Strategies to Mitigate the Bioactivation of 2-Anilino-7-Aryl-Pyrrolo[2,1-f][1,2,4]triazines: Identification of Orally Bioavailable, Efficacious ALK Inhibitors

Abstract

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.

Discovery of <i>N</i>-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-<i>N</i>′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor

“…was synthesized by reacting commercially available 15 with 2-bromopropane using a sodium hydroxymethanesulfinate promoted one-pot reaction. 16) Oxidation of 16 with m-chloroperoxybenzoic acid (mCPBA), followed by reduction of the nitro group using iron powder in acetic acid (AcOH), provided compound 18, which was converted to 20 in two steps by employing procedures similar to those described for 14a-14l. The synthesis of 25 is shown in Chart 6.…”

“…Compound 29 was synthesized by reacting 26 17) with 13a under basic conditions, followed by the removal of the tertbutoxycarbonyl group and reductive amination (Chart 7).…”

“…The residue was treated with acetonitrile, EtOH and water to give 25 (133 mg, 49%). tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate 17) 26 (686 mg, 2.24 mmol) and DIPEA (0.47 mL, 2.69 mmol) in NMP (4 mL) was irradiated with microwaves at 120°C for 20 min. Water was added to this reaction mixture, and the resulting solid was filtered and dried in vacuo.…”

Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

“…To the best of our knowledge, this is the first time 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine kinase inhibitors are exemplified [71]. Two potent and selective ALK inhibitors (38 and 39, Figure 8) were published and have shown excellent PD responses and efficacies in NPM-ALK + ALCL xenografts with good ADME properties [71,74]. An optimized synthetic route to this scaffold was also developed in collaboration with the internal process chemistry group [75].…”

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy

“…Mesaros and co-workers discovered compound 22 as a potent ALK inhibitor displaying IC 50 of 6 nM along with high selectivity over IR (Fig. 9 ) [ 94 ]. In PK studies, 22 showed good iv half-life ( t 1/2 = 3.4 h), low clearance (12 mL/min/kg) and good stability in rat liver microsomes.…”