Well, if I had to make three specific changes:
1. PC's don't choose 2 scores but raise all scores at levels 4/8. Barbarians may need tweaking.
2. Get rid of expertise feats. Fix monsters if necessary.
3. No limits on free attacks per round nor opportunity attacks on your turn. Some free attacks redefined as opportunity attacks, possibly some opportunity attacks removed for balance.
But seeing as there's no way I can pick just three things, I'll split em into three groups
1. Reduce the # of feats, powers and items:
- powers should be merged into power-source lists, and these should be not much larger than a current class; but with all the gunk removed. Some keywords may need to be added because classes should retain unique class riders, which would be implemented via keywords.
- feats: just trash a bunch of them, and merge similar feats - i.e. don't have Implement Focus
and Weapon Focus, but merge them. Don't have Great X but Great Defense etc. Most feats should have fewer prerequisites since they've been merged with similar feats on similar lines. Feats that do require prerequisites should be easily sorted into groups to make levelling easy; i.e. avoid ability score prerequisites and prefer class/power source/weapon prerequisites etc. The aim should be to fit the maximum amount of variety and spice into 100 feats - if a feat is too specific, it should simply be cut. Avoid tier distinctions where possible.
- items: most can simply be trashed. Items should avoid using rules that encourage centering builds around them (e.g. flaming/frost) unless these are common and easily exchanged: the game is about characters, not items. Whatever the case, to discourage pigeonholing, things like "flaming" should not replace damage types but simply add damage - so the original power still matters and resistance to it's type still matters.
2. Make the math work. I don't care how - as long as it's not an "optional" extra. Get rid of expertise, Masterwork armor, Scaling in defense feats, selective ability score increases (either increase them all or not at all). My preference would be to simply drop them all, and drop many enhancement bonuses, and rebalance monsters to this a slower attack/defense progression - it's better for high level monsters to slaughter PC's than for a dragged out unwinnable contest in which they simply never hit, and conversely it's better for PC to quickly overcome underlevelled opponents that may get in a lucky shot rather than a safe but slow combat. Thus, it's necessary to scale damage at least as much as attacks/defenses. Monster math should be akin to a simplified, abstracted PC math, not an entirely separate beast (thus scaling of PC's and NPC's would by definition be comparable).
3. Clean up combat rules. Get rid of weird exceptions like "only 1 free action attack per round" and "no immediate actions and opportunity actions on your turn" and try to make the whole thing shorter. A good test: if a random D&D player is not likely to know the rule, it's a bad rule no matter how justified.