Lipid-based conjugates for systemic, central nervous system, peripheral nervous system, and ocular delivery

A conjugate or a pharmaceutically acceptable salt thereof, comprising:

• (i) one or more Nucleic Acid Agent;
• and
• (ii) one or more Lipid-Based Ligand Unit, wherein each Lipid-Based Ligand Unit independently is:
• wherein:
• L is a lipid moiety;
• B is H, C1-C6 alkyl, or a nucleobase moiety;
• V is —O—, —NRV—, or —C(RV)2—;
• each RV independently is H or C1-C6 alkyl optionally substituted with one or more halogen;
• Q is —(CRaRa)n—NH—* in which * denotes attachment to L;
• or Q is C6-C10 arylene or 5- to 10-membered heteroarylene, wherein the C6-C10 arylene or 5- to 10-membered heteroarylene is optionally substituted with one or more RQ;
• each RQ independently is halogen or C1-C6 alkyl optionally substituted with one or more halogen;
• X is H, halogen, or —ORX;
• RX 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;
• or RX and R4 together form C1-C6 alkylene;
• 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;
• each Ra 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;
• or R4 and RX together form C1-C6 alkylene;
• each R5 independently is H, halogen, or C1-C6 alkyl optionally substituted with one or more halogen;
• and
• n is an integer ranging from about 0 to about 10;
• and
• when the Lipid-Based Ligand Unit is at the 3′-terminus of a Nucleic Acid Agent,
• # is an attachment to the rest of the conjugate;
• and
• ## is H, —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, wherein each RY independently is H or C1-C6 alkyl optionally substituted with one or more halogen or cyano;
• or
• when the Lipid-Based Ligand Unit is at the 5′-terminus of a Nucleic Acid Agent,
• # is H, —P(RZ)2, —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, wherein each RZ independently is H or C1-C6 alkyl optionally substituted with one or more halogen or cyano;
• and
• ## is an attachment to the rest of the conjugate;
• or
• each of # and ## independently is an attachment to the rest of the conjugate.