Lipid compound for gene delivery and lipid nanoparticle comprising same

Abstract

Disclosed herein are a lipid compound based on a biodegradable isocyanide or a biodegradable carboxylic acid terminal group, a preparation method therefor, and a use thereof in the preparation of a lipid compound for gene delivery. Further disclosed herein are a lipid compound for gene delivery, a preparation method therefor, and a use thereof in gene delivery. Further disclosed herein are a liposome and a lipid nanoparticle that comprise the lipid compound for gene delivery, and a gene delivery composition comprising the lipid compound, the liposome, or the lipid nanoparticle. The lipid compound for gene delivery, the liposome, the lipid nanoparticle, and the gene delivery composition herein enable more selective and efficient delivery and release of biomolecules, such as nucleic acids, in immune tissues and organs in vivo.

Description

Lipid compounds for gene delivery and lipid nanoparticles comprising the same

[0001] Cross reference to related applications

[0002] This application claims priority to PCT application No. PCT / CN2024 / 103431, filed on July 03, 2024, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application belongs to the field of gene loading and delivery, and specifically relates to a lipid compound for gene delivery, a preparation method thereof, and use thereof in gene delivery. This document also relates to a liposome and a lipid nanoparticle comprising the lipid compound, a gene delivery composition comprising the lipid compound, the liposome, or the lipid nanoparticle. BACKGROUND

[0004] Lipid nanoparticles (LNP) are currently the most effective non-viral carrier form in nucleic acid drug delivery. A classic lipid nanoparticle is composed of four kinds of lipids, including ionizable lipids, cholesterol, neutral phospholipids, and polyethylene glycol (PEG) lipids, which coat nucleic acid molecules. Currently, there are three drugs using LNP delivery carriers approved by FDA, including siRNA drugs using MC3 lipids, and new crown mRNA vaccines using SM-102 and ALC-0315 lipids, respectively.

[0005] After systemic administration, traditional LNP is mainly distributed in liver tissue. This phenomenon is proved to be completed by LNP binding to specific lipoproteins in the plasma and being mediated by hepatocyte membrane surface receptors. This tissue distribution characteristic of LNP is often desired to be avoided in some drug delivery scenarios. In tumor therapeutic vaccines, whether through intravenous administration or intramuscular injection, the ideal action site of nucleic acid vaccines should be tissues and organs with concentrated immune cells, such as the spleen and lymph nodes. Drug delivery targeting the spleen or lymph nodes also has broad application prospects in the fields of in vivo CAR-T cell therapy and in vivo TCR-T cell therapy. In general immunological concepts, the liver is an organ with certain immune tolerance and immune suppression functions, which is contrary to the treatment principle of therapeutic nucleic acid vaccines or immune cell therapy. Therefore, there is an urgent need for a class of LNP carriers with spleen and lymph node targeting delivery function to complete the delivery of nucleic acid drugs.

[0006] Due to the natural high liver enrichment ability of LNP, the existing technology often reduces the apparent charge of LNP to achieve nucleic acid delivery to the spleen by adding an additional negatively charged component to the classic LNP formula (SORT technology published by Daniel Siegwart et al., 2020). This method requires the addition of a high proportion of a new negatively charged component to the LNP formula, which increases the complexity of the overall LNP formulation process. The release of nucleic acid molecules by LNP in cells relies on the ionizable lipid to form a positive charge by protonation in the endosome and escape the endosome by interacting with the negatively charged envelope to complete the intracellular delivery. The addition of a high proportion of negatively charged lipids to some extent contradicts the above delivery principle, thereby affecting the intracellular delivery efficiency.

[0007] Therefore, it is particularly important to rely on the special ionizable lipid structure to achieve efficient spleen and lymph node delivery in the classic four-component lipid LNP formula. SUMMARY

[0008] To solve the above problems, the purpose of the present disclosure is to provide a plurality of lipid compounds, a preparation method thereof, and the use thereof in gene delivery, particularly efficient delivery to the spleen and lymph nodes. According to the technical solution of the present disclosure, a series of ionizable lipid compounds are prepared based on the classic Ugi four-component reaction. The ionizable lipid compounds prepared by the present disclosure have an asymmetric hydrophobic long chain structure, the molecular structure is more flexible, and the target cell membrane can be better combined, so that efficient intracellular nucleic acid delivery can be achieved for different target cells, especially efficient nucleic acid delivery to the spleen and lymph nodes.

[0009] According to an aspect of the present disclosure, a lipid compound of formula (I) is provided, or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0010] wherein X is O or S;

[0011] R II is hydrogen, or is selected from group (C) comprising a substituted or unsubstituted hydrocarbon group having a carbon number of 1-11, a substituted or unsubstituted heterocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0012] R III is selected from group (A) comprising a group comprising at least one ionizable tertiary amine structure;

[0013] R I and R IV are each independently selected from group (B) comprising a substituted or unsubstituted aliphatic group having a carbon number of 11-30 or a substituted or unsubstituted heteroaliphatic group; and

[0014] R II selected from group (C) include substituted or unsubstituted hydrocarbyl groups having a carbon count of 1-11, substituted or unsubstituted heterohydrocarbyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups;

[0015] R II are the same or different. II

[0016] In some embodiments, group A includes groups comprising at least one ionizable tertiary amine structure, wherein the groups comprising at least one ionizable tertiary amine structure have a carbon count of 3-11 and are represented by the general formula,

[0017] wherein R a is a C1-C6 substituted or unsubstituted alkylene; R b , R c each independently is a C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, which optionally can be substituted with 1, 2, or 3 substituents selected from -OH, -SH, -NR d R d or phenyl, wherein R d , R d each independently is hydrogen or C1-C3 alkyl; or R b , R c together with the N atom to which they are attached form a 5-12 membered heterocyclic or heteroaromatic ring comprising 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, which 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with one or more C1-C6 alkyl or oxo (=0); or R a , R b together with the N atom to which they are attached form a 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with C1-C6 alkylene, which 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with C1-C6 alkylene comprises 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, which 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with C1-C6 alkylene is optionally substituted with one or more C1-C6 alkyl or oxo (=0); or R a , R b , R c ​together with the N atom to which they are attached form a 5- to 12-membered heterocyclic or heteroaromatic ring optionally substituted with C1-C6alkylene, the 5- to 12-membered heterocyclic or heteroaromatic ring optionally substituted with C1-C6alkylene comprising 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5- to 12-membered heterocyclic or heteroaromatic ring optionally substituted with C1-C6alkylene being optionally substituted with one or more C1-C6alkyl or oxo (=0);

[0018] Group B includes substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms, wherein the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms optionally comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 groups independently selected from -C=C-, -C≡C-, -NH-, -NH2, -OH, -OR m -O-, -C(O)-, -C(OR n )-, -C(O)O-, -SH, -SR o -S-, -C(S)-, -C(SR p )-, -C(S)O-, and -P(O)-, wherein R m , R n , R o , and R p are each independently substituted or unsubstituted C1-C 14 aliphatic hydrocarbon groups; and

[0019] Group C includes substituted or unsubstituted hydrocarbon groups having 1-11 carbon atoms, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups, wherein the substituted or unsubstituted hydrocarbon groups having 1-11 carbon atoms, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups optionally comprise 1, 2, 3, 4, or 5 groups independently selected from -C=C-, -C≡C-, -NH-, -NH2, -OH, -OR m ', -O-, -C(O)-, -C(OR n ')-, -C(O)O-, -SH, -SR o ', -S-, -C(S)-, -C(SR p ')-, -C(S)O-, and -P(O)-, wherein R m ', R n ', R o ', and R p ' are each independently substituted or unsubstituted C1-C 14aliphatic hydrocarbon group, the hydrocarbon group, heterocarbon group, aryl group, or heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -N02, and -OH.

[0020] In some embodiments, there is provided a lipid compound of Formula (I) A , or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0021] wherein R II , R I , R II , R III , and R IV are as defined in the disclosure.

[0022] Group A, Group B, and Group C are as defined in the disclosure.

[0023] In some embodiments, R II ' is selected from Group (C) comprising a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having a carbon number of 1-11, and R II is selected from Group (C) comprising a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having a carbon number of 1-11.

[0024] In some embodiments, R II ' is hydrogen, and R II is selected from Group (C) comprising a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having a carbon number of 1-11.

[0025] In some embodiments, there is provided a lipid compound of Formula (I) B , or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0026] wherein R II , R I , R II , R III , and R IV are as defined in the disclosure.

[0027] Group A, Group B, and Group C are as defined in the disclosure.

[0028] According to an aspect of the disclosure, there is provided a lipid compound of Formula (I) , or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0029] wherein X is O or S;

[0030] R II is selected from hydrogen, substituted or unsubstituted C1-C8alkyl, or substituted or unsubstituted C1-C8heteroalkyl;

[0031] R III is selected from group (A) comprising a group comprising at least one ionizable tertiary amine structure, wherein the group comprising at least one ionizable tertiary amine structure has a number of carbon atoms from 3 to 11 and is represented by the following general formula,

[0032] wherein R a is C1-C6substituted or unsubstituted alkylene; R b , R c are each independently C1-C6substituted or unsubstituted alkyl, C2-C6substituted or unsubstituted alkenyl, C2-C6substituted or unsubstituted alkynyl, which optionally can be substituted with 1, 2, or 3 substituents selected from -OH, -SH, -NR d R d , or phenyl, wherein R d , R d are each independently hydrogen or C1-C3alkyl; or R b , R c together with the N atom to which they are attached form a 5-12 membered heterocyclic or heteroaromatic ring comprising 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, which 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with one or more C1-C6alkyl or oxo (=0);

[0033] R I and R IV are each independently selected from group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a number of carbon atoms from 11 to 30; and

[0034] Group B comprises a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a number of carbon atoms from 11 to 30, wherein the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a number of carbon atoms from 11 to 30 optionally comprises 1, 2, 3, or 4 groups independently selected from -C=C-, -C≡C-, -0-, -C(O)-, -C(OR n )-, -C(O)O-, -S-, -C(S)-, -C(SR p )-, and -C(S)O-, wherein R n and R peach independently is a substituted or unsubstituted C1-C8 aliphatic hydrocarbon group; and

[0035] R II is selected from group (C) and includes a substituted or unsubstituted hydrocarbon group having a carbon number of 1-11, a substituted or unsubstituted heterocarbon group.

[0036] According to an aspect of the present disclosure, there is provided a lipid compound, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, selected from the group consisting of lipid compounds represented by:

[0037] According to another aspect of the present disclosure, there is provided a use of the lipid compound of formula (I) of the present disclosure, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a liposome and / or a lipid nanoparticle.

[0038] According to another aspect of the present disclosure, there is provided a liposome. The lipid nanoparticle of the present disclosure comprises the lipid compound of formula (I) of the present disclosure, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the liposome of the present disclosure further comprises a phospholipid and a cholesterol.

[0040] According to another aspect of the present disclosure, there is provided a lipid nanoparticle. The lipid nanoparticle of the present disclosure comprises the lipid compound of formula (I) of the present disclosure, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the lipid nanoparticle of the present disclosure further comprises a phospholipid, a structural lipid, a PEG lipid, and optionally a nucleic acid.

[0042] According to another aspect of the present disclosure, there is provided a pharmaceutical composition. The pharmaceutical composition of the present disclosure comprises the lipid compound of formula (I) of the present disclosure and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition of the present disclosure comprises the liposome of the present disclosure comprising the lipid compound of formula (I) and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition of the present disclosure comprises the lipid nanoparticle of the present disclosure comprising the lipid compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

[0043] Delivery efficiency of a nucleic acid in the present disclosure refers to a greater accumulation amount of the nucleic acid, a higher transcription amount of the nucleic acid (e.g., delivery of DNA), a higher translation amount of a target protein (e.g., delivery of mRNA), a higher inhibition efficiency of transcription and translation of a target mRNA (e.g., delivery of miRNA), etc. in a target cell, tissue, organ. According to some embodiments of the present disclosure, the delivery of the lipid nanoparticle has a higher delivery efficiency than direct delivery of the nucleic acid (without using a delivery vehicle). The delivery efficiency is manifested in some embodiments as an amount of a protein translated from a delivered mRNA generated in a target cell or in an animal body. The lipid compound of the present disclosure and the lipid nanoparticle protecting the lipid compound are particularly suitable for efficiently delivering a nucleic acid, including RNA, e.g., mRNA, to an immune organ and / or tissue, e.g., spleen and / or lymph node, etc. The lipid compound of the present disclosure can also be referred to as a "spleen-targeting lipid".

[0044] Accordingly, in an aspect of the present disclosure, there is provided a lipid compound of Formula (I) or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof, a lipid nanoparticle comprising the lipid compound of Formula (I) or an N-oxide, a stereoisomer or a pharmaceutically acceptable salt thereof, or a use of a pharmaceutical composition comprising the lipid compound or the lipid nanoparticle, and a pharmaceutically acceptable carrier or excipient, in delivering a nucleic acid including DNA or RNA, e.g., mRNA, to an immune organ and / or tissue,

[0045] wherein X is O or S;

[0046] R II is hydrogen, or is selected from the group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon atom number of 1-11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0047] R III is selected from the group (A) comprising a group comprising at least one ionizable tertiary amine structure;

[0048] R I and R IV are each independently selected from the group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a carbon atom number of 11-30; and

[0049] R II is selected from the group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon atom number of 1-11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0050] In some embodiments, the immune organ and / or tissue comprises a spleen, a lymph node, etc.

[0051] In some embodiments, R II ', R I ', R II ', R III ', and R IV as defined in the present disclosure.

[0052] In an aspect of the present disclosure, there is provided a use of a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, a lipid nanoparticle comprising the lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the lipid compound or the lipid nanoparticle, and a pharmaceutically acceptable carrier or excipient, in the manufacture of a medicament for delivering a nucleic acid including DNA or RNA such as mRNA to an immune organ and / or tissue,

[0053] wherein R II ', R I ', R II ', R III ', and R IV as defined in the present disclosure.

[0054] In some embodiments, the immune organ and / or tissue comprises spleen, lymph node, etc.

[0055] In an aspect of the present disclosure, there is provided a use of a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, a lipid nanoparticle comprising the lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the lipid compound or the lipid nanoparticle, and a pharmaceutically acceptable carrier or excipient, in the manufacture of a medicament for delivering a nucleic acid including DNA or RNA such as mRNA to an immune organ and / or tissue,

[0056] wherein R II ', R I ', R II ', R III ', and R IV as defined in the present disclosure.

[0057] In some embodiments, the immune organ and / or tissue comprises spleen, lymph node, etc.

[0058] In an aspect of the present disclosure, there is provided a method of delivering a nucleic acid to an immune organ and / or tissue, wherein the method uses a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, a lipid nanoparticle comprising the lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the lipid compound or the lipid nanoparticle, and a pharmaceutically acceptable carrier or excipient, delivers the nucleic acid, including DNA or RNA such as mRNA,

[0059] wherein R II ', R I , R II , R III and R IV as defined in the present disclosure.

[0060] In some embodiments, the immune organ and / or tissue comprises spleen, lymph node, etc. DETAILED DESCRIPTION

[0061] The above and other objects, components, and advantages will become apparent from the following more detailed description when taken in conjunction with the accompanying drawings, which together illustrate by way of example specific embodiments in which like reference numerals, designations, or symbols indicate similar, though not necessarily identical, elements or features. It is to be noted that the following detailed description is merely exemplary and is not intended to limit the scope of the application, as described in the appended claims. If not specifically mentioned, the following detailed description does not imply any specific process that can not be understood by those skilled in the art in view of the prior art. If the manufacturer of a reagent or instrument is not mentioned, it is considered to be a conventional product that can be obtained by commercial purchase.

[0062] As used in the claims and specification, the terms "including," "containing," and "having," or any variation thereof, shall be construed as indicating the inclusion of an element, but not the exclusion of any other element of the process, composition, or method. The terms "at least one" and "one or more" can be used interchangeably. The term "single" is used to indicate one and only one. Similarly, other specific integer values are to be understood as used herein to mean that particular value, and not any other value. The terms "preferably," "preferred," "prefer," "optionally," "may," and similar terms are used to indicate optional features, i.e., features that are optional in embodiments of the application. Unless otherwise stated, ranges described as "between a and b" include "a" and "b."

[0063] While various improvements have been described herein with reference to particular embodiments of the present disclosure, it will be understood that such description is by way of illustration only and is not intended to be limiting of the scope of any inventive process claimed. Thus, the scope and content of any inventive process claimed will be limited only by the terms of the appended claims in their broadest form or as modified in their prosecution history or as set forth in any continuing application. Furthermore, it is to be understood that the features of any specific embodiment discussed herein can be combined with one or more features of any one or more other embodiments discussed or considered herein, unless otherwise stated.

[0064] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEd., John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEd., Cambridge University Press, Cambridge, 1987.

[0065] Unless otherwise expressly stated, all ranges encompassed by a range herein are inclusive of the recited endpoint.

[0066] When a range is listed herein, it is intended to encompass each value and sub-range within the range. For example, "C1-C6" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4C 4-6 C 4-5 and C 5-6 In some implementations, C0 indicates that the number of carbon atoms is 0, meaning that the group is absent.

[0067] When any variable appears more than once in any ingredient, in formula (I), or in any other formula describing and depicting the compounds of this disclosure, its definition at each occurrence is independent of its definition at every other occurrence. Furthermore, combinations of substituents and / or variables are permitted only when such combinations produce stable compounds.

[0068] definition

[0069] As used herein, the term "alkyl group" refers to a chemical group comprising hydrogen and carbon. Alkyl groups can be substituted or unsubstituted. Alkyl groups can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic, and include alkyl, alkenyl, and alkynyl groups, among others. Alkyl groups can be fully saturated, monounsaturated, or polyunsaturated, and can include divalent and polyvalent groups, having a specified number of carbon atoms (i.e., C1-C1). 10 This refers to 1 to 10 carbon atoms (including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbon atoms). When a hydrocarbon group contains heteroatoms such as N, O, or S, it is also called a "heterohydrocarbon group." As used herein, the term "heterohydrocarbon group" refers to a divalent substituent, which is a monovalent hydrocarbon group having one hydrogen atom replaced by a chemical valence. As used herein, the term "heterohydrocarbon group" refers to a divalent substituent, which is a monovalent heterohydrocarbon group having one hydrogen atom replaced by a chemical valence.

[0070] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. The term "C"... i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. Unless otherwise stated, an alkyl group may contain 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, neopentyl, etc. As used herein, the term "alkylene" refers to a divalent substituent, which is a monovalent alkyl group having one hydrogen atom substituted in valence.

[0071] As used herein, the term "alkenyl" refers to straight-chain or branched hydrocarbon groups having at least one carbon-carbon double bond, and includes groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Unless otherwise indicated, an alkenyl group can contain 2 to 10 carbon atoms. In certain embodiments, an alkenyl group can contain 2 to 6 carbon atoms, such as 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In certain embodiments, an alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl groups include ethylene (vinyl), propenyl, butenyl, pentenyl, 1 -methyl-2-buten- 1 -yl, 5-hexenyl, and the like. As used herein, the term "alkenylene" refers to a divalent substituent which is a monovalent alkenyl group having one hydrogen atom replaced by a valence.

[0072] As used herein, the term "alkynyl" refers to straight-chain or branched hydrocarbon groups having at least one carbon-carbon triple bond. Unless otherwise indicated, an alkynyl group can contain 2 to 10 carbon atoms. In certain embodiments, an alkynyl group contains 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In certain embodiments, an alkynyl group contains 2 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1 -propynyl, 2-propynyl, and the like. As used herein, the term "alkynylene" refers to a divalent substituent which is a monovalent alkynyl group having one hydrogen atom replaced by a valence.

[0073] As used herein, the term "alkoxy" refers to the group -O-alkyl, wherein alkyl has the meaning as defined herein.

[0074] As used herein, the term "cycloalkyl" refers to non-aromatic, saturated monocyclic and polycyclic ring systems in which all ring-forming atoms are carbon. Unless otherwise specified, a cycloalkyl group can contain 3 to 10 ring-forming carbon atoms (i.e. C 3-10 Cycloalkyl). In certain embodiments, a cycloalkyl group can comprise 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6 ring-forming carbon atoms, and the like. In particular, a cycloalkyl group can be monocyclic or bicyclic. Alternatively, a bicyclic cycloalkyl group can include fused, spirocyclic, and bridged cycloalkyl structures.

[0075] On the other hand, it also includes cycloalkyl rings in which one, two, or three heteroatoms are replaced by cyclic carbon atoms. Such groups are referred to as "heterocyclic groups" or "heterocycles," which are cycloalkyl groups as defined above but with at least one heteroatom selected from N, O, and S as a cyclic atom. Unless otherwise stated, heterocyclic groups may contain 3 to 10 cyclic atoms (i.e., 3 to 10-membered heterocyclic groups). In some embodiments, heterocyclic groups may contain 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, etc. In particular, heterocyclic groups may be monocyclic or bicyclic. Optionally, bicyclic heterocyclic groups may include fused, spirocyclic, and bridged heterocyclic structures. Non-limiting examples of heterocyclic groups include ethylene oxide, pyrrolyl, piperidinyl, tetrahydropyranyl, piperazineyl, pyrrolylyl, and morpholinyl. Heterocyclic groups can also be described by the number of carbon atoms. For example, C 3-6 A heterocyclic group refers to a heterocyclic group containing three to six cyclic carbon atoms, and may also contain at least one heteroatom, such as one, two, or three heteroatoms as cyclic atoms. In some embodiments, the heterocyclic group or heterocycle contains one or two heteroatoms as cyclic atoms. In some embodiments, the heterocyclic group may be monocyclic or bicyclic, such as fused bicyclic and spirobicyclic. In the context of this disclosure, the terms "heterocyclic group" and "heterocycle" are used interchangeably.

[0076] As used herein, the term "aliphatic group" refers to a substituted or unsubstituted straight-chain and / or branched, saturated or unsaturated hydrocarbon group, including straight-chain, branched, or cyclic alkyl, alkenyl, and alkynyl groups. In some embodiments, the term "aliphatic group" may be used interchangeably with "hydrocarbon group." In some embodiments, the aliphatic group comprises one or more, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 unsaturated carbon-carbon double bond (-C=C-), carbon-carbon triple bond (-C≡C-) groups, and / or any combination thereof.

