Lipids and compositions thereof

Abstract

The present disclosure relates to cationic and / or ionizable lipids and nucleic acid-lipid particle compositions comprising the cationic and / or ionizable lipids. The present disclosure also relates to methods of using and delivering the described lipids and lipid-containing particles.

Description

Cross-referencing

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 511,824, filed July 3, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Lipids are amphiphilic molecules containing three domains: a polar head group, a hydrophobic tail region, and a linker between the two domains. Lipid-containing particles have been used as transport carriers for the entry of therapeutic agents (such as nucleic acids, small molecule compounds, and proteins) into cells and other intracellular compartments. Cationic lipids, ionizable lipids, and other types of lipids have been explored for mRNA delivery. Summary of the Invention

[0003] Despite the proven efficacy of various lipid-containing particle compositions, there remains a need to improve the safety, efficacy, and specificity of such nanoparticle-based transporters. In some embodiments, lipid-containing particle compositions as described herein exhibit improved delivery efficiency. In some embodiments, lipid-containing particle compositions as described herein exhibit improved toxicity properties. In some embodiments, lipid-containing particle compositions as described herein exhibit improved tolerability (e.g., liver tolerance). In some embodiments, lipid-containing particle compositions as described herein comprise lipids as described herein. Without wishing to be bound by any particular theory, this disclosure provides the insight that certain modifications to the lipid structure exhibit improved tolerability (e.g., liver tolerance) while maintaining delivery performance. In some embodiments, structural modifications include halogenation of the aliphatic chain of the lipid. In some embodiments, the lipids described herein comprise halogens. In some embodiments, the lipids described herein comprise F. Without wishing to be bound by any particular theory, in some embodiments, this disclosure provides the insight that lipids comprising halogens (e.g., F) surprisingly exhibit improved tolerability compared to otherwise identical lipids not containing halogens (e.g., F). In some aspects, a compound of formula I' is described herein:

[0004] Or its N-oxide or its pharmaceutically acceptable salt. in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is a halogen, -OH, -OR10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0 or 1.

[0005] In some respects, r is 0. In some respects, this paper describes a compound of formula I'-a:

[0006] in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R)10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is a halogen, -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

[0007] In some respects, r is 1. In some respects, this paper describes a compound of formula I:

[0008] Or its N-oxide or its pharmaceutically acceptable salt. in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted.4-12 alkylene or -C 3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

[0009] In some implementations, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 Or C 1-10 Alkyl group. In some embodiments, each R5, R6, R7, R8 or R9 is independently hydrogen, deuterium, halogen, methyl, ethyl or isopropyl.

[0010] In some respects, this paper describes a compound of formula II:

[0011] Or its N-oxide or a pharmaceutically acceptable salt thereof, wherein: L1 is a substituted or unsubstituted linear C3- chain. 12 Alkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 Alkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 Alkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-6 Alkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 6-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 Alkylene-; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2、-CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; Each R 11 Independently selected from hydrogen, deuterium, halogens, -CN, -C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3 or 4.

[0012] In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10 In another implementation, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10 In some embodiments, p is 1, 2, or 3; and q is 1, 2, or 3. In another embodiment, p is 1, and q is 1. In yet another embodiment, p is 1, and q is 3. In yet another embodiment, p is 3, and q is 1. In yet another embodiment, p is 3, and q is 3.

[0013] In some respects, this paper describes a compound of formula III:

[0014] Or its N-oxide or its pharmaceutically acceptable salt.

[0015] On the other hand, this paper describes a compound of formula III-a:

[0016] Or its N-oxide or its pharmaceutically acceptable salt.

[0017] In some respects, this paper describes a compound of formula IV:

[0018] Or its N-oxide or a pharmaceutically acceptable salt thereof. In some embodiments, X1 is -C(=O)-O- or -OC(=O)-. In some embodiments, X2 is -C(=O)-O- or -OC(=O)-.

[0019] On the other hand, this paper describes a compound of formula IV-a:

[0020] Or its N-oxide or its pharmaceutically acceptable salt.

[0021] In some respects, this paper describes a compound of formula V:

[0022] in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1 or L2 is substituted, then L1 or L2 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each R1 and R2 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

[0023] In some embodiments, this document describes a compound of formula VI, or its N-oxide or pharmaceutically acceptable salt:

[0024] in: X is O, S, or C(R) 11 )2; L 11 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 12 Is it a substituted or unsubstituted linear C3-? 12Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 13 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 14 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 15 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 16 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; Where L 11 L 12 L 13 L 14 L 15 or L 16 If replaced, then L 11 L 12 L 13 L 14 L 15 or L 16 Substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-6 Alkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 6-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; X11 It is a covalent bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X 12 It is a covalent bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each R 12 R 14 R 15 and R 16 Independently, it is hydrogen, deuterium, halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; L 17 Is it substituted or unsubstituted -C1- 24 alkylene-; wherein L 17 Optionally assigned to 10 R 11 replace; R 17 It is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2、-CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; Each R 11 Independently selected from hydrogen, deuterium, halogens, -CN, -C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl); and t can be 0, 1, 2, 3 or 4.

[0025] In some implementations, each variable group of formula V is independent as described herein.

[0026] In some embodiments, at least one of R1, R2, and R3 is not hydrogen or deuterium. In some embodiments, R1, R2, and R3 are each independently a halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, at least one of R1, R2, and R3 is a halogen, C 2-6 alkenyl or branched C 3-10 Alkyl group. In some embodiments, at least one of R1, R2, and R3 is a fluorinated or isopropyl group. In some aspects, R1 is a halogen, -CN, or -OR group. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6Alkyne group. In one respect, R1 is halogen, -CN, -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R1 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group. In another aspect, R1 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, or tert-hexyl. In some embodiments, R1 is a halogen or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R1 is a halogen or isopropyl. In some embodiments, R1 is F. In some embodiments, R1 is Cl. In some embodiments, R1 is Br. In some embodiments, R1 is I. In some embodiments, R1 is isopropyl. In some embodiments, R1 is C. 2-6 Alkenyl. In some embodiments, R1 is... In some respects, R2 is halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In one respect, R2 is halogenated, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R2 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group. In another aspect, R2 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, or tert-hexyl. In some embodiments, R2 is a halogen or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R2 is a halogen or isopropyl. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Br. In some embodiments, R2 is I. In some embodiments, R2 is isopropyl. In some aspects, R3 is a halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In one respect, R3 is halogenated, -CN, or -OR. 10 -N(R) 102. C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R3 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R3 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, or tert-hexyl. In some embodiments, R3 is a halogen or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R3 is a halogen or isopropyl. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Br. In some embodiments, R3 is I. In some embodiments, R3 is isopropyl. In some embodiments, at least one of R2 and R3 is a halogen, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 Alkyl group. In some respects, R3 is halogen, -OR 10 Or branch C 3-10 Alkyl group; and R1 and R2 are hydrogen. On the other hand, R3 is halogen, -OR 10 Or branch C 3-10 Alkyl group; R2 is a halogen, -OR 10 Or branch C 3-10 Alkyl group and R1 is hydrogen. On the other hand, R3 is halogen, -OR 10 Or branch C 3-10 Alkyl group; R2 is a halogen, -OR 10 Or branch C 3-10 Alkyl and R1 is C 2-6 Alkenyl. In some respects, R3 is F or branched C. 3-10 Alkyl group; and R1 and R2 are hydrogen. On the other hand, R3 is F or branched C. 3-10 Alkyl; R2 is F or branched C 3-10 Alkyl group and R1 is hydrogen. On the other hand, R3 is F or branched C. 3-10 Alkyl; R2 is F or branched C 3-10 Alkyl and R1 is In some respects, R3 is Cl or branched C. 3-10 Alkyl group; and R1 and R2 are hydrogen. On the other hand, R3 is Cl or branched C. 3-10 Alkyl group; R2 is Cl or branched C 3-10 Alkyl group and R1 is hydrogen. On the other hand, R3 is Cl or branched C. 3-10 Alkyl; R2 is F or branched C 3-10 Alkyl and R1 is .

[0027] In some implementations, R3 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group; and R1 and R2 are hydrogen. In some embodiments, R3 is halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group; R2 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 The alkyl group is used, and R1 is hydrogen. In some embodiments, R1 is H; and R2 and R3 are each independently halogenated, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, R1 is H; and R2 and R3 are each independently halogenated, -OR 10 C 2-6 alkenyl or branched C 3-6 Alkyl group. In some embodiments, R1 is H; R2 is H, halogen, isopropyl, isobutyl, sec-butyl, or tert-butyl; and R3 is halogen, -OR 10 Or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R1 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-6 Alkyl group; and R2 and R3 are each independently H.

[0028] In some embodiments, each of R1, R2, and R3 is hydrogen or deuterium, then at least one of L1, L2, and L3 is substituted with 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon of L1, L2, or L3. 1-10 Alkyl or deuterium. In some respects, L1 is substituted or unsubstituted -C4- 10 alkylene or -C 3-12 Alkenylalkylene. On the other hand, L1 is a halogenated, straight-chain or branched C-type carbon. 1-6 Alkyl or C 1-2 Halogenated alkyl-substituted -C4- 10 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L1 is a -C4- substituted with a fluorinated, methyl, or isopropyl group. 10 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, each L2 and L3 is independently substituted or unsubstituted -C.4-10 alkylene or -C 3-12 Alkenylalkylene. In one aspect, L2 and L3 are identical. In another aspect, L2 and L3 are different. In some embodiments, each L2 and L3 is independently substituted with a -C. 4-10 alkylene or -C 3-12 Alkenylalkylene, wherein the substituent is a halogen or a straight-chain or branched C. 1-6 Alkyl group. In some embodiments, each L2 and L3 is independently substituted -C. 4-10 alkylene or -C 3-12 alkenylalkylene, wherein -C 4-10 The alkylene group is replaced by a fluorinated group, a methyl group, or an isopropyl group.

[0029] In some respects, L4 is either substituted or unsubstituted -C1- 12 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 Substitution. In some embodiments, L4 is a substituted or unsubstituted -C1-6 alkylene or -C 3-12 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 Replacement. In another embodiment, L4 is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-(CH2)2-CH2-, -CH2-(CH2)3-CH2-, or -CH2-(CH2)4-CH2-. In another embodiment, L4 is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH(CH3)-CH2-, -CH2-(CH2)2-CH2-, -CH2-(CH2)3-CH2-, or -CH2-(CH2)4-CH2-. In some embodiments, L4 is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In some embodiments, L4 is -CH2-CH(CH3)-CH2-. In some embodiments, L4 is -CH2-CH(CH3)-CH2-. In some implementations, L4 is -CD2-CD2-. In some implementations, R4 is -OH, -OR. 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-C0-9alkylene-N(R) 11 )2、-OC(=O)-C0-9alkylene-R 11 -(O-CO-9 alkylene-) n R 11-CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R) 11 2. In one aspect, R4 is -OH, -CH(CH3)-CH2-OH, or -OC(=O)-(CH2)3-N(Me)2. In some embodiments, R4 is -OH. In some embodiments, R4 is -N(R 11 2. In some implementations, R4 is -N(R 11 )2, where each R 11 Independently hydrogen or C 1-6 Alkyl group. In some embodiments, R4 is -NMe2.

[0030] In some respects, this article describes compounds having the following structures: , , , , , , , , , , , , , , , , , , , or .

[0031] In some respects, this paper describes compounds having the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0032] In some respects, this document describes a nanoparticle composition comprising a lipid component, wherein the lipid component comprises compounds disclosed herein (e.g., compounds of formula I', I'-a, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI).

[0033] In some aspects, this document describes a lipid component that further comprises structural lipids. In some aspects, the structural lipids comprise cholesterol, codostrum, sitosterol, ergosterol, campesterol, stigmasterol, phytosterol, tomatidine, ursolic acid, or α-tocopherol. In some embodiments, the lipid component further comprises PEG lipids. In some aspects, the PEG lipids are PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, or PEG-modified dialkylglycerol. In some embodiments, the lipid component further comprises cationic and / or ionizable lipids. In some embodiments, the cationic and / or ionizable lipids are 3-(bisdodecylamino)-N1,N1,4-tris(dodecyl)-1-piperazine ethylamine (KL10), N1-[2-(bisdodecylamino)ethyl]-N1,N4,N4-tris(dodecyl)-1,4-piperazine diethylamine (KL22), 14,25-bis(tetrazyl)-15,18,21,24-tetraaza-octacosane (KL25), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxacyclopentane (DLin-K-DMA), and 4-(dimethylamino)butyrate trihexadecano-6,9,28,31-tetraen-19-yl ester (DLin- MC3-DMA, 2,2-dioleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxacyclopentane (DLin-KC2-DMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), 2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA), (2R)-2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA) (2R) or (2S)-2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]propyl-1-amine (Octyl-CLinDMA (2S)). In some aspects, the lipid component also comprises phospholipids, structural lipids, and PEG lipids.In some embodiments, the lipid component comprises about 30% to about 60% of the compounds disclosed herein (e.g., compounds of formula I', I'-a, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI), about 0% to about 30% of phospholipids, about 20% to about 50% of structural lipids, and about 0% to about 10% of PEG lipids. In some embodiments, the nanoparticle composition of compounds of formula I', I'-a, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI further comprises therapeutic and / or preventative agents. In some aspects, the therapeutic and / or preventative agents are nucleic acids. In some embodiments, the therapeutic and / or preventative agents are ribonucleic acid (RNA). In some embodiments, the RNA is small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), or messenger RNA (mRNA). In another embodiment, the RNA is mRNA. In some embodiments, the mRNA comprises at least one nucleic acid modification. In some embodiments, the at least one nucleic acid modification comprises N1-methylpseuuridine (M1Ψ).

[0034] In some respects, this document describes a pharmaceutical composition comprising a nanoparticle composition of a compound of formula I', I'-a, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI, and a pharmaceutically acceptable carrier.

[0035] In some aspects, this document describes a method for delivering a therapeutic agent to a subject in need, the method comprising administering a nanoparticle composition or pharmaceutical composition disclosed herein to the subject, thereby delivering the therapeutic agent to the subject. In some embodiments, this document discloses a method for generating a polypeptide of interest in cells, the method comprising contacting the cells with a nanoparticle composition or pharmaceutical composition of a compound of formula I', I'-a, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI, wherein the therapeutic agent is mRNA, wherein the mRNA encodes the polypeptide of interest. In some embodiments, the mRNA is capable of being translated in cells to generate the polypeptide of interest.

[0036] In some aspects, this document discloses a method for selectively delivering a therapeutic agent to a mammalian organ, the method comprising administering to a mammal a nanoparticle composition or pharmaceutical composition of a compound of formula I', I'-a, I, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI. In some embodiments, administering the nanoparticle composition or pharmaceutical composition comprises contacting the mammalian organ with the nanoparticle composition, thereby delivering the therapeutic agent to the organ. In some aspects, the therapeutic agent is delivered to the organ.

[0037] In some embodiments, this document discloses a method for treating a disease or condition in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a nanoparticle composition of a compound of formula I', I'-a, I, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI, or a pharmaceutical composition of the nanoparticle composition according to any of the claims. In some embodiments, the disease or condition is cancer.

[0038] Other aspects and advantages of this disclosure will be readily apparent to those skilled in the art from the following detailed description, which shows and describes only illustrative embodiments thereof. As will be appreciated, this disclosure is capable of having other and different embodiments, and several details thereof can be modified in various obvious respects, all without departing from this disclosure. Therefore, the drawings and descriptions are to be considered illustrative in nature and not restrictive. Incorporation

[0039] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is expressly and individually indicated to be incorporated by reference. Where a publication, patent, or patent application incorporated by reference contradicts the disclosure contained in this specification, this specification is intended to supersede and / or give precedence to any such contradictory material. Attached Figure Description

[0040] Various aspects of this disclosure are specifically set forth in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description and accompanying drawings, which illustrate illustrative embodiments utilizing the principles of this disclosure, in which: Figure 1 The transfection of the AML12 cell line with FLuc mRNA LNP is shown. Cells were transfected with 200 ng FlucmRNA encapsulated in LNP, and expression was analyzed after 24 hours. Transfection was performed in triplicate.

[0041] Figure 2Cell viability of the AML12 cell line during transfection with FLuc mRNA LNP is shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and viability was assessed using Promega's CellTiter-Glo® luminescent cell viability assay. Transfection was performed in triplicate.

[0042] Figure 3 The results of transfection of the B16F10 cell line with FLuc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and expression was analyzed 24 hours later. Transfection was performed in triplicate.

[0043] Figure 4 The results of cell viability of the B16F10 cell line during transfection with FLuc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and viability was assessed using Promega's CellTiter-Glo® luminescent cell viability assay. Transfection was performed in triplicate.

[0044] Figure 5 The results of transfecting the MC38.K cell line with Fluc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and expression was analyzed 24 hours later. Transfection was performed in triplicate.

[0045] Figure 6 The results of cell viability of the MC38.K cell line during transfection with FLuc mRNA LNP are shown. Cells were transfected with 200 ng Fluc mRNA encapsulated in LNP, and viability was assessed using Promega's CellTiter-Glo® luminescent cell viability assay. Transfection was performed in triplicate.

[0046] Figure 7 Results of in vitro luminescent signals from the liver are shown. Fluc mRNA LNPs were injected into 20g CD1 mice (Naïve) via tail vein injection (1.0 mg / kg) on ​​days 0 and 2. Sampling and IVIS imaging were performed 18 hours after the second administration (day 3). n=5 mice per group.

[0047] Figure 8 Analysis of Flux expression as a function of the surface pKa of lipid nanoparticles is shown. Arrows indicate baseline expression per emission intensity.

[0048] Figure 9 The results show a comparison of body weight between two fluorinated ionizable lipids. Changing the position of the fluorinated moiety produced significant differences in body weight and tolerability.

[0049] Figure 10 The results of transfection of AML12, B16F10, and MC38.K cell lines with FLuc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and expression was analyzed 24 hours later. Transfection was performed in triplicate.

[0050] Figure 11 The results of cell viability in AML12, B16F10, and MC38.K cell lines during transfection with FLuc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and viability was assessed using Promega's CellTiter-Glo® luminescent cell viability assay. Transfection was performed in triplicate.

[0051] Figure 12 The image shows a crab-eating macaque ( Macaca fascicularis Results of absolute reticulocyte, erythrocyte, and hematocrit counts, as well as hEPO protein expression (6 hours) in Cynomolgus monkeys following a single IV infusion of 0.3 mg / kg hEPO mRNA LNP. N=3.

[0052] Figure 13 The results of body weight, temperature, and liver blood chemistry in cynomolgus monkeys following a single IV infusion of 0.3 mg / kg hEPO mRNA LNP are shown. N=3.

[0053] Figure 14 The results of body weight, temperature, and liver blood chemistry in cynomolgus monkeys over four weeks following weekly infusion of 0.1 mg / kg hEPO mRNA LNP are shown. N=3.

[0054] Figure 15 Results of hematocrit (HCT) and absolute reticulocyte count in cynomolgus monkeys over four weeks following weekly infusions of 0.1 mg / kg hEPO mRNA LNP are shown. Treatment was administered intravenously on days 0, 7, 14, and 21. N=3.

[0055] Figure 16 The results of serum hEPO quantification in cynomolgus monkeys after weekly treatment with 0.1 mg / kg hEPO mRNA-LNP are shown (N=3).

[0056] Figure 17 The results show the quantification of compound 23 in cynomolgus monkey serum after weekly treatment with 0.1 mg / kg hEPO-mRNA LNP. N=3.

[0057] Figure 18 The results of a comparative study on the tolerance of compound 23 and benchmark 1 are shown.

[0058] Figure 19 The results of a comparative study on the intratumoral delivery efficiency of compound 23 and baseline 1 are shown.

[0059] Figure 20 The results of an in vitro comparative study on the expression of firefly luciferase in LNPs containing various fluorinated compound pairs and non-fluorinated compound pairs are presented.

[0060] Figure 21 The transfection of the AML12 cell line with FLuc mRNA LNP is shown. Cells were transfected with 200 ng FlucmRNA encapsulated in LNP, and expression was analyzed after 24 hours. Transfection was performed in triplicate.

[0061] Figure 22 Cell viability of the AML12 cell line during transfection with FLuc mRNA LNP is shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and viability was assessed using Promega's CellTiter-Glo® luminescent cell viability assay. Transfection was performed in triplicate.

[0062] Figure 23 The results of transfection of the B16F10 cell line with FLuc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and expression was analyzed 24 hours later. Transfection was performed in triplicate.

[0063] Figure 24 The results of cell viability of the B16F10 cell line during transfection with FLuc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and viability was assessed using Promega's CellTiter-Glo® luminescent cell viability assay. Transfection was performed in triplicate.

[0064] Figure 25 The results of transfecting the MC38.K cell line with Fluc mRNA LNP are shown. Cells were transfected with 200 ng of Fluc mRNA encapsulated in LNP, and expression was analyzed 24 hours later. Transfection was performed in triplicate.

[0065] Figure 26The results of cell viability of the MC38.K cell line during transfection with FLuc mRNA LNP are shown. Cells were transfected with 200 ng Fluc mRNA encapsulated in LNP, and viability was assessed using Promega's CellTiter-Glo® luminescent cell viability assay. Transfection was performed in triplicate.

[0066] Figure 27 Results of in vitro luminescent signals from the liver are shown. Fluc mRNA LNPs were injected into 20g CD1 mice (Naïve) via tail vein injection (1.0 mg / kg) on ​​days 0 and 2. Sampling and IVIS imaging were performed 18 hours after the second administration (day 3). n=5 mice per group.

[0067] Figure 28 Results of in vitro luminescent signals from the spleen are shown. Fluc mRNA LNPs were injected into 20g CD1 mice (Naïve) via tail vein injection (1.0 mg / kg) on ​​days 0 and 2. Sampling and IVIS imaging were performed 18 hours after the second administration (day 3). n=5 mice per group.

[0068] Figure 29 Analysis of Flux expression as a function of the surface pKa of lipid nanoparticles is shown. Arrows indicate baseline expression per emission intensity.

[0069] Figure 30 The figures show body weight, white blood cell count, and lymphocyte count over a three-week period during the tolerance study.

[0070] Figure 31 The in vitro luminescence of liver, tumor, and spleen organs was shown after intravenous injection of 1.0 mg / kg peripheral LNP. Detailed Implementation

[0071] This disclosure relates to cationic and / or ionizable lipids and lipid-containing particles comprising the same. This disclosure also relates to methods for delivering therapeutic agents (such as nucleic acids) to mammalian cells, methods for generating polypeptides of interest in mammalian cells, and methods for treating diseases or conditions in mammals in need. For example, a method for generating a polypeptide of interest in a cell may include the steps of contacting the lipid-containing particles described herein with a cell to deliver mRNA encoding the polypeptide of interest into the cell, and whereby the mRNA can be translated to generate the polypeptide of interest. As another example, a method for delivering a therapeutic agent to mammalian cells or organs may include administering a lipid-containing particle containing a therapeutic agent to a subject, wherein the administration includes contacting the cell or organ with the lipid-containing particle, thereby delivering the therapeutic agent to the cell or organ. In some embodiments, the particle comprises a compound described herein. In some embodiments, the particle is a compound described herein. In some embodiments, the compound is any one of compounds 1-54.

[0072] In some respects, this paper describes compounds containing formula I':

[0073] Or its N-oxide or a pharmaceutically acceptable salt thereof. In some embodiments, L1 is a substituted or unsubstituted straight-chain -C3- 12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain -C 4-12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L3 is a substituted or unsubstituted linear-C-chain. 4-12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, if L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 Substitution. In some implementations, L4 is substituted or unsubstituted -C1- 24 alkylene or -C 3-24Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 Replacement. In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, each R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkynyl group. In some embodiments, at least one of R1, R2, and R3 is not hydrogen or deuterium. In some embodiments, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted with 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium. In some embodiments, R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 2. In some implementations, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl group). In some embodiments, n is an integer from 0 to 20. In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, 3, 4, or 5. In some embodiments, r is 0 or 1.

[0074] In some respects, this paper describes a compound of formula I'-a:

[0075] Or its N-oxide or a pharmaceutically acceptable salt thereof. In some embodiments, L1 is a substituted or unsubstituted straight-chain -C3- 12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain -C 4-12 alkylene or -C 3-12Alkenylalkylene. In some embodiments, L3 is a substituted or unsubstituted linear-C-chain. 4-12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, if L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 Substitution. In some implementations, L4 is substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 Replacement. In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, each R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkynyl group. In some embodiments, at least one of R1, R2, and R3 is not hydrogen or deuterium. In some embodiments, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted with 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium. In some embodiments, R4 is -OH, -OR10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 2. In some implementations, each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl group). In some embodiments, n is an integer from 0 to 20. In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, 3, 4, or 5.

[0076] In some respects, this paper describes compounds comprising formula I: L1, or its N-oxide, or a pharmaceutically acceptable salt thereof. In some embodiments, L1 is a substituted or unsubstituted straight-chain -C3- 12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain -C 4-12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L3 is a substituted or unsubstituted linear-C-chain. 4-12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, if L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 Substitution. In some implementations, L4 is substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 Replacement. In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R).10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, each R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkynyl group. In some embodiments, at least one of R1, R2, and R3 is not hydrogen or deuterium. In some embodiments, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted with 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium. In some embodiments, R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 2. In some implementations, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6Alkyne group. In some implementations, each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl group). In some embodiments, n is an integer from 0 to 20. In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, 3, 4, or 5.

[0077] In some respects, this paper describes compounds containing the structure of formula II: L1, or its N-oxide, or a pharmaceutically acceptable salt thereof. In some embodiments, L1 is a substituted or unsubstituted straight-chain -C3- 12 Alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain -C 4-12 Alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain -C 4-12 Alkylene. In some embodiments, if L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 Substitution. In some implementations, L4 is substituted or unsubstituted -C1- 24 Alkylene. In some embodiments, L4 is optionally surrounded by 1 to 10 R... 11 Replacement. In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, each R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 An alkynyl group, provided that at least one of R1, R2, and R3 is not hydrogen or deuterium, or when each of R1, R2, and R3 is hydrogen or deuterium, then at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium. In some embodiments, R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 2. In some implementations, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl group). In some embodiments, n is an integer from 0 to 20. In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, 3, 4, or 5.

[0078] In some embodiments, the compound comprises the structure of formula III: , or its N-oxide or a pharmaceutically acceptable salt thereof. In some embodiments, the compound comprises a structure of formula III-a: , or its N-oxide or a pharmaceutically acceptable salt thereof. In some embodiments, the compound comprises a structure of formula IV: , or its N-oxide or a pharmaceutically acceptable salt thereof. In some embodiments, the compound comprises a structure of formula IV-a: , or its N-oxide or its pharmaceutically acceptable salt.

[0079] In some embodiments, this document describes a compound of formula V:

[0080] Or its N-oxide or a pharmaceutically acceptable salt thereof. In some embodiments, L1 is a substituted or unsubstituted straight-chain -C3- 12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain -C 4-12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, L3 is a substituted or unsubstituted linear-C-chain. 4-12 alkylene or -C 3-12 Alkenylalkylene. In some embodiments, if L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 Substitution. In some implementations, L4 is substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 Replacement. In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10-C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, each R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkynyl group. In some embodiments, at least one of R1, R2, and R3 is not hydrogen or deuterium. In some embodiments, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted with 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium. In some embodiments, R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 2. In some implementations, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some implementations, each R 11Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl group). In some embodiments, n is an integer from 0 to 20. In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, q is 0, 1, 2, 3, 4, or 5.

