Substituted nucleosides, nucleotides and analogs thereof

A method for ameliorating or treating a viral infection caused by a virus comprising administering to or contacting a cell in a subject with an effective amount of a compound selected from Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt of the foregoing, wherein the virus is selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus and a metapneumovirus, and wherein the compound is selected from Formula (I), Formula (II), and Formula (III) has one of the following structures:

• wherein:
• B1A B1B and B1C are independently an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;
• R1A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid,
• and
• the dashed line (------) of Formula (I) is absent;
• R2A is selected from the group consisting of an unsubstituted C1-6 alkyl, a halogen substituted C1-6 alkyl, a hydroxy substituted C1-6 alkyl, an alkoloxy alkoxy substituted C1-6 alkyl, a sulfenyl substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted —O—C1-6 alkyl, an optionally substituted —O—C3-6 alkenyl, an optionally substituted —O—C3-6 alkynyl and cyano;
• R3A is selected from the group consisting of OH, —OC(═O)R″A and an optionally substituted O-linked amino acid;
• R1B is selected from the group consisting of O−, OH,
• an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
• R1C and R2C are independently selected from the group consisting of O−, OH, an optionally substituted C1-6 alkoxy,
• an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
• or
• R1C is
• and R2C is O−or OH;
• R2B and R3 R3C are independently selected from the group consisting of an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted —O—C1-6 alkyl, an optionally substituted —O—C3-6 alkenyl, an optionally substituted —O—C3-6 alkynyl and cyano;
• R4C is selected from the group consisting of OH, —OC(═O)R″C and an optionally substituted O-linked amino acid;
• R4A, R3B and R5C are independently a halogen;
• R5A, R4B and R6C are independently hydrogen or halogen;
• R6A, R7A and R8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C1-6 alkyl), an optionally substituted *—(CR15AR16A)p—O—C1-24 alkyl, an optionally substituted *—(CR17AR18A)q—O—C1-24 alkenyl,
• R6A is
• and R7A is absent or hydrogen;
• or
• R6A and R7A are taken together to form a moiety selected from the group consisting of an optionally substituted
• and an optionally substituted
• wherein the oxygens connected to R6A and R7A, the phosphorus and the moiety form a six-membered to ten-membered ring system;
• R9A is independently selected from the group consisting of an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3-6 cycloalkenyl, NR3OAR31A NR30AR31A, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
• R10A and R11A are independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;
• R12A, R13A and R14A are independently absent or hydrogen;
• each R15A, each R16A, each R17A and each R18A are independently hydrogen, an optionally substituted C1-24 alkyl or alkoxy;
• R19A, R20A, R22A, R23A, R5B, R6B, R8B, R9B, R9C, R10C, R12C and R13C are independently selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl;
• R21A, R24A, R7B, R10B, R11C and R14C are independently selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C1-24 alkyl and an optionally substituted —O-aryl;
• R25A, R29A, R11B and R15C are independently selected from the group consisting of hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl;
• R16C, R17C and R18C are independently absent or hydrogen;
• R26A and R27A are independently —C≡N or an optionally substituted substituent selected from the group consisting of C2-8 organylcarbonyl, C2-8 alkoxycarbonyl and C2-8 organylaminocarbonyl;
• R28A is selected from the group consisting of hydrogen, an optionally substituted C1-24-alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl;
• R30A and R31A are independently selected from the group consisting of hydrogen, an optionally substituted C1-24-alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl;
• for Formula (III), ------- is a single bond or a double bond;
• when ------- is a single bond, each R7C and each R8C is independently hydrogen or halogen;
• and
• when ------- is a double bond, each R7C is absent and each R8C is independently hydrogen or halogen;
• R″A and R″C are independently an optionally substituted C1-24-alkyl;
• m and n are independently 0 or 1;
• p and q are independently selected from the group consisting of 1, 2 and 3;
• r is 1 or 2;
• Z1A, Z2A, Z3A, Z4A, Z1B, Z2B and Z1C are independently O or S;
• and
• provided that when R1A is
• wherein R8A is an unsubstituted C1-4 alkyl or phenyl optionally para-substituted with a halogen or methyl and R9A is methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tryptophan, methionine and proline;
• R3A is OH;
• R4A is fluoro;
• R5A is fluoro or hydrogen;
• and B1A is an unsubstituted uracil;
• then R2A cannot be —OCH3;
• provided that when R1A is H;
• R3A is OH;
• R4A is fluoro;
• R5A is fluoro;
• and B1A is an unsubstituted cytosine;
• then R2A cannot be allenyl;
• and
• provided that when R1A is H;
• R3A is OH;
• R4A is fluoro;
• R5A is fluoro;
• and B1A is an unsubstituted cytosine;
• then R2A cannot be ethynyl.