[0077] As used herein, the term "heteroaliphatic group" refers to a substituted or unsubstituted straight-chained and / or branched, saturated or unsaturated, carbon hydride group containing a heteroatom selected from N, O, and S, including straight-chained, branched, or cyclic alkyl, alkenyl, and alkynyl groups. In some embodiments, the term "heteroaliphatic group" can be used interchangeably with "heterocarbyl." In some embodiments, the heteroatom contained in the heteroaliphatic group can form a backbone of the heteroaliphatic group together with carbon atoms, such as, but not limited to, -C-N-C-, -C-O-C-, -C-O-O-C, -C-S-C-, -C-S-S-C, and the like group structures or any combination thereof. In some embodiments, the heteroatom contained in the heteroaliphatic group can be a substituent attached to a carbon atom, such as, but not limited to, -C≡N, -C=N-, -C-N=, -C=O, -C-OH, -C=S, -C-SH, and the like substituent structures. In some of the described embodiments, the heteroatom contained in the heteroaliphatic group can be any combination of the above-listed group structures. In some embodiments, the heteroaliphatic group contains one or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 unsaturated carbon-carbon double bonds (-C=C-), carbon-carbon triple bonds (-C≡C-), -NH-, -NH2-, OH, -OR m -O-, -C(O)-, -C(OR n -C(O)O-, -SH, -SR o -S-, -C(S)-, -C(SR p -C(S)O-, -P(O)-, and / or any combination thereof, wherein R m , R n , R o , and R p are each independently a substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group, such as a C1-C 12 , C1-C 10 , C1-C8, C1-C6, C1-C4 aliphatic hydrocarbon group. Non-limiting specific examples of substituted or unsubstituted C1-C 14 aliphatic hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl and i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene (vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0078] As used herein, the term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system having at least one aromatic ring. Unless otherwise specified, aryl groups can be 6- to 10-membered. In certain embodiments, aryl groups can contain 6 ring-forming carbon atoms. All atoms within a carbocyclic aryl group are carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like. The terms "aryl" and "aromatic ring" can be used interchangeably in the context of the present disclosure.

[0079] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic ring system, or a fused or bridged bicyclic ring system, wherein the ring system contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and at least one ring is an aromatic ring. Unless otherwise specified, heteroaryl groups can be 5- to 10-membered. In certain embodiments, heteroaryl groups can be 5- or 6-membered. In certain embodiments, heteroaryl groups can contain one, two, or three heteroatoms. In certain embodiments, heteroaryl groups can contain one or two heteroatoms. Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isoindazolyl, isoquinolyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl, quinolyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, tetrazolyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heteroaryl groups include at least one ring having at least one heteroatom as described above and at least one aromatic ring. For example, a ring having at least one heteroatom can be fused to one, two, or three carbocyclic rings, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, or another monocyclic heterocyclic ring. Non-limiting examples of fused heteroaryl groups include 1,2,3,5,8,8a-hexahydroindolizine, 2,3-dihydrobenzofuran, 2,3-dihydroindole, 2,3-dihydrobenzothiophene, and the like. The terms "heteroaryl" and "heteroaromatic ring" can be used interchangeably in the context of the present disclosure.

[0080] As used herein, the term "oxo" refers to a divalent oxygen atom and the structure of oxo can be shown as =0.

[0081] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine, or fluorides, chlorides, bromides, and iodides. In certain embodiments, non-limiting examples of halo include fluorine, chlorine, and bromine, or fluorides, chlorides, and bromides, more particularly fluorine and chlorine, or fluorides and chlorides.

[0082] As used herein, the term "heteroatom" refers to nitrogen (N), oxygen (O), and sulfur (S), and can include any oxidized form of nitrogen and sulfur, and any quaternized form of a basic nitrogen, unless otherwise indicated.

[0083] As used herein, the terms "substituted," "substituted," "substitution" when referring to a chemical group means that the chemical group has one or more hydrogen atoms removed and replaced with a substituent. As used herein, the term "substituent" has its ordinary meaning known in the art and refers to a chemical moiety covalently attached to a parent group or, if appropriate, fused to a parent group. It is understood that substitution of a given atom is limited by valence. It is understood that a substituent can be further substituted.

[0084] When a moiety is indicated as being "optionally" substituted in formula (I) or any embodiment thereof, this indicates that formula (I) or embodiments thereof encompasses compounds in which the moiety is substituted with the indicated substituents and compounds in which the moiety does not contain the indicated substituents (i.e., in which the moiety is unsubstituted).

[0085] The compounds provided herein are described with reference to general formulas and specific compounds. In addition, the compounds of the present disclosure can exist in a variety of different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, pharmaceutically acceptable salts, tautomers, stereoisomers, racemic mixtures, positional isomers, prodrugs, solvated forms, different crystal or polymorphic forms, and active metabolites, among others.

[0086] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness and none of the properties that are undesirable of the free acids / bases form of a specific compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can include salts with inorganic or organic bases and inorganic or organic acids. In cases where the compounds of the disclosure contain one or more acidic or basic groups, the disclosure also includes the corresponding pharmaceutically acceptable salts thereof. Thus, compounds of the disclosure containing an acidic group, such as a carboxyl group, can exist in salt form and can be used in accordance with the disclosure, for example, alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. Further non-limiting examples of such salts include lithium, sodium, potassium, calcium, magnesium, barium, or salts with ammonia or organic amines such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or an amino acid. These salts are readily obtained by reacting the compound having an acidic group with a suitable base such as lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide. Other base salts of the compounds of the disclosure include, but are not limited to, copper (I), copper (II), iron (II), iron (III), manganese (II), and zinc salts. Compounds of the disclosure containing one or more basic groups, such as groups that can be protonated, can exist in salt form and can be used in accordance with the disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfosalicylic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, pamoic acid, mandelic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid, or aspartic acid, and other acids known to those skilled in the art. The salts formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), toluenesulfonates, carbonates, bicarbonates, formates, acetates, sulfobenzoates, trifluoromethanesulfonates, oxalates, malonates, maleates, succinates, tartrates, malates, pamoates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates, and glutamates. Furthermore, the stoichiometry of the salts formed from the compounds of the disclosure can be an integer multiple or a non-integer multiple of 1.

[0087] Compounds of the disclosure containing a basic nitrogen-containing group can be quaternized using agents such as C 1-4 haloalkanes, for example, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; diC 1-4Alkyl sulfates, such as dimethyl, diethyl, and dipentyl sulfates; C 10-18 Alkyl halides, such as decyl, dodecyl, lauryl, myristyl, and stearyl chloride, bromide, and iodide; and aryl C 1-4 Alkyl halides, such as benzyl chloride and phenethyl bromide.

[0088] If the compounds of the present disclosure contain both an acidic group and a basic group in the molecule, the present disclosure includes, in addition to the above-mentioned salt forms, internal salts or betaines (zwitterions). The corresponding salts can be obtained by customary methods known to those skilled in the art, for example by contacting them with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with the anions or cations of other salts. The present disclosure also includes all salts of the compounds of the present disclosure which, due to low physiological compatibility, are not directly suitable for pharmaceuticals, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts. For an overview of more suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0089] The lipid compounds of the present disclosure, and their pharmaceutically acceptable salts, can exist in non-solvated and solvated forms. The term “solvate,” as used herein, refers to a molecular complex comprising a lipid compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules. The term “hydrate” is used when the solvent is water.

[0090] The lipid compounds of the present disclosure can have one or more chiral (asymmetric) centers. The present disclosure encompasses all stereoisomeric forms of the lipid compounds of the present disclosure. The asymmetric centers present in the lipid compounds of the present disclosure can independently of one another have the (R) or (S) configuration. When bonds to chiral carbons are depicted in the structural formulae of the present disclosure as straight lines, or when compound names are depicted without the (R) or (S) designation of chiral carbons, it is understood that both the (R) and (S) configuration of each such chiral carbon, and thus each enantiomer or diastereomer, and mixtures thereof, are included in the formula or name. The production of a particular stereoisomer or mixtures thereof can be identified in the examples obtaining such stereoisomer or mixtures, but this in no way limits that all stereoisomers and mixtures thereof are included within the scope of the present disclosure.

[0091] The present disclosure includes all possible enantiomeric and diastereomeric forms and mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers in all proportions. Thus, enantiomeric forms, as the pure left- and right-handed enantiomers, racemic forms and mixtures of two enantiomers in all proportions are subject of the present disclosure. In the case of cis / trans isomers, the present disclosure includes the cis form and the trans form as well as mixtures of these forms in all proportions. If desired, individual stereoisomers can be prepared by the separation of mixtures by conventional methods, e.g. by chromatography or crystallization, by using stereospecifically homogeneous synthesis starting materials or by stereoselective synthesis. Optionally, derivatization can be performed prior to the separation of the stereoisomers. The separation of the stereoisomeric mixtures can be performed either during an intermediate step of the synthesis of the lipid compounds of the present disclosure or on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of a crystalline product or crystalline intermediate which has been derivatized, if necessary, with a reagent containing a known stereochemical configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy.

[0092] Unless otherwise stated, structures depicted herein are also meant to include all isomeric forms of the substance so described, e.g., where a structure is depicted as a single enantiomer, the present disclosure also includes other enantiomeric forms and mixtures of the two. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms, e.g., the presence of one or more deuterium, tritium, carbon-13, carbon-14, nitrogen-15, oxygen-17, oxygen-18, sulfur-33, sulfur-34, sulfur-35, chlorine-35, chlorine-36, bromine-79, bromine-81, iodine-123, iodine-124, iodine-125, iodine-127, and / or fluorine-19 atoms. Such isotopically enriched atoms can be present in the place of the corresponding atoms normally found in the compounds of the present disclosure. Such isotopically enriched compounds are useful in metabolic studies, as tracer compounds, and in the preparation of other isotopically enriched compounds. The isotopically enriched compounds of the present disclosure can be prepared using techniques known to those skilled in the art. 2 H (i.e., D) and 3 H; carbon, e.g. 11 C, 13 C and 14 C; chlorine, e.g. 36 Cl; fluorine, e.g. 18 F; iodine, e.g. 123 I and 125 I; nitrogen, e.g. 13 N and 15 N; oxygen, e.g. 15 O, 17 O and 18 O; phosphorus, e.g. 32 P; and sulfur, e.g. 35 S. Certain isotopically enriched compounds of the present disclosure, for example, those into which radioactive isotopes are incorporated, are useful in medical and / or biological assays. In particular, deuterium can be present in the place of hydrogen, for example, as in deuterium oxide (heavy water) and deuterium chloride (heavy salt). Tritium can be present in the place of hydrogen, for example, as in tritiated water and tritiated salt. Isotopically enriched compounds of the present disclosure can be prepared using techniques known to those skilled in the art. 2Compounds of the depicted structures that differ in the replacement of hydrogen) by H or D) can provide certain therapeutic advantages, for example, due to higher metabolic stability, increased half-life in vivo, or reduced dosage requirements, and can be used in some specific cases. Isotopic variants of the compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and using appropriate isotopically-labeled reagents in place of the non-labeled reagents previously employed.

[0093] Pharmaceutically acceptable solvates according to the present disclosure can include those wherein the solvent can be isotopically substituted, e.g., D20, d6-acetone, d6-DMSO.

[0094] As used herein, the term "lipid" refers to a class of organic compounds that are derivatives (e.g., esters) of fatty acids and are generally characterized as being insoluble in water but soluble in many organic solvents. Lipids are generally classified into at least three categories: (1) "simple lipids" including fats and oils as well as waxes; (2) "compound lipids" including phospholipids and glycolipids; (3) "derived lipids" such as steroids.

[0095] As used herein, the term "phospholipid" refers to a lipid molecule composed of two hydrophobic fatty acid "tails" and a hydrophilic "head" composed of a phosphate group. These two components are most often bound together through a glycerol molecule, and thus, in this context, the phospholipid is preferably a glycerol-phospholipid. In addition, the phosphate group is often modified with simple organic molecules such as choline (i.e., yielding phosphocholine) or ethanolamine (i.e., yielding phosphoethanolamine). In some embodiments, the phospholipid can be selected from the following group, including but not limited to: 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-di-undecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof.

[0096] As used herein, the term "structural lipid" refers to a sterol and also to a lipid containing a sterol moiety. In some embodiments, the structural lipid can be selected from the following group, including but not limited to: cholesterol, coprostanol, sitosterol, ergosterol, campesterol, soysterol, brassicasterol, tomatidine, tomatin, ursolic acid, a-tocopherol, hovenine, phytosterol, steroid, and mixtures thereof. In some embodiments, the structural lipid is cholesterol.

[0097] As used herein, the term "PEG lipid", or alternatively referred to as a PEGylated lipid, refers to any suitable lipid modified with a PEG (polyethylene glycol) group. In some embodiments, the PEG lipid can be selected from the group comprising, but 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. In some embodiments, specific examples of PEG lipids include, but are not limited to, C14-PEG2000 (1,2-dimyristoyl-rac-glycerol, methoxypolyethylene glycol-2000 (DMG-PEG2000)) and C18-PEG5000 (1,2-distearoyl-rac-glycerol, methoxypolyethylene glycol-5000 (DSG-PEG5000)).

[0098] As used herein, the term "hydrophobic lipid" refers to a compound having a nonpolar group, including, but not limited to, long chain saturated and unsaturated aliphatic hydrocarbon groups and such groups are optionally substituted with one or more aromatic, cycloaliphatic, or heterocyclic groups. Suitable examples include, but are not limited to, diacylglycerol, dialkylglycerol, N-N-dialkylamino, 1,2-diacyloxy-3-aminopropane, and 1,2-dialkyl-3-aminopropane.

[0099] As used herein, the terms “cationic lipid” and “ionizable lipid” are used interchangeably to refer to lipids and their salts that have one, two, three or more fatty acid or aliphatic alkyl chains and a pH-titrile amino head group (e.g., alkylamino or dialkylamino head group). Cationic lipids are generally protonated (i.e., positively charged) at pH below their pKa and substantially neutral at pH above their pKa. The cationic lipids of this disclosure may also be referred to as titrable cationic lipids. In some embodiments, the cationic lipid comprises: an ionizable tertiary amine (e.g., pH-titrile) head group; a C18 alkyl chain, wherein each alkyl chain independently has 0 to 3 (e.g., 0, 1, 2, or 3) double bonds; and an ether, ester, or ketal bond between the head group and the alkyl chain. These cationic lipids include (but are not limited to) DSDMA, DODMA, DLinDMA, DLenDMA, γ-DLenDMA, DLin-K-DMA, DLin-K-C2-DMA (also known as DLin-C2K-DMA, XTC2, and C2K), DLin-K-C3-DMA, DLin-K-C4-DMA, DLen-C2K-DMA, γ-DLen-C2K-DMA, DLin-M-C2-DMA (also known as MC2), DLin-M-C3-DMA (also known as MC3), and (DLin-MP-DMA) (also known as 1-B11). In some embodiments, the ionizable lipid is heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) (SM102).

[0100] As used herein, "nucleic acid" includes double-stranded RNA, single-stranded RNA, isolated RNA (e.g., partially purified RNA), substantially pure RNA, synthetic RNA, recombinantly produced RNA, and altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution, and / or alteration of one or more nucleotides. Such alterations can include the addition of non-nucleotide material at the end(s) of an interfering RNA or internally (e.g., at one or more nucleotides of the RNA). The nucleotides in the RNA molecules of the disclosure can also include non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs can be referred to as analogs or analogs of naturally occurring RNA. As used herein, the terms "ribonucleic acid" and "RNA" refer to molecules containing at least one ribonucleotide residue, including siRNA, antisense RNA, single-stranded RNA, microRNA, mRNA, non-coding RNA, and multivalent RNA. A ribonucleotide is a nucleotide with a hydroxyl group at the 2' position of the beta-D-ribofuranose moiety. These terms include double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), isolated RNA (e.g., partially purified RNA), substantially pure RNA, synthetic RNA, recombinantly produced RNA, and modified and altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution, modification, and / or alteration of one or more nucleotides. Alterations of RNA can include the addition of non-nucleotide material at the end(s) of an interfering RNA or internally (e.g., at one or more nucleotides of the RNA), the nucleotides in the RNA molecules including non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs can be referred to as analogs.

[0101] As used herein, the term "liposome" refers to a vesicle which has at least one lipid bilayer, preferably a spherical vesicle. Liposomes are capable of carrying an aqueous solution, a compound, a drug, or other substance in a compartment (i.e., an internal cavity or space) surrounded by the at least one lipid bilayer.

[0102] As used herein, the term "lipid nanoparticle" refers to a lipid formulation that can be used to deliver a therapeutic nucleic acid (e.g., mRNA) to a target site of interest (e.g., a cell, tissue, organ, etc.). In some embodiments, a lipid nanoparticle is a nucleic acid-lipid particle, which is typically composed of a nucleic acid, a cationic lipid (e.g., a lipid compound of the disclosure), a non-cationic lipid (e.g., a phospholipid), a PEG-lipid, and optionally a structural lipid (e.g., cholesterol). Typically, the therapeutic nucleic acid (e.g., mRNA) can be encapsulated in the lipid portion of the lipid nanoparticle, thereby protecting it from enzymatic degradation.

[0103] Lipid compounds

[0104] The lipid compounds disclosed herein can be used for gene delivery, specifically in liposomes and lipid nanoparticles, to deliver therapeutic and / or preventative agents, such as nucleic acids, to cells or organs. When used in the preparation of liposomes and lipid nanoparticles, the lipid compounds of this disclosure may also be referred to as "ionizable lipids," "ionizable lipid compounds," "cationic lipids," or "cationic lipid compounds."

[0105] In one respect, the lipid compounds disclosed herein are lipid compounds having the structure shown in formula (I), or their N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0106] Where X is O or S;

[0107] R II 'Is hydrogen, or selected from group (C) including substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heteroaryl groups having 1-11 carbon atoms;

[0108] R III The group selected from group (A) includes a group comprising at least one ionizable tertiary amine structure;

[0109] R I and R IV Each is independently selected from group (B), comprising substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms; and

[0110] R II Selected from group (C) including substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heteroaryl groups having 1-11 carbon atoms.

[0111] In some implementation schemes, R II 'Is hydrogen or a hydrocarbon group selected from group C, for example, having 1-8 carbon atoms, such as 1-6, 1-4, specifically, for example, C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, primary butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. In some embodiments, R II 'With R II They are the same. In some implementations, R II 'With R II They are different.

[0112] In this paper, groups containing at least one ionizable tertiary amine structure can be collectively referred to as a group of groups, namely group group A.

[0113] In some embodiments, the group comprising at least one ionizable tertiary amine structure is a group having a total of 3-11 carbon atoms. In some embodiments, the group comprising at least one ionizable tertiary amine structure is a group having the following general formula:

[0114] wherein R a is a Ci-C6, e.g., Ci-C4, substituted or unsubstituted alkylene; R b , R c each independently is a Ci-C6, e.g., Ci-C4, substituted or unsubstituted alkyl, a C2-C6, e.g., C2-C4, substituted or unsubstituted alkenyl, a C2-C6, e.g., C2-C4, substituted or unsubstituted alkynyl, which optionally can be substituted with 1, 2, or 3 substituents selected from the group consisting of -OH, -SH, -NR d R d , or phenyl, wherein R d , R d each independently is hydrogen or Ci-C3alkyl; or R b , R c together with the N atom to which they are attached form a 5-12 membered heterocyclic or heteroaromatic ring comprising 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, which 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with one or more Ci-C6, e.g., Ci-C4, alkyl or oxo (=0); or R a , R b together with the N atom to which they are attached form a 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with Ci-C6, e.g., Ci-C4, alkylene, which 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with alkylene comprises 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, which 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more Ci-C6, e.g., Ci-C4, alkyl or oxo (=0); or R a , R b , R c together with the N atom to which they are attached form a 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with Ci-C6, e.g., Ci-C4, alkylene, which 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with alkylene comprises 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, which 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more Ci-C6, e.g., Ci-C4, alkyl or oxo (=0).

[0115] In some embodiments, R b , R cTogether with the N atom it is attached to, it forms a 5-12 member, such as a 5-6 member, heterocyclic or heteroaromatic ring. This 5-12 member, such as a 5-6 member, heterocyclic or heteroaromatic ring can be a monocyclic, fused bicyclic, spirocyclic, or bridged bicyclic ring, etc. In some embodiments, R... b R c Together with the N atom it is attached to, it forms a 5-, 6-, 7-, or 8-membered monocyclic heterocyclic or heteroaromatic ring, containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N. In some embodiments, R b R c Non-limiting embodiments of heterocycles or heteroaromatic rings formed together with the N atoms they are attached to include, but are not limited to, the following heterocycles and heteroaromatic rings:

[0116] In some implementation schemes, R a R b Together with the N atom it is attached to, it forms a C1-C6, for example, C1-C4, alkylene ring with optional substitution of 5-12, for example, 5-6 membered heterocycles or heteroaromatic rings. These alkylene rings can be monocyclic, fused bicyclic, spirocyclic, or bridged bicyclic rings, etc. In some embodiments, R... a R b Together with the attached N atom, it forms a C1-C6, such as C1-C4, alkylene-substituted 5-, 6-, 7-, or 8-membered monocyclic heterocycle or heteroaromatic ring, containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein at least one heteroatom is N. In some embodiments, R a R b Non-limiting examples of heterocycles or heteroaromatic rings, which together with the N atom to which they are attached, form C1-C6 (e.g., C1-C4) alkylene rings with optional substitution of 5-12 (e.g., 5-6) members, including but not limited to the following heterocycles: * indicates the position attached to other parts of the compound molecule.

