Compounds and compositions for intracellular delivery of nucleic acid-based therapeutics and methods thereof

A compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV:

• or an isomer, or a salt thereof, wherein:
• R1 and R2 are the same or different, each independently alkyl, alkenyl, or alkynyl;
• or alternatively R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclyl;
• R3 is a C1-18 alkylene, C2-18 alkenylene, or C2-18 alkynylene, or together with the adjacent nitrogen atom forms a ring structure comprising 3-18 carbon atoms;
• R4 is a C1-18 alkylene, C2-18 alkenylene, or C2-18 alkynylene;
• R5 and R8 are the same or different, each independently a bond, or a C1-28 alkylene, C2-28 alkenylene, or C2-28 alkynylene;
• R6 and R9 are the same or different, each independently hydrogen or a linear C1-28 alkyl or C2-28 alkenyl;
• R7 and R10 are the same or different, each independently hydrogen or a linear C1-28 alkyl or C2-28 alkenyl;
• X1 is a bond, —O—, —CO—, —OC—O—, or —O—CO—;
• X2 and X4 are the same or different, each independently methylene (—CH2—), —S—, —S—S—, —O—, —O—CO—, —CO—O—, or —NR—, wherein R is a lower alkyl;
• and
• X3 and X5 are the same or different, each independently a methylene (—CH2—), —S—, —S—S—, —O—, —O—CO—, —CO—O—, or —NR—, wherein R is a lower alkyl,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1 is a C1-18 alkylene, C2-18 alkenylene, or C2-18 alkynylene;
• R2 is a C1-18 alkylene, C2-18 alkenylene, or C2-18 alkynylene, C3-8 carbocyclylene, 3- to 8-membered heterocyclylene, or C1-18 heteroalkylene;
• R3 and R5 are the same or different, each independently a bond or a C1-28 alkylene, C2-28 alkenylene, or C2-28 alkynylene;
• R4, R6, and R7 are the same or different, each independently hydrogen or a C1-28 alkyl, C2-28 alkenyl, or C2-28 alkynyl, each optionally substituted by one, two, or three substituents independently selected from —OR, —SR, —S—S—R, —O—CO—R, —CO—OR, —CO—NRaRb, —NRa—CO—R, —O—CO—NRaRb, —NRa—CO—OR, —NRaRb, and —S—CO—R, wherein R at each occurrence is independently hydrogen or a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or icosyl;
• and Ra and Rb are independently hydrogen or lower alkyl;
• X1 is —OH, —SH, —N(R)2, C5-8 carbocyclyl, heterocyclyl, or hydrogen, or absent, wherein R at each occurrence is independently a lower alkyl or hydrogen;
• X2 is —O—CO—, —CO—O—, —NR—CO—, or —CO—NR—, wherein R is a lower alkyl or hydrogen;
• and
• X3, X4, and X5 are each independently —O—CO—, —CO—O—, —NR—CO—, —CO—NR—, a bond, or absent, wherein R is a lower alkyl or hydrogen,
• wherein the longest chain of atoms in the compound is between 18 and 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1 is an optionally substituted C1-18 alkylene, C2-18 alkenylene, or C2-8 alkynylene;
• R2 and R4 are the same or different, each independently a bond or a C1-28 alkylene, C2-28 alkenylene, or C2-28 alkynylene;
• R3 and R5 are the same or different, each independently hydrogen or a C1-28 alkyl, C2-28 alkenyl, or C2-28 alkynyl;
• X1 is —OH, —OR, —CO—OR, —CO—R, —O—CO—R, —SH, —SR, —N(R)2, a C5-8 carbocyclyl, a heterocyclyl, hydrogen, or absent, wherein R at each occurrence is independently hydrogen, or an optionally substituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or icosyl;
• and
• X2 and X3 are the same or different, each independently —O—CO—, —CO—O—, —CO—, —NR—CO—, —CO—NR—, a bond, or absent, wherein R is a lower alkyl or hydrogen,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1 is a C1-18 alkylene, C2-18 alkenylene, or C2-18 alkynylene, each optionally substituted by one, two, or three substituents independently selected from —OR, —SR, —S—S—R, —O—CO—R, —CO—OR, —CO—NRaRb, —NRa—CO—R, —O—CO—NRaRb, —NRa—CO—OR, —NRaRb, and —S—CO—R,
• wherein R at each occurrence is independently hydrogen or lower alkyl;
• and Ra and Rb are independently hydrogen or lower alkyl;
• n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• R2 is a C8 alkylene, C2-18 alkenylene, or C2-18 alkynylene;
• R3 is a C8 alkyl, C2-18 alkenyl, or C2-18 alkynyl, or a C5-8 carbocyclyl, heterocyclyl, hydrogen, or absent;
• R4, R6, and R8 are the same or different, each independently a bond or a C1-28 alkylene, C2-28 alkenylene, or C2-28 alkynylene;
• R5, R7, and R9 are the same or different, each independently a bond or a C2-28 alkyl, C2-28 alkenyl, or C2-28 alkynyl;
• X1 is a methylene (—CH2—), —O—, —S—, —S—S—, —NR— in which R is a lower alkyl, —CO—NR— in which R is a lower alkyl, —NR—CO— in which R is a lower alkyl or hydrogen, —O—CO—, —CO—O—, —CO—, —O—CO—O—, a C5-8carbocyclylene, a heterocyclylene, a bond, or absent;
• and
• X2, X3, and X4 are the same or different, each independently a methylene (—CH2—), —O—, —S—, —S—S—, —NR— in which R is a lower alkyl, —CO—NR— in which R is a lower alkyl, —NR—CO— in which R is a lower alkyl or hydrogen, —O—CO—, —CO—O—, —CO—, —O—CO—O—, a C5-8 carbocyclylene, a heterocyclylene, a bond, or absent,
• wherein the longest chain of atoms in the compound is between 18 and 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1 is a C8 alkylene, C2-18 alkenylene, or C2-18 alkynylene, each optionally substituted by one, two, or three substituents independently selected from —OR, —SR, —S—S—R, —O—CO—R, —CO—OR, —CO—NRaRb, —NRa—CO—R, —O—CO—NRaRb, —NRa—CO—OR, —NRaRb, and —S—CO—R, wherein R at each occurrence is independently hydrogen or lower alkyl;
