5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

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• 作者：Ashok Arasappan^a ; ^{ashok.arasappan@merck.com} ; Frank Bennett^a ; Vinay Girijavallabhan^a ; Yuhua Huang^a ; Regina Huelgas^a ; Carmen Alvarez^a ; Lei Chen^a ; Stephen Gavalas^a ; Seong-Heon Kim^a ; Aneta Kosinski^a ; Patrick Pinto^a ; Razia Rizvi^a ; Randall Rossman^a ; Bandarpalle Shankar^a ; Ling Tong^a ; Francisco Velazquez^a ; Srikanth Venkatraman^a ; Vishal A. Verma^a ; Joseph Kozlowski^a ; Neng-Yang Shih^a ; John J. Piwinski^a ; Malcolm MacCoss^a ; Cecil D. Kwong^b ; Jeremy L. Clark^b ; Anita T. Fowler^b ; Feng Geng^b ; Hollis S. Kezar III^b ; Abhijit Roychowdhury^b ; Robert C. Reynolds^b ; Joseph A. Maddry^b ; Subramaniam Ananthan^b ; John A. Secrist III^b ; Cheng Li^a ; Robert Chase^a ; Stephanie Curry^a ; Hsueh-Cheng Huang^a ; Xiao Tong^a ; F. George Njoroge^a
• 关键词：HCV Replication inhibitor ; HCV Replicase inhibitor ; Carbanucleoside-like ; 5-Aryl pyrimidine ; 5-Benzothiazolyl pyrimidine ; C&ndash ; H arylation
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 May, 2012
• 卷：22
• 期：9
• 页码：3229-3234
• 文件大小：4512 K

摘要

Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.