N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: Indazoles as phenol isosteres with improved pharmacokinetics

2,4-Dianilino pyrimidines with a phenolic group at the 4-position are potent inhibitors of Lck tyrosine kinase enzyme activity, but they have poor pharmacokinetic properties. Analogues where the 4-position was replaced by 4-amino(5-methyl-1H-indazole) had comparable enzyme potency and improved pharmacokinetic properties. 2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure–activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.