Synthesis and biological evaluation of novel 7-substituted 3-(4-phenoxyphenyl)thieno[3,2-c]pyridin-4-amines as potent Bruton's tyrosine kinase (BTK) inhibitors

Bioorg Med Chem. 2015 Oct 1;23(19):6250-7. doi: 10.1016/j.bmc.2015.08.039. Epub 2015 Aug 28.

Abstract

A series of novel 7-substituted 3-(4-phenoxyphenyl)thieno[3,2-c]pyridin-4-amines as potent BTK inhibitors were designed, synthesized and evaluated. These thieno[3,2-c]pyridin-4-amine derivatives displayed variant inhibitory activities against BTK in vitro. Among these, 7-pyrazol-4-yl substituted 3-(4-phenoxyphenyl)thieno[3,2-c]pyridin-4-amine subseries showed high BTK inhibition and several compounds displayed superior BTK inhibitory activity. Comprehensive SAR was disclosed and compound 13b showed excellent potency (IC₅₀=11.8 nM), outstanding hydrophilicity (AlogP=3.53), and relatively good kinase selectivity, being a promising lead for further evaluation.

Keywords: BTK inhibitors; Inhibitory activity; Kinase selectivity; Thieno[3,2-c]pyrid-4-amine.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Amines / chemical synthesis
  • Amines / chemistry*
  • Amines / metabolism
  • Humans
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Amines
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human