYSA-N

物化性质

• 沸点：
  522.2±60.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  69
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide 、 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 18.17h， 以12%的产率得到N²-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N⁸-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine
  参考文献：
  名称：

  Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4-d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N²-(2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N⁸-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine (BOS172722)

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.8b00690
• 作为产物：
  描述：

  3-(3-methoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 反应 19.5h， 生成 N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide
  参考文献：
  名称：

  Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4-d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N²-(2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N⁸-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine (BOS172722)

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.8b00690

文献信息

• [EN] INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS
  申请人：CANCER REC TECH LTD

  公开号：WO2014037750A1

  公开（公告）日：2014-03-13

  The present invention relates to compounds of formula (I), wherein R, R, 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。
• 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。
• 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。
• Inhibitor compounds
  申请人：Cancer Research Technology Limited

  公开号：US11046688B2

  公开（公告）日：2021-06-29

  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。
• US9409907B2
  申请人：——

  公开号：US9409907B2

  公开（公告）日：2016-08-09