Structure-based design of 2,4-diaminopyrimidine derivatives bearing a pyrrolyl group as ALK and ROS1 inhibitors

Abstract

Twenty-eight 2,4-diaminopyrimidine derivatives (9a–9n and 10a–10n) bearing a pyrrolyl moiety were designed and synthesized based on the co-crystal structure of ceritinib with ALKwt protein and compound 10d bearing sulfonamide (R1) and 4-methylpiperazinyl (R2) moiety was of great promising.

Identification of highly potent 2,4‐diarylaminopyrimidine analogs of a typical piperidinyl‐4‐ol moiety as promising antitumor ALK inhibitors

“…In initial exploration, the structure–activity relationships (SARs) study was focused on the modification of the hydrophobic pocket portion. Ceritinib was reported to be ineffective against the ALK G1202R mutation due to the higher steric hindrance of isopropoxyl, [ 26 ] thereby replacing isopropoxyl with a smaller methoxy group so as to enter the protein cavity. The effects of the R 1 section on antiproliferative activities were discussed, by keeping the “head” structure as methylamine acyl or isopropyl sulfonyl and the “tail” as piperidinyl or morpholinyl, and four sets of comparative data were obtained in Table 1 (e.g., L1 vs. L2 , L3 vs. L4 , L5 vs. L6 , and L7 vs. L8 ).…”

Antiproliferative Activity of (−)‐Isopulegol‐based 1,3‐Oxazine, 1,3‐Thiazine and 2,4‐Diaminopyrimidine Derivatives

“…[ 16 , 17 , 18 ] Among the existing large numbers of structurally diverse pyrimidine derivatives, 2,4‐diaminopyrimidines have attracted considerable attention due to their important chemopreventive and chemotherapeutic effects. [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] This structural motif is involved in numerous biological activities – mainly concerning cancer – with action mechanisms related to folate metabolism inhibition, [38] kinase inhibitor activity[ 26 , 39 , 40 , 41 , 42 , 43 , 44 ] and apoptosis induction. [ 22 , 45 , 46 ] For example, Ceritinib (Zykadia™), [47] Alectinib (Alecensa TM ), [48] Brigatinib (Alunbrig™), [49] Lorlatinib, (Lorbrena TM ), [50] small‐molecule antineoplastic anaplastic lymphoma kinase (ALK) inhibitors, and others are used for the treatment of patients with non‐small cell lung cancer.…”