Orally-bioavailable nucleoside analogs
Inventors
Burns, Christopher J. • COBURN, Glen • Chu, Guo-Hua • Condon, Stephen M. • Boyd, Steven A. • Pevear, Daniel C.
Assignees
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Publication Number
US-11638715-B2
Publication Date
2023-05-02
Expiration Date
Abstract
Described herein are orally-bioavailable nucleoside analogs and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of coronavirus infections, including SARS-CoV-2 infection.
Core Innovation
The invention relates to a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. The compound is defined by variable substituents X, G, R11, R12, R13, R14, R15, R16, R21, R22, R25, and R26, together with optional substituent sets R11a, R12a, R15a, R21a, R22a, R25a, and R26a. The structural framework permits optional substitution, oxo formation, and cycloalkyl or heterocycloalkyl formation when substituents are taken together as stated.
X is hydrogen or —CN, and G is hydrogen, —C(=O)R21, —C(=O)OR21, or C1-C6 alkyl optionally substituted with one or more R11a. R14 is —OH or fluoro, and R13 is hydrogen or C1-C6 alkyl. R15 is hydrogen, —C(=O)R25, —C(=O)OR25, —CH2—O—C(=O)R25, —CH2—O—C(=O)OR25, or C1-C6 alkyl optionally substituted with one or more R15a, and R16 is —C(=O)R26, —C(=O)OR26, —CH2—O—C(=O)R26, or —CH2—O—C(=O)OR26.
R21, R22, R25, and R26 are broadly defined as C1-C6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and alkylene-linked variants, with optional independent substitution by the corresponding R-group sets. The disclosure also includes a proviso that when G and X take specified combinations, at least one of R11, R12, or R15 is not hydrogen. Example compounds include pyrrolo[2,1-f][1,2,4]triazinyl-, purine-, or nucleoside-like scaffolds bearing tetrahydrofuran and cyano motifs, with ester, acyl, amide, and protecting-group variants.
Claims Coverage
The provided material centers on one broad independent claim family directed to a Formula (II) compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. The inventive features cover the Formula (II) scaffold, variable X and G positions, multiple R-group families, optional substitution and ring formation, a conditional proviso for specified G/X combinations, and a separate independent method claim directed to treating viral infection by administration.
Formula (II) compound with variable substituents
A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is hydrogen or —CN; G is hydrogen, —C(=O)R21, —C(=O)OR21, or C1-C6 alkyl optionally substituted with one or more R11a; and the variables R11, R12, R13, R14, R15, R16, R21, R22, R25, and R26 are defined by the listed substituent classes and optional substitution patterns.
Optional substitution, oxo formation, and ring formation
Each of R11a, R12a, R15a, R21a, R22a, R25a, and R26a is independently selected from the listed functional-group options, and the claim language allows two substituents on the same atom to form an oxo or, in specified cases, a cycloalkyl or heterocycloalkyl.
Conditional proviso for specified G and X combinations
Provided that when G is the specified structural option and X is —CN, or when G is the specified structural option and X is hydrogen, then at least one of R11, R12, or R15 is not hydrogen.
Dependent narrowing of R22, R15, and R25
Dependent refinements define R22 as C1-C6 alkyl or C1-C6 alkylene(aryl) optionally substituted by R22a, define R15 as hydrogen or —C(=O)R25, and define R25 as C1-C6 alkyl, C1-C6 aminoalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(aryl), optionally substituted by R25a.
Method of treating viral infection by administration
A method treats a viral infection by administering to a subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer.
Overall, the claim coverage is a broad Formula (II) chemical genus with variable X, G, and multiple substituent positions, optional oxo and ring-forming provisions, and a conditional non-hydrogen requirement for specified G/X combinations. The dependent claim set further narrows selected substituent definitions and includes a therapeutic method claim.
Stated Advantages
Useful for treating viral infections, preferably coronavirus infections.
The description enumerates coronavirus infection examples including SARS-CoV, SARS-CoV-2, and MERS.
Orally-bioavailable nucleoside analogs are provided.
Documented Applications
Treating viral infections by administering a therapeutically effective amount of the claimed compound, including pharmaceutically acceptable salts, solvates, or stereoisomers.
Treating coronavirus infections, including SARS-CoV, SARS-CoV-2, and MERS.
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