We should have been working on a replacement for the last 30 years.
The private sector has been working this for a long time. Check some of the links posted above. And no, manned spaceflight is not the be all end all. Getting us able to reduce the cost per pound in orbit is what we need now. Please note that humans really don’t do well in space in the long run (we’re built for gravity). We’ve got a bunch to do to figure out how to deal with that before we go to places like Mars. Personally, if we get going out to the Legrange points on a regular basis with unmanned missions until we get the biology right that would be just fine.