Inhibitors of cysteine proteases and methods of use thereof
Inventors
Arnold, Lee D. • Jennings, Andy • Keung, Walter
Assignees
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Publication Number
US-11472793-B2
Publication Date
2022-10-18
Expiration Date
Abstract
The disclosure provides compounds, such as compounds of Formula II, with warheads and their use in treating medical diseases or disorders, such as viral infections. Pharmaceutical compositions and methods of making various compounds with warheads are provided. The compounds are contemplated to inhibit proteases, such as the 3C, CL- or 3CL-like protease.
Core Innovation
The disclosed invention concerns compounds represented by a specified core structure, including fused polycyclic or heteroaromatic scaffolds with amide/carbonyl, urea/amide-like, and nitrile or cyano functionality. The compounds show variable substituents across depicted members, including halogen, fluorinated, methoxy, alkoxy, hydroxyl, sulfone-like, and heteroaryl substituents, together with stereochemical variants and related scaffold changes.
The core structure defines R3 as a C1-C8 alkyl substituted by Rx, and Rx as N(Ry)C(O)Ry, where Ry is independently selected, for each occurrence, from H and C1 alkyl. RB is optionally substituted by one, two or three halogen substituents.
The disclosure includes representative compound series and example compounds described as viral protease inhibitor compounds, together with compound structures and associated structure files. The examples are presented as specific chemical structures within the same general compound family and show variation in substituents and stereochemistry, including fused lactam/amide-containing regions and amide linkages consistent with the claimed structural class.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim with three main inventive features: R3 as C1-C8 alkyl substituted by Rx, Rx as N(Ry)C(O)Ry with Ry independently selected from H or C1 alkyl, and RB optionally substituted by one, two or three halogen substituents. Dependent claims further refine Rx and the halogen substitution count on RB.
C1-C8 alkyl substituted by Rx at R3
R3 is a C1-C8 alkyl substituted by Rx.
Rx as N(Ry)C(O)Ry with Ry as H or C1 alkyl
Rx is N(Ry)C(O)Ry, wherein Ry is independently selected, for each occurrence, from H and C1 alkyl.
RB optionally substituted by one to three halogens
RB is optionally substituted by one, two or three halogen substituents.
Rx as NHC(O)C1 alkyl
Rx is defined in a dependent claim as NHC(O)C1 alkyl.
RB substituted with three halogens
RB is substituted with three halogens.
RB substituted with up to three halogens
RB is substituted by up to three halogens.
Overall, the claims cover a compound scaffold defined by R3 as a C1-C8 alkyl bearing an Rx amide-form substituent, with Rx limited to N(Ry)C(O)Ry where Ry is H or C1 alkyl, and RB limited to optional halogen substitution from one to three halogens. Dependent claims narrow Rx to NHC(O)C1 alkyl and further constrain RB to exactly three halogens or up to three halogens.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Antiviral activity evaluation against SARS-CoV-2 Mpro in an enzymatic assay, with IC50 values and stated calculation methodology with controls.
Cytopathic effect assay evaluation against HCoV 229E and HCoV OC43, with EC50 and cytotoxicity CC50 results reported using categorical outcomes (A-D).
Example compounds are described as viral protease inhibitor example compounds.
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