pwkenny

Hi @edgriffen I would be wary substituting with 4-pyrazolyl (Design 5) since this effectively extends the pi system of the isoquinoline and, at very least, would be expected to lead to a reduction in solubility (worse things have happened when pi systems of fused aromatics have been extended). Is pyrazole a substituent on an aromatic carbon in the MedChemica’s ADMET rule database or a replacement for phenyl? I would anticipate less disruption (relative to methylsulfone analogs) to binding modes for Designs 1/2 than Designs 3/4.

I see fluoro as a higher priority than the C7 substituents in Designs 2 and 4 (less likely to disrupt binding mode; no 7-fluoroisoquinolines appear to have been synthesized). The pKa values reported for 6-aminoisoquinoline and 7-aminoisoquinoline (7.2 and 6.2 respectively) suggest that C6 ‘feels’ the pull of the isoquinoline N to a greater extent than C7 and is consequently in less ‘need’ of protection than C7.

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mc-robinson

Thanks, @pwkenny. The potential fluoro protection at C7 has now been actioned for synthesis, along with attempting to move the sulfone over to that position.

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pwkenny

Thanks for letting me know, Matt, and good luck with the synthesis and assays. I would anticipate a greater loss of potency to result from putting methylsulfonyl at C7 than at C6 but still think it would be worth doing.