Substituted nucleosides, nucleotides and analogs thereof

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

• wherein:
• B1A is
• X1 is N (nitrogen) or —CRB6;
• X2 is N (nitrogen) or —CRB6a;
• X3 is N (nitrogen) or —CRB6b;
• X4 is N (nitrogen) or —CRB6c;
• RB1, RB1a, RB1b and RB1c are independently hydrogen or deuterium;
• RB2 is NRB4aRB4b;
• RB2b is NRB4a1RB4b1;
• RB2c is NRB4a2RB4b2;
• RB2a is selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C3-6 cycloalkyl;
• RB3 is hydrogen, deuterium, halogen or NRB5aRB5b;
• RB3b is hydrogen, deuterium, halogen or NRB5a1RB5b1;
• RB3c is hydrogen, deuterium, halogen or NRB5a2RB5b2;
• RB4a, RB4a1 and RB4a2 are independently hydrogen or deuterium;
• RB4b, RB4b1 and RB4b2 are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-6 cycloalkyl, —C(═O)RB7 and —C(═O)ORB8;
• RB5a is hydrogen or deuterium;
• RB5b is selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-6 cycloalkyl, —C(═O)RB9 and —C(═O)ORB10;
• RB5a1 and RB5a2 are independently hydrogen or deuterium;
• RB5b1 and RB5b2 are independently selected from the group consisting of hydrogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-6 cycloalkyl, —C(═O)RB9 and —C(═O)ORB10;
• RB6a, RB6b and RB6c are independently selected from the group consisting of hydrogen, deuterium, halogen, —C≡N, —C(═O)NH2, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl;
• RB7, RB8, RB9 and RB10 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 C5-10 cycloalkenyl, an optionally substituted C6-10 aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl (C1-6 alkyl), an optionally substituted heteroaryl (C1-6 alkyl) and an optionally substituted heterocyclyl (C1-6 alkyl);
• R1A is hydrogen, deuterium, an optionally substituted acyl, an optionally substituted O-linked amino acid or
• R2A, R3A, R5A and RA are independently hydrogen or deuterium;
• R4A is fluoro;
• R6A is selected from the group consisting of —OH, —OC(═O)R″A and an optionally substituted O-linked amino acid;
• R7A is —OH, —OC(═O)R″B, fluoro or chloro;
• R8A is an optionally substituted C1-3 alkyl, an optionally substituted C3-6 allenyl or an optionally substituted C2-6 alkynyl;
• R9A and R10A are independently selected from the group consisting of O−, —OH, an optionally substituted —O—C1-24 alkyl, an optionally substituted —O—C2-24 alkenyl, an optionally substituted —O—C2-24 alkynyl, an optionally substituted —O—C3-6 cycloalkyl, an optionally substituted —O—C5-10 cycloalkenyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-aryl (C1-6 alkyl), an optionally substituted *—O—(CR11AR12A)p—O—C1-24 alkyl, an optionally substituted *—O—(CR13AR14A)q—O—C2-24 alkenyl,
• an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
• or
• R9A is
• and R10A is O− or OH;
• or
• R9A and R10A are taken together to form a moiety selected from an optionally substituted
• and an optionally substituted
• wherein the phosphorus and the moiety form a six-membered to ten-membered ring system and wherein the asterisks indicate the points of attachment of the moieties;
• each R11A, each R12A, each R13A and each R14A are independently hydrogen, deuterium, an optionally substituted C1-24 alkyl or alkoxy;
• R15A, R16A, R18A and R19A are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-24 alkyl and an optionally substituted aryl;
• R17A and R20A are independently selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl;
• R21A is selected from the group consisting of hydrogen, deuterium, an optionally substituted C1-24 alkyl and an optionally substituted aryl;
• R22A and R23A are independently selected from the group consisting of —C≡N, an optionally substituted C2-8 organylcarbonyl, an optionally substituted C2-8 alkoxycarbonyl and an optionally substituted C2-8 organylaminocarbonyl;
• R24A is selected from the group consisting of hydrogen, deuterium, 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 C5-10 cycloalkenyl;
• R25A, R26A and R27A are independently absent, hydrogen or deuterium;
• p and q are independently selected from 1, 2 and 3;
• r is 1 or 2;
• s is 0 or 1;
• R″A and R″B are independently an optionally substituted C1-24 alkyl;
• and
• Z1A and Z2A are independently oxygen (O) or sulfur (S);
• and
• provided that when X1 is N or CH, B1A is
• and R1A is hydrogen or triphosphate, then R8A is not methyl;
• and
• provided that the compound of Formula (I) is not
• or a pharmaceutically acceptable salt thereof.