Hepatitis B core protein modulators

Inventors

Turner, William • Arnold, Lee Daniel • Maag, Hans • Li, Leping • Bures, Mark • Haydar, Simon • Francis, Samson

Assignees

Indiana University Research and Technology Corp • Assembly Biosciences Inc

Abstract

The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.

Core Innovation

The disclosure concerns substituted thiazole- and pyridine-containing N-((thiazolyl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepine-8-carboxamide derivatives and related dibenzo[b,f][1,4]thiazepine/oxazepine carboxamide compounds, including pharmaceutically acceptable salts and hydrochloride salts. The material also describes synthetic preparation and characterization of related heteroaryl and fused heterocyclic compounds, including substituted aminomethyl thiazole-linked aryl analogs, bithiazole and heteroaryl analogs, and dibenzo[b,f][1,4]thiazepine-associated compounds.

The compounds and intermediates are prepared through multi-step synthesis and related transformations that include late-stage coupling, Suzuki coupling, reductive amination, hydrogenation, mesylation, azide substitution, deprotection, salt formation, SNAr, S-alkylation, Pd/C hydrogenation, hydrolysis, CDI-mediated coupling, and oxidative ring transformations. The disclosure further includes sulfur-linked nitrobenzoate/benzoic acid intermediates, regioisomer mixtures, conversion of nitro groups to amino groups, and sulfone or 5,5-dioxide motif formation.

Additional content provides specific compound series and intermediates, including thiazolyl–dibenzo[b,f][1,4]thiazepine-8-carboxamide 5,5-dioxide derivatives, dibenzo[b,e][1,4]diazepine-8-carboxylate compounds, and substituted benzimidazole or heteroaryl amide compounds. The document provides analytical characterization and structural depictions for multiple exemplified compounds and intermediates, including TLC, LC-MS, HPLC purity, mass, and 1H NMR data.

Claims Coverage

The consolidated claim coverage centers on a compound defined by a specific chemical formula, or a pharmaceutically acceptable salt thereof, with dependent claims adding a pharmaceutically acceptable composition including an excipient and a method of treating hepatitis B infection by administration. Three inventive feature areas are present across the claim sets: the formula-defined compound, the pharmaceutical composition, and the therapeutic treatment method.

Overall, the claims cover a formula-defined compound or pharmaceutically acceptable salt, extend to a pharmaceutically acceptable composition with an excipient, and further cover a method of treating hepatitis B infection by administering an effective amount to a patient.

Stated Advantages

Documented Applications