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In medicinal chemistry, is there a rule for which aromatic heterocycles are stable?

I've heard that heterocycles with 3+ adjacent nitrogens for example are unstable. However looking in ChEMBL at the molecules currently in human clinical trials, there are a fair number of 1,2,3-triazoles and tetrazoles, so clearly that rule is not absolute. For six-membered rings, 1,2,3,4-tetrazine and 1,2,3-triazine don't seem to be used, but neither is 1,2,4,5-tetrazine which doesn't have 3 adjacent nitrogens. Mixing nitrogen and oxygen, 1,2,5-oxadiazole and 1,3,4-oxadiazole are very rare but do show up a couple of times, but 1,2,3-oxadiazole isn't used.

I'm wondering if there is a general rule about which heterocycles would be stable, including ones with fused rings and a fairly large number of adjacent heteroatoms? For example (in smiles notation) how about c1nnnc2c1cccc2 or c1cccc2n1nnc2 or n1cccc2n1ncc2?

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Or how about something even more unusual, like a pyridinone/pyrone with some extra nitrogens? c1(=O)[nH]nncc1

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Alex I
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    https://chemistry.stackexchange.com/questions/171869/stability-of-hexazine https://chemistry.stackexchange.com/questions/42612/stability-of-isomers-of-n4o – Mithoron Jan 04 '24 at 15:19
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    "heterocycles with 3+ adjacent nitrogens for example are unstable" - I doubt if there's anything so clear cut in chemistry. You can have even ten or more nitrogens in a row, but the issue what is this "stability" comes up... along with explosions. – Mithoron Jan 04 '24 at 15:27
  • @Mithoron Yup, I know stability is relative - I mean medchem stable, as in “wouldn’t spontaneously react with random stuff inside the cell”. It appears 1,2,4,5-tetrazine isn’t stable in that sense, but tetrazole is. I’m mainly curious about what happens with similar 5+5, 5+6 and 6+6 fused rings, incl when the bridging atom is a nitrogen – Alex I Jan 04 '24 at 15:36

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