Lipid monomers for therapeutic delivery of rna

A compound of Formula (III):

• wherein:
• B is a modified or unmodified nucleobase;
• X is O or S;
• Y is O or NRa;
• D1 is H, a hydroxyl protecting group, or a reactive phosphorus group;
• D2 is H, a hydroxyl protecting group, or a reactive phosphorus group;
• or D1 and D2 together form a protecting group for both the oxygen and Y they are attached to;
• Z2 is —O—, —NRa—, *—OC(═O)—, *—NRaC(═O)—, —OC(═O)O—, *—NRaC(═O)O—, *—OC(═O)NRb—, *—NRaC(═O)NRb—, *—OC(═S)—, *—NRaC(═S)—, —OC(═S)O—, *—NRaC(═S)O—, *—OC(═S)NRb—, *—NRaC(═S)NRb—, *—OC(═O)S—, *—NRaC(═O)S—, *—OS(O)x—, or *—NRaS(O)x—;
• wherein * refers to the direction toward the ring containing X;
• R2 is -(G-L)m-R;
• each instance of G is independently C1-C8alkylene or C3-C10 cycloalkylene;
• each instance of L is independently —O—, —NRa—, —C(═O)—, *—OC(═O)—, *—C(═O)O—, *—NRaC(═O)—, *—C(═O)NRb—, —OC(═O)O—, *—NRaC(═O)O—, *—OC(═O)NRb—, *—NRaC(═O)NRb—, *—OC(═S)—, *—C(═S)O—, *—NRaC(═S)—, *—C(═S)NRb—, —OC(═S)O—, *—NRaC(═S)O—, *—OC(═S)NRb—, *—NRaC(═S)NRb—, *—OC(═O)S—, *—SC(═O)O—, *—NRaC(═O)S—, *—SC(═O)NRb—, *—OS(O)x—, *—S(O)xO—, *—NRaS(O)x—, or *—S(O)xNRb—;
• wherein * refers to the direction toward the ring containing X;
• each instance of Ra is independently H or C1-C6 alkyl;
• each instance of Rb is independently H or C1-C6 alkyl;
• and
• R is C12-C32 alkyl or C12-C32 alkenyl;
• x is 1 or 2;
• and
• m is 0, 1, or 2;
• provided that when X is O, Y is O, and Z2 is —O—, then
• (i) R is substituted with -L″-(CH2)0-3—R″, wherein:
• L″ is absent, —O—, —NRa—, —C(═O)—, *—OC(═O)—, *—C(═O)O—, *—NRaC(═O)—, *—C(═O)NRb—, —OC(═O)O—, *—NRaC(═O)O—, *—OC(═O)NRb—, *—NRaC(═O)NRb—, *—OC(═S)—, *—C(═S)O—, *—NRaC(═S)—, *—C(═S)NRb—, —OC(═S)O—, *—NRaC(═S)O—, *—OC(═S)NRb—, *—NRaC(═S)NRb—, *—OC(═O)S—, *—SC(═O)O—, *—NRaC(═O)S—, *—SC(═O)NRb—, *—OS(O)x—, *—S(O)xO—, *—NRaS(O)x—, or *—S(O)xNRb—;
• wherein * refers to the direction toward R;
• and
• R″ is a monocyclic, fused, bridged or spiro ring moiety, wherein the ring moiety is optionally substituted with one or more C1-C6 alkyl, oxo, or phenyl, wherein the alkyl or phenyl is optionally substituted with one or more halogen, phenyl, or phenoxy, wherein the phenyl or phenoxy is optionally substituted with one or more halogen or C1-C6 alkoxy;
• (ii) R is C12-C32 alkenyl;
• (iii) m is 1 or 2;
• and L is —O— or *—C(═O)NRb—;
• or
• (iv) m is 1 or 2, and at least one G is C3-C10 cycloalkylene;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula (IV):

• wherein:
• each instance of G′ is independently C1-C8alkylene or C3-C8 cycloalkylene;
• each instance of L′ is independently *—NRcC(═O)—;
• wherein * refers to the direction toward the pyrrolidine-2,5-dione ring;
• each instance of R is independently H, C1-C32 alkyl, or C2-C32 alkenyl;
• R is C4-C32 alkyl or C4-C32 alkenyl;
• and
• m is 0, 1, or 2;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

An oligonucleotide comprising at least one lipophilic monomer of the following formula:

• wherein for formula (V) and (VII),
• X is O or S;
• Y is O or NRa;
• D1 is H, a hydroxyl protecting group, or a reactive phosphorus group;
• D2 is H, a hydroxyl protecting group, or a reactive phosphorus group;
• or D1 and D2 together form a protecting group for both the oxygen and Y they are attached to;
• Z1, Z2, and Z3 are each independently —O—, —NRa—, *—OC(═O)—, *—NRaC(═O)—, —OC(═O)O—, *—NRaC(═O)O—, *—OC(═O)NRb—, *—NRaC(═O)NRb—, *—OC(═S)—, *—NRaC(═S)—, —OC(═S)O—, *—NRaC(═S)O—, *—OC(═S)NRb—, *—NRaC(═S)NRb—, *—OC(═O)S—, *—NRaC(═O)S—, *—OS(O)x—, or *—NRaS(O)x—;
• wherein * refers to the direction toward the ring containing X;
• R1, R2, and R3 are each independently H, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, or -(G-L)m-R, provided that at least one of R1, R2, and R3 is -(G-L)m-R;
• each instance of G is independently C1-C8 alkylene;
• each instance of L is independently —O—, —NRa—, —C(═O)—, *—OC(═O)—, *—C(═O)O—, *—NRaC(═O)—, *—C(═O)NRb—, —OC(═O)O—, *—NRaC(═O)O—, *—OC(═O)NRb—, *—NRaC(═O)NRb—, *—OC(═S)—, *—C(═S)O—, *—NRaC(═S)—, *—C(═S)NRb—, —OC(═S)O—, *—NRaC(═S)O—, *—OC(═S)NRb—, *—NRaC(═S)NRb—, *—OC(═O)S—, *—SC(═O)O—, *—NRaC(═O)S—, *—SC(═O)NRb—, *—OS(O)x—, *—S(O)xO—, *—NRaS(O)x—, or *—S(O)xNRb—;
• wherein * refers to the direction toward the ring containing X;
• each instance of Ra is independently H or C1-C6 alkyl;
• each instance of Rb is independently H or C1-C6 alkyl;
• and
• each instance of R is independently C12-C32 alkyl or C12-C32 alkenyl;
• x is 1 or 2;
• n is 0 or 1;
• m is 0, 1, or 2;
• and
• for formula (VIII),
• each instance of G′ is independently C1-C8 alkylene or C3-C8 cycloalkylene;
• each instance of L′ is independently *—NRcC(═O)—;
• wherein * refers to the direction toward the pyrrolidine-2,5-dione ring;
• each instance of Rc is independently H, C1-C32 alkyl, or C2-C32 alkenyl;
• R is C4-C32 alkyl or C4-C32 alkenyl;
• and
• m is 0, 1, or 2.