[0081] In some embodiments, the compound comprises the following structures, or their N-oxides, or their pharmaceutically acceptable salts: , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0082] In some aspects, this document describes a nanoparticle composition comprising the compounds described herein and a lipid component. In some embodiments, the lipid component comprises structural lipids such as cholesterol, codostrum, sitosterol, ergosterol, campesterol, stigmasterol, phytosterol, ursolic acid, α-tocopherol, or combinations thereof. In some embodiments, the nanoparticle composition comprises polyethylene glycol (PEG) lipids. In some embodiments, the PEG lipids comprise PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol, or combinations thereof. In some embodiments, the lipid component also comprises cationic and / or ionizable lipids. In some embodiments, the nanoparticle composition also comprises therapeutic and / or preventative agents. In some embodiments, the therapeutic and / or preventative agent is a nucleic acid. In some embodiments, the therapeutic and / or preventative agent is ribonucleic acid (RNA). In some embodiments, the RNA is small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), or messenger RNA (mRNA). In some embodiments, the RNA is mRNA. In some embodiments, the mRNA encodes a polypeptide related to an immune response. For example, the mRNA may encode a polypeptide containing interleukins or interferons.

[0083] In some aspects, this document describes methods for contacting cells with compounds or nanoparticle compositions described herein, wherein the compounds or nanoparticle compositions described herein deliver nucleic acids described herein into the cells. In some embodiments, the methods include treating cell-related diseases or conditions. In some embodiments, the methods include expressing nucleic acids, wherein the expression of nucleic acids produces peptides for treating diseases or conditions.

[0084] Nanoparticle Composition In some embodiments, this document provides LNP compositions comprising aminolipids, phospholipids, PEG-lipids, cholesterol or derivatives thereof, payloads or any combination thereof for delivering therapeutic agents to mammalian cells or organs.

[0085] Amino lipids Some of the embodiments described herein include aminolipid compounds having the structure of formula (I'):

[0086] Or its N-oxide or its pharmaceutically acceptable salt. in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is a halogen, -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0 or 1.

[0087] In some implementations, r is 0. In some implementations, r is 1. In some implementations, X1 is a covalent bond. In some implementations, X2 is a covalent bond. In some implementations, at least one of X1 and X2 is not a covalent bond. In some implementations, X1 is a covalent bond and X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is a covalent bond and X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10)-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, the two R5s are the same. In some embodiments, the two R5s are different. In some embodiments, the two R6s are the same. In some embodiments, the two R6s are different. In some embodiments, the two R7s are the same. In some embodiments, the two R7s are different. In some embodiments, the two R8s are the same. In some embodiments, the two R8s are different. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, -OR. 10 Or C 1-10 Alkyl group. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, or C. 1-10 Alkyl group. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, or C. 1-8 Alkyl group. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, or C. 1-6 Alkyl group. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, fluorinated, or methyl. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, methyl, ethyl, or isopropyl. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen or deuterium. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-10 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R7, R8, or R9 is H. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-8 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R7, R8, or R9 is H. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R7, R8, or R9 is H. In some embodiments, each R6 is hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R6 is not hydrogen, and R5, R7, R8, or R9 is H. In some embodiments, each R7 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R7 is not hydrogen, and R5, R6, R8, or R9 is H. In some embodiments, each R8 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R8 is not hydrogen, and R5, R6, R7, or R9 is H. In some embodiments, R9 is hydrogen, halogen, or C.1-6 Alkyl group, and R5, R6, R7, or R8 is hydrogen (H). In some embodiments, R9 is not hydrogen, and R5, R6, R7, or R8 is hydrogen (H). In some embodiments, R9 is a halogen or carbonyl group. 1-6 The alkyl group, and R5, R6, R7, or R8 is H. In some embodiments, one of R5 is methyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is ethyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C3 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C4 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C5 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C6 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C7 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is a C8 alkyl group, and the other R5s, as well as R6, R7, R8, or R9, are hydrogen (H). In some embodiments, one of R5 is a C9 alkyl group, and the other R5s, as well as R6, R7, R8, or R9, are hydrogen (H). In some embodiments, one of R5 is a C... 10 Alkyl group, and the other R5s, as well as R6, R7, R8, or R9, are H. In some embodiments, one of the R5s is... And the other R5s, as well as R6, R7, R8, or R9, are H. In some implementations, one of R5s is... In some embodiments, one of R6 is methyl, and the other R6, R5, R7, R8, or R9 is H. In some embodiments, one of R7 is methyl, and the other R7, R5, R6, R8, or R9 is H. In some embodiments, one of R8 is methyl, and the other R8, R5, R6, R7, or R9 is H. In some embodiments, R9 is methyl, and R5, R6, R7, or R8 is H. In some embodiments, R4 is a halogen. In some embodiments, R4 is -OH, -OR. 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-)n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2.

[0088] In some embodiments, the compound of formula I' has the structure of formula I'-a, or its N-oxide or pharmaceutically acceptable salt:

[0089] in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is a halogen, -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

[0090] In some embodiments, X1 is a covalent bond. In some embodiments, X2 is a covalent bond. In some embodiments, at least one of X1 and X2 is not a covalent bond. In some embodiments, X1 is a covalent bond and X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is a covalent bond and X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10-C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 -C(=O)-, -SS, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, the two R5s are the same. In some embodiments, the two R5s are different. In some embodiments, the two R6s are the same. In some embodiments, the two R6s are different. In some embodiments, the two R8s are the same. In some embodiments, the two R8s are different. In some embodiments, each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, -OR. 10 Or C 1-10 Alkyl group. In some embodiments, each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, or C. 1-6 Alkyl group. In some embodiments, each R5, R6, R8, or R9 is independently hydrogen, deuterium, fluorinated, or methyl. In some embodiments, each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, methyl, ethyl, or isopropyl. In some embodiments, each R5, R6, R8, or R9 is independently hydrogen or deuterium. In some embodiments, each R5, R6, R8, or R9 is independently hydrogen. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-10 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R8, or R9 is H. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-8 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R8, or R9 is H. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R8, or R9 is H. In some embodiments, each R6 is hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R6 is not hydrogen, and R5, R8, or R9 is H. In some embodiments, each R8 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R8 is not hydrogen, and R5, R6, or R9 is H. In some embodiments, R9 is hydrogen, halogen, or C. 1-6Alkyl group, and R5, R6, or R8 is hydrogen (H). In some embodiments, R9 is not hydrogen, and R5, R6, or R8 is hydrogen (H). In some embodiments, R9 is a halogen or carbonyl group. 1-6 Alkyl group, and R5, R6, or R8 is H. In some embodiments, one of R5 is methyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is ethyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is C3 alkyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is C4 alkyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is C5 alkyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is C6 alkyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is C7 alkyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is C8 alkyl, and the other R5, as well as R6, R8, or R9, is H. In some embodiments, one of R5 is a C9 alkyl group, and the other R5s, as well as R6, R8, or R9, are H. In some embodiments, one of R5 is C6. 10 Alkyl group, and the other R5s, as well as R6, R8, or R9, are H. In some embodiments, one of the R5s is... And the other R5s, as well as R6, R8, or R9, are H. In some implementations, one of R5s is... And the other R5 as well as R6, R8, or R9 are H. In some embodiments, one of R6 is methyl, and the other R6 as well as R5, R8, or R9 are H. In some embodiments, one of R8 is methyl, and the other R8 as well as R5, R6, R7, or R9 are H. In some embodiments, R9 is methyl, and R5, R6, R7, or R8 are H. In some embodiments, R4 is a halogen. In some embodiments, R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10)2 or -C(=O)-C0-9 alkylene-N(R 10 )2.

[0091] Some of the embodiments described herein include aminolipid compounds having the structure of formula (I):

[0092] Or its N-oxide or pharmaceutically acceptable salt. in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10)-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

[0093] In some implementations, the two R5s are the same. In some implementations, the two R5s are different. In some implementations, the two R6s are the same. In some implementations, the two R6s are different. In some implementations, the two R7s are the same. In some implementations, the two R7s are different. In some implementations, the two R8s are the same. In some implementations, the two R8s are different. In some implementations, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 Or C 1-10 Alkyl group. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, or C. 1-6 Alkyl group. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, fluorinated, or methyl. In some embodiments, each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, methyl, ethyl, or isopropyl. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-10Alkyl group, wherein at least one R5 is not hydrogen, and R6, R7, R8, or R9 is H. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-8 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R7, R8, or R9 is H. In some embodiments, each R5 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R5 is not hydrogen, and R6, R7, R8, or R9 is H. In some embodiments, each R6 is hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R6 is not hydrogen, and R5, R7, R8, or R9 is H. In some embodiments, each R7 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R7 is not hydrogen, and R5, R6, R8, or R9 is H. In some embodiments, each R8 is independently hydrogen, halogen, or C. 1-6 Alkyl group, wherein at least one R8 is not hydrogen, and R5, R6, R7, or R9 is H. In some embodiments, R9 is hydrogen, halogen, or C. 1-6 Alkyl group, and R5, R6, R7, or R8 is hydrogen (H). In some embodiments, R9 is not hydrogen, and R5, R6, R7, or R8 is hydrogen (H). In some embodiments, R9 is a halogen or carbonyl group. 1-6 The alkyl group, and R5, R6, R7, or R8 is H. In some embodiments, one of R5 is methyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is ethyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C3 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C4 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C5 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C6 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C7 alkyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is a C8 alkyl group, and the other R5s, as well as R6, R7, R8, or R9, are hydrogen (H). In some embodiments, one of R5 is a C9 alkyl group, and the other R5s, as well as R6, R7, R8, or R9, are hydrogen (H). In some embodiments, one of R5 is a C... 10 Alkyl group, and the other R5s, as well as R6, R7, R8, or R9, are H. In some embodiments, one of the R5s is... And the other R5s, as well as R6, R7, R8, or R9, are H. In some implementations, one of R5s is... Furthermore, the other R5 and R6, R7, R8, or R9 are H. In some embodiments, one of R6 is methyl, and the other R6 and R5, R7, R8, or R9 are H. In some embodiments, one of R7 is methyl, and the other R7 and R5, R6, R8, or R9 are H. In some embodiments, one of R8 is methyl, and the other R8 and R5, R6, R7, or R9 are H. In some embodiments, R9 is methyl, and R5, R6, R7, or R8 are H.

[0094] In some embodiments, the compound of formula I' or formula I has the structure of formula Ia, or its N-oxide or pharmaceutically acceptable salt:

[0095] Each of R5, R5', R6, R6', R7, R7', R8, R8', or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

[0096] In some embodiments, R5 and R5' are the same. In some embodiments, R5 and R5' are different. In some embodiments, R6 and R6' are the same. In some embodiments, R6 and R6' are different. In some embodiments, R7 and R7' are the same. In some embodiments, R7 and R7' are different. In some embodiments, R8 and R8' are the same. In some embodiments, R8 and R8' are different. In some embodiments, each R5, R5', R6, R6', R7, R7', R8, R8', or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 Or C 1-10 Alkyl group. In some embodiments, each R5, R5', R6, R6', R7, R7', R8, R8', or R9 is independently hydrogen, deuterium, halogen, or C. 1-6Alkyl group. In some embodiments, each R5, R5', R6, R6', R7, R7', R8, R8', or R9 is independently hydrogen, deuterium, fluorinated, or methyl. In some embodiments, each R5, R5', R6, R6', R7, R7', R8, R8', or R9 is independently hydrogen, deuterium, halogen, methyl, ethyl, or isopropyl. In some embodiments, R5 is a halogen or C. 1-10 Alkyl group, and R5', R6, R6', R7, R7', R8, R8', or R9 is H. In some embodiments, R5 is a halogen or C. 1-8 Alkyl group, and R5', R6, R6', R7, R7', R8, R8', or R9 is H. In some embodiments, R5 is a halogen or C. 1-6 Alkyl group, and R5', R6, R6', R7, R7', R8, R8', or R9 is H. In some embodiments, R6 is a halogen or C. 1-6 Alkyl group, and R5', R5, R6', R7, R7', R8, R8', or R9 is H. In some embodiments, R7 is a halogen or C. 1-6 Alkyl group, and R5', R5, R6', R6, R7', R8, R8', or R9 is H. In some embodiments, R8 is a halogen or C. 1-6 Alkyl group, and R5', R5, R6', R6, R7', R7, R8', or R9 is H. In some embodiments, R9 is a halogen or C. 1-6Alkyl group, and R5', R5, R6', R6, R7', R7, R8', or R8 is H. In some embodiments, R5 is methyl, and R5', R6', R6, R7', R7, R8', R8, or R9 is H. In some embodiments, one of R5 is ethyl, and the other R5, as well as R6, R7, R8, or R9, are H. In some embodiments, one of R5 is C3 alkyl, and R5', R6', R6, R7', R7, R8', R8, or R9 are H. In some embodiments, one of R5 is C4 alkyl, and R5', R6', R6, R7', R7, R8', R8, or R9 are H. In some embodiments, one of R5 is C5 alkyl, and R5', R6', R6, R7', R7, R8', R8, or R9 are H. In some embodiments, one of R5 is a C6 alkyl group, and R5', R6', R6, R7', R7, R8', R8, or R9 is hydrogen (H). In some embodiments, one of R5 is a C7 alkyl group, and R5', R6', R6, R7', R7, R8', R8, or R9 is hydrogen (H). In some embodiments, one of R5 is a C8 alkyl group, and R5', R6', R6, R7', R7, R8', R8, or R9 is hydrogen (H). In some embodiments, one of R5 is a C9 alkyl group, and R5', R6', R6, R7', R7, R8', R8, or R9 is hydrogen (H). In some embodiments, one of R5 is a C6 alkyl group. 10 Alkyl group, and R5', R6', R6, R7', R7, R8', R8, or R9 is H. In some embodiments, R5 is... And R5', R6', R6, R7', R7, R8', R8, or R9 are H. In some implementations, R5 is In some embodiments, one of R6 is methyl, and R5', R5, R6', R7', R7, R8', R8, or R9 is H. In some embodiments, one of R7 is methyl, and R5', R5, R6', R6, R7', R8', R8, or R9 is H. In some embodiments, one of R8 is methyl, and R5', R5, R6', R6, R7', R7, R8', or R9 is H. In some embodiments, R9 is methyl, and R5', R5, R6', R6, R7', R7, R8', or R8 is H.

[0097] In some embodiments, the compound of formula I' or formula I has the structure of formula Ib, or its N-oxide or pharmaceutically acceptable salt: .

[0098] In some implementations, R6 is hydrogen, deuterium, halogen, -CN, or -OR. 10 Or C 1-10 Alkyl group. In some embodiments, R6 is hydrogen. In some embodiments, R6 is methyl group.

[0099] In some embodiments, the compound of formula I'-a or formula I has the structure of formula II, or its N-oxide or pharmaceutically acceptable salt:

[0100] Or its N-oxide or pharmaceutically acceptable salt, wherein: L1 is a substituted or unsubstituted linear C3- chain. 12 Alkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 Alkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 Alkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-6 Alkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 6-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 Alkylene-; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2、-CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Heteroalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; Each R 11 Independently selected from hydrogen, deuterium, halogens, -CN, -C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3 or 4.

[0101] In some embodiments, the compound of formula I'-a or formula I has the structure of formula II, or its N-oxide or pharmaceutically acceptable salt:

[0102] Or its N-oxide or pharmaceutically acceptable salt, wherein: L1 is an unsubstituted straight-chain C4-8 alkylene; L2 is an unsubstituted linear-C 6-10 Alkylene; L3 is an unsubstituted linear-C 6-10 Alkylene; L4 is an unsubstituted -C1-4 alkylene-; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 or -OC(=O)-C0-9 alkylene-N(R) 10 )2; Each R 10 Independently hydrogen or C 1-3 alkyl; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3 or 4.

[0103] In some embodiments, the compound of formula I'-a or formula I has the structure of formula II, or its N-oxide or pharmaceutically acceptable salt:

[0104] Or its N-oxide or pharmaceutically acceptable salt, wherein: L1 is an unsubstituted straight-chain C4-8 alkylene; L2 is an unsubstituted linear-C 6-10 Alkylene; L3 is an unsubstituted linear-C 6-10 Alkylene; L4 is an unsubstituted -C1-4 alkylene-; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; R4 is -OH or -OC(=O)-C3 alkylene-N(Me)2; Each R 10 Independently hydrogen or C 1-3 alkyl; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3 or 4.

[0105] In some embodiments, the compound of formula I'-a or formula I has the structure of formula II, or its N-oxide or pharmaceutically acceptable salt:

[0106] Or its N-oxide or pharmaceutically acceptable salt, wherein: L1 is an unsubstituted straight-chain C4-8 alkylene; L2 is an unsubstituted linear-C 6-10 Alkylene; L3 is an unsubstituted linear-C 6-10 Alkylene; L4 is an unsubstituted -C1-4 alkylene-; X1 is -C(=O)-O- or -OC(=O); X2 is -C(=O)-O- or -OC(=O-); Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; R4 is -OH or -OC(=O)-C3 alkylene-N(Me)2; Each R 10 Independently hydrogen or C 1-3 alkyl; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3 or 4.

[0107] In some implementations, p equals q. In some implementations, p does not equal q. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, q is 1. In some implementations, q is 2. In some implementations, q is 3. In some implementations, q is 4. In some implementations, p is 1 and q is 1. In some implementations, p is 1 and q is 3. In some implementations, p is 3 and q is 3. In some implementations, p is 3 and q is 4. In some implementations, p is 4 and q is 3.

[0108] In some embodiments, the compound of formula I'-a or formula I has the structure of formula III, or its N-oxide or pharmaceutically acceptable salt: .

[0109] In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 X1 can be -C(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10 X1 is -C(=O)-. In some embodiments, X1 is -C(=O)-O- or -OC(=O)-. In some embodiments, X1 is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, X1 is -C(=O)-O-. In some embodiments, X1 is -OC(=O)-.

[0110] In some implementations, X2 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 X2 can be -C(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10 X2 is -C(=O)-. In some embodiments, X2 is -C(=O)-O- or -OC(=O)-. In some embodiments, X2 is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, X2 is -C(=O)-O-. In some embodiments, X2 is -OC(=O)-.

[0111] In some implementations, X1 is -C(=O)-O- and X2 is -OC(=O)-. In some implementations, X1 is -C(=O)-O- and X2 is -C(=O)-O-. In some implementations, X1 is -OC(=O)- and X2 is -OC(=O)-. In some implementations, X1 is -OC(=O)- and X2 is -C(=O)-O-.

[0112] In some embodiments, the compound of formula I'-a or formula I has the structure of formula III-a, or its N-oxide or pharmaceutically acceptable salt: .

[0113] In some embodiments, the compound of formula I'-a or formula I has the structure of formula IV, or its N-oxide or pharmaceutically acceptable salt: .

[0114] In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 X1 can be -C(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10 X1 is -C(=O)-. In some embodiments, X1 is -C(=O)-O- or -OC(=O)-. In some embodiments, X1 is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, X1 is -C(=O)-O-. In some embodiments, X1 is -OC(=O)-.

[0115] In some implementations, X2 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 X2 can be -C(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10X2 is -C(=O)-. In some embodiments, X2 is -C(=O)-O- or -OC(=O)-. In some embodiments, X2 is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, X2 is -C(=O)-O-. In some embodiments, X2 is -OC(=O)-.

[0116] In some implementations, X1 is -C(=O)-O- and X2 is -OC(=O)-. In some implementations, X1 is -C(=O)-O- and X2 is -C(=O)-O-. In some implementations, X1 is -OC(=O)- and X2 is -OC(=O)-. In some implementations, X1 is -OC(=O)- and X2 is -C(=O)-O-.

[0117] In some embodiments, the compound of formula I'-a or formula I has the structure of formula IV-a, or its N-oxide or pharmaceutically acceptable salt: .

[0118] In some embodiments, this document describes a compound of formula V, or its N-oxide or pharmaceutically acceptable salt:

[0119] in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1 or L2 is substituted, then L1 or L2 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each R1 and R2 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

[0120] In some embodiments, this document describes a compound of formula V, or its N-oxide or pharmaceutically acceptable salt:

[0121] in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1 or L2 is substituted, then L1 or L2 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each R1 and R2 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1 and R2 is not hydrogen or deuterium; Alternatively, when each of R1 and R2 is hydrogen or deuterium, at least one of L1 and L2 is substituted by 1-5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10-OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. -OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

[0122] In some implementations, X1 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 X1 can be -C(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X1 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10 X1 is -C(=O)-. In some embodiments, X1 is -C(=O)-O- or -OC(=O)-. In some embodiments, X1 is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, X1 is -C(=O)-O-. In some embodiments, X1 is -OC(=O)-.

[0123] In some implementations, X2 is -C(=O)-O-, -OC(=O-), -OC(=O)-O-, or -C(=O)-N(R). 10 )-、-N(R 10 X2 can be -C(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, or -C(=O)-N(R). 10 - or -N(R) 10 X2 is -C(=O)-. In some embodiments, X2 is -C(=O)-O- or -OC(=O)-. In some embodiments, X2 is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some embodiments, X2 is -C(=O)-O-. In some embodiments, X2 is -OC(=O)-.

[0124] In some implementations, X1 is -C(=O)-O- and X2 is -OC(=O)-. In some implementations, X1 is -C(=O)-O- and X2 is -C(=O)-O-. In some implementations, X1 is -OC(=O)- and X2 is -OC(=O)-. In some implementations, X1 is -OC(=O)- and X2 is -C(=O)-O-.

[0125] In some embodiments, at least one of R1, R2, and R3 is not hydrogen or deuterium. In some embodiments, R1, R2, and R3 are each independently a halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, at least one of R1, R2, and R3 is a halogen, C 2-6 alkenyl or branched C 3-10 Alkyl group. In some embodiments, at least one of R1, R2, and R3 is a fluorinated or isopropyl group. In some aspects, R1 is a halogen, -CN, or -OR group. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In one respect, R1 is halogen, -CN, -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R1 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group. In another aspect, R1 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, or tert-hexyl. In some embodiments, R1 is a halogen or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R1 is a halogen or isopropyl. In some embodiments, R1 is F. In some embodiments, R1 is Cl. In some embodiments, R1 is Br. In some embodiments, R1 is I. In some embodiments, R1 is isopropyl. In some embodiments, R1 is C. 2-6 Alkenyl. In some embodiments, R1 is... In some respects, R2 is halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In one respect, R2 is halogenated, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R2 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group. In another aspect, R2 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, or tert-hexyl. In some embodiments, R2 is a halogen or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R2 is a halogen or isopropyl. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Br. In some embodiments, R2 is I. In some embodiments, R2 is isopropyl. In some aspects, R3 is a halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In one respect, R3 is halogenated, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R3 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group. On the other hand, R3 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, or tert-hexyl. In some embodiments, R3 is a halogen or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R3 is a halogen or isopropyl. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Br. In some embodiments, R3 is I. In some embodiments, R3 is isopropyl. In some embodiments, at least one of R2 and R3 is a halogen, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 Alkyl group. In some respects, R3 is halogen, -OR 10 Or branch C 3-10 Alkyl group; and R1 and R2 are hydrogen. On the other hand, R3 is halogen, -OR10 Or branch C 3-10 Alkyl group; R2 is a halogen, -OR 10 Or branch C 3-10 Alkyl group and R1 is hydrogen. On the other hand, R3 is halogen, -OR 10 Or branch C 3-10 Alkyl group; R2 is a halogen, -OR 10 Or branch C 3-10 Alkyl and R1 is C 2-6 Alkenyl. In some respects, R3 is F or branched C. 3-10 Alkyl group; and R1 and R2 are hydrogen. On the other hand, R3 is F or branched C. 3-10 Alkyl; R2 is F or branched C 3-10 Alkyl group and R1 is hydrogen. On the other hand, R3 is F or branched C. 3-10 Alkyl; R2 is F or branched C 3-10 Alkyl and R1 is In some respects, R3 is Cl or branched C. 3-10 Alkyl group; and R1 and R2 are hydrogen. On the other hand, R3 is Cl or branched C. 3-10 Alkyl group; R2 is Cl or branched C 3-10 Alkyl group and R1 is hydrogen. On the other hand, R3 is Cl or branched C. 3-10 Alkyl; R2 is F or branched C 3-10 Alkyl and R1 is .

[0126] In some implementations, R3 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group; and R1 and R2 are hydrogen. In some embodiments, R3 is halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 Alkyl group; R2 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 The alkyl group is used, and R1 is hydrogen. In some embodiments, R1 is H; and R2 and R3 are each independently halogenated, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, R1 is H; and R2 and R3 are each independently halogenated, -OR 10 C 2-6 alkenyl or branched C 3-6Alkyl group. In some embodiments, R1 is H; R2 is H, halogen, isopropyl, isobutyl, sec-butyl, or tert-butyl; and R3 is halogen, -OR 10 Or isopropyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R1 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-6 Alkyl group; and R2 and R3 are each independently H.

[0127] In some embodiments, each of R1, R2, and R3 is hydrogen or deuterium, and at least one of L1, L2, and L3 is substituted with 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon of L1, L2, or L3. 1-10 Alkyl or deuterium. In some embodiments, each of R1, R2, and R3 is hydrogen or deuterium, and at least one of L1, L2, and L3 is substituted with 1-2 substituents, and at least one of the substituents is not a straight-chain C that is substituted at the terminal carbon of L1, L2, or L3. 1-10 Alkyl or deuterium. In some embodiments, each of R1, R2, and R3 is hydrogen or deuterium, and at least one of L1, L2, and L3 is halogenated or has a straight or branched carbon. 1-3 Alkyl substitution.

[0128] In some implementations, L1 is substituted or unsubstituted -C4- 10 Alkylene. In some embodiments, L1 is a substituted or unsubstituted -C 3-12 Alkenylalkylene. In some embodiments, L1 is a halogenated, straight-chain, or branched C-type carbon. 1-6 Alkyl or C 1-2 Halogenated alkyl-substituted -C4- 10 Alkylene. In some embodiments, L1 is a halogenated, straight-chain, or branched C. 1-6 Alkyl or C 1-2 Halogenated alkyl-substituted -C4- 10 Alkenylalkylene. In some embodiments, L1 is a -C4- substituted with a fluorinated, methyl, or isopropyl group. 10 Alkylene.

[0129] In some embodiments, L1 is a substituted or unsubstituted straight-chain C3 alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C4 alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C5 alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C6 alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C7 alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C8 alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C9 alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C... 10 Alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C. 11 Alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C. 12 Alkylene. In some embodiments, L1 is... In some implementations, L1 is... In some implementations, L1 is... In some implementations, L1 is... In some implementations, L1 is... In some implementations, L1 is... .

[0130] In some implementations, -L1-R1 is In some implementations, -L1-R1 is... In some implementations, -L1-R1 is... In some implementations, -L1-R1 is... In some implementations, -L1-R1 is... In some implementations, -L1-R1 is... In some implementations, -L1-R1 is... In some implementations, -L1-R1 is... .

[0131] In some embodiments, L1 is a substituted or unsubstituted straight-chain C3 alkenyl alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C4 alkenyl alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C5 alkenyl alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C6 alkenyl alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C7 alkenyl alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C8 alkenyl alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C9 alkenyl alkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C3 alkenyl alkylene. 10Alkenylalkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C. 11 Alkenylalkylene. In some embodiments, L1 is a substituted or unsubstituted straight-chain C. 12 Alkenylalkylene.

[0132] In some embodiments, L2 is a substituted or unsubstituted straight-chain C3 alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C4 alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C5 alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C6 alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C7 alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C8 alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C9 alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C... 10 Alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C. 11 Alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C. 12 Alkylene. In some embodiments, L2 is... In some implementations, L2 is... In some implementations, L2 is... In some implementations, L2 is... In some implementations, L2 is... In some implementations, L2 is... In some implementations, L2 is... .

