Identification and optimisation of 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors

  • Bioorg Med Chem Lett. 2015 Sep 1;25(17):3575-81. doi: 10.1016/j.bmcl.2015.06.067.
Robin A Fairhurst  1 ,  Marc Gerspacher  2 ,  Patricia Imbach-Weese  2 ,  Robert Mah  2 ,  Giorgio Caravatti  2 ,  Pascal Furet  2 ,  Christine Fritsch  2 ,  Christian Schnell  2 ,  Joachim Blanz  2 ,  Francesca Blasco  2 ,  Sandrine Desrayaud  2 ,  Daniel A Guthy  2 ,  Mark Knapp  2 ,  Dorothee Arz  2 ,  Jasmin Wirth  2 ,  Esther Roehn-Carnemolla  2 ,  Van Huy Luu  2
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland. Electronic address: [email protected].
  • 2. Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland.
PMID: 26199119 DOI: 10.1016/j.bmcl.2015.06.067
Abstract

A cyclisation within a 4',5-bisthiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors led to a novel 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole tricyclic sub-series. The synthesis and optimisation of this 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole sub-series and the expansion to a related tricyclic 4,5-dihydrothiazolo[4,5-h]quinazoline sub-series are described. From this work analogues including 11, 12, 19 and 23 were identified as potent and selective PI3Kα Inhibitor in vivo tool compounds.

Keywords
Kinase inhibitor; Oncology; Phosphatidylinositol-3-kinase-alpha.