I'm just going to drop some of my favorite adult 2d animated series that are not bastard ugly and don't rely on projectile vomit and other "gross" jokes to be entertaining (at the very least, they are a far cry from whatever Big Mouth has going on).
Scavengers Reign follows three groups of survivors who crash land on an alien planet as they traverse various ecosystems to get to safety. There is a lot of thought put into the flora and fauna they encounter, and it explores their relationships with each other and with the crew members as they are assimilated into the environment. Plus, the art is absolutely beautiful.
Unfortunately, season 2 is very very unlikely to be greenlit (but I'm holding out hope and still think it's worth watching).
Pantheon is one that is incredibly underrated. It's about two teenagers uncovering the development of uploaded intelligence, the transfer of human minds into computers. Maddie Kim is a bullied, computer savvy freshman who lost her dad to cancer while Caspian Keyes is an apathetic prodigy living within an abusive household. Overall, it covers themes of grief, love, and what it means to be human. It gets pretty philosophical and mind-fucky at times, and I love how the animation reflects that. Just look at that title sequence:
And thankfully, this one was finished.
Inside Job is about an ambitious but overworked engineer working for the shadow government. I'll admit that this can lean into some crass humor/animation, but I think it's well balanced with other aspects of the show. I love the mc's characterization. Reagan is motivated but feels held back by the incompetence of her boss and co-workers. She wants to move through the ranks but has a hard time taking care of herself. She becomes best friends with the male lead, her foil, but never falls in love with him romantically. The series is overall both hilarious and relatable.
This one has also been canceled after the first season :(
Creature Commandos has a clear comic book style and is about a group of imprisoned nonhumans sent to protect a princess from Circe. Like Inside Job, it can lean into some sexual humor, but it pales in comparison to the show's characterizations. I really only remember their compelling backstories and how each character was affected by them.
It's a short watch of 7 episodes, and season 2 is in production.
Bojack is fairly well-known, but I can't not include it. Even though I personally had to adjust to the art style, it's not something I ever thought of as ugly. And the animation at some points is memorable and really highlights the more serious scenes. The comedy is also well-balanced and includes a lot of dry humor and visual gags.
(Just remembered that the first 2 seasons are kind of hard to watch, so I totally understand if it's not worth going through for you)
This is more of an honorable mention because I've never watched it and I'm a little offput by their faces. However, I do plan on giving it a chance because one of the creators of Scavengers Reign also worked on it.