Lipid compounds for gene delivery and lipid nanoparticles comprising same

Abstract

Disclosed herein are lipid compounds comprising isonitrile or carboxylic acid end groups, methods for their preparation and their use in the preparation of lipid compounds useful for gene delivery. Also disclosed herein are lipid compounds useful for gene delivery, methods for their preparation and their use in gene delivery. Also disclosed herein are liposomes and lipid nanoparticles comprising the lipid compounds useful for gene delivery, and gene delivery compositions comprising the lipid compounds, liposomes, or lipid nanoparticles. The lipid compounds, liposomes, lipid nanoparticles and gene delivery compositions useful for gene delivery enable efficient recombination, protection, intracellular and targeted delivery and release of biomolecules, such as nucleic acids, in both in vitro and in vivo tissues and organs.

Description

Lipid compounds for gene delivery and lipid nanoparticles containing the same

[0001] This application claims priority to Chinese Patent Application No. 202211727565.0 filed on December 30, 2022 and Chinese Patent Application No. 202310803747.X filed on June 30, 2023, the entireties of which are hereby incorporated by reference.

[0002] The present invention belongs to the field of gene loading and delivery, and specifically relates to a lipid compound that can be used for gene delivery, a method for preparing the lipid compound, and its use in gene delivery. The present invention also relates to liposomes and lipid nanoparticles containing the lipid compound, and a gene delivery composition containing the lipid compound, the liposome, or the lipid nanoparticle.

[0003] Currently, a large number of different types of nucleic acids are being developed as therapeutic agents for treating a variety of diseases. These nucleic acids include DNA in gene therapy, plasmid-based interfering nucleic acids, and small interfering nucleic acids for RNA interference (RNAi), including siRNA, miRNA, antisense molecules, ribozymes, and aptamers.

[0004] Effective nucleic acid drug delivery requires that therapeutic nucleic acid molecules be delivered into the target cells. In vivo, naked nucleic acid molecules will be broken down and cleared by a large number of nucleases. Moreover, due to the natural negative charge of nucleic acid molecules, it is difficult for them to directly penetrate the negatively charged cell membrane. Therefore, a special delivery system is required to protect the nucleic acid molecules and assist them in entering the target cells. Lipid nanoparticles are currently the most effective carrier form for nucleic acid drug delivery, and have been verified in a variety of marketed drugs including the new crown mRNA vaccine. Classic lipid nanoparticles are composed of four lipid-coated nucleic acid molecules, including ionizable lipids, cholesterol, neutral phospholipids, and polyethylene glycol (PEG) lipids. Among them, ionizable lipids determine the efficiency of the lipid nanoparticles in delivering nucleic acid molecules in vitro and in vivo. Delivering therapeutic nucleic acid molecules to the subject is important for its therapeutic effect and this is often hindered by the limited ability of ionizable lipids to reach the targeted cells and tissues. It is crucial to expand and optimize the structure of ionizable lipids to enter the targeted tissue cells.

[0005] One of the basic challenges that medical practitioners are facing now is that a large number of different types of nucleic acids are currently being developed as therapeutic agents for the treatment of various diseases. These nucleic acids include the DNA in gene therapy, the plasmid small interfering nucleic acids (interfering nucleic acid, iNA), antisense molecules, ribozymes, antagomirs, microRNAs and aptamers for RNA interference (RNAi), etc. Along with the development of these nucleic acids, there is a need to produce lipid formulations that are easy to prepare and can be easily delivered to target tissues. People expect to develop novel ionizable lipids to meet the demand of effectively delivering nucleic acid drugs in gene therapy.

[0006] Isonitriles are among the strangest, most fascinating, and most unique functional groups in organic chemistry. Their high reactivity allows their carbon atoms to participate in a wide range of organic reactions. Indeed, they can attack activated electrophiles with nucleophiles, be attacked by various nucleophiles as electrophiles, participate in common [4+1] cycloadditions as carbenes, and serve as free radical acceptors to form imino radical intermediates. Finally, the presence of a lone pair of electrons at the terminal carbon atom explains their powerful metal coordination properties, enabling the preparation of countless coordination complexes. However, current research has primarily focused on short-chain and aromatic isonitriles, while research on lipid-based isonitriles with biodegradable groups is virtually nonexistent.

[0007]

[0008] In order to solve the above problems, the present disclosure aims to provide a variety of lipid compounds, preparation methods thereof and their use in gene delivery. Another object of the present disclosure is to provide a novel lipid compound containing an isonitrile or carboxylic acid end group, preparation methods thereof and their use.

[0009] Daniel Anderson's research group at MIT has reported (Nature biotechnology, 2019) the use of the Ugi three-component reaction to prepare ionizable lipids with symmetrical hydrophobic long chains, but the diversity of its structure is quite limited by the number of components and symmetry, and the rigid ring structure of the linker also affects the freedom of the lipid to fuse with the target cell membrane, limiting its ability to fuse cell membranes to a certain extent. According to the technical solution of the present disclosure, based on the classic Ugi four-component reaction and its variants, a series of ionizable lipid compounds containing various topological structures can be produced with higher throughput. The ionizable lipid compounds produced by the present disclosure have a structure with an asymmetric hydrophobic long chain, a more flexible molecular structure, and can better bind to the target cell membrane, thereby achieving efficient intracellular delivery of nucleic acids for different target cells. The LNPs prepared from these lipid compounds have different particle sizes, and the efficiency of delivering nucleic acid molecules also has a tendency towards different cell types.

[0010] According to one aspect of the present disclosure, there is provided a lipid compound of formula (I), or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0011] wherein X is O or NH; Y is O or S; Z is absent or Z is O, NH or S;

[0012] R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms;

[0013] R I 、R II 、R III and R IV are each independently selected from group (A) comprising a group containing at least one ionizable tertiary amine structure, group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, and group (C) comprising a substituted or unsubstituted hydrocarbon group, substituted or unsubstituted heterohydrocarbon group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group having less than 11 carbon atoms,

[0014] The conditions are:

[0015] (1) When R I 、R II 、R III and R IV when any one of the three is a group containing at least one ionizable tertiary amine structure, any two of the remaining three are the same or different substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl groups having less than 11 carbon atoms, and the other is a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11-30 carbon atoms; or, any two of the remaining three are the same or different substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms, and the other is a substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group having less than 11 carbon atoms;

[0016] or

[0017] (2) When R I 、R II 、R III and R IVWhen any two of the groups are the same or different groups containing at least one ionizable tertiary amine structure, one of the remaining two is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, and the other is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms.

[0018] In some embodiments, R I 、R II 、R III and R IV Only one of the groups is a group comprising at least one ionizable tertiary amine structure.

[0019] In some embodiments, group A includes a group comprising at least one ionizable tertiary amine structure, wherein the group comprising at least one ionizable tertiary amine structure has 3 to 11 carbon atoms and is represented by the following general formula:

[0020] Among them, R a is a C1-C6 substituted or unsubstituted alkylene group; R b 、R c are each independently C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, which may be optionally substituted by 1, 2 or 3 selected from -OH, -SH, -NR d R d ' or phenyl substituted, wherein R d 、R d ' are each independently hydrogen or C1-C3 alkyl; or R b 、R c Together with the nitrogen atom to which it is attached, it forms a 5-12 membered heterocyclic or heteroaromatic ring, the 5-12 membered heterocyclic or heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, and the 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6 alkylene, the 5-12 membered heterocyclic ring 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6 alkylene is optionally substituted with one or more C1-C6 alkyl or oxo (=O); or R a 、Rb 、R c Together with the N atom to which it is attached, it forms a 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6 alkylene, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6 alkylene 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6 alkylene is optionally substituted with one or more C1-C6 alkyl or oxo (=O).

[0021] In some embodiments, 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 contain 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)- groups, wherein R m 、R n 、R o and R p are each independently substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group.

[0022] In some embodiments, Group C includes substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl groups having 1 to 11 carbon atoms, wherein the substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl groups having 1 to 11 carbon atoms optionally contain 1, 2, 3, 4, or 5 independently selected from deuterium, halogen, -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)- groups, wherein R m '、Rn '、R o ' and R p ' are each independently substituted or unsubstituted C1-C 14 wherein the aliphatic hydrocarbon group is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH.

[0023] In some embodiments, R II ' is hydrogen, or is selected from Group C.

[0024] In some embodiments, R I 、R II 、R III and R IV The following conditions are met:

[0025] R I Selected from Group A, R II and R III Selected from Group B, and R IV Selected from Group C; or

[0026] R I Selected from Group A, R II and R IV Selected from Group B, and R III Selected from Group C; or

[0027] R I Selected from Group A, R III and R IV Selected from Group B, and R II Selected from Group C; or

[0028] R II Selected from Group A, R I and R III Selected from Group B, and R IV Selected from Group C; or

[0029] R II Selected from Group A, R I and R IV Selected from Group B, and R III Selected from Group C; or

[0030] R II Selected from Group A, R III and R IV Selected from Group B, and R I Selected from Group C; or

[0031] R III Selected from Group A, R I and R II Selected from Group B, and R IV Selected from Group C; or

[0032] R III Selected from Group A, R I and R IV Selected from Group B, and R II Selected from Group C; or

[0033] R III Selected from Group A, R II and R IV Selected from Group B, and R I Selected from Group C; or

[0034] R IV Selected from Group A, R I and R II Selected from Group B, and R III Selected from Group C; or

[0035] R IV Selected from Group A, R I and R III Selected from Group B, and R II Selected from Group C; or

[0036] R IV Selected from Group A, R II and R III Selected from Group B, and R I Selected from Group C.

[0037] In some embodiments, R I 、R II 、R III and R IV Each independently further optionally comprises at least one degradable group.

[0038] In some embodiments, R I 、R II 、R III and R IV When each is independently selected from Group B, it optionally further comprises at least one degradable group.

[0039] In some embodiments, the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SS-, -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-, where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 are each independently substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group.

[0040] In some embodiments,

[0041] When R III and R IV When selected from Group B, R III and R IV Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms;

[0042] When R II and R IV When selected from Group B, R II and R IV Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms;

[0043] When R II and R III When selected from Group B, R II and R III Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms;

[0044] When R I and R IV When selected from Group B, R I and R IV Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms;

[0045] When R I and R II When selected from Group B, R I and R II Any one of has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms; and / or

[0046] When R I and R III When selected from Group B, R I and R III Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms.

[0047] In some embodiments,

[0048] When R III and R IV When selected from Group B, R III and R IV Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms;

[0049] When R II and R IV When selected from Group B, R II and R IV Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms;

[0050] When R II and R III When selected from Group B, R II and R III Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms;

[0051] When R I and R IV When selected from Group B, R I and R IV Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms;

[0052] When R I and R II When selected from Group B, R I and R II Any one of has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms; and / or

[0053] When R I and R III When selected from Group B, R I and R III Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms.

[0054] In some embodiments,

[0055] When R III and R IV When selected from Group B, R III and R IV At least one of comprises at least one degradable group;

[0056] When R II and R IV When selected from Group B, RII and R IV At least one of comprises at least one degradable group;

[0057] When R II and R III When selected from Group B, R II and R III At least one of comprises at least one degradable group;

[0058] When R I and R IV When selected from Group B, R I and R IV At least one of comprises at least one degradable group;

[0059] When R I and R II When selected from Group B, R I and R II At least one of comprises at least one degradable group; and / or

[0060] When R I and R III When selected from Group B, R I and R III At least one of the comprises at least one degradable group.

[0061] In some embodiments,

[0062] When R III and R IV When selected from Group B, R III and R IV Only one of them contains a degradable group;

[0063] When R II and R IV When selected from Group B, R II and R IV Only one of them contains a degradable group;

[0064] When R II and R III When selected from Group B, R II and R III Only one of them contains a degradable group;

[0065] When R I and R IV When selected from Group B, R I and R IV Only one of them contains a degradable group;

[0066] When R I and R IIWhen selected from Group B, R I and R II only one of contains a degradable group; and / or

[0067] When R I and R III When selected from Group B, R I and R III Only one of the 5′-amino acids contains a degradable group.

[0068] In some embodiments, there is provided a formula (I A ), or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0069] Among them, R II '、R I 、R II 、R III and R IV As defined in this disclosure.

[0070] Group A, Group B and Group C are as defined in this disclosure.

[0071] In some embodiments, R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms, for example, R II ' is hydrogen or a hydrocarbon group selected from group C, such as a hydrocarbon group having 1-8 carbon atoms, such as 1-6, 1-4, specifically such as C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0072] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B, and R II Selected from Group C.

[0073] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B, R II Selected from Group C, and R II ' is hydrogen or selected from Group C.

[0074] In some embodiments, there is provided a formula (I A-1 ), or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0075] Among them, R II '、R I 、R III and R IV As defined in this disclosure.

[0076] Group A, Group B and Group C are as defined in this disclosure.

[0077] In some embodiments, R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms, for example, R II ' is hydrogen or a hydrocarbon group selected from group C, such as a hydrocarbon group having 1-8 carbon atoms, such as 1-6, 1-4, specifically such as C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0078] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B.

[0079] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B, and R II ' is hydrogen or selected from Group C.

[0080] In some embodiments, there is provided a formula (I A-2 ), or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0081] Among them, R I 、R III and R IV As defined in this disclosure.

[0082] Group A, Group B and Group C are as defined in this disclosure.

[0083] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B.

[0084] In some embodiments, there is provided a formula (I B ), or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0085] Among them, R II '、R I 、R II 、R III and R IV As defined in this disclosure.

[0086] Group A, Group B and Group C are as defined in this disclosure.

[0087] In some embodiments, R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms, for example, R II ' is hydrogen or a hydrocarbon group selected from group C, such as a hydrocarbon group having 1-8 carbon atoms, such as 1-6, 1-4, specifically such as C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0088] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B, and R II Selected from Group C.

[0089] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B, R II Selected from Group C, and R II ' is hydrogen or selected from Group C.

[0090] According to another aspect of the present disclosure, there is provided a method for preparing a lipid compound according to formula (I) of the present disclosure, the method comprising the following steps:

[0091] (i) the first reactant (R III -NH2 and the second reactant (R II -C(O)-R II ') is dissolved in ethanol and reacted to form a first mixture;

[0092] (ii) adding the third reactant (HY-C(O)-R IV ), after reaction, to form a second mixture;

[0093] (iii) adding 1-isocyanatocyclohexene to the second mixture obtained in step (ii), and obtaining a compound having structural formula (I1) after reaction and purification;

[0094] (iv) removing the cyclovinylamide group from the product of the above step (compound of formula (I1)) under acidic conditions to obtain the compound acid having the structural formula (I2).

[0095] (v) the product of the above step (the compound of formula (I2)) and the fourth reactant (R I -OH or R I -NH2) and, after dehydration condensation reaction, purified to obtain a lipid compound having structural formula (I') or (I").

[0096] The first three steps of the reaction constitute the classic Ugi tetrahedral reaction with cyclovinyl isocyanide as the fixed component. By selectively removing the cyclovinylamide structure, the variable R I The type of the X group in the structure of formula (I) can be changed by selecting the structure of the fourth reactant.

[0097] According to an alternative embodiment of the present disclosure, a combination of carbon dioxide and alcohol is used to replace the third reactant. The lipid compound prepared by this method has the following general structural formula (I3), IV Combined with the amide structure to form a carbamate structure.

[0098] According to an alternative embodiment of the present disclosure, the above alternative can be further replaced by a combination of the following steps: (I) using carbon dioxide and tert-butanol to replace the third reactant to generate a tert-butyloxycarbonyl protected amino structure; (II) removing the BOC protecting group and the cyclovinylamide group simultaneously under acidic conditions to obtain an intermediate with an amino acid structure; (iii) further introducing a secondary amine containing R IV The target lipid compound is prepared by the amide of the group, and the type of the X group in the structure of formula (I) is changed by the choice of the structure of the fourth reactant. Compared with the classic Ugi four-component reaction, the above alternative scheme prepares a modular lipid precursor that can be conveniently used in the R of formula (I). IV The introduction of connecting groups such as -O-, -S-, and -NH- connected to the carbonyl group can further regulate the lipid compound of formula (I) in R IV This is difficult to achieve using the classic Ugi four-component reaction using carboxylic acid as the third reactant.

[0099] According to another aspect of the present disclosure, there is provided a method for preparing a lipid compound according to formula (I) of the present disclosure, the method comprising the following steps:

[0100] The first reactant (R I -NC), the second reactant (R II -C(O)-R II '), the third reactant (R III -NH2) and the fourth reactant (HY-C(O)-R IV ) are mixed, and reacted in one step at room temperature to obtain a lipid compound having structural formula (I”).

[0101] According to another aspect of the present disclosure, provided is use of the lipid compound of formula (I) of the present disclosure or its N-oxide, stereoisomer or pharmaceutically acceptable salt in preparing liposomes and / or lipid nanoparticles.

[0102] According to another aspect of the present disclosure, a liposome is provided. The lipid nanoparticles of the present disclosure comprise the lipid compound of formula (I) of the present disclosure or its N-oxide, stereoisomer or pharmaceutically acceptable salt.

[0103] In some embodiments, the liposomes of the present disclosure further comprise phospholipids and cholesterol.

[0104] According to another aspect of the present disclosure, a lipid nanoparticle is provided. The lipid nanoparticle of the present disclosure comprises the lipid compound of formula (I) of the present disclosure or its N-oxide, stereoisomer or pharmaceutically acceptable salt.

[0105] In some embodiments, the lipid nanoparticles of the present disclosure further comprise phospholipids, structural lipids, PEG lipids, and optionally nucleic acids.

[0106] The delivery efficiency of nucleic acids in the present disclosure refers to more nucleic acid accumulation in target cells, tissues, and organs, higher nucleic acid transcription amount (e.g., delivery of DNA), higher target protein translation amount (e.g., delivery of mRNA), higher target mRNA transcription and translation inhibition efficiency (e.g., delivery of miRNA), etc. According to some embodiments of the present disclosure, the delivery of the lipid nanoparticles has a higher delivery efficiency than the direct delivery of nucleic acids (not applicable to delivery vectors). This delivery efficiency, in some embodiments, is manifested as the amount of protein compiled by the delivered mRNA generated in the target cell or animal body.

[0107] According to another aspect of the present disclosure, a pharmaceutical composition is provided. The pharmaceutical composition of the present disclosure comprises a 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 a liposome comprising a 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 a lipid nanoparticle comprising a lipid compound of formula (I) of the present disclosure and a pharmaceutically acceptable carrier or excipient.

[0108] Another object of the present disclosure is to provide lipid compounds containing isonitrile or carboxylic acid end groups, methods for preparing the same, and uses thereof in preparing lipid compounds for gene delivery. The lipid compounds containing isonitrile or carboxylic acid end groups disclosed herein can be synthesized into a more easily degradable, more efficient ionizable lipid compound for nucleic acid (DNA, RNA, etc.) or plasmid delivery through Ugi, Passerini, and other isonitrile-based specific multicomponent reactions.

[0109] Compared with the prior art, the lipid compounds containing isonitrile or carboxylic acid end groups disclosed herein can be used to prepare ionizable lipids (NCLs) through a one-step isonitrile-based multi-component reaction method. These can be combined with other existing lipid molecules to prepare LNPs that encapsulate nucleic acids or plasmids, effectively completing RNA delivery. Furthermore, due to the ester bonds carried by the lipid isonitrile, the ionizable lipids (NCLs) are more easily degraded in vivo, significantly reducing their toxicity compared to traditional amide bonds. The technology of the present invention is simple to synthesize, uses inexpensive raw materials, and is suitable for large-scale production.

[0110] According to another aspect of the present disclosure, there is provided a lipid compound of formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0111] Among them, R A is selected from substituted or unsubstituted aliphatic and heteroaliphatic groups, R A optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH;

[0112] R B is a degradable group containing a degradable bond selected from the following group: Where a represents the A The connected position, b represents the connection with R C Connected position, R B1 and R B2are each independently selected from H and substituted or unsubstituted C 1-6 an alkyl group optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH;

[0113] R C is selected from substituted or unsubstituted aliphatic and heteroaliphatic groups, R C optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH; and

[0114] R D Selected from -NC or -COOH.

[0115] In some embodiments, R of the lipid compound of formula (II) of the present disclosure is A The group contains a branched central carbon atom; further, the branched central carbon atom is located at R B The α, β or γ position of the group.

[0116] According to another aspect of the present disclosure, a method for preparing the lipid compound of formula (II) of the present disclosure is provided, the preparation method comprising the following synthetic route:

[0117] When R B Selected from R D When -NC is selected,

[0118] When R B Selected from R D When selected from -COOH,

[0119] According to another aspect of the present disclosure, there is provided a use of a lipid compound of formula (II) of the present disclosure in the preparation of an ionizable lipid, wherein the ionizable lipid is a lipid compound of formula (I), (III), (IV), (V) and (VI) of the present disclosure as shown below.

[0120] Wherein, each substituent in the formula (I), (III), (IV), (V) and (VI) is as defined herein.

[0121] According to another aspect of the present disclosure, there is provided a lipid compound of formula (III), (IV), (V) and (VI), or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0122] Wherein, each substituent in formula (III), (IV), (V) and (VI) is as defined herein.

[0123] According to another aspect of the present disclosure, a liposome is provided, comprising the following three components: cholesterol, phospholipid, and one or more lipid compounds selected from formula (I), (III), (IV), (V) and (VI).

[0124] According to another aspect of the present disclosure, a drug delivery system is provided, which comprises the liposome of the present disclosure as a delivery vehicle.

[0125] According to another aspect of the present disclosure, a lipid nanoparticle is provided, comprising the following four components: one or more lipid compounds selected from formula (I), (III), (IV), (V) and (VI), phospholipids, structural lipids, and PEG lipids.

[0126] According to another aspect of the present disclosure, a method for preparing lipid nanoparticles is provided, which comprises co-assembling one or more lipid compounds selected from formula (I), (III), (IV), (V) and (VI) with other lipid molecules, wherein the other lipids are one or more selected from the following groups: phospholipids, structural lipids, and PEG lipids, etc.

[0127] According to another aspect of the present disclosure, a lipid nanoparticle encapsulating a nucleic acid molecule is provided, wherein the lipid nanoparticle encapsulating the nucleic acid molecule uses the lipid nanoparticle of the present disclosure as a delivery vehicle.

[0128] According to another aspect of the present disclosure, a plasmid-encapsulated lipid nanoparticle is provided, wherein the plasmid-encapsulated lipid nanoparticle uses the lipid nanoparticle of the present disclosure as a delivery vehicle.

[0129] According to another aspect of the present disclosure, a method for preparing lipid nanoparticles encapsulating nucleic acid molecules or plasmids is provided, the method comprising the following steps:

[0130] 1. Dissolve various lipid compounds in an organic solvent such as ethanol that is miscible with water;

[0131] 2. Disperse the nucleic acid molecules or plasmids in an acidic aqueous solution with a pH < 7;

[0132] 3. Prepare lipid nanoparticles by rapidly mixing the above two solutions in a certain volume ratio. This rapid mixing can be achieved by direct mixing using microfluidics, impinging streams, or pipetting equipment.

[0133] Figures 1-6 show the transfection results of LNPs composed of the lipid compounds disclosed in the Examples in 293T cells.

[0134] 7-12 show the transfection results of LNPs composed of the lipid compounds disclosed in the Examples in A549 cells.

[0135] FIG13 shows the transfection results of LNPs composed of the lipid compounds disclosed in the Examples in 293T (top) and A549 cells (bottom).

[0136] FIG14 shows the one-dimensional H-NMR spectrum of lipid 175.

[0137] Figure 15 shows the different R values ​​of some lipid compounds based on the backbone of lipid 175. II Hydrogen spectrum splitting peaks of substituents.

[0138] Figure 16 shows the different R values ​​of some lipid compounds based on the backbone of lipid 284. II Hydrogen spectrum splitting peaks of substituents.

[0139] FIG17 shows the expression of eGFP after LNPs containing eGFP-expressing plasmid DNA were prepared using lipids 284, 424 and a control lipid and administered to cells.

[0140] FIG18 shows the RSV true virus neutralizing antibody titer detected after LNPs containing RSV-mRNA were prepared using lipid 174 and sm102 disclosed herein and administered intramuscularly to mice.

[0141] The above and other objects, components and advantages will become apparent from the following more detailed description of specific embodiments, as illustrated and exemplified in the accompanying drawings, in which like reference numerals, symbols, etc. represent like parts, components or features of the specific embodiments. It should be noted that any process not specifically described below is readily understood or comprehensible to one skilled in the art with reference to the prior art. Reagents or instruments used without manufacturer designation are deemed to be commercially available conventional products.

[0142] In terms of their scope of use, the terms "comprises," "comprising," and "having," or any variations thereof, as used in the claims and description herein, will be considered to indicate an open group that may include unspecified other elements. The terms "at least one" and "one or more" can be used interchangeably. The term "single" is used to indicate one and only one of something. Similarly, when a specific number of things is required, other specific integer values, such as "two," will be used. The terms "preferably," "preferred," "preferably," "optionally," "may," and similar terms are used to indicate that the cited item, condition, or step is an optional (i.e., not required) feature in the embodiment. Unless otherwise stated, a range described as "between a and b" includes the values ​​of "a" and "b."

