Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure—activity relationship study

Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core

“…Benzo[b]carbazolone 3 and indazole 6 represent two different types of structures, especially the benzo [b]carbazolones that are not frequently used as templates of TK inhibitors and only limited structure-activity relationship studies have been reported. [22][23][24] To ultimately explore the structure variations of benzo [b]carbazolones as ALK inhibitors, [25][26][27][28] we recently conducted a structural optimization by introducing a rotatable C8-side chain to the tetracyclic center that led to the potent ALK inhibitor 7 27,28 (SOMCL-13-93) ( Figure 2), which showed high potency against both wild ALK and L1196M gatekeeper mutant with IC 50 values of 3.4 and 3.9 nM, respectively. Compound 7 is also highly potent to inhibit the proliferation of ALK-dependent lung cancer H3122 cells and showed >100 % tµMor growth inhibition (TGI) in the NIH-3T3 xenografts at the dose of 20.0 mg/kg.…”

Recent Developments in the Synthesis of Indole‐Pyrazole Hybrids

“…Jiang and co‐workers synthesized various benzyl‐linked indole‐C2 pyrazole hybrids ( 65 ‐ 67 ) and pyrazole‐bearing benzo[ b ]carbazolones ( 70 – 74 ) as illustrated in Schemes 11 & 12, and studied their anaplastic lymphoma kinase (ALK) inhibitory activities [49] . The intermediate, tert ‐butyl 6‐cyano‐2‐(2‐(4‐ethyl‐3‐iodophenyl)propan‐2‐yl)‐1 H ‐indole‐3‐carboxylate ( 64 ) was prepared starting from ethyl (2‐(4‐ethyl‐3‐iodophenyl)‐2‐methylpropanoyl)carbamate ( 63 ) by following the literature procedure [50] .…”

Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

“…On the other hand, alectinib is another FDA approved, highly selective, orally active, potent, and CNS penetrant ALK inhibitor which has shown a promising therapeutic window for the patients treated with crizotinib harboring ALK secondary mutations. [88][89][90][91][92][93] Alectinib is non-DAAPalogue drug which comprised of benzo[b]carbazolone structural motif [94][95][96][97] that is not ubiquitous template in second or even third generation TKIs. In medicinal chemistry campaign limited structure-activity relationship (SAR) investigation has been reported for benzo[b]carbazolone core possibly due to difficulty in chemical synthesis.…”

“…In medicinal chemistry campaign limited structure-activity relationship (SAR) investigation has been reported for benzo[b]carbazolone core possibly due to difficulty in chemical synthesis. [97][98][99][100][101] However, recently reported JH-VIII-157-02 has been potent against the G1202R mutant and comprised of benzo[b]carbazolone core. 102 In the designing and development of next-generation ALK-TKIs, the 2,4-diarylaminopyrimidine (DAAP) structural moiety has been incorporated extensively.…”