A novel Syk family kinase inhibitor: Design, synthesis, and structure–activity relationship of 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives

Biophysical and Mechanistic Insights into Novel Allosteric Inhibitor of Spleen Tyrosine Kinase

“…Due to the critical role of Syk in both allergic and autoimmune human diseases, repeated efforts have been made to develop an inhibitor of Syk kinase activity (22)(23)(24)(25)(26)(27). Despite the selectivity achieved by some ATP competitive inhibitors, the high conservation of key residues in the kinase domain make it challenging to find selective ATP competitive kinase inhibitors.…”

“…The potential for a Syk inhibitor to ameliorate both allergic and autoimmune human diseases has created considerable interest for the development of an inhibitor, but finding a selective Syk inhibitor has been limiting (22)(23)(24)(25)(26)(27). We report here a novel allosteric inhibitor of Syk, compound X1 (see Fig.…”

Palladium‐Catalyzed Coupling of Aldehyde‐Derived Hydrazones: Practical Synthesis of Triazolopyridines and Related Heterocycles

“…The reaction with 1,3‐dichloroisoquinoline proceeds selectively at the 1‐position (Table 3, entry 2). Bicyclic heterocycles with four nitrogen atoms are particularly attractive in the development of biologically active compounds; representative examples of their use include [1,2,4]triazolo[4,3‐a]pyrimidines,12a,b,c [1,2,4]triazolo[4,3‐c]pyrimidines,12d [1,2,4]triazolo[4,3‐a]pyrazines,12e and [1,2,4]triazolo[4,3‐b]pyridazines 12b,f. The great versatility of our methodology is demonstrated by the fact that all these heterocyclic systems are available through the same two‐step palladium‐catalyzed‐coupling/oxidative‐cyclization sequence (Table 3, entries 4–10).…”

3‐aminopyrazolopyrazine derivatives as spleen tyrosine kinase inhibitors

“…Several classes of ATP‐competitive Syk inhibitors have been identified, among which fostamatinib ( 1 ), BIIB‐057 ( 2 ), and GS‐9973 ( 3 ) have been advanced into different stages of clinical investigation (Figure ). Although the clinical study of fostamatinib for rheumatoid arthritis was discontinued due to the dose‐limiting adverse effects, recent investigations revealed that the compound exhibited promising efficacy in B‐cell leukemia and lymphoma .…”