[0143] Although various improvements have been described herein with reference to specific embodiments of the present disclosure, it should be understood that such description is by way of illustration only and should not be construed as limiting the scope of any claimed invention. Accordingly, the scope and content of any claimed disclosure will be limited solely by the terms of the appended claims in their current form or as amended during prosecution or as implemented in any continuation application. Furthermore, it should be understood that, unless otherwise indicated, features of any specific embodiment discussed herein may be combined with one or more features of any one or more embodiments otherwise discussed or contemplated herein.

[0144] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry as well as 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, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modem Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0145] All ranges cited herein are inclusive unless expressly stated otherwise.

[0146] When a range of values ​​is listed, it is intended that every value and subrange within that range be included. For example, “C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, 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 3-4 、C 4-6 、C 4-5 and C 5-6 In some embodiments, C0 represents that the number of carbon atoms is 0, ie, the group does not exist.

[0147] When any variable occurs more than one time in any constituent or in Formula (I) or in any other formula depicting and describing compounds of the present disclosure, its definition on each occurrence is independent of its definition at every other occurrence. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0148] definition

[0149] As used herein, the term "hydrocarbyl" refers to a chemical group containing hydrogen and carbon. Hydrocarbyl groups may be substituted or unsubstituted. Hydrocarbyl groups may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic, and include alkyl, alkenyl and alkynyl groups. Hydrocarbyl groups may be fully saturated, monounsaturated or polyunsaturated, and may include divalent and polyvalent groups, having a specified number of carbon atoms (i.e., C1-C 10 "alkyl" refers to 1 to 10 carbon atoms, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbon atoms). When a hydrocarbyl group contains heteroatoms such as N, O, S, etc., it is also referred to as a "heterohydrocarbyl group". As used herein, the term "hydrocarbylene" refers to a divalent substituent that is a monovalent hydrocarbyl group having one hydrogen atom replaced by a valence. As used herein, the term "heterohydrocarbylene" refers to a divalent substituent that is a monovalent heterohydrocarbyl group having one hydrogen atom replaced by a valence.

[0150] As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. i-j"alkyl" refers to an alkyl group having i to j carbon atoms. Unless otherwise specified, an alkyl group may contain 1 to 10 carbon atoms. In certain 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- and isopropyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like. As used herein, the term "alkylene" refers to a divalent substituent that is a monovalent alkyl group having one hydrogen atom replaced by a valency.

[0151] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon radical with at least one carbon-carbon double bond, and includes groups with "cis" and "trans" orientations, or alternatively, "E" and "Z" directions. Unless otherwise indicated, alkenyl can contain 2 to 10 carbon atoms. In certain embodiments, alkenyl 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, the alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl include ethylene (vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-butene-1-yl, 5-hexenyl, etc. As used herein, the term "alkenylene" refers to a divalent substituent, which is a monovalent alkenyl with a hydrogen atom replaced by a valence.

[0152] As used herein, the term "alkynyl" refers to a straight or branched hydrocarbon group having at least one carbon-carbon triple bond. Unless otherwise indicated, an alkynyl group may contain 2 to 10 carbon atoms. In certain embodiments, the alkynyl group contains 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. In certain embodiments, the alkynyl group contains 2 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc. 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.

[0153] As used herein, the term "alkoxy" refers to the group -O-alkyl, wherein alkyl has the meaning defined herein.

[0154] As used herein, the term "cycloalkyl" refers to non-aromatic, saturated monocyclic and polycyclic ring systems in which all ring atoms are carbon. Unless otherwise specified, a cycloalkyl group may contain 3 to 10 ring carbon atoms (i.e., C3- 10Cycloalkyl). In certain embodiments, the cycloalkyl group can 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 ring-forming carbon atoms, etc. In particular, the cycloalkyl can be monocyclic or bicyclic. Alternatively, the bicyclic cycloalkyl group can include fused, spirocyclic and bridged cycloalkyl structures.

[0155] On the other hand, also include the cycloalkyl ring that wherein 1,2 or 3 heteroatoms replace into ring carbon atom.This type of group is referred to as " heterocyclic radical " or " heterocycle ", and it refers to as defined above but with at least one heteroatom selected from N, O and S as the cycloalkyl group of ring-forming atoms.Unless otherwise indicated, heterocyclic radical group can contain 3 to 10 ring-forming atoms (i.e. 3 to 10 yuan of heterocyclic radicals).In certain embodiments, heterocyclic radical group can 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 ring-forming atoms etc.Especially, heterocyclic radical group can be monocycle or bicyclic.Alternatively, bicyclic heterocyclic radical group can include condensation, spirocycle and bridged heterocyclic radical structure. Non-limiting examples of heterocyclyl groups include oxiranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, pyrrolidinyl, and morpholinyl. Heterocyclyl groups can also be described by using the number of carbon atoms. For example, C 3-6 Heterocyclyl refers to a heterocyclyl group containing three to six ring-forming carbon atoms, and can also contain at least one heteroatom, such as 1, 2 or 3 heteroatoms as ring-forming atoms. In certain embodiments, the heterocyclyl group or heterocycle contains 1 or 2 heteroatoms as ring-forming atoms. In certain embodiments, the heterocyclyl group can be monocyclic or bicyclic, such as fused bicyclic and spiro bicyclic. In the context of the present disclosure, the terms "heterocyclyl" and "heterocycle" can be used interchangeably.

[0156] As used herein, the term "aliphatic group" refers to a substituted or unsubstituted linear and / or branched, saturated or unsaturated hydrocarbon group, including linear, branched or cyclic alkyl, alkenyl and alkynyl groups. In some embodiments, the term "aliphatic group" can be used interchangeably with "hydrocarbon group". In some embodiments, the aliphatic group contains one or more, for example 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-), and / or any combination thereof.

[0157] As used herein, the term "heteroaliphatic group" refers to a substituted or unsubstituted linear and / or branched, saturated or unsaturated hydrocarbon group containing heteroatoms selected from N, O, and S, including linear, branched, or cyclic alkyl, alkenyl, and alkynyl groups. In some embodiments, the term "heteroaliphatic group" can be used interchangeably with "heterohydrocarbon group." In some embodiments, the heteroatoms contained in the heteroaliphatic group can form the backbone of the heteroaliphatic group together with the carbon atoms, such as, but not limited to, -CNC-, -COC-, -COOC, -CSC-, -CSSC, or any combination thereof. In some embodiments, the heteroatoms contained in the heteroaliphatic group can be substituents attached to carbon atoms, such as, but not limited to, -C≡N, -C=N-, -CN=, -C=O, -C-OH, -C=S, -C-SH, or other substitution structures. In some of the embodiments, the heteroatoms contained in the heteroaliphatic group can be any combination of the above-listed group structures. In some embodiments, a heteroaliphatic group contains one or more, e.g., 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 substituted or unsubstituted C1-C 14 Aliphatic hydrocarbon groups, such as C1-C 12 、C1-C 10 , C1-C8, C1-C6, C1-C4 aliphatic hydrocarbon, substituted or unsubstituted C1-C 14 Specific non-limiting examples of aliphatic hydrocarbon groups include, but are not limited to, methyl, ethyl, n- and isopropyl, n-butyl, sec-butyl, isobutyl, tert-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.

[0158] 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 indicated, an aryl group can be 6 to 10 members. In certain embodiments, an aryl group 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. In the context of the present disclosure, the terms "aryl" and "aromatic ring" can be used interchangeably.

[0159] 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, a heteroaryl group can be 5 to 10 members. In certain embodiments, a heteroaryl group can be 5-membered or 6-membered. In certain embodiments, a heteroaryl group can contain one, two, or three heteroatoms. In certain embodiments, a heteroaryl group can contain one or two heteroatoms. The limiting examples of heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl, quinolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, tetrazolyl, indolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl etc.Heteroaryl groups include at least one heteroatomic ring and at least one aromatic ring with at least one as above.For example, there is at least one heteroatomic ring can be fused to one, two or three carbocyclic rings, for example aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring or another monocyclic heterocycle. Non-limiting examples of fused heteroaryl groups include 1,2,3,5,8,8a-hexahydroindolizine, 2,3-dihydrobenzofuran, 2,3-dihydroindole, 2,3-dihydrobenzothiophene, etc. In the context of the present disclosure, the terms "heteroaryl" and "heteroaromatic ring" are used interchangeably.

[0160] As used herein, the term "oxo" refers to a divalent oxygen atom and the structure of oxo may be shown as =0.

[0161] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine, or fluoride, chloride, bromide and iodide. In certain embodiments, non-limiting examples of halo include fluorine, chlorine and bromine, or fluoride, chloride and bromide, more particularly fluorine and chlorine, or fluoride and chloride.

[0162] As used herein, the term "heteroatom" refers to nitrogen (N), oxygen (O), and sulfur (S), and can include any oxidized forms of nitrogen and sulfur, and any quaternized forms of basic nitrogen, unless otherwise specified.

[0163] As used herein, the terms "substituted," "substituted," and "substituted with" when referring to a chemical group mean that the chemical group has one or more hydrogen atoms removed and replaced by a substituent. As used herein, the term "substituent" has its ordinary meaning as known in the art and refers to a chemical moiety that is 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 may be further substituted.

[0164] When it is stated in Formula (I) or any embodiment thereof that a moiety is "optionally" substituted, this means that Formula (I) or its embodiments encompasses compounds that are substituted with the indicated substituents on that moiety and compounds that do not contain the indicated substituents on that moiety (i.e., wherein the moiety is unsubstituted).

[0165] The compounds provided herein are described with reference to general formulae and specific compounds. In addition, the compounds of the present disclosure may 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 crystalline forms or polymorphs, and active metabolites.

[0166] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that maintain the biological effectiveness of the free acid / alkaline form of a particular compound and are not undesirable biologically or otherwise. Pharmaceutically acceptable salts can include salts formed with inorganic bases or acids and organic bases or acids. In the case where the compounds of the present disclosure contain one or more acidic or basic groups, the disclosure also includes their corresponding pharmaceutically acceptable salts. Therefore, compounds of the present disclosure containing acidic groups (such as carboxyl groups) can exist in salt form and can be used according to the disclosure, for example, alkali metal salts, alkaline earth metal salts, aluminum salts or ammonium salts. More non-limiting examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines (such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine or amino acids). For example, by reacting a compound with an acidic group with a suitable base (e.g., lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide), these salts are readily available. Other alkali salts of compounds of the present disclosure include, but are not limited to, copper (I), copper (II), iron (II), iron (III), manganese (II), and zinc salts. Compounds of the present disclosure contain one or more basic groups, such as groups that can be protonated, which can exist in the form of salts and can be used according to the disclosure in the form of addition salts thereof 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, naphthalene disulfonic acid, sulfoacetic 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, as well as others known to those skilled in the art. The salt formed is especially hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), toluenesulfonate, carbonate, bicarbonate, formates, acetate, sulfoacetate, trifluoromethanesulfonate, oxalate, malonate, maleate, succinate, tartrate, malate, pamoate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate and glutamate. In addition, the stoichiometry of the salt formed by the compounds of the present disclosure can be an integer multiple or a non-integer multiple of 1.

[0167] Compounds of the present disclosure containing basic nitrogen-containing groups can be treated with reagents such as C 1-4 Quaternization of alkyl halides, for example, methyl, ethyl, isopropyl and tert-butyl chloride, bromine and iodine; di-C 1-4Alkyl sulfates, such as dimethyl sulfate, diethyl sulfate, and dipentyl sulfate; C 10-18 Alkyl halides, such as decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aryl C 1-4 Alkyl halides, such as benzyl chloride and phenethyl bromide.

[0168] If the compounds of the present disclosure contain both acidic and basic groups in the molecule, the disclosure also includes, in addition to the above-mentioned salt forms, inner salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The disclosure also includes all salts of the compounds of the present disclosure, which are not directly suitable for pharmaceutical use due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts. For a review of more suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, 2002).

[0169] The lipid compounds of the present disclosure and their pharmaceutically acceptable salts can exist in unsolvated and solvated forms. As used herein, the term "solvate" refers to a molecular complex comprising a lipid compound of the present disclosure or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable solvent molecules. For example, the term "hydrate" is used when the solvent is water.

[0170] The lipid compounds of the present invention may have one or more chiral (asymmetric) centers. The present disclosure encompasses all stereoisomeric forms of the lipid compounds of the present invention. The asymmetric centers present in the lipid compounds of the present invention may have (R) or (S) configurations independently of one another. When the bond to the chiral carbon is described as a straight line in the structural formula of the present invention, or when the compound name is described without the (R) or (S) chiral name of the chiral carbon, it is understood that the (R) and (S) configurations of each such chiral carbon and therefore each enantiomer or diastereomer and mixtures thereof are included in the formula or name. The production of a specific stereoisomer or mixture thereof can be identified in the examples in which such stereoisomers or mixtures are obtained, but this in no way limits all stereoisomers and mixtures thereof to being included within the scope of the present invention.

[0171] The present disclosure includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers in all ratios. Therefore, enantiomers are enantiomerically pure forms (as left-handed and right-handed enantiomers), racemic forms and two enantiomers in all ratios of mixtures of all the disclosed themes. In the case of cis / trans isomers, the present disclosure includes mixtures of all ratios of cis-form and trans-form and these forms. If necessary, single stereoisomers can be prepared by conventional methods (such as by chromatography or crystallization, by using stereochemically uniform synthesis starting materials or by stereoselective synthesis). Optionally, derivatization can be carried out before stereoisomer separation. The separation of stereoisomer mixtures can be carried out in an intermediate step during the synthesis of lipid compounds of the present disclosure, or can be carried out on final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which have been derivatized, if necessary, with reagents containing stereocenters of known configuration. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy.

[0172] Unless otherwise stated, structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, in other words, compounds in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Such compounds are termed "isotopic variants". The present disclosure is intended to include all pharmaceutically acceptable isotopic variants of the compounds of Formula (I). Examples of isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, such as 2 H (ie, 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 Certain isotopic variants of the compounds of formula (I), for example those incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution studies. In particular, those having isotopic variations which occur only after substitution with heavier isotopes, for example with deuterium ( 2H or D) replaces hydrogen) in the depicted structure of different compounds may provide certain therapeutic advantages, for example, due to greater metabolic stability, increased in vivo half-life or reduced dosage requirements, and therefore may be used in some specific situations. Isotopic variations of the compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed.

[0173] Pharmaceutically acceptable solvates according to the present disclosure may include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

[0174] As used herein, the term "lipid" refers to a class of organic compounds that are derivatives of fatty acids (e.g., esters) and are generally characterized by being insoluble in water but soluble in many organic solvents. Lipids are generally divided into at least three categories: (1) "simple lipids," which include fats and oils, as well as waxes; (2) "complex lipids," which include phospholipids and glycolipids; and (3) "derivative lipids," such as steroids.

[0175] As used herein, the term "phospholipid" refers to a lipid molecule consisting of two hydrophobic fatty acid "tails" and a hydrophilic "head" consisting of a phosphate group. These two components are most often bound together by a glycerol molecule, and therefore, in this context, phospholipids are preferably glycero-phospholipids. In addition, the phosphate group is often modified by a simple organic molecule such as choline (i.e., to produce phosphocholine) or ethanolamine (i.e., to produce phosphoethanolamine). In some embodiments, the phospholipid can be selected from the following group, which includes but is 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 (D SPC), 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-cholestyrene hemisuccinyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dialinolenoyl-sn-glycero-3-phosphocholine, 1,2-arachidonoyl-sn-glycero-3-phosphocholine, 1,2-bisdocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0PE), 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.

[0176] As used herein, the term "structured lipid" refers to sterol and also refers to a lipid containing a sterol moiety. In some embodiments, the structured lipid can be selected from the group consisting of, but not limited to, cholesterol, coprosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatine, tomatin, ursolic acid, α-tocopherol, hornane, phytosterol, steroids, and mixtures thereof. In some embodiments, the structured lipid is cholesterol.

[0177] As used herein, the term "PEG lipid", or alternatively referred to as 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 following group, including 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, the 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)).

[0178] As used herein, the term "hydrophobic lipid" refers to a compound having a non-polar 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 groups, cycloaliphatic groups, or heterocyclic groups. Suitable examples include but are not limited to diacylglycerols, dialkylglycerols, NN-dialkylamino, 1,2-diacyloxy-3-aminopropane, and 1,2-dialkyl-3-aminopropane.

[0179] As used herein, the terms "cationic lipid" and "ionizable lipid" are used interchangeably herein to include lipids and salts thereof having one, two, three or more fatty acid or fatty alkyl chains and a pH-titrable amino head group (e.g., an alkylamino or dialkylamino head group). Cationic lipids are typically protonated (i.e., positively charged) at a pH lower than the pKa of the cationic lipid and are substantially neutral at a pH higher than the pKa. Cationic lipids of the present disclosure may also be referred to as titratable cationic lipids. In some embodiments, the cationic lipid comprises: an ionizable tertiary amine (e.g., pH-titrable) 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. Such 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-((undecanoxy)hexyl)amino)octanoate) (SM102).

[0180] As used herein, "nucleic acid" includes double-stranded RNA, single-stranded RNA, isolated RNA (such as partially purified RNA), substantially pure RNA, synthetic RNA, recombinantly produced RNA, and altered RNA that differs from naturally occurring RNA by adding, deleting, substituting, and / or changing one or more nucleotides. Such alterations may include, for example, adding non-nucleotide substances to the ends or interior of an interfering RNA (e.g., at one or more nucleotides of the RNA). The nucleotides in the RNA molecules of the present disclosure may also include non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs may 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. Ribonucleotides are nucleotides having a hydroxyl group at the 2' position of the β-D-ribofuranose moiety. These terms include double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), isolated RNA (such as partially purified RNA), substantially pure RNA, synthetic RNA, recombinantly produced RNA, and modified and altered RNA that differs from naturally occurring RNA by addition, deletion, substitution, modification, and / or change of one or more nucleotides. Alterations to RNA may include, for example, the addition of non-nucleotide substances to the ends or interior of an interfering RNA (e.g., at one or more nucleotides of the RNA), and nucleotides in the RNA molecule include non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs may be referred to as analogs.

[0181] As used herein, the term "liposome" refers to a vesicle, preferably a spherical vesicle, having at least one lipid bilayer. Liposomes are capable of carrying aqueous solutions, compounds, drugs, or other substances in a compartment (i.e., an internal cavity or space) surrounded by at least one lipid bilayer.

[0182] As used herein, the term "lipid nanoparticle" refers to a lipid formulation that can be used to deliver therapeutic nucleic acids (e.g., mRNA) to a target site of interest (e.g., cells, tissues, organs, etc.). In some embodiments, the 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 present disclosure), a non-cationic lipid (e.g., a phospholipid), a PEG-lipid, and an optional structural lipid (e.g., cholesterol). Typically, the therapeutic nucleic acid (e.g., mRNA) can be encapsulated in the lipid portion of the lipid nanoparticle to protect it from enzymatic degradation.

[0183] lipid compounds

[0184] The lipid compounds of the present disclosure can be used for gene delivery, specifically in liposomes and lipid nanoparticles to deliver therapeutic and / or prophylactic agents, such as nucleic acids, to cells or organs. When used to prepare liposomes and lipid nanoparticles, the lipid compounds of the present disclosure may also be referred to as "ionizable lipids," "ionizable lipid compounds," "cationic lipids," or "cationic lipid compounds."

[0185] In one aspect, the lipid compound of the present disclosure is a lipid compound having a structure represented by formula (I) or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0186] wherein X is O or NH; Y is O or S; Z is absent or Z is O, NH or S;

[0187] R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms;

[0188] R I 、R II 、R III and R IV are each independently selected from group (A) comprising a group containing at least one ionizable tertiary amine structure, group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, and group (C) comprising a substituted or unsubstituted hydrocarbon group, substituted or unsubstituted heterohydrocarbon group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group having less than 11 carbon atoms,

[0189] The conditions are:

[0190] (1) When R I 、R II 、R III and R IVwhen any one of the three is a group containing at least one ionizable tertiary amine structure, any two of the remaining three are the same or different substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl groups having less than 11 carbon atoms, and the other is a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11-30 carbon atoms; or, any two of the remaining three are the same or different substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms, and the other is a substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl group having less than 11 carbon atoms;

[0191] or

[0192] (2) When R I 、R II 、R III and R IV When any two of the groups are the same or different groups containing at least one ionizable tertiary amine structure, one of the remaining two is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, and the other is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms.

[0193] In some embodiments, R II ' is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms. In some embodiments, "substituted" means optionally substituted by 1, 2, or 3 groups selected from C1-C6 alkoxy, -OH, -SH, or -NR d R d' substituted by a substituent, wherein R d 、R d' Each is independently C1-C3 alkyl. In some embodiments, R II 'Selected from group C, the specific limitations of group C below are applicable to R II '. R II ' is hydrogen or a hydrocarbon group selected from group C, such as a hydrocarbon group having 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms, specifically C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, 2-butyl, tert-butyl, pentyl, hexyl, etc. In some embodiments, R II 'with R II In some embodiments, RII 'with R II are different.

[0194] Herein, the groups comprising at least one ionizable tertiary amine structure may be collectively referred to as a group of groups, namely group A. Thus, in the lipid compound of formula (I), R I 、R II 、R III and R IV can each independently be a group containing at least one ionizable tertiary amine structure selected from Group A. I 、R II 、R III and R IV When any two of R are groups containing at least one ionizable tertiary amine structure, they may be the same or different. I 、R II 、R III and R IV Only one of the groups is a group comprising at least one ionizable tertiary amine structure.

[0195] In some embodiments, the group comprising at least one ionizable tertiary amine structure is a group having a total carbon number of 3 to 11. In some embodiments, the group comprising at least one ionizable tertiary amine structure is a group having the following general formula:

[0196] Among them, R a is a C1-C6, for example, a C1-C4, substituted or unsubstituted alkylene group; R b 、R c Each is independently C1-C6 such as C1-C4 substituted or unsubstituted alkyl, C2-C6 such as C2-C4 substituted or unsubstituted alkenyl, C2-C6 such as C2-C4 substituted or unsubstituted alkynyl, which may be optionally substituted by 1, 2 or 3 selected from -OH, -SH, -NR d R d' or substituted by a phenyl group, wherein R d 、R d' are each 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 heterocyclic or heteroaromatic ring, the 5-12 membered heterocyclic or heteroaromatic ring contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with one or more C1-C6, such as C1-C4, alkyl or oxo (=O); or R a 、R bTogether with the N atom to which it is attached, it forms a 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6, for example, C1-C4 alkylene, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more C1-C6, for example, C1-C4 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6, for example, C1-C4 alkylene, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more C1-C6, for example, C1-C4 alkyl, or oxo (=O).

[0197] In some embodiments, R b 、R c Together with the N atom to which it is attached, it forms a 5-12 membered, for example, 5-6 membered, heterocyclic or heteroaromatic ring. The 5-12 membered, for example, 5-6 membered, heterocyclic or heteroaromatic ring can be a monocyclic, fused bicyclic, spirocyclic bicyclic or bridged bicyclic ring. In some embodiments, R b 、R c Together with the nitrogen atom to which it is attached, it forms a 5-membered, 6-membered, 7-membered or 8-membered monocyclic heterocyclic or heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein at least one heteroatom is N. In some embodiments, R b 、R c Non-limiting examples of heterocyclic or heteroaromatic rings formed together with the nitrogen atom to which they are attached include, but are not limited to, the following heterocyclic and heteroaromatic rings:

[0198] In some embodiments, R a 、R b Together with the N atom to which it is attached, it forms a C1-C6, for example, C1-C4, alkylene optionally substituted 5-12, for example, 5-6, heterocyclic or heteroaromatic ring, which can be a monocyclic, fused bicyclic, spirocyclic or bridged bicyclic ring. In some embodiments, R a 、R bTogether with the N atom to which it is attached, it forms a C1-C6, such as a C1-C4, alkylene optionally substituted 5-, 6-, 7- or 8-membered monocyclic heterocyclic ring 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 optionally substituted 5-12-membered, for example 5-6-membered, heterocyclic or heteroaromatic rings formed together with the N atom to which they are attached include but are not limited to the following heterocyclic rings: * indicates the position connected to other parts in the compound molecule,

[0199] In some embodiments, R a 、R b 、R c Together with the N atom to which it is attached, it forms a C1-C6, for example, C1-C4, alkylene optionally substituted 5-12, for example, 5-6, heterocyclic or heteroaromatic ring, which can be a monocyclic, fused bicyclic, spirocyclic or bridged bicyclic ring. In some embodiments, R a 、R b 、R c Together with the N atom to which it is attached, it forms a C1-C6, such as a C1-C4, alkylene optionally substituted 5-, 6-, 7- or 8-membered monocyclic heterocyclic ring 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 、R c The non-limiting examples of the optionally substituted 5-12 membered, for example 5-6 membered, heterocyclic ring or heteroaromatic ring formed together with the N atom to which it is connected include but are not limited to the following heteroaromatic rings: * indicates the position connected to other parts in the compound molecule,

[0200] In some embodiments, Group A includes a group comprising at least one ionizable tertiary amine structure as shown in the following structure:

[0201] Herein, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11 to 30 carbon atoms may be collectively referred to as a group, namely, group B. Therefore, in the lipid compound of formula (I), R I 、R II 、R IIIand R IV Each of them can be independently a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms selected from group B. I 、R II 、R III and R IV When any two of the groups are substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11 to 30 carbon atoms selected from group B, they may be the same or different.

