Nakajima, Ryota;Oono, Hiroyuki;Sugiyama, Sakae;Matsueda, Yohei;Ida, Tomohide;Kakuda, Shinji;Hirata, Jun;Baba, Atsushi;Makino, Akito;Matsuyama, Ryo;White, Ryan D.;Wurz, Ryan Ρ.;Shin, Youngsook;Min, Xiaoshan;Guzman-Perez, Angel;Wang, Zhulun;Symons, Antony;Singh, Sanjay K.;Mothe, Srinivasa Reddy;Belyakov, Sergei;Chakrabarti, Anjan;Shuto, Satoshi published 《Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists》 in 2020. The article was appeared in 《ACS Medicinal Chemistry Letters》. They have made some progress in their research.COA of Formula: C7H5BrClNO2 The article mentions the following:
The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analog of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analog 3a was found to be a potent RORγt inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analog, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production And Methyl 3-bromo-6-chloropicolinate (cas: 1214328-96-7) was used in the research process.
N-Arylation of a wide range of NH substrates by reaction with boronic acid in the presence of cupric acetate and either triethylamine or pyridine at room temperature. The reaction works even for poorly nucleophilic substrates such as arylamide. So Methyl 3-bromo-6-chloropicolinate(cas: C7H5BrClNO2) can also undergo this reaction.