• and Ra and Rb are independently hydrogen or lower alkyl;
• n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• R2 is a C1-18 alkylene, C2-18 alkenylene, or C2-18 alkynylene;
• R3 is a C8 alkyl, C2-18 alkenyl, or C2-18 alkynyl, or a C5-8 carbocyclyl, heterocyclyl, hydrogen, or absent;
• R4, R6, and R8 are the same or different, each independently a bond or a C1-28 alkylene, C2-28 alkenylene, or C2-28 alkynylene;
• R5, R7, and R9 are the same or different, each independently a bond or a C2-28 alkyl, C2-28 alkenyl, or C2-28 alkynyl;
• X1 is a methylene (—CH2—), —O—, —S—, —S—S—, —NR— in which R is a lower alkyl, —CO—NR— in which R is a lower alkyl, —NR—CO— in which R is a lower alkyl or hydrogen, —O—CO—, —CO—O—, —CO—, —O—CO—O—, a C5-8 carbocyclylene, a heterocyclylene, a bond, or absent;
• and
• X2, X3, and X4 are the same or different, each independently a methylene (—CH2—), —O—, —S—, —S—S—, —NR— in which R is a lower alkyl, —CO—NR— in which R is a lower alkyl, —NR—CO— in which R is a lower alkyl or hydrogen, —O—CO—, —CO—O—, —CO—, —O—CO—O—, a C5-8 carbocyclylene, a heterocyclylene, a bond, or absent,
• wherein the longest chain of atoms in the compound is between 18 and 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1 is a C2-18 alkyl, C2-18 alkenyl, or C2-8 alkynyl, a C5-8 carbocyclyl, a heterocyclyl, hydrogen, or absent;
• R2 is a C1-18 alkylene, C2-18 alkenylene, or C5-8 alkynylene;
• R3 is a C1-18 alkylene, C2-18 alkenylene, or C5-8 alkynylene, each optionally substituted by one, two, or three substituents independently selected from —OR, —SR, —S—S—R, —O—CO—R, —CO—OR, —CO—NRaRb, —NRa—CO—R, —O—CO—NRaRb, —NRa—CO—OR, —NRaRb, and —S—CO—R, wherein R at each occurrence is independently hydrogen or lower alkyl;
• and Ra and Rb are independently hydrogen or lower alkyl;
• n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• R4 and R8 are the same or different, each independently a bond or a C1-28 alkylene C2-28 alkenylene, or C2-28 alkynylene;
• R5 and R9 are the same or different, each independently hydrogen or a C1-28 alkyl, C2-28 alkenyl, or C2-28 alkynyl;
• R6 and R7 are the same or different, each independently a bond or a C1-8 alkylene C2-18 alkenylene, or C2-18 alkynylene;
• X1 is a methylene (—CH2—), —O—, —S—, —S—S—, —NR— in which R is a lower alkyl, —CO—NR— in which R is a lower alkyl, —NR—CO— in which R is a lower alkyl or hydrogen, —O—CO—, —CO—O—, —CO—, —O—CO—O—, a C5-8 carbocyclylene, a heterocyclylene, a bond, or absent;
• and
• X2, and X3 are the same or different, each independently a methylene (—CH2—), —O—, —S—, —S—S—, —NR— in which R is a lower alkyl, —CO—NR— in which R is a lower alkyl, —NR—CO— in which R is a lower alkyl or hydrogen, —O—CO—, —CO—O—, —CO—, —O—CO—O—, a C5-s carbocyclylene, a heterocyclylene, a bond, or absent,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• or an isomer, or a salt thereof, wherein:
• Y1 and Y2 are the same or different, each independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, an alkenylene, and an alkynylene, wherein R is independently a hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• X is selected from —S—, —S—S—, —O—, —CH2—, alkenylene, and alkynylene, —NR—, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• R1 and R2 are the same or different, each independently selected from carbocyclyl, alkyl, alkenyl, and alkynyl, each optionally substituted;
• R3 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, each, except hydrogen and halogen, optionally substituted;
• Z is selected from alkylene, alkenylene, alkynylene, and carbocyclylene;
• and
• m is an integer selected from 1 to 24,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• or an isomer, or a salt thereof, wherein:
• Y1 and Y2 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, alkenylene, and alkynylene, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• X1 and X2 are the same or different and are independently selected from —S—, —S—S—, —O—, —CH2—, alkenylene, alkynylene, and —NR—, wherein R is hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• R1 and R2 are the same or different and independently selected from alkyl, alkenyl, alkynyl, and heterocyclyl, each optionally substituted;
• R3 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, each optionally substituted;
• and
• m and n are each independently an integer selected from 1 to 24,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• or an isomer, or a salt thereof, wherein:
• X1, X2, and X3 are independently selected from —CH2—, —O—, —S—, and —NR—, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• R1 and R2 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, each, except hydrogen and halogen, optionally substituted;
• R3 and R4 are selected from carbocyclyl, alkyl, alkenyl, and alkynyl, each optionally substituted;
• and
• m is 0, 1, 2, 3, 4, or 5,
• wherein the longest chain of atoms in the compound is between 18 and 70 atoms;
• or an isomer, or a salt thereof, wherein:
• X1 and X2 are the same or different moieties selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, an alkene, and an alkyne, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl group;
