I have some humble comments on the 'OSM Christmas Top 10 List'.
[i] Comparing head to head MMV 639565 & 670945 with MMV 668959 & 669009 [changing 4-Cl/4-OCHF2-Ph to either THP or N-linked Piperidine], there is a drastic loss in potency; that probably suggests the need of pi-pi interaction/aryl group at that position.
In that context, compounds S, U & W may not be beneficial; moreover, the presence of the -OH group may render metabolic instability as we have seen in MMV 670947 [related].
[ii] Keeping in mind the potency and hERG data MMV 670936, the compound V [From the Top 10 List] looks interesting; though -OH group will probably improve the potency, it may lead to metabolism.
Accordingly, modifying -OH to -OMe may avoid these issue [also we know, -OMe is well tolerated in MMV 669844]. Secondly, 3, 5-di fluorophenyl may be used instead.
Look forward to the feedback.