The crew of a scientific exploration vessel is out of communication with the rest of civilization for 2 months conducting research in an area of space that is completely disruptive to communication.

When it's time to head home, they try to contact Starfleet but they can't. They travel to outposts and find them destroyed. They visit a member planet and its surface has been wiped clean of all life.

Realizing the enormity of what has happened, that they can reach nobody in the federation, they begin trying to contact other factions to determine how wide spread the devastation is. But there is no response.

Their ship has only basic defensive capabilities. Obviously a massively powerful force has devastated all of the civilizations they could find in the quadrant. It sinks in that the crew of the ship may represent either a portion or the entirety of their species. So, the decision is made to run, to find a place to set up a colony that is so remote and shielded from scans and communication that they reduce the risk of being found by whatever destroyed the Federation, its allies and its enemies.

They find such a place, they set up a small colony, they try to find a way to live and continue. But, ultimately, they know they have to find more. There are some crew members that represent the only member of their species on the ship and, even the largest species group doesn't represent a large enough genetic pool to survive more than a few generations, let alone thrive.

So, with the home base established someplace safe, the crew begins to go out in their exploration vessel to determine what happened, to find survivors, to find new allies, and to attempt to rebuild the interstellar society they had once known.

The ultimate course of the show would be a realization that there are intergalactic forces at work on a scale Starfleet had never even considered and that there were technologies to be found that allowed for very fast intragalactic travel as well as unlocking the possibility of reliable intergalactic travel.