- Synthesis and Structure-Activity Relationship of Tetra-Substituted Cyclohexyl Diol Inhibitors of Proviral Insertion of Moloney Virus (PIM) Kinases
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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.
- 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.
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p. 14885 - 14904
(2021/01/07)
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- TETRASUBSTITUTED CYCLOHEXYL COMPOUNDS AS KINASE INHIBITORS
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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.
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Page/Page column 105
(2012/09/11)
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