[0117] In some implementation schemes, R a R b R c Together with the N atom it is attached to, it forms a C1-C6, for example, C1-C4, alkylene ring with optional substitution of 5-12, for example, 5-6 membered heterocycles or heteroaromatic rings. These alkylene rings can be monocyclic, fused bicyclic, spirocyclic, or bridged bicyclic rings, etc. In some embodiments, R... a R b R ctogether with the N atom to which they are attached form a 5- to 12-membered, e.g., 5- to 6-membered, heterocyclic or heteroaromatic ring, optionally substituted with C1-C6, e.g., C1-C4, alkylene, wherein at least one heteroatom is N. In some embodiments, R a , R b , R c together with the N atom to which they are attached form a 5- to 12-membered, e.g., 5- to 6-membered, heterocyclic or heteroaromatic ring, optionally substituted with C1-C6, e.g., C1-C4, alkylene, wherein at least one heteroatom is N. In some embodiments, R

[0118] In some embodiments, Group A includes groups comprising at least one ionizable tertiary amine structure as shown in the following structures:

[0119] In this context, substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having from 11 to 30 carbon atoms can be collectively referred to as a group of groups, i.e., Group B. When R I and R IV are substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having from 11 to 30 carbon atoms selected from Group B, they can be the same or different.

[0120] In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups selected from Group B have from 11 to 30 carbon atoms, e.g., 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 carbon atoms. In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups selected from Group B have, e.g., from 11 to 16 carbon atoms, from 11 to 25 carbon atoms, from 16 to 25 carbon atoms, from 16 to 30 carbon atoms, or a range of carbon atoms between any two of the recited values within the range of 11 to 30.

[0121] In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups selected from Group B comprise from 1 to 8 heteroatoms independently selected from N, O, S, and the like, e.g., 1, 2, 3, 4, 5, 6, 7, and 8 heteroatoms. In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups selected from Group B comprise, e.g., from 1 to 2 heteroatoms, from 1 to 3 heteroatoms, from 1 to 4 heteroatoms, from 1 to 5 heteroatoms, or a range of heteroatoms between any two of the recited values within the range of 1 to 8.

[0122] In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group selected from Group B has 11-30 atoms including carbon atoms and N, O, S, and the like heteroatoms, for example, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30 atoms. In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group selected from Group B has, for example, 11-16 atoms, 11-25 atoms, 16-25 atoms, 16-30 atoms, or a range of atoms between any two of the recited values within the range of 11-30.

[0123] In some embodiments, Group B includes substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms as shown in the following structures:

[0124] In this document, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl groups having less than 11 carbon atoms can be collectively referred to as a group of groups, namely Group C.

[0125] In some embodiments, the substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group selected from Group C has 1-11 carbon atoms, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 carbon atoms. In some embodiments, the substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group selected from Group C has, for example, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, or a range of carbon atoms between any two of the recited values within the range of 1-11.

[0126] In some embodiments, the substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group selected from Group C comprises 1-5 heteroatoms independently selected from N, O, S, and the like, for example 1, 2, 3, 4, and 5 heteroatoms. In some embodiments, the substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group selected from Group C comprises, for example, 1-2 heteroatoms, 1-3 heteroatoms, 1-4 heteroatoms, or a range of heteroatoms between any two of the recited values in the range of 1-5.

[0127] In some embodiments, the substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group selected from Group C has 1-11 atoms including carbon atoms and N, O, S, and the like heteroatoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 atoms. In some embodiments, the substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group selected from Group C has, for example, 1-6 atoms, 1-7 atoms, 1-8 atoms, 1-9 atoms, 1-10 atoms, 1-11 atoms, or a range of atoms between any two of the recited values in the range of 1-11.

[0128] In some embodiments, the substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group selected from Group C is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH.

[0129] In some embodiments, substituted or unsubstituted hydrocarbyl groups include linear, branched, or cyclic alkyl, alkenyl, and alkynyl groups. In some embodiments, substituted or unsubstituted hydrocarbyl groups contain one or more, for example, 1, 2, 3, 4, or 5, unsaturated carbon-carbon double bond (-C=C-), carbon-carbon triple bond (-C≡C-) groups, and / or any combination thereof. In some embodiments, substituted or unsubstituted heterohydrocarbyl groups include linear, branched, or cyclic heteroalkyl, heteroalkenyl, and heteroalkynyl groups containing a heteroatom selected from N, O, and S. In some embodiments, the heteroatoms contained in substituted or unsubstituted heterohydrocarbyl groups can together with carbon atoms form a backbone of a heteroaliphatic group, for example, but not limited to, -C-N-C-, -C-O-C-, -C-O-O-C, -C-S-C-, -C-S-S-C, and the like group structures or any combination thereof. In some embodiments, the heteroatoms contained in substituted or unsubstituted heterohydrocarbyl groups can be substituents attached to carbon atoms, for example, but not limited to, -C≡N, -C=N-, -C-N=, -C=O, -C-OH, -C=S, -C-SH, and the like substituent structures. In some of the described embodiments, the heteroatoms contained in substituted or unsubstituted heterohydrocarbyl groups can be any combination of the above-listed group structures. In some embodiments, the heteroaliphatic group contains one or more, for example, 1, 2, 3, 4, or 5, unsaturated carbon-carbon double bond (-C=C-), carbon-carbon triple bond (-C≡C-), -NH-, -NH2, -OH, -OR m -O-, -C(O)-, -C(OR n -C(O)O-, -SH, -SR o -S-, -C(S)-, -C(SR p -C(S)O-, and -P(O)-, wherein R m , R n , R o , and R p each independently is a substituted or unsubstituted C1-C 14 aliphatic hydrocarbyl group, for example, a C1-C 12 , C1-C 10 , C1-C8, C1-C6, C1-C4 aliphatic hydrocarbyl group. Non-limiting specific examples of substituted or unsubstituted C1-C 14 aliphatic hydrocarbyl groups include, but are not limited to, methyl, ethyl, n-propyl and i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene (vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0130] In some embodiments, Group C includes substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl groups having fewer than 11 carbon atoms as shown in the following structures:

[0131] In some embodiments, R I and R IV each independently optionally comprises at least one degradable group. The lipid compounds of the present disclosure preferably comprise a degradable group that, upon entering a cell, tissue, or organ, the degradable group comprised in the lipid compound of the present disclosure is cleaved, thereby causing the lipid compound to partially or completely degrade, thereby reducing or completely eliminating the toxicity of the lipid compound to the cell. The introduction of a degradable group can accelerate the metabolism of the lipid in organs such as the liver, thereby reducing the accumulation of the lipid in the body, reducing potential toxicity.

[0132] In some embodiments, the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -S-S-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -NR 1 C(O)-, -C(O)NR 2 -, -NR 3 C(O)O-, -OP(O)OR 4 O-, -OCR 5 (OR 6 )O-, -CR 7 (OR 8 )O-, -CH(OR 9 )O-, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 each independently is a substituted or unsubstituted C1-C 14 aliphatic hydrocarbyl group, including linear, branched, cyclic alkane, alkene, alkyne, or polyunsaturated hydrocarbyl groups, such as C1-C 12 , C1-C 10 , C1-C8, C1-C6, C1-C4 aliphatic hydrocarbyl group, substituted or unsubstituted C1-C 14Non-limiting examples of aliphatic hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl and i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene (vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0133] In some embodiments, R I and R IV each independently comprise at least one degradable group.

[0134] In some embodiments, only one of R I and R IV comprises at least one degradable group. In some embodiments, the degradable group is an ester group, i.e., -C(O)-O-; or an ester bond is included in the degradable group.

[0135] In some embodiments, only one of R I and R IV comprises one, two, or three degradable groups. In some embodiments, the degradable group is an ester group, i.e., -C(O)-O-; or an ester bond is included in the degradable group.

[0136] In some embodiments, only one of R I and R IV comprises one, two, or three ester groups or ester bonds, e.g., R I comprises one, two, or three ester groups or ester bonds and R IV comprises one, two, or three ester groups or ester bonds.

[0137] In some embodiments, R I and R IV each independently comprise at least one degradable group. In some embodiments, the degradable group is an ester group, i.e., -C(O)-O-; or an ester bond is included in the degradable group.

[0138] In some embodiments, R I and R IV each independently comprise one, two, or three degradable groups. In some embodiments, the degradable group is an ester group, i.e., -C(O)-O-; or an ester bond is included in the degradable group.

[0139] In some embodiments, R I and R IV each independently comprise one, two, or three ester groups or ester bonds, e.g., R I comprises one, two, or three ester groups or ester bonds and R IV comprises one, two, or three ester groups or ester bonds.

[0140] In some embodiments, R II is hydrogen or selected from group C, R III is selected from group A, R II is selected from group C, R I and R IV is selected from group B, groups A, B and C are as defined herein;

[0141] Preferably, R I and R IV comprises a degradable group, for example the degradable group is an ester group, i.e. -C(O)-O-; or the degradable group comprises an ester bond,

[0142] Preferably, when R I and / or R IV does not comprise a degradable group, R I and / or R IV is selected from the group consisting of:

[0143] Preferably, when R I and / or R IV comprises a degradable group, R I and / or R IV is selected from the group consisting of:

[0144] In some embodiments, the lipid compound of the present disclosure has the general structure (I) A )

[0145] wherein R II , R I , R II , R III and R IV are as defined in the present disclosure.

[0146] groups A, B and C are as defined in the present disclosure.

[0147] In some embodiments, R II is selected from group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of 1-11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and R II is selected from group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of 1-11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. In some embodiments, R II and R IIare the same. In some embodiments, R II are different. II are different.

[0148] In some embodiments, R II is selected from substituted or unsubstituted alkyl having a carbon number of 1-11, for example, substituted or unsubstituted C1-C8 alkyl, C1-C6 alkyl, C1-C4 alkyl, and R II is selected from substituted or unsubstituted alkyl having a carbon number of 1-11, for example, substituted or unsubstituted C1-C8 alkyl, C1-C6 alkyl, C1-C4 alkyl. In some embodiments, R II are the same. In some embodiments, R II are different. II are different. II are different.

[0149] In some embodiments, R II is selected from substituted or unsubstituted C1-C4 alkyl, and R II is selected from substituted or unsubstituted C1-C4 alkyl. R II and R II are the same, or are different.

[0150] In some embodiments, R II is hydrogen, and R II is selected from group (C) comprising substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group having a carbon number of 1-11.

[0151] In some embodiments, R II is hydrogen, and R II is selected from substituted or unsubstituted cycloalkyl having a carbon number of 3-11, for example, substituted or unsubstituted C3-C8 cycloalkyl, C3-C6 cycloalkyl, C3-C4 cycloalkyl.

[0152] In some embodiments, R II is hydrogen, and R II is selected from substituted or unsubstituted C3-C4 cycloalkyl, for example, cyclopropyl, cyclobutyl.

[0153] In some embodiments, the lipid compound of the present disclosure has the following general structural formula (I B )

[0154] wherein R II , R I , R II , R III and RIV As defined in the present disclosure, for example, the definition of structural general formula (I) A ) includes the definition of various embodiments, which are not repeated here.

[0155] In some embodiments of the present disclosure, a lipid compound of formula (I), or an N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,

[0156] wherein X is O or S;

[0157] R II is selected from hydrogen, substituted or unsubstituted C1-C8alkyl, or substituted or unsubstituted C1-C8heteroalkyl;

[0158] R III is selected from group (A) comprising a group comprising at least one ionizable tertiary amine structure, wherein the group comprising at least one ionizable tertiary amine structure has a number of carbon atoms of 3-11 and is represented by the following general formula,

[0159] wherein R a is C1-C6substituted or unsubstituted alkylene; R b , R c each independently is C1-C6substituted or unsubstituted alkyl, C2-C6substituted or unsubstituted alkenyl, C2-C6substituted or unsubstituted alkynyl, which optionally can be substituted with 1, 2, or 3 substituents selected from -OH, -SH, -NR d R d or phenyl, wherein R d , R d each independently is hydrogen or C1-C3alkyl; or R b , R c together with the N atom to which they are attached form a 5-12 membered heterocyclic or heteroaromatic ring comprising 1, 2, or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, which 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with one or more C1-C6alkyl or oxo (=O);

[0160] R I and R IV each independently is selected from group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a number of carbon atoms of 11-30; and

[0161] Group B includes a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a carbon count of 11-30, wherein the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a carbon count of 11-30 optionally comprises 1, 2, 3, or 4 groups independently selected from -C=C-, -CºC-, -0-, -C(O)-, -C(OR n )-, -C(O)O-, -S-, -C(S)-, -C(SR p )-, and -C(S)O-, wherein R n and R p are each independently a substituted or unsubstituted C1-C8 aliphatic hydrocarbon group; and

[0162] R II is selected from Group (C) including a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group having a carbon count of 1-11.

[0163] In some embodiments, a lipid compound of Formula (I A ), or an N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, is provided,

[0164] wherein R II ', R I , R II , R III , and R IV are as defined in the disclosure.

[0165] In some embodiments, a lipid compound of Formula (I B ), or an N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, is provided,

[0166] wherein R II ', R I , R II , R III , and R IV are as defined in the disclosure.

[0167] In some embodiments, R II ' is selected from hydrogen, or a substituted or unsubstituted C1-C8 alkyl, such as C1-C6 alkyl, C1-C4 alkyl including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, primary butyl, secondary butyl, tertiary butyl, pentyl, hexyl, and the like. In some embodiments, R II ' is the same as R II . In some embodiments, R II ' is different from R II .

[0168] In some embodiments, R I and R IV are each independently selected from Group B, wherein the substituted or unsubstituted aliphatic selected from Group B has 11-30 carbon atoms, and the substituted or unsubstituted heteroaliphatic selected from Group B has 11-30 atoms including carbon atoms and N, O, S, and the like heteroatoms.

[0169] In some embodiments, R I and R IV each independently have a number of carbon atoms of 16 to 30, and the other has a number of carbon atoms of 11 to 25.

[0170] In some embodiments, R I and R IV each independently have a number of carbon atoms of 16 to 25, and the other has a number of carbon atoms of 11 to 16.

[0171] In some embodiments, R I and R IV each independently optionally comprise at least one degradable group.

[0172] In some embodiments, the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -S-S-, -OCR 5 (OR 6 )O-, -CR 7 (OR 8 )O-, -CH(OR 9 )O-, wherein R 5 , R 6 , R 7 , R 8 and R 9 are each independently a substituted or unsubstituted C1-C8 aliphatic hydrocarbon group, preferably the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-; or the degradable group comprises an ester linkage.

[0173] In some embodiments, at least one of R I and R IV comprises at least one degradable group, for example the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-, or the degradable group comprises an ester linkage.

[0174] In some embodiments, only one of R I and R IV comprises one, two, or three degradable groups, for example the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-, or the degradable group comprises an ester linkage; and the other does not comprise a degradable group.

[0175] In some embodiments, R I and R IV each independently comprises one, two, or three degradable groups, for example, the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-, or an ester bond is included in the degradable group.

[0176] In some embodiments, the group A comprises a group represented by the following structure:

[0177] In some embodiments, the group B comprises a group represented by the following structure:

[0178] In some embodiments, the group C comprises a group represented by the following structure:

[0179] In some embodiments, when R I and / or R IV does not comprise a degradable group, R I and / or R IV is selected from a group represented by the following structure:

[0180] In some embodiments, when R I and / or R IV comprises a degradable group, R I and / or R IV is selected from a group represented by the following structure:

[0181] In some embodiments, R III is selected from

[0182] In some embodiments, R II is selected from

[0183] In some embodiments of the disclosure, there is provided a lipid compound of Formula (I), or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0184] wherein X is O or S;

[0185] R II is selected from hydrogen, or substituted or unsubstituted C1-C8alkyl;

[0186] R IIIselected from group (A) comprises a group comprising at least one ionizable tertiary amine structure, wherein the group comprising at least one ionizable tertiary amine structure has a number of carbon atoms from 3 to 11 and is represented by the general formula

[0187] wherein R a is a C1-C6substituted or unsubstituted alkylene; R b , R c each independently is a C1-C6substituted or unsubstituted alkyl, C2-C6substituted or unsubstituted alkenyl, C2-C6substituted or unsubstituted alkynyl, which optionally can be substituted with 1, 2, or 3 substituents selected from the group consisting of -OH, -SH, -NR d R d or phenyl, wherein R d , R d each independently is hydrogen or C1-C3alkyl;

[0188] R I and R IV each independently is selected from group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a number of carbon atoms from 11 to 30; and

[0189] group B comprises a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a number of carbon atoms from 11 to 30, wherein the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a number of carbon atoms from 11 to 30 optionally comprises 1, 2, 3, or 4 groups independently selected from -C=C-, -CºC-, -O-, -C(O)-, -C(O)O-, -S-, -C(S)-, and -C(S)O-; and

[0190] R II is selected from group (C) comprising a substituted or unsubstituted hydrocarbon group having a number of carbon atoms from 1 to 11.

[0191] In some embodiments, a lipid compound of Formula (I A ), or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, is provided,

[0192] wherein R II , R I , R II , R III , and R IV are as defined in the disclosure.

[0193] In some embodiments, a lipid compound of Formula (I B ), or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, is provided,

[0194] wherein R II , R I , R II , R III , and R IV are as defined in the present disclosure.

[0195] In some embodiments, R II is selected from hydrogen, or substituted or unsubstituted C1-C8 alkyl, for example C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, and the like. In some embodiments, R II is the same as R II . In some embodiments, R II is different from R II .

[0196] In some embodiments, R I and R IV are each independently selected from Group B, wherein the substituted or unsubstituted aliphatic selected from Group B has 11-30 carbon atoms, and the substituted or unsubstituted heteroaliphatic selected from Group B has 11-30 atoms including carbon atoms and N, O, S, and the like heteroatoms. In some embodiments, either R I or R IV has a number of carbon atoms from 16 to 30, and the other has a number of carbon atoms from 11 to 25. In some embodiments, either R I or R IV has a number of carbon atoms from 16 to 25, and the other has a number of carbon atoms from 11 to 16.

[0197] In some embodiments, R I and R IV each independently optionally comprise at least one degradable group.

[0198] In some embodiments, the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, preferably the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-; or an ester bond is included in the degradable group.

[0199] In some embodiments, at least one of R I and R IV comprises at least one degradable group, for example the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-, or an ester bond is included in the degradable group.

[0200] In some embodiments, RI and only one of R IV contains one or two degradable groups, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or an ester bond is included in the degradable group; and the other does not contain a degradable group.

[0201] In some embodiments, R I and R IV each independently contains one or two degradable groups, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or an ester bond is included in the degradable group.

[0202] In some embodiments, the group A includes a group represented by the following structure:

[0203] In some embodiments, the group B includes a group represented by the following structure:

[0204] In some embodiments, the group C includes a group represented by the following structure:

[0205] In some embodiments, when R I and / or R IV does not contain a degradable group, R I and / or R IV is selected from a group represented by the following structure:

[0206] In some embodiments, when R I and / or R IV contains a degradable group, R I and / or R IV is selected from a group represented by the following structure:

[0207] In some embodiments, R III is selected from

[0208] In some embodiments, R III is selected from

[0209] In some embodiments, R III is selected from

[0210] for example R III is

[0211] In some embodiments, R II is selected from

[0212] In some embodiments, R II is selected from

[0213] In some embodiments, R II is selected from hydrogen, and R II is selected from methyl, ethyl, n-propyl and i-propyl, n-butyl, sec-butyl, i-butyl, t-butyl, cyclopropyl and cyclobutyl.

[0214] In some embodiments, R II is selected from methyl, ethyl, n-propyl and i-propyl, n-butyl, sec-butyl, i-butyl and t-butyl, and R II is selected from methyl, ethyl, n-propyl and i-propyl, n-butyl, sec-butyl, i-butyl and t-butyl, R II and R II are the same or are different.

[0215] In some embodiments, the lipid compound of formula (I) of the present disclosure is a lipid compound as shown below:

[0216] In some embodiments, the lipid compound of formula (I) of the present disclosure has a molecular weight in the range of about 500 g / mol to about 1400 g / mol; preferably the lipid compound has a molecular weight in the range of about 600 g / mol to about 1200 g / mol; preferably the lipid compound has a molecular weight in the range of about 600 g / mol to about 1000 g / mol; more preferably the lipid compound has a molecular weight in the range of about 700 g / mol to about 1000 g / mol.

[0217] The lipid compound of formula (I) of the present disclosure is used for nucleic acid delivery to achieve the introduction of nucleic acids (e.g. DNA, RNA) into organelles, cells, tissues or organisms.

[0218] Liposomes

[0219] In some aspects, the present disclosure relates to liposomes. The liposomes of the present disclosure comprise the lipid compounds of the present disclosure as described above. The lipid compounds of the present disclosure can also be referred to as cationic lipids or ionizable lipids when used for the preparation of the liposomes of the present disclosure.

[0220] In some embodiments, the lipid compound comprises about 10 mol% to about 90 mol%, for example about 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, 60 mol%, 65 mol%, 70 mol%, 75 mol%, 80 mol%, 85 mol%, 90 mol%, or a range between any of the foregoing, of the total molar amount of the components that make up the liposome.

[0221] In some embodiments, the liposome of the present disclosure further comprises a phospholipid and a cholesterol.

[0222] In some embodiments, the phospholipid comprises about 0 mol% to about 20 mol%, or a range between any of the foregoing, of the total molar amount of the components that make up the liposome.

[0223] In some embodiments, the cholesterol comprises about 30 mol% to about 50 mol%, or a range between any of the foregoing, of the total molar amount of the components that make up the liposome.

[0224] In one aspect, the present disclosure provides use of the liposome of the present disclosure as a delivery vehicle, for example, for delivering plasmids, nucleic acids such as RNA.

[0225] In one aspect, the present disclosure provides a drug delivery system comprising the liposome of the present disclosure as a delivery vehicle, for example, for delivering plasmids, nucleic acids including DNA and RNA, such as mRNA.

[0226] Methods of preparing liposomes are widely known in the art. The liposomes of the present disclosure can be prepared using conventional methods well known to those skilled in the art.

[0227] Lipid Nanoparticles

[0228] In some aspects, the present disclosure relates to lipid nanoparticles. The lipid nanoparticles of the present disclosure comprise the lipid compound of the present disclosure as described above. The lipid compound of the present disclosure can also be referred to as a cationic lipid or an ionizable lipid when used in the preparation of the lipid nanoparticles of the present disclosure.

