Development of a Late-Stage Diversification Strategy for the 4- and 5-Positions of 4,5,6-Trisubstituted Indazoles
Joyann S Barber1, Alexander Burtea1, Michael R Collins1
1Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121, United States.
Abstract:
Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.
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Stability of Substituted Cyclohexanes
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
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