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-11524940-B1
Publication Date
2022-12-13
Expiration Date
Abstract
The disclosure provides compounds 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 disclosure relates to viral protease inhibitor compounds represented by chemical structures or pharmaceutically acceptable salts thereof. The compounds are defined by Markush-style substituent variables including R1, R2, R3, RB, Rx, Ry, and RA, with ring-size limitations for heteroaryl and heterocycle groups and optional substitution by halogen, cyano, hydroxyl, oxo, alkoxy, alkyl, and nitrogen- or sulfur-containing functional groups. The scaffold includes an NHC(O)RB group and heteroaryl or heterocycle ring systems selected from specified ring-size ranges.
The disclosed embodiments include indole-2-carboxamide and indole-2-carbonyl-containing compounds, heteroaryl and bicyclic or fused ring motifs, cyano or nitrile functionalities, and variations in stereochemistry. Additional embodiments show benzimidazole, imidazo[4,5-b]pyridine, benzothiazole, chloropyrrole-like, methoxy-indole, quinolinone-containing amino acid derivatives, pyrazole, indazolyl, oxindolinyl, benzofuran, 2,3-dihydrobenzofuran, oxopyrrolidinyl, azaspiro, and cyclopropyl-containing ring systems within the same chemical space. The examples are presented as specific chemical structures and representative compound instances consistent with the claim variable sets.
The disclosure also includes warhead-containing compound scaffolds, including iminoimidazolidinone warhead moieties, non-iminoimidazolidinone warhead examples such as sulfonyl/S(O)2-containing functionality, and covalent cysteine-protease inhibitor embodiments. The content describes compounds represented by Formula II and conjugate forms represented by Formula III, together with pharmaceutically acceptable salt, stereoisomer, and prodrug forms. The examples include structure-represented embodiments with fluorinated substituents, halogenation, methoxy or alkoxy oxygen substituents, sulfur-containing motifs, nitrile-bearing motifs, cyclopropyl or cycloalkyl groups, and stereochemically defined examples supported by spectroscopic characterization.
Claims Coverage
The consolidated claim coverage includes three independent claims directed to compounds or pharmaceutically acceptable salts defined by Markush-style substituent variables. Across the claims, the inventive features center on constrained selections for R1, R2, R3, RB, Rx, Ry, and RA, with overlapping coverage around heteroaryl/heterocycle ring-size ranges, the NHC(O) linkage at R2, and enumerated optional substitution patterns.
Markush-defined compound scaffold with variable substituent groups
A compound represented by a defined structure or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C8 alkyl, C3-C10 cycloalkyl, and C6 aryl with optional substitution by halogen, cyano, and C1-8 alkyl; R2 is NHC(O)RB or a specific structural fragment; R3 is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle with optional substitution by RA; RB is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle with optional substitution by Rx; and Rx, Ry, and RA are independently selected from defined functional-group sets.
Constrained NHC(O)-(5-10 membered heteroaryl) scaffold
A compound represented by a defined structure or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C8 alkyl and C3-C10 cycloalkyl with optional substitution by halogen and C1-8 alkyl; R2 is NHC(O)-(5-10 membered heteroaryl) with optional substitution by halogen, OCH3, OH, C1-C8 alkyl, and C1-C8 alkoxy; and R3 is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle with optional substitution by RA.
Specific substituent sets for Rx, Ry, and RA
Rx is independently selected from halogen, hydroxyl, oxo, cyano, OCHF2, OCF3, C(O)O(CH3), and multiple nitrogen-containing carbonyl-related, alkyl, cycloalkyl, alkoxy, and heteroalkyl options; Ry is hydrogen or C1-C8 alkyl optionally substituted by halogens; and RA is independently selected from halogen, cyano, hydroxyl, oxo, OCF3, OCHF2, S-CH3, S(O)2-CH3, NH2, O-phenyl, O-(C1-C8 alkyl)-phenyl, N(Ry)2, N(Ry)(C1-C8 alkyl)C(O)O-phenyl, N(Ry)(C1-C8 alkyl)C(O)N(Ry)2, C(O)OC(CH3)3, and alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, and cycloalkyl options.
Across the independent claims, the coverage is directed to compound classes defined by a common Markush scaffold and constrained substituent choices for R1, R2, R3, RB, Ry, Rx, and RA. The claims use ring-size-limited heteroaryl and heterocycle selections together with enumerated functional-group inventories to define the inventive scope.
Stated Advantages
Substantial antiviral evaluation is provided using an enzymatic SARS-CoV-2 Mpro fluorescence assay with IC50 calculation and cellular HCoV 229E/OC43 CPE viability assays with EC50/CC50 categories, including activity tables.
Documented Applications
Use as viral protease inhibitors targeting Cathepsin K, coronavirus Mpro, Caspase 3, Calpain 1, and Cathepsin S.
Treating viral infections, including coronavirus infection such as SARS-CoV-2 (COVID-19).
Inhibiting viral transmission, viral replication, viral protein expression minimization, and/or viral release inhibition.
Combination therapy with other antivirals.
Pharmaceutical compositions and kits including dosage forms and carriers.
Enzymatic inhibition evaluation using a SARS-CoV-2 Mpro fluorescence assay with IC50 calculation.
Cellular antiviral activity evaluation using HCoV 229E and HCoV OC43 cytopathic effect viability assays with EC50/CC50 categories.
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