Learning to design.. baby steps

While reading about the recent advancements for TYK2 inhibitors, I came across this article by  Matsumoto et.al. (2025) and started wondering how did they synthesize such molecules? Of course its pre-cursor Deucravacitinib aka BMS-986165, had a fascinating story itself (Wrobleski et. al.(2019) but that's for another day..) and I started reading about the synthesis part casually and went into deep slumber of thoughts. 

Hydrophobic gray pocket in TYK2 pseudokinase domain Wrobleski et. al. (2019)

Being a tumbling comp chemist myself, designing a molecule feels easy and hard at times. You stuff methyl magically into hydrophobic pocket sometimes and you get a nice potency boost (for reference, Deucravacitinib story did this), while sometimes you cycle through hoofs and land on new core of the molecules, gaining novelty. It feels easy when you just have to connect dots on the screen while moving around the protein pocket several times, but when thinking from medicinal chemist perspective, synthesizing it is equally hard.

So, let's try to understand how the authors synthesized or came to the highly potent structure with a bit of SAR.

(TBC)