[0229] In some embodiments, the lipid compound comprises about 10 mol% to about 90 mol%, e.g., about 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, 60 mol%, 65 mol%, 70 mol%, 75 mol%, 80 mol%, 85 mol%, 90 mol%, or a range between any two of the foregoing, based on the total molar amount of the components that make up the lipid nanoparticle. Preferably, the lipid compound comprises about 10 mol% to about 70 mol%, more preferably, the lipid compound comprises about 20 mol% to about 50 mol%.

[0230] In some embodiments, the lipid compound of the present disclosure further comprises a phospholipid, a structural lipid, or a PEG lipid.

[0231] In some embodiments, the phospholipid comprises about 0 mol% to about 20 mol%, or a range between any two of the foregoing, based on the total molar amount of the components that make up the lipid nanoparticle.

[0232] In some embodiments, the structural lipid comprises about 30 mol% to about 50 mol%, or a range between any two of the foregoing, based on the total molar amount of the components that make up the lipid nanoparticle.

[0233] In some embodiments, the PEG lipid comprises about 0 mol% to about 10 mol%, or a range between any two of the foregoing, based on the total molar amount of the components that make up the lipid nanoparticle.

[0234] In some embodiments, the lipid nanoparticle of the present disclosure further comprises a nucleic acid.

[0235] In some embodiments, the N / P ratio of the lipid compound to the nucleic acid is about 1.1:1 to 10:1, or a range between any two of the foregoing. In this context, the N / P ratio can be defined as the ratio of the number of N atoms of ionizable groups contained in the lipid compound (which can also be referred to as “cationic lipid” or “ionizable lipid”) to the number of P atoms of phosphate groups of the nucleic acid in the lipid nanoparticle comprising the nucleic acid. The N / P ratio can be calculated based on, for example, 1 pg of RNA typically contains about 3 nmol of phosphate residues, provided that the RNA presents a statistical distribution of bases. The “N” value of the lipid compound can be calculated according to its molecular weight and the relative content of cationic groups. If there is more than one lipid compound, the N value should be calculated based on all the lipid compounds contained in the lipid nanoparticle.

[0236] In some embodiments, the ratio of the lipid compound to the nucleic acid is calculated as a mass ratio.

[0237] In some embodiments, examples of nucleic acids include single- and double- stranded DNA, single- and double- stranded RNA, and hybrid molecules having a mixture of single- and double- stranded DNA and RNA. In some embodiments, examples of nucleic acids include any type of RNA, such as messenger RNA (mRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), single guide RNA (sgRNA), CRISPR RNA (crRNA), trans-activating RNA (tracrRNA), plasmid DNA (pDNA), mini-circle DNA, genomic DNA (gNDA), and any fragment thereof. In some embodiments, the nucleic acid comprised by the lipid nanoparticles of the present disclosure can be a mixture of one or more nucleic acid molecules.

[0238] In some embodiments, the lipid nanoparticles of the present disclosure further comprise a plasmid.

[0239] In some embodiments, the apparent pKa value of the lipid nanoparticles of the present disclosure is between about 5.5 to about 8.5, for example, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5; the apparent pKa value of the lipid nanoparticles of the present disclosure is within a range between any two of the above-mentioned values, for example, between about 5.8 to about 8.2, between about 6.6 to about 8.2, or between about 7.0 to about 8.0.

[0240] In one aspect, the present disclosure provides the use of the lipid nanoparticles as delivery vehicles, for example, for delivering plasmids, nucleic acids such as RNA.

[0241] In one aspect, the present disclosure provides a drug delivery system comprising the lipid nanoparticles of the present disclosure as delivery vehicles, for example, for delivering plasmids, nucleic acids such as RNA.

[0242] In one aspect, the present disclosure provides the lipid nanoparticles encapsulating nucleic acid molecules such as RNA.

[0243] In one aspect, the present disclosure provides the lipid nanoparticles encapsulating plasmids.

[0244] Methods for preparing lipid nanoparticles are widely known in the art. The lipid nanoparticles of the present disclosure can be prepared using conventional methods well known to those skilled in the art.

[0245] Nucleic acid delivery

[0246] In contrast to the traditional lipid nanoparticles which are mainly distributed in the liver tissue after systemic administration, the present inventors surprisingly found that the lipid nanoparticles composed of the lipid compounds of the present disclosure can efficiently deliver the nucleic acid drugs, such as mRNA, to the tissues where immune cells are concentrated, such as the spleen and lymph nodes, significantly increasing the distribution efficiency of the nucleic acid drugs in the immune tissues such as the spleen and lymph nodes. The spleen and lymph nodes are the main sites where immune cells are concentrated, and can efficiently deliver the nucleic acid drugs to these tissues, which plays an important role in improving the immunogenicity of the drugs.

[0247] In some aspects, the present disclosure relates to the use of the lipid compounds of the present disclosure, i.e., the lipid compounds of Formula (I) or N-oxides, stereoisomers or pharmaceutically acceptable salts thereof, the lipid nanoparticles comprising the lipid compounds of Formula (I) or N-oxides, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions comprising the lipid compounds or the lipid nanoparticles and a pharmaceutically acceptable carrier or excipient, for delivering nucleic acids to immune organs and / or tissues.

[0248] In some embodiments, the nucleic acids include DNA and RNA, such as mRNA.

[0249] In some embodiments, the immune organs and / or tissues include, but are not limited to, the spleen, lymph nodes, etc.

[0250] In some aspects, the present disclosure relates to the use of the lipid compounds of the present disclosure, i.e., the lipid compounds of Formula (I) or N-oxides, stereoisomers or pharmaceutically acceptable salts thereof, the lipid nanoparticles comprising the lipid compounds of Formula (I) or N-oxides, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions comprising the lipid compounds or the lipid nanoparticles and a pharmaceutically acceptable carrier or excipient, for preparing a medicament for delivering nucleic acids to immune organs and / or tissues.

[0251] In some embodiments, the nucleic acids include DNA and RNA, such as mRNA.

[0252] In some embodiments, the immune organs and / or tissues include, but are not limited to, the spleen, lymph nodes, etc.

[0253] In some aspects, the present disclosure relates to a lipid compound of the present disclosure, i.e., a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, a lipid nanoparticle comprising a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the lipid compound or the lipid nanoparticle, and a pharmaceutically acceptable carrier or excipient, for use in delivering a nucleic acid to an immune organ and / or tissue.

[0254] In some embodiments, the nucleic acid comprises DNA and RNA, e.g., mRNA.

[0255] In some embodiments, the immune organ and / or tissue comprises, but is not limited to, spleen, lymph node, etc.

[0256] In some aspects, the present disclosure relates to a method of delivering a nucleic acid to an immune organ and / or tissue, wherein the method uses a lipid compound of the present disclosure, i.e., a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, a lipid nanoparticle comprising a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the lipid compound or the lipid nanoparticle, and a pharmaceutically acceptable carrier or excipient.

[0257] In some embodiments, the nucleic acid comprises DNA and RNA, e.g., mRNA.

[0258] In some embodiments, the immune organ and / or tissue comprises, but is not limited to, spleen, lymph node, etc.

[0259] Pharmaceutical composition

[0260] In some aspects, the present disclosure relates to a pharmaceutical composition comprising a lipid compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt as provided herein, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises a lipid nanoparticle as provided herein, and at least one pharmaceutically acceptable carrier or excipient.

[0261] As used herein, the term "pharmaceutically acceptable carrier or adjuvant" means a carrier or adjuvant that can be used in preparing a pharmaceutical composition and that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes a carrier or adjuvant that is acceptable for veterinary use as well as human pharmaceutical use. A pharmaceutically acceptable carrier or adjuvant as used herein includes one and more than one such carrier or adjuvant. The specific carrier or adjuvant used will depend on the means and purpose of the application of the compounds of the disclosure. Suitable carriers and adjuvants are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C, et al. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. One or more of buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, flavors, sweeteners, perfuming agents, flavoring agents, diluents, and other known additives, can also be included in the pharmaceutical compositions provided herein, insofar as they do not incompatibly affect the properties

[0262] The compositions of the present disclosure can be formulated into various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, suppositories, and the like. The form is dependent on the intended means of administration and therapeutic application.

[0263] The pharmaceutical compositions of the present disclosure can be prepared by any of the well-known pharmaceutical techniques, e.g., effective formulation and administration procedures. The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. For example, formulation of pharmaceutical products is discussed in Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients, 3rdEd., American Pharmaceutical Association, Washington, 1999.

[0264] Examples

[0265] To describe the application in further detail, the following examples are presented. The examples described herein serve to illustrate the lipid compounds, methods of preparation, lipid nanoparticles, and pharmaceutical compositions provided herein and should not be construed to limit the scope thereof in any way.

[0266] During synthesis, it can be necessary and / or desirable to protect sensitive or reactive groups of any of the molecules involved. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene and P. G. M. Wutts, Protective Groups in Organic Synthesis, 4thEd., John Wiley and Sons, which are readily removed at a convenient subsequent stage. Methods well known in the art can be used to optionally remove the protecting groups at a convenient subsequent stage.

[0267] The lipid compounds of the present disclosure can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. Variations on the reactions outlined in these reaction schemes can also be made by one skilled in the art and are contemplated to be within the scope of the present disclosure. Furthermore, other methods of preparing the lipid compounds of the present disclosure according to the reaction schemes and examples described herein will be apparent to those skilled in the art. Unless otherwise indicated, all variables are defined as above. Generally, in the chemical procedures, all reagents and starting materials are either commercially available or can be readily prepared by one skilled in the art.

[0268] Example 1

[0269] Synthesis of lipid isonitrile structures follows:

[0270] Dissolve oleic acid (2.8247 g, 1 eq), N-Boc-3-amino-1-propanol (1.7523 g, 1 eq), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.9170 g, 1 eq), 4-(dimethylamino)pyridine (0.1222 g, 0.1 eq) in a 250 mL single neck flask with 50 mL DCM, stir well at room temperature for 18 h. After the reaction is completed, remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE). After passing through the column, dissolve the product in 10 mL DCM, slowly drop into 10 mL TFA, stir well for 3 h. After the reaction is completed, add 20 mL saturated sodium bicarbonate solution, extract with DCM three times, dry over anhydrous sodium sulfate, filter, and remove the solvent by rotary evaporation to obtain the crude 3-aminopropyl oleate. Take 3-aminopropyl oleate (4.2230 g, 1 eq), sodium chlorodifluoroacetate (2.3623 g, 2 eq), potassium carbonate (3.4553 g, 2 eq) in a 500 mL single neck flask, add 100 mL DMF, replace nitrogen, and heat up. Stir at 100 °C in an oil bath for 12 h. Cool down to room temperature, add 100 mL dichloromethane, and wash with a large amount of deionized water four times and saturated brine once. Dry over anhydrous sodium sulfate. Remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE).

[0271] 1 H NMR (500 MHz, CDC13, ppm): δ 5.34 (m, 2H), 4.21 (t, 2H), 3.51 (t, 2H), 2.31 (t, 2H), 2.01 (m, 6H), 1.61 (m, 2H), 1.26 (m, 20H), 0.88 (t, 3H). LCMS (APCI): 350.2 m / z (M+H + ) Chemical Formula: C 22 H 39 NO2

[0272] Example 2

[0273] The synthesis of the lipid isonitrile structure is as follows:

[0274] N-Boc-γ-aminobutyric acid (2.1604 g, 1 eq), cis-9-octadecenol (2.8561 g, 1 eq), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.0378 g, 1 eq), 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were sequentially dissolved in a 250 mL single-neck flask containing 50 mL DCM, and stirred at room temperature for 18 h. After the reaction was completed, the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10 mL DCM, and then slowly dropped into 10 mL TFA, and stirred for 3 h. After the reaction was completed, 20 mL saturated sodium bicarbonate solution was added, extracted with DCM three times, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain the crude (Z)-dodec-9-en-1-yl-4-aminobutanoate. (Z)-Dodec-9-en-1-yl-4-aminobutanoate (4.9320 g, 1 eq), sodium chlorodifluoroacetate (2.6457 g, 2 eq), potassium carbonate (3.8699 g, 2 eq) were placed in a 500 mL single-neck flask, 100 mL DMF was added, and after replacement with nitrogen, the temperature was raised, and stirred at 100 °C for 12 h in an oil bath. After cooling to room temperature, 100 mL dichloromethane was added, and then washed with a large amount of deionized water four times, and saturated brine once, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE).

[0275] 1 H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.06 (t, 2H), 3.16 (t, 2H), 2.35 (t, 2H), 2.01 (m, 4H), 1.80 (m, 2H), 1.60 (m, 2H), 1.29 (m, 22H), 0.88 (t, 3H). LCMS (APCI): 364.2 m / z (M+H + ) Chemical Formula: C 23 H 41 NO2

[0276] Example 3

[0277] The synthesis of the lipid isonitrile structure is as follows:

[0278] Nonanoic acid (1.6325 g, 1 eq), N-Boc-γ-amino-1-propanol (1.9136 g, 1 eq), dicyclohexyl carbodiimide (2.0216 g, 1 eq), 4-(dimethylamino)pyridine (0.1312 g, 0.1 eq) were sequentially dissolved in a 250 mL single neck flask containing 50 mL DCM, stirred well at room temperature for 18 h. After the reaction was completed, the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10 mL DCM, slowly dropped into 10 mL TFA, stirred well for 3 h. After the reaction was completed, 20 mL saturated sodium bicarbonate solution was added, extracted with DCM three times, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain the crude 3-aminopropanol nonanoate. 3- Aminopropanol nonanoate (3.5120 g, 1 eq), sodium chlorodifluoroacetate (3.1182 g, 2 eq), potassium carbonate (4.5603 g, 2 eq) were taken in a 500 mL single neck flask, 100 mL DMF was added, and the nitrogen was replaced after which the temperature was increased, and stirred at 100 °C in an oil bath for 12 h. The temperature was decreased to room temperature, 100 mL dichloromethane was added, and then washed with a large amount of deionized water four times and saturated brine once, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE).

[0279] 1 H NMR (500 MHz, CDCl3, ppm): δ 4.21 (t, 2H), 3.51 (t, 2H), 2.31 (t, 2H), 2.03 (m, 2H), 1.61 (m, 2H), 1.29 (m, 10H), 0.88 (t, 3H). LCMS (APCI): 225.9 m / z (M+H + ) Chemical Formula: C 13 H 23 NO2

[0280] Example 4

[0281] The synthesis of the lipid isonitrile structure is as follows:

[0282] N-Boc-γ-aminobutyric acid (2.1604 g, 1 eq), n-octanol (1.3819 g, 1 eq), dicyclohexyl carbodiimide (2.0216 g, 1 eq), 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were sequentially dissolved in a 250 mL single-neck flask containing 50 mL DCM, and stirred at room temperature for 18 h. After the reaction was completed, the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10 mL DCM, and then slowly dropped into 10 mL TFA, and stirred for 3 h. After the reaction was completed, 20 mL saturated sodium bicarbonate solution was added, extracted with DCM three times, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain crude octyl 4-aminobutyrate. Octyl 4-aminobutyrate (4.3068 g, 1 eq), sodium chlorodifluoroacetate (3.7796 g, 2 eq), potassium carbonate (5.5284 g, 2 eq) were taken in a 500 mL single-neck flask, 100 mL DMF was added, and after replacement with nitrogen, the temperature was raised, and stirred at 100 °C in an oil bath for 12 h. The temperature was lowered to room temperature, 100 mL dichloromethane was added, and then washed with a large amount of deionized water four times, and saturated brine once, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE).

[0283] 1 H NMR (500 MHz, CDCl3, ppm): δ 4.06 (t, 2H), 3.16 (t, 2H), 2.35 (t, 2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.29 (m, 10H), 0.88 (t, 3H). LCMS (APCI): 225.9 m / z (M+H + ) Chemical Formula: C 13 H 23 NO2

[0284] Example 5

[0285] The synthesis of the lipid isonitrile structure is as follows:

[0286] Boc-8-aminooctanoic acid (1.9179 g, 1.45 eq), 9-heptadecanol (1.3080 g, 1 eq), dicyclohexyl carbodiimide (1.0523 g, 1 eq), 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) were sequentially dissolved in a 250 mL single-neck flask containing 50 mL DCM, and stirred thoroughly at room temperature for 18 h. After the reaction was completed, the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10 mL DCM, and then slowly dropped into 10 mL TFA, and stirred thoroughly for 3 h. After the reaction was completed, 20 mL saturated sodium bicarbonate solution was added, extracted with DCM three times, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain the crude 9-heptyl-8-aminooctanoate. 9-Heptyl-8-aminooctanoate (3.1020 g, 1 eq), sodium chlorodifluoroacetate (1.4740 g, 2 eq), potassium carbonate (2.1560 g, 2 eq) were taken in a 500 mL single-neck flask, 100 mL DMF was added, and the nitrogen was replaced after which the temperature was increased, and stirred at 100 °C in an oil bath for 12 h. The temperature was decreased to room temperature, 100 mL dichloromethane was added, and then washed with a large amount of deionized water four times, and saturated brine once, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE).

[0287] 1 H NMR (500 MHz, CDCl3, ppm): δ 4.47 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 34H), 0.88 (t, 6H). LCMS (APCI): 408.3 m / z (M+H + ) Chemical Formula: C 26 H 49 NO2

[0288] Example 6

[0289] The synthesis of the lipid isonitrile structure is as follows:

[0290] Dissolve 2-hexyldecanoic acid (1.7325 g, 1 eq), N-Boc-6-amino-1-hexanol (1.5386 g, 0.8 eq), dicyclohexyl carbodiimide (1.6506 g, 1 eq), 4-(dimethylamino)pyridine (0.0977 g, 0.1 eq) in a 250 mL single-neck flask containing 50 mL DCM, and stir at room temperature for 18 h. After the reaction is completed, remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE). Dissolve the product after passing through the column in 10 mL DCM, slowly drop 10 mL TFA, and stir for 3 h. After the reaction is completed, add 20 mL saturated sodium bicarbonate solution, extract with DCM three times, dry over anhydrous Na2SO4, filter, and remove the solvent by rotary evaporation to obtain the crude 2-hexyl-6-aminodecanoate hexyl ester. Take 2-hexyl-6-aminodecanoate hexyl ester (3.0350 g, 1 eq), sodium chlorodifluoroacetate (1.7953 g, 2 eq), and potassium carbonate (2.6263 g, 2 eq) in a 500 mL single-neck flask, add 100 mL DMF, replace nitrogen, and heat to stir at 100 °C for 12 h. Cool to room temperature, add 100 mL dichloromethane, wash with deionized water four times, and wash with saturated brine once. Dry over anhydrous sodium sulfate. Remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE).

[0291] 1 H NMR (500 MHz, CDCl3, ppm): δ 4.08 (t, 2H), 3.40 (t, 2H), 2.30 (m, 1H), 1.80 (m, 2H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 366.2 m / z (M+H + ) Chemical Formula: C 23 H 43 NO2

[0292] Boc-8-aminooctanoic acid (1.9179 g, 1.45 eq), 2-heptan-2-methylethanol (0.8072 g, 1 eq), dicyclohexyl carbodiimide (1.0523 g, 1 eq), 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) were sequentially dissolved in a 250 mL single-neck flask containing 50 mL DCM, and stirred thoroughly at room temperature for 18 h. After the reaction was completed, the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10 mL DCM, and slowly dropped into 10 mL TFA, and stirred thoroughly for 3 h. After the reaction was completed, 20 mL saturated sodium bicarbonate solution was added, extracted with DCM three times, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain the crude 8-aminooctanoic acid heptadecan-9-yl ester. 8-aminooctanoic acid heptadecan-9-yl ester (3.1020 g, 1 eq), sodium chlorodifluoroacetate (1.4740 g, 2 eq), potassium carbonate (2.1560 g, 2 eq) were taken in a 500 mL single-neck flask, 100 mL DMF was added, and after replacement with nitrogen, the temperature was raised, and stirred at 100 °C in an oil bath for 12 h. The temperature was lowered to room temperature, 100 mL dichloromethane was added, and washed with a large amount of deionized water four times, and saturated brine once, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE).

[0293] 1 H NMR (500 MHz, CDCl3, ppm): δ 4.47 (m, 2H), 3.38 (t, 2H), 2.29 (t, 2H), 2.09 (m, 1H), 1.65 (m, 4H), 1.50-1.26 (m, 18H), 0.88 (t, 3H), 0.80 (t, 3H). LCMS (APCI): 310.1 m / z (M+H + ) Chemical Formula: C 19 H 35 NO2

[0294] Boc-8-aminooctanoic acid (1.9179 g, 1.45 eq), 3-undecanol (0.8788 g, 1 eq), dicyclohexyl carbodiimide (1.0523 g, 1 eq), 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) were sequentially dissolved in a 250 mL single neck flask containing 50 mL DCM, stirred well at room temperature for 18 h. After the reaction was completed, the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10 mL DCM, slowly dropped into 10 mL TFA, stirred well for 3 h. After the reaction was completed, 20 mL saturated sodium bicarbonate solution was added, extracted with DCM three times, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain the crude 8-aminooctanoic acid heptadecan-9-yl ester. 8-aminooctanoic acid heptadecan-9-yl ester (3.1020 g, 1 eq), sodium chlorodifluoroacetate (1.4740 g, 2 eq), potassium carbonate (2.1560 g, 2 eq) were taken in a 500 mL single neck flask, 100 mL DMF was added, and the flask was purged with nitrogen and heated in an oil bath at 100 °C for 12 h. The temperature was lowered to room temperature, 100 mL dichloromethane was added, and the mixture was washed with a large amount of deionized water four times and saturated brine once, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE).

