1395285-83-2Relevant academic research and scientific papers
Synthesis and Structure-Activity Relationship of Tetra-Substituted Cyclohexyl Diol Inhibitors of Proviral Insertion of Moloney Virus (PIM) Kinases
Han, Wooseok,Ding, Yu,Chen, Zheng,Langowski, John L.,Bellamacina, Cornelia,Rico, Alice,Nishiguchi, Gisele A.,Lan, Jiong,Atallah, Gordana,Lindvall, Mika,Lin, Song,Zang, Richard,Feucht, Paul,Zavorotinskaya, Tatiana,Dai, Yumin,Garcia, Pablo,Burger, Matthew T.
, p. 14885 - 14904 (2021/01/07)
Overexpression of PIM 1, 2, and 3 kinases is frequently observed in many malignancies. Previously, we discovered a potent and selective pan-PIM kinase inhibitor, compound 2, currently in phase I clinical trials. In this work, we were interested in replacing the amino group on the cyclohexane ring in compound 2 with a hydroxyl group. Structure-based drug design led to cellularly potent but metabolically unstable tetra-substituted cyclohexyl diols. Efforts on the reduction of Log D by introducing polar heterocycles improved metabolic stability. Incorporating fluorine to the tetra-substituted cyclohexyl diol moiety further reduced Log D, resulting in compound 14, a cellularly potent tetra-substituted cyclohexyl diol inhibitor with moderate metabolic stability and good permeability. We also describe the development of efficient and scalable synthetic routes toward synthetically challenging tetra-substituted cyclohexyl diol compounds. In particular, intermediate 36 was identified as a versatile intermediate, enabling a large-scale synthesis of highly substituted cyclohexane derivatives.
TETRASUBSTITUTED CYCLOHEXYL COMPOUNDS AS KINASE INHIBITORS
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, (2012/09/11)
The present invention provides a compound of formula (I): as further described herein, and pharmaceutically acceptable salts, enantiomers, rotamers, tautomers, or racemates thereof. Also provided are methods of treating a disease or condition mediated by PIM kinase using the compounds of Formula I, and pharmaceutical compositions comprising such compounds.
