1208109-00-5Relevant articles and documents
5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors
Arasappan, Ashok,Bennett, Frank,Girijavallabhan, Vinay,Huang, Yuhua,Huelgas, Regina,Alvarez, Carmen,Chen, Lei,Gavalas, Stephen,Kim, Seong-Heon,Kosinski, Aneta,Pinto, Patrick,Rizvi, Razia,Rossman, Randall,Shankar, Bandarpalle,Tong, Ling,Velazquez, Francisco,Venkatraman, Srikanth,Verma, Vishal A.,Kozlowski, Joseph,Shih, Neng-Yang,Piwinski, John J.,MacCoss, Malcolm,Kwong, Cecil D.,Clark, Jeremy L.,Fowler, Anita T.,Geng, Feng,Kezar III, Hollis S.,Roychowdhury, Abhijit,Reynolds, Robert C.,Maddry, Joseph A.,Ananthan, Subramaniam,Secrist III, John A.,Li, Cheng,Chase, Robert,Curry, Stephanie,Huang, Hsueh-Cheng,Tong, Xiao,Njoroge, F. George
, p. 3229 - 3234 (2012)
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.
Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors
Bennett, Frank,Kezar III, Hollis S.,Girijavallabhan, Vinay,Huang, Yuhua,Huelgas, Regina,Rossman, Randall,Shih, Neng-Yang,Piwinski, John J.,MacCoss, Malcolm,Kwong, Cecil D.,Clark, Jeremy L.,Fowler, Anita T.,Geng, Feng,Roychowdhury, Abhijit,Reynolds, Robert C.,Maddry, Joseph A.,Ananthan, Subramaniam,Secrist III, John A.,Li, Cheng,Chase, Robert,Curry, Stephanie,Huang, Hsueh-Cheng,Tong, Xiao,George Njoroge,Arasappan, Ashok
scheme or table, p. 5144 - 5149 (2012/09/07)
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC50) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC50) was low.
SUBSTITUTED PYRIDINE AND PYRIMIDINE DERIVATIVES AND THEIR USE IN TREATING VIRAL INFECTIONS
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Page/Page column 118-119, (2010/04/03)
The present invention provides compounds of Formula (I): and tautomers, isomers, and esters of said compounds, and pharmaceutically acceptable salts, solvates, and prodrugs of said compounds, wherein wherein each of R, R1, X, Y, Z, R2, R3, R4, R5, R6, R7, R8, R9, R18, R19 and n is selected independently and as defined herein. Compositions comprising such compounds are also provided. The compounds of the invention are effective as inhibitors of HCV, and are useful, alone and together with other therapeutic agents, in treating or preventing diseases or disorders such as viral infections and virus-related disorders.