[0295] 1 H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 22H), 0.88 (m, 6H). LCMS (APCI): 324.1 m / z (M+H + ) Formula: C 20 H 37 NO2

[0296] In an embodiment, isonitrile compounds were synthesized following similar synthetic reaction steps, summarized as follows:

[0297] 1 H NMR (500 MHz, CDC13, ppm): δ 5.34 (m, 2H), 4.21 (t, 2H), 3.51 (t, 2H), 2.31 (t, 2H), 2.01 (m, 6H), 1.61 (m, 2H), 1.26 (m, 20H), 0.88 (t, 3H). LCMS (APCI): 350.2 m / z (M+H + ) Formula: C 22 H 39 NO2

[0298] 1 H NMR (500 MHz, CDC13, ppm): δ 5.34 (m, 2H), 4.06 (t, 2H), 3.16 (t, 2H), 2.35 (t, 2H), 2.01 (m, 4H), 1.80 (m, 2H), 1.60 (m, 2H), 1.29 (m, 22H), 0.88 (t, 3H). LCMS (APCI): 364.2 m / z (M+H + ) Chemical Formula: C 23 H 41 NO2

[0299] 1 H NMR (500 MHz, CDC13, ppm): δ 4.21 (t, 2H), 3.51 (t, 2H), 2.31 (t, 2H), 2.03 (m, 2H), 1.61 (m, 2H), 1.29 (m, 10H), 0.88 (t, 3H). LCMS (APCI): 225.9 m / z (M+H + ) Chemical Formula: C 13 H 23 NO2

[0300] 1 H NMR (500 MHz, CDC13, ppm): δ 4.06 (t, 2H), 3.16 (t, 2H), 2.35 (t, 2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.29 (m, 10H), 0.88 (t, 3H). LCMS (APCI): 225.9 m / z (M+H + ) Chemical Formula: C 13 H 23 NO2

[0301] 1 H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 22H), 0.88 (m, 6H). LCMS (APCI): 324.1 m / z (M+H + ) Chemical Formula: C 20 H 37 NO2

[0302] 1H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.37 (t, 2H), 2.28 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 26H), 0.88 (m, 6H). LCMS (APCI): 352.1 m / z (M+H + ) Chemical Formula: C 22 H 41 NO2

[0303] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.37 (t, 2H), 2.28 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 30H), 0.88 (m, 6H). LCMS (APCI): 380.1 m / z (M+H + ) Chemical Formula: C 24 H 45 NO2

[0304] 1 H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 34H), 0.88 (t, 6H). LCMS (APCI): 408.3 m / z (M+H + ) Chemical Formula: C 26 H 49 NO2

[0305] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (m, 2H), 3.37 (t, 2H), 2.30 (m, 2H), 1.65 (m, 5H), 1.50-1.26 (m, 20H), 0.88 (m, 6H). LCMS (APCI): 341.5 m / z (M-H + ) Chemical Formula: C 20 H 37 NO2

[0306] 1H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 2H), 3.38 (t, 2H), 2.29 (t, 2H), 2.09 (m, IH), 1.65 (m, 4H), 1.50-1.26 (m, 18H), 0.88 (t, 3H), 0.80 (t, 3H). LCMS (APCI): 310.1 m / z (M+H + ) having the chemical formula: C 19 H 35 NO2

[0307] 1 H NMR (500 MHz, CDC13, ppm): δ 3.99 (d, 2H), 3.38 (t, 2H), 2.31 (m, 2H), 1.65 (m, 5H), 1.50-1.26 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 352.1 m / z (M+H + ) having the chemical formula: C 22 H 41 NO2

[0308] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (d, 2H), 3.38 (t, 2H), 2.33 (m, 2H), 1.65 (m, 5H), 1.50-1.26 (m, 28H), 0.88 (t, 6H). LCMS (APCI): 380.1 m / z (M+H + ) having the chemical formula: C 24 H 45 NO2

[0309] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (d, 2H), 3.38 (t, 2H), 2.33 (m, 2H), 1.65 (m, 5H), 1.50-1.26 (m, 30H), 0.88 (t, 6H). LCMS (APCI): 380.1 m / z (M+H + ) having the chemical formula: C 24 H 47 NO2

[0310] 1H NMR (500 MHz, CDC13, ppm): δ 3.96 (d, 2H), 3.38 (t, 2H), 2.33 (m, 2H), 1.65 (m, 5H), 1.50-1.26 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 408.3 m / z (M+H + ) Chemical Formula: C 26 H 49 NO2

[0311] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 3.38 (t, 2H), 2.30 (m, 1H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 310.1 m / z (M+H + ) Chemical Formula: C 19 H 35 NO2

[0312]

[0313] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 3.38 (t, 2H), 2.30 (m, 1H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 310.1 m / z (M+H + ) Chemical Formula: C 19 H 35 NO2

[0314] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (m, 2H), 3.38 (t, 2H), 2.29 (m, 3H), 1.66-1.10 (m, 23H), 0.88 (t, 3H). LCMS (APCI): 296.1 m / z (M+H + ) Chemical Formula: C 18 H 33 NO2

[0315] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 3.39 (t, 2H), 2.31 (m, 1H), 1.66-1.25 (m, 28H), 0.88 (t, 6H). LCMS (APCI): 338.1 m / z (M+H+ ). Chemical Formula: C 21 H 39 NO2

[0316] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 3.39 (t, 2H), 2.31 (m, 1H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 366.2 m / z (M+H + ). Chemical Formula: C 23 H 43 NO2

[0317] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 3.39 (t, 2H), 2.31 (m, 1H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 366.2 m / z (M+H + ). Chemical Formula: C 23 H 43 NO2

[0318] 1 H NMR (500 MHz, CDC13, ppm): δ 4.21 (t, 2H), 3.51 (t, 2H), 2.25 (d, 2H), 1.83 (m, 1H), 1.66-1.14 (m, 22H), 0.88 (t, 6H). LCMS (APCI): 310.1 m / z (M+H + ). Chemical Formula: C 19 H 35 NO2

[0319] 1 H NMR (500 MHz, CDC13, ppm): δ 4.21 (t, 2H), 3.51 (t, 2H), 2.25 (d, 2H), 1.83 (m, 1H), 1.66-1.14 (m, 22H), 0.88 (t, 6H). LCMS (APCI): 310.1 m / z (M+H + ). Chemical Formula: C 21 H 39 NO2

[0320] 1H NMR (500 MHz, CDC13, ppm): δ 4.21 (t, 2H), 3.51 (t, 2H), 2.25 (d, 2H), 1.83 (m, 1H), 1.66-1.14 (m, 30H), 0.88 (t, 6H). LCMS (APCI): 366.1 m / z (M+H + ) Chemical Formula: C 23 H 43 NO2

[0321] 1 H NMR (500 MHz, CDC13, ppm): δ 4.21 (t, 2H), 3.51 (t, 2H), 2.25 (d, 2H), 2.02 (m, 2H), 1.83 (m, 1H), 1.42-1.14 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 394.2 m / z (M+H + ) Chemical Formula: C 25 H 47 NO2

[0322] 1 H NMR (500 MHz, CDC13, ppm): δ 4.06 (t, 2H), 3.38 (t, 2H), 2.31 (m, 2H), 1.67 (m, 6H), 1.44-1.20 (m, 15H), 0.88 (t, 6H). LCMS (APCI): 296.1 m / z (M+H + ) Chemical Formula: C 18 H 33 NO2

[0323] 1 H NMR (500 MHz, CDC13, ppm): δ 4.10 (t, 2H), 3.38 (t, 2H), 2.31 (m, 2H), 1.67 (m, 5H), 1.44-1.20 (m, 16H), 0.88 (t, 6H). LCMS (APCI): 296.1 m / z (M+H + ) Chemical Formula: C 18 H 33 NO2

[0324] 1H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 3.38 (t, 2H), 2.29 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 21H), 0.88 (t, 6H). LCMS (ESI): 324.3 m / z. Chemical Formula: C 20 H 37 NO2

[0325] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 3.38 (t, 2H), 2.29 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 23H), 0.88 (t, 6H). LCMS (ESI): 338.3 m / z. Chemical Formula: C 21 H 39 NO2

[0326] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.64 (m, 4H), 1.50-1.26 (m, 24H), 0.88 (t, 6H). LCMS (ESI): 338.3 m / z. Chemical Formula: C 21 H 39 NO2

[0327] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.64 (m, 4H), 1.50-1.26 (m, 24H), 0.88 (t, 6H). LCMS (ESI): 338.3 m / z. Chemical Formula: C 21 H 39 NO2

[0328] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.64 (m, 4H), 1.50-1.26 (m, 26H), 0.88 (t, 6H). LCMS (ESI): 352.3 m / z. Chemical Formula: C 22 H 41 NO2

[0329] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.64 (m, 4H), 1.50-1.26 (m, 26H), 0.88 (t, 6H). LCMS (ESI): 352.3 m / z. Chemical Formula: C 22 H 41 NO2

[0330] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.64 (m, 4H), 1.50-1.26 (m, 26H), 0.88 (t, 6H). LCMS (ESI): 352.3 m / z. Chemical Formula: C 22 H 41 NO2

[0331] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 3.38 (t, 2H), 2.29 (t, 2H), 1.64 (m, 4H), 1.50-1.26 (m, 26H), 0.88 (t, 6H). LCMS (ESI): 352.3 m / z. Chemical Formula: C 22 H 41 NO2

[0332] In an embodiment, degradable acid-based components were synthesized and summarized as follows:

[0333] Synthesis of compound c70:

[0334] In a 50 ml round bottom flask, 3-cyanopropanal dimethyl acetal (1.0 eq, 7.74 mmol, 1.00 g) and n-octanol (3.0 eq, 23.23 mmol, 3.02 g) were added. Then 4-methylbenzenesulfonic acid pyridinium (0.05 eq, 0.39 mmol, 0.10 g) was added and reacted at 105 °C for 24 h. The solvent was removed under vacuum and the residue was purified by flash column (0-10% EA in PE). The purified product was dissolved in 4 ml of ethanol and potassium hydroxide (2.5 eq) was added and reacted at 110 °C for 24 h. The pH was adjusted to about 5 with 1M hydrochloric acid and then extracted with EA and dried, and the solvent was removed under vacuum to obtain a colorless oil.

[0335] 1H NMR (500 MHz, CDC13, ppm): δ 4.51 (t, 1H), 3.57 (m, 2H), 3.41 (m, 2H), 2.28 (m, 2H), 1.96 (m, 2H), 1.50-1.26 (m, 24H), 0.88 (t, 6H). LCMS (ESI): 343.2 m / z. Chemical Formula: C 20 H 40 O4

[0336] Synthesis of compound c75:

[0337] In a 50 ml round bottom flask was added 10 ml water and 10 ml tetrahydrofuran, 2-hexyldecanoic acid (1.0 eq, 10 mmol), propylene oxide (10.0 eq, 100 mmol) and sodium hydroxide (0.1 eq, 1 mmol). Stirred at room temperature overnight. Extracted with diethyl ether twice, combined the organic phases and dried, removed the solvent under vacuum and purified the residue by flash column (0-10% EA in PE). Dissolved the purified product (1.0 eq) in dichloromethane, added triethylamine (1.1 eq) and succinic anhydride (1.1 eq) and stirred at room temperature overnight. Removed the solvent under vacuum and purified the residue by flash column (0-10% EA in PE) to get a colorless oil.

[0338] 1 H NMR (500 MHz, CDC13, ppm): δ 5.15 (m, 1H), 4.18 (m, 1H), 4.08 (m, 1H), 2.68 (m, 2H), 2.62 (m, 2H), 2.34 (m, 1H), 1.58 (m, 2H), 1.46 (m, 2H), 1.25 (m, 23H), 0.88 (t, 6H). LCMS (ESI): 413.3 m / z. Chemical Formula: C 23 H 42 O6

[0339] Synthesis of compound c76:

[0340] In a 50 ml round bottom flask, add 10 ml water and 10 ml tetrahydrofuran, add 2-hexyl decanoic acid (1.0 eq, 10 mmol), propylene oxide (10.0 eq, 100 mmol) and sodium hydroxide (0.1 eq, 1 mmol). Stir at room temperature overnight. Extract with methyl tert-butyl ether twice, combine the organic phases and dry, remove the solvent in vacuo, and purify the residue by flash column (0-10% EA in PE). Dissolve the purified product (1.0 eq) in dichloromethane, add triethylamine (1.1 eq) and succinic anhydride (1.1 eq), and react at room temperature overnight. Remove the solvent in vacuo, and purify the residue by flash column (0-10% EA in PE) to give a colorless oil.

[0341] 1 H NMR (500 MHz, CDC13, ppm): δ 5.15 (m, 1H), 4.18 (m, 1H), 4.08 (m, 1H), 2.68 (m, 2H), 2.62 (m, 2H), 2.34 (m, 1H), 1.58 (m, 4H), 1.46 (m, 2H), 1.25 (m, 20H), 0.88 (t, 9H). LCMS (ESI): 427.3 m / z. Chemical Formula: C 24 H 44 O6

[0342] In the examples, carboxylic acid compounds were synthesized following similar synthetic reaction steps, summarized as follows:

[0343] 1 H NMR (500 MHz, CDC13, ppm): δ 5.15 (m, 1H), 4.18 (m, 1H), 4.08 (m, 1H), 2.68 (m, 2H), 2.62 (m, 2H), 2.34 (m, 1H), 1.58 (m, 4H), 1.46 (m, 2H), 1.25 (m, 20H), 0.88 (t, 9H). LCMS (ESI): 427.3 m / z. Chemical Formula: C 20 H 38 O4

[0344]

[0345] 1 H NMR (500 MHz, CDC13, ppm): δ 5.15 (m, 1H), 4.18 (m, 1H), 4.08 (m, 1H), 2.68 (m, 2H), 2.62 (m, 2H), 2.34 (m, 1H), 1.58 (m, 4H), 1.46 (m, 2H), 1.25 (m, 20H), 0.88 (t, 9H). LCMS (ESI): 427.3 m / z. Chemical Formula: C 21 H 40 O4

[0346] 1H NMR (500 MHz, CDC13, ppm): δ 4.66 (s, 2H), 2.34 (m, 6H), 1.58 (m, 2H), 1.50-1.26 (m, 14H), 0.88 (t, 3H). LCMS (ESI): 295.2 m / z. Chemical Formula: C 17 H 28 O4

[0347] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 16H), 0.88 (t, 3H). LCMS (ESI): 299.2 m / z. Chemical Formula: C 17 H 32 O4

[0348] In an embodiment, carboxylic acid compounds were synthesized following similar synthetic reaction procedures, summarized as follows:

[0349] 1 H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 1H), 2.29 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 20H), 0.88 (m, 6H). LCMS (APCI): 327.5 m / z (M-H + ). Chemical Formula: C 19 H 36 O4

[0350] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 2.28 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 26H), 0.88 (m, 6H). LCMS (APCI): 369.6 m / z (M-H + ). Chemical Formula: C 22 H 42 O4

[0351] 1 H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 2.28 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 30H), 0.88 (m, 6H). LCMS (APCI): 397.6 m / z (M-H + ). Chemical Formula: C24 H 46 O4

[0352] 1 H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 1H), 2.29 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 34H), 0.88 (t, 6H). LCMS (APCI): 425.7 m / z (M-H + ) Formula: C 26 H 50 O4

[0353] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (m, 2H), 2.30 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 20H), 0.88 (m, 6H). LCMS (APCI): 341.5 m / z (M-H + ) Formula: C 20 H 38 O4

[0354] 1 H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 2H), 2.29 (m, 4H), 2.09 (m, 1H), 1.65 (m, 4H), 1.50-1.26 (m, 16H), 0.88 (t, 3H), 0.80 (t, 3H). LCMS (APCI): 313.5 m / z (M-H + ) Formula: C 18 H 34 O4

[0355] 1 H NMR (500 MHz, CDC13, ppm): δ 3.99 (d, 2H), 2.31 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 369.6 m / z (M-H + ) Formula: C 22 H 42 O4

[0356]

[0357] 1H NMR (500 MHz, CDC13, ppm): δ 3.97 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 28H), 0.88 (t, 6H). LCMS (APCI): 397.6 m / z (M-H + ). Chemical Formula: C 24 H 46 O4

[0358] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 30H), 0.88 (t, 6H). LCMS (APCI): 411.7 m / z (M-H + ). Chemical Formula: C 25 H 48 O4

[0359] 1 H NMR (500 MHz, CDC13, ppm): δ 3.96 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 425.7 m / z (M-H + ). Chemical Formula: C 26 H 50 O4

[0360] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 327.5 m / z (M-H + ). Chemical Formula: C 19 H 36 O4

[0361] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 327.5 m / z (M-H + ). Chemical Formula: C 19 H 36 O4

[0362] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (m, 2H), 2.29 (m, 3H), 1.66-1.10 (m, 25H), 0.88 (t, 3H). LCMS (APCI): 313.5 m / z (M-H + ) Formula: C 18 H 34 O4

[0363] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 28H), 0.88 (t, 6H). LCMS (APCI): 355.5 m / z (M-H + ) Formula: C 21 H 40 O4

[0364] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 383.6 m / z (M-H + ) Formula: C 23 H 44 O4

[0365] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 383.6 m / z (M-H + ) Formula: C 23 H 44 O4

[0366] 1 H NMR (500 MHz, CDC13, ppm): δ 4.12 (t, 2H), 2.46 (t, 2H), 2.22 (d, 2H), 1.83 (m, 1H), 1.66-1.14 (m, 22H), 0.88 (t, 6H). LCMS (APCI): 327.5 m / z (M-H + ) Formula: C 19 H36 O4

[0367] 1 H NMR (500 MHz, CDC13, ppm): δ 4.12 (t, 2H), 2.46 (t, 2H), 2.22 (d, 2H), 1.83 (m, 1H), 1.66-1.14 (m, 26H), 0.88 (t, 6H). LCMS (APCI): 355.5 m / z (M-H + ) Formula: C 21 H 40 O4

[0368] 1 H NMR (500 MHz, CDC13, ppm): δ 4.12 (t, 2H), 2.46 (t, 2H), 2.22 (d, 2H), 1.83 (m, 1H), 1.66-1.14 (m, 30H), 0.88 (t, 6H). LCMS (APCI): 383.6 m / z (M-H + ) Formula: C 23 H 44 O4

[0369] 1 H NMR (500 MHz, CDC13, ppm): δ 4.12 (t, 2H), 2.46 (t, 2H), 2.22 (d, 2H), 1.97 (m, 2H), 1.83 (m, 1H), 1.42-1.14 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 411.7 m / z (M-H + ) Formula: C 25 H 48 O4

[0370] 1 H NMR (500 MHz, CDC13, ppm): δ 4.05 (t, 2H), 2.35 (m, 4H), 1.60 (m, 6H), 1.44-1.20 (m, 15H), 0.88 (t, 6H). LCMS (APCI): 313.5 m / z (M-H + ) Formula: C 18 H 34 O4

[0371] 1H NMR (500 MHz, CDC13, ppm): δ 4.10 (t, 2H), 2.35 (m, 4H), 1.60 (m, 5H), 1.44-1.20 (m, 16H), 0.88 (t, 6H). LCMS (APCI): 313.5 m / z (M-H + ). Formula: C 18 H 34 O4

[0372] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 8H), 0.88 (t, 3H). LCMS (ESI): 243.2 m / z. Formula: C 13 H 24 O4

[0373] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 10H), 0.88 (t, 3H). LCMS (ESI): 257.2 m / z. Formula: C 14 H 26 O4

[0374] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 12H), 0.88 (t, 3H). LCMS (ESI): 271.2 m / z. Formula: C 15 H 28 O4

[0375] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 10H), 0.88 (t, 3H). LCMS (ESI): 257.2 m / z. Formula: C 14 H 26 O4

[0376] 1H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 12H), 0.88 (t, 3H). LCMS (ESI): 271.2 m / z. Chemical Formula: C 15 H 28 O4

[0377] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 14H), 0.88 (t, 3H). LCMS (ESI): 285.2 m / z. Chemical Formula: C 16 H 30 O4

[0378] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 16H), 0.88 (t, 3H). LCMS (ESI): 299.2 m / z. Chemical Formula: C 17 H 32 O4

[0379] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 18H), 0.88 (t, 3H). LCMS (ESI): 313.2 m / z. Chemical Formula: C 18 H 34 O4

[0380] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 10H), 0.88 (t, 3H). LCMS (ESI): 257.2 m / z. Chemical Formula: C 14 H 26 O4

[0381] 1H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 12H), 0.88 (t, 3H). LCMS (ESI): 271.2 m / z. Chemical Formula: C 15 H 28 O4

[0382] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 14H), 0.88 (t, 3H). LCMS (ESI): 285.2 m / z. Chemical Formula: C 16 H 30 O4

[0383] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 12H), 0.88 (t, 3H). LCMS (ESI): 271.2 m / z. Chemical Formula: C 15 H 28 O4

[0384] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 14H), 0.88 (t, 3H). LCMS (ESI): 285.2 m / z. Chemical Formula: C 16 H 30 O4

[0385] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 16H), 0.88 (t, 3H). LCMS (ESI): 299.2 m / z. Chemical Formula: C 17 H 32 O4

[0386] 1H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 18H), 0.88 (t, 3H). LCMS (ESI): 313.2 m / z. Chemical Formula: C 18 H 34 O4

[0387] 1 H NMR (500 MHz, CDC13, ppm): δ 4.13 (t, 2H), 2.34 (m, 4H), 1.58 (m, 6H), 1.50-1.26 (m, 16H), 0.88 (t, 3H). LCMS (ESI): 299.2 m / z. Chemical Formula: C 17 H 32 O4

[0388] 1 H NMR (500 MHz, CDC13, ppm): δ 5.65 (m, 1H), 5.55 (m, 1H), 4.65 (d, 2H), 2.32 (t, 2H), 2.11 (m, 2H), 1.61 (m, 2H), 1.50-1.26 (m, 18H), 0.88 (t, 3H). LCMS (ESI): 311.2 m / z. Chemical Formula: C 18 H 32 O4

[0389] 1 H NMR (500 MHz, CDC13, ppm): δ 4.66 (s, 2H), 2.34 (m, 6H), 1.58 (m, 2H), 1.50-1.26 (m, 16H), 0.88 (t, 3H). LCMS (ESI): 309.2 m / z. Chemical Formula: C 18 H 30 O4

[0390] 1 H NMR (500 MHz, CDC13, ppm): δ 5.65 (m, 1H), 5.55 (m, 1H), 4.65 (d, 2H), 2.32 (t, 2H), 2.11 (m, 2H), 1.61 (m, 2H), 1.50-1.26 (m, 16H), 0.88 (t, 3H). LCMS (ESI): 297.2 m / z. Chemical Formula: C 17 H 30 O4

[0391] In an embodiment, a thioacid class of compounds assembly was synthesized, summarized as follows:

[0392] Synthesis of compound c22:

[0393] In a 50 ml round bottom flask, sodium hydrosulfide solid (2.0 eq, 10 mmol, 0.56 g) and 6 ml of methanol were added. Stirring in an ice bath at 0 °C, tetradecanoyl chloride (5 mmol) was slowly added dropwise through a constant pressure dropping funnel. Reaction at 0 °C for 1 h, then moved to room temperature for 2 h. The reaction was poured into water, acidified with 1 N HC1 solution (10 ml), extracted with 4*15 ml of ethyl acetate. The organic phase was combined, washed with saturated brine twice, dried with anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed by suction filtration, and the solvent was removed by rotary evaporation to obtain a yellow oil.

