A Main Boss is any Leader/Boss enemy NPC whose defeat is key to moving the narrative in Too Human forward, and are usually part of the storyline for an extended period of time.
In other words, these Bosses are primarily very important to the story, and as such, are typically the hardest to defeat. This is contrasted by Sub-Bosses (who are event-instigators or the "right-hand men" of Main Bosses), and by Common Bosses (who are more like Sub-Bosses, except that they are far more common and have no importance in the game beyond their existence at that point in time).
Loki and GRNDL (Grendel) are suspected to be Main Bosses in the Too Human Trilogy.
Grendel: Main Boss of Hall of Heros
Hod: Main Boss of Ice Forest
The Everlasting Hate: Main Boss of World Serpent
Hel: Main Boss of Helheim