Design and synthesis of novel pyrrolo[2,3-d]pyrimidine derivatives as potent JAK3 and SYK dual inhibitors

Janus kinase (JAK) and spleen tyrosine kinase (SYK) are two crucial tyrosine kinases implicated in the immune modulation and represent launched therapeutic targets for immunological disorders. Nevertheless, the monotherapy targeting a single kinase encounters challenges related to drug resistance and inadequate efficacy. In this case, the exploration of inhibitors targeting both JAK and SYK has emerged as a promising therapeutic strategy. In this study, a series of novel pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized to selectively inhibit both JAK3 and SYK. The lead compound, 6e, demonstrated an IC50 value of 2.14 mu M against JAK3 and 7.10 mu M against SYK, while exhibiting negligible activity against GSK3 beta (IC50 > 50 mu M), providing a hit scaffold for the development of selective JAK/SYK dual inhibitors.