[0133] In some embodiments, L2 is a substituted or unsubstituted straight-chain C3 alkenyl alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C4 alkenyl alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C5 alkenyl alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C6 alkenyl alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C7 alkenyl alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C8 alkenyl alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C9 alkenyl alkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C3 alkenyl alkylene. 10 Alkenylalkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C. 11 Alkenylalkylene. In some embodiments, L2 is a substituted or unsubstituted straight-chain C. 12 Alkenylalkylene.

[0134] In some implementations, -L2-R2 is In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... In some implementations, -L2-R2 is... .

[0135] In some embodiments, L3 is a substituted or unsubstituted straight-chain C3 alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C4 alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C5 alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C6 alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C7 alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C8 alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C9 alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C... 10 Alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C. 11 Alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C. 12 Alkylene. In some embodiments, L3 is... In some implementations, L3 is... In some implementations, L3 is... In some implementations, L3 is... In some implementations, L3 is... In some implementations, L3 is... In some implementations, L3 is... .

[0136] In some embodiments, L3 is a substituted or unsubstituted straight-chain C3 alkenyl alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C4 alkenyl alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C5 alkenyl alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C6 alkenyl alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C7 alkenyl alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C8 alkenyl alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C9 alkenyl alkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C3 alkenyl alkylene. 10 Alkenylalkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C. 11 Alkenylalkylene. In some embodiments, L3 is a substituted or unsubstituted straight-chain C. 12 Alkenylalkylene.

[0137] In some implementations, -L3-R3 is In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... In some implementations, -L3-R3 is... .

[0138] In some implementations, each L2 and L3 is independently either substituted or unsubstituted -C. 4-10 Alkylene. In some embodiments, each L2 and L3 is independently substituted or unsubstituted -C. 3-12 Alkenylalkylene. In some embodiments, L2 and L3 are the same. In some embodiments, L2 and L3 are different. In some embodiments, each L2 and L3 is independently substituted -C. 4-10 Alkylene, wherein the substituent is a halogen or a straight-chain or branched C. 1-6Alkyl group. In some embodiments, each L2 and L3 is independently substituted -C. 4-10 Alkylene, wherein -C 4-10 The alkylene group is substituted with a fluorinated group, a methyl group, or an isopropyl group. In some embodiments, each L2 and L3 is independently a substituted -C group. 4-10 Alkenylalkylene, wherein the substituent is a halogen or a straight-chain or branched C. 1-6 Alkyl group. In some embodiments, each L2 and L3 is independently substituted -C. 4-10 alkenylalkylene, wherein -C 4-10 The alkylene group is substituted with a fluorinated group, a methyl group, or an isopropyl group. In some embodiments, each L2 and L3 is independently an unsubstituted -C group. 2-6 Alkylene. In some embodiments, each L2 and L3 is independently unsubstituted -C 2-4 Alkylene. In some embodiments, each L2 and L3 is independently unsubstituted -C 3-6 Alkylene. In some embodiments, L2 is substituted or unsubstituted -C 3-12 Alkenylalkylene. In some embodiments, L3 is substituted or unsubstituted -C 3-12 Alkenylalkylene. In some embodiments, each L2 is independently unsubstituted -C. 3-6 Alkylene, and L3 is an unsubstituted -C 3-6 Alkenylalkylene.

[0139] In some implementations, L4 is substituted or unsubstituted -C1- 12 Alkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 Substitution. In some implementations, L4 is substituted or unsubstituted -C 3-24 Alkenylalkylene groups, wherein L4 is optionally surrounded by 1 to 10 R groups. 11 Substitution. In some implementations, L4 is substituted or unsubstituted -C 3-12 Alkenylalkylene. In some embodiments, L4 is substituted or unsubstituted -C 3-6 Alkenyl alkylene. In some embodiments, L4 is a substituted or unsubstituted -C1-6 alkylene; wherein L4 is optionally surrounded by 1 to 10 R... 11Replacement. In some embodiments, L4 is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-(CH2)2-CH2-, -CH2-(CH2)3-CH2-, or -CH2-(CH2)4-CH2-. In some embodiments, L4 is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In some embodiments, L4 is -CH2-. In some embodiments, L4 is -CH2-CH2-. In some embodiments, L4 is -CH2-CH(CH3)-CH2-. In some embodiments, L4 is -CD2-CD2-.

[0140] In some implementations, R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-C0-9alkylene-N(R) 11 )2、-OC(=O)-C0-9alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R) 11 2. In some embodiments, R4 is -OH, -CH(CH3)-CH2-OH, or -OC(=O)-(CH2)3-N(Me)2. In some embodiments, R4 is -OH or -OC(=O)-C2-4 alkylene-N(R 11 2. In some embodiments, R4 is -OH or -OC(=O)-C3-6 alkylene-N(R 11 2. In some embodiments, R4 is -OH. In some embodiments, R4 is -OC(=O)-C3-6 alkylene-N(Me)2. In some embodiments, R4 is a halogen. In some embodiments, R4 is F.

[0141] In some implementations, -L4-R4 is In some implementations, -L4-R4 is... In some implementations, -L4-R4 is... In some implementations, -L4-R4 is... In some implementations, -L4-R4 is... In some implementations, -L4-R4 is... In some implementations, -L4-R4 is... In some implementations, -L4-R4 is... In some implementations, -L4-R4 is... .

[0142] In some implementations, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some implementations, n is 2, 3, 4, 5, or 6. In some implementations, n is 3, 4, 5, or 6. In some implementations, n is 0, 1, 2, 3, 4, or 5. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 5.

[0143] In some implementations, each R 10 Independently hydrogen or C 1-10 Alkyl group. In some embodiments, each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Halogenated alkyl or C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently, it is hydrogen and C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-10 Halogenated alkyl or C 3-10 Cycloalkyl. In some embodiments, each R 10 Independently hydrogen or C 1-6 Alkyl group. In some embodiments, each R 10 It can be either hydrogen or methyl.

[0144] In some implementations, each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl). In some embodiments, each R 11 Independently, they are hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl). In some embodiments, each R 11 Independently, it is hydrogen, deuterium, halogen, or carbon. 1-6 alkyl.

[0145] In some embodiments, this document describes a compound of formula VI, or its N-oxide or pharmaceutically acceptable salt: , in: X is O, S, or C(R) 11 )2; L 11 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 -replace; L 12 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 -replace; L 13 Is it a substituted or unsubstituted linear C3-? 12Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 -replace; L 14 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 -replace; L 15 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 -replace; L 16 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 -replace; Where L 11 L 12 L 13 L 14 L 15 or L 16 If replaced, then L 11 L 12 L 13 L 14 L 15 or L 16 Substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-6 Alkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 6-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; X 11 It is a covalent bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X 12 It is a covalent bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each R 12 R 14 R 15 and R 16 Independently, it is hydrogen, deuterium, halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; L 17 Is it substituted or unsubstituted -C1- 24 alkylene-; wherein L 17 Optionally assigned to 10 R 11 replace; R 17 It is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2、-CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; Each R 11 Independently selected from hydrogen, deuterium, halogens, -CN, -C 1-6 Alkyl, C 1-10Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl); and t can be 0, 1, 2, 3 or 4.

[0146] In some implementations, X is O, S, or C(R) 11 2. In some implementations, X is O. In some implementations, X is S. In some implementations, X is C(R). 11 2. In some implementations, X is C(R) 11 )2 and each R 11 Independently, it is hydrogen, deuterium, halogen, -C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0147] In some implementations, L 11 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 11 It is an unsubstituted linear C3- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 11 Is it a substituted or unsubstituted linear C3- 12 Alkylene. In some embodiments, L 11 It is a substituted or unsubstituted straight-chain C3 alkylene group. In some embodiments, L 11 It is a substituted or unsubstituted straight-chain C4 alkylene group. In some embodiments, L11 It is a substituted or unsubstituted straight-chain C5 alkylene group. In some embodiments, L 11 It is a substituted or unsubstituted straight-chain C6 alkylene group. In some embodiments, L 11 It is a substituted or unsubstituted straight-chain C7 alkylene group. In some embodiments, L 11 It is a substituted or unsubstituted straight-chain C8 alkylene group. In some embodiments, L 11 It is a substituted or unsubstituted straight-chain C9 alkylene group. In some embodiments, L 11 Is it a substituted or unsubstituted linear C? 10 Alkylene. In some embodiments, L 11 Is it a substituted or unsubstituted linear C? 11 Alkylene. In some embodiments, L 11 Is it a substituted or unsubstituted linear C? 12 Alkylene. In some embodiments, L 11 yes In some implementations, L 11 yes In some implementations, L 11 yes In some implementations, L 11 yes In some implementations, L 11 yes In some implementations, L 11 yes In some implementations, L 11 yes In some implementations, L 11 A methylene unit is -CR 11 =CR 11 - Replacement. In some implementations, L 11 One methylene unit is replaced by -CH=CH-. In some embodiments, L 11 yes In some implementations, L 11 One to five elements are selected from halogen, deuterium, -CN, halogen, -C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups.

[0148] In some implementations, L 12 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 12It is an unsubstituted linear C3- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 12 Is it a substituted or unsubstituted linear C3- 12 Alkylene. In some embodiments, L 12 It is a substituted or unsubstituted straight-chain C3 alkylene group. In some embodiments, L 12 It is a substituted or unsubstituted straight-chain C4 alkylene group. In some embodiments, L 12 It is a substituted or unsubstituted straight-chain C5 alkylene group. In some embodiments, L 12 It is a substituted or unsubstituted straight-chain C6 alkylene group. In some embodiments, L 12 It is a substituted or unsubstituted straight-chain C7 alkylene group. In some embodiments, L 12 It is a substituted or unsubstituted straight-chain C8 alkylene group. In some embodiments, L 12 It is a substituted or unsubstituted straight-chain C9 alkylene group. In some embodiments, L 12 Is it a substituted or unsubstituted linear C? 10 Alkylene. In some embodiments, L 12 Is it a substituted or unsubstituted linear C? 11 Alkylene. In some embodiments, L 12 Is it a substituted or unsubstituted linear C? 12 Alkylene. In some embodiments, L 12 yes In some implementations, L 12 yes In some implementations, L 12 yes In some implementations, L 12 yes In some implementations, L 12 yes In some implementations, L 12 yes In some implementations, L 12 yes In some implementations, L 12 A methylene unit is -CR 11 =CR 11 - Replacement. In some implementations, L 12 One methylene unit is replaced by -CH=CH-. In some embodiments, L 12 yes In some implementations, L 12One to five elements are selected from halogen, deuterium, -CN, halogen, -C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups.

[0149] In some implementations, L 13 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 13 It is an unsubstituted linear C3- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 13 Is it a substituted or unsubstituted linear C3- 12 Alkylene. In some embodiments, L 13 It is a substituted or unsubstituted straight-chain C3 alkylene group. In some embodiments, L 13 It is a substituted or unsubstituted straight-chain C4 alkylene group. In some embodiments, L 13 It is a substituted or unsubstituted straight-chain C5 alkylene group. In some embodiments, L 13 It is a substituted or unsubstituted straight-chain C6 alkylene group. In some embodiments, L 13 It is a substituted or unsubstituted straight-chain C7 alkylene group. In some embodiments, L 13 It is a substituted or unsubstituted straight-chain C8 alkylene group. In some embodiments, L 13 It is a substituted or unsubstituted straight-chain C9 alkylene group. In some embodiments, L 13 Is it a substituted or unsubstituted linear C? 10 Alkylene. In some embodiments, L 13 Is it a substituted or unsubstituted linear C? 11 Alkylene. In some embodiments, L 13 Is it a substituted or unsubstituted linear C? 12 Alkylene. In some embodiments, L 13 yes In some implementations, L 13 yes In some implementations, L 13 yes In some implementations, L 13 yes In some implementations, L 13 yes In some implementations, L 13yes In some implementations, L 13 yes In some implementations, L 13 A methylene unit is -CR 11 =CR 11 - Replacement. In some implementations, L 13 One methylene unit is replaced by -CH=CH-. In some embodiments, L 13 yes In some implementations, L 13 One to five elements are selected from halogen, deuterium, -CN, halogen, -C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups.

[0150] In some implementations, L 14 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 14 It is an unsubstituted linear C3- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 14 Is it a substituted or unsubstituted linear C3- 12 Alkylene. In some embodiments, L 14 It is a substituted or unsubstituted straight-chain C3 alkylene group. In some embodiments, L 14 It is a substituted or unsubstituted straight-chain C4 alkylene group. In some embodiments, L 14 It is a substituted or unsubstituted straight-chain C5 alkylene group. In some embodiments, L 14 It is a substituted or unsubstituted straight-chain C6 alkylene group. In some embodiments, L 14 It is a substituted or unsubstituted straight-chain C7 alkylene group. In some embodiments, L 14 It is a substituted or unsubstituted straight-chain C8 alkylene group. In some embodiments, L 14 It is a substituted or unsubstituted straight-chain C9 alkylene group. In some embodiments, L 14 Is it a substituted or unsubstituted linear C? 10 Alkylene. In some embodiments, L 14 Is it a substituted or unsubstituted linear C? 11 Alkylene. In some embodiments, L 14 Is it a substituted or unsubstituted linear C?12 Alkylene. In some embodiments, L 14 yes In some implementations, L 14 yes In some implementations, L 14 yes In some implementations, L 14 yes In some implementations, L 14 yes In some implementations, L 14 yes In some implementations, L 14 yes In some implementations, L 14 A methylene unit is -CR 11 =CR 11 - Replacement. In some implementations, L 14 One methylene unit is replaced by -CH=CH-. In some embodiments, L 14 yes In some implementations, L 14 One to five elements are selected from halogen, deuterium, -CN, halogen, -C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups.

[0151] In some implementations, L 15 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 15 It is an unsubstituted linear C3- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 15 Is it a substituted or unsubstituted linear C3- 12 Alkylene. In some embodiments, when L 15 When it is a C0 alkylene group, L 15 It is a covalent bond. In some implementations, L 15 It is a substituted or unsubstituted straight-chain C2-alkylene group. In some embodiments, L 15 It is a substituted or unsubstituted straight-chain C3 alkylene group. In some embodiments, L 15 It is a substituted or unsubstituted straight-chain C4 alkylene group. In some embodiments, L15 It is a substituted or unsubstituted straight-chain C5 alkylene group. In some embodiments, L 15 It is a substituted or unsubstituted straight-chain C6 alkylene group. In some embodiments, L 15 It is a substituted or unsubstituted straight-chain C7 alkylene group. In some embodiments, L 15 It is a substituted or unsubstituted straight-chain C8 alkylene group. In some embodiments, L 15 It is a substituted or unsubstituted straight-chain C9 alkylene group. In some embodiments, L 15 Is it a substituted or unsubstituted linear C? 10 Alkylene. In some embodiments, L 15 Is it a substituted or unsubstituted linear C? 11 Alkylene. In some embodiments, L 15 Is it a substituted or unsubstituted linear C? 12 Alkylene. In some embodiments, L 15 yes In some implementations, L 15 yes In some implementations, L 15 yes In some implementations, L 15 yes In some implementations, L 15 yes In some implementations, L 15 yes In some implementations, L 15 yes In some implementations, L 15 A methylene unit is -CR 11 =CR 11 - Replacement. In some implementations, L 15 One methylene unit is replaced by -CH=CH-. In some embodiments, L 15 yes In some implementations, L 15 One to five elements are selected from halogen, deuterium, -CN, halogen, -C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups.

[0152] In some implementations, L 16 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 16It is an unsubstituted linear C3- 12 Alkylene, wherein one or more methylene units of the group are optionally and independently -CR 11 =CR 11 - Replacement. In some implementations, L 16 Is it a substituted or unsubstituted linear C3- 12 Alkylene. In some embodiments, when L 16 When it is a C0 alkylene group, L 16 It is a covalent bond. In some implementations, L 16 It is a substituted or unsubstituted straight-chain C2-alkylene group. In some embodiments, L 16 It is a substituted or unsubstituted straight-chain C3 alkylene group. In some embodiments, L 16 It is a substituted or unsubstituted straight-chain C4 alkylene group. In some embodiments, L 16 It is a substituted or unsubstituted straight-chain C5 alkylene group. In some embodiments, L 16 It is a substituted or unsubstituted straight-chain C6 alkylene group. In some embodiments, L 16 It is a substituted or unsubstituted straight-chain C7 alkylene group. In some embodiments, L 16 It is a substituted or unsubstituted straight-chain C8 alkylene group. In some embodiments, L 16 It is a substituted or unsubstituted straight-chain C9 alkylene group. In some embodiments, L 16 Is it a substituted or unsubstituted linear C? 10 Alkylene. In some embodiments, L 16 Is it a substituted or unsubstituted linear C? 11 Alkylene. In some embodiments, L 16 Is it a substituted or unsubstituted linear C? 12 Alkylene. In some embodiments, L 16 yes In some implementations, L 16 yes In some implementations, L 16 yes In some implementations, L 16 yes In some implementations, L 16 yes In some implementations, L 16 yes In some implementations, L 16 yes In some implementations, L 16 A methylene unit is -CR 11 =CR 11 - Replacement. In some implementations, L16 One methylene unit is replaced by -CH=CH-. In some embodiments, L 16 yes In some implementations, L 16 One to five elements are selected from halogen, deuterium, -CN, halogen, -C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups.

[0153] In some implementation schemes, X 11 It is a covalent bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X 11 It is a covalent bond. In some implementations, X 11 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 - or -N(R) 10 )-C(=O)-. In some implementations, X 11 It is -C(=O)-O- or -OC(=O)-. In some implementations, X 11 It is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X 11 It is -C(=O)-O-. In some implementations, X 11 It is -OC(=O)-.

[0154] In some implementation schemes, X 12 It is a covalent bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, SS, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X 12 It is a covalent bond. In some implementations, X 12 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 - or -N(R) 10 )-C(=O)-. In some implementations, X 12 It is -C(=O)-O- or -OC(=O)-. In some implementations, X 12It is -C(=O)-O-, -OC(=O)-, -SS-, -C(=O)-S-, or -C(C=S)-O-. In some implementations, X 12 It is -C(=O)-O-. In some implementations, X 12 It is -OC(=O)-.

[0155] In some implementation schemes, X 11 It is a covalent bond and X 12 It is a covalent bond. In some implementations, X 11 It is a covalent bond and X 12 It is -C(=O)-O- or -OC(=O)-. In some implementations, X 11 It is -C(=O)-O- or -OC(=O-) and X 12 It is a covalent bond. In some implementations, X 11 It is -C(=O)-O- and X12 is -OC(=O)-. In some implementations, X 11 It is -C(=O)-O- and X 12 It is -C(=O)-O-. In some implementations, X 11 It is -OC (=O)- and X 12 It is -OC (=O)-. In some implementations, X 11 It is -OC (=O)- and X 12 It is -C(=O)-O-.

[0156] In some implementation schemes, R 12 It is hydrogen, deuterium, halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, R 12 It is hydrogen. In some implementations, R 12 It is deuterium. In some implementations, R 12 It is a halogen. In some implementations, R 12 It is F. In some implementations, R 12 It is Cl. In some implementations, R 12 It is Br. In some implementations, R 12 It is I. In some implementations, R 12 Yes -CN. In some implementations, R 12 Yes - OR 10 In some implementations, R 12 It is -N(R)10 2. In some implementation schemes, R 12 It is a branch C 3-10 Alkyl group. In some embodiments, R 12 It is C 3-10 Cycloalkyl. In some embodiments, R 12 It is C 2-6 Alkenyl. In some embodiments, R 12 It is C 2-6 Alkyne group.

[0157] In some implementation schemes, R 14 It is hydrogen, deuterium, halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, R 14 It is hydrogen. In some implementations, R 14 It is deuterium. In some implementations, R 14 It is a halogen. In some implementations, R 14 It is F. In some implementations, R 14 It is Cl. In some implementations, R 14 It is Br. In some implementations, R 14 It is I. In some implementations, R 14 Yes -CN. In some implementations, R 14 Yes - OR 10 In some implementations, R 14 It is -N(R) 10 2. In some implementation schemes, R 14 It is a branch C 3-10 Alkyl group. In some embodiments, R 14 It is C 3-10 Cycloalkyl. In some embodiments, R 14 It is C 2-6 Alkenyl. In some embodiments, R 14 It is C 2-6 Alkyne group.

[0158] In some implementation schemes, R 15 It is hydrogen, deuterium, halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, R15 It is hydrogen. In some implementations, R 15 It is deuterium. In some implementations, R 15 It is a halogen. In some implementations, R 15 It is F. In some implementations, R 15 It is Cl. In some implementations, R 15 It is Br. In some implementations, R 15 It is I. In some implementations, R 15 Yes -CN. In some implementations, R 15 Yes - OR 10 In some implementations, R 15 It is -N(R) 10 2. In some implementation schemes, R 15 It is a branch C 3-10 Alkyl group. In some embodiments, R 15 It is C 3-10 Cycloalkyl. In some embodiments, R 15 It is C 2-6 Alkenyl. In some embodiments, R 15 It is C 2-6 Alkyne group.

[0159] In some implementation schemes, R 16 It is hydrogen, deuterium, halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group. In some embodiments, R 16 It is hydrogen. In some implementations, R 16 It is deuterium. In some implementations, R 16 It is a halogen. In some implementations, R 16 It is F. In some implementations, R 16 It is Cl. In some implementations, R 16 It is Br. In some implementations, R 16 It is I. In some implementations, R 16 Yes -CN. In some implementations, R 16 Yes - OR 10 In some implementations, R 16 It is -N(R) 10 2. In some implementation schemes, R 16 It is a branch C 3-10 Alkyl group. In some embodiments, R 16 It is C 3-10Cycloalkyl. In some embodiments, R 16 It is C 2-6 Alkenyl. In some embodiments, R 16 It is C 2-6 Alkyne group.

[0160] In some implementation schemes, yes In some implementations, -L 11 -X 11 -L 12 -R 12 It is -C3- 10 Alkylene-C(=O)-O-C3- 10 Alkylene-H. In some embodiments, -L 11 -X 11 -L 12 -R 12 It is -C3- 10 Alkylene-OC(=O)-C3- 10 Alkylene-H. In some embodiments, -L 11 -X 11 -L 12 -R 12 It is -C3- 10 Alkylene -CH=CH-C3- 10 Alkylene-H. In some embodiments, yes In some implementation schemes, yes .

[0161] In some implementation schemes, yes In some implementations, -L 13 -X 12 -L 14 -R 15 It is -C3- 10 Alkylene-C(=O)-O-C3- 10 Alkylene-H. In some embodiments, -L 13 -X 12 -L 14 -R 15 It is -C3- 10 Alkylene-OC(=O)-C3- 10 Alkylene-H. In some embodiments, -L 13 -X 12 -L 14 -R 15 It is -C3- 10 Alkylene -CH=CH-C3- 10Alkylene-H. In some embodiments, yes In some implementation schemes, yes .

[0162] In some implementations, L 17 Is it substituted or unsubstituted -C1- 12 Alkylene; wherein L 17 Optionally assigned to 10 R 11 Replacement. In some implementations, L 17 Is it substituted or unsubstituted -C 3-24 alkenylalkylene, wherein L 17 Optionally assigned to 10 R 11 Replacement. In some implementations, L 17 Is it substituted or unsubstituted -C 3-12 Alkenylalkylene. In some embodiments, L 17 Is it substituted or unsubstituted -C 3-6 Alkenylalkylene. In some embodiments, L 17 It is a substituted or unsubstituted -C1-6 alkylene group; wherein L 17 Optionally assigned to 10 R 11 Replacement. In some implementations, L 17 It is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-(CH2)2-CH2-, -CH2-(CH2)3-CH2-, or -CH2-(CH2)4-CH2-. In some embodiments, L 17 It is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In some implementations, L 17 It is -CH2-. In some implementations, L 17 It is -CH2-CH2-. In some implementations, L 17 It is -CH2-CH2-CH2-. In some implementations, L 17 It is -CH2-CH(CH3)-CH2-. In some implementations, L 17 It is -CD2-CD2-.

[0163] In some implementation schemes, R 17 It is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-C0-9alkylene-N(R) 11 )2、-OC(=O)-C0-9alkylene-R 11-(O-CO-9 alkylene-) n R 11 -CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R) 11 2. In some implementation schemes, R 17 It is -OH, -CH(CH3)-CH2-OH, or -OC(=O)-(CH2)3-N(Me)2. In some embodiments, R 17 It is -OH or -OC(=O)-C2-4 alkylene-N(R) 11 2. In some implementation schemes, R 17 It is -OH or -OC(=O)-C3-6 alkylene-N(R) 11 2. In some implementation schemes, R 17 It is -OH. In some implementations, R 17 It is -OC(=O)-C3-6 alkylene-N(Me)2. In some embodiments, R 17 It is a halogen. In some implementations, R 17 It is F.

[0164] In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes In some implementations, -L 17 -R 17 yes .

[0165] In some implementations, t is 0. In some implementations, t is 1. In some implementations, t is 2. In some implementations, t is 3. In some implementations, t is 4.

[0166] Any combination of groups described above for various variables is considered herein. Throughout this specification, those skilled in the art will select groups and their substituents to provide stable moieties and compounds.

[0167] Exemplary compounds of formula I', I'-a, I, Ia, Ib, II, III, III-a, IV, IV-a, V, or VI include the compounds described in Tables 1, 2, and 3.

[0168] This document describes nanoparticle compositions comprising the compounds described herein. In some embodiments, the nanoparticle composition is a lipid nanoparticle (LNP). In some embodiments, the LNP comprises an aminolipid, phospholipid, PEG-lipid, cholesterol or a derivative thereof, a payload, or any combination thereof. In some embodiments, the LNP composition comprises an aminolipid. In some embodiments, the LNP composition comprises an aminolipid having the structure of formula I', I'-a, I, Ia, Ib, II, III, III-a, IV, IV-a, or V, or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the LNP comprises multiple aminolipids. For example, the LNP composition may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, or more aminolipids. As another example, the LNP composition may comprise at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 9, at least 10, or at least 20 aminolipids. For example, an LNP composition may contain up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 9, up to 10, up to 20 or up to 30 amino lipids.

[0169] In some embodiments, the LNP composition described herein comprises a first aminolipid. In some embodiments, the LNP composition comprises a first aminolipid and a second aminolipid. In some embodiments, the LNP composition comprises a first aminolipid, a second aminolipid, and a third aminolipid. In some embodiments, the LNP composition comprises a first aminolipid, a second aminolipid, a third aminolipid, and a fourth aminolipid. In some embodiments, the first aminolipid is selected from Tables 1-3. In some embodiments, the second aminolipid is selected from Tables 1-3. In some embodiments, the third aminolipid is selected from Tables 1-3. In some embodiments, the fourth aminolipid is selected from Tables 1-3. In some embodiments, the LNP composition does not contain a fourth aminolipid. In some embodiments, the LNP composition does not contain a third aminolipid. In some embodiments, the molar ratio of the first aminolipid to the second aminolipid is from about 0.01 to about 100. In some embodiments, the molar ratio of the first aminolipid to the second aminolipid is from about 0.05 to about 20. In some embodiments, the molar ratio of the first aminolipid to the second aminolipid is from about 0.1 to about 10. In some embodiments, the molar ratio of the first aminolipid to the second aminolipid is from about 0.20 to about 5. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid is about 0.25 to about 4. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid is about 0.25, about 0.33, about 0.5, about 1, about 2, about 3, or about 4.

