8-(6-chloropyridazin-3-yl)-2-thia-8-azaspiro[4.5]decane 2,2-dioxide | 1588960-02-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 8-(6-chloropyridazin-3-yl)-2-thia-8-azaspiro[4.5]decane 2,2-dioxide
• 英文别名: 8-(6-Chloropyridazin-3-yl)-2lambda6-thia-8-azaspiro[4.5]decane 2,2-dioxide；8-(6-chloropyridazin-3-yl)-2λ6-thia-8-azaspiro[4.5]decane 2,2-dioxide
• CAS: 1588960-02-4
• 化学式: C₁₂H₁₆ClN₃O₂S
• 分子量: 301.797
• InChiKey: YHWWVVYALZSLKB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  71.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine 、 8-(6-chloropyridazin-3-yl)-2-thia-8-azaspiro[4.5]decane 2,2-dioxide 在 tris-(dibenzylideneacetone)dipalladium(0) 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 生成 8-(6-((9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridazin-3-yl)-2-thia-8-azaspiro[4.5]-decane 2,2-dioxide
  参考文献：
  名称：

  Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

  摘要：

  We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

  DOI：

  10.1021/jm500118j
• 作为产物：
  描述：

  3,6-二氯哒嗪 、 2-thia-8-azaspiro[4.5]decane 2,2-dioxide hydrochloride 在 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 为溶剂， 以91%的产率得到8-(6-chloropyridazin-3-yl)-2-thia-8-azaspiro[4.5]decane 2,2-dioxide
  参考文献：
  名称：

  Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

  摘要：

  We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

  DOI：

  10.1021/jm500118j