Since most have already been mentioned.
Demon from Dragon:The Bruce Lee Story game.
Giant Scorpion thing from God of War III on Hard and Titan difficulty took me awhile to beat it, more then all the other bosses including Zeus. though thinking back it doesn't seem like it would be that hard.
Superman and Shao Khan in Injustice and the new MK are a decent challenge on medium so i can only imagine the brutality of fighting them on hard and very hard. thankfully there isn't a trophy for that or i would probably put myself through it.