[0202] In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group selected from Group B has 11-30 carbon atoms, for example, 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 group selected from Group B has, for example, 11-16 carbon atoms, 11-25 carbon atoms, 16-25 carbon atoms, 16-30 carbon atoms, or a range of carbon atoms between any two values ​​within the range of 11-30.

[0203] In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group selected from Group B contains 1-8 heteroatoms independently selected from N, O, S, etc., such as 1, 2, 3, 4, 5, 6, 7, and 8 heteroatoms. In some embodiments, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group selected from Group B contains, for example, 1-2 heteroatoms, 1-3 heteroatoms, 1-4 heteroatoms, 1-5 heteroatoms, or a range between any two values ​​within the range of 1-8.

[0204] 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 heteroatoms such as N, O, and S, such as 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 between any two values ​​within the range of 11-30 atoms.

[0205] In some embodiments, Group B includes a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms as shown in the following structure:

[0206] Herein, the substituted or unsubstituted hydrocarbon group, substituted or unsubstituted heterohydrocarbon group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group having less than 11 carbon atoms may be collectively referred to as a group, i.e., group C. Therefore, in the lipid compound of formula (I), R I 、R II 、R III and R IV Each of them may be independently a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms selected from Group C. I 、R II 、R III and R IV Any two of them are substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heteroaryl groups having less than 11 carbon atoms selected from group B, and they may be the same or different.

[0207] 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 to 11 carbon atoms, such as 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 to 6 carbon atoms, 1 to 7 carbon atoms, 1 to 8 carbon atoms, 1 to 9 carbon atoms, 1 to 10 carbon atoms, 1 to 11 carbon atoms, or a range of carbon atoms between any two values ​​within the range of 1 to 11.

[0208] 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 contains 1-5 heteroatoms independently selected from N, O, S, etc., such as 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 contains, for example, 1-2 heteroatoms, 1-3 heteroatoms, 1-4 heteroatoms, or a range between any two values ​​within the range of 1-5.

[0209] 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 to 11 atoms, including carbon atoms and heteroatoms such as N, O, and S, such as 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 to 6 atoms, 1 to 7 atoms, 1 to 8 atoms, 1 to 9 atoms, 1 to 10 atoms, 1 to 11 atoms, or a range of atoms between any two values ​​within the range of 1 to 11.

[0210] 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 following group: deuterium, halogen, -NO2, and -OH.

[0211] In some embodiments, the substituted or unsubstituted hydrocarbon group includes a linear, branched or cyclic alkyl, alkenyl and alkynyl group. In some embodiments, the substituted or unsubstituted hydrocarbon group contains one or more, for example 1, 2, 3, 4 or 5, unsaturated carbon-carbon double bonds (-C=C-), carbon-carbon triple bonds (-C≡C-) groups, and / or any combination thereof. In some embodiments, the substituted or unsubstituted heteroalkyl group includes a linear, branched or cyclic heteroalkyl, heteroalkenyl and heteroalkynyl group containing heteroatoms selected from N, O and S. In some embodiments, the heteroatoms contained in the substituted or unsubstituted heteroalkyl group can form the main chain of a heteroaliphatic group together with carbon atoms, such as, but not limited to, group structures such as -CNC-, -COC-, -COOC, -CSC-, -CSSC, or any combination thereof. In some embodiments, the heteroatoms contained in the substituted or unsubstituted heteroalkyl group may be substituents attached to carbon atoms, such as, but not limited to, -C≡N, -C=N-, -CN=, -C=O, -C-OH, -C=S, -C-SH and other substitution structures. In some of the embodiments, the heteroatoms contained in the substituted or unsubstituted heteroalkyl group may be any combination of the group structures listed above. In some embodiments, the heteroaliphatic group contains one or more, such as 1, 2, 3, 4 or 5, 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- and -P(O)- groups, wherein R m '、R n '、R o ' and R p ' are each independently substituted or unsubstituted C1-C 14 Aliphatic hydrocarbon groups, such as C1-C 12 、C1-C 10 , C1-C8, C1-C6, C1-C4 aliphatic hydrocarbon, substituted or unsubstituted C1-C 14 Specific non-limiting examples of aliphatic hydrocarbon groups include, but are not limited to, methyl, ethyl, n- and isopropyl, n-butyl, sec-butyl, isobutyl, tert-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.

[0212] In some embodiments, Group C includes a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms as shown in the following structure:

[0213] In some embodiments, R I Selected from Group A, R III and R IV Selected from Group B, and R II Selected from Group C; or

[0214] R I Selected from Group A, R II and R IV Selected from Group B, and R III Selected from Group C; or

[0215] R II Selected from Group A, R I and R IV Selected from Group B, and R III Selected from Group C; or

[0216] R III Selected from Group A, R I and R IV Selected from Group B, and R II Selected from Group C; or

[0217] R IV Selected from Group A, R I and R II Selected from Group B, and R III Selected from Group C; or

[0218] R IV Selected from Group A, R I and R III Selected from Group B, and R II Selected from Group C.

[0219] In some embodiments, R I Selected from Group A, R II and R III Selected from Group B, and R IV Selected from Group C; or

[0220] R II Selected from Group A, R I and R III Selected from Group B, and R IV Selected from Group C; or

[0221] R II Selected from Group A, RIII and R IV Selected from Group B, and R I Selected from Group C; or

[0222] R III Selected from Group A, R I and R II Selected from Group B, and R IV Selected from Group C; or

[0223] R III Selected from Group A, R II and R IV Selected from Group B, and R I Selected from Group C; or

[0224] R IV Selected from Group A, R II and R III Selected from Group B, and R I Selected from Group C.

[0225] In some embodiments, R I 、R II 、R III and R IV Each independently optionally contains at least one degradable group. The lipid compounds disclosed herein preferably contain a degradable group. Upon entry into cells, tissues, or organs, the degradable group contained in the lipid compounds disclosed herein breaks down, thereby partially or completely degrading the lipid compounds, thereby reducing or completely eliminating the toxicity of the lipid compounds to cells. The introduction of degradable groups can accelerate lipid metabolism in organs such as the liver, thereby reducing lipid accumulation in the body and lowering potential toxicity.

[0226] In some embodiments, the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SS-, -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-, where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R7 、R 8 and R 9 are each independently substituted or unsubstituted C1-C 14 Aliphatic hydrocarbon groups include straight-chain, branched-chain, cyclic alkanes, alkenes, alkynes or polyunsaturated hydrocarbon groups, such as C1-C 12 、C1-C 10 , C1-C8, C1-C6, C1-C4 aliphatic hydrocarbon, substituted or unsubstituted C1-C 14 Specific non-limiting examples of aliphatic hydrocarbon groups include, but are not limited to, methyl, ethyl, n- and isopropyl, n-butyl, sec-butyl, isobutyl, tert-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.

[0227] In some embodiments, R I 、R II 、R III and R IV In some embodiments, when R III and R IV When selected from Group B, R III and R IV At least one of contains at least one degradable group; when R II and R IV When selected from Group B, R II and R IV At least one of contains at least one degradable group; when R I and R IV When selected from Group B, R I and R IV At least one of contains at least one degradable group; when R I and R II When selected from Group B, R I and R II At least one of contains at least one degradable group; when R I and R III When selected from Group B, R I and R III At least one of contains at least one degradable group; and / or, when R II and R III When selected from Group B, R II and R III At least one of the comprises at least one degradable group.

[0228] In some embodiments, R I 、RII 、R III and R IV In some embodiments, when R III and R IV When selected from Group B, R III and R IV Only one of them contains at least one degradable group; when R II and R IV When selected from Group B, R II and R IV Only one of them contains at least one degradable group; when R I and R IV When selected from Group B, R I and R IV Only one of them contains at least one degradable group; when R I and R II When selected from Group B, R I and R II Only one of them contains at least one degradable group; when R I and R III When selected from Group B, R I and R III contains at least one degradable group; and / or, when R II and R III When selected from Group B, R II and R III In some embodiments, the degradable group is an ester group, i.e., -C(O)-O-; or the degradable group includes an ester bond.

[0229] In some embodiments, R I 、R II 、R III and R IV In some embodiments, when R III and R IV When selected from Group B, R III and R IV Only one of them contains a degradable group; when R II and R IV When selected from Group B, R II and R IV Only one of them contains a degradable group; when R I and R IV When selected from Group B, R I and R IV Only one of them contains a degradable group; when R I and R II When selected from Group B, R Iand R II Only one of them contains a degradable group; when R I and R III When selected from Group B, R I and R III contains a degradable group; and / or, when R II and R III When selected from Group B, R II and R III In some embodiments, the degradable group is an ester group, i.e., -C(O)-O-; or the degradable group includes an ester bond.

[0230] In some embodiments, when selected from Group B, R I 、R II 、R III and / or R IV In some embodiments, when R I and R IV When selected from Group B, R I and / or R IV In some embodiments, when selected from Group B, R I 、R II 、R III and / or R IV In some embodiments, when R I and R IV When selected from Group B, R I and R IV Only one of them contains an ester group or ester bond, for example R I Contains an ester group or ester bond or R IV Contains an ester group or ester bond.

[0231] In some embodiments, R II ' is hydrogen or selected from Group C, R III Selected from Group A, R II Selected from Group C, R I and R IV selected from Group B, Groups A, B and C are as defined herein;

[0232] Preferably, R I and R IV At least one or only one contains a degradable group, for example, the degradable group is an ester group, i.e., -C(O)-O-; or the degradable group includes an ester bond,

[0233] Preferably, when R I and / or R IV When no degradable group is included, RI and / or R IV A group selected from the following structures:

[0234] Preferably, when R I and / or R IV When containing a degradable group, R I and / or R IV A group selected from the following structures:

[0235] Preferably, when R I and / or R IV When containing a degradable group, R I and / or R IV Has the following structure:

[0236] Among them, R d is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene having 1 to 11 carbon atoms, wherein the alkylene or heteroalkylene is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH, preferably R d is a substituted or unsubstituted alkylene group having 1 to 11 carbon atoms, such as an alkylene group, and preferably R d It is a substituted or unsubstituted straight-chain hydrocarbylene group having 1-11 carbon atoms, such as a straight-chain alkylene group. The number of carbon atoms in the straight-chain alkylene group is, for example, 1-11, 2-11, 2-10, 3-10, etc.

[0237] R e There is no or is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene having 1 to 4 carbon atoms, the alkylene or heteroalkylene being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH, preferably R e There is no or a substituted or unsubstituted straight-chain alkylene group with a carbon number of 1-4, such as a straight-chain alkylene group, wherein the carbon number of the straight-chain alkylene group is, for example, 1-4, 1-3, or 1-2, such as R e is absent or is methylene, ethylene, propylene or butylene, preferably R e Absent or represented by methylene or ethylene.

[0238] R f and R gare each independently a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted heterohydrocarbon group having 1 to 11 carbon atoms, wherein the hydrocarbon group or heterohydrocarbon group is optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH, preferably R f and R g Each is independently a substituted or unsubstituted hydrocarbon group having 1 to 11 carbon atoms, such as an alkyl group, and preferably R f and R g Each is independently a substituted or unsubstituted straight-chain hydrocarbon group having 1-11 carbon atoms, such as a straight-chain alkyl group, and the number of carbon atoms of the straight-chain alkylene group is, for example, 1-11, 1-10, 1-9, 1-8, etc. For example, R f and R g are each independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, or undecyl, R f and R g Can be the same or different.

[0239] Preferably, R I and R IV At least one, or only one such as R I or R IV Selected from the group consisting of:

[0240] In some embodiments, the lipid compounds of the present disclosure have the following structural formula (I A )

[0241] Among them, R II '、R I 、R II 、R III and R IV As defined in this disclosure.

[0242] Group A, Group B and Group C are as defined in this disclosure.

[0243] In some embodiments, R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms, for example, R II ' is hydrogen or a hydrocarbon group selected from group C, such as a hydrocarbon group having 1-8 carbon atoms, such as 1-6, 1-4, specifically such as C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0244] In some embodiments, R II 'It's hydrogen.

[0245] In some embodiments, R II 'Selected from group C, such as a hydrocarbon group with 1-8 carbon atoms, such as 1-6, 1-4, specifically such as C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.

[0246] In some embodiments, R III Selected from Group A.

[0247] In some embodiments, R III The group selected from Group A, which contains at least one ionizable tertiary amine structure, is a group having the following general formula:

[0248] Among them, R a is a C1-C6, for example, a C1-C4, substituted or unsubstituted alkylene group; R b 、R c Each is independently C1-C6 such as C1-C4 substituted or unsubstituted alkyl, C2-C6 such as C2-C4 substituted or unsubstituted alkenyl, C2-C6 such as C2-C4 substituted or unsubstituted alkynyl, which may be optionally substituted by 1, 2 or 3 selected from -OH, -SH, -NR d R d' or substituted by a phenyl group, wherein R d 、R d' are each 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 heterocyclic or heteroaromatic ring, the 5-12 membered heterocyclic or heteroaromatic ring contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with one or more C1-C6, such as C1-C4, 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6, for example, C1-C4 alkylene, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more C1-C6, for example, C1-C4 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6, for example, C1-C4 alkylene, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more C1-C6, for example, C1-C4 alkyl, or oxo (=O).

[0249] In some embodiments, R b 、R c Together with the N atom to which it is attached, it forms a 5-12 membered, for example, 5-6 membered, heterocyclic or heteroaromatic ring. The 5-12 membered, for example, 5-6 membered, heterocyclic or heteroaromatic ring can be a monocyclic, fused bicyclic, spirocyclic bicyclic or bridged bicyclic ring. In some embodiments, R b 、R c Together with the nitrogen atom to which it is attached, it forms a 5-membered, 6-membered, 7-membered or 8-membered monocyclic heterocyclic or heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O, S, wherein at least one heteroatom is N. In some embodiments, R b 、R c Non-limiting examples of heterocyclic or heteroaromatic rings formed together with the nitrogen atom to which they are attached include, but are not limited to, the following heterocyclic and heteroaromatic rings:

[0250] In some embodiments, R a 、R b Together with the N atom to which it is attached, it forms a C1-C6, for example, C1-C4, alkylene optionally substituted 5-12, for example, 5-6, heterocyclic or heteroaromatic ring, which can be a monocyclic, fused bicyclic, spirocyclic or bridged bicyclic ring. In some embodiments, R a 、R b Together with the N atom to which it is attached, it forms a C1-C6, such as a C1-C4, alkylene optionally substituted 5-, 6-, 7- or 8-membered monocyclic heterocyclic ring 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 optionally substituted 5-12-membered, for example 5-6-membered, heterocyclic or heteroaromatic rings formed together with the N atom to which they are attached include but are not limited to the following heterocyclic rings: * indicates the position connected to other parts in the compound molecule,

[0251] In some embodiments, R a 、R b 、R c Together with the N atom to which it is attached, it forms a C1-C6, for example, C1-C4, alkylene optionally substituted 5-12, for example, 5-6, heterocyclic or heteroaromatic ring, which can be a monocyclic, fused bicyclic, spirocyclic or bridged bicyclic ring. In some embodiments, R a 、R b 、R c Together with the N atom to which it is attached, it forms a C1-C6, such as a C1-C4, alkylene optionally substituted 5-, 6-, 7- or 8-membered monocyclic heterocyclic ring 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 、R c The non-limiting examples of the optionally substituted 5-12 membered, for example 5-6 membered, heterocyclic ring or heteroaromatic ring formed together with the N atom to which it is connected include but are not limited to the following heteroaromatic rings: * indicates the position connected to other parts in the compound molecule,

[0252] In some embodiments, R III Selected from Group A, Group A includes a group containing at least one ionizable tertiary amine structure represented by the following structure:

[0253] In some embodiments, R I and R IV Each is independently selected from Group B.

[0254] In some embodiments, R I and R IV Each independently selected from Group B, the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group selected from Group B has 11-30 carbon atoms, for example, 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 group selected from Group B has, for example, 11-16 carbon atoms, 11-25 carbon atoms, 16-25 carbon atoms, 16-30 carbon atoms, or a range between any two values ​​within the range of 11-30 carbon atoms.

[0255] In some embodiments, R I and R IV Each is independently selected from Group B, and the substituted or unsubstituted heteroaliphatic group selected from Group B contains 1-8 heteroatoms independently selected from N, O, S, etc., such as 1, 2, 3, 4, 5, 6, 7 and 8 heteroatoms. In some embodiments, the substituted or unsubstituted heteroaliphatic group selected from Group B contains, for example, 1-2 heteroatoms, 1-3 heteroatoms, 1-4 heteroatoms, 1-5 heteroatoms, or the number of heteroatoms contained is within the range of any two values ​​within the range of 1-8.

[0256] In some embodiments, R I and R IV Each independently selected from Group B, the substituted or unsubstituted heteroaliphatic group selected from Group B has 11-30 atoms, including carbon atoms and heteroatoms such as N, O, and S, such as 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 heteroaliphatic group selected from Group B has, for example, 11-16 atoms, 11-25 atoms, 16-25 atoms, 16-30 atoms, or a range between any two values ​​within the range of 11-30 atoms.

[0257] In some embodiments, R I and R IV Each is independently selected from Group B, which includes substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11 to 30 carbon atoms as shown in the following structure:

[0258] In some embodiments, R I and R IV Any one of has 16 to 30 carbon atoms or 16 to 30 total atoms, and the other has 11 to 25 carbon atoms or 11 to 25 total atoms, preferably, R I and R IV Any one of has 16 to 25 carbon atoms or 16 to 25 total atoms, and the other has 11 to 16 carbon atoms or 11 to 16 total atoms.

[0259] In some embodiments, R I and R IV At least one of the comprises at least one degradable group.

[0260] In some embodiments, the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SS-, -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-, where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 are each independently substituted or unsubstituted C1-C 14 For example, C1-C 10 , C1-C6, C1-C4 aliphatic hydrocarbon group, preferably the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-; or the degradable group includes an ester bond.

[0261] In some embodiments, R I and R IV Each contains at least one degradable group, for example, the degradable group is an ester group, ie, -C(O)O- or -OC(O)-; or the degradable group includes an ester bond.

[0262] In some embodiments, R I and R IV Each contains a degradable group, for example, the degradable group is an ester group, ie, -C(O)O- or -OC(O)-; or the degradable group includes an ester bond.

[0263] In some embodiments, R I and R IV Only one of the degradable groups contains at least one degradable group, for example, the degradable group is an ester group, ie, -C(O)O- or -OC(O)-; or the degradable group includes an ester bond.

[0264] In some embodiments, R I and R IVAny one of them contains 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 includes an ester bond, while the other does not contain a degradable group.

[0265] In some embodiments, R I and R IV Only one of them contains a degradable group, for example, the degradable group is an ester group, ie, -C(O)O- or -OC(O)-; or the degradable group includes an ester bond.

[0266] In some embodiments, R I and R IV Any one of them contains a degradable group, for example, the degradable group is an ester group, i.e., -C(O)O- or -OC(O)-; or the degradable group includes an ester bond, while the other does not contain a degradable group.

[0267] In some embodiments, when R I and / or R IV When no degradable group is included, R I and / or R IV A group selected from the following structures:

[0268] In some embodiments, when R I and / or R IV When containing a degradable group, R I and / or R IV A group selected from the following structures:

[0269] In some embodiments, when R I and / or R IV When containing a degradable group, R I and / or R IV Has the following structure:

[0270] Among them, R d is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene having 1 to 11 carbon atoms, wherein the alkylene or heteroalkylene is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH, preferably R d is a substituted or unsubstituted alkylene group having 1 to 11 carbon atoms, such as an alkylene group, and preferably R dis a substituted or unsubstituted straight-chain hydrocarbylene group having 1-11 carbon atoms, such as a straight-chain alkylene group, wherein the number of carbon atoms of the straight-chain alkylene group is, for example, 1-11, 2-11, 2-10, 3-10, etc.;

[0271] R e There is no or is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene having 1 to 4 carbon atoms, the alkylene or heteroalkylene being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH, preferably R e There is no or a substituted or unsubstituted straight-chain alkylene group with a carbon number of 1-4, such as a straight-chain alkylene group, wherein the carbon number of the straight-chain alkylene group is, for example, 1-4, 1-3, or 1-2, such as R e is absent or is methylene, ethylene, propylene or butylene, preferably R e absent or is a methylene or ethylene group;

[0272] R f and R g are each independently a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted heterohydrocarbon group having 1 to 11 carbon atoms, wherein the hydrocarbon group or heterohydrocarbon group is optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH, preferably R f and R g Each is independently a substituted or unsubstituted hydrocarbon group having 1 to 11 carbon atoms, such as an alkyl group, and preferably R f and R g Each is independently a substituted or unsubstituted straight-chain hydrocarbon group having 1-11 carbon atoms, such as a straight-chain alkyl group, wherein the number of carbon atoms of the straight-chain alkyl group is, for example, 1-11, 1-10, 1-9, 1-8, etc. For example, R f and R g are each independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, or undecyl, R f and R g Can be the same or different.

[0273] In some embodiments, when R I and / or R IV When containing a degradable group, R I and / or R IV are each independently selected from the group consisting of:

[0274] In some embodiments, R II Selected from Group C.

[0275] In some embodiments, R II 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 to 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 of Group C has, for example, 1 to 6 carbon atoms, 1 to 7 carbon atoms, 1 to 8 carbon atoms, 1 to 9 carbon atoms, 1 to 10 carbon atoms, 1 to 11 carbon atoms, or has a carbon atom number within the range of 1 to 11.

[0276] In some embodiments, R II The substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl group selected from Group C contains 1-5 heteroatoms independently selected from N, O, S, etc., such as 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 of Group C contains, for example, 1-2 heteroatoms, 1-3 heteroatoms, 1-4 heteroatoms, or the number of heteroatoms contained is within the range of any two values ​​within the range of 1-5.

[0277] In some embodiments, R II 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 to 11 atoms, including carbon atoms and heteroatoms such as N, O, and S, such as 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 of Group C has, for example, 1 to 6 atoms, 1 to 7 atoms, 1 to 8 atoms, 1 to 9 atoms, 1 to 10 atoms, 1 to 11 atoms, or has an atom number in the range of any two values ​​within the range of 1 to 11.

[0278] 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 following group: deuterium, halogen, -NO2, and -OH.

[0279] In some embodiments, the substituted or unsubstituted hydrocarbon group includes a linear, branched or cyclic alkyl, alkenyl and alkynyl group. In some embodiments, the substituted or unsubstituted hydrocarbon group contains one or more, for example 1, 2, 3, 4 or 5, unsaturated carbon-carbon double bonds (-C=C-), carbon-carbon triple bonds (-C≡C-) groups, and / or any combination thereof. In some embodiments, the substituted or unsubstituted heteroalkyl group includes a linear, branched or cyclic heteroalkyl, heteroalkenyl and heteroalkynyl group containing heteroatoms selected from N, O and S. In some embodiments, the heteroatoms contained in the substituted or unsubstituted heteroalkyl group can form the main chain of a heteroaliphatic group together with carbon atoms, such as, but not limited to, group structures such as -CNC-, -COC-, -COOC, -CSC-, -CSSC, or any combination thereof. In some embodiments, the heteroatoms contained in the substituted or unsubstituted heteroalkyl group may be substituents attached to carbon atoms, such as, but not limited to, -C≡N, -C=N-, -CN=, -C=O, -C-OH, -C=S, -C-SH and other substitution structures. In some of the embodiments, the heteroatoms contained in the substituted or unsubstituted heteroalkyl group may be any combination of the group structures listed above. In some embodiments, the heteroaliphatic group contains one or more, such as 1, 2, 3, 4 or 5, 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- and -P(O)- groups, wherein R m '、R n '、R o ' and R p ' are each independently substituted or unsubstituted C1-C 14 Aliphatic hydrocarbon groups, such as C1-C 12 、C1-C 10 , C1-C8, C1-C6, C1-C4 aliphatic hydrocarbon, substituted or unsubstituted C1-C 14 Specific non-limiting examples of aliphatic hydrocarbon groups include, but are not limited to, methyl, ethyl, n- and isopropyl, n-butyl, sec-butyl, isobutyl, tert-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.

[0280] In some embodiments, R II Selected from Group C, which includes substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups having less than 11 carbon atoms as shown in the following structures:

[0281] In some embodiments, R II It is tert-butyl.

[0282] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B, and R II Selected from Group C.

[0283] In some embodiments, R III Selected from Group A, R I and R IV Selected from Group B, R II Selected from Group C, and R II ' is hydrogen or selected from Group C.

[0284] In some embodiments, R II ' is hydrogen or selected from Group C, R III Selected from Group A, R II Selected from Group C, R I and R IV is selected from Group B, Groups A, B and C are as defined herein; further, R II '、R I 、R II 、R III and R IV The ranges may preferably be as defined herein for each of these groups.

