A new structural class of histamine H4 receptor antagonists (6−14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H4 antagonists, functional H4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H4 pharmacology. It is a potent H4 antagonist in functional assays across species (FLIPR Ca2+ flux, K b < 5.7 nM), has high (>190×) selectivity for H4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED50 = 37 μmol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED50 = 72 μmol/kg, rat).