Is it possible to lose the game by focusing only on completing the main quest and then being stuck in an area where all enemies are too difficult?

In other words, is completing side quests mandatory to gain enough strength in this game too defeat all enemies?

Can new players succeed just by focusing on main quests or will doing so make their character too weak?

This is just my opinion but, I'd say definitely yes. Even with side tasks, the end fights are near impossible.

Well rough guide.. finish act 1 lvl 8
Act 2 16
Act 3 18
Final fight 21-22.
Theres a learning curve in DOS2.. start with classic (or whatever difficulty you like), then if you like increase difficulty.
And enjoy to journey!