• R1 and R2 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, each except hydrogen and halogen optionally substituted;
• R3 and R4 are the same or different and are independently selected from carbocyclyl, alkyl, alkenyl, and alkynyl;
• and
• m and n are the same or different and are each an integer selected from 1 to 24,
• wherein the longest chain of atoms in the compound is between 18 and 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1, R2, R3, R4 and R5 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, each, except hydrogen and halogen, optionally substituted;
• X1, X2, and X3 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkenylene, and alkynylene, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• X4 is selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkenylene, and alkynylene, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• or X4 is a linear alkyl group comprising 0 to 10 methylene units;
• Y1 and Y2 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkylene, alkenylene, or alkynylene, and carbocyclylene, wherein R at each occurrence is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl;
• and
• m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,
• wherein the longest chain of atoms in the compound is between 18 and 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1, R2, R3, R4, R5, R6, and R7 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, each except hydrogen and halogen optionally substituted;
• X1, X2, X3, X4, X5 and X6 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkylene, alkenylene, alkynylenes, carbocyclyl, and a bond, wherein R at each occurrence is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl;
• X7 and X8 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkylene, alkenylene, or alkynylene, and carbocycylyl, wherein R at each occurrence is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl;
• or X7 and X8 are each independently a linear alkyl group comprising 0 to 10 methylene units;
• Y1, Y2, Y3, and Y4 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, alkenylene, and an alkynylene wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• and
• n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1, R2, R3, and R4 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, each except hydrogen and halogen optionally substituted;
• X1, X2, X, and X4 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkenylene, alkynylene, and a bond, wherein R at each occurrent is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl;
• X5 and X6 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—NR—, alkenylene, alkynylene, and a bond, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• or X5 and X6 are each independently a linear alkyl group comprising 0 to 10 methylene units;
• Y1, Y2, Y3, and Y4 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, alkenylene, alkynylene, and a bond, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• the central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic, or anti-aromatic ring system;
• and
• n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• or an isomer, or a salt thereof, wherein:
• R1, R2, R3, R4, R5, and R6 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, each except hydrogen and halogen optionally substituted;
• X1, X2, X3, X4, X5, and X6 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkenylene, alkynylene, and cyclic alkylene or heteroalkylenes, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• X7 and X8 are the same or different and are independently selected from —(C═O)O—, —O—(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkenylene, alkynylene, and cyclic alkylene or heteroalkylenes, wherein R is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• or X7 and X8 are each a linear alkyl group comprising 0 to 10 methylene units;
• Y1, Y2, Y3, and Y4 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, alkenylene, alkynylenes, and cyclic alkylene or heteroalkylenes, wherein R at each occurrence is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, group;
• the central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic, or anti-aromatic ring system;
• and
• n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms;
• and
• or an isomer, or a salt thereof, wherein:
• R1, R2, R3, R4, R5, and R6 the same or different and are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, each except hydrogen and halogen optionally substituted;
• X1, X2, X3, X4, and X5 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, —NR—, alkylene, alkenylene, alkynylene, cycloalkylene, and heterocyclylene, wherein R is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, and heterocyclyl;
• Y1, Y2, and Y3 are the same or different and are independently selected from —(C═O)O—, —O(C═O)—, —(C═O)S—, —S(C═O)—, —NR(C═O)—, —(C═O)NR—, —O—, —S—, —S—S—, —CH2—, alkylene, alkenylene, alkynylene, cycloalkylene, and heterocyclylene, wherein R is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl;
• and
• m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10,
• wherein the longest chain of atoms in the compound is between 18 to 70 atoms.