Substituted nucleosides, nucleotides and analogs thereof
AssigneeAlios BioPharma, Inc.
InventorsLawrence M. Blatt, Leonid Beigelman, Julian Alexander Symons, David Bernard Smith
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Abstract
Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.
Claims63
A method for ameliorating or treating a betacoronavirus infection comprising contacting a cell infected with the betacoronavirus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:
- wherein:
- B1A is
- wherein RG2 is an unsubstituted C1-6 alkyl;
- R3A is halo, OH, —OC(═O)R″A or an unsubstituted O-linked α-amino acid;
- R4A is OH or halo;
- Ra1 and Ra2 are independently hydrogen or deuterium;
- RA is hydrogen or deuterium;
- R1A is selected from the group consisting of hydrogen,
- R2A is halo or —(CH2)1-6halogen;
- R5A is selected from the group consisting of an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl and an unsubstituted C2-6 alkynyl;
- R6A and R7A are independently selected from the group consisting of absent, hydrogen and
- or
- R6A is
- and R7A is absent or hydrogen;
- R8A is an absent, hydrogen, an optionally substituted phenyl or an optionally substituted naphthyl;
- R9A is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
- R10A and R11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
- R12A and R13A are independently absent or hydrogen;
- R14A is O− or OH;
- R22A and R23A are each hydrogen;
- R24A is selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted —O—C1-24 alkyl;
- m is 0 or 1;
- s is 0, 1, 2 or 3;
- and
- Z1A, Z2A, Z3A and Z4A are each O;
- and
- wherein when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, -thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
A method for ameliorating or treating a MERS viral infection comprising contacting a cell infected with the MERS virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:
- wherein:
- B1A is
- wherein RG2 is an unsubstituted C1-6 alkyl;
- R3A is halo, OH, —OC(═O)R″A or an unsubstituted O-linked α-amino acid;
- R4A is OH or halo;
- Ra1 and Ra2 are independently hydrogen or deuterium;
- RA is hydrogen or deuterium;
- R1A is selected from the group consisting of hydrogen,
- R2A is halo or —(CH2)1-6halogen;
- R5A is selected from the group consisting of an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl and an unsubstituted C2-6 alkynyl;
- R6A and R7A are independently selected from the group consisting of absent, hydrogen and
- or
- R6A is
- and R7A is absent or hydrogen;
- R8A is an optionally substituted phenyl or an optionally substituted naphthyl;
- R9A is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative, wherein the main-chain carboxylic acid group has been converted to an ester group;
- R10A and R11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative;
- R12A and R13A are independently absent or hydrogen;
- R14A is O− or OH;
- R22A and R23A are each hydrogen;
- R24A is selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted —O—C1-24 alkyl;
- m is 0 or 1;
- s is 0, 1, 2 or 3;
- and
- Z1A, Z2A, Z3A and Z4A are O;
- and
- wherein when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.
Dependencies are inferred from the claim text.