A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.

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The regioselectivity of Pd-catalyzed malonate or sulfonylacetate addition to dihydropyran derivatives is highly dependent upon the substitution pattern of the dihydropyran nucleus and is governed by electronic, rather than steric factors. In certain instances, subtle steric features also play a role in controlling regioselectivity by altering the conformation of the intermediate η3-allyl Pd-complex.

Reduction of bicyclic ketal 1 gave functionalized pyran derivatives 7a or 7b in a highly stereoselective manner, depending upon the reduction conditions utilized. For example, treatment of ketal 1 with TiCl4/Et3SiH produced exclusively diol 7b with the 2,5-syn relationship in good yield. Alternatively, reduction of ketal 1 by DIBALH gave 2,5-anti-diol 7a stereoselectively. Alane reductions of ketal 1 were highly stereoselective also; however, the syn/anti selectivity observed was strongly dependent on the ratio of reagents employed for in situ generation of the alane. Lewis acid catalyzed allylation of ketal 1 gave pyran 10 in a stereospecific alkylation reaction.

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