[0285] In some embodiments, the lipid compounds of the present disclosure have the following structural formula (I A-1 )

[0286] Among them, R II '、R I 、R III and R IV As defined in the present disclosure, for example, for the general structural formula (I A ) including the limitations of various implementation schemes, will not be repeated here.

[0287] In some embodiments, the lipid compounds of the present disclosure have the following structural formula (I A-2 )

[0288] Among them, R I 、R III and R IV As defined in the present disclosure, for example, for the general structural formula (I A ) including the limitations of various implementation schemes, will not be repeated here.

[0289] In some embodiments, the lipid compounds of the present disclosure have the following structural formula (I B )

[0290] Among them, R II '、R I 、R II 、R III and R IV As defined in the present disclosure, for example, for the general structural formula (I A ) including the limitations of various implementation schemes, will not be repeated here.

[0291] In some embodiments, R II 'It is hydrogen;

[0292] R II Selected from Group C, such as C1-C6 alkyl, C1-C4 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, 1-butyl, 2-butyl, t-butyl, pentyl, hexyl, etc., and another example is t-butyl;

[0293] R III Selected from group A, for example, a group having the following general formula:

[0294] Among them, R a 、R b 、R c Each is independently C1-C6, such as C1-C4, substituted or unsubstituted alkyl, which may be optionally substituted by 1, 2 or 3 groups selected from -OH, -SH, -NR d R d' or substituted by a phenyl group, wherein R d 、R d' Each independently is hydrogen or C1-C3 alkyl, for example, R a 、R b 、R c Each is independently a C1-C6, for example a C1-C4 alkyl group,

[0295] For example, Group A includes groups comprising at least one ionizable tertiary amine structure as shown in the following structure:

[0296] and

[0297] R I and R IV Each independently selected from Group B, R I and R IV At least one of the groups contains a degradable group, such as an ester group, i.e., -C(O)O- or -OC(O)-; or the degradable group includes an ester bond, for example, group B includes a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms as shown in the following structure:

[0298] In some embodiments, the lipid compound of formula (I) of the present disclosure is selected from the lipid compounds shown in Table 1-Table 8: lipid numbers 1-1075.

[0299] In some embodiments, the lipid compound of formula (I) of the present disclosure is a lipid compound as follows: lipid number 16, 30, 60, 108, 113, 157, 158, 159, 160, 161, 162, 163, 166, 170, 173, 174, 175, 176, 188, 189, 194, 195, 223, 226, 227, 229, 230, 232, 233, 234, 235, 236, 237, 238, 239, 240, 284, 285, 286, 287, 292, 293, 294, 295, 304, 325, 326, 327, 401, 402, 406, 407, 408, 409, 420, 424, 431, 445, 446, 447, 583, 595, 598, 607, 613, 641, 675, 685, 914, 915, 920, 921, 922, 923, 924, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 949, 950, 951, 952, 954, 955, 958, 959, 960, 961, 962, 963, 964, 966-1051, and 1053-1057.

[0300] In some embodiments, the lipid compound of formula (I) of the present disclosure is a lipid compound as shown below: lipid numbers 317, 1058-1075.

[0301] In some embodiments, the lipid compound of formula (I) of the present disclosure is a lipid compound as shown below:

[0302] In some embodiments of the present disclosure, having the same R I 、R III 、R IV Group and R II’ A series of formulas (I A ) structure of lipids, different R II The group has a regular change in the structure of lipids. And when R II When it is a tert-butyl group or a derivative structure containing a tert-butyl group, the conformation of the lipid has significant characteristics. Taking the backbone of lipid 175 as an example, its one-dimensional nuclear magnetic spectrum is shown in Figure 14. The chemical shifts δ3.43, δ3.71, δ3.08 and δ3.26 correspond to H 1 、H 2 、H 3 and H 4 This type of four-group multiple peak is only found in R II The group is tert-butyl, or a larger group containing tert-butyl (as shown in Figure 15 and the table below). 1 、H 2 、H 3 With H 4 Four different chemical shifts appear, which may be the central carbon atom (with R II The tert-butyl group is directly connected to the chain (direction A and B) due to the restriction of chain rotation. This restriction is caused by the restriction of the chain rotation in the direction A and B. II The steric effect of the groups is highly relevant.

[0303] Further analysis revealed that δ3.71(H1 ) is a set of sextets, which indicates that in addition to the coupled splitting of the protons on the adjacent carbon, the H further contains another proton on the same carbon atom (H 2 ) coupling splitting, which also verifies from another aspect that when the substituent is tert-butyl, H 1 and H 2 In addition, it is found that when R II When the group is methyl, ethyl, or isopropyl, this interval is two groups of multiple peaks close to each other, which means that when R II When the group volume is small, chain A and chain B are relatively free to rotate. Further comparison of lipid delivery mRNA efficiency shows that R II Lipids with tert-butyl or tert-butyl-containing derivative structures (175, 944, 945, 946, 947, etc.) are more likely to show high delivery efficiency in mRNA delivery in mice.

[0304] The same NMR spectrum characteristics can also be observed in the structure with lipid 284 as the main skeleton, as shown in Figure 16 and the table below

[0305] By preparing R II is tert-butyl, R I With R IV For lipids with short chain groups (ethyl and butyl), a quadruplet peak was found in the one-dimensional NMR spectrum (not shown in this paper) between the chemical shift of 3-4 ppm, which indicates that the structural features in the NMR spectrum have no correlation with the length of the hydrophobic lipid chain, but only with the R II Group related.

[0306] 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.

[0307] The lipid compound of formula (I) disclosed herein is used for nucleic acid delivery to achieve the introduction of nucleic acids (eg, DNA, RNA) into organelles, cells, tissues or organisms.

[0308] In one aspect, the lipid compound of the present disclosure is a lipid compound having a structure represented by formula (III) or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0309] R I 、R II and R IV are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, and (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, provided that: R I 、R II and R IV There is only one group containing at least one ionizable tertiary amine structure.

[0310] In some embodiments, R I (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, R II and R IV Any one of them is selected from (A) a group containing at least one ionizable tertiary amine structure, and the other is selected from (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms.

[0311] In some embodiments, R I 、R II and R IV As defined for the corresponding groups in the lipid compound of formula (I).

[0312] In one aspect, the lipid compound of the present disclosure is a lipid compound having a structure represented by formula (IV) or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0313] R I 、R II and R III are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, and (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, provided that: R I 、R II and R III There is only one group containing at least one ionizable tertiary amine structure.

[0314] In some embodiments, R I (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, R II and R IIIAny one of them is selected from (A) a group containing at least one ionizable tertiary amine structure, and the other is selected from (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms.

[0315] In some embodiments, R I 、R II and R III As defined for the corresponding groups in the lipid compound of formula (I).

[0316] In one aspect, the lipid compound of the present disclosure is a lipid compound having a structure represented by formula (V) or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0317] R1 V 、R2 V 、R3 V and R4 V are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, and (C) a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, provided that: R1 V 、R2 V 、R3 V and R4 V There is only one group containing at least one ionizable tertiary amine structure.

[0318] In one aspect, the lipid compound of the present disclosure is a lipid compound having a structure represented by formula (VI) or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof,

[0319] R1 VI 、R2 VI and R3 VI are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, and (C) a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, provided that: R1 VI 、R2 VI and R3 VI There is only one group containing at least one ionizable tertiary amine structure.

[0320] The lipid compounds disclosed herein are used for nucleic acid delivery to achieve the introduction of nucleic acids (eg, DNA, RNA) into organelles, cells, tissues or organisms.

[0321] Lipid compounds containing isonitrile or carboxylic acid end groups

[0322] The lipid compounds of the present disclosure comprising isonitrile or carboxylic acid end groups can be used to prepare ionizable lipids.

[0323] The lipid compound containing an isonitrile or carboxylic acid end group disclosed herein is a lipid compound having a structure represented by formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0324] Among them, R A is selected from substituted or unsubstituted aliphatic and heteroaliphatic groups, R A optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH;

[0325] R B is a degradable group containing a degradable bond selected from the following group: Where a represents the A The connected position, b represents the connection with R C Connected position, R B1 and R B2 are each independently selected from H and substituted or unsubstituted C 1-6 an alkyl group optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH;

[0326] R C is selected from aliphatic groups and heteroaliphatic groups, R C optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH; and

[0327] R D Selected from -NC or -COOH.

[0328] In some embodiments, R D is -NC, the lipid compound containing an isonitrile end group of the present disclosure has the formula (II A ) shows the structure:

[0329] In some embodiments, R Dis -COOH, the lipid compound comprising a carboxylic acid end group of the present disclosure has the formula (II B ) shows the structure:

[0330] In some embodiments, R A is selected from a substituted or unsubstituted straight-chain aliphatic group having 6 to 20 carbon atoms and a substituted or unsubstituted straight-chain heteroaliphatic group having 6 to 20 carbon atoms, wherein the straight-chain aliphatic group and the straight-chain heteroaliphatic group are optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH.

[0331] In some embodiments, R A The number of carbon atoms is within the range of 6-20 and can be any two values.

[0332] In some embodiments, R A Selected from the group consisting of A ) is a substituted or unsubstituted branched aliphatic group or a substituted or unsubstituted branched heteroaliphatic group:

[0333] in,

[0334] R A1 is absent or is selected from substituted or unsubstituted C 1-4 an alkyl group optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH;

[0335] Branching center group R T Selected from the group consisting of:

[0336] Where a represents the A1 Connected position, or R A1 If it does not exist, it is directly compared with R B connected locations;

[0337] R A2 and R A3 Each independently selected from a substituted or unsubstituted aliphatic group and a substituted or unsubstituted heteroaliphatic group having 1 to 12 carbon atoms, the aliphatic group and the heteroaliphatic group being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH;

[0338] R A4is absent or is selected from hydrogen, a substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, and a substituted or unsubstituted heteroaliphatic group, which aliphatic group and heteroaliphatic group are optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH;

[0339] R A2 The number of carbon atoms n A2 、R A3 The number of carbon atoms n A3 and R A4 The number of carbon atoms n A4 The sum is in the range of 2-24.

[0340] In some embodiments, R A1 The number of carbon atoms is within the range between any two values ​​within the range of 1-4.

[0341] In some embodiments, R A2 and R A3 The number of carbon atoms is within the range between any two values ​​within the range of 1-12.

[0342] In some embodiments, R A4 The number of carbon atoms is within the range between any two values ​​within the range of 1-12.

[0343] In some embodiments, R A2 The number of carbon atoms n A2 、R A3 The number of carbon atoms n A3 and R A4 The number of carbon atoms n A4 The sum is in the range of 2-18, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and in the range between any two of the above values.

[0344] In some embodiments, R A Selected from the following groups:

[0345] In some embodiments, R C is selected from a substituted or unsubstituted straight-chain aliphatic group having 2 to 18 carbon atoms and a substituted or unsubstituted straight-chain heteroaliphatic group having 2 to 18 carbon atoms, the straight-chain aliphatic group and the straight-chain heteroaliphatic group being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH, and R D It is connected to the terminal of the straight-chain aliphatic group or the straight-chain heteroaliphatic group.

[0346] In some embodiments, R C Selected from the group consisting of B ) is a substituted or unsubstituted branched aliphatic group or a substituted or unsubstituted branched heteroaliphatic group:

[0347] in,

[0348] R C1 is absent or is selected from substituted or unsubstituted C 1-4 an alkyl group optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH;

[0349] Branching center group R T’ Selected from the group consisting of:

[0350] Where a represents the C1 Connected position, or R C1 If it does not exist, it is directly compared with R B connected locations;

[0351] R C2 and R C3 Each independently selected from a substituted or unsubstituted aliphatic group and a substituted or unsubstituted heteroaliphatic group having 1 to 12 carbon atoms, the aliphatic group and the heteroaliphatic group being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH;

[0352] R C4 is absent or is selected from hydrogen, a substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, and a substituted or unsubstituted heteroaliphatic group, which aliphatic group and heteroaliphatic group are optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH;

[0353] R C2 The number of carbon atoms n C2 、R C3 The number of carbon atoms n C3 and R C4 The number of carbon atoms n C4 The sum is in the range of 2-24;

[0354] R D With R C2 、R C3 and R C4 Any and only one end of the group is connected.

[0355] In some embodiments, R C1The number of carbon atoms is within the range between any two values ​​within the range of 1-4.

[0356] In some embodiments, R C2 and R C3 The number of carbon atoms is within the range between any two values ​​within the range of 1-12.

[0357] In some embodiments, R C4 The number of carbon atoms is within the range between any two values ​​within the range of 1-12.

[0358] In some embodiments, R C2 The number of carbon atoms n C2 、R C3 The number of carbon atoms n C3 and R C4 The number of carbon atoms n C4 The sum is in the range of 2-18, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and in the range between any two of the above values.

[0359] In some embodiments, R A The group contains a branched central carbon atom; further, the branched central carbon atom is located at R B The α, β or γ position of the group.

[0360] In some embodiments, R C is selected from substituted or unsubstituted straight-chain aliphatic groups having 2 to 11 carbon atoms.

[0361] In some embodiments, R C Selected from the following groups:

[0362] In some embodiments, R A A substituted or unsubstituted straight-chain aliphatic group having 6 to 20 carbon atoms, which is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; or

[0363] R A Selected from the group consisting of A’ ) is a substituted or unsubstituted branched aliphatic group or a substituted or unsubstituted branched heteroaliphatic group:

[0364] in,

[0365] R A1 is absent or is selected from substituted or unsubstituted C1-4 an alkyl group optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH;

[0366] Branching center group R T yes Where a represents the A1 Connected position, or R A1 If it does not exist, it is directly compared with R B connected locations;

[0367] R A2 and R A3 Each is independently selected from a substituted or unsubstituted aliphatic group having 1 to 12 carbon atoms, the aliphatic group being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH;

[0368] R A2 The number of carbon atoms n A2 and R A3 The number of carbon atoms n A3 The sum is in the range of 2-18;

[0369] R B is a degradable group containing a degradable bond selected from the following group: Where a represents the A The connected position, b represents the connection with R C connected locations;

[0370] R C A substituted or unsubstituted straight-chain aliphatic group having 2 to 18 carbon atoms, the straight-chain aliphatic group being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; and

[0371] R D Selected from -NC or -COOH.

[0372] In some embodiments, the lipid compound of formula (II) of the present disclosure is a lipid compound as shown below:

[0373] In one aspect, the present disclosure provides a method for preparing a lipid compound of formula (II), which comprises the following synthetic route:

[0374] When R B Selected from R D When -NC is selected,

[0375] In some embodiments, the synthetic route of the lipid compound of formula (II) comprises:

[0376] The N-Boc-protected alcohol of Compound A (1 eq) and the carboxylic acid of Compound B (1 eq) were dissolved in a single-necked flask filled with DCM. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1 eq) and 4-(dimethylamino)pyridine (0.1 eq) were then added and stirred thoroughly at room temperature overnight. After the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in DCM, and an equal volume of TFA was slowly added dropwise, with thorough stirring for 3 hours. After the reaction, an equal volume of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain a crude product. The crude product (1 eq) was dissolved in a single-necked flask filled with DMF, and sodium chlorodifluoroacetate (2 eq) and potassium carbonate (2 eq) were added. The system was purged with nitrogen, heated, and stirred in an oil bath at 100°C for 12 hours. The mixture was cooled to room temperature, dichloromethane was added, and the mixture was washed four times with a large amount of deionized water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0377] In some embodiments, the synthetic route of the lipid compound of formula (II) comprises:

[0378] The N-Boc-protected carboxylic acid of Compound C (1 eq) and the alcohol of Compound D (1 eq) were dissolved in a single-necked flask filled with DCM. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1 eq) and 4-(dimethylamino)pyridine (0.1 eq) were then added and stirred thoroughly at room temperature overnight. After the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in DCM, and an equal volume of TFA was slowly added dropwise, with thorough stirring for 3 h. After the reaction, an equal volume of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain a crude product. The crude product (1 eq) was dissolved in a single-necked flask filled with DMF, and sodium chlorodifluoroacetate (2 eq) and potassium carbonate (2 eq) were added. The system was purged with nitrogen, heated, and stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, dichloromethane was added, and the mixture was washed four times with a large amount of deionized water and once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0379] In some embodiments, the first step is the same as described above and will not be described in detail. The second step is to dissolve the intermediate (2 mol / L concentration) in a 50% TFA solution in DCM, stir at room temperature for 2 hours, and wash with water to obtain a primary amine. The primary amine (5 mol / L) is then dissolved in a formic acid solution and reacted at 90°C overnight. After the reaction is completed, excess formic acid is removed by rotary evaporation, washed with water, extracted, and passed through a column to obtain a formamide intermediate. Under an ice bath, formamide and DABCO (3 equivalents) are dissolved in DCM, and a solution of triphosgene in DCM is slowly added dropwise. The reaction is stirred for half an hour, and the reaction solution is then poured into a 0.5 M saturated sodium carbonate solution, extracted with DCM, dried over anhydrous sodium sulfate, and passed through a column to obtain the target isonitrile compound.

[0380] In some embodiments, the first step is the same as described above and will not be described in detail; the second step is to dissolve the intermediate (2 mol / L concentration) in a 50% TFA solution in DCM, stir at room temperature for 2 hours, and wash with water to obtain a primary amine. The primary amine (5 mol / L) is then dissolved in a formic acid solution and reacted at 90°C overnight. After the reaction is completed, the excess formic acid is removed by rotary evaporation, washed with water, extracted, and passed through a column to obtain a formamide intermediate. Under nitrogen protection, the formamide intermediate is dissolved in DMF (0.5 mol / L), the reaction temperature is controlled at -50°C, a 3M DMF solution of SOCl2 (1.1 equivalents) is added dropwise, and then anhydrous sodium carbonate (2 equivalents) is added. The reaction temperature is gradually restored to room temperature and stirred overnight. After the reaction is completed, 2 times the volume of water is added, extracted with EA, washed with saturated brine, dried, and passed through a column to obtain the target isonitrile compound.

[0381] In some embodiments, the first step is the same as described above and will not be described in detail. The second step is to dissolve the intermediate (2 mol / L concentration) in a 50% TFA solution in DCM, stir at room temperature for 2 hours, and wash with water to obtain a primary amine. The primary amine (5 mol / L) is then dissolved in a formic acid solution and reacted at 90°C overnight. After the reaction is completed, the excess formic acid is removed by rotary evaporation, washed with water, extracted, and passed through a column to obtain a formamide intermediate. Under an ice bath, the formamide intermediate is dissolved in DCM (1 mol / L), diisopropylamine (3 equivalents) is added, and then trichlorophosphine (1.1 equivalents) is slowly added dropwise. The reaction is carried out at 0°C for 1 hour, and then at room temperature for 8 hours. After the reaction is completed, a saturated sodium carbonate solution is added to a weakly alkaline pH, stirred at room temperature for 1 hour, an equal volume of water is added, extracted with DCM, dried over anhydrous sodium sulfate, and passed through a column to obtain the target isonitrile compound.

[0382] In some embodiments, the first step is the same as described above and is not described in detail. The second step is as follows: the intermediate (2 mol / L concentration) is dissolved in a 50% TFA in DCM solution, stirred at room temperature for 2 hours, and washed with water to obtain a primary amine. The primary amine is dissolved in DCM (4 mol / L), an equal volume of 50% aqueous NaOH solution is added, chloroform (1 equivalent) is added, and a phase transfer catalyst, triethylbenzylammonium chloride (10 g / L), is added, and the reaction is refluxed overnight. An equal volume of water is added to dilute the mixture, the mixture is extracted with DCM, dried over anhydrous sodium sulfate, and filtered through a column to obtain the target isonitrile.

[0383] In some embodiments, the first step is the same as described above and is not described in detail. The second step is to dissolve the resulting iodinated intermediate in THF, add AgCN (1.1 equivalents), heat under reflux, and vigorously stir for 2 hours. An equal volume of water is added, followed by a dropwise addition of an aqueous solution of KCN (3 equivalents), and stir for 20 minutes. The organic solvent is removed by rotary evaporation, and the mixture is extracted with EA, dried over anhydrous sodium sulfate, and filtered to obtain the target isonitrile compound.

[0384] When R B Selected from R D When selected from -COOH,

[0385] In some embodiments, the synthetic route of the lipid compound of formula (II) comprises:

[0386] The diol of Compound E (1 eq) and the carboxylic acid of Compound F (1 eq) were dissolved in a single-necked flask filled with DCM. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1 eq) and 4-(dimethylamino)pyridine (0.1 eq) were then added and stirred thoroughly at room temperature overnight. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in acetone and added dropwise to an aqueous solution of chromium trioxide in sulfuric acid for one hour. The pH of the system was adjusted to a weak base with saturated sodium bicarbonate solution, and the mixture was extracted twice with diethyl ether. The aqueous phase was then acidified with sulfuric acid, extracted with diethyl ether, and dried. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-20% EA in PE).

[0387] In some embodiments, the synthetic route of the lipid compound of formula (II) comprises:

[0388] The diacid of Compound G (1 eq) and the alcohol of Compound H (1 eq) were dissolved in DCM in a one-necked flask. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1 eq) and 4-(dimethylamino)pyridine (0.1 eq) were then added and stirred thoroughly at room temperature overnight. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-20% EA in PE).

[0389] In some embodiments, the first step reaction is the same as described above and will not be repeated; the second step reaction: the obtained cyano intermediate is dissolved in 20% sulfuric acid solution, heated to 80°C and reacted overnight, and after the reaction is completed, 3 volumes of water are added, followed by extraction with EA, drying over anhydrous sodium sulfate, and then column chromatography to obtain the target carboxylic acid compound.

[0390] In some embodiments, the first step reaction is the same as described above and will not be repeated; the second step reaction: the obtained trichloro intermediate is dissolved in a 10% sulfuric acid solution, heated to 90°C and reacted overnight, and after the reaction is completed, 3 volumes of water are added, followed by extraction with EA, drying over anhydrous sodium sulfate, and then column chromatography to obtain the target carboxylic acid compound.

[0391] In some embodiments, the first step is the same as described above and will not be described in detail. The second step is as follows: under nitrogen protection, magnesium chips (1 equivalent) are placed in THF, and the THF solution of the iodinated intermediate is slowly added dropwise at room temperature, gradually heated to reflux, and reacted for 4 hours. After the reaction is resolved, an excess of dry ice is added, and the reaction is stirred vigorously for 2 hours. After returning to room temperature, an equal volume of water is added, and the pH is adjusted to 2 with dilute hydrochloric acid, extracted with EA, dried over anhydrous sodium sulfate, and separated by column to obtain the target carboxylic acid compound.

[0392] In some embodiments, the anhydride is dissolved in THF (2 mol / L), alcohol (1 equivalent) is slowly added dropwise, the mixture is gradually heated to reflux, the reaction is allowed to proceed overnight, an equal volume of water is added, and the pH is then adjusted to 2 with dilute hydrochloric acid. The mixture is extracted with EA, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain the target carboxylic acid compound.

[0393] Lipid compounds containing isonitrile or carboxylic acid end groups for the preparation of ionizable lipids

[0394] In one aspect, the present disclosure provides the use of a lipid compound of formula (II) in the preparation of an ionizable lipid, wherein the ionizable lipid is a lipid compound of formula (I), (III), (IV), (V), (VI) and (VII) of the present disclosure as shown below.

[0395] Wherein, each substituent in the formula (I), (III), (IV), (V) and (VI) is as defined herein.

[0396] In one aspect, the present disclosure provides the use of a lipid compound of formula (II) in the preparation of an ionizable lipid of formula (I) of the present disclosure, wherein the preparation comprises the following Ugi reaction synthesis route:

[0397] Among them, R I 、R II 、R II '、R III and R IV As defined herein, R I -NC and R IV Each -COOH group is independently selected from the lipid compound of formula (II) disclosed herein.

[0398] In some embodiments, the synthetic route for preparing the ionizable lipids of formula (I) of the present disclosure comprises:

[0399] Amine (1 mmol, 1.0 eq) and aldehyde or ketone (1 mmol, 1.0 eq) were dissolved in 10 mL of ethanol. The mixture was stirred for 10 minutes, and then acid (1 mmol, 1.0 eq) was added and stirred for an additional 10 minutes. Isocyanate (1 mmol, 1.0 eq) was added and the resulting solution was stirred at room temperature for 12 hours. The solvent was removed in vacuo, and the residue was purified by flash column purification (0-5% MeOH in DCM) to obtain the desired product.

[0400] In one aspect, the present disclosure provides the use of a lipid compound of formula (II) in the preparation of an ionizable lipid of formula (III) of the present disclosure, wherein the preparation comprises the following Passerini reaction synthesis route:

[0401] Among them, R I 、R II and R IV As defined herein, R I -NC and R IV Each -COOH group is independently selected from the lipid compound of formula (II) disclosed herein.

[0402] In some embodiments, the synthetic route for preparing the ionizable lipid of formula (III) of the present disclosure comprises:

[0403] The acid (1 mmol, 1.0 eq) was added to 5 mL of water, followed by the addition of aldehyde (1 mmol, 1.0 eq) and isocyanate (1 mmol, 1.0 eq), and the mixture was stirred vigorously at room temperature. After 4 hours of reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-5% MeOH in DCM).

