Uracil derivatives having virus replication inhibitory activity and pharmaceutical composition comprising the same
Inventors
Sato, Jun • SHIBAYAMA, Hiromitsu • HIRAI, Keiichiro • UNOH, YUTO • UEHARA, Shota • Yonezawa, Shuji • Kurahashi, Kana • Kojima, Eiichi
Assignees
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Publication Number
US-12545687-B2
Publication Date
2026-02-10
Expiration Date
Abstract
The present invention provides a compound exhibiting coronavirus 3CL protease inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same.Provided is a compound represented by Formula (I):wherein Ring A is a ring represented by:wherein X is a single bond or the like, R2 is substituted or unsubstituted aromatic carbocyclyl or the like, R3c is substituted or unsubstituted aromatic carbocyclyl or the like, R3 is substituted or unsubstituted aromatic carbocyclyl or the like, R3a is a hydrogen atom or the like, R3b is a hydrogen atom, R8a is substituted or unsubstituted aromatic carbocyclyl or the like, and R8b is a hydrogen atom or the like,R1 is a substituted or unsubstituted aromatic heterocyclyl, m is 0 or the like, R5a is each independently a hydrogen atom or the like, R5b is each independently a hydrogen atom or the like, R6 is cyano or the like, and R7a and R7b are each independently a hydrogen atom or the like, or a pharmaceutically acceptable salt of the compound.
Core Innovation
The disclosed subject matter provides a class of coronavirus 3CL protease inhibitors in the form of Formula (I) compounds, including uracil-derivative compounds, pharmaceutically acceptable salts, and allowable structural variations within the defined substituents and Ring A structures. The scope includes isomers, keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers, rotamers, isotope-labeled and radiolabeled forms, and pharmaceutically acceptable salts, solvates, hydrates, crystal polymorphs, co-crystals, and prodrugs.
The compounds are described as having coronavirus activity, including virus replication inhibitory activity associated with inhibition of 3CL protease, and as coronavirus 3CL protease inhibitor candidates. The coronavirus scope includes HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2, alpha coronavirus, beta coronavirus, and COVID-19 context, with therapeutic and prophylactic utility stated for human coronavirus infections.
The disclosure also presents multiple compound series and specific final compounds, together with associated LC/MS characterization and, in some instances, 1H-NMR signals and retention time and m/z information for compound embodiments. It further describes compound series with substituted heteroaromatic and fused ring scaffolds, deuterated forms, and broader formulation context using pharmaceutically acceptable carriers or diluents.
Claims Coverage
The consolidated claim coverage centers on a compound selected from a specified group, or a pharmaceutically acceptable salt thereof, together with method claims for treating selected coronaviruses in humans by administering a therapeutically effective amount, and pharmaceutical composition claims including a pharmaceutically acceptable carrier or diluent. Across the consolidated material, the claim coverage includes three inventive features.
Selected compound group and pharmaceutically acceptable salts
A compound selected from the group consisting of the disclosed compounds, or a pharmaceutically acceptable salt thereof.
Treating enumerated coronaviruses by human administration
A method for treating a selected coronavirus, including HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, or SARS-CoV-2, by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a human in need.
Pharmaceutical composition with pharmaceutically acceptable carrier or diluent
A pharmaceutical composition that includes the compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
Overall, the claims cover a defined compound group and pharmaceutically acceptable salts, therapeutic administration for treating enumerated coronavirus infections in humans, and pharmaceutical compositions comprising the compound with a pharmaceutically acceptable carrier or diluent.
Stated Advantages
Coronavirus 3CL protease inhibitory activity.
Coronavirus replication inhibition.
Therapeutically and prophylactically useful for human coronavirus infections.
Weak CYP inhibition.
Metabolic stability.
High solubility.
Selectivity related to coronavirus 3CL protease.
Pharmacokinetics-related attributes including bioavailability and clearance are described.
The disclosed compounds are useful as therapeutic agents for coronavirus-associated disease.
The disclosed compounds are useful as prophylactic agents for coronavirus-associated disease.
Provides 3CL-protease inhibitory coronavirus therapeutics distinct from prior 3CL inhibitors.
Documented Applications
Therapeutic and prophylactic treatment of human coronavirus infections, including SARS-CoV, MERS-CoV, SARS-CoV-2, HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43, by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a human in need.
Use as a coronavirus replication inhibitor, including use against alpha coronavirus and beta coronavirus.
Use in coronavirus 3CL protease inhibition.
Use of coronavirus-related pharmaceutical compositions including a compound of Formula (I) as a coronavirus 3CL protease inhibitor and as a coronavirus replication inhibitor, including for SARS-CoV-2.
SARS-CoV-2 entry-related cytopathic effect suppression in HEK293T/ACE2/TMPRSS2 cells.
SARS-CoV-2 3CL protease inhibitory activity evaluation using a fluorescence/LC-MS substrate-peptide assay.
Therapeutic and prophylactic use for coronavirus-associated disease.
Pharmaceutical compositions containing the compound or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
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