HCV NS3 protease inhibitors
Inventors
Liverton, Nigel J. • Summa, Vincenzo • Harper, Steven • McCauley, John A. • Romano, Joseph J. • Rudd, Michael T.
Assignees
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Publication Number
US-9738661-B2
Publication Date
2017-08-22
Expiration Date
Abstract
The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
Core Innovation
The patent describes a compound family defined by formula (I) with tightly restricted structural options, including one or more rings selected from specified ring units and substituent variables R1, R2, R3, R6, Y, Z, M, X, and each R10 independently H. The definition includes Y selected from —OC(O)—, Z as a direct bond, X selected from —(CH2)0-3O—, and M selected from C1-C12 alkylenes and C2-C12 alkenylenes substituted with 1 to 2 substituents F independently selected from C1-C8 alkyl and —CH2. The disclosure presents stereodefined examples and related intermediates, with LRMS ESI m/z values, LCMS or LRMS m/z values, and NMR references reported for characterized compounds.
The examples describe structurally related fused heterocycle and bicyclic compounds, including diazatricyclo, oxadiazacyclooctadecine, triazatricyclo, tetraazapentacyclo, tetraazahexacyclo, and triazapentacyclo frameworks. The compounds include carboxylate, carboxylic acid, carboxamide, ester, sulfonamide, amino-acid derived side chain functionalities, vinyl, cyclopropylsulfonyl, triazole, aryl or heteroaryl substituents, and phthalimide-like isoquinoline dione motifs. The content also notes transformations among intermediates and final compounds, including oxidation, hydrogenation, decobalting, coupling, deprotection, and formation of cyclized or bicyclic scaffolds.
The disclosure further includes example compounds such as triazole-containing products, carboxamide 19-oxide derivatives, vinylcyclopropane carboxylic acid derivatives, cycloalkyl- and amino-acid derivatives, and piperidine-based and pyrrolidine-based intermediates. Named compounds include 3-methyl-N({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine, t-Butyl (3R)(3S)-3-(allyloxy)piperidine-1-carboxylate, and (2S)-[{[(1R,2S)-2-allylcyclopentyl]oxy}carbonyl)amino](cyclopentyl)acetic acid. The patent text is centered on defining and exemplifying members of the compound family rather than stating a separate biological mechanism.
Claims Coverage
The claim coverage centers on a compound of formula (I) with enumerated ring, linker, and substituent limitations, including each R10 independently H. The claim set also includes dependent coverage that narrows substituent M and extends to pharmaceutical compositions with a pharmaceutically acceptable carrier and optional second therapeutic agent categories. Overall, the inventive features comprise the formula (I) compound definition, the narrowed M selections, and the composition claims built around it.
Formula (I) compound with enumerated ring and substituent selections
A compound of formula (I) wherein one or more rings are selected from a specified group; R1 is selected from —CO2R10 and —CONR10SO2R6; R2 is selected from —CH=CH2; R3 is C1-C6 alkyl; R6 is C3 cycloalkyl; Y is selected from —OC(O)—; Z is a direct bond; M is selected from C1-C12 alkylenes and C2-C12 alkenylenes substituted with 1 to 2 substituents F independently selected from C1-C8 alkyl and —CH2; X is selected from —(CH2)0-3O—; and each R10 is independently H.
Specific allowable substituent M structures
The compound further defines M by selected alkyl and alkenyl structures, including enumerated linkage and branching patterns terminating in Y groups.
Pharmaceutical composition with effective amount and pharmaceutically acceptable carrier
A pharmaceutical composition comprising an effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier.
Pharmaceutical composition with an optional second therapeutic agent category
The pharmaceutical composition further includes a second therapeutic agent selected from HCV antiviral agents, immunomodulators, and anti-infective agents.
Pharmaceutical composition with HCV protease and NS5B polymerase inhibitors
The pharmaceutical composition further includes a second therapeutic agent selected from HCV protease inhibitors and HCV NS5B polymerase inhibitors.
The claims cover a narrowly defined formula (I) compound with constrained ring, linker, and substituent options, and extend to pharmaceutical compositions containing the compound with a pharmaceutically acceptable carrier. Additional dependent coverage specifies optional co-therapy categories, including HCV antiviral agents, immunomodulators, anti-infective agents, HCV protease inhibitors, and HCV NS5B polymerase inhibitors.
Stated Advantages
HCV NS3 protease inhibition for treating or preventing HCV infection.
Reducing symptom likelihood or severity.
Documented Applications
Treating or preventing HCV infection using the macrocyclic compounds as HCV NS3 protease inhibitors.
Inhibiting NS3 protease and treating HCV.
Reducing symptom likelihood or severity.
Using the compounds in screening assays involving NS3 protease activity, including a TRF assay, with Ki and IC50 relationships.
Administering pharmaceutical compositions containing the compounds together with pharmaceutically acceptable carriers, optionally with a second therapeutic agent.
Combination use with a second therapeutic agent selected from HCV antiviral agents, immunomodulators, and anti-infective agents.
Combination use with a second therapeutic agent selected from HCV protease inhibitors and HCV NS5B polymerase inhibitors.
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