[0404] In some embodiments, the preparation comprises the following reaction synthesis route:

[0405] Among them, R I 、R II and R IV As defined herein, R I -NC and R IV Each -COOH group is independently selected from the lipid compound of formula (II) disclosed herein.

[0406] In some embodiments, the synthetic route for preparing the ionizable lipid of formula (III) of the present disclosure comprises:

[0407] Take alcohol (1.5 mmol, 1.5 eq) and add it to 2 mL of THF. Add isocyanate (1.0 mmol, 1.0 eq) and acid (1.5 mmol, 1.5 eq.), then add 2-iodoacylbenzoic acid (2 mmol, 2.0 eq.), and react at 40 ° C for 24 hours. After the reaction is completed, the solvent is removed in vacuo and the residue is purified by flash column (0-5% MeOH in DCM).

[0408] In one aspect, the present disclosure provides the use of a lipid compound of formula (II) in the preparation of an ionizable lipid of formula (IV) of the present disclosure, wherein the preparation comprises the following Ugi-Smiles reaction synthesis route:

[0409] Among them, R I 、R II and R III As defined herein, R I -NC is selected from the lipid compounds of formula (II) disclosed herein.

[0410] In some embodiments, the synthetic route for preparing the ionizable lipid of formula (IV) of the present disclosure comprises:

[0411] Amine (1 mmol, 1.0 eq) and aldehyde (1 mmol, 1.0 eq) were dissolved in 10 mL of toluene. The mixture was stirred for 10 minutes, followed by the addition of phenol (1 mmol, 1.0 eq) and an additional 10 minutes. Isocyanate (1 mmol, 1.0 eq) was added and the resulting solution was stirred at 100° C. for 24 hours. The solvent was removed in vacuo, and the residue was purified by flash column purification (0-5% MeOH in DCM) to afford the desired product.

[0412] In one aspect, the present disclosure provides the use of a lipid compound of formula (II) in the preparation of an ionizable lipid of formula (V) of the present disclosure, wherein the preparation comprises the following reaction synthesis route:

[0413] Among them, R1 V 、R2 V 、R3 V and R4 V As defined herein, R1 IV -NC is selected from the lipid compounds of formula (II) disclosed herein.

[0414] In some embodiments, the synthetic route for preparing the ionizable lipid of formula (V) of the present disclosure comprises:

[0415] Aldehyde (1 mmol, 1.0 eq) was added to 2.5 mL of DMF (or other N-dimethylformamide source), followed by the addition of amine (1 mmol, 1.0 eq) and isocyanate (1 mmol, 1.0 eq), and the mixture was stirred vigorously at room temperature. After 16 hours of reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-5% MeOH in DCM).

[0416] In one aspect, the present disclosure provides the use of a lipid compound of formula (II) in the preparation of an ionizable lipid of formula (VI) of the present disclosure, wherein the preparation comprises the following reaction synthesis route:

[0417] Among them, R1 VI 、R2 VI and R3 VI As defined herein, Each is independently selected from the lipid compounds of formula (II) disclosed herein.

[0418] In some embodiments, the synthetic route for preparing the ionizable lipid of formula (VI) of the present disclosure comprises:

[0419] Take the imino ester (1 mmol, 1.0 eq) and add it to 2.5 mL of THF, add silver oxide (0.1 mmol, 0.1 eq) and ligand (0.2 mmol, 0.2 eq.), then add the first isocyanide (1 mmol, 1.0 eq), and react at -30 ° C for 24 hours. Then add the second isocyanide (1 mmol, 1.0 eq), react at 0 ° C for 12 hours, and then react at room temperature for 12 hours. After the reaction is completed, the solvent is removed in vacuo and the residue is purified by flash column (0-5% MeOH in DCM).

[0420] liposomes

[0421] 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. When used to prepare the liposomes of the present disclosure, the lipid compounds of the present disclosure may also be referred to as cationic lipids or ionizable lipids.

[0422] In some embodiments, in the liposomes of the present disclosure, the lipid compound accounts for about 10 mol% to about 90 mol%, such as 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 any range therebetween, based on the total molar amount of the components constituting the liposomes. Preferably, the lipid compound accounts for about 10 mol% to about 70 mol%, more preferably, the lipid compound accounts for about 20 mol% to about 50 mol%.

[0423] In some embodiments, the liposomes of the present disclosure further include phospholipids and cholesterol.

[0424] In some embodiments, the phospholipids comprise about 0 mol% to about 20 mol%, or a range of any value between about 0 mol% and about 20 mol%, based on the total molar amount of the components constituting the liposomes.

[0425] In some embodiments, the cholesterol accounts for about 30 mol% to about 50 mol%, or any range between about 30 mol% and about 50 mol%, based on the total molar amount of the components constituting the liposome.

[0426] In one aspect, the present disclosure provides use of the liposomes of the present disclosure as a delivery vehicle, for example, a delivery vehicle for delivering plasmids, nucleic acids such as RNA.

[0427] In one aspect, the present disclosure provides a drug delivery system comprising the liposome of the present disclosure as a delivery vector, for example, for delivering plasmids, nucleic acids such as RNA.

[0428] Methods for 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.

[0429] lipid nanoparticles

[0430] In some aspects, the present disclosure relates to lipid nanoparticles. The lipid nanoparticles of the present disclosure comprise the lipid compounds of the present disclosure as described above. When used to prepare the lipid nanoparticles of the present disclosure, the lipid compounds of the present disclosure may also be referred to as cationic lipids or ionizable lipids.

[0431] In some embodiments, in the lipid nanoparticles of the present disclosure, the lipid compound accounts for about 10 mol% to about 90 mol%, such as 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 any range therebetween, based on the total molar amount of the components constituting the lipid nanoparticle. Preferably, the lipid compound accounts for about 10 mol% to about 70 mol%, more preferably, the lipid compound accounts for about 20 mol% to about 50 mol%.

[0432] In some embodiments, the lipid compounds of the present disclosure further comprise a phospholipid, a structured lipid, or a PEG lipid.

[0433] In some embodiments, the phospholipid comprises about 0 mol% to about 20 mol%, or a range of any value between about 0 mol% and about 20 mol%, based on the total molar amount of the components constituting the lipid nanoparticle.

[0434] In some embodiments, the structural lipids comprise about 30 mol% to about 50 mol%, or a range of any value between about 30 mol% and about 50 mol%, based on the total molar amount of the components constituting the lipid nanoparticles.

[0435] In some embodiments, the PEG lipid comprises about 0 mol% to about 10 mol%, or a range of any value between about 0 mol% and about 10 mol%, based on the total molar amount of the components constituting the lipid nanoparticle.

[0436] In some embodiments, the lipid nanoparticles of the present disclosure further comprise a nucleic acid.

[0437] 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 values ​​of 1.1:1 to 10:1. In this article, the N / P ratio can be defined as the ratio of the number of N atoms of the ionizable group contained in the lipid compound (also referred to as "cationic lipid" or "ionizable lipid") to the number of P atoms of the phosphate group of the nucleic acid in the lipid nanoparticle containing the nucleic acid. The N / P ratio can be based on the following calculation: for example, 1 μg 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 based on its molecular weight and the relative content of the cationic group. If there is more than one lipid compound, the N value should be calculated based on all lipid compounds contained in the lipid nanoparticle.

[0438] In some embodiments, the ratio of the lipid compound to the nucleic acid is calculated as a mass ratio.

[0439] In some embodiments, the example of nucleic acid includes single-stranded and double-stranded DNA, single-stranded and double-stranded RNA and a hybrid molecule with a mixture of single-stranded and double-stranded DNA and RNA. In some embodiments, the example of nucleic acid includes any type of RNA, such as messenger RNA (mRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), single-stranded guide RNA (sgRNA), CRISPR RNA (crRNA), trans-activating RNA (tracrRNA), plasmid DNA (pDNA), small circle DNA, genomic DNA (gNDA) and any fragment thereof. In some embodiments, the nucleic acid included in the lipid nanoparticle of the present disclosure can be a mixture of one or more nucleic acid molecules.

[0440] In some embodiments, the lipid nanoparticles of the present disclosure further comprise a plasmid.

[0441] In one aspect, the present disclosure provides the use of lipid nanoparticles as delivery vehicles, such as delivery vehicles for the delivery of plasmids, nucleic acids such as RNA.

[0442] In one aspect, the present disclosure provides a drug delivery system comprising the lipid nanoparticles of the present disclosure as a delivery vehicle, for example, for delivering plasmids, nucleic acids such as RNA.

[0443] In one aspect, the present disclosure provides lipid nanoparticles that entrap nucleic acid molecules, such as RNA.

[0444] In one aspect, the present disclosure provides plasmid-entrapped lipid nanoparticles.

[0445] The preparation methods of 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.

[0446] Pharmaceutical composition

[0447] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a lipid compound or stereoisomer or pharmaceutically acceptable salt of formula (I) 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.

[0448] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein, a pharmaceutically acceptable carrier or excipient includes one or more such carriers or excipients. The specific carrier or excipient used will depend on the manner and purpose of the application of the compound of the present disclosure. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, 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 buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, flavorings, diluents and other known additives may also be included to provide a refined presentation of the drug (i.e., the compound or pharmaceutical composition provided herein) or to aid in the production of a pharmaceutical product (i.e., the drug).

[0449] The compositions of the present disclosure can be formulated into a variety of forms. These include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, suppositories, etc. The form depends on the intended mode of administration and therapeutic application.

[0450] The pharmaceutical compositions of the present disclosure can be prepared by any well-known pharmaceutical techniques (e.g., effective formulations and administration procedures). The above considerations on effective formulations and administration procedures are well known in the art and are described in standard textbooks. For example, 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, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients, 3rd edition, American Pharmaceutical Association, Washington, 1999, the formulation of drug products is discussed.

[0451] Example

[0452] To describe the present invention in more detail, the following examples are presented. The examples described herein are intended to illustrate the lipid compounds, preparation methods, lipid nanoparticles, and pharmaceutical compositions provided herein and should not be interpreted in any way as limiting their scope.

[0453] During the synthesis process, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in TW Greene and PGM Wutts, Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons. The protecting groups are optionally removed at a convenient subsequent stage using methods well known in the art.

[0454] The lipid compounds of the present invention can be easily prepared according to the following reaction schemes and examples or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, variants known to those skilled in the art but not mentioned in more detail may also be used. In addition, other methods for preparing the lipid compounds of the present invention will be apparent to those skilled in the art based on the reaction schemes and examples described herein. Unless otherwise stated, all variables are as defined above. In general, in the chemical procedures, all reagents and starting materials can be purchased from commercial suppliers or can be easily prepared by those skilled in the art.

[0455] Example 1

[0456] The structure of synthetic lipid isonitrile is as follows:

[0457] 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), and 4-(dimethylamino)pyridine (0.1222 g, 0.1 eq) were dissolved sequentially in 50 mL of DCM in a 250 mL single-necked flask and stirred thoroughly at room temperature for 18 hours. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, followed by the slow addition of 10 mL of TFA, and stirred thoroughly for 3 hours. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to yield crude 3-aminopropyl oleate. 3-Aminopropyl oleate (4.2230 g, 1 eq), sodium chlorodifluoroacetate (2.3623 g, 2 eq), and potassium carbonate (3.4553 g, 2 eq) were placed in a 500 mL single-necked bottle. 100 mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0458] 1 H NMR (500MHz, CDCl3, ppm): δ5.34(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):350.2m / z(M+H + ). Chemical formula: C22 H 39 NO2

[0459] Example 2

[0460] The structure of synthetic lipid isonitrile is as follows:

[0461] 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), and 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were dissolved sequentially in 50 mL of DCM in a 250 mL single-necked flask and stirred thoroughly at room temperature for 18 h. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, followed by the slow addition of 10 mL of TFA, and stirred thoroughly for 3 h. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to yield crude (Z)-dodec-9-en-1-yl-4-aminobutyrate. (Z)-Dodec-9-en-1-yl-4-aminobutyrate (4.9320 g, 1 eq), sodium chlorodifluoroacetate (2.6457 g, 2 eq), and potassium carbonate (3.8699 g, 2 eq) were placed in a 500 mL single-necked flask. 100 mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0462] 1 H NMR (500MHz, CDCl3, ppm): δ5.34(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):364.2m / z(M+H + ). Chemical formula: C 23 H 41 NO2

[0463] Example 3

[0464] The structure of synthetic lipid isonitrile is as follows:

[0465] Nonanoic acid (1.6325 g, 1 eq), N-Boc-γ-amino-1-propanol (1.9136 g, 1 eq), dicyclohexylcarbodiimide (2.0216 g, 1 eq), and 4-(dimethylamino)pyridine (0.1312 g, 0.1 eq) were dissolved sequentially in 50 mL of DCM in a 250 mL single-necked flask and stirred thoroughly at room temperature for 18 hours. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise, and stirred thoroughly for 3 hours. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain crude 3-aminononanoic acid propyl ester. 3-Aminononanoic acid propyl ester (3.5120 g, 1 eq), sodium chlorodifluoroacetate (3.1182 g, 2 eq), and potassium carbonate (4.5603 g, 2 eq) were placed in a 500 mL single-necked flask. 100 mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0466] 1 H NMR (500MHz, CDCl3, ppm): δ4.21(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):225.9m / z(M+H + ). Chemical formula: C 13 H 23 NO2

[0467] Example 4

[0468] The structure of synthetic lipid isonitrile is as follows:

[0469] N-Boc-γ-aminobutyric acid (2.1604 g, 1 eq), n-octanol (1.3819 g, 1 eq), dicyclohexylcarbodiimide (2.0216 g, 1 eq), and 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were dissolved sequentially in a 250 mL single-necked flask containing 50 mL of DCM and stirred thoroughly at room temperature for 18 h. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise, and stirred thoroughly for 3 h. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain crude 4-aminobutyric acid octyl ester. 4-Aminobutyric acid octyl ester (4.3068g, 1 eq), sodium chlorodifluoroacetate (3.7796g, 2 eq), and potassium carbonate (5.5284g, 2 eq) were placed in a 500mL single-necked flask. 100mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 hours. The mixture was cooled to room temperature, 100mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0470] 1 H NMR (500MHz, CDCl3, ppm): δ4.06(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):225.9m / z(M+H + ). Chemical formula: C 13 H 23 NO2

[0471] Example 5

[0472] The structure of synthetic lipid isonitrile is as follows:

[0473] Boc-8-aminocaprylic acid (1.9179 g, 1.45 eq), 9-heptadecanol (1.3080 g, 1 eq), dicyclohexylcarbodiimide (1.0523 g, 1 eq), and 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) were sequentially dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred at room temperature for 18 h. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column purification (0-10% EA in PE). The product after column purification was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred for 3 h. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain crude 9-heptyl-8-aminocaprylate. 9-Heptyl-8-aminooctanoate (3.1020 g, 1 eq), sodium chlorodifluoroacetate (1.4740 g, 2 eq), and potassium carbonate (2.1560 g, 2 eq) were placed in a 500 mL single-necked flask. 100 mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0474] 1 H NMR (500MHz, CDCl3, ppm): δ4.47(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):408.3m / z(M+H + ). Chemical formula: C 26 H 49 NO2

[0475] Example 6

[0476] The structure of synthetic lipid isonitrile is as follows:

[0477] 2-Hexyldecanoic acid (1.7325 g, 1 eq), N-Boc-6-amino-1-hexanol (1.5386 g, 0.8 eq), dicyclohexylcarbodiimide (1.6506 g, 1 eq), and 4-(dimethylamino)pyridine (0.0977 g, 0.1 eq) were sequentially dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred thoroughly at room temperature for 18 hours. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column purification (0-10% EA in PE). The product after column purification was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise, and stirred thoroughly for 3 hours. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain crude 2-hexyl-6-aminodecanoate. 2-Hexyl-6-aminodecanoate (3.0350 g, 1 eq), sodium chlorodifluoroacetate (1.7953 g, 2 eq), and potassium carbonate (2.6263 g, 2 eq) were placed in a 500 mL single-necked flask. 100 mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0478] 1 H NMR (500MHz, CDCl3, ppm): δ4.08(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):366.2m / z(M+H + ). Chemical formula: C 23 H 43 NO2

[0479] Boc-8-aminocaprylic acid (1.9179 g, 1.45 eq), 2-heptyl-2-methylethanol (0.8072 g, 1 eq), dicyclohexylcarbodiimide (1.0523 g, 1 eq), and 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) were dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred at room temperature for 18 h. After the reaction, the solvent was removed in vacuo, and the residue was purified by flash column purification (0-10% EA in PE). The product after column purification was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred for 3 h. After the reaction was completed, 20 mL of saturated sodium bicarbonate solution was added, and the product was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain the crude product 8-aminocaprylic acid heptadecane-9-ester. 8-Aminooctanoate heptadecan-9-yl ester (3.1020 g, 1 eq), sodium chlorodifluoroacetate (1.4740 g, 2 eq), and potassium carbonate (2.1560 g, 2 eq) were placed in a 500 mL single-necked flask. 100 mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0480] 1 H NMR (500MHz, CDCl3, ppm): δ4.47(m,2H),3.38(t,2H),2.29(t,2H),2.09(m,1H),1.6 5(m,4H),1.50-1.26(m,18H),0.88(t,3H),0.80(t,3H).LCMS(APCI):310.1m / z(M+H + ). Chemical formula: C 19 H 35 NO2

[0481] Boc-8-aminocaprylic acid (1.9179 g, 1.45 eq), 3-undecanol (0.8788 g, 1 eq), dicyclohexylcarbodiimide (1.0523 g, 1 eq), and 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) were dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred at room temperature for 18 h. After the reaction, the solvent was removed in vacuo, and the residue was purified by flash column purification (0-10% EA in PE). The product after column purification was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred for 3 h. After the reaction was completed, 20 mL of saturated sodium bicarbonate solution was added, and the product was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain the crude product 8-aminocaprylic acid heptadecane-9-ester. 8-Aminooctanoate heptadecan-9-yl ester (3.1020 g, 1 eq), sodium chlorodifluoroacetate (1.4740 g, 2 eq), and potassium carbonate (2.1560 g, 2 eq) were placed in a 500 mL single-necked flask. 100 mL of DMF was added, the atmosphere was replaced with nitrogen, the temperature was raised, and the mixture was stirred in an oil bath at 100°C for 12 h. The mixture was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was washed four times with copious amounts of deionized water and once with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE).

[0482] 1 H NMR (500MHz, CDCl3, ppm): δ4.47 (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): 324.1m / z (M+H) + ). Chemical formula: C 20 H 37 NO2

[0483] In the examples, isonitrile compounds were synthesized according to similar synthesis reaction steps, which are summarized as follows:

[0484] 1 H NMR (500MHz, CDCl3, ppm): δ5.34(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):350.2m / z(M+H + ). Chemical formula: C 22 H 39 NO2

[0485] 1 H NMR (500MHz, CDCl3, ppm): δ5.34(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):364.2m / z(M+H + ). Chemical formula: C 23 H 41 NO2

[0486] 1 H NMR (500MHz, CDCl3, ppm): δ4.21(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):225.9m / z(M+H + ). Chemical formula: C 13 H 23 NO2

[0487] 1 H NMR (500MHz, CDCl3, ppm): δ4.06(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):225.9m / z(M+H + ). Chemical formula: C 13 H 23 NO2

[0488] 1 H NMR (500MHz, CDCl3, ppm): δ4.47 (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): 324.1m / z (M+H) + ). Chemical formula: C 20 H 37 NO2

[0489] 1 H NMR (500MHz, CDCl3, ppm): δ4.87 (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): 352.1m / z (M+H) + ). Chemical formula: C 22 H 41 NO2

[0490] 1 H NMR (500MHz, CDCl3, ppm): δ4.87(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):380.1m / z(M+H + ). Chemical formula: C 24 H 45 NO2

[0491] 1 H NMR (500MHz, CDCl3, ppm): δ4.47(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):408.3m / z(M+H + ). Chemical formula: C 26 H 49 NO2

[0492] 1 H NMR (500MHz, CDCl3, ppm): δ3.97 (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): 341.5m / z (MH + ). Chemical formula: C 20 H 37 NO2

[0493] 1H NMR (500MHz, CDCl3, ppm): δ4.47(m,2H),3.38(t,2H),2.29(t,2H),2.09(m,1H),1.6 5(m,4H),1.50-1.26(m,18H),0.88(t,3H),0.80(t,3H).LCMS(APCI):310.1m / z(M+H + ). Chemical formula: C 19 H 35 NO2

[0494] 1 H NMR (500MHz, CDCl3, ppm): δ3.99 (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): 352.1m / z (M+H) + ). Chemical formula: C 22 H 41 NO2

[0495] 1 H NMR (500MHz, CDCl3, ppm): δ3.97(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):380.1m / z(M+H + ). Chemical formula: C 24 H 45 NO4

[0496] 1 H NMR (500MHz, CDCl3, ppm): δ3.97(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):380.1m / z(M+H + ). Chemical formula: C 24 H 45 NO4

[0497] 1H NMR (500MHz, CDCl3, ppm): δ3.96 (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): 408.3m / z (M+H) + ). Chemical formula: C 26 H 49 NO2

[0498] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 3.38 (t, 2H), 2.30 (m, 1H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 310.1m / z (M+H + ). Chemical formula: C 19 H 35 NO2

[0499] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 3.38 (t, 2H), 2.30 (m, 1H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 310.1m / z (M+H + ). Chemical formula: C 19 H 35 NO2

[0500] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (m, 2H), 3.38 (t, 2H), 2.29 (m, 3H), 1.66-1.10 (m, 23H), 0.88 (t, 3H). LCMS (APCI): 296.1m / z (M+H + ). Chemical formula: C 18 H 33 NO2

[0501] 1H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 3.39 (t, 2H), 2.31 (m, 1H), 1.66-1.25 (m, 28H), 0.88 (t, 6H). LCMS (APCI): 338.1m / z (M+H + ). Chemical formula: C 21 H 39 NO2

[0502] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 3.39 (t, 2H), 2.31 (m, 1H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 366.2m / z (M+H + ). Chemical formula: C 23 H 43 NO2

[0503] 1 H NMR (500MHz, CDCl3, ppm): δ4.08(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):366.2m / z(M+H + ). Chemical formula: C 23 H 43 NO2

[0504] 1 H NMR (500MHz, CDCl3, ppm): δ4.21(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):310.1m / z(M+H + ). Chemical formula: C 19 H 35 NO2

[0505] 1H NMR (500MHz, CDCl3, ppm): δ4.21(t,2H),3.51(t,2H),2.25(d,2H),1.83(m,1H),1.66-1.14(m,26H),0.88(t,6H).LCMS(APCI):338.1m / z(M+H + ). Chemical formula: C 21 H 39 NO2

[0506] 1 H NMR (500MHz, CDCl3, ppm): δ4.21(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):366.1m / z(M+H + ). Chemical formula: C 23 H 43 NO2

[0507] 1 H NMR (500MHz, CDCl3, ppm): δ4.21(t,2H),3.51(t,2H),2.25(d,2H),2.02(m,2 H),1.83(m,1H),1.42-1.14(m,32H),0.88(t,6H).LCMS(APCI):394.2m / z(M+H + ). Chemical formula: C 25 H 47 NO2

[0508] 1 H NMR (500MHz, CDCl3, ppm): δ4.06 (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): 296.1m / z (M+H) + ). Chemical formula: C 18 H 33 NO2

[0509] 1H NMR (500MHz, CDCl3, ppm): δ4.10 (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): 296.1m / z (M+H) + ). Chemical formula: C 18 H 33 NO2

[0510] In the examples, carboxylic acid compounds were synthesized according to similar synthetic reaction steps, which are summarized as follows:

[0511] 1 H NMR (500MHz, CDCl3, ppm): δ4.47 (m, 1H), 2.29 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 20H), 0.88 (m, 6H). LCMS (APCI): 327.5m / z (MH + ). Chemical formula: C 19 H 36 O4

[0512] 1 H NMR (500MHz, CDCl3, ppm): δ4.87 (m, 1H), 2.28 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 26H), 0.88 (m, 6H). LCMS (APCI): 369.6m / z (MH + ). Chemical formula: C 22 H 42 O4

[0513] 1 H NMR (500MHz, CDCl3, ppm): δ4.87 (m, 1H), 2.28 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 30H), 0.88 (m, 6H). LCMS (APCI): 397.6m / z (MH + ). Chemical formula: C 24 H 46 O4

[0514] 1H NMR (500MHz, CDCl3, ppm): δ4.47 (m, 1H), 2.29 (m, 4H), 1.65 (m, 4H), 1.50-1.26 (m, 34H), 0.88 (t, 6H). LCMS (APCI): 425.7m / z (MH + ). Chemical formula: C 26 H 50 O4

[0515] 1 H NMR (500MHz, CDCl3, ppm): δ3.97 (m, 2H), 2.30 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 20H), 0.88 (m, 6H). LCMS (APCI): 341.5m / z (MH + ). Chemical formula: C 20 H 38 O4

[0516] 1 H NMR (500MHz, CDCl3, ppm): δ4.47(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):313.5m / z(MH) + ). Chemical formula: C 18 H 34 O4

