2-(butylamino)-4-[(4-hydroxycyclohexyl)amino]-N-{[4-(1H-imidazol-1-yl)phenyl]methyl}pyrimidine-5-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(butylamino)-4-[(4-hydroxycyclohexyl)amino]-N-{[4-(1H-imidazol-1-yl)phenyl]methyl}pyrimidine-5-carboxamide
• 化学式: C₂₅H₃₃N₇O₂
• 分子量: 463.583
• InChiKey: NPVXOWLPOFYACO-XUTJKUGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.52
• 重原子数：
  34.0
• 可旋转键数：
  10.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  116.99
• 氢给体数：
  4.0
• 氢受体数：
  8.0

反应信息

• 作为产物：
  描述：

  2,4-二氯-5-嘧啶甲酰氯 在 lithium hydroxide monohydrate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 7.5h， 生成 2-(butylamino)-4-[(4-hydroxycyclohexyl)amino]-N-{[4-(1H-imidazol-1-yl)phenyl]methyl}pyrimidine-5-carboxamide
  参考文献：
  名称：

  Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis

  摘要：

  The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

  DOI：

  10.1021/jm4013888

文献信息

• [EN] THERAPUETIC USES OF SELECTED PYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY<br/>[FR] UTILISATIONS THÉRAPEUTIQUES DE COMPOSÉS SÉLECTIONNÉS DE PYRIMIDINE AYANT UNE ACTIVITÉ TYROSINE KINASE ANTIMÈRE
  申请人：UNIV NORTH CAROLINA

  公开号：WO2015157127A1

  公开（公告）日：2015-10-15

  Uses of pyrimidines with anti-Mer tyrosine kinase activity as anti-infective agents, immunostimulatory and immunomodulatory agents, anti-cancer agents (including against MerTK -/- tumors and ITD and TKD mutant forms of Acute Myeloid Leukemia (AML)), and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.

  将嘧啶类化合物用作抗Mer酪氨酸激酶活性的抗感染剂、免疫刺激剂和免疫调节剂、抗癌剂（包括对MerTK -/-肿瘤和急性髓样白血病（AML）的ITD和TKD突变形式），以及作为辅助剂与化疗、放疗或其他肿瘤标准治疗联合使用。
• PYRIMIDINE COMPOUNDS FOR THE TREATMENT OF CANCER
  申请人：THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

  公开号：US20150038481A1

  公开（公告）日：2015-02-05

  Described are compounds of Formula I or Formula II: wherein: ring A is a 5- or 6-membered heteroaryl group; dashed lines are optional double bonds; X is N or O; Y is a carbon atom or an S or N heteroatom in ring A in any suitable location; and substituents are as given herein. Compositions containing the same and methods of using the same in treating cancers such as acute lymphoblastic leukemia are also described.

  描述了公式I或公式II的化合物：其中：环A是一个5或6成员的杂环芳基团；虚线是可选的双键；X是N或O；Y是一个碳原子或在环A中的S或N杂原子，可以位于任何合适的位置；取代基如本文所述。还描述了含有这些化合物的组合物以及使用它们治疗白血病等癌症的方法。
• THERAPEUTIC USES OF SELECTED PYRIMIDINE COMPOUNDS WITH ANTI-MER TYROSINE KINASE ACTIVITY
  申请人：The University of North Carolina at Chapel Hill

  公开号：US20150290194A1

  公开（公告）日：2015-10-15

  Uses of pyrimidines with anti-Mer tyrosine kinase activity as anti-infective agents, immunostimulatory and immunomodulatory agents, anti-cancer agents (including against MerTK −/− tumors and ITD and TKD mutant forms of Acute Myeloid Leukemia (AML)), and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.

  嘌呤类化合物具有抗Mer酪氨酸激酶活性，并可用作抗感染剂、免疫刺激剂和免疫调节剂、抗癌剂（包括对MerTK -/- 肿瘤和急性髓细胞白血病（AML）的ITD和TKD突变形式），以及与化疗、放疗或其他标准护理方法结合使用的辅助剂。
• MERTK-SPECIFIC PYRIMIDINE COMPOUNDS
  申请人：The University of North Carolina at Chapel Hill

  公开号：US20150291609A1

  公开（公告）日：2015-10-15

  The present invention includes pyrimidine compounds that selectively inhibit Mer tyrosine kinase (MerTK) activity and/or Tyro3 tyrosine kinase activity, and use of these pyrimidine compounds as anti-cancer agents, immunostimulatory and immunomodulatory agents, anti-platelet agents, anti-infective agents, and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.

  本发明包括选择性抑制Mer酪氨酸激酶（MerTK）活性和/或Tyro3酪氨酸激酶活性的嘧啶化合物，并将这些嘧啶化合物用作抗癌剂、免疫刺激剂和免疫调节剂、抗血小板剂、抗感染剂以及作为辅助剂与化疗、放疗或其他肿瘤标准治疗联合使用的药物。
• US9567326B2
  申请人：——

  公开号：US9567326B2

  公开（公告）日：2017-02-14