This paper describes the development of a relatively feasible, economic, and safe method for the multigram-scale synthesis of BIIB068, an efficient reversible BTK inhibitor. The new process is highlighted by an economical construction of a 2-amino-4 substituted pyrimidine employing a simple nucleophilic substitution reaction and a green reduction of the cyano group. The developed process provided an overall yield of 32

To overcome drug resistance caused by ALK kinase mutations especially G1202R, two series of novel 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety were designed, synthesized and evaluated for their biological activities. Among all the target compounds, B10 efficiently inhibited the proliferation of ALK-positive Karpas299 and H2228 cells both with IC50 values of 0.07 μM. In addition, B10 exhibited remarkable enzymatic inhibitory potency with IC50 values of 4.59 nM, 2.07 nM and 5.95 nM toward ALKWT, ALKL1196M and ALKG1202R, respectively. Furthermore, B10 induced apoptosis in H2228 cell and caused cell cycle arrest in G2/M phase. Ultimately, the binding modes of B10 with ALKWT and ALKG1202R were ideally established, which further confirmed the structural basis in accordance with the SARs analysis. These results indicated that B10 was a potent ALK inhibitor for ALKG1202R mutation treatment and deserved for further investigation.

Abstract The base-induced formal [4+3] cycloaddition reaction of C,N-cyclic azomethine imines with aza-ortho-quinone methides, generated in situ, is reported. This protocol provided an efficient method for the synthesis of biologically important 1,2,4-triazepine derivatives, with a wide substrate scope and excellent functional-group tolerance, and it gives moderate to excellent yields under mild conditions. Several of the derivatives exhibited in vitro antitumor activities against the A2780 cell line in a screening of the cancer cell lines HCT-116, H2228, and A2780 by an MTT assay.