Macrocyclic inhibitors of flaviviridae viruses
Inventors
Aciro, Caroline • Chiva, Jean Yves • Dean, David Kenneth • Highton, Adrian John • Jansa, Petr • Keats, Andrew John • Lazarides, Linos • Mackman, Richard • Poullennec, Karine G. • Schrier, Adam James • Siegel, Dustin Scott • Steadman, Victoria Alexandra • Watt, Greg
Assignees
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Publication Number
US-10472392-B2
Publication Date
2019-11-12
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 to pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters and prodrugs thereof. The compounds are defined by constrained structural elements A, A1, A2, L1, X1 and multiple substituent variables R1 through R9, with m being 1, 2, 3, 4 or 5. The definitions specify optional substitution patterns selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, cycloalkyl, aryl(C1-C4)alkyl, heterocycloalkyl(C1-C4)alkyl, and various heteroatom-containing groups such as OR9, SR9, S(O)R9, S(O)2R9, and N(R9)2.
Within Formula I, A is CH2, A1 is a (C2-C5)alkenylene with an sp3 carbon atom optionally replaced by O, S(O)n, NH, or N((C1-C4)alkyl), and A2 is —CH(R8)-heteroarylene optionally substituted by OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, halo, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, cyano and (C1-C8)alkyl. L1 is —O—C(O), and X1 is —NH— or —N(CH3)—. The structure further constrains R1 and R2 to form —C(=O)— when taken together with the carbon to which they are both attached, and defines R3 as H or (C1-C4)alkyl optionally substituted with halo, cyano, hydroxyl or (C1-C4)alkoxy.
The patent also constrains the substituent environment through definitions of R4a and R4b, R5a and R5b, and R6a and R6b. R4a and R4b are independently H or (C1-C5)alkyl with optional substituents including cyano, COOH, halo, hydroxyl, amino, (C1-C5)alkoxy, mono(C1-C5)alkylamino, di(C1-C5)alkylamino, aryl and heteroaryl, while R5a and R5b are independently H or (C1-C5)alkyl with optional substituents including N3, cyano, COOH, halo, hydroxyl, amino, alkylamino, (C1-C5)alkoxy, aryl and heteroaryl. In addition, R5a and R5b together can form a spirocycle having Formula (a), with optional replacement of ring atoms by nitrogen, oxygen or sulfur and optional substituents on a ring atom. R6a and R6b together form the spirocycle of Formula (a), and R8 is defined as H or various ring, alkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl options with optional substitution including cyano.
Claims Coverage
The provided claim coverage centers on one independent claim defining a compound of Formula I with tightly constrained structural elements and substitution options, and a secondary claim set directed to pharmaceutical compositions with defined additional therapeutic agent classes.
Compound of Formula I with variable constrained substitution framework
A compound of Formula I, or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein A is CH2; A1 is (C2-C5)alkenylene with an sp3 carbon optionally replaced by O, S(O)n, NH, or N((C1-C4)alkyl), and with optional substitution on an sp3 or sp2 carbon by selected groups; A2 is —CH(R8)-heteroarylene optionally substituted by OR9, SR9, S(O)R9, S(O)2R9, N(R9)2, halo, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, cyano and (C1-C8)alkyl; L1 is —O—C(O); X1 is —NH— or —N(CH3)—; R1 and R2 together form —C(=O)—; R3 is H or (C1-C4)alkyl optionally substituted; R4a and R4b independently are H or (C1-C5)alkyl with optional substituents; R5a and R5b independently are H or (C1-C5)alkyl with optional substituents or together form a spirocycle having Formula (a) with optional ring-atom replacements and optional ring-atom substituents; R6a and R6b together form a spirocycle having Formula (a); R8 is H or selected substituted groups; each R9 is independently selected; and m is 1, 2, 3, 4 or 5.
Pharmaceutical composition including a defined additional therapeutic agent class
A pharmaceutical composition including the compound of Formula I and at least one additional therapeutic agent chosen from interferons, ribavirin, HCV NS3 protease inhibitors, HCV NS5A inhibitors, HCV NS5B polymerase inhibitors (nucleoside or nucleotide, or non-nucleoside), or TLR-7 agonists, or mixtures thereof.
Across the provided claim set, the core coverage is directed to compounds defined by Formula I with constrained structural elements and substitution options, and the secondary coverage adds pharmaceutical compositions that can further include specified additional therapeutic agent classes, including interferons, ribavirin, HCV inhibitors, and TLR-7 agonists.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Cyclophilin A PPlase/TR-FRET competitive binding assay with cyclophilin A, with classification ranges reported for IC50, EC50 and % inhibition (Table 1).
Anti-HCV activity in Huh-7 HCV replicon cells with reported IC50, EC50 and % inhibition classification ranges (Table 1).
Pharmaceutical composition use with an additional therapeutic agent selected from interferons, ribavirin, HCV NS3 protease inhibitors, HCV NS5a inhibitors, HCV NS5B polymerase inhibitors (nucleoside or nucleotide, or non-nucleoside), or TLR-7 agonists, or mixtures thereof; alternatively ribavirin, telaprevir, boceprevir, or sofosbuvir.
Use against Flaviviridae viral infection, including hepatitis C virus (HCV), with treatment involving reduction of viral load and clearance of viral RNA in mammals.
Use against Coronaviridae viral infection.
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