Just about any major 4X game could have made this list since they're all focused on expansion, have sprawling maps, and provide plenty of replay value.
For the real goods, though, look no further than Sins Of A Solar Empire. Whether you want to establish an empire and deal with economic and political issues or just conquer the stars, Sins has dozens of gameplay possibilities.
Between the story mode and the game's random maps, there are immediately hundreds of hours at your fingertips — but that's just the start. The game supports a bevy of mods, including those for popular fandoms such as Star Trek, Star Wars, Mass Effect, and Stargate.
For example, the insanely-detailed Armada 3 mod is still the best Star Trek game that's ever been made, even if it's only a fan-made total conversion mod.