[0517] 1 H NMR (500MHz, CDCl3, ppm): δ3.99 (d, 2H), 2.31 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 369.6m / z (MH + ). Chemical formula: C 22 H 42 O4

[0518] 1H NMR (500MHz, CDCl3, ppm): δ3.97 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 28H), 0.88 (t, 6H). LCMS (APCI): 397.6m / z (MH + ). Chemical formula: C 24 H 46 O4

[0519] 1 H NMR (500MHz, CDCl3, ppm): δ3.97 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 30H), 0.88 (t, 6H). LCMS (APCI): 411.7m / z (MH + ). Chemical formula: C 25 H 48 O4

[0520] 1 H NMR (500MHz, CDCl3, ppm): δ3.96 (d, 2H), 2.33 (m, 4H), 1.65 (m, 5H), 1.50-1.26 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 425.7m / z (MH + ). Chemical formula: C 26 H 50 O4

[0521] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 327.5m / z (MH + ). Chemical formula: C 19 H 36 O4

[0522] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 24H), 0.88 (t, 6H). LCMS (APCI): 327.5m / z (MH + ). Chemical formula: C19 H 36 O4

[0523] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (m, 2H), 2.29 (m, 3H), 1.66-1.10 (m, 25H), 0.88 (t, 3H). LCMS (APCI): 313.5m / z (MH + ). Chemical formula: C 18 H 34 O4

[0524] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 28H), 0.88 (t, 6H). LCMS (APCI): 355.5m / z (MH + ). Chemical formula: C 21 H 40 O4

[0525] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 383.6m / z (MH + ). Chemical formula: C 23 H 44 O4

[0526] 1 H NMR (500MHz, CDCl3, ppm): δ4.08 (t, 2H), 2.30 (m, 3H), 1.66-1.25 (m, 32H), 0.88 (t, 6H). LCMS (APCI): 383.6m / z (MH + ). Chemical formula: C 23 H 44 O4

[0527] 1H NMR (500MHz, CDCl3, ppm): δ4.12(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):327.5m / z(MH) + ). Chemical formula: C 19 H 36 O4

[0528] 1 H NMR (500MHz, CDCl3, ppm): δ4.12(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):355.5m / z(MH + ). Chemical formula: C 21 H 40 O4

[0529] 1 H NMR (500MHz, CDCl3, ppm): δ4.12(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):383.6m / z(MH) + ). Chemical formula: C 23 H 44 O4

[0530] 1 H NMR (500MHz, CDCl3, ppm): δ4.12(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):411.7m / z(MH) + ). Chemical formula: C 25 H 48 O4

[0531] 1H NMR (500MHz, CDCl3, ppm): δ4.05 (t, 2H), 2.35 (m, 4H), 1.60 (m, 6H), 1.44-1.20 (m, 15H), 0.88 (t, 6H). LCMS (APCI): 313.5m / z (MH + ). Chemical formula: C 18 H 34 O4

[0532] 1 H NMR (500MHz, CDCl3, ppm): δ4.10 (t, 2H), 2.35 (m, 4H), 1.60 (m, 5H), 1.44-1.20 (m, 16H), 0.88 (t, 6H). LCMS (APCI): 313.5m / z (MH + ). Chemical formula: C 18 H 34 O4

[0533] Example 7

[0534] Lipid 1-324 was prepared by the following steps,

[0535] (i-1) The first reactant (R III -NH2, 1 mmol, 1.0 equiv) and a second reactant selected from library b (aldehyde R II -C(O)-H, 1 mmol, 1.0 equivalent) was dissolved in ethanol and stirred for 10 minutes to form a first mixture; when the second reactant was selected from the ketone compound in library b (R II -C(O)-R II '), the amount of the second reactant was increased to three times the equivalent (3 mmol), and the reaction temperature was increased to 40°C in step (iii);

[0536] (ii) adding a third reactant (HY-C(O)-R IV , 1 mmol, 1.0 equiv), and stirred for 10 minutes to form a second mixture;

[0537] (iii) 1-Isocyanocyclohexene (1 mmol, 1.0 equivalent) was added to the second mixture obtained in step (ii), and the mixture was stirred at room temperature for 12 hours. After removing the solvent, the mixture was purified by silica gel column chromatography to obtain a compound having the general structure (Ia) (elution gradient: from dichloromethane containing 0% methanol by volume to dichloromethane containing 10% methanol by volume, and 0.1% ammonia in methanol).

[0538] (iv) The product of the above step (Formula (Ia), 1 mmol, 1.0 equivalent) was dissolved in 9.5 mL of tetrahydrofuran, 0.5 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 12-18 hours. The mixture was neutralized with solid sodium bicarbonate and then filtered. The solvent was removed in vacuo, and the residue was dissolved in sodium bicarbonate solution at pH = 10 and washed with dichloromethane. The aqueous layer was then acidified and extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to obtain the compound of formula (Ib).

[0539] (v) The product of the above step (Formula (Ib), 1 mmol, 1.0 equivalent), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 mmol, 1.0 equivalent) and 4-dimethylaminopyridine (0.1 mmol, 0.1 equivalent) were dissolved in 20 mL of dichloromethane, and the fourth reactant (R I -OH or R I -NH2, 1 mmol, 1.0 equivalent) and stirred overnight. The resulting solution was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Filtered, the solvent was removed in vacuo, and the lipid compound having the general structure (I') or (I") was obtained by silica gel column chromatography (elution gradient, from dichloromethane containing 0% methanol by volume to dichloromethane containing 10% methanol, 0.1% ammonia).

[0540] Lipid 325 was prepared by the following steps,

[0541] Step 1: Dissolve the amine from library a (1 mmol, 1.0 equiv) and the aldehyde from library b (1 mmol, 1.0 equiv) in 10 mL of methanol. Stir for 10 minutes, then add isocyanocyclohexene (1 mmol, 1.0 equiv) and stir for an additional 10 minutes. The resulting solution is stirred under carbon dioxide at room temperature for 12 hours. After removing the solvent, a crude product containing a cyclovinylamide structure is obtained.

[0542] Step 2: Dissolve the product from Step 1 in 9.5 mL of tetrahydrofuran, add 0.5 mL of concentrated hydrochloric acid, and stir at room temperature for 12-18 hours. Neutralize with solid sodium bicarbonate and filter. Remove the solvent in vacuo, then dissolve the residue in sodium bicarbonate solution at pH 10 and wash with dichloromethane. The aqueous layer is then acidified and extracted with dichloromethane. Combine the organic phases and dry over anhydrous sodium sulfate. After filtration, remove the solvent in vacuo to yield the crude product.

[0543] Step 3: Dissolve the crude product from Step 2 (1 mmol, 1.0 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 mmol, 1.0 equiv), and 4-dimethylaminopyridine (0.1 mmol, 0.1 equiv) in 20 mL of dichloromethane. Add the fourth component from Library d (1 mmol, 1.0 equiv) and stir overnight. The resulting solution is washed twice with saturated brine, and the organic phase is dried over anhydrous sodium sulfate. Filter, remove the solvent in vacuo, and chromatograph the resulting product on a silica gel column (elution gradient from 0% methanol in dichloromethane to 10% methanol in dichloromethane, 0.1% ammonia).

[0544] Lipid 325 :

[0545] 1 H NMR (500MHz, CDCl3, ppm): δ4.86(m,1H),4.32(m,1H),3.73(s,3H),3.19(m,4 H),2.33(m,10H),1.79(m,2H),1.61(m,2H),1.51-1.18(m,58H),0.87(t,9H). MS:m / z 752.9(M+H + ). Chemical formula: C 45 H 89 N3O5

[0546] Lipids 326-327 were prepared by the following steps,

[0547] Step 1: Dissolve the amine from library a (1 mmol, 1.0 equiv) and the aldehyde from library b (1 mmol, 1.0 equiv) in 10 mL of tert-butanol. Stir for 10 minutes, then add isocyanocyclohexene (1 mmol, 1.0 equiv) and stir for an additional 10 minutes. The resulting solution is stirred under carbon dioxide at room temperature for 12 hours. After removal of the solvent, intermediate 1 containing the cyclovinylamide structure is obtained.

[0548] Step 2: Dissolve the product from Step 1 in 30% trifluoroacetic acid in dichloromethane and stir at room temperature for 3-5 hours. Remove the solvent in vacuo to yield the secondary amine intermediate 2.

[0549] Step 3: Dissolve the crude product from the previous step (1 mmol, 1.0 eq) and triethylamine (1 mmol, 1 eq) in 10 mL of dichloromethane. Add 4-nitrobenzoyl chloroformate (1 mmol, 1 eq.) in 10 mL of dichloromethane dropwise at low temperature. React at room temperature for 6 h. Wash the reaction mixture with saturated sodium carbonate solution, collect the organic phase, and dry it. After desolventization, intermediate 3 is obtained.

[0550] Step 4: Dissolve Intermediate 3 in 9.5 mL of tetrahydrofuran, add 0.5 mL of concentrated hydrochloric acid, and stir at room temperature for 12-18 hours. Neutralize with solid sodium bicarbonate and filter. Remove the solvent in vacuo, then dissolve the residue in sodium bicarbonate solution at pH 10 and wash with dichloromethane. The aqueous layer is then acidified and extracted with dichloromethane. The organic phases are combined and dried over anhydrous sodium sulfate. After filtration, the solvent is removed in vacuo to yield Intermediate 4.

[0551] Step 5: Dissolve intermediate 4, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 mmol), and 4-dimethylaminopyridine (0.1 mmol) in 20 mL of dichloromethane. Add the fourth component of library d (1 mmol, 1.0 equivalent) and stir overnight. The resulting solution is washed twice with saturated brine, and the organic phase is dried over anhydrous sodium sulfate. Filter, remove the solvent in vacuo, and chromatograph the resulting product on a silica gel column (elution gradient from 0% methanol in dichloromethane to 10% methanol in dichloromethane, 0.1% ammonia).

[0552] Lipid 326 :

[0553] 1 H NMR (500MHz, CDCl3, ppm): δ5.34(m,2H),4.1-3.9(m,1H),3.73(m,1H),3.45(m,1H),3.21(m,1H),3 .08-3.01(m,3H),,2.33(m,8H),2.00(m,4H),1.79-1.54(m,6H),1.51-1.18(m,49H),0.87(t,6H). MS:m / z 678.8(M+H + ). Chemical formula: C 42 H 84 N4O2

[0554] Lipid 327 :

[0555] 1H NMR (500MHz, CDCl3, ppm): δ5.34 (m, 2H), 4.1-3.9 (m, 3H), 3.73 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H) ),3.08(m,1H),2.33(m,8H),2.00(m,4H),1.79-1.54(m,6H),1.51-1.18(m,49H),0.87(t,6H). MS:m / z 678.8(M+H + ). Chemical formula: C 42 H 83 N3O3

[0556] Lipid 401-1075 was prepared by the following steps,

[0557] (i-1) The first reactant (R III -NH2, 1 mmol, 1.0 equiv) and a second reactant selected from library b (aldehyde R II -C(O)-H, 1 mmol, 1.0 equivalent) was dissolved in ethanol and stirred for 10 minutes to form a first mixture; when the second reactant was selected from the ketone compound in library b (R II -C(O)-R II '), the amount of the second reactant was increased to three times the equivalent (3 mmol), and the reaction temperature was increased to 40°C in step (iii);

[0558] (ii) adding a third reactant (HY-C(O)-R IV , 1 mmol, 1.0 equiv) and stirred for 10 minutes to form a second mixture;

[0559] (iii) adding a fourth reactant (R) selected from library e to the second mixture obtained in step (ii) I -NC, 1 mmol, 1.0 equivalent, (1 mmol, 1.0 equivalent), stirred at room temperature for 12 hours, and after removing the solvent, the compound having the general structure (Ia) was obtained by silica gel column chromatography (elution gradient: from dichloromethane containing 0% methanol by volume to dichloromethane containing 10% methanol, 0.1% ammonia solution in methanol).

[0560] The compounds included in library a, library b, library c, library d, and library e are specifically shown below.

[0561] Library a

[0562] Library B

[0563] Library c

[0564] Library d

[0565] Library

[0566] Synthesis of some key reaction intermediates:

[0567] Synthesis of 1-Isocyanocyclohexene :

[0568] Cyclohexanone (4.9072 g, 1 eq), formamide (3.3780 g, 1.5 eq), and p-toluenesulfonic acid monohydrate (0.4755 g, 0.05 eq) were placed in a 250 mL single-necked flask. 100 mL of toluene was added and the mixture was refluxed at 140°C for 24 h. The solvent was removed by rotary evaporation, and the residue was purified by flash column chromatography to yield N-(1-cycloethenyl)formamide (0-60% EA in PE).

[0569] N-(1-cycloethenyl)formamide (1.6460 g, 1 eq) and 1,4-diazabicyclo[2.2.2]octane (4.4262 g, 3 eq) were placed in a 100 mL single-necked flask, added to 32.88 mL of dichloromethane, and stirred in an ice-water bath. Triphosgene (2.6152 g, 0.67 eq) dispersed in 28.62 mL of dichloromethane was added dropwise via a constant pressure dropping funnel. After stirring for 2 h, the mixture was washed with saturated sodium bicarbonate solution, and the aqueous phase was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). 1 H NMR (500MHz, CDCl3, ppm): δ5.92 (s, 1H), 2.22 (m, 2H), 2.10 (m, 2H), 1.69 (m, 2H), 1.57 (m, 2H). MS:m / z 108.2(M+H + ). Chemical formula: C7H9N.

[0570] Synthesis of compound a8 :

[0571] Tert-butyl 2-(methylamino)ethylcarbamate (0.5000 g, 1 eq) and 2-bromoethanol (0.5379 g, 1.5 eq) were dissolved in 10 mL of toluene and refluxed at 115° C. for 5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was purified by flash column purification (0-10% MeOH in DCM). The product after column purification was dissolved in 50% trifluoroacetic acid in dichloromethane and reacted for 4 hours. The solvent was removed in vacuo to obtain the product.

[0572] 1 H NMR (500MHz, CDCl3, ppm): 3.86 (t, 2H), 3.38 (m, 4H), 3.22 (t, 2H), 2.87 (s, 3H). MS:m / z 119.1(M+H + ). Chemical formula: C5H 14 N2O.

[0573] Synthesis of compound a9 :

[0574] Tert-butyl 2-(methylamino)propylcarbamate (0.5000 g, 1 eq) and 2-bromoethanol (0.4978 g, 1.5 eq) were dissolved in 10 mL of toluene and refluxed at 115° C. for 5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was purified by a rapid column purification (0-10% MeOH in DCM). The product after the column was dissolved in 50% trifluoroacetic acid in dichloromethane and reacted for 4 hours. The solvent was removed in vacuo to obtain the product.

[0575] 1 H NMR (500MHz, CDCl3, 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). MS:m / z 131.1(M+H + ). Chemical formula: C6H 16 N2O.

[0576] Synthesis of compound a10 :

[0577] Tert-butyl 2-(methylamino)ethylcarbamate (0.5000 g, 1 eq) and 4-bromo-1-butanol (0.6096 g, 1.5 eq) were dissolved in 10 mL of toluene and refluxed at 115° C. for 5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was purified by flash column purification (0-10% MeOH in DCM). The product after column purification was dissolved in 50% trifluoroacetic acid in dichloromethane and reacted for 4 hours. The solvent was removed in vacuo to obtain the product.

[0578] 1 H NMR (500MHz, CDCl3, 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 + ). Chemical formula: C8H 20 N2O.

[0579] Synthesis of compound a13 :

[0580] 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. for 5 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was purified by flash column purification (0-10% MeOH in DCM). The product after column purification was dissolved in 50% trifluoroacetic acid in dichloromethane and reacted for 4 hours. The solvent was removed in vacuo to obtain the product.

[0581] 1 H NMR (500MHz, CDCl3, ppm): 3.86 (t, 2H), 3.38 (m, 4H), 3.22 (t, 2H), 2.87 (s, 3H), 1.71 (m, 2H), 1.52 (m, 2H). MS:m / z 147.2(M+H + ). Chemical formula: C7H 18 N2O.

[0582] Synthesis of compound b5 :3-(dimethylamino)propionaldehyde

[0583] Add dimethylamine aqueous solution (2 eq, 24 mmol) to 5 mL of water, then add sodium hydroxide (2 eq, 24 mmol) and stir in an ice bath. Slowly add 3-chloropropionaldehyde diethyl acetal (1 eq, 12 mmol) dropwise, stir at 0°C for 0.5 h, then stir at 30°C overnight. After the reaction is complete, adjust the pH of the system to neutral with hydrochloric acid, and extract twice with dichloromethane. Dry the organic phase over anhydrous magnesium sulfate, and remove the solvent in vacuo to obtain crude 3-dimethylaminopropionaldehyde diethyl acetal. Dissolve 3-dimethylaminopropionaldehyde diethyl acetal (1 mmol) in 5 mL of tetrahydrofuran, add 5 mL of 2M hydrochloric acid, and react at 40°C overnight. Remove the solvent in vacuo to obtain 3-(dimethylamino)-n-propionaldehyde hydrochloride.

[0584] 1 H NMR (500MHz, CDCl3, ppm): δ9.48 (s, 1H), 2.64 (s, 6H), 2.52 (m, 4H).

[0585] Synthesis of compound b6 :4-(dimethylamino)-n-butyraldehyde

[0586] 4-Dimethylaminobutyraldehyde diethyl acetal (1 mmol) was dissolved in 5 mL of tetrahydrofuran, 5 mL of 2M hydrochloric acid was added, and the mixture was reacted overnight at 40° C. The solvent was removed in vacuo to obtain 4-(dimethylamino)-butyraldehyde hydrochloride.

[0587] 1 H NMR (500MHz, CDCl3, ppm): δ9.36 (s, 1H), 2.40 (m, 4H), 2.16 (s, 6H), 1.56 (m, 2H).

[0588] Synthesis of compound b15 :

[0589] Oleic acid (9.6036 g, 34 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (9.7767 g, 26.6 mmol), 1,2-ethylene glycol (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 and then washed with saturated aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under vacuum. The residue was purified by silica gel chromatography (0-50% ethyl acetate in hexanes) to provide 2-hydroxyethyl oleate. 2-Hydroxyethyl oleate (4.5713 g, 14 mmol) was dissolved in 200 mL of dichloromethane and 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 evaporated under vacuum. The residue was purified by flash column purification (0-30% EA in PE) to give 2-oxoethyl oleate.

[0590] 1H NMR (500MHz, CDCl3, ppm): δ5.37(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.

[0591] Synthesis of compound c17 :

[0592] 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 the atmosphere was replaced with nitrogen three times. Succinic anhydride (1.7891 g, 1.2 eq) dissolved in 50 mL of ultra-dry dichloromethane was added dropwise via a constant pressure dropping funnel. The mixture was allowed to react overnight at room temperature, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-20% EA in PE). 1 H NMR (500MHz, CDCl3, ppm): δ5.37(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(MH + ). Chemical formula: C 22 H 40 O4.

[0593] Synthesis of compound c18 :

[0594] 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 the atmosphere was replaced with nitrogen three times. Glutaric anhydride (2.0399 g, 1.2 eq) dissolved in 50 mL of ultra-dry dichloromethane was added dropwise via a constant pressure dropping funnel. The mixture was allowed to react overnight at room temperature, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-20% EA in PE).

[0595] 1H NMR (500MHz, CDCl3, ppm): δ5.37(m,2H), 4.09(t,2H), 2.64(m,2H), 2.43(m,2H), 2.02(m,6H), 1.62(m,2H), 1.37-1.27(m,22H), 0.88(t,3H). MS:m / z 382.1(MH + ). Chemical formula: C 23 H 42 O4.

[0596] Synthesis of compound c19 :

[0597] 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 ultra-dry dichloromethane and the atmosphere was replaced with nitrogen three times. Adipic acid (1.2561 g, 1 eq) dissolved in 50 mL of ultra-dry dichloromethane was added dropwise via a constant pressure dropping funnel. The mixture was allowed to react overnight at room temperature, washed twice with saturated sodium bicarbonate solution, twice with saturated brine, and dried over anhydrous sodium sulfate. Filtered, the solvent removed in vacuo, and the residue purified by flash column chromatography (0-20% EA in PE).

[0598] 1 H NMR (500MHz, CDCl3, ppm): δ5.37(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(MH + ). Chemical formula: C 24 H 44 O4.

[0599] Synthesis of compound c22 :

[0600] To a 50ml round-bottom flask, add solid sodium hydrosulfide (2.0eq, 10mmol, 0.56g) and 6ml of methanol. Stir in an ice bath at 0°C, then slowly add tetradecanoyl chloride (5mmol) dropwise via a constant pressure dropping funnel. Incubate at 0°C for 1 hour, then bring to room temperature for 2 hours. Pour the reaction into water, acidify with 1N HCl solution (10ml), and extract with 4x15ml of ethyl acetate. Combine the organic phases, wash twice with saturated brine, and dry over anhydrous magnesium sulfate. Remove the anhydrous magnesium sulfate by suction, and remove the solvent by rotary evaporation to yield a yellow oil.

[0601] 1 H NMR (500MHz, CDCl3, ppm): δ5.0 (s, 1H), 2.30 (t, 2H), 1.62 (m, 2H), 1.36-1.18 (m, 20H), 0.88 (t, 3H).

[0602] Synthesis of compound d5 :

[0603] Nonanoic acid (1.6325 g, 1 eq), N-Boc-γ-amino-1-propanol (1.9136 g, 1 eq), dicyclohexylcarbodiimide (2.0216 g, 1 eq), and 4-(dimethylamino)pyridine (0.1312 g, 0.1 eq) were dissolved sequentially in a 250 mL single-necked flask containing 50 mL of DCM and stirred thoroughly at room temperature for 18 h. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred thoroughly for 3 h. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d5.

[0604] 1 H NMR (500MHz,CDCl3,ppm):δ4.21(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.

[0605] Synthesis of compound d7 :

[0606] N-Boc-γ-aminobutyric acid (2.1604 g, 1 eq), n-octanol (1.3819 g, 1 eq), dicyclohexylcarbodiimide (2.0216 g, 1 eq), and 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred thoroughly at room temperature for 18 h. After the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred thoroughly for 3 h. After the reaction was completed, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d7.

[0607] 1 H NMR (500MHz,CDCl3,ppm):δ4.06(t,2H),2.69(t,2H),2.35(t,2H),1.80(m,2H),1.60(m,2H),1.29(m,10H),0.88(t,3H). Chemical formula: C 12 H 25 NO2.

[0608] Synthesis of compound d9 :

[0609] 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), and 4-(dimethylamino)pyridine (0.1222 g, 0.1 eq) were dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred thoroughly at room temperature for 18 h. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred thoroughly for 3 h. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d9. H NMR (500MHz,CDCl3,ppm):δ5.34(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.

[0610] Synthesis of compound d10 :

[0611] 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), and 4-(dimethylamino)pyridine (0.1299 g, 0.1 eq) were dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred thoroughly at room temperature for 18 h. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column chromatography (0-10% EA in PE). The product after column chromatography was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred thoroughly for 3 h. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d10.

[0612] 1 H NMR (500MHz,CDCl3,ppm):δ5.34(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.

[0613] Synthesis of compound d11 :

[0614] 2-Hexyldecanoic acid (1.7325 g, 1 eq), N-Boc-6-amino-1-hexanol (1.5386 g, 0.8 eq), dicyclohexylcarbodiimide (1.6506 g, 1 eq), and 4-(dimethylamino)pyridine (0.0977 g, 0.1 eq) were dissolved sequentially in a 250 mL single-necked flask containing 50 mL of DCM and stirred thoroughly at room temperature for 18 h. After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by flash column purification (0-10% EA in PE). The product after column purification was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred thoroughly for 3 h. After completion of the reaction, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d11.

[0615] 1H NMR (500MHz,CDCl3,ppm):δ4.08(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.

[0616] Synthesis of compound d12(a14) :

[0617] Boc-8-aminocaprylic acid (1.9179 g, 1.45 eq), 9-heptadecanol (1.3080 g, 1 eq), dicyclohexylcarbodiimide (1.0523 g, 1 eq), and 4-(dimethylamino)pyridine (0.0623 g, 0.1 eq) were dissolved in a 250 mL single-necked flask containing 50 mL of DCM and stirred at room temperature for 18 h. After the reaction, the solvent was removed in vacuo, and the residue was purified by flash column purification (0-10% EA in PE). The product after column purification was dissolved in 10 mL of DCM, and then 10 mL of TFA was slowly added dropwise and stirred for 3 h. After the reaction was completed, 20 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation to obtain compound d12.

[0618] 1 H NMR (500MHz,CDCl3,ppm):δ4.47(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.

[0619] Tables 1 to 8 show the four reactant structures corresponding to each lipid. Each set of reactant compositions corresponds to a set of R in formula (I). I 、R II (R II '), R III and R IV structure.

