Development of Scaffold Synthesis for the Preparation of New Insulin-Like Growth Factor 1 Receptor Inhibitors

Abstract

The synthesis of new insulin-like growth factor 1 receptor (IGF-1R) inhibitors is reported. The described molecules have a new sulfonyl-indazole structure. We describe the process research and development for the scaffold synthetic procedure in order to provide the large amount of product required for lead optimization, candidate selection, and preclinical studies.

Ag/Cu-Mediated Decarboxylative Cyanation of Arene Carboxylic Acids Using NH4+/N,N-Dimethylformamide as Combined Cyanide Source

“…97～99 ℃ (Lit. [37] 102～104 ℃); 1 H NMR (400 MHz, CDCl 3 ) δ: 8.41 (dd, J＝9.2, 4.8 Hz, 1H), 7.62 (dd, J＝7.2, 2.8 Hz, 1H), 7.56～ 7.52 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ: 166.1, 163.5, 128.5, 128.4, 122.9, 122.6, 121.1, 120.9, 113.7, 110.5, 110.4; 19 F NMR (377 MHz, CDCl 3 ) δ: -99.4～ -99.5 (1F).…”

Direct Access to 3-Aminoindazoles by Buchwald-Hartwig C-N Coupling Reaction

“…Thus, the preparation of such products typically involved an aromatic nucleophilic substitution between hydrazine and benzonitriles or thioamides 16 substituted in ortho position by a leaving group like fluorine, 3b,4,17 or also sometimes by chlorine 18 or a nitro group. 19 Moreover, finally using similar cyclization conditions, introduction of the amino group could also result from the reaction of different amines on the 2halobenzyl chloroimidates, which were synthesized by the addition of a protected hydrazine on 2-halobenzyl acids followed by chlorination. 20 A new approach, which allows the direct incorporation of elaborated amines at the 3 position of the indazole nucleus, is therefore needed.…”

Two-Step Synthesis of Substituted 3-Aminoindazoles from 2-Bromobenzonitriles

“…Their synthesis typically involved an aromatic nucleophilic substitution between hydrazine and o -substituted benzonitriles. The leaving group used for the reaction to succeed is mainly fluorine , but also more rarely chlorine or a nitro group . 3-Aminoindazoles substituted on the amino group were prepared as well by reaction of hydrazine with N -substituted fluoroarylthioamides .…”

“…The leaving group used for the reaction to succeed is mainly fluorine 1,7 but also more rarely chlorine 8 or a nitro group. 9 3-Aminoindazoles substituted on the amino group were prepared as well by reaction of hydrazine with Nsubstituted fluoroarylthioamides. 10 The main drawback of these methods is the low yields and harsh conditions when ofluorobenzonitriles are deactivated by an electron-donating group.…”