[0170] In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 4:1:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 1:1:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 2:1:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 2:2:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 3:2:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 3:1:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 5:1:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 3:3:1. In some embodiments, the molar ratio of the first amino lipid to the second amino lipid to the third amino lipid is about 4:4:1.

[0171] In some embodiments, the LNP composition comprises one or more amino lipids. In some embodiments, the one or more amino lipids account for about 40 mol% to about 65 mol% of the total lipids present in the particles. In some embodiments, the one or more amino lipids account for about 40 mol%, about 41 mol%, about 42 mol%, about 43 mol%, about 44 mol%, about 45 mol%, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, about 50 mol%, about 51 mol%, about 52 mol%, about 53 mol%, about 54 mol%, about 55 mol%, about 56 mol%, about 57 mol%, about 58 mol%, about 59 mol%, about 60 mol%, about 61 mol%, about 62 mol%, about 63 mol%, about 64 mol%, or about 65 mol% of the total amino lipids present in the particles. In some embodiments, the first amino lipid accounts for about 1 mol% to about 99 mol% of the total amino lipids present in the particles. In some embodiments, the first amino lipid accounts for about 16.7 mol% to about 66.7 mol% of the total amino lipids present in the particles. In some embodiments, the first amino lipid accounts for about 20 mol% to about 60 mol% of the total amino lipids present in the particles. In some embodiments, the amino lipid is an ionizable lipid.

[0172] In some embodiments, the disclosed aminolipids can be converted into N-oxides. In some embodiments, the N-oxides are formed by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid and / or hydrogen peroxide). Therefore, N-oxide compounds of the described aminolipids are disclosed herein, which may be specified as N→O or N, where valence and structure permit. + -0 - In some embodiments, the nitrogen in the compounds disclosed herein can be converted to N-hydroxy or N-alkoxy. For example, N-hydroxy compounds can be prepared by oxidizing the parent amine with an oxidizing agent such as ra-CPBA. All nitrogen-containing compounds shown and claimed are also contemplated. Therefore, N-hydroxy and N-alkoxy (e.g., N-OR, where R is a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14 membered carbon ring, or 3-14 membered heterocyclic) derivatives of the described amino lipids are also disclosed herein.

[0173] In some embodiments, the aminolipids described herein may take the form of salts, such as pharmaceutically acceptable salts. This disclosure covers all pharmaceutically acceptable salts of aminolipids. As used herein, the term "aminolipid" also includes its pharmaceutically acceptable salts and its diastereomeric, enantiomeric, and epimeric forms.

[0174] In some embodiments, the aminolipids described herein have one or more stereocenters, each of which exists independently in an R or S configuration. The lipids presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as suitable mixtures thereof. The lipids provided herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers, as well as suitable mixtures thereof. In some embodiments, the lipids described herein are prepared into their individual stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereomeric compounds, and recovering the optically pure enantiomers. In some embodiments, the separation of enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomeric compounds are separated based on differences in solubility using a separation / resolution technique. In other embodiments, the separation of stereoisomers is performed by chromatography, or by forming diastereomeric salts and separating them by recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In one respect, stereoisomers are obtained through stereoselective synthesis.

[0175] In some embodiments, lipids such as aminolipids are substituted based on the structures disclosed herein. In some embodiments, lipids such as aminolipids are unsubstituted. In another embodiment, the lipids described herein are labeled with isotopes (e.g., with radioisotopes) or by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0176] In some embodiments, the compounds described herein (e.g., aminolipids) include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into this lipid include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, for example... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S,18 F, 36 Cl. In one aspect, the isotope-labeled lipids described herein, such as radioisotopes, are... 3 H and 14 Those incorporating C can be used in drug and / or substrate tissue distribution assays. In one respect, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0177] In some embodiments, the asymmetric carbon atoms of the aminolipid are present in an enantiomeric enriched form. In some embodiments, the asymmetric carbon atoms of the aminolipid have an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (S)- or (R)-configuration.

[0178] Table 1. Exemplary amino lipids

[0179] Table 2. Additional Exemplary Aminolipids

[0180] Table 3. Additional Exemplary Aminolipids

[0181] In some embodiments, the LNP composition comprises aminolipids. Exemplary aminolipids include, but are not limited to, the lipids listed in Tables 1, 2, and 3. In some embodiments, the LNP composition comprises an aminolipid having the structure of Formula I', Formula I'-a, Formula I, Formula Ia, Formula Ib, Formula II, Formula III, Formula III-a, Formula IV, Formula IV-a, or Formula V, or a pharmaceutically acceptable salt thereof. In some embodiments, the LNP comprises multiple aminolipids. In some embodiments, the LNP composition comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, or more aminolipids. In other embodiments, the LNP composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 9, at least 10, or at least 20 aminolipids. In some embodiments, the LNP composition comprises up to 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 9, at most 10, at most 20, or at most 30 aminolipids.

[0182] Additional cations and / or ionizable lipids In some embodiments, the ionizable lipid comprises one or more ionizable nitrogen atoms. In some embodiments, at least one of the one or more ionizable nitrogen atoms is positively charged. In some embodiments, at least 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, 90 mol%, 95 mol%, or 99 mol% of the ionizable nitrogen atoms in the LNP composition are positively charged. In some embodiments, the amino lipid comprises a primary amine, secondary amine, tertiary amine, imine, amide, guanidine moiety, histidine residue, lysine residue, arginine residue, or any combination thereof. In some embodiments, the amino lipid comprises a primary amine, secondary amine, tertiary amine, guanidine moiety, or any combination thereof. In some embodiments, the amino lipid comprises a tertiary amine.

[0183] In some embodiments, the aminolipid is a cationic lipid. In some embodiments, the aminolipid is an ionizable lipid. In some embodiments, the aminolipid contains one or more nitrogen atoms. In some embodiments, the aminolipid contains one or more ionizable nitrogen atoms. Exemplary cationic and / or ionizable lipids include, but are not limited to, 3-(bisdodecylamino)-N1,N1,4-tris(dodecyl)-1-piperazine ethylamine (KL10), N1-[2-(bisdodecylamino)ethyl]-N1,N4,N4-tris(dodecyl)-1,4-piperazine diethylamine (KL22), 14,25-bis(tetrazyl)-15,18,21,24-tetraaza-octacosane (KL25), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxacyclopentane (DLin-K-DMA), and 4-(dimethylamino)butyrate heptadecyl-6,9,28,31-tetraen-19-yl ester (DLin-MC). 3-DMA), 2,2-dioleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxacyclopentane (DLin-KC2-DMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), 2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA), (2R)-2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA) (2R) and (2S)-2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA (2S)).

[0184] PEG-lipids In some embodiments, the described LNP composition comprises a PEG-lipid. In some embodiments, the described LNP composition comprises two or more PEG-lipids. Exemplary PEG-lipids include, but are not limited to, PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol, and mixtures thereof. For example, one or more PEG-lipids may comprise PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, PEG-DSPE lipids, or combinations thereof. In some embodiments, the PEG moiety is an optionally substituted linear or branched polymer of ethylene glycol or ethylene oxide. In some embodiments, the PEG moiety is substituted with, for example, one or more alkyl, alkoxy, acyl, hydroxyl, or aryl groups. In some embodiments, the PEG moiety comprises a PEG copolymer, such as PEG-polyurethane or PEG-polypropylene (see, for example, J. Milton Harris, Poly(ethylene glycol) chemistry: biotechnical and biomedical applications (1992)). In some embodiments, the PEG portion does not include PEG copolymers; for example, it may be a PEG monomer. Exemplary PEG-lipids include, but are not limited to, PEG-dilaurylglycerol, PEG-dimyristoylglycerol (PEG-DMG), PEG-dipalmitoylglycerol, PEG-distearylglycerol (PEG-DSPE), PEG-dipalmitoylglycerol, PEG-distearylglycerol, PEG-dilaurylimidazoldicarboxamide, PEG-dimyristoylimidazoldicarboxamide, PEG-distearylimidazoldicarboxamide, PEG-cholesterol, and PEG-DMB (3,4-bistetradecyloxybenzyl-ω-methyl-poly(ethylene glycol) ether), 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine-N-[methoxy(polyethylene glycol)-2000].

[0185] In some embodiments, the PEG-lipid is a PEG-lipid conjugate, such as PEG coupled with a dialkyloxypropyl group (e.g., PEG-DAA conjugate), PEG coupled with a diacylglycerol group (e.g., PEG-DAG conjugate), PEG coupled with cholesterol, PEG coupled with phosphatidylethanolamine, and PEG coupled with a ceramide (see, for example, U.S. Patent No. 5,885,613), cationic PEG lipids, polyoxazoline (POZ)-lipid conjugates (e.g., POZ-DAA conjugate; see, for example, WO2010 / 006282), polyamide oligomers (e.g., ATTA-lipid conjugates), and mixtures thereof.

[0186] In some embodiments, the PEG lipid is a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, or a PEG-modified dialkylglycerol.

[0187] In some embodiments, the PEG-lipid comprises one or more ethylene glycol units, such as at least 1, at least 2, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 120, or at least 150 ethylene glycol units. In some embodiments, the number-average molecular weight of the PEG-lipid is from about 200 Da to about 5000 Da. In some embodiments, the number-average molecular weight of the PEG-lipid is from about 500 Da to about 3000 Da. In some embodiments, the number-average molecular weight of the PEG-lipid is from about 750 Da to about 2500 Da. In some embodiments, the number-average molecular weight of the PEG-lipid is from about 750 Da to about 2500 Da. In some embodiments, the number-average molecular weight of the PEG-lipids is about 500 Da, about 750 Da, about 1000 Da, about 1250 Da, about 1500 Da, about 1750 Da, or about 2000 Da. In some embodiments, the polydispersity index (PDI) of one or more PEG-lipids is less than 2. In some embodiments, the PDI of one or more PEG-lipids is at most 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0. In some embodiments, the PDI of one or more PEG-lipids is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0.

[0188] In some embodiments, PEG-lipids comprise about 0.1 mol% to about 10 mol% of the total lipids present in the particles. In some embodiments, PEG-lipids comprise about 0.1 mol% to about 6 mol% of the total lipids present in the particles. In some embodiments, PEG-lipids comprise about 0.5 mol% to about 5 mol% of the total lipids present in the particles. In some embodiments, PEG-lipids comprise about 1 mol% to about 3 mol% of the total lipids present in the particles. In some embodiments, PEG-lipids comprise about 2.0 mol% to about 2.5 mol% of the total lipids present in the particles. In some embodiments, PEG-lipids comprise approximately 1 mol%, approximately 1.1 mol%, approximately 1.2 mol%, approximately 1.3 mol%, approximately 1.4 mol%, approximately 1.5 mol%, approximately 1.6 mol%, approximately 1.7 mol%, approximately 1.8 mol%, approximately 1.9 mol%, approximately 2.0 mol%, approximately 2.1 mol%, approximately 2.2 mol%, approximately 2.3 mol%, approximately 2.4 mol%, approximately 2.5 mol%, approximately 2.6 mol%, approximately 2.7 mol%, approximately 2.8 mol%, approximately 2.9 mol%, or approximately 3.0 mol% of the total lipids present in the particles.

[0189] In some embodiments, the LNP composition contains a variety of PEG-lipids, such as at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different PEG-lipids.

[0190] Phospholipids In some embodiments, the described LNP composition comprises phospholipids. In some embodiments, the phospholipid comprises lipids selected from: phosphatidylcholine (PC), phosphatidylethanolamine, glycerophospholipids, sphingophospholipids, guriserohosuhono, sphingolipid phosphonoyl lipids, natural lecithin, and hydrogenated phospholipids. In some embodiments, the phospholipid comprises phosphatidylcholine. Exemplary phosphatidylcholine includes, but is not limited to, soybean phosphatidylcholine, egg yolk phosphatidylcholine (EPC), distearylphosphatidylcholine, 1,2-distearyl-sn-glycerol-3-phosphocholine (DSPC), dipalmitoylphosphatidylcholine, dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), palmitoyloleoylphosphatidylcholine (POPC), dimyristoylphosphatidylcholine (DMPC), and dioleoylphosphatidylcholine (DOPC). In some specific embodiments, the phospholipid is DSPC.

[0191] In some embodiments, the phospholipid comprises phosphatidylethanolamine. In some embodiments, the phosphatidylethanolamine is distearate, dipalmitoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphatidylethanolamine (DMPE), 16-O-Monome Le PE, 16-O-dimethyl PE, 18-1-trans PE, palmitoyloleoylphosphatidylethanolamine (POPE), or 1-stearoyl-2-oleoylphosphatidylethanolamine (SOPE). In some embodiments, the phospholipid comprises glycerophospholipids. In some embodiments, the glycerophospholipid is phosphatal phospholipid, phosphatidyl ester, or phosphatidylcholine. In some embodiments, the glycerophospholipid is phosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, palmitoyloleoylphosphatidylglycerol (POPG), or lysophosphatidylcholine. In some embodiments, the phospholipid comprises sphingophospholipid. In some embodiments, the sphingophospholipid is sphingomyelin, ceramide phosphoethanolamine, ceramide phosphoglycerate, or ceramide phosphoglycerate phosphate. In some embodiments, the phospholipid comprises natural lecithin. In some embodiments, the natural lecithin is egg yolk lecithin or soybean lecithin. In some embodiments, the phospholipid comprises hydrogenated phospholipids. In some embodiments, the hydrogenated phospholipid is hydrogenated soybean phosphatidylcholine. In some embodiments, the phospholipid is selected from: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearatelphosphatidylcholine, and dilinoleoylphosphatidylcholine.

[0192] In some embodiments, the phospholipid comprises a lipid selected from the following: 1,2-distearyl-sn-glycerol-3-phosphate choline (DSPC), 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycerol-3-phosphate choline (DLPC), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC), 1,2-dipalmitoyl-sn 1,2-Diundecanoyl-sn-glycerol-3-phosphocholine (DPPC), 1-Palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), 1,2-Di-O-octadecenyl-sn-glycerol-3-phosphocholine (18:0 diether PC), 1-Oleoyl-2-cholesterolylhemisuccinoyl-sn-glycerol-3-phosphocholine (OChemsPC), 1-Hexadecyl-sn-glycerol-3-phosphocholine (C16 Lyso PC), 1,2-Dilinoleoyl-sn-glycerol-3-phosphocholine, 1,2-Diarachidonicoyl-sn-glycerol-3-phosphocholine, 1,2-Didocoshexaenoyl-sn-glycerol-3-phosphocholine, 1,2-Di-Dicosahedronyl-sn-glycerol-3-phosphocholine, 1,2-Di-Dicosahedronyl-sn-glycerol-3-phosphocholine, 1,2-Diphyranoyl-sn-glycerol-3-phosphoethanolamine (ME) 16.0PE), 1,2-distearate-sn-glycerol-3-phosphate ethanolamine, 1,2-dilinoleoyl-sn-glycerol-3-phosphate ethanolamine, 1,2-dilinolenoyl-sn-glycerol-3-phosphate ethanolamine, 1,2-diarachidonicoyl-sn-glycerol-3-phosphate ethanolamine, 1,2-bis(docosahexaenooyl-sn-glycerol-3-phosphate ethanolamine), 1,2-dioleoyl-sn-glycerol-3-phosphate sodium salt (DOPG), and sphingomyelin.

[0193] In some embodiments, the phospholipid comprises a phospholipid moiety and one or more fatty acid moieties. In some embodiments, the phospholipid moiety comprises phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, 2-lysophosphatidylcholine, or sphingomyelin. In some embodiments, the fatty acid moiety comprises lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, α-linolenic acid, erucic acid, phytic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, benzolic acid, docosapentaenoic acid, or docosahexaenoic acid. In some specific embodiments, the phospholipid is functionalized with one or more alkynes or crosslinked with one or more alkynes, which may undergo copper-catalyzed cycloaddition upon exposure to an azide.

[0194] In some embodiments, the LNP composition comprises multiple phospholipids, such as at least 2, 3, 4, 5 or more different phospholipids. In some embodiments, the phospholipids account for 1 mol% to 20 mol% of the total lipids present in the particles. In some embodiments, the phospholipids account for about 5 mol% to about 15 mol% of the total lipids present in the particles. In some embodiments, the phospholipids account for about 8 mol% to about 12 mol% of the total lipids present in the particles. In some embodiments, the phospholipids account for about 9 mol%, 10 mol%, or 11 mol% of the total lipids present in the particles.

[0195] Structural lipids In some embodiments, the LNP composition comprises a structural lipid. In some embodiments, the structural lipid is a steroid, sterol, alkyl resoreinol, cholesterol or a derivative thereof, codostrum, sitosterol, ergosterol, campesterol, stigmasterol, brassosterol, lycopene, tomatine, ursolic acid, α-tocopherol, or a combination thereof. In some embodiments, the structural lipid is cholesterol, codostrum, sitosterol, ergosterol, campesterol, stigmasterol, brassosterol, lycopene, ursolic acid, or α-tocopherol. In some embodiments, the structural lipid is a corticosteroid, such as prednisolone, dexamethasone, prednisone, and hydrocortisone. In some embodiments, cholesterol or a derivative thereof is cholesterol, 5-heptadecyl resoreinol, or cholesterol hemisuccinate. In some embodiments, the structural lipid is cholesterol.

[0196] In some embodiments, the structural lipid is a cholesterol derivative. In some embodiments, the cholesterol derivative is a polar cholesterol analog. In some embodiments, the polar cholesterol analog is 5α-cholesterol, 5β-cosanosterol, cholesteryl-(2′-hydroxy)-ethyl ether, cholesteryl-(4′-hydroxy)-butyl ether, or 6-ketocholesterol. In some embodiments, the polar cholesterol analog is cholesteryl-(4′-hydroxy)-butyl ether. In some embodiments, the cholesterol derivative is a nonpolar cholesterol analog. In some embodiments, the nonpolar cholesterol analog is 5α-cholesterol, cholesterone, 5α-cholesterone, 5β-cholesterone, or decanoic acid cholesterol ester.

[0197] In some embodiments, cholesterol or its derivatives comprise 20 mol% to 50 mol% of the total lipids present in the particles. In some embodiments, cholesterol or its derivatives comprise approximately 20 mol%, approximately 21 mol%, approximately 22 mol%, approximately 23 mol%, approximately 24 mol%, approximately 25 mol%, approximately 26 mol%, approximately 27 mol%, approximately 28 mol%, approximately 29 mol%, approximately 30 mol%, approximately 31 mol%, approximately 32 mol%, approximately 33 mol%, approximately 34 mol%, approximately 35 mol%, approximately 36 mol%, approximately 37 mol%, approximately 38 mol%, approximately 39 mol%, approximately 40 mol%, approximately 41 mol%, approximately 42 mol%, approximately 43 mol%, approximately 44 mol%, approximately 45 mol%, approximately 46 mol%, approximately 47 mol%, approximately 48 mol%, or approximately 50 mol% of the total lipids present in the particles.

[0198] antioxidants In some embodiments, the LNP described herein comprises one or more antioxidants. In some embodiments, the one or more antioxidants act to reduce the degradation of cationic lipids, payload, or both. In some embodiments, the one or more antioxidants comprise hydrophilic antioxidants. In some embodiments, the one or more antioxidants are chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and citrate. In some embodiments, the one or more antioxidants are EDTA. In some embodiments, the one or more antioxidants comprise lipophilic antioxidants. In some embodiments, the lipophilic antioxidants comprise vitamin E isomers or polyphenols. In some embodiments, the one or more antioxidants are present in the LNP composition at a concentration of at least 1 mM, at least 10 mM, at least 20 mM, at least 50 mM, or at least 100 mM. In some embodiments, the one or more antioxidants are present in the particles at a concentration of about 20 mM.

[0199] Payload The nanoparticle compositions or LNPs described herein can be designed to deliver payloads, such as therapeutic agents. Exemplary therapeutic agents include, but are not limited to, antibodies (e.g., monoclonal antibodies, chimeric antibodies, humanized antibodies, nanobodies and fragments thereof), cholesterol, hormones, peptides, proteins, chemotherapeutic agents and other types of antitumor agents, low molecular weight drugs, vitamins, cofactors, nucleosides, nucleotides, oligonucleotides, enzyme nucleic acids, antisense nucleic acids, triple-stranded oligonucleotides, antisense DNA or RNA compositions, chimeric DNA:RNA compositions, allylases, aptamers, ribozymes, decoys and their analogues, plasmids and other types of expression vectors and small nucleic acid molecules, RNAi agents, short interfering nucleic acids (siNA), messenger ribonucleic acid (messenger RNA). The therapeutic agent can be an RNAi agent, short interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miRNA), or short hairpin RNA (shRNA) molecule. Other therapeutic agents include peptide nucleic acid (PNA), locked nucleic acid ribonucleotide (LNA), morpholinonucleotide, threonine nucleic acid (TNA), glycol nucleic acid (GNA), sisiRNA (small internal fragmented interfering RNA), aiRNA (asymmetric interfering RNA), and siRNA with one, two, or more mismatches between the sense and antisense strands. These agents are intended to reach relevant cells and / or tissues, such as cell cultures, objects, or organisms. The therapeutic agent can be purified or partially purified, and can be naturally occurring, synthetic, or chemically modified. In some embodiments, the therapeutic agent is an RNAi agent, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), microRNA (miRNA), or short hairpin RNA (shRNA) molecule. In some embodiments, the therapeutic agent is mRNA.

[0200] In some embodiments, the payload comprises one or more nucleic acids (i.e., one or more nucleic acid molecular entities). In some embodiments, the nucleic acid is a single-stranded nucleic acid. In some embodiments, the single-stranded nucleic acid is DNA. In some embodiments, the single-stranded nucleic acid is RNA. In some embodiments, the nucleic acid is a double-stranded nucleic acid. In some embodiments, the double-stranded nucleic acid is DNA. In some embodiments, the double-stranded nucleic acid is RNA. In some embodiments, the double-stranded nucleic acid is a DNA-RNA hybrid. In some embodiments, the nucleic acid is messenger RNA (mRNA), microRNA, asymmetric interfering RNA (aiRNA), small hairpin RNA (shRNA), or Dicer substrate dsRNA. In some embodiments, the nucleic acid contains a promoter. In some embodiments, the nucleic acid contains a tumor-selective motif, wherein the tumor-selective motif increases the expression of the nucleic acid in cells associated with a disease or symptom (e.g., cancer) compared to its expression in normal cells.

[0201] In some embodiments, the payload (such as one or more RNA molecules) is completely encapsulated within the lipid portion of the particle, thereby protecting the RNA from nuclease degradation. Complete encapsulation can indicate that the RNA in the nucleic acid-lipid particle is not significantly degraded after exposure to serum or nuclease assays that would significantly degrade free DNA or RNA. In some embodiments, the nucleic acid-lipid particle composition comprises an RNA molecule that is completely encapsulated within the lipid portion of the particle, such that approximately 30% to approximately 100%, approximately 40% to approximately 100%, approximately 50% to approximately 100%, approximately 60% to approximately 100%, approximately 70% to approximately 100%, approximately 80% to approximately 100%, approximately 90% to approximately 100%, approximately 30% to approximately 95%, approximately 40% to approximately 95%, approximately 50% to approximately 95%, approximately 60% to approximately 95%, approximately 70% to approximately 95%, approximately 80% to approximately 95%, approximately 85% to approximately 95%, approximately 85% to approximately 95%, approximately 85% to approximately 95%, approximately 80 ... % to 95%, about 90% to 95%, about 30% to 90%, about 40% to 90%, about 50% to 90%, about 60% to 90%, about 70% to 90%, about 80% to 90%, or at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% (or any fraction or range thereof) have RNA encapsulated therein.

[0202] Other lipids In some embodiments, the disclosed nanoparticles or LNP compositions comprise accessory lipids. In some embodiments, the disclosed LNP compositions comprise neutral lipids. In some embodiments, the disclosed LNP compositions comprise stealth lipids. In some embodiments, the disclosed LNP compositions comprise additional lipids.

[0203] As used herein, “neutral lipids” suitable for the lipid compositions of this disclosure include, for example, various neutral lipids, uncharged lipids, or zwitterionic lipids. Examples of neutral phospholipids suitable for this disclosure include, but are not limited to, 5-heptadecylbenzene-1,3-diol (resorcinol), dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC), dimyristoylphosphatidylcholine (DMPC), phosphatidylcholine (PLPC), 1,2-distearyl-sn-glycerol-3-phosphocholine (DAPC), phosphatidylethanolamine (PE), methionine phosphatidylcholine (EPC), dilaurylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), 1-myristoyl-2-palmitoylphosphatidylcholine (MPPC), and 1-palmitoyl-2-myristoylphosphatidylcholine. Choline (PMPC), 1-palmitoyl-2-stearoylphosphatidylcholine (PSPC), 1,2-disarachido-sn-glycerol-3-phosphatecholine (DBPC), 1-stearoyl-2-palmitoylphosphatidylcholine (SPPC), 1,2-biseicosenoyl-sn-glycerol-3-phosphatecholine (DEPC), palmitoyloleoylphosphatidylcholine (POPC), lysophosphatidylcholine, dioleoylphosphatidylethanolamine (DOPE), dilinoleoylphosphatidylcholine, distearate, dimyristoylphosphatidylethanolamine (DSPE), dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), palmitoyloleoylphosphatidylethanolamine (POPE), lysophosphatidylethanolamine, and combinations thereof. In some embodiments, the neutral phospholipid may be selected from SPC and dimyristoylphosphatidylethanolamine (DMPE). In some implementations, the neutral phospholipid is DSPC. Neutral lipids can stabilize LNPs and improve LNP processing.

[0204] "Assistant lipids" can refer to lipids that enhance transfection (e.g., transfection of nanoparticles containing bioactive agents). The mechanisms by which assistant lipids enhance transfection include improved particle stability. In some embodiments, assistant lipids enhance membrane cohesion. Assistant lipids may include steroids, sterols, and alkyl resorcinols. Assistant lipids suitable for use in this disclosure may include, but are not limited to, cholesterol, 5-heptadecyl resorcinol, and cholesterol hemisuccinate. In some embodiments, the assistant lipid is cholesterol. In some embodiments, the assistant lipid comprises cholesterol hemisuccinate.

[0205] "Hidden lipids" can refer to lipids that alter the duration for which nanoparticles can remain in vivo (e.g., in the blood). Hidden lipids can aid in formulation processes, for example, by reducing particle aggregation and controlling particle size. The hidden lipids used herein can modulate the pharmacokinetic properties of LNPs. Hidden lipids suitable for the lipid compositions of this disclosure may include, but are not limited to, hidden lipids having a hydrophilic head group attached to the lipid moiety. Information on hidden lipids suitable for the lipid compositions of this disclosure and the biochemistry of such lipids can be found in Romberg et al., Pharmaceutical Research, Vol. 25, No. 1, 2008, pp. 55-71 and Hoekstra et al., Biochimica et Biophysica Acta 1660 (2004) 41-52. Additional suitable PEG lipids are disclosed, for example, in WO 2006 / 007712.

[0206] In some embodiments, the stealth lipid is a PEG-lipid. In one embodiment, the hydrophilic head group of the stealth lipid comprises a polymer moiety selected from polymers based on PEG (sometimes referred to as poly(ethylene oxide)), poly(oxazoline), poly(vinyl alcohol), poly(glycerol), poly(N-vinylpyrrolidone), polyamino acids, and poly(N-(2-hydroxypropyl)methacrylamide). The stealth lipid may comprise a lipid moiety. In some embodiments, the lipid moiety of the stealth lipid may be derived from diacylglycerol or diacylimidazolium dicarboxamide, including those comprising a dialkylglycerol or dialkylimidazolium dicarboxamide group having an alkyl chain length independently comprising about C4 to about C40 saturated or unsaturated carbon atoms, wherein the chain may comprise one or more functional groups such as amides or esters. The dialkylglycerol or dialkylimidazolium dicarboxamide group may also comprise one or more substituted alkyl groups.