[0394] 1 H NMR (500 MHz, CDC13, ppm): δ 5.0 (s, 1H), 2.30 (t, 2H), 1.62 (m, 2H), 1.36-1.18 (m, 20H), 0.88 (t, 3H).

[0395] Chlorosulfuric acid (5.5 mmol, 1.1 eq) and benzotriazole (15 mmol, 3 eq) were dissolved in 20 ml of DCM, and a solution of 8-((2-methylnonyl)oxy)-8-oxooctanoic acid (5 mmol, 1.0 eq) in dichloromethane was slowly added dropwise. Stirring at room temperature for 2 hours. The white solid was removed by filtration, and the organic phase was washed with 1 M sodium hydroxide solution. The solvent was removed under vacuum to obtain the crude product. The crude product was added to a mixed solution of sodium hydrosulfide (15 mmol, 3 eq) in water and acetonitrile, and stirred at room temperature for 3 h. After the reaction was completed, the solution was acidified by 2 M HC1 solution, extracted with DCM, and the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE) to obtain a colorless oil.

[0396] 1 H NMR (500 MHz, CDC13, ppm): δ 3.93 (m, 1H), 3.86 (m, 1H), 2.33 (m, 3H), 1.65 (m, 4H), 1.50-1.26 (m, 18H), 0.88 (m, 3H), 0.80 (m, 3H). LCMS (ESI): 329.3. Chemical formula: C 18 H 34 O3S

[0397] 1H NMR (500 MHz, CDC13, ppm): δ 4.87 (m, 1H), 2.28 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 30H), 0.88 (m, 6H). LCMS (ESI): 413.3 m / z. Chemical Formula: C 24 H 46 O3S

[0398] 1 H NMR (500 MHz, CDC13, ppm): δ 3.99 (d, 2H), 2.31 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 24H), 0.88 (t, 6H). LCMS (ESI): 385.2 m / z. Chemical Formula: C 22 H 42 O3S

[0399] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 28H), 0.88 (t, 6H). LCMS (ESI): 413.2 m / z. Chemical Formula: C 24 H 46 O3S

[0400] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 30H), 0.88 (t, 6H). LCMS (ESI): 427.3. Chemical Formula: C 25 H 48 O3S

[0401] 1 H NMR (500 MHz, CDC13, ppm): δ 3.97 (m, 2H), 2.30 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 20H), 0.88 (m, 6H). LCMS (ESI): 357.3 m / z. Chemical Formula: C 20 H 38 O3S

[0402] 1H NMR (500 MHz, CDC13, ppm): δ 3.96 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 32H), 0.88 (t, 6H). LCMS (ESI): 427.3 m / z. Chemical Formula: C 26 H 50 O

[0403] 1 H NMR (500 MHz, CDC13, ppm): δ 4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 28H), 0.88 (t, 6H). LCMS (ESI): 371.2 m / z. Chemical Formula: C 21 H 40 O3S

[0404] 1 H NMR (500 MHz, CDC13, ppm): δ 2.30 (m, 2H), 1.58 (m, 2H), 1.27 (m, 16H), 0.88 (t, 3H). LCMS (ESI): 215.3 m / z. Chemical Formula: C 12 H 24 OS

[0405] 1 H NMR (500 MHz, CDC13, ppm): δ 2.30 (m, 2H), 1.58 (m, 2H), 1.27 (m, 18H), 0.88 (t, 3H). LCMS (ESI): 229.3 m / z. Chemical Formula: C 13 H 26 OS

[0406] 1 H NMR (500 MHz, CDC13, ppm): δ 2.30 (m, 2H), 1.58 (m, 2H), 1.27 (m, 22H), 0.88 (t, 3H). LCMS (ESI): 257.3 m / z. Chemical Formula: C 15 H 30 OS

[0407] 1 H NMR (500 MHz, CDC13, ppm): δ 2.30 (m, 2H), 1.58 (m, 2H), 1.27 (m, 24H), 0.88 (t, 3H). LCMS (ESI): 271.3 m / z. Chemical Formula: C16 H 32 OS

[0408] Composition of the library of example 7 and synthesis of some components

[0409] The following specifically shows the compounds included in library a, library b, library c, library d and library e, and the synthesis of some compounds.

[0410] Library a

[0411] Library b

[0412] Library c

[0413] Library d

[0414] Library e

[0415] Synthesis of some key reaction intermediates:

[0416] Synthesis of 1-isocyano cyclohexene:

[0417] Take cyclohexanone (4.9072 g, 1 eq), formamide (3.3780 g, 1.5 eq), p-toluenesulfonic acid monohydrate (0.4755 g, 0.05 eq) in a 250 mL single-neck flask, add 100 mL of toluene, condense reflux at 140°C for 24 h. Remove the solvent by rotary evaporation, and purify the residue by flash column (0-60% EA in PE) to obtain N-(1-cyclovinyl) formamide.

[0418] Take N-(1-cyclovinyl) formamide (1.6460 g, 1 eq) and 1,4-diazabicyclo[2.2.2]octane (4.4262 g, 3 eq) in a 100 mL single-neck flask, add 32.88 ml of dichloromethane, and stir in an ice water bath. Add triphosgene (2.6152 g, 0.67 eq) dispersed in 28.62 mL of dichloromethane through a constant pressure dropping funnel. After stirring for 2 h, wash with saturated sodium bicarbonate solution, extract the aqueous phase with dichloromethane three times. Dry the organic phase with anhydrous sodium sulfate. Remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE). 1 H NMR (500 MHz, CDCl3, ppm): δ 5.92 (s, 1H), 2.22 (m, 2Η), 2.10 (m, 2H), 1.69 (m, 2Η), 1.57 (m, 2H). MS: m / z 108.2 (M+H + ). Chemical formula: C7H9N.

[0419] Synthesis of compound a8:

[0420] Dissolve tert-butyl 2-(methylamino)ethylcarbamate (0.5000 g, 1 eq) and 2-bromoethanol (0.5379 g, 1.5 eq) in 10 mL of toluene and reflux at 115 °C under nitrogen atmosphere for 5 hours. Remove the solvent under vacuum and purify the residue by flash column (0-10% MeOH in DCM). Dissolve the post column product in 50% trifluoroacetic acid in dichloromethane and react for 4 hours. Remove the solvent under vacuum to obtain the product.

[0421] 1 H NMR (500 MHz, CDC13, ppm): 3.86 (t, 2H), 3.38 (m, 4H), 3.22 (t, 2H), 2.87 (s, 3H). MS: m / z 119.1 (M+H + ). Formula: C5H 14 N2O.

[0422] Synthesis of compound a9:

[0423] Dissolve tert-butyl 2-(methylamino)ethylcarbamate (0.5000 g, 1 eq) and 2-bromoethanol (0.5379 g, 1.5 eq) in 10 mL of toluene and reflux at 115 °C under nitrogen atmosphere for 5 hours. Remove the solvent under vacuum and purify the residue by flash column (0-10% MeOH in DCM). Dissolve the post column product in 50% trifluoroacetic acid in dichloromethane and react for 4 hours. Remove the solvent under vacuum to obtain the product.

[0424] 1 H NMR (500 MHz, CDC13, ppm): 3.86 (t, 2H), 3.38 (m, 4H), 3.22 (t, 2H), 2.87 (s, 3H). MS: m / z 119.1 (M+H + ). Formula: C5H 16 N2O.

[0425] Synthesis of compound a10:

[0426] tert-Butyl 2-(methylamino)ethylcarbamate (0.5000 g, 1 eq) and 4-bromo- 1-butanol (0.6587 g, 1.5 eq) were dissolved in 10 mL of toluene and refluxed at 115 °C under a nitrogen atmosphere for 5 hours. The solvent was removed in vacuo and the residue was purified by flash column (0-10% MeOH in DCM). The product after column was dissolved in 50% trifluoroacetic acid in dichloromethane and reacted for 4 hours. The solvent was removed in vacuo to yield the product.

[0427] 1 H NMR (500 MHz, CDC13, ppm): 3.72 (t, 2H), 3.53 (m, 2H), 3.45 (m, 2H), 3.38 (m, 2H), 2.98 (s, 3H), 2.00 (m, 2H), 1.71 (m, 2H), 1.52 (m, 2H). MS: m / z 161.2 (M+H + ) Formula: C8H 20 N2O.

[0428] Synthesis of compound a13:

[0429] tert-Butyl 2-(methylamino)ethylcarbamate (0.5000 g, 1 eq) and 4-bromo- 1-butanol (0.6587 g, 1.5 eq) were dissolved in 10 mL of toluene and refluxed at 115 °C under a nitrogen atmosphere for 5 hours. The solvent was removed in vacuo and the residue was purified by flash column (0-10% MeOH in DCM). The product after column was dissolved in 50% trifluoroacetic acid in dichloromethane and reacted for 4 hours. The solvent was removed in vacuo to yield the product.

[0430] 1 H NMR (500 MHz, CDC13, ppm): 3.72 (t, 2H), 3.53 (m, 2H), 3.45 (m, 2H), 3.38 (m, 2H), 2.98 (s, 3H), 2.00 (m, 2H), 1.71 (m, 2H), 1.52 (m, 2H). MS: m / z 161.2 (M+H + ) Formula: C7H 18 N2O.

[0431] Synthesis of compound b5: 3-(dimethylamino)propanal

[0432] Aqueous dimethylamine solution (2 eq, 24 mmol) was added to 5 mL water, sodium hydroxide (2 eq, 24 mmol) was added, and the mixture was stirred in an ice bath. 3-Chloropropanal diethyl acetal (1 eq, 12 mmol) was added slowly dropwise, and the mixture was stirred at 0 °C for 0.5 h and then at 30 °C overnight. After the reaction was completed, the pH of the system was adjusted to neutral with hydrochloric acid, and the mixture was extracted with dichloromethane twice. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under vacuum to obtain crude 3-dimethylaminopropanal diethyl acetal. 3-Dimethylaminopropanal diethyl acetal (1 mmol) was dissolved in 5 mL tetrahydrofuran, 5 mL 2M hydrochloric acid was added, and the mixture was reacted at 40 °C overnight. The solvent was removed under vacuum to obtain 3-(dimethylamino)propanal hydrochloride.

[0433] 1 H NMR (500 MHz, CDCl3, ppm): δ 9.48 (s, 1H), 2.64 (s, 6H), 2.52 (m, 4H).

[0434] Synthesis of compound b6: 4-(dimethylamino)butanal

[0435] 4-Dimethylaminobutanal diethyl acetal (1 mmol) was dissolved in 5 mL tetrahydrofuran, 5 mL 2M hydrochloric acid was added, and the mixture was reacted at 40 °C overnight. The solvent was removed under vacuum to obtain 4-(dimethylamino)butanal hydrochloride.

[0436] 1 H NMR (500 MHz, CDCl3, ppm): δ 9.36 (s, 1H), 2.40 (m, 4H), 2.16 (s, 6H), 1.56 (m, 2H).

[0437] Synthesis of compound b15:

[0438] Oleic acid (9.6036 g, 34 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (9.7767 g, 26.6 mmol), 1,2-ethanediol (10.5519 g, 170 mmol), 4-(dimethylamino)pyridine (2.0769 g, 17 mmol), and N,N-diisopropylethylamine (8.7883 g, 68 mmol) were dissolved in dichloromethane (400 mL). The reaction was stirred at room temperature under nitrogen for 18 hours, then washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under vacuum. The residue was purified by silica gel chromatography (0-50% ethyl acetate in hexanes) to give 2-hydroxyethyl oleate. 2-Hydroxyethyl oleate (4.5713 g, 14 mmol) was dissolved in 200 mL of dichloromethane, then dissolved in Dess-Martin periodinane (8.9070 g, 21 mmol). The reaction was stirred at room temperature under nitrogen for 3 hours. Sodium thiosulfate pentahydrate (50% w / v, 200 mL) was added to the reaction and stirred for an additional 15 minutes. The organic layer was then separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under vacuum. The residue was purified by flash column (0-30% EA in PE) to give 2-oxoethyl oleate.

[0439] 1 H NMR (500 MHz, CDC13, ppm): δ 5.37 (m, 2H), 4.67 (s, 2H), 2.44 (m, 2H), 2.04 (m, 4H), 1.66 (m, 2H), 1.37-1.27 (m, 20H), 0.88 (t, 3H). MS: m / z 325.1 (M+H + ). Chemical Formula: C 20 H 36 O3.

[0440] Synthesis of compound c17:

[0441] Oleyl alcohol (4.0000 g, 1 eq) and 4-(dimethylamino)pyridine (0.1820 g, 0.1 eq) were dissolved in 100 mL of ultra-dry dichloromethane, and nitrogen was replaced three times. Succinic anhydride (1.7891 g, 1.2 eq) dissolved in 50 mL of ultra-dry dichloromethane was added dropwise through a constant pressure dropping funnel. The reaction was carried out at room temperature overnight, the solvent was removed under vacuum, and the residue was purified by flash column (0-20% EA in PE). 1H NMR (500 MHz, CDC13, ppm): δ 5.37 (m, 2H), 4.09 (t, 2H), 2.69 (m, 2H), 2.62 (m, 2H), 2.02 (m, 4H), 1.62 (m, 2H), 1.37-1.27 (m, 22H), 0.88 (t, 3H). MS: m / z 368.0 (M-H + ) Chemical Formula: C 22 H 40 O4.

[0442] Synthesis of compound c18:

[0443] Oleyl alcohol (4.0000 g, 1 eq) and 4-(dimethylamino)pyridine (0.1820 g, 0.1 eq) were dissolved in 100 mL of super dry dichloromethane, nitrogen was replaced for three times. Glutaric anhydride (2.0399 g, 1.2 eq) dissolved in 50 mL of super dry dichloromethane was added dropwise through a constant pressure dropping funnel. The reaction was carried out at room temperature overnight, the solvent was removed under vacuum, and the residue was purified by flash column (0-20% EA in PE).

[0444] 1 H NMR (500 MHz, CDC13, ppm): δ 5.37 (m, 2H), 4.09 (t, 2H), 2.69 (m, 2H), 2.62 (m, 2H), 2.02 (m, 4H), 1.62 (m, 2H), 1.37-1.27 (m, 22H), 0.88 (t, 3H). MS: m / z 368.0 (M-H + ) Chemical Formula: C 23 H 42 O4.

[0445] Synthesis of compound c19:

[0446] Oleyl alcohol (3.0025 g, 1 eq), N-ethyldiisopropylamine (3.4346 g, 2.5 eq), dicyclohexylcarbodiimide (2.1933 g, 1 eq) and 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were dissolved in 100 mL of super dry dichloromethane, nitrogen was replaced for three times. Adipic acid (1.2561 g, 1 eq) dissolved in 50 mL of super dry dichloromethane was added dropwise through a constant pressure dropping funnel. The reaction was carried out at room temperature overnight, washed with saturated sodium bicarbonate solution twice, saturated brine twice, and dried with anhydrous sodium sulfate. Filtration, the solvent was removed under vacuum, and the residue was purified by flash column (0-20% EA in PE).

[0447] 1H NMR (500 MHz, CDC13, ppm): δ 5.37 (m, 2H), 4.09 (t, 2H), 2.44 (m, 2H), 2.33 (m, 2H), 2.02 (m, 2H), 1.62 (m, 6H), 1.37-1.27 (m, 22H), 0.88 (t, 3H). MS: m / z 396.1 (M-H) + ) Chemical Formula: C 24 H 44 O4.

[0448] Synthesis of compound c22:

[0449] In a 50ml round bottom flask, sodium hydride solid (2.0eq, 10mmol, 0.56g) and 6ml methanol were added. Stirring in 0°C ice bath, tetradecanoyl chloride (5mmol) was added slowly through a constant pressure dropping funnel. 0°C reaction for 1h, then moved to room temperature for 2h. The reaction was poured into water, acidified with 1N HC1 solution (10ml), extracted with 4*15ml ethyl acetate. The organic phase was combined, washed with saturated brine twice, dried with anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by suction filtration, and the solvent was removed by rotary evaporation to obtain a yellow oil.

[0450] 1 H NMR (500 MHz, CDC13, ppm): δ 5.0 (s, 1H), 2.30 (t, 2H), 1.62 (m, 2H), 1.36-1.18 (m, 20H), 0.88 (t, 3H).

[0451] Synthesis of compound d6:

[0452] Nonanoic acid (1.6325g, 1eq), N-Boc-γ-amino-1-propanol (1.9136g, 1eq), dicyclohexyl carbodiimide (2.0216g, 1eq), 4-(dimethylamino)pyridine (0.1312g, 0.1eq) were dissolved in a 250ml single-necked flask containing 50ml DCM, respectively, and stirred thoroughly at room temperature for 18h. After the reaction was completed, the solvent was removed by vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10ml DCM, and then slowly dropped into 10ml TFA, and stirred thoroughly for 3h. After the reaction was completed, 20ml saturated sodium bicarbonate solution was added, extracted with DCM three times, dried with anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d5.

[0453] 1H NMR (500 MHz, CDC13, ppm): δ 4.21 (t, 2H), 2.69 (t, 2H), 2.31 (t, 2H), 2.03 (m, 2H), 1.61 (m, 2H), 1.29 (m, 10H), 0.88 (t, 3H). Chemical Formula: C 12 H 25 NO2.

[0454] Synthesis of compound d7:

[0455] N-Boc-γ-aminobutyric acid (2.1604 g, 1 eq), n-octanol (1.3819 g, 1 eq), dicyclohexyl carbodiimide (2.0216 g, 1 eq), 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were sequentially dissolved in a 250 mL single-neck flask containing 50 mL DCM, and stirred at room temperature for 18 h. After the reaction was completed, the solvent was removed under vacuum, and the residue was purified by flash column (0-10% EA in PE). After passing through the column, the product was dissolved in 10 mL DCM, and then slowly dropped into 10 mL TFA, and stirred for 3 h. After the reaction was completed, 20 mL saturated sodium bicarbonate solution was added, extracted with DCM three times, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d7.

[0456] 1 H NMR (500 MHz, CDC13, ppm): δ 4.21 (t, 2H), 2.69 (t, 2H), 2.31 (t, 2H), 2.03 (m, 2H), 1.61 (m, 2H), 1.29 (m, 10H), 0.88 (t, 3H). Chemical Formula: C 12 H 25 NO2.

[0457] Synthesis of compound d9:

[0458] Dissolve oleic acid (2.8247 g, 1 eq), N-Boc-3-amino-1-propanol (1.7523 g, 1 eq), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.9170 g, 1 eq), 4- (dimethylamino)pyridine (0.1222 g, 0.1 eq) in a 250 mL single-neck flask containing 50 mL DCM, respectively, and stir thoroughly at room temperature for 18 h. After the reaction is completed, remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE). Dissolve the product after passing through the column in 10 mL DCM, and slowly drop 10 mL TFA into it. Stir thoroughly for 3 h. After the reaction is completed, add 20 mL saturated sodium bicarbonate solution, extract with DCM three times, dry over anhydrous Na2SO4, filter, and remove the solvent by rotary evaporation to obtain compound d9. H NMR (500 MHz, CDC13, ppm): δ 5.34 (m, 2H), 4.21 (t, 2H), 2.69 (t, 2H), 2.31 (t, 2H), 2.01 (m, 6H), 1.61 (m, 2H), 1.26 (m, 20H), 0.88 (t, 3H). Chemical formula: C 21 H 41 NO2.

[0459] Synthesis of compound d10:

[0460] Dissolve N-Boc-γ-aminobutyric acid (2.1604 g, 1 eq), cis-9-octadecenol (2.8561 g, 1 eq), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.0378 g, 1 eq), 4- (dimethylamino)pyridine (0.1299 g, 0.1 eq) in a 250 mL single-neck flask containing 50 mL DCM, respectively, and stir thoroughly at room temperature for 18 h. After the reaction is completed, remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE). Dissolve the product after passing through the column in 10 mL DCM, and slowly drop 10 mL TFA into it. Stir thoroughly for 3 h. After the reaction is completed, add 20 mL saturated sodium bicarbonate solution, extract with DCM three times, dry over anhydrous Na2SO4, filter, and remove the solvent by rotary evaporation to obtain compound d10.

[0461] 1 H NMR (500 MHz, CDC13, ppm): δ 5.34 (m, 2H), 4.06 (t, 2H), 2.69 (t, 2H), 2.35 (t, 2H), 2.01 (m, 4H), 1.80 (m, 2H), 1.60 (m, 2H), 1.29 (m, 22H), 0.88 (t, 3H). Chemical formula: C 22 H 43 NO2.

[0462] Synthesis of compound d11:

[0463] Dissolve 2-hexyldecanoic acid (1.7325 g, 1 eq), N-Boc-6-amino-1-hexanol (1.5386 g, 0.8 eq), dicyclohexyl carbodiimide (1.6506 g, 1 eq), 4-(dimethylamino)pyridine (0.0977 g, 0.1 eq) in a 250 mL single-neck flask containing 50 mL DCM, and stir at room temperature for 18 h. After the reaction is completed, remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE). After passing through the column, dissolve the product in 10 mL DCM, slowly drop 10 mL TFA, and stir for 3 h. After the reaction is completed, add 20 mL saturated sodium bicarbonate solution, extract with DCM three times, dry over anhydrous Na2SO4, filter, and remove the solvent by rotary evaporation to obtain compound d11.

