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5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors. 2012
Ashok Arasappan, and
Frank Bennett, and
Vinay Girijavallabhan, and
Yuhua Huang, and
Regina Huelgas, and
Carmen Alvarez, and
Lei Chen, and
Stephen Gavalas, and
Seong-Heon Kim, and
Aneta Kosinski, and
Patrick Pinto, and
Razia Rizvi, and
Randall Rossman, and
Bandarpalle Shankar, and
Ling Tong, and
Francisco Velazquez, and
Srikanth Venkatraman, and
Vishal A Verma, and
Joseph Kozlowski, and
Neng-Yang Shih, and
John J Piwinski, and
Malcolm MacCoss, and
Cecil D Kwong, and
Jeremy L Clark, and
Anita T Fowler, and
Feng Geng, and
Hollis S Kezar, and
Abhijit Roychowdhury, and
Robert C Reynolds, and
Joseph A Maddry, and
Subramaniam Ananthan, and
John A Secrist, and
Cheng Li, and
Robert Chase, and
Stephanie Curry, and
Hsueh-Cheng Huang, and
Xiao Tong, and
F George Njoroge
Merck Research Laboratories, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. ashok.arasappan@merck.com
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.
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