[0207] The structures and properties of accessory lipids, neutral lipids, occult lipids and / or other lipids are also described in WO2017173054A1, WO2019067999A1, US20180290965A1, US20180147298A1, US20160375134A1, US8236770, US8021686, US8236770B2, US7371404B2, US7780983B2, US7858117B2, US20180200186A1, US20070087045A1, WO2018119514A1 and WO2019067992A1, all of which are incorporated herein by reference in their entirety.

[0208] LNP formulations The LNPs described herein can be designed for one or more specific applications or targets. Elements of the nanoparticle composition can be selected based on a specific application or target, and / or based on efficacy, toxicity, cost, ease of use, and availability. Similarly, specific formulations of the nanoparticle composition can be selected for a specific application or target.

[0209] In some embodiments, the described LNP formulations are designed for one or more specific applications or targets. For example, nanoparticle compositions can be designed to deliver therapeutic agents, such as RNA, to specific cells, tissues, organs, or systems or groups thereof within a mammal. The biochemical properties of the nanoparticle composition can be altered to increase selectivity for specific bodily targets. For example, particle size can be tailored based on the fenestration size of different organs. The therapeutic agents contained in the nanoparticle composition can also be selected based on one or more desired delivery targets. For example, the therapeutic agent can be selected for a specific indication, symptom, disease, or condition, and / or for delivery to specific cells, tissues, organs, or systems or groups thereof (e.g., localized or specific delivery). In some embodiments, the nanoparticle composition may include mRNA encoding a polypeptide of interest, which can be translated intracellularly to produce the polypeptide of interest. Such compositions can be designed for specific delivery to specific organs.

[0210] The amount of therapeutic agent in the LNP composition depends on the size, composition, desired target and / or application, or other properties of the nanoparticle composition. For example, the amount of RNA contained in the nanoparticle composition depends on the size, sequence, and other characteristics of the RNA. In some embodiments, the wt / wt ratio of the lipid component to the therapeutic agent in the nanoparticle composition is from about 5:1 to about 60:1, such as about 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, and 60:1. In some embodiments, the wt / wt ratio of the lipid component to the therapeutic agent is from about 10:1 to about 40:1. In some embodiments, the wt / wt ratio is about 20:1. In some cases, the amount of therapeutic agent in the nanoparticle composition is measured using absorption spectroscopy (e.g., UV-Vis spectroscopy).

[0211] In some embodiments, the LNP composition comprises one or more nucleic acids, such as RNA. In some embodiments, one or more RNAs, lipids, and their amounts may be selected to provide a specific N / P ratio. The N / P ratio may be selected from about 1 to about 30. The N / P ratio may be selected from about 2 to about 10. In some embodiments, the N / P ratio is about 0.1 to about 50. In some embodiments, the N / P ratio is about 2 to about 8. In some embodiments, the N / P ratio is about 2 to about 15, about 2 to about 10, about 2 to about 8, about 2 to about 6, about 3 to about 15, about 3 to about 10, about 3 to about 8, about 3 to about 6, about 4 to about 15, about 4 to about 10, about 4 to about 8, or about 4 to about 6. In some embodiments, the N / P ratio is about 2 to about 8. In some embodiments, the N / P ratio is about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, or about 6.5. In some embodiments, the N / P ratio is about 4 to about 6. In some embodiments, the N / P ratio is about 4, about 4.5, about 5, about 5.5, or about 6. In some embodiments, the N / P ratio is about 6 to about 8. In some embodiments, the N / P ratio is about 6.5, about 7, about 7.5, or about 8.

[0212] In some embodiments, the LNPs are formed with an average encapsulation efficiency ranging from about 50% to about 70%, about 70% to about 90%, or about 90% to about 100%. In some embodiments, the LNPs are formed with an average encapsulation efficiency ranging from about 75% to about 95%. In some embodiments, the nucleic acid (e.g., RNA) encapsulation efficiency of the nanoparticles described herein is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the nucleic acid encapsulation efficiency of the nanoparticles described herein is about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 90% to about 99%, or about 95% to about 99%. In some embodiments, the nucleic acid encapsulation efficiency of the nanoparticles described herein is about 90% to about 99%.

[0213] In some embodiments, the nanoparticles described herein have a median diameter of about 10 nm to about 500 nm. In some embodiments, the median diameter of the nanoparticles described herein is about 50 nm to about 150 nm, about 60 nm to about 140 nm, about 70 nm to about 130 nm, about 80 nm to about 120 nm, or about 90 nm to about 110 nm. In some embodiments, the median diameter of the nanoparticles described herein is about 60 nm, about 65 nm, about 70 nm, about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 105 nm, about 110 nm, about 115 nm, or about 120 nm. The particle size and particle size distribution of the nanoparticles can be measured by light scattering using, for example, a Zetasizer Ultra ZSU 5700 (Malvern, USA). In some embodiments, the particle size distribution is unimodal.

[0214] Pharmaceutical Composition In one aspect, this document discloses pharmaceutical compositions comprising one or more of the compounds, nanoparticle compositions, or LNPs described herein. For example, a pharmaceutical composition may comprise one or more LNP compositions containing one or more different payloads. In some embodiments, the payload comprises a nucleic acid as described herein. In some embodiments, the payload comprises RNA as described herein. In some embodiments, the payload comprises mRNA or a population of mRNAs encoding the same or different polypeptides. For example, an LNP may encapsulate a population of mRNAs encoding at least one interleukin and at least one interferon. In some embodiments, the payload comprises at least one tumor-selective motif or tumor-selective element for selectively increasing the expression of the payload in cancer cells.

[0215] Pharmaceutical compositions may also contain one or more pharmaceutically acceptable excipients, carriers, or auxiliary ingredients, such as those described herein. General guidance on the formulation and manufacture of pharmaceutical compositions and formulations is available. Excipients or carriers may include any component other than the compounds disclosed herein, other lipid components, and payloads. Excipients may impart functional (e.g., drug release rate control) and / or non-functional (e.g., processing aids or diluents) characteristics to the formulation. The selection of excipients and carriers may depend on factors such as the specific administration modality, the effect of the excipient on solubility and stability, and the nature of the dosage form. Parenteral formulations are typically aqueous or oily solutions or suspensions. Excipients or carriers such as sugars (including but not limited to glucose, mannitol, sorbitol, etc.), salts, carbohydrates, and buffers (preferably buffered to a pH of 3 to 9) may be used. In some embodiments, LNP compositions may be formulated as sterile non-aqueous solutions or in a dry form for use in conjunction with suitable media such as sterile pyrogen-free water (WFI).

[0216] In some embodiments, the excipient or carrier may constitute more than 50% of the total mass or volume of the pharmaceutical composition comprising the nanoparticle composition. For example, the excipient or carrier may constitute 50%, 60%, 70%, 80%, 90%, or more of the pharmaceutical composition. In some embodiments, the pharmaceutically acceptable excipient or carrier is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, the pharmaceutical composition may comprise one or more nanoparticle compositions between 0.1% and 100% (wt / wt). In some embodiments, the nanoparticle composition and / or pharmaceutical composition is refrigerated or frozen for storage and / or transportation (e.g., stored at temperatures of 4°C or lower, such as between about -150°C and about 0°C, or between about -80°C and about -20°C). In some embodiments, the nanoparticle composition and / or pharmaceutical composition are refrigerated or frozen at about -5°C, -10°C, -15°C, -20°C, -25°C, -30°C, -40°C, -50°C, -60°C, -70°C, -80°C, -90°C, -130°C, or -150°C.

[0217] The described LNP compositions and / or pharmaceutical compositions can be administered to any patient or subject, including those who may benefit from the therapeutic effects provided by delivering a payload to one or more specific cells, tissues, organs, or systems, or groups thereof. In some embodiments, the subject is a mammal such as a human. In some embodiments, the subject is a non-human primate or mammal, including commercially relevant mammals such as cattle, pigs, calves, sheep, cats, dogs, mice, and / or rats.

[0218] Pharmaceutical compositions comprising one or more nanoparticles can be prepared by any method known or developed in the field of pharmacology. Generally, such preparation methods involve associating the active ingredient with an excipient and / or one or more other auxiliary ingredients, and then, if desired or necessary, dividing, shaping, and / or packaging the product into desired single or multiple dose units.

[0219] The pharmaceutical compositions according to this disclosure can be prepared, packaged, and / or sold in batches in single unit dose form and / or in multiple single unit dose forms. As used herein, a “unit dose” is a discrete amount of a pharmaceutical composition (e.g., a nanoparticle composition) containing a predetermined amount of an active ingredient. The amount of active ingredient is generally equal to the dose of the active ingredient to be applied to the subject, and / or an appropriate fraction of such dose, such as half or one-third of such dose. Pharmaceutical compositions can be prepared in a variety of forms suitable for a variety of routes and methods of administration. For example, pharmaceutical compositions can be prepared in liquid dosage forms (e.g., emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, and elixirs), injectable forms, solid dosage forms (e.g., capsules, tablets, pills, powders, and granules), dosage forms for topical and / or transdermal application (e.g., ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, and patches), suspensions, powders, and other forms.

[0220] method The compounds, nanoparticle compositions (e.g., nanoparticle compositions comprising the compounds described herein), LNP compositions (e.g., LNPs comprising the compounds described herein), or pharmaceutical compositions disclosed herein can be used in methods for regulating gene expression in cells in vivo and in vitro. In some embodiments, the method includes contacting cells with the LNP composition or pharmaceutical composition described herein. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the method includes contacting a population of cells.

[0221] In some embodiments, LNPs containing the compounds described herein can increase cell transfection efficiency, such as, for example... Figure 1 , Figure 3 , Figure 5 , Figure 10 , Figure 20 and Figure 21As shown. In some embodiments, LNPs containing the compound increase cell transfection efficiency by at least 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 1.0-fold, 2.0-fold, 5.0-fold, 10.0-fold, or more compared to comparable LNPs without the compound described herein. In some embodiments, LNPs containing the compound described herein can transfect cells without reducing cell viability. For example, Figure 2 , Figure 4 , Figure 6 , Figure 11 , Figure 22 , Figure 24 and Figure 26 The comparable cell viability of LNPs containing the compound is shown compared to the cell viability of cells transfected with comparable LNPs that do not contain the compound described herein.

[0222] In some embodiments, LNPs containing the compounds described herein can transfect cells in vitro at levels comparable to comparable LNPs without the compound. For example, Figure 7 and Figure 8 The comparable transfection efficiency of LNPs containing the compounds described herein to ex vivo cells is shown compared to a baseline lipid (e.g., a lipid without the compounds described herein, baseline 1). In some embodiments, LNPs containing the compounds do not cause in vivo toxicity (e.g., as shown in [example description]). Figure 9 , Figure 13 and Figure 18 (As shown). In some embodiments, LNPs containing the compounds described herein can be transfected into cells in vivo at levels comparable to comparable LNPs without the compound. For example, Figure 12 The comparable transfection efficiency of LNPs containing the compounds described herein to cells in vivo is shown compared to a baseline lipid (e.g., a lipid without the compounds described herein, baseline 1).

[0223] In one aspect, this document discloses methods for treating a disease or symptom in a subject. In one embodiment, the disease or symptom can be treated by applying a payload. In some embodiments, the disease or symptom is cancer or cancer-related. The payload contained in the LNP composition may also be able to alter the transcription rate of a given species, thereby affecting gene expression.

[0224] In some embodiments, the nanoparticle compositions disclosed herein (e.g., nanoparticle compositions comprising the compounds described herein), LNP compositions (e.g., LNPs comprising the compounds described herein), or pharmaceutical compositions are administered at least once over a period of time (e.g., once every 2 days, twice a week, once a week, weekly, three times a month, twice a month, once a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, once a year). In some embodiments, the composition is administered two or more times over a period of time (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100 times). In some embodiments, the method includes administering a therapeutically effective amount of the disclosed compounds, nanoparticle compositions (e.g., nanoparticle compositions comprising the compounds described herein), LNP compositions (e.g., LNPs comprising the compounds described herein), or pharmaceutical compositions via various forms and routes (including, for example, intratumoral, oral, or topical application). In some embodiments, the composition may be administered via: intratumoral, parenteral, intravenous, subcutaneous, intramuscular, intradermal, intraperitoneal, intracerebral, subarachnoid, intraocular, intrasternal, transocular, endothelial, local, intranasal, intrapulmonary, transrectal, intraarterial, intrasheathal, inhalation, intralesional, intradermal, epidural, intracystic, subcapsular, intracardiac, transtracheal, subepidermal, subarachnoid, or intraspinal administration, such as by injection or infusion. In some embodiments, the composition may be administered via absorption through epithelial or mucosal skin linings (e.g., oral mucosal, rectal, and intestinal mucosal application). In some embodiments, the compounds disclosed herein, nanoparticle compositions (e.g., nanoparticle compositions comprising the compounds described herein), LNP compositions (e.g., LNPs comprising the compounds described herein), or pharmaceutical compositions are delivered via a variety of routes of administration.

[0225] The actual dosage level of the pharmaceutical agent disclosed herein can be varied to obtain an amount of agent that achieves the desired therapeutic response to a particular subject, composition, and administration mode without toxicity to the subject (e.g., for immunization or for treatment). The selected dosage level can depend on a variety of pharmacokinetic factors, including the activity of the particular composition of the invention employed, route of administration, time of administration, excretion rate, duration of treatment, other drugs, compounds, and / or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical field.

[0226] Dosing regimens can be adjusted to provide the optimal desired response (e.g., therapeutic and / or prophylactic response). For example, a single bolus injection can be administered, several separate doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by an emergency situation in the treatment. For ease of administration and uniform dosing, it is particularly advantageous to formulate the parenteral composition in unit dosage form. As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dose for a subject (e.g., for immunization or for treatment); each unit contains a predetermined amount of active agent calculated to produce the desired therapeutic effect in association with a desired drug delivery system. The specifications of the unit dosage forms disclosed herein can be determined by and directly depend on: (a) the unique characteristics of the active agent and the specific therapeutic effect to be achieved, and (b) the inherent limitations of such active agents in the art for mixing to treat an individual's sensitivity. Dosage can be determined by reference to the plasma or local concentration of a cyclic polynucleotide or antibody or its antigen-binding fragment. Dosage can be determined by reference to the plasma or local concentration of a linear polynucleotide or antibody or its antigen-binding fragment.

[0227] The compounds, nanoparticle compositions (e.g., nanoparticle compositions comprising the compounds described herein), LNP compositions (e.g., LNPs comprising the compounds described herein), or pharmaceutical compositions disclosed herein may be unit dosage forms suitable for a precise single-dose administration. In a unit dosage form, the formulation may be divided into unit doses containing an appropriate amount of the composition. In a unit dosage form, the formulation may be divided into unit doses containing an appropriate amount of one or more linear polynucleotides, antibodies, or antigen-binding fragments thereof, and / or therapeutic agents. The unit dose may be a packaged form containing discrete amounts of the formulation. Non-limiting examples are packaged injections, vials, and ampoules. The aqueous suspension compositions disclosed herein may be packaged in single-dose, non-resealable containers. Multi-dose, resealable containers may be used, for example, with or without preservatives. The formulations disclosed herein for injection may be present in unit dosage forms, for example, in ampoules, or in multi-dose containers containing preservatives.

[0228] In some embodiments, this document describes a method for delivering a therapeutic agent to a subject in need, the method comprising administering the nanoparticle composition or pharmaceutical composition described herein to the subject, thereby delivering the therapeutic agent to the subject. In some embodiments, the therapeutic agent is the payload described herein. In some embodiments, the therapeutic agent comprises a nucleic acid (e.g., mRNA) described herein. In some embodiments, the therapeutic agent encodes a polypeptide of interest (e.g., cytokine). In some embodiments, the therapeutic agent may be expressed by cells in contact with the nanoparticle composition or pharmaceutical composition described herein. In some embodiments, the method comprises selectively delivering the therapeutic agent to a mammalian organ. In some embodiments, the method comprises selectively expressing the therapeutic agent in cells. For example, the therapeutic agent comprises a tumor-selective motif or tumor-selective element for selectively expressing the therapeutic agent in cells associated with a disease or symptom (e.g., cancer cells). In some embodiments, the method treats a disease or symptom of the subject. In some embodiments, the disease or symptom is cancer.

[0229] The terminology used herein is for descriptive purposes only and is not intended to be limiting. In this application, unless otherwise specified, the use of the singular includes the plural. As used herein, the singular forms “a,” “an,” and “the / said” are intended to also include the plural forms, unless the context clearly indicates otherwise.

[0230] In this application, unless otherwise stated, the use of “or” means “and / or”. As used herein, the terms “and / or” and “any combination thereof” and their grammatical equivalents are used interchangeably. These terms can convey that any combination is specifically intended. For illustrative purposes only, the phrases “A, B and / or C” or “A, B, C or any combination thereof” can mean “A alone; B alone; C alone; A and B; B and C; A and C; and A, B and C.” The term “or” can be used conjunctively or disjunctively unless the context specifically indicates disjunctive use.

[0231] The terms "about" or "approximately" can mean within an acceptable range of error for a particular value as determined by a person skilled in the art, the acceptable range of error depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, in accordance with practice in the art, "about" can mean within one or more standard deviations. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude of the value, within five times, or within two times. Where a particular value is described in this application and claims, unless otherwise stated, the term "about" should be assumed to mean within an acceptable range of error for the particular value.

[0232] As used in this specification and claims, the terms “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unlisted elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of this disclosure, and vice versa. Furthermore, the compositions of this disclosure can be used to implement the methods of this disclosure.

[0233] The references to “some embodiments,” “implementation,” “one embodiment,” or “other embodiments” in this specification mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least some embodiments of this disclosure, but not necessarily in all embodiments. For ease of understanding of this disclosure, a number of terms and phrases are defined below.

[0234] As used herein, the term "derivative" refers to a chemical or biological substance that is structurally related to a second substance and can be derived from the second substance through modification of the second substance. Specifically, if the first compound is a derivative of the second compound, and the second compound is associated with chemical and / or biological activity, then the first compound differs from the second compound in at least one structural feature while retaining (at least to some extent) the chemical and / or biological activity of the second compound and at least one associated structural feature (e.g., sequence, fragment, functional group, etc.). Where appropriate and upon reading this disclosure, those skilled in the art will be able to determine the structural features of the second compound that must be maintained in the first compound to retain the chemical and / or biological activity of the second compound, and the determinations that can be used to demonstrate the retention of such chemical and / or biological activity. Exemplary "derivatives" may include prodrugs, metabolites, enantiomers, diastereomers, esters (e.g., acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonates, sulfate esters, and esters containing disulfide bonds), ethers, amides, carbonates, thiocarbonates, etc. N -Acyl derivatives, N - Acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N -Mannich base ( N -Mannich base), Schiff base, amino acid conjugate, phosphate ester, metal salt, sulfonate, etc. In some cases, derivatives may include negligible substitutions of the parent compound (i.e., additional alkyl / alkylene groups) that retain the chemical and / or biological activity of the parent compound.

[0235] The term "pharmaceutical acceptable" means that a substance is approved or permitted by a federal or state regulatory agency or is listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals (including humans).

[0236] "Pharmaceutical acceptable excipients, carriers or diluents" are excipients, carriers or diluents that can be applied to a subject together with a drug and that do not impair the pharmacological activity of the drug and are non-toxic when applied in a dose sufficient to deliver a therapeutic amount of the drug.

[0237] "Pharmaceutically acceptable salts" can be acid or base salts that are generally considered in the art to be suitable for contact with human or animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications. Such salts include inorganic and organic acid salts with basic residues such as amines, and basic or organic salts with acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, aminosulfonic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pyric acid, succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanonic acids such as acetic acid, HOOC-(CH2)n-COOH (where n is 0-4), etc. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Those skilled in the art will recognize from this disclosure and the knowledge of the art that other pharmaceutically acceptable salts include those listed in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, page 1418 (1985). In general, pharmaceutically acceptable acid or base salts can be synthesized by any conventional chemical method from a parent compound containing a basic or acidic moiety. In short, such salts can be prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in a suitable solvent.

[0238] As used herein, the term "therapeutic effective amount" means the amount of a drug (e.g., nucleic acid, medicine, payload, composition, therapeutic agent, diagnostic agent, preventive agent, etc.) to be delivered, which, when applied to a subject suffering from or susceptible to an infection, disease, symptom, and / or condition, is sufficient to treat, improve, diagnose, prevent, and / or delay the onset of the infection, disease, symptom, and / or condition.

[0239] The ranges provided in this document should be understood as abbreviated forms of all values ​​within that range. For example, the range 1 to 50 should be understood to include any number, combination of numbers, or subrange from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all interpolated decimal values ​​between the integers mentioned above, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. Regarding subranges, "nested subranges" extending from either endpoint of the range are particularly considered. For example, nested subranges of exemplary ranges 1 to 50 may include 1 to 10, 1 to 20, 1 to 30 and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20 and 50 to 10 in another direction.

[0240] The term "object" refers to an animal that is used as a subject of treatment, observation, or experimentation. By way of example only, objects include, but are not limited to, mammals, including, but not limited to, humans or non-human mammals such as non-human primates, cattle, horses, dogs, sheep, or cats.

[0241] The terms “treat / treated / treating / treatment” mean to alleviate or improve a condition and / or related symptoms (e.g., tumor formation or tumor). “Treatment / treatment” can refer to the application of an LNP composition to a subject after the onset or suspected onset of a disease or symptom. “Treatment / treatment” includes the concept of “paroxysmal,” which refers to reducing the frequency or severity of any symptoms or other adverse effects associated with the disease or symptom and / or side effects associated with it. The term “treatment / treatment” also encompasses the concept of “management,” which refers to reducing the severity of a patient’s specific disease or symptom, or delaying its recurrence, such as prolonging the remission period for patients already suffering from the disease. It should be understood that, although not excluded, treating a condition or symptom does not require the complete elimination of the condition, symptom, or related symptoms.

[0242] Unless otherwise stated, the term "substituted" means that one or more hydrogen groups in a given structure are replaced by a specified substituent, which includes, but is not limited to: halogenated, alkyl, alkenyl, alkynyl, aryl, heterocyclic, mercapto, alkylthio, oxo, thiooxy, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, arylalkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxyl, alkoxyalkyl, carboxylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, arylalkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic groups. It should be understood that the substituent may be further substituted. Exemplary substituents include amino, alkylamino, etc.

[0243] As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule that is substituted at a specified atomic position, thereby replacing one or more hydrogen atoms on the specified atom, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution produces a stable compound. Combinations of substituents and / or variables are only permissible if such combinations produce a stable compound. Those skilled in the art will note that any carbon and heteroatom having an apparent unsatisfied valence as described or shown herein is considered to have a sufficient number of hydrogen atoms to satisfy the described or shown valence. In some cases, one or more substituents having a double bond as a connecting point (e.g., "oxo" or "=0") may be described, shown, or listed herein within the group of substituents, wherein the structure may show only a single bond as a connecting point with the core structure of formula (I), (Ia), (II), (IIa), (III), or (IIIa). Those skilled in the art will understand that while only single bonds are shown, double bonds are intended for those substituents.

[0244] The term "alkyl" refers to a straight-chain or branched hydrocarbon chain group having one to twenty carbon atoms, connected to the rest of the molecule by single bonds. Alkyl groups containing up to 10 carbon atoms are called C1-C. 10 Alkyl groups, similarly, for example, alkyl groups containing up to six carbon atoms are C1-C6 alkyl groups. Alkyl groups containing other numbers of carbon atoms (and other parts defined herein) are represented in a similar manner. Alkyl groups include, but are not limited to, C1-C6 alkyl groups. 14 Alkyl, C1-C 13 Alkyl, C1-C 12 Alkyl, C1-C 11 Alkyl, C1-C 10Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C3-C8 alkyl, and C4-C8 alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, etc. In some embodiments, the alkyl group is methyl or ethyl. In some embodiments, the alkyl group is -CH(CH3)2 or -C(CH3)3. Unless otherwise specifically stated in the specification, the alkyl group may optionally be substituted as described below. "alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain to which the remainder of the molecule is attached. In some embodiments, the alkylene group is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene group is -CH2-. In some embodiments, the alkylene group is -CH2CH2-. In some embodiments, the alkylene group is -CH2CH2CH2-.

[0245] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group. Heteroalkyl groups can include nitrile, amide, ester, ether, amine, thioether, thioester, urethane, carbonate, polyether, polyamine, etc.

[0246] The term "halo," or alternatively, "halogen" or "halide," refers to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogroup is a fluorinated, chlorinated, or brominated group. When used as a prefix, the halogroup does not indicate the number of instances. For example, alkyl halides include methyl derivatives -CH2F, -CHF2, and -CF3.

[0247] The term "haloalkyl" refers to an alkyl group in which at least one and possibly more hydrogen atoms have been replaced by a halogen. For example, haloalkyl groups include methyl derivatives -CH2F, -CHF2, and -CF3. Haloalkyl groups are not limited in terms of the number of halogens and carbon atoms. Generally, haloalkyl refers to C1-C2 alkyl groups. 12 Halogenated alkyl groups.

[0248] The term "aryl" refers to a group derived from a hydrocarbon ring system containing at least one aromatic ring. In some embodiments, the aryl group comprises hydrogen and 6 to 30 carbon atoms. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded through aromatic ring atoms) or bridged ring system. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of anthracene, naphthylene, phenanthrene, anthracene, azulene, benzene, benzoxene, fluorene, indene, indene, naphthalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl group is phenyl. Unless otherwise specifically stated in the specification, the aryl group may optionally be substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S(O)2NH-C1-C6 alkyl, etc. In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, -NO2, -S(O)2NH2, -S(O)2NHCH3, -S(O)2NHCH2CH3, -S(O)2NHCH(CH3)2, -S(O)2N(CH3)2, or -S(O)2NHC(CH3)3. In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with halogen. In some embodiments, the aryl group is substituted with an alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl group, wherein each alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl group is independently unsubstituted or substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.

[0249] The term "alkenyl" refers to an alkyl group of a type in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R a )=CR a 2, where R a This refers to the remaining portion of the alkenyl group, which may be the same or different. In some embodiments, R... aIt is H or alkyl. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2. "Alkenyl" or "alkenyl chain" refers to an alkylene group in which at least one carbon-carbon double bond is present. In some embodiments, the alkenyl group is -CH=CH-, -CH2CH2CH=CH-, or -CH=CHCH2CH2-. In some embodiments, the alkenyl group is -CH=CH-. In some embodiments, the alkenyl group is -CH2CH2CH=CH-. In some embodiments, the alkenyl group is -CH=CHCH2CH2-.

[0250] The term "alkynyl" refers to an alkyl group of a type in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group has the formula -C≡CR a , where R a This refers to the remaining portion of the alkynyl group. In some embodiments, R a It is H or an alkyl group. In some embodiments, the alkynyl group is selected from ethynyl (i.e., acetylenyl), propynyl (i.e., propynyl), butynyl, pentynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, and -CH2C≡CH. The term "alkynyl group" or "alkynyl chain" refers to an alkylene group in which at least one carbon-carbon triple bond is present. In some embodiments, the alkynyl group is -C≡C-, -CH2CH2C≡C-, or -C≡CCH2CH2-. In some embodiments, the alkynyl group is -C≡C-. In some embodiments, the alkynyl group is -CH2CH2C≡C-. In some embodiments, the alkynyl group is -C≡CCH2CH2-.

