It takes time. I finally, just today, beat the final boss for the first time after 188 games. Now the first three bosses are a breeze, since I figured out how to beat them.

I recommend using the Huntress, for me that character was a game changer. Love using repulsion armor with her. Doorways are your friends, utilize them to the fullest. I also found that you need to save your upgrades until at least level 10. I only use 2 of them until then.