Single aisle become very problematic when you go much over 200 seats because loading/unloading take forever. It's OK for longer range operations since the turn times are less critical, but to be economically viable, a new 200-250 passenger aircraft needs to be economical not just for long haul, but for 1-2 hour flights as well. Otherwise the market is too small.
That was a big factor in the flop of the 757-300. It's operating costs were quite good for the time, but it's turn times were horrid.
I still think Boeing's best bet would be a "767X" - 767 fuselage, updated composite wing, modern avionics, and new state-of-the-art engines. They'd just need to convince an engine company to do a new 45k thrust class engine.