Macrocyclic inhibitors of Flaviviridae viruses
Inventors
Steadman, Victoria Alexandra • Poullennec, Karine G. • Lazarides, Linos • Aciro, Caroline • Dean, David Kenneth • Keats, Andrew John • Siegel, Dustin Scott • Schrier, Adam James • Mackman, Richard • Jansa, Petr
Assignees
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Publication Number
US-9062092-B2
Publication Date
2015-06-23
Expiration Date
Abstract
Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
Core Innovation
The invention relates to compounds of Formula I and pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, or prodrugs thereof. The compounds are defined by variable moieties A, A1, A2, X1 and L1, together with substituents R1 through R11, and the structural definitions allow optional replacement of a sp3 carbon atom of A1 by —O—, —S(O)n—, —NH—, or —N((C1-C4)alkyl)-.
A1 is defined as (C1-C5)alkylene, (C2-C5)alkenylene, (C2-C5)alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene, aryl(C1-C2)alkylene, heteroaryl(C1-C2)alkylene, cycloalkyl(C1-C2)alkylene or heterocycloalkyl(C1-C2)alkylene, with optional substitution by halo, alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, cycloalkyl, and substituents such as —OR9, —SR9, —S(O)R9, —S(O)2R9 and —N(R9)2. A2 is defined as —CH(R8)-arylene, —CH(R8)-heteroarylene, —CH(R8)-heterocycloalkylene, —CH(R8)-cycloalkylene, arylene, cycloalkylene, (C1-C3)alkylene, (C2-C3)alkenylene or (C2-C3)alkynylene, with optional substitution by halo, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, cyano, (C1-C8)alkyl, —OR9, —SR9, —S(O)R9, —S(O)2R9 and —N(R9)2.
L1 is defined as —O—C(O)—, —O—CH2, —NR11—CH2—, —NH—C(R10)2, or —NH—S(O)2—, and X1 is a bond, —O—, —NH—, —N((C1-C4)alkyl)- or heterocycloalkylene. R1 and R2 are independently H, alkyl, alkenyl, alkynyl, halo, cyano or —C(O)(C1-C4)alkyl, or together form —C(=O)—, —C(=S)— or —C(=N(C1-C4)alkyl)—; R3 is H or (C1-C4)alkyl optionally substituted with halo, cyano, hydroxyl or (C1-C4)alkoxy.
The structure scope also includes optional spirocycle configurations, where R5a and R5b and/or R6a and R6b together form a spirocycle having Formula (a). One or more carbon ring atoms of Formula (a) is optionally replaced by nitrogen, oxygen, or sulfur, and the ring atom is optionally substituted with oxo, —N(C1-C4)alkoxy, halo, hydroxyl, —NH2, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, —OC(O)R9, —C(O)2R9, and —S(O)2R9.
Claims Coverage
The consolidated claim coverage centers on one broad Formula I compound class with extensive structural variability across the A/A1/A2/L1/X1 framework, substituent definitions for R1 through R11, and an optional spirocycle configuration via Formula (a).
Formula I compound class with pharmaceutically acceptable forms
A compound of Formula I, or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, defined by the claimed structural variables and permitted variants.
Variable linkages and substitution patterns
A is a bond, —O—, —S(O)n—, —NH—, or —N((C1-C4)alkyl)- or (C1-C2)alkylene; A1 and A2 are defined by multiple alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene, heterocycloalkylene and related substituted forms; X1 is a bond, —O—, —NH—, —N((C1-C4)alkyl)- or heterocycloalkylene; and L1 is selected from —O—C(O)—, —O—CH2, —NR11—CH2—, —NH—C(R10)2, or —NH—S(O)2—.
Substituent ranges and spirocycle options
R1 and R2 are independently H, alkyl, alkenyl, alkynyl, halo, cyano or —C(O)(C1-C4)alkyl, or together form —C(=O)—, —C(=S)— or —C(=N(C1-C4)alkyl)—; R3 is H or (C1-C4)alkyl optionally substituted with halo, cyano, hydroxyl or (C1-C4)alkoxy; R4a/R4b, R5a/R5b, and R6a/R6b include broader substituent choices, and R5a/R5b and/or R6a/R6b may together form a spirocycle having Formula (a) with optional heteroatom replacement and listed ring substituents.
Claim coverage is anchored by the broad Formula I scaffold, with extensive structural variability across the core linkage units, linker groups, and substituent definitions. The claim also explicitly allows spirocycle configurations through Formula (a), including heteroatom replacement and defined ring substituents.
Stated Advantages
Reduced viral load.
Clearance of viral RNA.
Documented Applications
Treatment of Flaviviridae viral infections, particularly hepatitis C virus (HCV).
Assessment of PPIase activity potency categories using IC50 ranges.
Cyclophilin A TR-FRET competitive binding measured using cyclosporine A–Cy5 and Eu-labeled anti-(6×His).
Anti-HCV activity in Huh-7 HCV replicon cells, with replicon IC50/EC50 and CC50 outcomes reported.
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