[0620] Table 1

[0621] Table 2

[0622] Table 3

[0623] Table 4

[0624] Table 5

[0625] Table 6

[0626] Table 7

[0627] Table 8

[0628] The structural formula of some of the lipids synthesized in this example is as follows:

[0629] The structural information of lipid 1-1075 synthesized in this example is as follows:

[0630] Lipid 16: 1 H NMR (500MHz, CDCl3, ppm): δ5.35(m,4H),4.91(s,1H),3.43(s,1H)3.26(t,2H),3.08(t,2 H),2.23(m,6H),2.00(s,8H),1.67(t,2H),1.47-1.29(m,49H),1.04(s,9H),0.87(t,6H). MS:m / z 770.8(M+H + ). Chemical formula: C 47 H 91 N3O3

[0631] Lipid 30: 1H NMR (500MHz, CDCl3, ppm): δ5.33(m,2H),4.23-3.92(br,1H),3.71(m,1H),3.42(m,1H),3.22(m,1H),3.08( t,1H),2.51-2.15(m,8H),1.99(m,4H),1.65(m,6H),1.51-1.18(m,38H),1.05-0.99(m,15H),0.88(m,6H). MS:m / z 677.3(M+H + ). Chemical formula: C 43 H 85 N3O2

[0632] Lipid 60: 1 H NMR (500MHz, CDCl3, ppm): δ5.33(m,2H),4.19-3.81(br,1H),3.71(br,1H),3.42(br,1H),3.22(br,1H),3.06 (br,1H),2.64(m,2H),2.30(m,10H),2.26(m,1H),2.14(t,3H),2.00(m,4H),1.51-1.18(m,52H),0.87(t,6H). MS:m / z 715.8(M+H + ). Chemical formula: C 45 H 86 N4O2

[0633] Lipid 108: 1 H NMR (500MHz, CDCl3, ppm): δ5.35(m,6H),4.18(br,1H),4.04(m,2H),3.76(br,1H),3.40(br,1H),3.24(br,1H),3.08(br,1H),2 .77(m,2H),2.69(m,4H),2.32(s,2H),2.23(m,6H),2.00(s,8H),1.71(br,2H),1.67(t,2H),1.51-1.18(m,45H),0.87(m,12H). MS:m / z 828.9(M+H + ). Chemical formula: C 52 H 97 N3O4

[0634] Lipid 113: 1H NMR (500MHz, CDCl3, ppm): δ5.35(m,2H),4.18(br,1H),4.04(m,2H),3.76(br,1H),3.40(br,1H),3.24(br,1H),3.08(br,1H),3 .01(m,4H),2.69(m,4H),2.32(s,2H),2.00(s,4H),1.71(br,2H),1.67(t,2H),1.51-1.18(m,45H),1.15(t,6H),0.87(m,12H). MS:m / z 762.9(M+H + ). Chemical formula: C 47 H 91 N3O4

[0635] Lipid 157: 1 H NMR (500MHz, CDCl3, ppm): δ5.39-5.31(m,10H),4.36-3.95(br,1H),3.76(br,1H),3.40(br,1H),3.24(br,1H),3.08(br,1H),2.8 4(m,8H),2.63-2.14(m,10H),2.03(m,4H),1.71(br,2H),1.67(m,2H),1.52-1.17(m,24H),1.03(s,9H),0.97(m,3H),0.86(m,3H). MS:m / z 697.2(M+H + ). Chemical formula: C 45 H 81 N3O2

[0636] Lipid 158: 1 H NMR (500MHz, CDCl3, ppm): δ4.53-3.92(br,1H),3.71(m,1H),3.42(m,1H),3.22(m,1H),3.08(m, 1H),2.63-2.14(m,8H),1.66(m,2H),1.51-1.18(m,42H),1.03(s,9H),0.97(m,6H),0.87(m,6H). MS:m / z 623.1(M+H + ). Chemical formula: C 39 H 79 N3O2

[0637] Lipid 159: 1H NMR (500MHz, CDCl3, ppm): δ4.53-3.92(br,1H),3.71(m,1H),3.42(m,1H),3.22(m,1H),3.08(m, 1H),2.63-2.14(m,8H),1.66(m,2H),1.51-1.18(m,46H),1.03(s,9H),0.97(m,6H),0.87(m,6H). MS:m / z 651.1(M+H + ). Chemical formula: C 41 H 83 N3O2

[0638] Lipid 160: 1 H NMR (500MHz, CDCl3, ppm): δ5.35(m,4H),4.56-3.93(br,1H),3.76(br,1H),3.40(br,1H),3.24(br,1H),3.08(br,1H), 2.79(m,2H),2.63-2.14(m,8H),2.03(m,4H),1.67(m,2H),1.58-1.13(m,40H),1.03(s,9H),0.97(m,6H),0.87(t,6H). MS:m / z 703.2(M+H + ). Chemical formula: C 45 H 87 N3O2

[0639] Lipid 161: 1 H NMR (500MHz, CDCl3, ppm): δ5.35(m,2H),4.88(br,1H),3.76(br,1H),3.61(br,1H),3.40(br,1H),3.24(br,1H),3.08(br,1H) ,2.60(m,4H),2.42(m,2H),2.32(s,2H),2.00(m,4H),1.67(t,2H),1.51-1.18(m,44H),1.12(m,6H),1.03(s,9H),0.87(t,6H). MS:m / z 720.8(M+H + ). Chemical formula: C 45 H 89 N3O3

[0640] Lipid 162: 1H NMR (500MHz, CDCl3, ppm): δ5.39-5.31(m,10H),4.36-3.95(br,1H),3.76(br,1H),3.40(br,1H),3.24(br,1H),3.08(br,1H),2.8 4(m,8H),2.63-2.14(m,8H),2.04(m,4H),1.71(br,2H),1.67(m,2H),1.52-1.17(m,24H),1.03(s,9H),0.97(m,9H),0.86(m,3H). MS:m / z 725.2(M+H + ). Chemical formula: C 47 H 85 N3O2

[0641] Lipid 163: 1 H NMR (500MHz, CDCl3, ppm): δ4.32(br,1H),4.13(t,2H),3.71(br,1H),3.42(br,1H),3.22(br,1H),3.08(b r,1H),2.32(m,4H),2.23(m,6H),2.05(t,2H),1.67(m,8H),1.51-1.18(m,26H),1.04(s,9H),0.87(t,6H). MS:m / z 596.1(M+H + ). Chemical formula: C 35 H 69 N3O4

[0642] Lipid 166: 1 H NMR (500MHz, CDCl3, ppm): δ5.35(m,2H),4.32(br,1H),4.13(t,2H),3.71(br,1H),3.53(s,1H),3.42(br,1H),3.22(br ,1H),3.08(br,1H),2.77(t,2H),2.23(m,6H),2.00(m,4H),1.67(m,2H),1.51-1.18(m,40H),1.04(s,9H),0.87(t,6H). MS:m / z 694.6(M+H + ). Chemical formula: C 41 H 79 N3O5

[0643] Lipid 170: 11H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 4H), 4.32 (br, 1H), 4.13 (t, 2H), 3.71 (br, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 3.00 (m, 4H), 2.77 (t, 2H), 2.00 (m, 4H), 1.67 (m, 8H), 1.51 - 1.18 (m, 36H), 1.04 (s, 9H), 0.87 (t, 6H). MS: m / z 704.6 (M + H + ). Chemical formula: C 43 H 81 N3O4

[0644] Lipid 173: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.32 (m, 4H), 2.23 (m, 6H), 2.05 (t, 2H), 1.67 (m, 8H), 1.​​​​​​​​​​​​​​​​​​​​​1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 4H), 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.77 (t, 2H), 2.23 (m, 6H), 2.00 (m, 4H), 1.67 (m, 8H), 1.51 - 1.18 (m, 52H), 1.04 (s, 9H), 0.87 (t, 9H). MS: m / z 858.9 (M + H + ). Chemical formula: C 54 H 103 N3O4

[0647] Lipid 176: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.53 (s, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.77 (t, 2H), 2.23 (m, 6H), 2.00 (m, 4H), 1.67 (m, 2H), 1.51 - 1.18 (m, 62H), 1.04 (s, 9H), 0.87 (t, 9H). MS: m / z 877.1 (M + H + ). Chemical formula: C 54 H 105 N3O5

[0648] Lipid 177: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 10H), 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.74 (m, 8H), 2.23 (m, 6H), 2.00 (m, 4H), 1.67 (m, 6H), 1.51 - 1.18 (m, 40H), 1.04 (s, 9H), 0.87 (t, 9H). MS: m / z 881.1 (M + H + ). Chemical formula: C 56 H 101 N3O4

[0649] Lipid 178: 11H NMR (500 MHz, CDCl3, ppm): δ 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 3.00 (m, 4H), 2.32 (m, 4H), 2.05 (t, 2H), 1.67 (m, 8H), 1.51 - 1.18 (m, 54H), 1.04 (s, 9H), 0.87 (t, 9H). MS: m / z 807.1 (M + H + ). Chemical formula: C 50 H 99 N3O4

[0650] Lipid 179: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 3.00 (m, 4H), 2.32 (m, 4H), 2.05 (t, 2H), 1.67 (m, 8H), 1.51 - 1.18 (m, 56H), 1.04 (s, 9H), 0.87 (t, 9H). MS: m / z 835.1 (M + H + ). Chemical formula: C<​​​​​​​​​​​​​​​​​​1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.53 (s, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 3.00 (m, 4H), 2.77 (t, 2H), 2.00 (m, 4H), 1.67 (m, 2H), 1.51 - 1.18 (m, 68H), 1.04 (s, 9H), 0.87 (t, 9H). MS: m / z 905.1 (M + H + ). Chemical formula: C 56 H 109 N3O5

[0653] Lipid 182: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 10H), 4.86 (m, 2H), 4.13 (t, 2H), 3.71 (br, 1H), 3.42 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 3.00 (m, 4H), 2.74 (m, 8H), 2.00 (m, 4H), 1.67 (m, 6H), 1.51 - 1.18 (m, 46H), 1.04 (s, 9H), 0.87 (t, 9H). MS: m / z 909.1 (M + H + ). Chemical formula: C 58 H 105 N3O4

[0654] Lipid 188: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.24 (br, 1H), 3.73 - 3.05 (br, 6H), 2.62 - 2.11 (m, 9H), 1.76 - 1.53 (m, 6H), 1.43 - 1.18 (m, 34H), 1.04 (s, 9H), 0.87 (m, 6H). MS: m / z 597.1 (M + H + ). Chemical formula: C 36 H 73 N3O3

[0655] Lipid 189: 1 1H NMR (500 MHz, CDCl3, ppm): δ+ ). Chemical formula: C 38 H 77 N3O3

[0656] Lipid 194: 1 H NMR (500MHz, CDCl3, ppm): δ4.24(br,1H), 3.73-3.05(br,6H), 2.62-2.11(m,9H), 1.76-1.53(m,4H), 1.43-1.18(m,42H), 1.04(s,9H), 0.87(t,6H). MS:m / z 639.1(M+H + ). Chemical formula: C 39 H 79 N3O3

[0657] Lipid 195: 1 H NMR (500MHz, CDCl3, ppm): δ5.34 (m, 4H), 4.24 (br, 1H), 3.73-3.05 (br, 6H), 2.83-2.11 ( m,11H),2.03(m,4H),1.76-1.53(m,8H),1.43-1.18(m,32H),1.04(s,9H),0.87(t,6H). MS:m / z 691.2(M+H + ). Chemical formula: C 43 H 83 N3O3

[0658] Lipid 223: 1 H NMR (500MHz, CDCl3, ppm): δ5.35(m,2H),4.13(br,1H),4.05(m,4H),3.72(br,1H),3.42(br,1H),3.30(br,1H),3.17(br,1H),2.55( m,4H),2.39(m,2H),2.31(m,2H),2.24(m,6H),2.02(m,4H),1.82(m,2H),1.61(m,6H),1.51-1.18(m,32H),1.02(s,9H),0.88(t,6H). MS:m / z 764.8(M+H + ). Chemical formula: C 45 H 85 N3O6

[0659] Lipid 226: 11H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.16 (br, 1H), 4.05 (m, 4H), 3.73 (br, 1H), 3.40 (br, 1H), 3.30 (br, 1H), 3.16 (br, 1H), 2.69 (m, 4H), 2.66 (m, 4H), 2.58 (m, 2H), 2.53 (m, 2H), 2.32 (t, 2H), 2.02 (m, 4H), 1.82 (m, 2H), 1.61 (m, 4H), 1.51 - 1.18 (m, 32H), 1.11 (m, 6H), 1.06 (s, 9H), 0.88 (t, 6H). MS: m / z 792.8 (M + H + ). Chemical formula: C 47 H 89 N3O6

[0660] Lipid 227: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.13 (br, 1H), 4.05 (m, 4H), 3.70 (br, 1H), 3.41 (br, 1H), 3.34 (br, 1H), 3.14 (br, 1H), 2.83 (m, 2H), 2.61 (m, 6H), 2.39 (m, 2H), 2.32 (m, 2H), 2.02 (m, 4H), 1.91 (m, 2H), 1.82 (m, 2H), 1.61 (m, 6H), 1.51 - 1.18 (m, 32H), 1.11 (m, 6H), 1.06 (s, 9H), 0.88 (t, 6H). MS: m / z 806.9 (M + H + ). Chemical formula: C 48 H 91 N3O6

[0661] Lipid 229: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.16 (br, 1H), 4.05 (m, 4H), 3.94 (m, 2H), 3.38 (br, 1H), 3.27 (br, 1H), 3.03 (br, 1H), 2.95 (br, 1H), 2.83 (m, 2H), 2.74 (m, 2H), 2.68 (m, 4H), 2.44 (m, 2H), 2.02 (m, 4H), 1.97 (m, 3H), 1.87 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 36H), 1.11 (s, 9H), 0.88 (t, 6H). MS: m / z 822.9 (M + H + ). Chemical formula: C48 H 91 N3O7

[0662] Lipid 230: 1 H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.16 (br, 1H), 4.05 (m, 4H), 3.90 (m, 2H), 3.39 (br, 1H), 3.26 (br, 1H), 3.03 (br, 1H), 2.97 (br, 1H), 2.83 (m, 2H), 2.74 (m, 2H), 2.69 (m, 2H), 2.44 (m, 2H), 2.35 (m, 2H), 2.12 (m, 2H), 2.02 (m, 4H), 1.95 (m, 3H), 1.87 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 36H), 1.11 (s, 9H), 0.88 (t, 6H). MS: m / z 836.9 (M + H + ). Chemical formula: C 49 H 93 N3O7

[0663] Lipid 232: 1 H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.86 (m, 1H), 4.17 (br, 1H), 4.06 (m, 2H), 3.76 (br, 1H), 3.41 (br, 1H), 3.27 (br, 1H), 3.08 (br, 2H), 2.70 (m, 4H), 2.34 (m, 2H), 2.32 (m, 2H), 2.26 (m, 6H), 2.02 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 58H), 1.05 (s, 9H), 0.88 (t, 9H). MS: m / z 947.1 (M + H + ). Chemical formula: C 58 H 111 N3O6

[0664] Lipid 233: 11H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.86 (m, 1H), 4.13 (br, 1H), 4.06 (m, 2H), 3.71 (br, 1H), 3.41 (br, 1H), 3.27 (br, 1H), 3.07 (br, 1H), 2.54 (m, 2H), 2.40 (m, 4H), 2.27 (m, 4H), 2.24 (m, 6H), 2.01 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 60H), 1.04 (s, 9H), 0.88 (t, 9H). MS: m / z 961.2 (M + H + ). Chemical formula: C 59 H 113 N3O6

[0665] Lipid 234: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.86 (m, 1H), 4.16 (br, 1H), 3.72 (br, 1H), 3.45 (br, 1H), 3.26 (br, 1H), 3.07 (br, 1H), 2.47 (m, 2H), 2.39 (m, 2H), 2.30 (m, 6H), 2.27 (m, 2H), 1.66 (m, 2H), 1.60 (m, 2H), 1.51 - 1.18 (m, 54H), 1.03 (s, 9H), 0.88 (t, 9H). MS: m / z 778.9 (M + H + ). Chemical formula: C 48 H 95 N3O4

[0666] Lipid 235: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.86 (m, 1H), 4.16 (br, 1H), 4.05 (m, 2H), 3.74 (br, 1H), 3.41 (br, 1H), 3.26 (br, 1H), 3.07 (br, 1H), 2.70 (m, 4H), 2.61 (m, 4H), 2.51 (m, 2H), 2.26 (m, 2H), 2.02 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 60H), 1.12 (m, 6H), 1.04 (s, 9H), 0.88 (t, 9H). MS: m / z 975.2 (M + H + ). Chemical formula: C 60 H 115 N3O6

[0667] Lipid 236: 11H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.86 (m, 1H), 4.13 (br, 1H), 4.05 (m, 2H), 3.69 (br, 1H), 3.42 (br, 1H), 3.27 (br, 1H), 3.06 (br, 1H), 2.70 (m, 4H), 2.57 (m, 2H), 2.51 (m, 2H), 2.44 (m, 2H), 2.39 (m, 2H), 2.27 (m, 2H), 2.02 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 60H), 1.12 (m, 6H), 1.04 (s, 9H), 0.88 (t, 9H). MS: m / z 989.2 (M + H + ). Chemical formula: C 61 H 117 N3O6

[0668] Lipid 237: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.86 (m, 1H), 4.13 (br, 1H), 3.72 (br, 1H), 3.45 (br, 1H), 3.24 (br, 1H), 3.07 (br, 1H), 2.56 (m, 4H), 2.42 (m, 2H), 2.30 (m, 2H), 2.24 (m, 2H), 1.80 (m, 2H), 1.66 (m, 2H), 1.61 (m, 2H), 1.51 - 1.18 (m, 52H), 1.12 (m, 6H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 806.9 (M + H + ). Chemical formula: C 50 H 99 N3O4

[0669] Lipid 238: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.86 (m, 1H), 4.16 (br, 1H), 4.05 (m, 2H), 3.92 (m, 2H), 3.39 (br, 1H), 3.26 (br, 1H), 3.03 (br, 1H), 2.97 (br, 1H), 2.83 (m, 2H), 2.72 (m, 2H), 2.68 (m, 4H), 2.45 (m, 2H), 2.02 (m, 4H), 1.98 (m, 3H), 1.86 (m, 4H), 1.62 (m, 4H), 1.51 - 1.18 (m, 60H), 1.12 (s, 9H), 0.88 (t, 9H). MS: m / z 1005.2 (M + H + ). Chemical formula: C61 H 117 N3O7

[0670] Lipid 239: 1 H NMR (500MHz, CDCl3, ppm): δ5.34(m,2H),4.85(m,1H),4.13(br,1H),4.05(m ,2H),3.94(m,2H),3.35(br,1H),3.13(br,1H),2.97(br,1H),2.90(br,1H), 2.70(m,4H),2.40(m,2H),2.27(m,4H),2.11(m,2H),2.02(m,4H),1.95(m,3 H),1.61(m,4H),1.51(m,2H),1.49-1.18(m,60H),1.06(s,9H),0.88(t,9H). MS:m / z 1019.2(M+H + ). Chemical formula: C 62 H 119 N3O7

[0671] Lipid 240: 1 H NMR (500MHz, CDCl3, ppm): δ4.86(m,1H),4.16(br,1H),3.93(m,2H),3.71(br,1H),3.45(br,1H),3.28(br,1H),3.04(br,1H), 2.82(m,2H),2.73(m,2H),2.43(m,2H),2.30(m,2H),1.98(m,3H),1.62(m,6H),1.51-1.18(m,56H),1.12(s,9H),0.88(t,9H). MS:m / z 836.9(M+H + ). Chemical formula: C 51 H 101 N3O5

[0672] Lipid 241: 11H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.16 (br, 1H), 4.10 (m, 2H), 4.06 (m, 2H), 3.73 (br, 1H), 3.44 (br, 1H), 3.25 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.38 (m, 2H), 2.29 (m, 1H), 2.24 (m, 6H), 2.02 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 905.1 (M + H + ). Chemical formula: C 55 H 105 N3O6

[0673] Lipid 242: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.16 (br, 1H), 4.10 (m, 2H), 4.06 (m, 2H), 3.73 (br, 1H), 3.45 (br, 1H), 3.25 (br, 1H), 3.08 (br, 1H), 2.72 (m, 2H), 2.58 (m, 2H), 2.38 (m, 2H), 2.29 (m, 1H), 2.24 (m, 6H), 2.12 (m, 2H), 2.02 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 919.1 (M + H + ). Chemical formula: C 56 H 107 N3O6

[0674] Lipid 243: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 736.8 (M + H + ). Chemical formula: C 45 H89 N3O4

[0675] Lipid 244: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.16 (br, 1H), 4.10 (m, 2H), 4.06 (m, 2H), 3.73 (br, 1H), 3.44 (br, 1H), 3.25 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.60 (m, 4H), 2.38 (m, 2H), 2.29 (m, 1H), 2.02 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 48H), 1.12 (t, 6H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 933.1 (M+H + )。Chemical formula: C 57 H 109 N3O6

[0676] Lipid 245: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 2H), 4.16 (br, 1H), 4.10 (m, 2H), 4.06 (m, 2H), 3.73 (br, 1H), 3.44 (br, 1H), 3.26 (br, 1H), 3.08 (br, 1H), 2.72 (m, 2H), 2.60 (m, 4H), 2.54 (m, 2H), 2.38 (m, 2H), 2.29 (m, 1H), 2.12 (m, 2H), 2.02 (m, 4H), 1.81 (m, 2H), 1.72 (m, 4H), 1.61 (m, 4H), 1.51 - 1.18 (m, 48H), 1.12 (t, 6H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 947.1 (M+H + )。Chemical formula: C 58 H 111 N3O6

[0677] Lipid 246: 11H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.60 (m, 4H), 2.44 (m, 2H), 2.27 (m, 1H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.12 (t, 6H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 764.9 (M + H + ). Chemical formula: C 47 H 93 N3O4

[0678] Lipid 284: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 764.9 (M + H + ). Chemical formula: C 47 H 93 N3O4

[0679] Lipid 285: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 4H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.77 (t, 2H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H) 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 40H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 816.9 (M + H + ). Chemical formula: C 51 H 97 N3O4

[0680] Lipid 286: 1 H NMR(500MHz, CDCl3, ppm): δ5.34(m, 2H), 4.13(br, 1Η), 4.05(m, 2H), 3.73(br, 1Η), 3.53(s, 1H), 3.47(br, 1Η), 3.22(br, 1Η), 3.08(br, 1H), 2.45(m, 2H), 2.28(m, 1H), 2.24(m, 6H), 2.18(m, 2H), 2.00(m, 4H), 1.80(m, 2H), 1.72(m, 4H), 1.60(m, 4H), 1.51 - 1.18(m, 46H), 1.02(s, 9H), 0.88(t, 9H). MS: m / z 834.9(M + H + ). Chemical formula: C 51 H 99 N3O5<00039,12><00039,13>Lipid 287: 1 H NMR(500MHz, CDCl3, ppm): δ5.34(m, 10H), 4.13(br, 1Η), 4.05(m, 2H), 3.73(br, 1Η), 3.47(br, 1Η), 3.22(br, 1Η), 3.08(br, 1H), 2.74(m, 8H), 2.45(m, 2H), 2.28(m, 1H), 2.24(m, 6H), 2.18(m, 2H), 2.00(m, 4H), 1.80(m, 2H), 1.72(m, 4H), 1.60(m, 4H), 1.51 - 1.18(m, 26H), 1.02(s, 9H), 0.88(t, 9H). MS: m / z 838.9(M + H + ). Chemical formula: C 53 H 95 N3O4<00039,14> <00039,15>Lipid 292: 1 H NMR(500MHz, CDCl3, ppm): δ4.13(br, 1Η), 4.05(m, 2H), 3.73(br, 1Η), 3.47(br, 1Η), 3.22(br, 1Η), 3.08(br, 1H), 2.60(m, 4H), 2.44(m, 2H), 2.27(m, 1H), 2.18(m, 2H), 1.80(m, 2H), 1.72(m, 4H), 1.60(m, 4H), 1.51 - 1.18(m, 46H), 1.12(t, 6H), 1.02(s, 9H), 0.88(t, 9H). MS: m / z 792.9(M + H + ). Chemical formula: C49 H 97 N3O4

[0683] Lipid 293: 1 H NMR (500 MHz, CDCl3, ppm): δ 5.35 (m, 4H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.77 (t, 2H), 2.60 (m, 4H), 2.45 (m, 2H), 2.28 (m, 1H), 2.18 (m, 2H), 2.00 (m, 4H) 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 40H), 1.12 (t, 6H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 845.0 (M + H + ). Chemical formula: C 53 H 101 N3O4

[0684] Lipid 294: 1 H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.53 (s, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.60 (m, 4H), 2.45 (m, 2H), 2.28 (m, 1H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 54H), 1.12 (t, 6H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 863.1 (M + H + ). Chemical formula: C 53 H 103 N3O5

[0685] Lipid 295: 1H NMR (500MHz, CDCl3, ppm): δ5.34(m,10H),4.13(br,1H),4.05(m,2H),3.73( br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.74(m,8H),2.60(m,4H) ,2.45(m,2H),2.28(m,1H),2.18(m,2H),2.00(m,4H),1.80(m,2H),1.72(m,4 H),1.60(m,4H),1.51-1.18(m,26H),1.12(t,6H),1.02(s,9H),0.88(t,9H). MS:m / z 867.0(M+H + ). Chemical formula: C 55 H 99 N3O4

