First of all, for the record I'm not fine with how Shepard's story ended, but I can accept that it *is* ended. These are not mutually exclusive concepts.
Secondly, I'm glad to hear that they're not just going to make the next game about another soldier saving the universe. Indeed, my preference would be for a smaller scale, more personal story with a much less military setting. Think 'Firefly', or 'Cowboy Bebop'. A small crew and a rusty old ship operating just outside the law. That kind of thing.
As for the "when and where", I think while there's certainly room for prequels, I'd rather see what the future has in-store for the galaxy we spent 3 games saving. Of course this means they'd have to pick a canon ending, but that's fine since "destroy" is the only viable choice. I mean Control and Synthesis are respectively a stagnant dystopia where the only antagonist can be cyber-Shep and her fleet of reaper drones (been there, space-magic'ed that) and a boring utopia where everyone glows green and shares happy-happy thoughts forever.
The way I see it, with Destroy the galaxy is free, but without certainty. The old infrastructure that was "Citadel Space" is smashed, most of the major homeworlds are in need of the kind of rebuilding that takes generations and there is massive numbers of displaced populations all over the galaxy. So lots of new colonies, old relays being opened and new ones being built, opening up unexplored clusters and a flood of new races to the galactic community. A real "wild west" of a galaxy.
I also see a lot of new powers rising out of the ashes, with a lot of the minor powers in the Terminus Systems left largely unharmed taking advantage of the power vacuum. I see Tuchanka and Rannoch becoming the new bastions of civilization-the first to rebuild anyway. Perhaps by this time the Spectres have become something more akin to the Justicars. Less of a black-ops organization and more of an order of guardians.
I think I'd also like it if Earth is a burnt husk of a planet, no longer able to support the majority of humanity.