Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors: A template-based approach

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 22; pp. 6178 - 6182
• Main Authors: Dwyer, Michael P., Keertikar, Kartik, Paruch, Kamil, Alvarez, Carmen, Labroli, Marc, Poker, Cory, Fischmann, Thierry O., Mayer-Ezell, Rosemary, Bond, Richard, Wang, Yan, Azevedo, Rita, Guzi, Timothy J.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2013; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; enzyme inhibitors; Humans; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Life Sciences & Biomedicine; Pan–Pim kinase; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; protein-serine-threonine kinases; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - chemistry; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; pyrazolo[1,5-a]pyrimidine; pyrimidines; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; structure-activity relationships; pyrazolo[1,5-a]pyrimidine; Pan–Pim kinase; SURVIVAL; POTENT; ACTIVATION; DESIGN; Pan-Pim kinase; PROSTATE-CANCER CELLS; KINASE INHIBITORS; LEUKEMIA

The synthesis and SAR development of a class of pyrazolo[1,5-a]pyrimidine-based Pim kinase inhibitors are detailed from an early HTS hit to a pan–Pim inhibitor such as 11j. The synthesis and hit-to-lead SAR development from a pyrazolo[1,5-a]pyrimidine-derived hit 5 to the identification of a series...