1′-alkyl modified ribose derivatives and methods of use

A conjugate or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises:

• (i) one or more Nucleic Acid Agents;
• (ii) one or more Ligands;
• and
• (iii) one or more Linker Units, wherein each Linker Unit independently is:
• wherein:
• X is —ORX;
• R1 is H, C1-C6 alkyl, or —(C1-C6 alkyl)-(C6-C10 aryl), wherein the C1-C6 alkyl or —(C1-C6 alkyl)-(C6-C10 aryl) is optionally substituted with one or more RXa;
• each RXa independently is halogen, C1-C6 alkyl, or —O—(C1-C6 alkyl), wherein the C1-C6 alkyl or —O—(C1-C6 alkyl) is optionally substituted with one or more halogen;
• Y is H, C1-C6 alkyl optionally substituted with one or more halogen, —P(RY)2, —P(ORY)(N(RY)2), —P(═O)(ORY)RY, —P(═S)(ORY)RY, —P(═O)(SRY)RY, —P(═S)(SRY)RY, —P(═O)(ORY)2, —P(═S)(ORY)2, —P(═O)(SRY)2, —P(═S)(SRY)2, or a hydroxy protecting group;
• each RY independently is H or C1-C6 alkyl optionally substituted with one or more halogen or cyano;
• Z is H, C1-C6 alkyl optionally substituted with one or more halogen, —P(RZ), —P(ORZ)(N(RZ)2), —P(═O)ORZ)RZ, —P(═S)(ORZ)RZ, —P(═O)(SRZ)RZ, —P(═S)(SRZ)RZ, —P(═O)(ORZ)2, —P(═S)(ORZ)2, —P(═O)(SRZ)2, —P(═S)(SRZ)2, or a hydroxy protecting group;
• each RZ independently is H or C1-C6 alkyl optionally substituted with one or more halogen or cyano;
• each Ra independently is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• or two Ra on two adjacent carbon atoms, together with the two adjacent carbon atoms, form a double bond;
• each Rb independently is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• R1 is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• R2 is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• R3 is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• R4 is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• each R5 independently is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• n is an integer ranging from 2 to 6;
• and
• # indicates a direct or indirect attachment to the Ligand, and each ##independently indicates a direct or indirect attachment to the Nucleic Acid Agent or another Linker Unit.