[0464] 1 H NMR (500 MHz, CDCl3, ppm): δ 4.08 (t, 2H), 2.69 (t, 2H), 2.30 (m, 1H), 1.80 (m, 2H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). Chemical formula: C 22 H 45 NO2.

[0465] Synthesis of compound d12 (a14):

[0466] Dissolve Boc-8-aminooctanoic acid (1.9179 g, 1.45 eq), 9-heptadecanol (1.3080 g, 1 eq), dicyclohexyl carbodiimide (1.0523 g, 1 eq), 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) in a 250 mL single-neck flask containing 50 mL DCM, and stir at room temperature for 18 h. After the reaction is completed, remove the solvent under vacuum, and purify the residue by flash column (0-10% EA in PE). After passing through the column, dissolve the product in 10 mL DCM, slowly drop 10 mL TFA, and stir for 3 h. After the reaction is completed, add 20 mL saturated sodium bicarbonate solution, extract with DCM three times, dry over anhydrous Na2SO4, filter, and remove the solvent by rotary evaporation to obtain compound d12.

[0467] 1H NMR (500 MHz, CDC13, ppm): δ 4.47 (m, 1H), 2.69 (t, 2H), 2.29 (t, 2H), 1.65 (m, 4H), 1.50-1.26 (m, 34H), 0.88 (t, 6H). Chemical Formula: C 25 H 51 NO2.

[0468] Synthesis of ionizable lipids of example 8

[0469] Each lipid was prepared by classical Ugi reaction using one reactant from each of the libraries a, b, c and e, each set of reactants corresponding to one set of R I , R II (R II '), R III and R IV structures in formula (I).

[0470] a4b16c6e11

[0471] 1 H NMR (500 MHz, CDC13, ppm): δ 5.73 (m, 1H), 4.87 (m, 1H), 3.42 (m, 2H), 3.19 (m, 2H), 2.39 (s, 2H), 2.34-2.21 (m, 10H), 1.83 (m, 2H), 1.62 (m, 4H), 1.48 (m, 12H), 1.37-1.18 (m, 50H), 0.88 (m, 9H). MS: m / z 779.2 (M+H + ). Chemical Formula: C 48 H 95 N3O4

[0472] a4b16c12e11

[0473] 1 H NMR (500 MHz, CDC13, ppm): δ 5.34 (m, 4H), 4.86 (m, 1H), 3.42 (m, 2H), 3.18 (m, 2H), 2.77 (m, 2H), 2.31 (m, 5H), 2.22 (m, 8H), 2.04 (m, 4H), 1.79 (m, 2H), 1.65 (m, 4H), 1.51-1.18 (m, 56H), 0.88 (m, 9H). MS: m / z 830.7. Chemical Formula: C 52 H 99 N3O4

[0474] a4b1c12e11

[0475] 1 H NMR (500 MHz, CDC13, ppm): δ 6.62 (t, 1H), 5.34 (m, 4H), 4.86 (m, 1H), 3.82 (d, 1H), 3.48 (m, 2H), 3.18 (m, 2H), 2.77 (t, 2H), 2.38 (td, 2H), 2.22 (m, 6H), 2.27 (t, 4H), 2.04 (m, 4H), 1.80 (m, 2H), 1.60 (m, 4H), 1.51-1.18 (m, 51H), 0.88 (t, 9H), 0.78 (m, 1H), 0.58 (m, 1H), 0.37 (m, 1H), 0.24 (m, 1H). MS: m / z 842.7. Formula: C 53 H 99 N3O4

[0476] a4b1c37e11

[0477] 1 H NMR (500 MHz, CDC13, ppm): δ 6.60 (m, 1H), 4.86 (m, 1H), 3.93 (m, 1H), 3.83 (m, 1H), 3.48 (m, 2H), 3.20 (m, 2H), 2.38-2.22 (m, 14H), 2.02 (m, 2H), 1.78 (m, 4H), 1.64 (m, 6H), 1.51-1.18 (m, 50H), 0.88 (m, 12H), 0.78 (m, 1H), 0.58 (m, 1H), 0.37 (m, 1H), 0.25 (m, 1H). Formula: C 53 H 101 N3O6

[0478] a4b1c37e10

[0479] 1 H NMR (500 MHz, CDC13, ppm): δ 6.64 (m, 1H), 4.06 (t, 2H), 3.93 (m, 1H), 3.83 (m, 1H), 3.50 (m, 2H), 3.20 (m, 2H), 2.38-2.22 (m, 13H), 2.01 (m, 2H), 1.82 (m, 4H), 1.64 (m, 8H), 1.51-1.18 (m, 42H), 0.88 (m, 12H), 0.79 (m, 1H), 0.60 (m, 1H), 0.39 (m, 1H), 0.26 (m, 1H). Formula: C 50 H 95N3O6

[0480] a4b1c6e10

[0481] 1 H NMR (500 MHz, CDC13, ppm): δ 6.65 (t, 1H), 4.05 (t, 2H), 3.82 (d, 1H), 3.48 (m, 2H), 3.21 (m, 2H), 2.38 (td, 2H), 2.22 (m, 6H), 2.27 (t, 4H), 1.80 (m, 2H), 1.60 (m, 8H), 1.51-1.18 (m, 46H), 0.88 (m, 9H), 0.78 (m, 1H), 0.59 (m, 1H), 0.38 (m, 1H), 0.25 (m, 1H). Formula: C 46 H 89 N3O4

[0482] a4b1c6e11

[0483] 1 H NMR (500 MHz, CDC13, ppm): δ 6.63 (t, 1H), 4.86 (m, 1H), 3.82 (d, 1H), 3.48 (m, 2H), 3.17 (m, 2H), 2.38 (td, 2H), 2.22 (m, 6H), 2.27 (t, 4H), 2.04 (m, 4H), 1.80 (m, 2H), 1.60 (m, 4H), 1.51-1.18 (m, 58H), 0.88 (m, 9H), 0.77 (m, 1H), 0.58 (m, 1H), 0.37 (m, 1H), 0.25 (m, 1H). Formula: C 49 H 95 N3O4

[0484] a4b16c73e11

[0485] 1 H NMR (500 MHz, CDC13, ppm): δ 5.73 (br, 1H), 4.86 (m, 1H), 4.66 (s, 2H), 3.41 (m, 2H), 3.20 (m, 2H), 2.34-2.22 (m, 18H), 1.79 (m, 2H), 1.62 (m, 6H), 1.51-1.18 (m, 52H), 0.88 (m, 9H). Formula: C 51 H 95 N3O6

[0486] a4b51c73e11

[0487] 1 H NMR (500 MHz, CDC13, ppm): δ 5.83 (br, 1H), 4.86 (m, 1H), 4.66 (s, 2H), 3.43 (m, 1H), 3.29 (m, 1H), 3.20 (m, 2H), 2.96 (s, 2H) 2.34-2.22 (m, 16H), 1.85 (m, 2H), 1.63 (m, 6H), 1.51-1.18 (m, 51H), 0.88 (m, 12H). Formula: C 52 H 97 N3O6

[0488] a4b17c73e11

[0489] 1 H NMR (500 MHz, CDC13, ppm): δ 5.74 (br, 1H), 4.86 (m, 1H), 4.66 (s, 2H), 3.53 (m, 2H), 3.36 (m, 2H), 3.23 (m, 2H), 2.41 (m, 2H), 2.34-2.22 (m, 14H), 2.11 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.61 (m, 6H), 1.51-1.18 (m, 46H), 0.88 (m, 9H), 0.81 (t, 6H). Formula: C 53 H 99 N3O6

[0490] a4b2c94e11

[0491] 1 H NMR (500 MHz, CDC13, ppm): δ 6.10 (br, 1H), 4.86 (m, 1H), 4.66 (s, 2H), 3.78 (br, 1H), 3.45 (br, 1H), 3.28 (br, 1H), 3.04 (br, 1H), 2.40-2.22 (m, 21H), 1.63 (m, 10H), 1.51-1.18 (m, 40H), 1.02 (s, 9H), 0.88 (m, 9H). Formula: C 53 H 99 N3O6

[0492] a4b51c37e11

[0493] 1H NMR (500 MHz, CDC13, ppm): δ 5.86 (br, 1H), 4.86 (m, 1H), 3.93 (m, 1H), 3.83 (m, 1H), 3.45 (m, 1H), 3.29 (m, 1H), 3.21 (m, 2H), 2.38-2.22 (m, 11H), 1.75 (m, 2H), 1.62 (m, 4H), 1.51-1.18 (m, 66H), 0.88 (m, 12H). Formula: C 53 H 103 N3O6

[0494] a4b51c37e10

[0495] 1 H NMR (500 MHz, CDC13, ppm): δ 5.89 (br, 1H), 4.05 (t, 2H), 3.93 (m, 1H), 3.83 (m, 1H), 3.42 (m, 1H), 3.31 (m, 1H), 3.22 (m, 2H), 2.38-2.22 (m, 15H), 1.75 (m, 4H), 1.62 (m, 10H), 1.51-1.18 (m, 46H), 0.88 (m, 12H). Formula: C 50 H 97 N3O6

[0496] a4b17c37e11

[0497] 1 H NMR (500 MHz, CDC13, ppm): δ 5.75 (br, 1H), 4.86 (m, 1H), 3.93 (m, 1H), 3.83 (m, 1H), 3.36 (m, 2H), 3.23 (m, 2H), 2.43 (m, 2H), 2.34-2.22 (m, 14H), 2.12 (m, 2H), 1.92 (m, 2H), 1.73 (m, 4H), 1.61 (m, 8H), 1.51-1.18 (m, 46H), 0.88 (m, 12H), 0.81 (t, 6H). Formula: C 54 H 105 N3O6

[0498] a4b17c37e10

[0499] 1H NMR (500 MHz, CDC13, ppm): δ 5.76 (br, 1H), 4.05 (t, 2H), 3.93 (m, 1H), 3.83 (m, 1H), 3.37 (m, 2H), 3.22 (m, 2H), 2.42 (m, 2H), 2.38-2.22 (m, 13H), 2.11 (m, 2H), 1.92 (m, 2H), 1.75 (m, 4H), 1.62 (m, 12H), 1.51-1.18 (m, 40H), 0.88 (m, 9H), 0.80 (m, 6H). Formula: C 51 H 99 N3O6

[0500] a4b2c58e10

[0501] 1 H NMR (500 MHz, CDC13, ppm): δ 11.05 (s, 1H), 4.16 (s, 1H), 4.05 (t, 2H), 3.93 (m, 1H), 3.85 (m, 1H), 3.64 (m, 2H), 3.52 (m, 1H), 3.09 (m, 1H), 2.44-2.22 (m, 15H), 1.96 (m, 2H), 1.78 (m, 3H), 1.62 (m, 12H), 1.51-1.18 (m, 45H), 0.88 (m, 12H). Formula: C 51 H 99 N3O5S

[0502] a3b2c58e10

[0503] 1 H NMR (500 MHz, CDC13, ppm): δ 10.96 (s, 1H), 4.19 (s, 1H), 4.05 (t, 2H), 3.95 (m, 1H), 3.85 (m, 1H), 3.62 (m, 2H), 3.50 (m, 1H), 3.11 (m, 1H), 2.65-2.22 (m, 12H), 1.81 (m, 3H), 1.62 (m, 10H), 1.51-1.18 (m, 50H), 0.88 (m, 12H). Formula: C 50 H 97 N3O5S

[0504] Preparation and physicochemical detection of lipid nanoparticles (LNPs)

[0505] Preparation of LNPs

[0506] Step 1. Preparation of lipid solution and nucleic acid solution: No special instructions, the aqueous solution involved in the examples is configured by removing nuclease-free deionized water. Take an ionizable lipid, phospholipid (DSPC or DOPE), cholesterol, PEG lipid (DMG-PEG2000) mixed in ethanol solution with a molar ratio of 50 / 10 / 38.5 / 1.5 (containing DSPC, formula 1) or 36.5 / 16 / 46.5 / 2.5 (containing DOPE, formula 2). At the same time, the nucleic acid (mass ratio of ionizable lipid / nucleic acid is 10 / 1) is dissolved in pH=3 citrate buffer solution, and finally the volume ratio of the above ethanol solution to citric acid solution is 1 / 3.

[0507] Step 2. Preparation of LNP by mixing lipid solution and nucleic acid solution: The lipid ethanol solution and nucleic acid aqueous solution prepared in step 1 are loaded into sterile syringes and loaded into the Precision Nanosystem Ignite instrument. The extrusion flow rates of the ethanol solution and the aqueous solution in the instrument program settings are set to 3 ml / min and 9 ml / min, respectively. Insert the microfluidic chip into the instrument and start LNP preparation, and collect the mixed solution through the chip.

[0508] Step 3. Purification of LNP solution: The LNP solution collected in step 2 is subjected to dialysis-concentration-filtration operation, and the final nucleic acid-loaded LNP solution is obtained for subsequent testing.

[0509] Particle size detection of LNP

[0510] The nucleic acid-loaded LNP solution obtained in step 3 is diluted so that the final lipid concentration is between 0.01 and 0.1 mg / ml. The diluted solution is added to the sample pool, and the particle size is detected in the Brookhaven NanoBrook Omni instrument. The data are shown in Table 1.

[0511] The following Table 1 lists the particle size of LNP encapsulated mRNA (luciferase).

[0512] Total nucleic acid determination and encapsulation efficiency test

[0513] The nucleic acid content in the LNP sample is determined by Quant-iT TM RNA detection kit (Thermofisher) was used for the assay. Detection of total RNA concentration: 5 μl of the sample to be tested was taken into a 2 ml ep tube, 245 μl of 1x TE Buffer was added, and after mixing evenly, it was the "diluted sample". 100 μl of the "diluted sample" was removed, 100 μl of 10% Triton X-100 solution was added, and it was mixed thoroughly, and then it was placed in a metal bath at 37°C and 300 rpm for 15 minutes. 80 μl of 1x TE Buffer was added to the enzyme-labeled plate, 20 ul of the sample after demulsification was taken and added to the enzyme-labeled plate, mixed evenly, and then 100 μl of fluorescent dye (2000 times diluted) solution was added;

[0514] Detection of free RNA concentration: 90 μl of 1x TE Buffer was added to the enzyme-labeled plate, 10 ul of the "diluted sample" was taken, and 100 μl of fluorescent dye (2000 times diluted) solution was added;

[0515] At the same time, a series of standard solutions with different concentrations were set in the enzyme-labeled plate as the quantitative standard curve. The fluorescence signal was detected on the enzyme-labeled instrument (excitation wavelength 480 nm, emission detection wavelength 520 nm). The fluorescence signal of each well was converted to the corresponding RNA concentration after standard curve conversion.

[0516] Table 1

[0517] Example 10 mRNA delivery in mice

[0518] The animal experiment was approved by the ethics committee of Zhejiang University of Technology. 6-8 weeks old male C57Bl / 6 mice were randomly divided into groups of 3. Each group of mice was injected with a kind of liposome nanoparticles loaded with luciferase (Luciferase) mRNA through the tail vein, and the dose was 0.25 mg / kg of mouse body weight (calculated by the mass of loaded mRNA). Six hours after receiving the injection of liposome nanoparticles, the luciferase substrate (D-Luciferin, dissolved in sterile PBS) was injected into the mouse body through the abdominal cavity at a dose of 150 mg / kg of mouse body weight, and within 10-15 minutes after injection, the dissection of the small animal and the collection of major organs were completed, and the chemiluminescence of the organs was detected in the live imaging system (IVIS).

[0519] The expression signal ratio of the spleen-enriched lipid LNP and the typical liver-enriched lipid LNP in the mouse spleen and liver was summarized in Table 2.

[0520] Table 2

[0521] From the above table, it can be found that the lipids a4b2c6e11, a4b2c6e10, a4b2c37e10, a4b2c12e11, a4b2c37e11, like the classic lipid SM102, after tail vein injection, the main mRNA expression is concentrated in the liver of mice, and the spleen signal is only between 0.58% and 1.01% of the liver signal. This result is also consistent with the general trend of LNP mRNA delivery in the field. When the RII and RII' groups of the lipid structure are not H, we surprisingly found that the in vivo expression distribution of the prepared LNP is concentrated in the spleen of mice. Compared with lipid a4b2c6e11, lipids a4b16c6e11, a4b1c6e11, a4b17c6e11, only the B component raw material is different, and the spleen / liver signal ratio of the spleen-enriched lipid LNP increases from 0.69% of a4b2c6e11 to 177.91% to 2704.28%; similarly, the spleen / liver signal ratio of a4b16c6e10 is as high as 593.22%, and the spleen / liver ratio of liver-enriched lipid a4b2c6e10 is only 0.58%;

[0522] In addition, we further found that when the RII group of the lipid is cyclopropyl and the RII' group is hydrogen, similar spleen enrichment properties are also exhibited: the spleen / liver ratio of lipid a4b1c6e11 is as high as 903.61%, and the spleen / liver ratio of lipid a4b1c6e10 is as high as 487.58%. Similar situations also occur in the comparison data of lipids a4b1c37e10 and a4b2c37e10.

[0523] Notably, the LNP prepared from the above lipids all use the same formulation ratio, and the only difference compared with liver-enriched lipids is the ionizable lipid structure. In the lipids where X is S in the general structure, we also found similar spleen enrichment phenomena, and the structures of lipids a4b2c58e10 and a4b2c12e11 are completely identical except for the difference in X atoms, with S for the former and O for the latter. We found that the lipid with X=O is still a typical liver-enriched lipid LNP, while the X=S lipid exhibits nearly equal expression levels in the spleen and liver (spleen / liver ratio 97.48%).

[0524] The main structural difference between the five liver-enriched lipids a4b2c6e11, a4b2c6e10, a4b2c37e10, a4b2c12e11, and a4b2c37e11 is the structure of the Rl and RIV hydrophobic long chains, but they do not have significant differences in tissue expression distribution. However, when the Rl of the lipid introduces a triple bond structure, the LNP also exhibits a tendency of spleen enrichment, with a spleen / liver signal ratio of 177.91% for a4b2c94e11, while the spleen / liver signal ratio of the control group a4b2c6e11 is only 0.69%.

[0525] Based on the above structure, we further tested the apparent pKa of the LNP prepared from the spleen lipid-enriched. Interestingly, the pKa of such spleen-enriched LNP is mostly between 7-8, while the liver lipid-enriched LNP tends to have a pKa between 6-6.7, and this difference in surface potential is likely to affect the ability of LNP to bind different components in serum, thus leading to significant changes in the final tissue distribution.

[0526] Table 3

[0527] While various improvements have been described herein with reference to particular embodiments of the present disclosure, it will be understood that such description is by way of illustration only and is not to be construed as limiting the scope of any claimed invention. Therefore, the scope and content of any claimed present disclosure is to be defined only by the terms of the claims as currently presented or as amended during the prosecution of the claims, or as practiced in any continuation application. Furthermore, it is to be understood that features of any of the specific embodiments discussed herein can be combined with one or more features of any one or more of the embodiments otherwise discussed or contemplated herein, unless otherwise stated.

Claims

1. A lipid compound of Formula (I), or an N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein X is O or S; R II is hydrogen, or is selected from the group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of from 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; R III selected from group (A) include groups comprising at least one ionizable tertiary amine structure; R I and R IV each independently is selected from the group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having a carbon atom number of 11-30; and R II The group (C) is selected from substituted or unsubstituted hydrocarbyl groups having a carbon count of 1 to 11, substituted or unsubstituted heterohydrocarbyl groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heteroaryl groups.

2. The lipid compound of claim 1, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Group A includes a group comprising at least one ionizable tertiary amine structure, wherein the number of carbon atoms of the group comprising at least one ionizable tertiary amine structure is 3 to 11 and represented by the following general formula, Among them, R a It is a C1-C6 substituted or unsubstituted alkylene group; R b R c Each of the following groups is independently a C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, or C2-C6 substituted or unsubstituted alkynyl, optionally consisting of one, two, or three groups selected from -OH, -SH, and -NR. d R d' Or substitution by a phenyl substituent, wherein R d R d' Each is independently hydrogen or C1-C3 alkyl; or R b R c Together with the N atom it is attached to, it forms a 5-12 membered heterocycle or heteroaromatic ring, which contains one, two, or three heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, and the 5-12 membered heterocycle or heteroaromatic ring is optionally substituted by one or more C1-C6 alkyl or oxo (=O); or R a R b Together with the N atom to which it is attached, it forms a 5-12 membered heterocycle or heteroaromatic ring optionally substituted with a C1-C6 alkylene group, the optionally substituted C1-C6 alkylene group comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, and the optionally substituted C1-C6 alkylene group is optionally substituted by one or more C1-C6 alkyl or oxo (=O); or R a R b R c Together with the N atom to which it is attached, it forms a 5-12 membered heterocycle or heteroaromatic ring optionally substituted with C1-C6 alkylene, the 5-12 membered heterocycle or heteroaromatic ring optionally substituted with C1-C6 alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocycle or heteroaromatic ring optionally substituted with C1-C6 alkylene or oxo (=O); Group B includes substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups of from 11 to 30 carbon atoms, wherein the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups of from 11 to 30 carbon atoms optionally contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 groups independently selected from -C=C-, -C≡C-, -C=O-, -C=S-, -C(=O)O-, -OC(O)-, -OC(O)O-, -C(O)NR'- -NH-, -NH2, -OH, -OR m , -O-, -C(O)-, -C(OR n )-, -C(O)O-, -SH, -SR o , -S-, -C(S)-, -C(SR p )-, -C(S)O-, and -P(O)-, wherein R m , R n , R o , and R p are each independently a substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group; and Group C includes substituted or unsubstituted hydrocarbyl groups of 1-11 carbon atoms, substituted or unsubstituted heterohydrocarbyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups, wherein the substituted or unsubstituted hydrocarbyl groups of 1-11 carbon atoms, substituted or unsubstituted heterohydrocarbyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups optionally include 1, 2, 3, 4, or 5 groups independently selected from -C=C-, -CºC-, -NH-, -NH2, -OH, -OR m' , -O-, -C(O)-, -C(OR n' )-, -C(O)O-, -SH, -SR o' , -S-, -C(S)-, -C(SR p' )-, -C(S)O-, and -P(O)-, wherein R m' , R n' , R o' , and R p' are each independently a substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group, the hydrocarbon, heterocarbon, aryl, or heteroaryl group being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH.

