Downtown San Diego is right by the zoo and I think after the zoo for the day that it would be fine wtih a 2 year old. The two year old is not going to be into La Jolla anymore then downtown. Your teen would like either.

Old Town is a great suggestion as well.

Where are you staying in Orange County?

I grew up in San Diego and have spent the last 11 years in Orange County. We rented a house in Newport a few times on the beach for a "local" vacation.

Your teen and two year old will like Downtown Disney.

One parking tip with Disney - if you eat at a resturant in DownTown or buy anything in downtown Disney they will validate your parking and it is often less then parking in the Disney lot and it is easier to get there. We generally do that.