[0251] The term "alkenylalkylene" refers to a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon double bond. In some embodiments, the alkenyl group comprises two to fifteen carbon atoms (C2-C4). 15 Alkenylalkylene), or two to twelve carbon atoms (C2-C4). 12 Alkenylalkylene), or three to twelve carbon atoms (C3-C4). 12 Alkenylalkylene), or three to ten carbon atoms (C3-C4). 10Alkenyl alkylene groups, etc. Alkenyl alkylene groups can be attached to the rest of the molecule via two single bonds. Non-limiting examples of alkenyl alkylene groups are: -CH2CH=CH-, -CH2CH=CHCH2-, -CH2(CH2)5CH=CH-, -CH2(CH2)4CH=CH(CH2)2CH2-, -CH2(CH2) 11 CH=CH- etc. In some embodiments, the alkenylalkylene group is a hydrocarbon chain containing one to five carbon-carbon double bonds. In some embodiments, the alkenylalkylene group is a hydrocarbon chain containing one carbon-carbon double bond. In some embodiments, the alkenylalkylene group is a hydrocarbon chain containing two carbon-carbon double bonds. In some embodiments, the alkenylalkylene group is a hydrocarbon chain containing three carbon-carbon double bonds. In some embodiments, the alkenylalkylene group is a hydrocarbon chain containing four carbon-carbon double bonds. In some embodiments, the alkenylalkylene group is a hydrocarbon chain containing five carbon-carbon double bonds. In some embodiments, the alkenyl group is optionally substituted by one or more of the following substituents: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 Replace; where R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 Alkyne group; and each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl).

[0252] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each of the atoms forming the ring (i.e., the skeleton atoms) is a carbon atom. In some embodiments, the cycloalkyl group is saturated or partially unsaturated. In some embodiments, the cycloalkyl group is a spirocyclic or bridging compound. In some embodiments, the cycloalkyl group is fused to an aromatic ring (in which case, the cycloalkyl group is bonded through the carbon atoms of the non-aromatic ring). Cycloalkyl groups include groups having 3 to 10 ring atoms. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to ten carbon atoms, three to eight carbon atoms, three to six carbon atoms, or three to five carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl or cyclohexenyl. In some embodiments, the monocyclic cycloalkyl group is cyclopentenyl. Polycyclic groups include, for example, adamantyl, 1,2-dihydronaphthyl, 1,4-dihydronaphthyl, tetrahydronaphthyl, decahydronaphthyl, 3,4-dihydronaphthyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. Unless otherwise specifically stated in the specification, cycloalkyl groups may optionally be substituted. Depending on the structure, the cycloalkyl groups may be monovalent or divalent (i.e., cycloalkylene groups).

[0253] The term "heterocycle" or "heterocyclic" refers to a heteroaromatic ring (also called a heteroaryl) and a heterocyclic alkyl ring (also called a heteroalicyclic group) comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein each heterocyclic group has 3 to 12 atoms in its ring system, and provided that no ring contains two adjacent O or S atoms. A "heterocyclic group" is a monovalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic, or bridging compound. Non-aromatic heterocyclic groups (also called heterocyclic alkyl groups) comprise rings having 3 to 12 atoms in their ring system, and aromatic heterocyclic groups comprise rings having 5 to 12 atoms in their ring system. Heterocyclic groups include benzo[a]-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinone, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxyl, piperazine, aziridinyl, aziridine, aziridine, oxaziridine, oxaziridine, thioaziridine, high-piperidinyl, oxaziridine, thioaziridine, oxazepinyl, diaziridine, thioaziridine, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxyl, 1,3-dioxacyclopentyl, and pyrazolinyl. Dithiaalkyl, dithiopentanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3h-indolyl, indololin-2-one, isoindololin-1-one, isoindololin-1,3-dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindololin-1,3-dithioketone, benzo[d]oxazol-2(3H)-one, 1H-benzo[d]imidazo-2(3H)-one, benzo[d]thiazol-2(3H)-one, and quinazinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazole, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cenolinyl, indazole, indoleazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, and furanylpyridinyl. Where possible, the aforementioned groups are C-linked (or C-bonded) or N - Connected. For example, groups derived from pyrrole include pyrrole-1-yl ( N(C-linked) or pyrrole-3-yl (C-linked) or both. Furthermore, groups derived from imidazole include imidazole-1-yl or imidazole-3-yl (both are... N (-linked) or imidazole-2-yl, imidazole-4-yl, or imidazole-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or both oxo groups (=O), such as pyrrolidone-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0254] The term "heterocyclic alkyl" refers to a cycloalkyl group comprising at least one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group can be a monocyclic or bicyclic ring system, which may include a fused ring system (where the heterocyclic alkyl group is bonded by non-aromatic ring atoms when fused with an aryl or heteroaryl ring) or a bridging ring system. The nitrogen, carbon, or sulfur atom in the heterocyclic alkyl group may optionally be oxidized. The nitrogen atom may optionally be quaternized. The heterocyclic alkyl group is partially or fully saturated. Examples of heterocyclic alkyl groups include, but are not limited to, dioxacyclopentyl, thienyl[1,3]dithiaalkyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbons in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms and 1 or 2 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms and 3 or 4 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 12 carbon atoms, 0 to 2 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 2 phosphorus atoms, and 0 to 1 sulfur atom in the ring. In some embodiments, the heterocyclic alkyl group has 2 to 12 carbon atoms, 1 to 3 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in that heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring, including heteroatoms). Unless otherwise specifically stated in the specification, the heterocyclic alkyl group may optionally be substituted. As used herein, the term "heterocyclic alkylene" may refer to a divalent heterocyclic alkyl group.

[0255] The term "heteroaryl" refers to an aryl group comprising one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryls can be monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, furazolyl, indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, cinnamoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthidine, and pteridine. Illustrative examples of monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazonyl. Illustrative examples of bicyclic heteroaryl groups include indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, cyclophosphine, quinazoline, quinoxaline, 1,8-naphthidine, and pteridine. In some embodiments, the heteroaryl group is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thiopheneyl, thiadiazolyl, or furanyl. In some embodiments, the heteroaryl group contains 0-6 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 4-6 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 nitrogen atoms, 0-1 oxygen atom, 0-1 phosphorus atom, and 0-1 sulfur atom in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms, 0-1 oxygen atom, and 0-1 sulfur atom in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group. In some embodiments, the heteroaryl group is partially reduced to form a heterocyclic alkyl group as defined herein. In some embodiments, the heteroaryl group is completely reduced to form a heterocyclic alkyl group as defined herein.

[0256] As used herein, the “N / P ratio” is, for example, the molar ratio of ionizable (e.g., within a physiological pH range) nitrogen atoms in one lipid (or multiple lipids) to phosphate groups in one nucleic acid molecular entity (or multiple nucleic acid molecular entities) in a nanoparticle composition comprising a lipid component and RNA. Ionizable nitrogen atoms may include, for example, nitrogen atoms that can be protonated at, say, about pH 1, about pH 2, about pH 3, about pH 4, about pH 5, about pH 6, about pH 7, about pH 7.5, or about pH 8 or higher. A physiological pH range may include, for example, the pH range of different cellular compartments (such as organs, tissues, and cells) and bodily fluids (such as blood, CSF, gastric juice, breast milk, bile, saliva, tears, and urine). In some specific embodiments, a physiological pH range refers to the pH range of mammals, for example, about 7.35 to about 7.45. In some embodiments, ionizable nitrogen atoms refer to those nitrogen atoms that can be ionized in a pH range between 5 and 14.

[0257] For payloads that do not contain phosphate groups, the N / P ratio can refer to the molar ratio of ionizable nitrogen atoms in the lipid to the total negative charge in the payload. For example, the N / P ratio of an LNP composition can refer to the molar ratio of the total ionizable nitrogen atoms in the LNP composition to the total negative charge present in the payload of the composition.

[0258] As used herein, aminolipids may contain at least one primary, secondary, or tertiary amine moiety that is protonable (or ionizable) in the pH range of 4 to 14. In some embodiments, one or more amine moieties act as hydrophilic head groups of the aminolipids described in Tables 1-3. When a majority of the amine moiety of an aminolipid (or multiple aminolipids) in a nucleic acid-lipid nanoparticle formulation is protonated at physiological pH, the nanoparticle may be referred to as a cationic lipid nanoparticle (cLNP). When a majority of the amine moiety of an aminolipid (or multiple aminolipids) in a nucleic acid-lipid nanoparticle formulation is not protonated at physiological pH, but may be protonated at acidic pH, such as endosomal pH, it may be referred to as an ionizable lipid nanoparticle (iLNP). The aminolipids constituting cLNPs may generally be referred to as cationic aminolipids (cLipid). The aminolipids constituting iLNPs may be referred to as ionizable aminolipids (iLipid). At physiological pH, the aminolipids described in Tables 1-3 may be iLipid or cLipid.

[0259] As used herein, a “lipid nanoparticle (LNP) composition” or “nanoparticle composition” is a composition comprising one or more of the described lipids. LNP compositions are typically on the order of micrometers or smaller and may comprise a lipid bilayer. Nanoparticle compositions encompass lipid nanoparticles (LNPs), liposomes (e.g., lipid vesicles), and lipid complexes. For example, a nanoparticle composition may be a liposome having a lipid bilayer with a diameter of 500 nm or smaller. The LNPs described herein may have an average diameter of about 1 nm to about 2500 nm, about 10 nm to about 1500 nm, about 20 nm to about 1000 nm, about 30 nm to about 150 nm, about 40 nm to about 150 nm, about 50 nm to about 150 nm, about 60 nm to about 130 nm, about 70 nm to about 110 nm, about 70 nm to about 100 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 nm to about 90 nm, about 80 nm to about 90 nm, or about 70 nm to about 80 nm. The LNPs described herein may have an average diameter of approximately 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, or greater. The LNPs described herein may be substantially non-toxic.

[0260] As used herein, “PEG lipid” or “PEG-lipid” refers to lipids containing polyethylene glycol components.

[0261] As used herein, "phospholipid" can refer to a lipid comprising a phosphate moiety and one or more carbon chains, such as unsaturated fatty acid chains. Phospholipids may include one or more multiple (e.g., double or triple) bonds. In some embodiments, phospholipids can facilitate fusion with membranes. For example, cationic phospholipids can interact with one or more negatively charged phospholipids in a membrane (e.g., a cell membrane or intracellular membrane). Fusion of phospholipids with a membrane can allow one or more elements of the LNP to cross the membrane, i.e., deliver one or more elements into the cell.

[0262] The term "therapeutic agent" can refer to any agent that, when applied to a subject, has a therapeutic, diagnostic, and / or preventative effect and / or induces the desired biological and / or pharmacological action. Therapeutic agents can also be referred to as "active substances" or "active agents." Such agents include, but are not limited to, cytotoxins, radioactive ions, chemotherapeutic agents, small molecule drugs, proteins, and nucleic acids.

[0263] As used herein, the term “nucleic acid” is used interchangeably with “nucleic acid molecular entity.” As used herein, the term “nucleic acid” refers to a polymer containing at least two nucleotides (i.e., deoxyribonucleotides or ribonucleotides) in single-stranded or double-stranded form, and includes DNA and RNA. A “nucleotide” contains a sugar, deoxyribose (DNA) or ribose (RNA), a base, and a phosphate group. Nucleotides are linked together by phosphate groups. A “base” includes purines and pyrimidines, which further include natural compounds adenine, thymine, guanine, cytosine, uracil, inosine, and natural analogs, as well as synthetic derivatives of purines and pyrimidines, including but not limited to modifications that place new reactive groups (such as, but not limited to, amines, alcohols, thiol groups, carboxylic acid esters, and alkyl halides). Nucleic acids include nucleic acids containing known nucleotide analogs or modified backbone residues or linked to them, which are synthetic, naturally occurring, or non-natural, and have binding properties similar to a reference nucleic acid. Examples of such analogues and / or modified residues include, but are not limited to, thiophosphates, aminophosphates, methylphosphonates, chiral methylphosphonates, 2'-O-methylribonucleotides, and peptide-nucleic acids (PNAs).

[0264] The term "nucleic acid" includes any oligonucleotide or polynucleotide, with segments containing up to 60 nucleotides typically called oligonucleotides and longer segments called polynucleotides. Deoxyribose oligonucleotides consist of a 5-carbon sugar called deoxyribose, which is covalently bonded to a phosphate ester at the 5' and 3' carbons to form alternating unbranched polymers. DNA can be, for example, antisense molecules, plasmid DNA, precondensed DNA, PCR products, vectors, expression cassettes, chimeric sequences, chromosomal DNA, or derivatives and combinations thereof. Ribosose oligonucleotides consist of similar repetitive structures in which the 5-carbon sugar is ribose. Therefore, the terms "polynucleotide" and "oligonucleotide" can refer to polymers or oligomers of nucleotide or nucleoside monomers composed of naturally occurring bases, sugars, and inter-sugar (backbone) linkages. The terms "polynucleotide" and "oligonucleotide" can also include functionally similar polymers or oligomers containing non-naturally occurring monomers or portions thereof. Such modified or substituted oligonucleotides are often superior to their natural forms due to properties such as enhanced cellular uptake, reduced immunogenicity, and increased stability in the presence of nucleases.

[0265] Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses its conserved modified variants (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences, as well as explicitly indicated sequences. Specifically, degenerate codon substitutions can be achieved by producing sequences in which the third position of one or more selected (or all) codons is substituted with a mixture of bases and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res., 19:5081 (1991); Ohtsuka et al., J. Biol. Chem., 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes, 8:91-98 (1994)).

[0266] This disclosure covers isolated or substantially purified nucleic acid molecules and compositions containing such molecules. As used herein, an "isolated" or "purified" DNA or RNA molecule is a DNA or RNA molecule that exists outside its natural environment. Isolated DNA or RNA molecules may exist in purified form or may exist in non-natural environments such as transgenic host cells. For example, an "isolated" or "purified" nucleic acid molecule or its biologically active portion is substantially free of other cell material or culture medium when produced by recombinant technology, or substantially free of chemical precursors or other chemicals when chemically synthesized. In one embodiment, the "isolated" nucleic acid does not contain sequences naturally side-attached to the nucleic acid in the genomic DNA of the organism from which the nucleic acid is derived (i.e., sequences located at the 5' and 3' ends of the nucleic acid). For example, in some embodiments, the isolated nucleic acid molecule may contain nucleotide sequences less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb, or 0.1 kb naturally side-attached to the nucleic acid molecule in the genomic DNA of the cell from which the nucleic acid is derived. Example

[0267] Example 1. Preparation method Lipid nanoparticles (mRNALNPs) encapsulating mRNA were formulated using microfluidic mixing with a PNI Ignite instrument. Briefly, lipids (ionizable:structural:auxiliary:PEG) were dissolved in ethanol and mixed with an aqueous solution of mRNA. These mRNA-loaded dispersions were then neutralized via overnight buffer exchange with a predetermined buffer. The resulting LNPs were then concentrated by centrifugation using an Amicon filter, filtered, the mRNA concentration was determined by ribogreen assay, and the mixture was frozen at -80°C until use.

[0268] Example 2. TNS Measurement Lipid nanoparticles (mRNALNPs) encapsulating mRNA were formulated using microfluidic mixing with a PNI Ignite instrument. Briefly, lipids (ionizable:structural:auxiliary:PEG) were dissolved in ethanol and mixed with an aqueous solution of mRNA. These mRNA-loaded dispersions were then neutralized via overnight buffer exchange with a predetermined buffer. The resulting LNPs were then concentrated by centrifugation using an Amicon filter, filtered, the mRNA concentration was determined by ribogreen assay, and the mixture was frozen at -80°C until use.

[0269] Example 3. In vitro experiment AML12 cells were grown to confluence in T75 flasks using DMEM-F12 complete medium, while B16F10 and MC38.K cells were grown in DMEM complete medium. Cells were seeded in white 96-well plates containing their respective media (AML12 = 20,000 cells / well, B16F10 and MC38.K = 5,000 cells / well). Lipid nanoparticles were first diluted to 50 μg / mL with Opti-MEM and pre-incubated with mouse serum for 30 min to obtain an LNP concentration of 8 μg / mL. The cell culture medium was replaced with Opti-MEM, and LNP (200 ng of mRNA-LNP) was added to the cells. The cells were returned to the incubator and allowed to transfect for 24 h. Afterward, 100 µL of Promega's ONE-Glo TM The EX luciferase assay system or Promega's CellTiter-Glo® luminescent cell viability assay were mixed in their respective wells and then the luminescent signal was recorded on a ThermoScientific Varioskan LUX multimode microplate reader. The results are shown in... Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 , Figure 10 , Figure 11 and Figure 21 Significant differences in transfection, as measured experimentally, were observed for different lipid formulations.

[0270] Table 4. Biological results of in vitro testing of luciferin signals via photon measurements.

[0271] Table 5. Biological results of in vitro testing of luciferin signals via photon measurements.

[0272] * As used herein, reference 1 or reference compound refers to:

[0273] Example 4. In vivo experiment Flux mRNA LNP was administered to CD1 mice via tail vein at two doses of 1.0 mg / kg on days 0 and 2. Bioluminescence was measured using an IVIS spectral imaging system 18 hours after the second dose. Mice were then treated with 150 mg / kg of fluorescein substrate administered via intraperitoneal injection. The mice were subsequently euthanized, and the lungs, liver, and spleen were harvested for ex vivo imaging. All procedures were performed according to the approved IACUC guidelines.

[0274] Day 0: (1) Set up the fume hood with a laptop computer for recording, a heat lamp for exposing veins (with space for 1 cage), 7 x 1 mL tuberculin syringes (with 28 g 1 / 2" needles), 14 x 4 gauze pads, 70% isopropanol, a balance, a temporary animal holding container, and test articles on wet ice. (2) Transfer the animals from R5030 to R5025 using a trolley. (3) Transfer one cage at a time (in group order) to the fume hood, place them under the heat lamp, and remove the lid / food / water. (4) Identify the animal cages. (5) Draw the test article into the tuberculin syringe, remove all air bubbles, and flush it into the TA container to avoid injuring the animal and retain the residue. (6) Soak one gauze pad in 70% isopropanol and place one gauze pad to one side to restrict blood flow. (7) Manually restrain the animal and make ear punches (Jackson Labs diagram, Braintree 2). (8) The animal was mechanically restrained via a tubular restraint (waiting for the nose to be within the gap before full restraint to ensure adequate oxygen flow) and the tail was wiped with 70% isopropyl alcohol gauze for disinfection. (9) The test items were re-validated according to the study design and 100 μL was administered to the animal via the left-side TV. (10) Before removing the needle, the thumb of the hand restraining the tail was placed on the injection site to prevent TA from leaking out of the injection site. (11) While the tail was still being held, the plug on the mechanical restraint was removed and the animal was removed from the mechanical restraint. (12) The fingers were removed from the injection site and the bleeding was stopped with gauze. (13) The animal was identified via a temporary tail tag while the wound was being held. (14) Once the bleeding stopped, the animal was weighed and placed in a temporary containment container. (15) Once all animals in the group had been administered the drug, all injection sites were observed to ensure that bleeding no longer occurred and they were returned to their original cages. (16) Repeat Steps 3-15 continue until all groups are complete and back to normal, then return to R5030. Day 1: (1) Set up the laptop computer, balance, and temporary animal holding container in the fume hood in R5030 for recording. (2) Verify the animals via tail tag (if the number is not visible, restrain the animal, verify via ear punch, and re-tagged with tail tag). (3) Once verified, weigh the animal and place it in the temporary holding container. (4) After weighing all the animals in the group, return them to their original cages. (5) Repeat steps 2-5 until all animals have been weighed. (6) Then return the animals to their feeding racks.Day 2: (1) Set up the fume hood with a heat lamp for exposing veins (with space for 1 cage), 7 1mL tuberculin syringes (with 28g 1 / 2" needles), 14 4×4 gauze pads, 70% isopropanol, a balance, a temporary animal holding container, test items on wet ice, and Wanda outside the fume hood, recording weight using a laptop. (2) Transfer the animals from R5030 to R5024 using a trolley. (3) Transfer one cage at a time (in group order) to the fume hood, place them under the heat lamp, and remove the lid / food / water. (4) Draw the test items into the tuberculin syringes, remove all air bubbles, and flush into the TA container to avoid animal injury and retain the residue. (5) Soak one gauze pad in 70% isopropanol and place one gauze pad to one side to restrict blood flow. (6) Manually restrain the animals and make ear punches (Jackson Labs diagram, Braintree 2). (7) The animal was mechanically restrained via a tubular restraint (waiting for the nose to be in the gap before full restraint to ensure adequate oxygen flow), and the tail was wiped with 70% isopropyl alcohol gauze for disinfection. (8) The test items were re-validated according to the study design, and the animal was administered 100 mg of medication via the left-side TV. μL. (9) Before removing the needle, place the thumb of the hand restraining the tail on the injection site to prevent TA from leaking out. (10) While the tail is still being held, remove the plug from the mechanical restraint and remove the animal from the restraint. (11) Remove the finger from the injection site and stop the bleeding with gauze. (12) Identify the animal by using a temporary tail tag while the wound is being held. (13) Once the bleeding has stopped, weigh the animal and place it in a temporary holding container. (14) Once all animals in the group have been administered the drug, observe all injection sites to ensure that bleeding has stopped and return them to their original cages. (16) Repeat steps 3-15 until all groups are completed. Complete and restore to normal, then return to R5030. Day 3: (1) Set up a laptop computer, balance and temporary animal holding container for recording in the fume hood in R5030. (2) Verify the animals by tail tag (if the number is not visible, restrain the animals, verify by ear punching, and re-tagged with tail tag). (3) Once verified, weigh the animals and place them in the temporary holding container. (4) After weighing all the animals in the group, return them to their original cages. (5) Repeat steps 2-5 until all animals have been weighed. (6) Then place the animals on a trolley and transfer them to R5033. (7) Inject the animals with 100 μL of furimazine by the CRADL technician and incubate for 5 minutes. (8) Euthanize the animals immediately once the timer goes off. (9) Cervical dislocation is performed by the technician, Wanda or the person performing the procedure.(10) After secondary methods and animal identification are confirmed, make a transverse abdominal incision to expose the internal organs. (11) Remove the spleen first and trim the connective tissue. (12) Carefully dissect the liver from the stomach, then separate all dorsal attachments, and remove it from the diaphragm. (13) Once the liver is removed, incise the diaphragm along the midline, incise the sternum along the midline, and break the ribs to expose the thoracic cavity. Remove the heart and thymus to allow free access to the lungs. (14) Remove the lungs by pulling the trachea and carefully cutting any connective tissue. (15) Place all organs in anatomical order (from top to bottom) and animal order (from left to right) on a black anti-luminescence / fluorescent pad. (16) Then image the organs in IVIS under autoluminescence conditions (stage height D) and then process the organs. (17) Repeat steps 7-14 until all groups are completed. (18) Clean the space according to the CRADL guidelines. Results are shown below. Figure 7 , Figure 8 and Figure 9 middle.

[0275] Example 5. NHP Research Experiment 1 Male cynomolgus macaques (Biomere, Richmond CA) aged 4–6 years and weighing 4–7 kg were used at the start of administration. The monkeys were housed in stainless steel cages and provided with a daily monkey diet of 5038, except during fasting periods. Filtered tap water was provided to the animals freely, including during fasting periods. The animal room temperature was maintained between 64–84°F, humidity between 30–70%, and a 12-hour light / dark cycle, except during the prescribed program. Pre-administration treatment with famotidine (0.5 mg / kg), diphenhydramine (5 mg / kg), and dexamethasone (1 mg / kg) was administered prior to LNP administration. Animals received a single intravenous IV infusion of human erythropoietin-encapsulated mRNA lipid nanoparticles (hEPOmRNA LNP, 0.3 mg / kg) using a SAI 3D programmable infusion pump. TM LNP was infused at 5 mL / kg / hour using a Lurlock adapter (Baxter 2C6227) and an extension kit. Body weight and temperature were monitored before and after administration, and blood samples were collected at 2, 6, 24, 48, and 168 hours before administration. All procedures were performed according to the approved IACUC guidelines. Results are shown in […]. Figure 12 and Figure 13 Improved tolerability was observed in novel lipid formulations of mRNA.

[0276] Example 6. Weekly dosing of experimental 2-LNP in NHP study Male cynomolgus macaques (Biomere, Richmond CA) aged 4–6 years and weighing 4–7 kg were used at the start of administration. The monkeys were housed in stainless steel cages and provided with 50 g of monkey food daily, except during fasting periods. Filtered tap water was provided to the animals freely, including during fasting periods. The animal room temperature was maintained between 64–84°F, humidity between 30–70%, and a 12-hour light / dark cycle, except during the prescribed program. Pre-administration treatment with famotidine (0.5 mg / kg), diphenhydramine (5 mg / kg), and dexamethasone (1 mg / kg) was administered prior to LNP administration. Animals received weekly intravenous IV infusions of human erythropoietin-encapsulated mRNA lipid nanoparticles (compound 23, hEPO mRNA-LNP, 0.1 mg / kg). A total of four doses were administered. Body weight and temperature were monitored before and after administration, and blood samples were collected at 2, 6, 24, 48, and 168 hours before administration. All procedures were performed in accordance with the approved IACUC guidelines. Results are shown in... Figure 14 , Figure 15 , Figure 16 and Figure 17 This example demonstrates consistent protein expression on repeated doses of encapsulated mRNA lipid nanoparticles (compound 23, hEPO mRNA-LNP) and clearance of compound 23 from serum. Fluctuations in body weight, temperature, and liver blood chemistry demonstrate reasonable tolerability of compound 23 at four doses. See also Figure 14 Among other things, Figure 15 Consistent erythrocyte production was demonstrated across four repeated doses. Among other things, Figure 16 This demonstrates that human erythropoietin is consistently expressed and secreted into the bloodstream after each dose, which leads to the production of red blood cells. Among other things, Figure 17 Compound 23 was shown to be cleared from the blood and no accumulation was observed during repeated administration.

[0277] Example 7. Comparative study of LNPs containing compound 23 and reference 1 Multiple-dose tolerability screening of compound 23-LNP: Compound 23 and baseline 1 were formulated using standard procedures and administered twice weekly (1.0 mg / kg, IV) to naïve Balb / c mice for four weeks. NT-β-actin mRNA LNP was administered to Balb / c mice via tail vein IV at a concentration of 1.0 mg / kg for a total of eight doses (twice weekly for four weeks). Body weight and blood samples were monitored before administration, 24 hours after the first dose, 24 hours after the fourth dose, and 24 hours after the eighth dose, and cytokines, blood chemistry, and liver / spleen weight were analyzed. Data analysis was performed in Graphpad Prism 10. Unless otherwise specified, values ​​are reported as mean + / - standard deviation. Comparable body weight or survival was found in compound 23, baseline 1, and delivery buffer. N=6 per group. Results are presented in... Figure 18 The results showed that the subjects exhibited comparable tolerance to LNPs containing compound 23, baseline 1, and delivery buffers in a mouse model.

[0278] Compound 23 was delivered intratumorally to baseline 1. Albino B6 mice were inoculated with MC38.K cancer cells. Once the tumor reached 250 mm... 3 Firefly luciferase mRNA-LNP, containing either reference 1 or compound 23 as an ionizable lipid component, was administered intratumorally at a dose of 1.0 mg / kg. Sampling and IVIS imaging were performed 18 hours post-administration. N=5 mice per group. Results are shown in... Figure 19 These results indicate that compound 23 exhibits delivery performance comparable to baseline 1.

