I know that this idea has not been well received by many in the past, but...
I've always been intrigued by the idea of a series set during or after the Fall of the Federation. Less comfy era, less perfect humans, less tech, more conflict and drama. Maybe still have pockets of Federation-loyal systems, maybe have one or several core worlds (not necessarily Earth) in turmoil, or even occupied (but not by a local rival like the Romulans or Klingons or Borg). The Federation of the late 24th Century would simply lose its cohesion for one or many reasons, and become a scattered collection of separate systems or small empires, many competing with each other for dwindling tech resources/knowledge, others outright hostile to each other.
No doubt others could flesh it out better than I'm doing.
And yes, there's a percentage of the fan base that rightly points out that part of Trek's allure is its optimistic view of the future, so a Fall of the Federation would not be Trek. Maybe. But IMHO, and as I once read, Trek's real center is its heart, the best of human values triumphing against adversity. There just doesn't seem to be much adversity left in the late-24th & early 25th Century.