3. The lipid compound or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, R I and R IV each independently is selected from the group B, wherein the substituted or unsubstituted aliphatic selected from the group B has 11-30 carbon atoms, and the substituted or unsubstituted heteroaliphatic selected from the group B has 11-30 atoms including carbon atoms and N, O, S and the like heteroatoms.

4. The lipid compound according to any one of claims 1 to 3, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, R I and the other of R IV has a number of carbon atoms of from 11 to 25.

5. The lipid compound of any one of claims 1 to 4, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, R I and the other of R IV has a number of carbon atoms of from 11 to 16.

6. The lipid compound of any one of claims 1 to 5, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, R I and R IV each independently optionally comprises at least one degradable group.

7. The lipid compound according to claim 6, characterized in that, wherein said degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -S-S-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -NR 1 C(O)-, -C(O)NR 2 -, -NR 3 C(O)O-, -OP(O)OR 4 O-, -OCR 5 (OR 6 )O-, -CR 7 (OR 8 )O-, -CH(OR 9 )O-, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group, preferably said degradable group is an ester group, i.e. -C(O)O- or -OC(O)-; or an ester bond is included in the degradable group.

8. The lipid compound or an N-oxide, isomer, or pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein, R I and at least one of R IV comprises at least one degradable group, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or the degradable group comprises an ester bond.

9. The lipid compound of any one of claims 1 to 8, or an N-oxide, isomer or pharmaceutically acceptable salt thereof, characterized in that, R I and only one of R IV comprises one, two or three degradable groups, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or an ester bond is comprised in the degradable group; while the other does not comprise a degradable group.

10. The lipid compound of any one of claims 1 to 9, or an N-oxide, isomer or pharmaceutically acceptable salt thereof, characterized in that, R I and R IV each independently contains one, two or three degradable groups, for example the degradable groups are ester groups, i.e. -C(O)O- or -OC(O)-, or the degradable groups include an ester bond.

11. The lipid compound of any one of claims 1 to 10, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, Group A includes the following groups of structures:

12. The lipid compound of any one of claims 1 to 11, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, Group B includes the following groups of structures:

13. The lipid compound of any one of claims 1 to 12, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, Group C includes the groups shown in the following structures:

14. The lipid compound of any one of claims 1 to 13, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, when R I and / or R IV does not contain a degradable group, R I and / or R IV is selected from the group consisting of the structures shown below:

15. The lipid compound of any one of claims 1 to 14, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, when R I and / or R IV comprising a degradable group, R I and / or R IV is selected from the group consisting of the structures shown below:

16. The lipid compound of any one of claims 1 to 15, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R II selected from hydrogen, substituted or unsubstituted Ci-C8alkyl, e.g., Ci-C6alkyl, Ci-C4alkyl, or substituted or unsubstituted Ci-C8heteroalkyl, e.g., Ci-C6heteroalkyl, Ci-C4heteroalkyl.

17. The lipid compound of any one of claims 1 to 14, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R II selected from substituted or unsubstituted C1-C8alkyl, e.g., C1-C6alkyl, C1-C4alkyl, substituted or unsubstituted C3-C8cycloalkyl, e.g., C3-C6cycloalkyl, C3-C4cycloalkyl, or substituted or unsubstituted C1-C8heteroalkyl, e.g., C1-C6heteroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C8heterocyclyl, e.g., C3-C6heterocyclyl, C3-C4heterocyclyl.

18. The lipid compound of any one of claims 1 to 17, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The lipid compound has the following general structural formula (I) A ):

19. The lipid compound of any one of claims 1-18, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R II is selected from group (C) and comprises a substituted or unsubstituted hydrocarbyl group having a carbon count of 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R II is selected from group (C) and comprises a substituted or unsubstituted hydrocarbyl group having a carbon count of 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

20. The lipid compound of any one of claims 1-18, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R II is hydrogen, and R II is selected from group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

21. The lipid compound of any one of claims 1 to 17, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The lipid compound has the following general structural formula (I) B ):

22. A lipid compound of Formula (I), or an N-oxide, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein X is O or S; R II selected from hydrogen, substituted or unsubstituted C1-C8alkyl, or substituted or unsubstituted C1-C8heteroalkyl; R III selected from group (A) include groups comprising at least one ionizable tertiary amine structure, wherein the number of carbon atoms of the group comprising at least one ionizable tertiary amine structure is from 3 to 11 and is represented by the following general formula, Among them, R a It is a C1-C6 substituted or unsubstituted alkylene group; R b R c Each of the following groups is independently a C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, or C2-C6 substituted or unsubstituted alkynyl, optionally consisting of one, two, or three groups selected from -OH, -SH, and -NR. d R d' Or substitution by a phenyl substituent, wherein R d R d' Each is independently hydrogen or C1-C3 alkyl; or R b R c Together with the N atom to which it is attached, it forms a 5-12 membered heterocycle or heteroaromatic ring, which contains 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, and the 5-12 membered heterocycle or heteroaromatic ring is optionally substituted by one or more C1-C6 alkyl or oxo (=O). R I and R IV each independently is selected from the group (B) comprising a substituted or unsubstituted aliphatic or a substituted or unsubstituted heteroaliphatic group having a carbon atom number of 11-30; and Group B includes substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having a carbon atom count of 11-30, wherein the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having a carbon atom count of 11-30 optionally include 1, 2, 3, or 4 groups independently selected from -C=C-, -C≡C-, -0-, -C(O)-, -C(OR n )-, -C(O)O-, -S-, -C(S)-, -C(SR p )-, and -C(S)O-, wherein R n and R p are each independently substituted or unsubstituted C1-C8 aliphatic hydrocarbon groups; and R II The group (C) includes substituted or unsubstituted hydrocarbyl groups having a carbon number of 1 to 11, substituted or unsubstituted heterohydrocarbyl groups.

23. The lipid compound of claim 22, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R II selected from hydrogen, or substituted or unsubstituted C1-C8alkyl, e.g., C1-C6alkyl, C1-C4alkyl.

24. The lipid compound of claim 22 or 23, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, R I and R IV each independently is selected from the group B, wherein the substituted or unsubstituted aliphatic selected from the group B has 11-30 carbon atoms, and the substituted or unsubstituted heteroaliphatic selected from the group B has 11-30 atoms including carbon atoms and N, O, S and the like heteroatoms.

25. The lipid compound or N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 22-24, wherein, R I and the other of R IV has a number of carbon atoms of from 11 to 25.

26. The lipid compound of any one of claims 22-25, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R I and the other of R IV has a number of carbon atoms of from 11 to 16.

27. The lipid compound of any one of claims 22-26, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R I and R IV each independently optionally comprises at least one degradable group.

28. The lipid compound of claim 27, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, wherein said degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -S-S-, -OCR 5 (OR 6 )O-, -CR 7 (OR 8 )O-, -CH(OR 9 )O-, wherein R 5 , R 6 , R 7 , R 8 and R 9 are each independently a substituted or unsubstituted C1-C8 aliphatic hydrocarbon group, preferably said degradable group is an ester group, i.e. -C(O)O- or -OC(O)-; or an ester bond is included in the degradable group.

29. The lipid compound or N-oxide, isomer, or pharmaceutically acceptable salt thereof, of any one of claims 22-28, wherein, R I and at least one of R IV comprises at least one degradable group, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or the degradable group comprises an ester bond.

30. The lipid compound or N-oxide, isomer, or pharmaceutically acceptable salt thereof, of any one of claims 22-29, wherein, R I and only one of R IV comprises one, two or three degradable groups, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or an ester bond is comprised in the degradable group; while the other does not comprise a degradable group.

31. The lipid compound or N-oxide, isomer, or pharmaceutically acceptable salt thereof, of any one of claims 22-30, wherein, R I and R IV each independently contains one, two or three degradable groups, for example the degradable groups are ester groups, i.e. -C(O)O- or -OC(O)-, or the degradable groups include an ester bond.

32. The lipid compound of any one of claims 22-31, or an N-oxide, isomer, or pharmaceutically acceptable salt thereof, wherein, Group A includes the following groups of structures:

33. The lipid compound of any one of claims 22 to 32, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Group B includes the following groups of structures:

34. The lipid compound of any one of claims 22-33, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Group C includes the groups shown in the following structures:

35. The lipid compound of any one of claims 22 to 34, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, when R I and / or R IV does not contain a degradable group, R I and / or R IV is selected from the group consisting of the structures shown below:

36. The lipid compound of any one of claims 22 to 35, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, when R I and / or R IV when R I and / or R IV is selected from the group consisting of the following structures:

37. The lipid compound of any one of claims 22 to 36, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R III selected from 38. The lipid compound of any one of claims 22 to 37, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R II selected from 39. The lipid compound of any one of claims 1 to 38, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The lipid compound is selected from the group consisting of lipid compounds as shown below:

40. The lipid compound of any one of claims 1 to 39, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, the lipid compound has a molecular weight in the range of 500 g / mol to 1400 g / mol; preferably the lipid compound has a molecular weight in the range of 700 g / mol to 1200 g / mol; more preferably the lipid compound has a molecular weight in the range of 700 g / mol to 1000 g / mol.

41. The lipid compound of any one of claims 1 to 40, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, for use in nucleic acid delivery.

42. Use of the lipid compound of any one of claims 1 to 41, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a liposome and / or a lipid nanoparticle.

43. A liposome, characterized in that, the liposome comprises the lipid compound of any one of claims 1 to 41, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof.

44. The liposome of claim 43, wherein, the lipid compound comprises about 10 mol% to about 90 mol%, preferably about 10 mol% to about 70 mol%, more preferably about 20 mol% to about 50 mol%, based on the total molar amount of the components constituting the liposome.

45. The liposome of claim 43 or 44, wherein, the liposome further comprises a phospholipid and a cholesterol.

46. The liposome of claim 45, wherein, the phospholipid comprises about 0 mol% to about 20 mol%, or a range between any values of about 0 mol% to about 20 mol%, based on the total molar amount of the components constituting the liposome.

47. The liposome of claim 45 or 46, wherein, the cholesterol comprises about 30 mol% to about 50 mol%, or a range between any values of about 30 mol% to about 50 mol%, based on the total molar amount of the components constituting the liposome.

48. A lipid nanoparticle, characterized in that, the lipid nanoparticle comprises the lipid compound of any one of claims 1 to 41, or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof.

49. The lipid nanoparticle of claim 48, wherein, the lipid compound comprises about 10 mol% to about 90 mol%, preferably about 10 mol% to about 70 mol%, more preferably about 20 mol% to about 50 mol%, based on the total molar amount of the components constituting the lipid nanoparticle.

50. The lipid nanoparticle of claim 48 or 49, wherein, the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG lipid.

51. The lipid nanoparticle of claim 50, wherein, the phospholipid comprises about 0 mol% to about 20 mol%, based on the total molar amount of the components constituting the lipid nanoparticle.

52. The lipid nanoparticle of claim 50 or 51, wherein, the structural lipid comprises about 30 mol% to about 50 mol%, based on the total molar amount of the components constituting the lipid nanoparticle.

53. The lipid nanoparticle of any one of claims 50-52, wherein, the PEG lipid comprises about 0 mol% to about 10 mol%, based on the total molar amount of the components constituting the lipid nanoparticle.

54. The lipid nanoparticle of any one of claims 50-53, wherein, the lipid nanoparticle further comprises a plasmid or a nucleic acid.

55. The lipid nanoparticle of claim 54, wherein, the N / P ratio of the lipid compound to the nucleic acid is about 1.1:1 to 10:

1.

56. The lipid nanoparticle of claim 50 or 51, wherein, the nucleic acid is RNA.

57. Use of the liposome according to any one of claims 43 to 47 or the lipid nanoparticle according to any one of claims 48 to 53 as a delivery vehicle.

58. The use according to claim 57, characterized in that The delivery vehicle is for delivering a plasmid or a nucleic acid.

59. A pharmaceutical composition comprising, The pharmaceutical composition comprises the lipid compound according to any one of claims 1 to 41, the liposome according to any one of claims 43 to 47 or the lipid nanoparticle according to any one of claims 48 to 53, and a pharmaceutically acceptable carrier or excipient.

60. Use of a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, a lipid nanoparticle comprising a lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the lipid compound or the lipid nanoparticle, and a pharmaceutically acceptable carrier or excipient, for the delivery of a nucleic acid including DNA or RNA, e.g., mRNA, to an immune organ and / or tissue, wherein X is O or S; R II is hydrogen, or is selected from the group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of from 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; R III selected from group (A) include groups comprising at least one ionizable tertiary amine structure; R I and R IV each independently is selected from the group (B) comprising a substituted or unsubstituted aliphatic or a substituted or unsubstituted heteroaliphatic group having a carbon atom number of 11-30; and R II The group selected from group (C) includes substituted or unsubstituted hydrocarbyl groups having a carbon count of 1 to 11, substituted or unsubstituted heterohydrocarbyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups.

61. The use according to claim 60, characterized in that, Group A includes a group comprising at least one ionizable tertiary amine structure, wherein the number of carbon atoms of the group comprising at least one ionizable tertiary amine structure is 3-11 and is represented by the following general formula, Among them, R a It is a C1-C6 substituted or unsubstituted alkylene group; R b R c Each of the following groups is independently a C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, or C2-C6 substituted or unsubstituted alkynyl, optionally consisting of one, two, or three groups selected from -OH, -SH, and -NR. d R d' Or substitution by a phenyl substituent, wherein R d R d' Each is independently hydrogen or C1-C3 alkyl; or R b R c Together with the N atom it is attached to, it forms a 5-12 membered heterocycle or heteroaromatic ring, which contains one, two, or three heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, and the 5-12 membered heterocycle or heteroaromatic ring is optionally substituted by one or more C1-C6 alkyl or oxo (=O); or R a R b Together with the N atom to which it is attached, it forms a 5-12 membered heterocycle or heteroaromatic ring optionally substituted with a C1-C6 alkylene group, the optionally substituted C1-C6 alkylene group comprising 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, and the optionally substituted C1-C6 alkylene group is optionally substituted by one or more C1-C6 alkyl or oxo (=O); or R a R b R c Together with the N atom to which it is attached, it forms a 5-12 membered heterocycle or heteroaromatic ring optionally substituted with C1-C6 alkylene, the 5-12 membered heterocycle or heteroaromatic ring optionally substituted with C1-C6 alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocycle or heteroaromatic ring optionally substituted with C1-C6 alkylene or oxo (=O); Group B comprises substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms, wherein the substituted or unsubstituted aliphatic or substituted heteroaliphatic groups having 11-30 carbon atoms optionally include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 independently selected from -C=C-, -C≡C-, -NH-, -NH2, -OH, -OR m , -O-, -C(O)-, -C(OR n )-, -C(O)O-, -SH, -SR o , -S-, -C(S)-, -C(SR p )-, -C(S)O-, and -P(O)-, wherein R m , R n , R o and R p are each independently a substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group; and Group C includes substituted or unsubstituted hydrocarbyl groups of 1-11 carbon atoms, substituted or unsubstituted heterohydrocarbyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups, wherein the substituted or unsubstituted hydrocarbyl groups of 1-11 carbon atoms, substituted or unsubstituted heterohydrocarbyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups optionally include 1, 2, 3, 4, or 5 groups independently selected from -C=C-, -CºC-, -NH-, -NH2, -OH, -OR m' , -O-, -C(O)-, -C(OR n' )-, -C(O)O-, -SH, -SR o' , -S-, -C(S)-, -C(SR p' )-, -C(S)O-, and -P(O)-, wherein R m′ , R n' , R o' , and R p' are each independently a substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group, the hydrocarbon, heterocarbon, aryl, or heteroaryl group being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH.

62. The use according to claim 60 or 61, characterized in that R I and R IV each independently is selected from the group B, wherein the substituted or unsubstituted aliphatic selected from the group B has 11-30 carbon atoms, and the substituted or unsubstituted heteroaliphatic selected from the group B has 11-30 atoms including carbon atoms and N, O, S and the like heteroatoms.

63. The use according to any one of claims 60 to 62, characterized in that, R I and the other of R IV has a number of carbon atoms of from 11 to 25.

64. The use according to any one of claims 60 to 63, characterized in that, R I and the other of R IV has a number of carbon atoms of from 11 to 16.

65. The use according to any one of claims 60 to 64, characterized in that, R I and R IV each independently optionally comprises at least one degradable group.

66. Use according to claim 65, characterized in that, wherein said degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -S-S-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -NR 1 C(O)-, -C(O)NR 2 -, -NR 3 C(O)O-, -OP(O)OR 4 O-, -OCR 5 (OR 6 )O-, -CR 7 (OR 8 )O-, -CH(OR 9 )O-, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group, preferably said degradable group is an ester group, i.e. -C(O)O- or -OC(O)-; or an ester bond is included in the degradable group.

67. The lipid compound of any one of claims 60-66, or an N-oxide, isomer, or pharmaceutically acceptable salt thereof, wherein, R I and at least one of R IV comprises at least one degradable group, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or the degradable group comprises an ester bond.

68. The lipid compound of any one of claims 60-67, or an N-oxide, isomer, or pharmaceutically acceptable salt thereof, wherein, R I and only one of R IV comprises one, two or three degradable groups, for example the degradable group is an ester group, i.e. -C(O)O- or -OC(O)-, or an ester bond is comprised in the degradable group; while the other does not comprise a degradable group.

69. The lipid compound of any one of claims 60-68, or an N-oxide, isomer, or pharmaceutically acceptable salt thereof, wherein, R I and R IV each independently contains one, two or three degradable groups, for example the degradable groups are ester groups, i.e. -C(O)O- or -OC(O)-, or the degradable groups include an ester bond.

70. The use according to any one of claims 60 to 69, characterized in that, Group A includes the following groups of structures:

71. The use according to any one of claims 60 to 70, characterized in that, Group B includes the following groups of structures:

72. The use according to any one of claims 60 to 71, characterized in that, Group C includes the groups shown in the following structures:

73. The use according to any one of claims 60 to 72, characterized in that, when R I and / or R IV does not contain a degradable group, R I and / or R IV is selected from the group consisting of the structures shown below:

74. The use according to any one of claims 60 to 73, characterized in that, when R I and / or R IV comprising a degradable group, R I and / or R IV is selected from the group consisting of the structures shown below:

75. The use according to any one of claims 60 to 74, characterized in that, R II is selected from hydrogen, substituted or unsubstituted Ci-C8alkyl, e.g., Ci-C6alkyl, Ci-C4alkyl, or substituted or unsubstituted Ci-C8heteroalkyl, e.g., Ci-C6heteroalkyl, Ci-C4heteroalkyl.

76. The use according to any one of claims 60 to 75, characterized in that, R II substituted or unsubstituted C1-C8alkyl, e.g., C1-C6alkyl, C1-C4alkyl, substituted or unsubstituted C3-C8cycloalkyl, e.g., C3-C6cycloalkyl, C3-C4cycloalkyl, or substituted or unsubstituted C1-C8heteroalkyl, e.g., C1-C6heteroalkyl, C1-C4heteroalkyl, substituted or unsubstituted C3-C8heterocyclyl, e.g., C3-C6heterocyclyl, C3-C4heterocyclyl.

77. The use according to any one of claims 60 to 76, characterized in that, The lipid compound has the following general structural formula (I) A ):

78. The use according to any one of claims 60-77, characterized in that R II R is selected from group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and R II R is selected from group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group.

79. The use according to any one of claims 60-77, characterized in that, R II is hydrogen, and R II is selected from group (C) comprising a substituted or unsubstituted hydrocarbyl group having a carbon count of 1 to 11, a substituted or unsubstituted heterohydrocarbyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

80. The use according to any one of claims 60 to 76, characterized in that, The lipid compound has the following general structure (I) B ):

81. The use according to any one of claims 60 to 80, characterized in that, The lipid compound is selected from the group consisting of lipid compounds as shown below:

82. The use according to any one of claims 60 to 81, characterized in that, The lipid compound has a molecular weight in the range of 500 g / mol to 1400 g / mol; preferably the lipid compound has a molecular weight in the range of 700 g / mol to 1200 g / mol; more preferably the lipid compound has a molecular weight in the range of 700 g / mol to 1000 g / mol.

83. The use according to any one of claims 60 to 82, characterized in that, The lipid nanoparticle comprises the lipid compound of Formula (I) or an N-oxide, a stereoisomer, or a pharmaceutically acceptable salt thereof, in a range of about 10 mol% to about 90 mol%, based on the total molar amount of components constituting the lipid nanoparticle, preferably in a range of about 10 mol% to about 70 mol%, more preferably in a range of about 20 mol% to about 50 mol%.

84. The use according to any one of claims 60 to 83, characterized in that, The lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG lipid.

85. The use according to any one of claims 60 to 84, characterized in that, The phospholipid is in a range of about 0 mol% to about 20 mol%, based on the total molar amount of components constituting the lipid nanoparticle.

86. The use according to any one of claims 60 to 85, characterized in that, The structural lipid is in a range of about 30 mol% to about 50 mol%, based on the total molar amount of components constituting the lipid nanoparticle.

87. The use according to any one of claims 60 to 86, characterized in that, The PEG lipid is in a range of about 0 mol% to about 10 mol%, based on the total molar amount of components constituting the lipid nanoparticle.

88. The use according to any one of claims 60 to 87, characterized in that, The lipid nanoparticle further comprises a plasmid or a nucleic acid.

89. The use according to claim 88, characterized in that The N / P ratio of the lipid compound to the nucleic acid is in a range of about 1.1:1 to 10:

1.

90. The use according to claim 88 or 89, characterized in that The nucleic acid is RNA, such as mRNA.

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