[0279] Example 8. Comparative Study - Effect of Fluorination on Transfection Efficiency Transfection efficiencies were compared among three pairs of compounds (compound 54 vs. compound 58, compound 68 vs. compound 67, and compound 37 vs. compound 61). For each pair, the compounds differed only in one fluorine substitution at the end of the alkyl chain. For example, the structures of compounds 54 and 58 are shown below:

[0280] Following a procedure similar to that in Examples 3 and 7, in vitro and in vivo comparisons of firefly luciferase expression data for fluorinated compounds versus non-fluorinated compounds were obtained. Results are shown in... Figure 20 In hepatocytes, statistically significant differences in transfection efficiency were observed between compound 54 and compound 58, and between compound 68 and compound 67.

[0281] Example 9. Synthesis of 8-[(2-hydroxyethyl)({6-[(9-methyldecyl)oxy]-6-oxohexyl})amino]octanoic acid heptadecan-9-yl ester This embodiment illustrates the following synthesis: 8-Bromooctanoic acid heptadecano-9-yl ester; Chemical formula: C 25 H 49 BrO2; Molecular weight: 461.57.

[0282] To a stirred solution of 8-bromooctanoic acid (25 g, 112 mmol, 1.0 equivalent) in dichloromethane (1 L), 4-(dimethylamino)pyridin-1-onium (13.8 g, 112 mmol, 1.0 equivalent) and {3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (64.4 g, 336 mmol, 3.0 equivalent) were added. The reaction mixture was stirred for 15 min, and heptadecanol (25.9 g, 101 mmol, 0.9 equivalent) was added. The reaction mixture was stirred at room temperature (rt) for 48 h. The reaction progress was monitored by TLC (SM was consumed). Water (250 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 × 250 mL). The obtained organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2: hexane with 0-2% ethyl acetate) to obtain a pale yellow liquid, heptadecano-9-yl 8-bromooctanoate (31.65 g, yield = 61.19%). 1H-NMR (400 MHz, CDCl3-d3): δ 4.88-4.84 (m, 1H), 3.54-3.38 (m, 2H), 2.28 (t, J =7.6 Hz, 2H), 1.88-1.76 (m, 2H), 1.64-1.58 (m, 2H), 1.50-1.49 (m, 4H), 1.44-1.41 (m, 2H), 1.36-1.29 (m, 4H), 1.25 (br, 24H), 0.87 (t, J = 7.2 Hz, 6H).

[0283] Example 10. Synthesis of heptadecano-9-yl ester of 8-[(2-hydroxyethyl)amino]octanoate This embodiment illustrates the following synthesis: To a stirred solution of 8-bromooctanoic acid (25 g, 112 mmol, 1.0 equivalent) in dichloromethane (1 L), 4-(dimethylamino)pyridin-1-onium (13.8 g, 112 mmol, 1.0 equivalent) and {3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (64.4 g, 336 mmol, 3.0 equivalent) were added. The reaction mixture was stirred for 15 min, and heptadecanol (25.9 g, 101 mmol, 0.9 equivalent) was added. The reaction mixture was stirred at room temperature (rt) for 48 h. The reaction progress was monitored by TLC (SM consumed). Water (250 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 × 250 mL). The obtained organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2: hexane with 0-2% ethyl acetate) to obtain a pale yellow liquid, heptadecano-9-yl 8-bromooctanoate (31.65 g, yield = 61.19%). 1 H-NMR (400 MHz, CDCl3-d3): δ 4.88-4.84 (m, 1H), 3.54-3.38 (m, 2H), 2.28 (t, J = 7.6 Hz, 2H), 1.88-1.76 (m, 2H),1.64-1.58 (m, 2H), 1.50-1.49 (m, 4H), 1.44-1.41 (m, 2H), 1.36-1.29 (m, 4H),1.25 (br, 24H), 0.87 (t, J = 7.2 Hz, 6H).

[0284] Example 11. Synthesis of heptadecano-9-yl ester of 8-[(2-hydroxyethyl)amino]octanoate This embodiment illustrates the following synthesis: To a stirred solution of 2-aminoethanol (794 mg, 13 mmol, 1.0 equivalent) in acetonitrile (50 mL), heptadecanoyl 8-bromooctanoate (6.0 g, 13 mmol, 1.0 equivalent) and ethylbis(prop-2-yl)amine (2.72 mL, 15.6 mmol, 1.2 equivalent) were added. The reaction was stirred at 55 °C for 4 days. The reaction progress was monitored by ELSD / TLC (87% product in the reaction mixture via ELSD). The reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (SiO2: dichloromethane in 0–12% methanol) to give heptadecanoyl 8-[(2-hydroxyethyl)amino]octanoate (2.1 g, yield = 36%) as a brown gel-like liquid. ELSD analysis Purity 97.47%, C 27 H 56 Calculated NO3 value [M+H] = 442.43, measured value = 442.35 (m / z, M+H) + ).

[0285] Example 12. Synthesis of 8-(benzyloxy)-1-octanol This embodiment illustrates the following synthesis: At 0 °C, sodium hydride (60% dispersion in mineral oil) (2.36 g, 103 mmol, 1.5 equivalent) was added to a stirred solution of 1,8-octanediol (10 g, 68.4 mmol, 1.0 equivalent) in dimethylformamide (100 mL) and stirred for 30 min at the same temperature. Then (bromomethyl)benzene (11.7 g, 68.4 mmol, 1.0 equivalent) was added to the RM, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with ice-cold water (250 mL) and extracted with ethyl acetate (50 × 3 mL). The resulting organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2: hexane, 0-15% ethyl acetate) to give 8-(benzyloxy)-1-octanol (7.4 g, yield = 45.78%) as a white solid. 1 H NMR (400 MHz, CDCl3-d3): δ 7.36-7.27 (m, 5H), 4.50 (s, 2H), 3.63(t, J = 6.8 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H), 1.64-1.52 (m, 3H), 1.41-1.32 (m, 9H).

[0286] Example 13. Synthesis of 8-(benzyloxy)octanal This embodiment illustrates the following synthesis: At 0 °C, pyridinium chlorochromate salt (10.1 g, 47 mmol, 1.5 equivalent) was added to a stirred solution of 8-(benzyloxy)-1-octanol (7.4 g, 31.3 mmol, 1.0 equivalent) in dichloromethane (250 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with pentane (500 mL) and stirred for 30 minutes by TLC monitoring. After 30 minutes, the mixture was filtered through a diatomaceous earth bed and washed with pentane (3 × 250 mL). The organic layer was concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2: hexane in 0-25% ethyl acetate) to give 8-(benzyloxy)octanal (7 g, yield = 95.1%) as a colorless liquid. 1 H NMR (400 MHz, CDCL3-d3): δ 9.75 (m, 1H), 7.36-7.27 (m, 5H), 4.49 (s, 2H), 3.46(t, J = 6.4 Hz, 2H), 2.43-2.39 (m, 2H), 1.66-1.57 (m, 4H), 1.41-1.25 (m, 6H).

[0287] Example 14. Synthesis of decylbenzyl ether This embodiment illustrates the following synthesis: At -78 °C, n-butyllithium (2.05 g, 32 mmol, 1.5 equivalents) was added dropwise to a stirred solution of triphenyl(prop-2-yl)phosphonium bromide (9.04 g, 23.5 mmol, 1.1 equivalents) in tetrahydrofuran (100 mL), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then cooled again to -78 °C, and 8-(benzyloxy)octaldehyde (5 g, 21.3 mmol, 1.0 equivalents) (dissolved in 20 mL THF) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (3 × 250 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a crude mixture. The crude product was purified by combi-flash chromatography (SiO2: hexane, 0-15% ethyl acetate) to obtain {[(9-methyldec-8-en-1-yl)oxy]methyl}benzene (3.5 g, yield = 62.99%) as a colorless liquid. 1 H NMR (400 MHz, CDCl3-d3): δ7.34-7.27 (m, 5H), 5.12-5.09 (m, 1H), 4.50 (s, 2H), 3.46 (t, J = 6.0 Hz, 2H), 1.96-1.94 (m, 2H), 1.68-1.59 (s, 6H), 1.37-1.32 (m, 9H).

[0288] Example 15. Synthesis of 9-methyl-1-decyl alcohol This example illustrates the following synthesis: A stirred solution of 10-(benzyloxy)-2-methyl-2-decene (3.5 g, 13.4 mmol, 1.0 equivalent) in tetrahydrofuran (50 mL) and methanol (50 mL) was degassed with nitrogen for 15 min, then 10% Pd / C (50% wet) (3.5 g, w / w) was added and the mixture was stirred at room temperature for 48 h under a hydrogen atmosphere. TLC showed the consumption of starting material and the formation of new spots. The reaction mixture was filtered through a diatomaceous earth bed and washed with a mixture of MeOH:THF (3 × 200 mL). The filtrate was collected and concentrated to give a crude product. The crude product was purified by combi-flash chromatography (SiO2: hexane in 0-20% ethyl acetate) to give 9-methyl-1-decyl alcohol (2 g, yield = 86.36%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 4.30 (t, J = 4.8 Hz, 1H), 3.38-3.31 (m,2H), 1.52-1.46 (m, 1H), 1.40-1.37 (m, 2H), 1.24 (bs, 10H), 1.13-1.12 (m, 2H),0.84 (d, J = 6.4 Hz, 6H).

[0289] Example 16. Synthesis of 9-methyldecyl 6-bromohexanoate This embodiment illustrates the following synthesis: To a stirred solution of 6-bromohexanoic acid (2.49 g, 12.8 mmol, 1.1 equivalents) in dichloromethane (166 mL), 4.45 g (23.2 mmol, 2 equivalents) and 4-(dimethylamino)pyridin-1-onium chloride (1.43 g, 11.6 mmol, 1.0 equivalents) were added. The reaction mixture was stirred for 15 min, and then 2 g (11.6 mmol, 1.0 equivalents) of 9-methyldecyl-1-ol was added. The reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by TLC (SM was consumed). Water (250 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 × 250 mL). The resulting organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography (SiO2: hexane in 0-2% ethyl acetate) to obtain 9-methyldecyl 6-bromohexanoate (2.0 g, yield = 49.32%) as a colorless liquid. 1 H NMR (400 MHz, CDCl3-d3): δ 4.05 (t, J =6.4 Hz, 2H), 3.55-3.39 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 1.87-1.77 (m, 2H), 1.67 (m, 4H), 1.52-1.45 (m, 3H), 1.30-1.25 (m, 10H), 1.15-1.13 (m, 2H), 0.86(d, J = 6.4 Hz, 6H).

[0290] Example 17. Synthesis of 8-[(2-hydroxyethyl)({6-[(9-methyldecyl)oxy]-6-oxohexyl})amino]octanoic acid heptadecan-9-yl ester This embodiment illustrates the following synthesis: N-ethylbis(isopropyl)amine (702 mg, 5.43 mmol, 3.0 equivalent) and heptadecanoyl 8-[(2-hydroxyethyl)amino]octanoate (0.8 g, 1.81 mmol, 1.0 equivalent) were added to a stirred solution of 9-methyldecyl 6-bromohexanoate (633 mg, 1.81 mmol, 1.0 equivalent) in acetonitrile (10 mL). The reaction was stirred at 95 °C for 16 h. The reaction progress was monitored by ELSD / TLC (81% product in the reaction mixture via ELSD). The reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (SiO2: 0-8% methanol in dichloromethane) to give a colorless liquid, 8-[(2-hydroxyethyl)({6-[(9-methyldecyl)oxy]-6-oxohexyl})amino]octanoic acid heptadecan-9-yl ester (335 mg, yield = 26.05%). The compound was dissolved in dichloromethane (10 mL), and 5 equivalents of anhydrous K2CO3 were added under a N2 atmosphere. The reaction mixture was vigorously stirred for 2-3 hours, and then filtered through a hydrophobic PTFE syringe filter (25 mm * 0.45 μm) using a glass syringe to obtain the desired compound. 1H-NMR (400 MHz, CDCl3-d3): δ 4.87-4.82 (m, 1H), 4.05 (t,J = 6.8 Hz, 2H), 3.52 (t, J = 5.2 Hz, 2H), 2.56 (t, J = 5.2 Hz, 2H), 2.46-2.41 (m, 4H), 2.31-2.25 (m, 4H), 1.67-1.57 (m, 7H), 1.55-1.38 (m, 9H), 1.38-1.25 (m, 42H), 1.51-1.11 (m, 2H), 0.89-0.85 (m, 12H). ELSD analysis: purity 98.98%, calculated value of C44H88NO5 [M+H] = 710.67, measured value = 710.50 (m / z, M+H+).

[0291] Example 18. Synthesis of heptadecano-9-yl ester of 8-((2-hydroxyethyl)(8-((9-methyldecyl)oxy)-8-oxooctyl)amino)octanoate This embodiment illustrates the following synthesis: To a stirred solution of 8-bromooctanoic acid (8.29 g, 37.1 mmol, 2.0 equivalents) in dichloromethane (166 mL), 14.2 g (74.3 mmol, 4 equivalents) and 4-(dimethylamino)pyridin-1-onium chloride (4.58 g, 37.1 mmol, 2 equivalents) were added. The reaction mixture was stirred for 15 min, and then 3.2 g (18.6 mmol, 1.0 equivalents) of 9-methyl-1-decyl alcohol was added. The reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by TLC (SM was consumed). Water (250 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 × 250 mL). The resulting organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography (SiO2:hexane, 0-2% ethyl acetate) to give 9-methyldecyl 8-bromooctanoate (3.8 g, yield = 54.22%) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃-d₃): δ 4.05 (t, J = 6.4 Hz, 2H), 3.55–3.39 (m, 2H), 2.29 (t, J = 7.6 Hz, 2H), 1.89–1.82 (m, 2H), 1.64–1.54 (m, 4H), 1.49–1.42 (m, 3H), 1.36–1.28 (m, 14H), 1.25–1.15 (m, 2H), 0.86 (d, J = 6.8 Hz, 6H).

[0292] Example 19. Synthesis of heptadecano-9-yl ester of 8-((2-hydroxyethyl)(8-((9-methyldecyl)oxy)-8-oxooctyl)amino)octanoate This embodiment illustrates the following synthesis: N-ethylbis(isopropyl)amine (0.96 g, 7.47 mmol, 3 equivalents) and 9-methyldecyl 8-bromooctanoate (1.03 g, 2.74 mmol, 1.1 equivalents) were added to a stirred solution of 8-[(2-hydroxyethyl)amino]octanoate heptadecanoate (1.1 g, 2.49 mmol, 1.0 equivalents) in acetonitrile (5 mL). The reaction was stirred at 90 °C for 16 h. The reaction progress was monitored by ELSD / TLC (91% product in the reaction mixture via ELSD). The reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (SiO2: dichloromethane in 0-8% methanol) to give 0.7 g, yield = 38.19%, of 8-[(2-hydroxyethyl)({8-[(9-methyldecyl)oxy]-8-oxooctyl})amino]octanoate heptadecanoate (0.7 g, yield = 38.19%) as a pale yellow liquid. 1 H-NMR (400 MHz, CDCl3-d3): δ 4.88-4.82 (m, 1H), 4.05 (t, J = 6.8 Hz, 2H), 3.69 (bs, 2H), 2.77-2.65 (br, 4H), 2.30-2.27 (m, 4H), 1.64-1.56 (m, 8H), 1.54-1.47 (m, 6H), 1.32-1.25 (m, 49H), 1.15-1.13 (m, 2H), 0.89-0.85 (m, 12H). ELSD analysis Purity 99.86%, C 46 H 92 Calculated NO5 value [M+H] = 738.70, measured value = 738.55 (m / z, M+H) + ).

[0293] Example 20. Synthesis of 1-octylnonyl octanoate of 8-({2-[4-(dimethylamino)butyryloxy]ethyl}[7-(9-methyldecyloxycarbonyl)heptyl]amino)octanoate This embodiment illustrates the following synthesis: To a stirred solution of 4-(dimethylamino)butyric acid (355 mg, 4 equivalents, 2.71 mmol) in dichloromethane (10 mL), 3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (519 mg, 2.71 mmol, 4 equivalents) and 4-(dimethylamino)pyridin-1-onium (82.7 mg, 677 μmol, 1 equivalent) were added and stirred for 15 min. Then, 1-octylnonyl octanoate of 8-{(2-hydroxyethyl)[7-(9-methyldecyloxycarbonyl)heptyl]amino}octanoate (0.5 g, 677 μmol, 1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by ELSD / TLC (58.22% product form in the reaction mixture containing 39% DMAP by ELSD). The reaction mixture was quenched with brine and extracted with DCM (2 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a crude mixture. The crude product was diluted with pentane and washed with acetonitrile (3 × 100 mL). The pentane layer was evaporated and distilled (at a temperature below 30 °C) to give 1-octylnonyl octanoate of 8-({2-[4-(dimethylamino)butyryloxy]ethyl}[7-(9-methyldecyloxycarbonyl)heptyl]amino)octanoate (340 mg, yield = 58.96%) as a colorless liquid. 1 H-NMR (400 MHz, CDCl3)- δ 4.87-4.84 (m, 1H), 4.10 (t, J = 6.4 Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 2.67-2.64 (m, 2H), 2.42 (t, J = 7.6 Hz, 4H), 2.35-2.31 (m, 2H), 2.30-2.25 (m, 6H), 2.20 (s, 6H), 1.81-1.74 (m, 2H), 1.62-1.56 (m, 5H), 1.52-1.46 (m, 4H), 1.44-1.37 (m, 4H), 1.30-1.25 (m, 48H), 1.15-1.11 (m, 2H), 0.89-0.85 (m, 12H). ELSD analysis Purity 99.49%, C 52 H 103 Calculated N₂O₆ [M+H] = 851.78, measured value = 851.60 (m / z, M+H) + ).

[0294] Example 21. Synthesis of 2-Octylated Decanoic Acid This embodiment illustrates the following synthesis: Sodium hydride (5.11 g, 128 mmol, 1.1 equivalents) was added to a stirred solution of decanoic acid (20 g, 116 mmol, 1.1 equivalents) in tetrahydrofuran (267 mL) at 0 °C and stirred for 30 min. Bis(isopropyl)aminolithium (14.9 g, 139 mmol, 1.2 equivalents) was added to the reaction mixture at -50 °C, and the reaction mixture was stirred at room temperature for 30 min. Then, 1-iodooctane (33.5 g, 139 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at 45 °C for 16 h. The reaction progress was monitored by TLC (SM was consumed). The reaction mixture was poured into a 1 mol / L HCl aqueous solution mixture (250 mL) and extracted with ethyl acetate (3 × 250 mL). The resulting organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography (SiO2:hexane, 0-2% ethyl acetate) to give 2-octyldecanoic acid (10 g, yield = 30.28%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6): δ 12.02 (bs, 1H), 2.20–2.13 (m, 1H), 1.48–1.43 (m, 2H), 1.37–1.34 (m, 2H), 1.32–1.22 (m, 24H), 0.86–0.85 (m, 6H).

[0295] Example 22. Synthesis of 7-bromoheptyl 2-octyldecanoate This embodiment illustrates the following synthesis: To a stirred solution of 2-octyldecanoic acid (4 g, 14.1 mmol, 1.0 equivalent) in dichloromethane (48 mL, 750 mmol), 10.8 g (56.2 mmol, 4 equivalent) and 4-(dimethylamino)pyridin-1-onium chloride (3.46 g, 28.1 mmol, 2 equivalent) were added. The reaction mixture was stirred for 15 min, and then 7-bromo-1-heptanol (2.74 g, 14.1 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by TLC (SM was consumed). Water (250 mL) was added to the reaction mixture, and the mixture was extracted with DCM (3 × 250 mL). The obtained organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (SiO2: hexane with 0-2% ethyl acetate) to obtain 7-bromoheptyl 2-octyldecanoate (3 g, yield = 46.23%) as a colorless liquid. 1H-NMR (400 MHz, CDCL3-d3): δ 4.08-4.04 (m, 2H), 3.53-3.38 (m, 2H), 2.39-2.28 (m, 2H), 1.87-1.75 (m, 2H), 1.64-1.55 (m, 3H), 1.45-1.39 (m, 3H), 1.36-1.34 (m, 3H), 1.25 (bs, 25H), 0.89-0.85 (m, 6H).

[0296] Example 23. Synthesis of 7-(2-hydroxyethylamino)heptyl 2-octyldecanoate This embodiment illustrates the following synthesis: To a stirred solution of 2-aminoethanol (393 μL, 6.5 mmol, 1.0 equivalent) in acetonitrile (5 mL), 7-bromoheptyl 2-octyldecanoate (3 g, 6.5 mmol, 1.0 equivalent) and N-ethylbis(isopropyl)amine (3.38 mL, 19.5 mmol, 3 equivalent) were added. The reaction was stirred at 55 °C for 72 h. The reaction progress was monitored by TLC / ELSD (22% product in the reaction mixture via ELSD). The reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (SiO2: dichloromethane, 0–12% methanol) to give 7-(2-hydroxyethylamino)heptyl 2-octyldecanoate (0.6 g, yield = 20.19%) as a brown liquid. 1 H-NMR (400MHz, CDCl3-d3): δ 4.02 (t, J = 6.8 Hz, 2H), 3.82 (t, J = 4.8 Hz, 2H), 2.97-2.94 (m, 2H), 2.80 (t, J = 3.6 Hz, 2H), 2.28-2.25 (m, 1H), 1.67 (bs, 2H), 1.58-1.51 (m, 4H), 1.41-1.25 (32H), 0.85-0.85 (m, 6H). ELSD analysis Purity 99.88%, C 27 H 56 Calculated NO3 value [M+H] = 442.43, measured value = 442.40 (m / z, M+H) + ).

[0297] Example 24. Synthesis of 7-((2-hydroxyethyl)(8-(((9-methyldecyl)oxy)-8-oxooctyl)amino)heptyl ester of 2-octyldecanoic acid This embodiment illustrates the following synthesis: N-ethylbis(isopropyl)amine (593 μL, 3.4 mmol, 2.5 equivalents) and 9-methyldecyl 8-bromooctanoate (513 mg, 1.36 mmol, 1.0 equivalents) were added to a stirred solution of 7-(2-hydroxyethylamino)heptyl 2-octyldecanoate (0.6 g, 1.36 mmol, 1.0 equivalents) in acetonitrile (6 mL). The reaction was stirred at 95 °C for 16 h. The reaction progress was monitored by ELSD / TLC (31% product in the reaction mixture via ELSD). The reaction mixture was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (SiO2: dichloromethane in 0–8% methanol) to give 7-{(2-hydroxyethyl)[7-(9-methyldecyloxycarbonyl)heptyl]amino}heptyl 2-octyldecanoate (140 mg, yield = 13.6%) as a colorless liquid. 1 H-NMR (400 MHz, CDCl3-d3): δ 4.17-4.03 (m, 4H), 3.66 (br, 2H), 2.73-2.69 (br, 2H), 2.45-2.43 (br, 6H), 2.33-2.26 (m, 3H), 1.68-1.51 (m, 12H), 1.41-1.39 (m, 3H), 1.32-1.24 (m, 49H), 1.17-1.12 (m, 2H), 0.89-0.85 (m, 12H). ELSD analysis Purity 98.21%, C 46 H 92 Calculated value of NO5 [M+H] = 738.70, measured value = 738.70 (m / z, M+H) + ).

[0298] Example 25. Synthesis of (2-bromoethoxy)(tert-butyl)bis(methyl)silane This embodiment illustrates the following synthesis: To a stirred solution of 2-bromoethanol (10 g, 80 mmol, 1.0 equivalent) in dichloromethane (50 mL), imidazole (21.8 g, 320 mmol, 4 equivalent) and (tert-butyl)(chloro)bis(methyl)silane (24.1 g, 160 mmol, 2 equivalent) were added, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with a brine solution (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (silica gel, 0–2% ethyl acetate gradient in hexane) to obtain (2-bromoethoxy)(tert-butyl)bis(methyl)silane (15 g, yield = 78.35%) as a colorless liquid. 1 H NMR (400MHz, CDCl3-d3): δ 3.89 (t, J = 6.4 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 0.89 (s, 9H), 0.08 (s, 6H).

[0299] Example 26. Synthesis of methyl 4-(methylamino)butyrate This embodiment illustrates the following synthesis: At 0 °C, thionyl chloride (6.09 g, 1.2 equivalents, 51.2 mmol) was added to a stirred solution of 4-(methylamino)butyric acid (5 g, 42.7 mmol) in methanol (50 mL, 1.23 mol). After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and ELSD. The reaction mixture was concentrated under reduced pressure to give methyl 4-(methylamino)butyrate (3.5 g, yield = 62.51%) as a colorless liquid. 1 H NMR (400 MHz, MeOD): δ 3.68 (s, 3H), 3.05 (t, J = 6.8 Hz, 2H),2.70 (s, 3H), 2.49 (t, J = 6.4 Hz, 2H), 1.97 (t, J = 6.4 Hz, 2H).

[0300] Example 27. Synthesis of methyl 4-({2-[(tert-butyl)bis(methyl)siloxy]ethyl}-N-methylamino)butyrate This embodiment illustrates the following synthesis: Potassium carbonate (6.32 g, 45.7 mmol, 3 equivalents) was added to a solution of methyl 4-(methylamino)butyrate (2 g, 15.2 mmol, 1 equivalent) in CH3CN (20 mL), and the reaction mixture was stirred at 50 °C for 30 min. Then, (2-bromoethoxy)(tert-butyl)bis(methyl)silane (4.74 g, 19.8 mmol, 1.3 equivalents) was added, and the reaction mixture was stirred at 85 °C for 5 h. The reaction progress was monitored by TLC, and the reaction mixture was concentrated under reduced pressure. The crude product was purified by rapid column chromatography (silica gel, 0-13% ethyl acetate gradient in hexane) to obtain methyl 4-({2-[(tert-butyl)bis(methyl)silyloxy]ethyl}-N-methylamino)butyrate (1.1 g, yield = 24.9%) as a colorless oil. ELSD analysis Purity 99.23%, C 14 H 32 Calculated NO3Si [M+H] = 290.22, measured value = 290.20 (m / z, M+H) + ).

