2-chloro-6-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine | 1257294-97-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: 2-chloro-6-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
• 英文别名: 2-Chloro-6-(2,2-dimethyl-4-oxetan-3-ylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine；4-[2-chloro-6-[[2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine
• CAS: 1257294-97-5
• 化学式: C₂₀H₂₈ClN₅O₂S
• 分子量: 437.994
• InChiKey: IGIIFANNBPIZLG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  82.2
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-乙基苯并咪唑 、 2-chloro-6-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以26%的产率得到4-(6-((2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine
  参考文献：
  名称：

  Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

  摘要：

  PI3K delta is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(alpha, beta, delta) and IB (gamma), which catalyze the phosphorylation of PIP2 to PIP3. PI3K delta is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3K delta inhibitors and describe a structural hypothesis for isoform (alpha, beta, gamma) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.

  DOI：

  10.1021/jm3003747
• 作为产物：
  描述：

  2-氯-4-(4-吗啉)-噻吩并[3,2-d]嘧啶-6-羧醛 、 3,3-二甲基-1-(氧杂环丁烷-3-基)哌嗪 在 sodium triacetoxyborohydride 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 21.0h， 以49%的产率得到2-chloro-6-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine
  参考文献：
  名称：

  Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

  摘要：

  PI3K delta is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(alpha, beta, delta) and IB (gamma), which catalyze the phosphorylation of PIP2 to PIP3. PI3K delta is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3K delta inhibitors and describe a structural hypothesis for isoform (alpha, beta, gamma) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.

  DOI：

  10.1021/jm3003747

文献信息

• Bicyclic pyrimidine PI3K inhibitor compounds selective for P110 delta, and methods of use
  申请人：Genentech, Inc.

  公开号：US08173650B2

  公开（公告）日：2012-05-08

  Formula I (Ia and Ib) compounds wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is O, including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  Formula I（Ia和Ib）化合物，其中（i）X1为N且X2为S，（ii）X1为CR7且X2为S，（iii）X1为N且X2为NR2，或（iv）X1为CR7且X2为O，包括立体异构体，互变异构体，代谢物和其药学上可接受的盐，对于抑制PI3K的δ异构体以及治疗由脂质激酶介导的疾病如炎症，免疫和癌症等有用。公开了使用Formula I化合物的方法，用于哺乳动物细胞中体外，体内和原位诊断，预防或治疗此类疾病或相关病理条件。
• BICYCLIC PYRIMIDINE PI3K INHIBITOR COMPOUNDS SELECTIVE FOR P110 DELTA, AND METHODS OF USE
  申请人：Castanedo Georgette

  公开号：US20120178736A1

  公开（公告）日：2012-07-12

  Formula I (Ia and Ib) compounds wherein (i) X 1 is N and X 2 is S, (ii) X 1 is CR 7 and X 2 is S, (iii) X 1 is N and X 2 is NR 2 , or (iv) X 1 is CR 7 and X 2 is 0, including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  Formula I（Ia和Ib）化合物中，其中（i）X1为N且X2为S，（ii）X1为CR7且X2为S，（iii）X1为N且X2为NR2，或（iv）X1为CR7且X2为0，包括立体异构体，互变异构体，代谢物和药学上可接受的盐，有用于抑制PI3K的δ异构体，并用于治疗由脂质激酶介导的疾病，例如炎症，免疫和癌症。公开了使用Formula I化合物的方法，用于哺乳动物细胞中的体外，体内和原位诊断，预防或治疗此类疾病或相关病理条件。
• US8173650B2
  申请人：——

  公开号：US8173650B2

  公开（公告）日：2012-05-08
• US8394796B2
  申请人：——

  公开号：US8394796B2

  公开（公告）日：2013-03-12