2. Academic Validation
  3. 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

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

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
  • 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.

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