[0301] Example 28. Synthesis of 4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)butyric acid This embodiment illustrates the following synthesis: At room temperature, lithium hydroxide monohydrate (580 mg, 13.8 mmol, 4 equivalents) was added to a solution of methyl 4-({2-[(tert-butyldimethylsilyl)oxy)ethyl}-N-methylamino)butyrate (1 g, 3.45 mmol) in a mixture of THF and water (10 mL, 1:1 v / v). The reaction mixture was then stirred at room temperature for 90 min. After the reaction was complete (monitored by TLC), the reaction mixture was neutralized with 1 M citric acid. The resulting mixture was then extracted with DCM (3 × 15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)butyric acid (610 mg, yield = 84%) as a viscous solid. 1 H NMR (400 MHz, CDCl3-d3): δ 4.99 (t, J = 5.2 Hz, 2H), 3.24-3.18 (m, 4H), 3.03 (s, 3H), 2.44-2.41 (m, 2H), 1.94-1.88 (m, 2H), 0.93 (s, 9H), 0.14 (s, 6H). ELSD analysis Purity 95.51%, C13 H 30 Calculated NO3Si [M+H] = 276.19, measured value = 276.05 (m / z, M+H) + ). Example 29. Synthesis of 1-octylnonyl octanoate of 8-({2-[4-({2-[(tert-butyl)bis(methyl)siloxy]ethyl}-N-methylamino)butyryloxy]ethyl}[7-(9-methyldecoxycarbonyl)heptyl]amino)octanoate) This embodiment illustrates the following synthesis: To a stirred solution of 4-({2-[(tert-butyl)bis(methyl)siloxy]ethyl}-N-methylamino)butyric acid (0.4 g, 4 equivalents, 1.45 mmol) in dichloromethane (10 mL), N,N-dimethyl-4-pyridylamine (177 mg, 4 equivalents, 1.45 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (278 mg, 4 equivalents, 1.45 mmol) were added and stirred for 15 min. Then, 1-octylnonyl octanoate of 8-{(2-hydroxyethyl)[7-(9-methyldecyloxycarbonyl)heptyl]amino}octanoate (268 mg, 363 μmol) was added. The reaction mixture was stirred at room temperature for 16 h. TLC showed the formation of new spots and the consumption of starting material. The reaction mixture was quenched with a saline solution (20 mL) and extracted with DCM (2 × 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum pressure. The crude product was purified by rapid column chromatography (silica gel, 0-2% ethyl acetate in hexane) to obtain 1-octylnonyl octanoate of 8-({2-[4-({2-[(tert-butyl)bis(methyl)silyloxy]ethyl}-N-methylamino)butyryloxy]ethyl}[7-(9-methyldecyloxycarbonyl)heptyl]amino)octanoate (230 mg, yield = 63.63%) as a colorless liquid. 1 H NMR (400 MHz, CDCl3-d3): δ 4.85 (quin, J = 6.0 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 3.72-3.65 (m, 3H), 2.66 (t, J = 6.4Hz, 2H), 2.50 (t, J= 6.4 Hz, 2H), 2.45-2.37 (m, 7H), 2.35-2.25 (m, 10H), 1.82-1.75 (m, 2H), 1.65-1.56 (m, 4H), 1.55-1.45 (m, 5H), 1.44-1.38 (m, 5H), 1.32-1.19 (m, 44H), 1.20-1.12 (m, 2H), 0.91-0.81 (m, 21H), 0.67 (s, 6H).

[0302] Example 30. Synthesis of 8-((2-((4-(((2-hydroxyethyl)(methyl)amino)butyryl)oxy)ethyl)(8-(((9-methyldecyl)oxy)-8-oxooctyl)amino)octanoic acid heptadecanyl-9-yl ester This embodiment illustrates the following synthesis: At 0 °C, 1 / 1 (99.5 mg, 5 equivalents, 1 mmol) of 1-octylnonyl octanoate (0.2 g, 201 μmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and ELSD. The reaction mixture was quenched with saturated sodium bicarbonate to adjust the pH to 8 and extracted with ethyl acetate (3 × 25 mL). The organic layers were combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude substance obtained was purified by rapid column chromatography (silica gel, 0-5% MeOH gradient in DCM) to give 1-octylnonyl octanoate (150 mg, yield = 70.3%) of 8-[(2-{4-[(2-hydroxyethyl)-N-methylamino]butyryloxy}ethyl)[7-(9-methyldecyloxycarbonyl)heptyl]amino]octanoate as a pale yellow liquid. The compound was dissolved in dichloromethane (5 mL) under a nitrogen atmosphere and filtered through a hydrophobic PTFE syringe filter (25 mm × 0.45 μm) using a glass syringe to obtain the desired compound. 1 H NMR (400 MHz, CDCl3-d3): δ 4.85 (quin, J = 6.4 Hz, 1H), 4.10 (t, J = 6.4 Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 3.57 (t, J= 5.2 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H), 2.51 (t, J = 5.2 Hz, 2H), 2.46-2.37 (m, 6H), 2.33 (t, J = 7.2Hz, 2H), 2.31-2.25 (m, 4H), 2.23 (s, 3H), 1.80 (quin, J = 7.2 Hz, 1H), 1.67-1.56 (m, 6H), 1.55-1.45 (m, 4H), 1.45-1.37 (m, 4H), 1.36-1.21 (m, 48H), 1.18-1.08 (m, 2H), 0.91-0.82 (m, 12H). ELSD analysis Purity 98.31%, C 53 H 105 Calculated N₂O₇ [M+H] = 881.79, measured value = 881.50 (m / z, M+H) + ).

[0303] Example 31. Synthesis of 7-{(2-hydroxyethyl)[5-(9-methyldecyloxycarbonyl)pentyl]amino}heptyl ester of 2-octyldecanoic acid This embodiment illustrates the following synthesis: N-ethylbis(isopropyl)amine (988 μL, 2.5 equivalence, 5.66 mmol) and 7-(2-hydroxyethylamino)heptyl 2-octyldecanoate (1 g, 2.26 mmol, 1.0 equivalence) were added to a stirred solution of 9-methyldecyl 6-bromohexanoate (791 mg, 2.26 mmol, 1.0 equivalence) in acetonitrile (10.9 mL), and the reaction mixture was stirred at 90 °C for 24 h. TLC showed that the starting material was consumed and new spots were formed. The reaction mixture was concentrated to give a crude product. The crude product was purified by rapid column chromatography (silica gel, 0-12% methanol gradient in DCM) to give 7-{(2-hydroxyethyl)[5-(9-methyldecoxycarbonyl)pentyl]amino}heptyl 2-octyldecanoate (150 mg, yield = 9.33%) as a colorless liquid. 1 H NMR (400 MHz, CDCl3-d3): δ 4.07 (t, J= 6.8 Hz,4H), 3.92 (bs, 1H), 3.10-2.91 (bd, 4H), 2.34-2.25 (m, 3H), 1.85-1.72 (bs,4H), 1.71-1.35 (m, 20H), 1.32-1.21 (m, 38H), 0.91-0.84 (m, 12H). ELSD analysis Purity 96.99%, C 44 H 88 Calculated NO5 value [M+H] = 710.67, measured value = 710.50 (m / z, M+H) + ).

[0304] Example 32. Synthesis of 2-octyldecanoic acid 7-((2-((4-(dimethylamino)butyryl)oxy)ethyl)(6-(((9-methyldecyl)oxy)-6-oxohexyl)amino)heptyl ester This embodiment illustrates the following synthesis: To a stirred solution of 4-(dimethylamino)butyric acid (111 mg, 4 equivalents, 845 μmol) in dichloromethane (721 μL), {3-[cyano(ethyl)amino]propyl}dimethylammonium chloride (162 mg, 4 equivalents, 845 μmol) and 4-(dimethylamino)pyridin-1-onium chloride (104 mg, 4 equivalents, 845 μmol) were added and stirred for 15 min. Then, 7-{(2-hydroxyethyl)[5-(9-methyldecyloxycarbonyl)pentyl]amino}heptyl ester of 2-octyldecanoic acid (150 mg, 211 μmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with a brine solution (10 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was diluted with pentane and washed with acetonitrile (3 × 50 mL). The pentane layer was evaporated and distilled (at a temperature below 30°C) to give 2-octyldecanoic acid 7-({2-[4-(dimethylamino)butyryloxy]ethyl}[5-(9-methyldecoxycarbonyl)pentyl]amino)heptyl ester (80 mg, yield = 46%) as a colorless liquid. 1 H NMR (400MHz, CDCl3-d3): δ 4.12 (t, J = 6.4 Hz, 2H), 4.07-4.03 (m, 4H), 2.66 (t, J =6.4 Hz, 2H), 2.48-2.41 (m, 4H), 2.35 (t, J= 7.2 Hz, 6H), 2.33-2.25 (m, 6H),1.87-1.81 (m, 2H), 1.68-1.55 (m, 8H), 1.51-1.38 (m, 7H), 1.35-1.21 (m, 43H),1.21-1.12 (m, 2H), 0.91-0.85 (m, 12H). ELSD analysis Purity 99.10%, C 50 H 99 Calculated N₂O₆ [M+H] = 823.75, measured value = 823.55 (m / z, M+H) + ).

[0305] Example 33. Synthesis of 8-((6-((9-methyldecyl)oxy)-6-oxohexyl)(2,2,3,3,7-pentamethyl-11-oxo-4,12-dioxa-7-aza-3-silazotetradecane-14-yl)amino)octadecaocate heptadeca-9-yl ester This embodiment illustrates the following synthesis: N,N-dimethyl-4-pyridylamine (155 mg, 1.27 mmol, 3 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (486 mg, 2.53 mmol, 6 equivalents) were added to a stirred solu...

Claims

1. A compound of formula I': Or its N-oxide or its pharmaceutically acceptable salt. in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl groups and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X2 is a covalent bond, -C(=O)-O-, -OC(=O-), -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is a halogen, -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 )2、-OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0 or 1.

2. The compound according to claim 1, wherein r is 0.

3. The compound according to claim 1 or 2, wherein X1 is -C(=O)-O-, -OC(=O-, -OC(=O)-O-, or -C(=O)-N(R) 10 )-、-N(R 10 -C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-, and X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R) 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O.

4. A compound of formula I: Or its N-oxide or its pharmaceutically acceptable salt. in: L1 is a substituted or unsubstituted linear C3- chain. 12 alkylene or -C 3-12 alkenylalkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 alkylene or -C 3-12 alkenylalkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-10 Alkyl, straight-chain or branched C 1-10 Heteroalkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl groups and substituted or unsubstituted 3- to 10-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 10-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2 or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 )2、-OC(=O)-R 10 C 1-10 Alkyl, C 1-10 Heteroalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Each R 11 Independently, it is hydrogen, deuterium, halogen, -CN, C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, 4, or 5; and q can be 0, 1, 2, 3, 4 or 5.

5. The compound according to any one of claims 1-4, wherein each R5, R6, R7, R8 or R9 is independently hydrogen, deuterium, halogen, -CN, -OR. 10 Or C 1-10 alkyl.

6. The compound according to any one of claims 1-4, wherein each R5, R6, R7, R8 or R9 is independently hydrogen, deuterium, halogen, methyl, ethyl or isopropyl.

7. The compound according to any one of claims 1-6, having the structure of formula II: Or its N-oxide or a pharmaceutically acceptable salt thereof, wherein: L1 is a substituted or unsubstituted linear C3- chain. 12 Alkylene; L2 is a linear-C chain, either substituted or unsubstituted. 4-12 Alkylene; L3 is a linear-C chain, either substituted or unsubstituted. 4-12 Alkylene; If L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-6 Alkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl groups and substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 6-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; L4 is either substituted or unsubstituted -C1- 24 Alkylene-; wherein L4 is optionally surrounded by 1 to 10 R 11 replace; X1 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S- or -C(C=S)-O-; X2 is -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each of R1, R2, and R3 is independently hydrogen, deuterium, halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; The condition is that at least one of R1, R2, and R3 is not hydrogen or deuterium; Alternatively, when each of R1, R2, and R3 is hydrogen or deuterium, at least one of L1, L2, and L3 is substituted by 1 to 5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon. 1-10 Alkyl or deuterium; R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2、-CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; Each R 11 Independently selected from hydrogen, deuterium, halogens, -CN, -C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 alkyl); n is an integer between 0 and 20; p is 0, 1, 2, 3, or 4; and q can be 0, 1, 2, 3 or 4.

8. The compound according to any one of claims 1-78, or its N-oxide, or its pharmaceutically acceptable salt, wherein X1 is -C(=O)-O-, -OC(=O-, -OC(=O)-O-, -C(=O)-N(R) 10 - or -N(R) 10 )-C(=O)-.

9. The compound according to any one of claims 1-8, or its N-oxide, or its pharmaceutically acceptable salt, wherein X2 is -C(=O)-O-, -OC(=O-, -OC(=O)-O-, -C(=O)-N(R) 10 - or -N(R) 10 )-C(=O)-.

10. The compound according to any one of claims 1-9, or its N-oxide, or its pharmaceutically acceptable salt, wherein p is 1, 2, 3, or 4; and q is 1, 2, 3, or 4.

11. The compound according to any one of claims 1-10, or its N-oxide, or its pharmaceutically acceptable salt, wherein p is 1, 2, or 3; and q is 1, 2, or 3.

12. The compound according to any one of claims 1-10, or its N-oxide, or its pharmaceutically acceptable salt, wherein p is 1 and q is 1.

13. The compound according to any one of claims 1-10, or its N-oxide, or its pharmaceutically acceptable salt, wherein p is 1 and q is 3.

14. The compound according to any one of claims 1-10, or its N-oxide, or its pharmaceutically acceptable salt, wherein p is 3 and q is 1.

15. The compound according to any one of claims 1-10, or its N-oxide, or its pharmaceutically acceptable salt, wherein p is 3 and q is 3.

16. The compound according to any one of claims 1-10, or its N-oxide, or its pharmaceutically acceptable salt, wherein p is 3 and q is 4.

17. The compound according to any one of claims 1-16, having the structure of formula III: Or its N-oxide or its pharmaceutically acceptable salt.

18. The compound according to any one of claims 1-16, having the structure of formula III-a: Or its N-oxide or its pharmaceutically acceptable salt.

19. The compound according to any one of claims 1-16, having the structure of formula IV: Or its N-oxide or its pharmaceutically acceptable salt.

20. The compound according to any one of claims 1-17 and 19, wherein X1 is -C(=O)-O- or -OC(=O)-.

21. The compound according to any one of claims 1-17 and 19-20, wherein X2 is -C(=O)-O- or -OC(=O)-.

22. The compound according to any one of claims 1-16, having the structure of formula IV-a: Or its N-oxide or its pharmaceutically acceptable salt.

23. The compound or its N-oxide or pharmaceutically acceptable salt according to any one of claims 1-22, wherein at least one of R1, R2 and R3 is not hydrogen or deuterium.

24. The compound according to any one of claims 1-23, or its N-oxide, or its pharmaceutically acceptable salt, wherein R1, R2, and R3 are each independently a halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

25. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein at least one of R1, R2, and R3 is a halogen, C 2-6 alkenyl or branched C 3-10 alkyl.

26. The compound according to any one of claims 1-25, or its N-oxide, or its pharmaceutically acceptable salt, wherein at least one of R1, R2, and R3 is a fluorinated group or an isopropyl group.

27. The compound according to any one of claims 1-24, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein R1 is a halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

28. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R1 is a halogen, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 alkyl.

29. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R1 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 alkyl.

30. The compound or its N-oxide or pharmaceutically acceptable salt according to any one of claims 1-24, wherein R1 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl or tert-hexyl.

31. The compound or its N-oxide or pharmaceutically acceptable salt according to any one of claims 1-24, wherein R1 is a halogen or isopropyl, isobutyl, sec-butyl or tert-butyl.

32. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R2 is a halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

33. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R2 is a halogen, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 alkyl.

34. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R2 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 alkyl.

35. The compound or its N-oxide or pharmaceutically acceptable salt according to any one of claims 1-24, wherein R2 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl or tert-hexyl.

36. The compound or its N-oxide or pharmaceutically acceptable salt according to any one of claims 1-24, wherein R2 is a halogen or isopropyl, isobutyl, sec-butyl or tert-butyl.

37. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R3 is a halogen, -CN, or -OR. 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group.

38. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R3 is a halogen, -CN, or -OR. 10 -N(R) 10 2. C 2-6 alkenyl or branched C 3-10 alkyl.

39. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R3 is a halogen, -OR 10 C 2-6 alkenyl or branched C 3-10 alkyl.

40. The compound or its N-oxide or pharmaceutically acceptable salt according to any one of claims 1-24, wherein R3 is a halogen, -OH, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl or tert-hexyl.

41. The compound or its N-oxide or pharmaceutically acceptable salt according to any one of claims 1-24, wherein R3 is a halogen or isopropyl, isobutyl, sec-butyl or tert-butyl.

42. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R3 is a halogen, -OR 10 Or branch C 3-10 Alkyl; and R1 and R2 are hydrogen.

43. The compound according to any one of claims 1-24, or its N-oxide, or its pharmaceutically acceptable salt, wherein R3 is a halogen, -OR 10 Or branch C 3-10 Alkyl group; R2 is a halogen, -OR 10 Or branch C 3-10 Alkyl group and R1 is hydrogen.

44. The compound according to any one of claims 1-43, or its N-oxide, or its pharmaceutically acceptable salt, wherein each R1, R2, and R3 is hydrogen or deuterium, and at least one of L1, L2, and L3 is substituted with 1-5 substituents, and at least one of the substituents is not a straight-chain carbon substituted at the terminal carbon of L1, L2, or L3. 1-10 Alkyl or deuterium.

45. The compound according to any one of claims 1-43, or its N-oxide, or its pharmaceutically acceptable salt, wherein L1 is a substituted or unsubstituted -C4- 10 alkylene or -C 3-12 Alkenylalkylene.

46. ​​The compound of claim 45, or its N-oxide, or its pharmaceutically acceptable salt, wherein L1 is a halogenated, straight-chain, or branched C. 1-6 Alkyl or C 1-2 Halogenated alkyl-substituted -C4- 10 alkylene or -C 3-12 Alkenylalkylene.

47. The compound of claim 46, its N-oxide, or a pharmaceutically acceptable salt thereof, wherein L1 is a -C substituted with a fluorinated group, methyl group, or isopropyl group. 4-10 alkylene or -C 3-12 Alkenylalkylene.

48. The compound according to any one of claims 1-47, or its N-oxide, or its pharmaceutically acceptable salt, wherein each L2 and L3 is independently a substituted or unsubstituted -C 4-10 alkylene or -C 3-12 Alkenylalkylene.

49. The compound according to any one of claims 1-48, or its N-oxide, or its pharmaceutically acceptable salt, wherein L2 and L3 are the same.

50. The compound according to any one of claims 1-43, or its N-oxide, or its pharmaceutically acceptable salt, wherein L2 and L3 are different.

51. The compound according to any one of claims 1-47, or its N-oxide, or its pharmaceutically acceptable salt, wherein each L2 and L3 is independently a substituted -C 4-10 alkylene or -C 3-12 Alkenylalkylene, wherein the substituent is a halogen or a straight-chain or branched C. 1-6 alkyl.

52. The compound according to any one of claims 1-47, or its N-oxide, or its pharmaceutically acceptable salt, wherein each L2 and L3 is independently a substituted -C 4-10 alkylene or -C 3-12 alkenylalkylene, wherein -C 4-10 alkylene or -C 3-12 The alkenylalkylene group is replaced by a fluorinated group, a methyl group, or an isopropyl group.

53. The compound according to any one of claims 1-52, or its N-oxide, or its pharmaceutically acceptable salt, wherein L4 is a substituted or unsubstituted -C1- 12 alkylene or -C 3-24 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace.

54. The compound according to any one of claims 1-52, or its N-oxide, or its pharmaceutically acceptable salt, wherein L4 is a substituted or unsubstituted -C1-6 alkylene or -C1-6 alkylene. 3-12 Alkenylalkylene; wherein L4 is optionally surrounded by 1 to 10 R 11 replace.

55. The compound according to any one of claims 1-52, or its N-oxide, or its pharmaceutically acceptable salt, wherein L4 is -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-(CH2)2-CH2-, -CH2-(CH2)3-CH2-, or -CH2-(CH2)4-CH2-.

56. The compound according to any one of claims 1-52, or its N-oxide, or its pharmaceutically acceptable salt, wherein L4 is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-.

57. The compound according to any one of claims 1-56, or its N-oxide, or its pharmaceutically acceptable salt, wherein R4 is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-C0-9alkylene-N(R) 11 )2、-OC(=O)-C0-9alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R) 11 )2.

58. The compound according to any one of claims 1-56, or its N-oxide, or its pharmaceutically acceptable salt, wherein R4 is -OH, -CH(CH3)-CH2-OH, or -OC(=O)-(CH2)3-N(Me)2.

59. A compound having the structure listed in Table 1, or its N-oxide or a pharmaceutically acceptable salt thereof.

60. A compound having the structure listed in Table 2, or its N-oxide or a pharmaceutically acceptable salt thereof.

61. A compound having the following structure, or its N-oxide, or its pharmaceutically acceptable salt: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or 。 62. A compound or its N-oxide or a pharmaceutically acceptable salt thereof, wherein the compound is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , or .

63. A compound of formula VI or its N-oxide or pharmaceutically acceptable salt: in: X is O, S, or C(R) 11 )2; L 11 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 12 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 13 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 14 Is it a substituted or unsubstituted linear C3-? 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 15 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; L 16 Is it a substituted or unsubstituted linear-C0- 12 Alkylene, wherein one or more methylene units of said group are optionally and independently -CR 11 =CR 11 -replace; Where L 11 L 12 L 13 L 14 L 15 or L 16 If replaced, then L 11 L 12 L 13 L 14 L 15 or L 16 Substituted by 1 to 5 substituents selected from the following: halogen, deuterium, -CN, straight-chain or branched C. 1-6 Alkyl, C 1-2 Haloalkyl, -C(=O)R 10 -C(=O)N(R) 10 )2、-OR 10 -N(R) 10 2. Substituted or unsubstituted C 3-6 Cycloalkyl groups and substituted or unsubstituted 3- to 6-membered heterocycloalkyl groups; wherein each substituted C 3-6 Cycloalkyl and substituted 3- to 6-membered heterocycloalkyl groups are denoted by 1-5 R groups. 11 replace; X 11 is a bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; X 12 is a bond, -C(=O)-O-, -OC(=O)-, -OC(=O)-O-, -C(=O)-N(R 10 )-、-N(R 10 )-C(=O)-, SS, -C(=O)-S- or -C(C=S)-O-; Each R 12 R 14 R 15 and R 16 Independently, it is hydrogen, deuterium, halogen, -CN, -OR 10 -N(R) 10 2. Branch C 3-10 Alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl group; L 17 Is it substituted or unsubstituted -C1- 24 alkylene-; wherein L 17 Optionally assigned to 10 R 11 replace; R 17 It is -OH, -OR 10 -OC(=O)-R 10 -C(=O)-OR 10 -OC(=O)-OR 10 -、-C(=O)-OC(=O)-R 10 -OC(=O)-C0-9 alkylene-R 11 -(O-CO-9 alkylene-) n R 11 -OC(=O)-C0-9alkylene-N(R) 10 )2、-N(R 10 )2、-CH(CH3)-CH2-OH or -C(=O)-C0-9 alkylene-N(R 10 )2; Each R 10 Independently, it is hydrogen and C 1-10 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; Each R 11 Independently selected from hydrogen, deuterium, halogens, -CN, -C 1-6 Alkyl, C 1-10 Heteroalkyl, C 1-10 Haloalkyl, C 3-10 Heterocyclic alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -C(O)OH, -C(O)-OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl)2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, -OH, -OC 1-6 Alkyl, -SH, -S(C 1-6 Alkyl), -S(O)(C 1-6 Alkyl), -S(O)2(C 1-6 alkyl) or -S(O)2NH(C 1-6 Alkyl); and t can be 0, 1, 2, 3 or 4.

64. The compound of claim 63 or its N-oxide or pharmaceutically acceptable salt thereof, wherein X is O.

65. The compound according to claim 63 or 64, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein X 11 It is a bond, -C(=O)-O- or -OC(=O)-.

66. The compound according to any one of claims 63-65, or its N-oxide, or its pharmaceutically acceptable salt, wherein X 12 It is a bond, -C(=O)-O- or -OC(=O)-.

67. The compound according to any one of claims 63-66, or its N-oxide, or its pharmaceutically acceptable salt, wherein L 16 It is a C0 alkylene and R 16 It is hydrogen.

68. The compound according to any one of claims 63-67, or its N-oxide, or its pharmaceutically acceptable salt, wherein L 15 It is a C0 alkylene and R 15 It is hydrogen.

69. A compound having the structure listed in Table 3, or its N-oxide or a pharmaceutically acceptable salt thereof.

70. A nanoparticle composition comprising a lipid component, wherein the lipid component comprises a compound according to any one of claims 1-69.

71. The nanoparticle composition of claim 70, wherein the lipid component further comprises structural lipids.

72. The nanoparticle composition according to claim 71, wherein the structural lipid comprises cholesterol, coccosterol, sitosterol, ergosterol, campesterol, stigmasterol, campesterol, lycopene, ursolic acid, or α-tocopherol.

73. The nanoparticle composition according to any one of claims 70-72, wherein the lipid component further comprises PEG lipids.

74. The nanoparticle composition according to claim 73, wherein the PEG lipid is PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, or PEG-modified dialkylglycerol.

75. The nanoparticle composition according to any one of claims 70-74, wherein the lipid component further comprises cationic and / or ionizable lipids.

76. The nanoparticle composition according to claim 75, wherein the cationic and / or ionizable lipid is 3-(bisdodecylamino)-N1,N1,4-tris(dodecyl)-1-piperazineethylamine (KL10), N1-[2-(bisdodecylamino)ethyl]-N1,N4,N4-tris(dodecyl)-1,4-piperazinediethylamine (KL22), 14,25-bistridecyl-15,18,21,24-tetraaza-octacosane (KL23). L25), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxacyclopentane (DLin-K-DMA), 4-(dimethylamino)butyric acid 37-carbon-6,9,28,31-tetraen-19-yl ester (DLin-MC3-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxacyclopentane Alkane (DLin-KC2-DMA), 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), 2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA), (2R)-2-({8-[(3β)-cholest-5-en-3-yloxy]prop-1-amine (Octyl-CLinDMA) Octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA(2R)), or (2S)-2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadec-9,12-dien-1-yloxy]prop-1-amine (Octyl-CLinDMA(2S)).

77. The nanoparticle composition according to any one of claims 70-76, wherein the lipid component further comprises phospholipids, structural lipids, and PEG lipids.

78. The nanoparticle composition according to any one of claims 70-77, wherein the lipid component comprises about 30% to about 60% of the compound according to claims 1-55, about 0% to about 30% of phospholipids, about 20% to about 50% of structural lipids and about 0% to about 10% of PEG lipids.

79. The nanoparticle composition according to any one of claims 70-78, further comprising a therapeutic agent and / or a preventive agent.

80. The nanoparticle composition of claim 79, wherein the therapeutic agent and / or preventive agent is a nucleic acid.

81. The nanoparticle composition according to any one of claims 79-80, wherein the therapeutic agent and / or preventive agent is ribonucleic acid (RNA).

82. The nanoparticle composition according to claim 81, wherein the RNA is small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), or messenger RNA (mRNA).

83. The nanoparticle composition according to any one of claims 81-82, wherein the RNA is mRNA.

84. The nanoparticle composition of claim 83, wherein the mRNA comprises at least one nucleic acid modification.

85. The nanoparticle composition according to claim 84, wherein the at least one nucleic acid modification comprises N1-methylpseuuridine (M1Ψ).

86. A pharmaceutical composition comprising a nanoparticle composition according to any one of claims 70-85 and a pharmaceutically acceptable carrier.

87. A method of delivering a therapeutic agent to a subject in need, the method comprising administering to the subject a nanoparticle composition according to any one of claims 70-85 or a pharmaceutical composition according to claim 86, thereby delivering the therapeutic agent to the subject.

88. A method for generating a polypeptide of interest in cells, the method comprising contacting the cells with a nanoparticle composition according to any one of claims 70-85 or a pharmaceutical composition according to claim 86, wherein the therapeutic agent is mRNA, wherein the mRNA encodes the polypeptide of interest.

89. The method of claim 88, wherein the mRNA can be translated in the cell to produce the polypeptide of interest.

90. A method of selectively delivering a therapeutic agent to a mammalian organ, the method comprising administering to the mammal a nanoparticle composition according to any one of claims 70-85 or a pharmaceutical composition according to claim 86.

91. The method of claim 90, wherein administering the nanoparticle composition or pharmaceutical composition comprises contacting the mammalian organ with the nanoparticle composition to deliver the therapeutic agent to the organ.

92. The method of claim 91, wherein the therapeutic agent is delivered to the organ.

93. A method for treating a disease or ailment of a subject in need, the method comprising administering to the subject a therapeutically effective amount of the nanoparticle composition according to any one of claims 70-85 or the pharmaceutical composition according to claim 86.

94. The method of claim 93, wherein the disease or symptom is cancer.

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