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    • The G R mutation is located at

    2023-05-24

    The G1202R mutation is located at the solvent front of the ALK kinase domain adjacent to the inhibitor's binding pocket. Although barely reported in the setting of crizotinib resistance, it has emerged as the most refractory mutation to both the first- and second-generation ALK inhibitors. The large basic residue 1202R is believed to diminish the binding affinity of inhibitors with ALK due to the steric hindrance [19,20]. From the binding modes, both the morpholinopiperidine ring in alectinib and the piperidine ring in ceritinib (blue color) possess steric hindrance with the 1202R residue, likely responsible for the loss of potency against this mutant. On the basis of this analysis, several research groups have reported structural modifications on both the G1202R-interaction fragments, and a few analogues of either alectinib (2) and ceritinib (3) were identified showing potent activity against this mutant [[21], [22], [23]]. Recently, we reported a series of 2,4-diarylaminopyrimidine analogues bearing a flexible amino RS-1 mg sidechain on the C2-benzene-1,3-diamine component to replace the solvent-interaction pocket that was occupied by the piperidine moiety in ceritinib (3). Among these compounds, compound 6 (Fig. 1) bearing a small flexible glycine side chain showed good in vitro and in vivo potency against ALK [24]. Compared with the piperidine ring in 3, the glycine side chain was smaller, more flexible and located at the meta-position of the aniline ring, which is far away from the G1202R. As such, the steric hindrance between 1202R and the glycine sidechain is minor, indicating an ample space for further structural tuning (Fig. 2). Based on this analysis and in view of the metabolic instability of the terminal primary amino moiety in 6, in this report we described our design of a series of new diarylaminopyrimidine analogues by incorporating a resorcinol moiety at the solvent front area of the ALK kinase domain. These compounds were found to show high potency against most of ALK resistant mutants, especially the challenging G1202R.
    Chemistry The synthesis of compounds 12a-r is described in Scheme 1, Scheme 2. The key intermediates 7a-d [[24], [25], [26]] and 8a-f [[27], [28], [29]] were prepared by following literature procedures. Condensation of N-Boc-protected glycine 9a with substituted nitroanilines in the presence of HATU, HOAt and DIPEA, followed by reduction afforded the desired intermediates 10a-e in 56–77% overall yields. Cross-coupling of compounds 10a-e with 7d was conducted in the presence of Pd2(dba)3, X-Phos, and Cs2CO3, and the products were subsequently treated with TFA to provide compounds 11a-e in 55–77% overall yields for two steps [24]. Compounds 11a and 11c-e were condensed with acid 8b followed by O-debenzylation using BCl3 to afford compounds 12a and 12c-e in 17–40% overall yields [27]. Meanwhile, compounds 12b and 12p were obtained in 27% and 25% overall yields, respectively from condensation of 11b with acid 8b following by treating with Pd/C under H2 atmosphere. Condensation of 11a with 8a in the presence of HATU, HOAt and DIPEA formed compound 12j in 74% yield. In addition, condensation of various acids 8c-f with 11d provided intermediates 12k’-n’ in 78–86% yields, which was followed by O-debenzylation to afford compounds 12k-n in 38–47% yields. As shown in Scheme 2, condensation of various N-Boc-protected amino acid derivatives 9b-e with 4-methoxy-3-nitroaniline, followed by reduction afforded intermediates 10f-i in 56–77% overall yields. Precursors 11f-i were prepared in 54–78% overall yields by Pd-catalyzed N-arylation of 10f-i with 7d, followed by N-Boc-deprotection. The final products 12f-i were obtained in 27–37% overall yields through condensation of 11f-i with acid 8b, followed by O-debenzylation using BCl3. Coupling of 7a-b with 10d followed by N-deprotection yielded compounds 11j-k, which were subsequently converted to compounds 12o and 12q in 36% and 29% overall yields, respectively by condensation with 8b followed by O-debenzylation. In addition, intermediate 11l was prepared through cross-coupling of 7c with 10a, followed by N-deprotection with TFA. Similarly, compound 12r was obtained in 26% overall yield by condensation of 11l with 8b followed by O-deprotection.