[0686] Lipid 304: 1 H NMR(500MHz, CDCl3,ppm):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

[0687] Lipid 314: 1 H NMR (500MHz, CDCl3, ppm): δ7.94-7.57(m,5H),5.34(m,4H),4.15(br,1H),4.06(m,2H),3.67(br,1H),3.58(br,2H) ,3.09(br,1H),2.32(m,4H),2.23(m,6H),2.17(m,2H),2.00(m,8H),1.67(m,8H),1.51-1.18(m,40H),0.87(t,6H). MS:m / z 839.1(M+H + ). Chemical formula: C 52 H 91 N3O3S

[0688] Lipid 315: 1H NMR (500MHz, CDCl3, ppm): δ5.34(m,4H),4.15(br,1H),4.06(m,2H),3.67(br,1H),3.58(br,2H),3.09(br ,1H),2.32(m,7H),2.23(m,6H),2.17(m,2H),2.00(m,8H),1.67(m,8H),1.51-1.18(m,40H),0.87(t,6H). MS:m / z 777.1(M+H + ). Chemical formula: C 47 H 89 N3O3S

[0689] Lipid 316: 1 H NMR (500MHz, CDCl3, ppm): δ5.34(m,2H),4.15(s,1H),3.67(br,1H),3.58(br,2H),3.09(br,1H),2 .32(m,4H),2.23(m,6H),2.00(m,4H),1.67(m,8H),1.51-1.18(m,40H),1.16(s,9H),0.87(t,6H). MS:m / z 692.8(M+H + ). Chemical formula: C 43 H 85 N3OS

[0690] Lipid 317: 1 H NMR (500MHz, CDCl3, ppm): δ4.86(m,1H),4.15(s,1H),3.67(br,1H),3.58(br,2H),3.09(br,1H),2 .32(m,4H),2.23(m,6H),2.05(t,2H),1.67(m,8H),1.51-1.18(m,54H),1.16(s,9H),0.87(t,9H). MS:m / z 823.1(M+H + ). Chemical formula: C 50 H 99 N3O3S

[0691] Lipid 401: 1H NMR (500MHz, CDCl3, ppm): δ5.90(m,1H),4.89(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,6H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,46H),1.02(s,9H),0.88(t,12H).MS:m / z 822.7. Chemical formula: C49H95N3O6

[0692] Lipid 402: 1 H NMR (500MHz, CDCl3, ppm): δ5.90(m,1H),4.89(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,6H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0693] Lipid 403: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6 H),2.24(m,2H),2.09(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,46H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 808.7. Chemical formula: C48H93N3O6

[0694] Lipid 404: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,12H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0695] Lipid 405: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0696] Lipid 406: 1 H NMR (500MHz, CDCl3, ppm): δ5.88(m,1H),4.80(m,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,6H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,50H),1.02(s,9H),0.88(t,12H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0697] Lipid 407: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(s,9H),0.88(t,12H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0698] Lipid 408: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,72H),1.02(s,9H),0.88(t,12H).MS:m / z 976.7. Chemical formula: C60H117N3O6

[0699] Lipid 409: 1 H NMR (500MHz, CDCl3, ppm): δ4.85(m,2H),3.93(m,1H),3.84(m,1H),3.73(br,1H),3.49(br,1H),3.26(br,1H),3.07(br,1H),2 .45(m,6H),2.24(m,2H),2.09(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(s,9H),0.88(m,12H).MS: m / z878.7. Chemical formula: C53H103N3O6

[0700] Lipid 410: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0701] Lipid 411: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1 H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.24(m,2H),1.89(m,1H),1.72(m, 6H),1.60(m,2H),1.51-1.18(m,68H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0702] Lipid 412: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0703] Lipid 413: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0704] Lipid 414: 1 H NMR (500MHz, CDCl3, ppm): δ4.86(m,2H),3.73(br,1H),3.64(s,1H),3.43(br,1H),3.25(br,1H),3.06( br,1H),2.45(m,6H),2.24(m,6H),1.60(m,6H),1.51-1.18(m,74H),1.02(s,9H),0.88(t,12H).MS:m / z 1004.7. Chemical formula: C62H121N3O6

[0705] Lipid 415: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6 H),2.24(m,2H),2.09(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0706] Lipid 416: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,70H),1.02(s,9H),0.88(t,12H).MS:m / z 976.7. Chemical formula: C60H117N3O6

[0707] Lipid 417: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,72H),1.02(s,9H),0.88(t,12H).MS:m / z 990.7. Chemical formula: C61H119N3O6

[0708] Lipid 418: 1H NMR (500MHz, CDCl3, ppm): δ5.95(m,1H),4.85(m,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08( br,1H),2.45(m,6H),2.24(m,6H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0709] Lipid 419: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6 H),2.24(m,2H),2.09(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,48H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 808.7. Chemical formula: C48H93N3O6

[0710] Lipid 420: 1 H NMR (500MHz, CDCl3, ppm): δ5.88(m,1H),4.86(m,2H),3.97(m,1H),3.82(m,1H),3.69(br,1H),3.44(br,1H),3.25(br,1H),3.08( br,1H),2.45(m,6H),2.24(m,2H),2.09(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(s,9H),0.88(m,12H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0711] Lipid 421: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6 H),2.24(m,2H),2.09(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,44H),1.02(s,9H),0.88(t,6H),0.80(t,6H).MS:m / z 794.7. Chemical formula: C47H91N3O6

[0712] Lipid 422: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.2 4(m,2H),2.09(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,54H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0713] Lipid 423: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.2 4(m,2H),2.09(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0714] Lipid 424: 1H NMR (500MHz, CDCl3, ppm): δ5.88(m,1H),4.89(m,1H),4.05(t,2H),3.97(m,1H),3.82(m,1H),3.69(br,1H),3.44(br,1H),3.25(br,1H),3.08( br,1H),2.45(m,6H),2.24(m,2H),2.13(m,1H),2.09(m,1H),1.72(m,6 H),1.60(m,2H),1.51-1.18(m,50H),1.02(s,9H),0.88(m,12H).MS:m / z 850.7. Chemical formula: C51H99N3O6

[0715] Lipid 425: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,54H),1.02(s,9H),0.88(t,12H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0716] Lipid 426: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0717] Lipid 427: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 2.09 (m, 1H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H), 0.80 (t, 3H). MS: m / z 850.7. Chemical formula: C51H99N3O6

[0718] Lipid 428: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 60H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 920.7. Chemical formula: C56H109N3O6

[0719] Lipid 429: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 62H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 934.7. Chemical formula: C57H111N3O6

[0720] Lipid 430: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0721] Lipid 431: 1 H NMR (500MHz, CDCl3, ppm): δ4.85(m,2H),3.93(m,1H),3.84(m,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0722] Lipid 432: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,70H),1.02(s,9H),0.88(t,12H).MS:m / z 976.7. Chemical formula: C60H117N3O6

[0723] Lipid 433: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.2 4(m,2H),2.09(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,54H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0724] Lipid 434: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0725] Lipid 435: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0726] Lipid 436: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0727] Lipid 437: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(s,9H),0.88(t,12H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0728] Lipid 438: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,72H),1.02(s,9H),0.88(t,12H).MS:m / z 990.7. Chemical formula: C61H119N3O6

[0729] Lipid 439: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 2.09 (m, 1H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 56H), 1.02 (s, 9H), 0.88 (t, 9H), 0.80 (t, 3H). MS: m / z 892.7. Chemical formula: C54H105N3O6

[0730] Lipid 440: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 66H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 962.7. Chemical formula: C59H115N3O6

[0731] Lipid 441: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 68H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 976.7. Chemical formula: C60H117N3O6

[0732] Lipid 442: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0733] Lipid 443: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,12H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0734] Lipid 444: 1 H NMR (500MHz, CDCl3, ppm): δ5.95(m,1H),4.85(m,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08( br,1H),2.45(m,6H),2.24(m,6H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0735] Lipid 445: 1H NMR (500MHz, CDCl3, ppm): δ4.05(t,2H),3.97(d,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2 .45(m,1H),2.29(t,4H),2.21(s,6H),1.76-1.55(m,13H),1.51-1.18(m,46H),1.02(s,9H),0.88(m,12H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0736] Lipid 446: 1 H NMR (500MHz, CDCl3, ppm): δ4.05(t,2H),3.97(d,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2 .45(m,1H),2.29(t,4H),2.21(s,6H),1.76-1.55(m,13H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0737] Lipid 447: 1 H NMR (500MHz, CDCl3, ppm): δ4.05(t,2H),3.97(d,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2 .45(m,1H),2.29(t,4H),2.21(s,6H),1.76-1.55(m,13H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0738] Lipid 448: 1 H NMR (500MHz, CDCl3, ppm): δ5.95(m,1H),4.05(m,4H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45 (m,6H),2.24(m,2H),2.13(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0739] Lipid 577: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0740] Lipid 578: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(m,12H),0.88(t,9H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0741] Lipid 579: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,70H),1.02(s,9H),0.88(t,12H).MS:m / z 976.7. Chemical formula: C60H117N3O6

[0742] Lipid 580: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(s,9H),0.88(t,12H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0743] Lipid 581: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0744] Lipid 582: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,68H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0745] Lipid 583: 1 H NMR (500MHz, CDCl3, ppm): δ4.86(m,2H),4.00(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br, 1H),2.45(m,6H),2.24(m,2H),1.76-1.55(m,17H),1.51-1.18(m,54H),1.02(s,9H),0.88(t,12H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0746] Lipid 584: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,52H),1.02(m,15H),0.88(t,6H).MS:m / z 836.7. Chemical formula: C50H97N3O6

[0747] Lipid 585: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,68H),1.02(m,12H),0.88(t,9H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0748] Lipid 586: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(m,12H),0.88(t,9H).MS:m / z 850.7. Chemical formula: C51H99N3O6

[0749] Lipid 587: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(m,12H),0.88(t,9H).MS:m / z 822.7. Chemical formula: C49H95N3O6

[0750] Lipid 588: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(m,12H),0.88(t,9H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0751] Lipid 589: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,74H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0752] Lipid 590: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(m,12H),0.88(t,9H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0753] Lipid 591: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,80H),1.02(s,9H),0.88(t,12H).MS:m / z 1004.7. Chemical formula: C62H121N3O6

[0754] Lipid 592: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,70H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0755] Lipid 593: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,68H),1.02(s,9H),0.88(t,12H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0756] Lipid 594: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,78H),1.02(s,9H),0.88(t,12H).MS:m / z 976.7. Chemical formula: C60H117N3O6

[0757] Lipid 595: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.11(m,2H),3.73(br,1H),3.37(br,2H),3.08(br,1H),2.30(m,3H) ,2.24(m,6H),1.84(m,4H),1.67(m,6H),1.54(m,4H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0758] Lipid 596: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,4H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(m,12H),0.88(t,9H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0759] Lipid 597: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,4H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,76H),1.02(s,9H),0.88(t,12H).MS:m / z 990.7. Chemical formula: C61H119N3O6

[0760] Lipid 598: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.11(m,2H),3.73(br,1H),3.37(br,2H),3.08(br,1H),2.30(m,3H) ,2.24(m,6H),1.84(m,4H),1.67(m,6H),1.54(m,4H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0761] Lipid 599: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,4H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0762] Lipid 600: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,4H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,74H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0763] Lipid 601: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45 (m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,72H),1.02(s,9H),0.88(t,12H).MS:m / z 976.7. Chemical formula: C60H117N3O6

[0764] Lipid 602: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6 H),2.24(m,2H),2.09(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,54H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0765] Lipid 603: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0766] Lipid 604: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0767] Lipid 605: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,68H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0768] Lipid 606: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0769] Lipid 607: 1 H NMR (500MHz, CDCl3, ppm): δ4.86(m,2H),4.00(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br, 1H),2.45(m,6H),2.24(m,2H),1.76-1.55(m,17H),1.51-1.18(m,62H),1.02(m,12H),0.88(t,9H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0770] Lipid 608: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 2.09 (m, 1H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 52H), 1.02 (m, 12H), 0.88 (t, 6H), 0.80 (t, 3H). MS: m / z 808.7. Chemical formula: C48H93N3O6

[0771] Lipid 609: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 60H), 1.02 (m, 12H), 0.88 (t, 9H). MS: m / z 864.7. Chemical formula: C52H101N3O6

[0772] Lipid 610: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 64H), 1.02 (m, 12H), 0.88 (t, 9H). MS: m / z 892.7. Chemical formula: C54H105N3O6

[0773] Lipid 611: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(m,12H),0.88(t,9H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0774] Lipid 612: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.02(m,12H),0.88(t,9H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0775] Lipid 613: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1 H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.24(m,2H),1.89(m,1H),1.72(m, 6H),1.60(m,2H),1.51-1.18(m,82H),1.02(s,9H),0.88(t,12H).MS:m / z 1004.7. Chemical formula: C62H12N3O6

[0776] Lipid 614: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.2 4(m,2H),2.09(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0777] Lipid 615: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,72H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0778] Lipid 616: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,76H),1.02(s,9H),0.88(t,12H).MS:m / z 976.7. Chemical formula: C60H117N3O6

[0779] Lipid 617: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,78H),1.02(s,9H),0.88(t,12H).MS:m / z 990.7. Chemical formula: C61H119N3O6

[0780] Lipid 618: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,74H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0781] Lipid 619: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,4H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,78H),1.02(s,9H),0.88(t,12H).MS:m / z 990.7. Chemical formula: C61H119N3O6

[0782] Lipid 620: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 4H), 2.09 (m, 1H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 60H), 1.02 (s, 9H), 0.88 (t, 9H), 0.80 (t, 3H). MS: m / z 878.7. Chemical formula: C53H103N3O6

[0783] Lipid 621: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 4H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 68H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 934.7. Chemical formula: C57H111N3O6

[0784] Lipid 622: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 4H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 72H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 962.7. Chemical formula: C59H115N3O6

[0785] Lipid 623: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 4H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 74H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 976.7. Chemical formula: C60H117N3O6

[0786] Lipid 624: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 4H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 4H), 2.13 (m, 1H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 70H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 948.7. Chemical formula: C58H113N3O6

[0787] Lipid 625: 1 1H NMR (�00 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 36H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 694.7. Chemical formula: C42H83N3O4

[0788] Lipid 626: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 778.7. Chemical formula: C48H95N3O4

[0789] Lipid 627: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.09 (m, 1H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 34H), 1.02 (s, 9H), 0.88 (t, 6H), 0.80 (t, ۳H). MS: m / z 680.7. Chemical formula: C41H81N3O4

[0790] Lipid 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 44H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 750.7. Chemical formula: C46H91N3O4

[0791] Lipid 629: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 764.7. Chemical formula: C47H93N3O4

[0792] Lipid 630: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 736.7. Chemical formula: C45H89N3O4

[0793] Lipid 631: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 44H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 750.7. Chemical formula: C46H91N3O4

[0794] Lipid 632: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 36H), 1.02 (m, 12H), 0.88 (t, 6H). MS: m / z 694.7. Chemical formula: C42H83N3O4

[0795] Lipid 633: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 778.7. Chemical formula: C48H95N3O4

[0796] Lipid 634: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.24 (m, 6H), 2.18 (m, 2H), 1.93 (m, 1H), 1.84 (m, 2H), 1.65 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 764.7. Chemical formula: C47H93N3O4

[0797] Lipid 635: 1 It should be noted that there is a small error in the original Chinese text where "1Η" was used instead of "1H" in some places, and this has been corrected in the translation. Also, "3H" in the translation of item should be "3H" which is a typo in the translation process and should be adjusted accordingly in a formal translation.1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 38H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 708.7. Chemical formula: C43H85N3O4

[0798] Lipid 636: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 792.7. Chemical formula: C49H97N3O4

[0799] Lipid 637: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.09 (m, 1H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 36H), 1.02 (s, 9H), 0.88 (t, 6H), 0.80 (t, 3H). MS: m / z 694.7. Chemical formula: C42H83N3O4

[0800] Lipid 638: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 764.7. Chemical formula: C47H93N3O4

[0801] Lipid 639: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 778.7. Chemical formula: C48H95N3O4

[0802] Lipid 640: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 44H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 750.7. Chemical formula: C46H91N3O4

[0803] Lipid 641: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 764.7. Chemical formula: C47H93N3O4

[0804] Lipid 642: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 38H), 1.02 (m, 12H), 0.88 (t, 6H). MS: m / z 708.7. Chemical formula: C43H85N3O4

[0805] Lipid 643: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 792.7. Chemical formula: C49H97N3O4

[0806] Lipid 644: 11H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.24 (m, 6H), 2.18 (m, 2H), 1.93 (m, 1H), 1.84 (m, 2H), 1.65 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 778.7. Chemical formula: C48H95N3O4

[0807] Lipid 645: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.90 (m, 1H), 4.81 (m, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), .80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 40H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 722.7. Chemical formula: C44H87N3O4

[0808] Lipid 646: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3. .2 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 806.7. Chemical formula: C50H99N3O4

[0809] Lipid 647: 11H NMR (500 MHz, CDCl3, ppm): δ 5.88 (m, 1H), 4.91 (m, 1H), 3.97 (m, 1H), 3.82 (m, 1H), 3.69 (br, 1H), 3.44 (br, 1H), 3.25 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.09 (m, 1H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 34H), 1.02 (s, 9H), 0.88 (m, 9H). MS: m / z 708.7. Chemical formula: C43H85N3O4

[0810] Lipid 648: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 7,78.7. Chemical formula: C48H95N3O4

[0811] Lipid 649: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 792.7. Chemical formula: C49H97N3O4

[0812] Lipid 650: 11H NMR (500 MHz, CDCl3, ppm): δ 4.13 (broad, 1H), 4.05 (multiplet, 2H), 3.73 (broad, 1H), 3.47 (broad, 1H), 3.22 (broad, 1H), 3.08 (broad, 1H), 2.45 (multiplet, 2H), 2.28 (multiplet, 1H), 2.24 (multiplet, 6H), 2.18 (multiplet, 2H), 1.80 (multiplet, 2H), 1.72 (multiplet, 4H), 1.60 (multiplet, 4H), 1.51 - 1.18 (multiplet, 46H), 1.02 (singlet, 9H), 0.88 (triplet, 9H). MS: m / z 764.7. Chemical formula: C47H93N3O4

[0813] Lipid 651: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (multiplet, 1H), 4.13 (broad, 1H), 3.73 (broad, 1H), 3.47 (broad, 1H), 3.22 (broad, 1H), 3.08 (broad, 1H), 2.45 (multiplet, 4H), 2.24 (multiplet, 6H), 2.18 (multiplet, 2H), 1.80 (multiplet, 2H), 1.72 (multiplet, 4H), 1.60 (multiplet, 4H), 1.51 - 1.18 (multiplet, 48H), 1.02 (singlet, 9H), 0.88 (triplet, 9H). MS: m / z 778.7. Chemical formula: C48H95N3O4

[0814] Lipid 652: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (multiplet, 2H), 4.13 (broad, 1H), 3.73 (broad, 1H), 3.47 (broad, 1H), 3.22 (broad, 1H), 3.08 (broad, 1H), 2.45 (multiplet, 4H), 2.24 (multiplet, 6H), 2.18 (multiplet, 2H), 1.80 (multiplet, 3H), 1.72 (multiplet, 4H), 1.60 (multiplet, 4H), 1.51 - 1.18 (multiplet, 40H), 1.02 (multiplet, 12H), 0.88 (triplet, 6H). MS: m / z 722.7. Chemical formula: C44H87N3O4

[0815] Lipid 653: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 7806.7. Chemical formula: C50H99N3O4

[0816] Lipid 654: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.24 (m, 6H), 2.18 (m, 2H), 1.93 (m, 1H), 1.84 (m, 2H), 1.65 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 764.7. Chemical formula: C49H99N3O4

[0817] Lipid 655: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 694.7. Chemical formula: C45H89N3O4

[0818] Lipid 656: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 54H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 820.7. Chemical formula: C51H101N3O4

[0819] Lipid 657: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.09 (m, 1H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 40H), 1.02 (s, 9H), 0.88 (t, 6H), 0.80 (t, 3H). MS: m / z 722.7. Chemical formula: C44H87N3O4

[0820] Lipid 658: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 792.7. Chemical formula: C49H97N3O4

[0821] Lipid 659: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 806.7. Chemical formula: C50H99N3O4

[0822] Lipid 660: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.​​​​​​​​​1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.02 (m, 12H), 0.88 (t, 6H). MS: m / z 736.7. Chemical formula: C45H89N3O4

[0825] Lipid 663: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 54H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 820.7. Chemical formula: C51H101N3O4

[0826] Lipid 664: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.24 (m, 6H), 2.18 (m, 2H), 1.93 (m, 1H), 1.84 (m, 2H), 1.65 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 806.7. Chemical formula: C50H99N3O4

[0827] Lipid 665: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 750.7. Chemical formula: C46H91N3O4

[0828] Lipid 666: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 56H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 834.7. Chemical formula: C52H103N3O4

[0829] Lipid 667: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.09 (m, 1H), 1.8 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.02 (s, 9H), 0.88 (t, 6H), 0.80 (t, 3H). MS: m / z 736. Chemistry formula: C45H89N3O4

[0830] Lipid 668: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 750.7. Chemical formula: C50H99N3O4

[0831] Lipid 669: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 54H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 820.7. Chemical formula: C51H101N3O4

[0832] Lipid 670: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 792.7. Chemical formula: C46H97N3O4

[0833] Lipid 671: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 806.7. Chemical formula: C50H99N3O4

[0834] Lipid 672: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 44H), 1.02 (m, 12H), 0.88 (t, 6H). MS: m / z 750.7. Chemical formula: C46H91N3O4

[0835] Lipid 673: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 56H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 834.7. Chemical formula: C52H103N3O4

[0836] Lipid 674, 230307 - E10: 11H NMR (500 MHz, CDCl3, ppm): δ 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.24 (m, 6H), 2.18 (m, 2H), 1.93 (m, 1H), 1.84 (m, 2H), 1.65 (m, 4H), 1.51 - 1.18 (m, 54H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 820.7. Chemical formula: C51H101N3O4

[0837] Lipid 675: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.92 (m, 1H), 5.34 (m, 2H), 4.81 (m, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 40H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 776.7. Chemical formula: C48H93N3O4

[0838] Lipid 676: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 860.7. Chemical formula: C54H105N3O4

[0839] Lipid 677: 11H NMR (500 MHz, CDCl3, ppm): δ 5.88 (m, 1H), 5.34 (m, 2H), 4.91 (m, 1H), 3.97 (m, 1H), 3.82 (m, 1H), 3.69 (br, 1H), 3.44 (br, 1H), 3.25 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.09 (m, 5H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 36H), 1.02 (s, 9H), 0.88 (m, 9H). MS: m / z 762.7. Chemical formula: C47H91N3O4

[0840] Lipid 678: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 832.7. Chemical formula: C52H101N3O4

[0841] Lipid 679: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 846.7. Chemical formula: C53H103N3O4

[0842] Lipid 680: 11H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 818.7. Chemical formula: C51H99N3O4

[0843] Lipid 681: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 48H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 832.7. Chemical formula: C52H101N3O4

[0844] Lipid 682: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 40H), 1.02 (m, 12H), 0.88 (t, 6H). MS: m / z 776.7. Chemical formula: C48H93N3O4

[0845] Lipid 683: 11H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 52H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 860.7. Chemical formula: C54H105N3O4

[0846] Lipid 684: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 2H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 2H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.93 (m, 1H), 1.84 (m, 2H), 1.65 (m, 4H), 1.51 - 1.18 (m, 50H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 846.7. Chemical formula: C53H103N3O4

[0847] Lipid 685: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.89 (m, 1H), 5.34 (m, 4H), 4.81 (m, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 34H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 774.7. Chemical formula: C48H91N3O4

[0848] Lipid 686: 11H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 4H), 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 858.7. Chemical formula: C54H103N3O4

[0849] Lipid 687: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.88 (m, 1H), 5.34 (m, 4H), 4.91 (m, 1H), 3.97 (m, 1H), 3.82 (m, 1H), 3.69 (br, 1H), 3.44 (br, 1H), 3.25 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.09 (m, 5H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 30H), 1.02 (s, 9H), 0.88 (m, 9H). MS: m / z 760.7. Chemical formula: C47H89N3O4

[0850] Lipid 688:<0​​​​​1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 4H), 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 44H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 844.7. Chemical formula: C53H101N3O4

[0852] Lipid 690: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 4H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 2H), 2.28 (m, 1H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 40H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 816.7. Chemical formula: C51H97N3O4

[0853] Lipid 691: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 4H), 4.89 (m, 1H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 42H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 830.7. Chemical formula: C52H99N3O4

[0854] Lipid 692: 11H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 4H), 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 34H), 1.02 (m, 12H), 0.88 (t, 6H). MS: m / z 774.7. Chemical formula: C48H91N3O4

[0855] Lipid 693: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 4H), 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 4H), 2.24 (m, 6H), 2.18 (m, 2H), 2.00 (m, 4H), 1.80 (m, 3H), 1.72 (m, 4H), 1.60 (m, 4H), 1.51 - 1.18 (m, 46H), 1.02 (s, 9H), 0.88 (t, 9H). MS: m / z 858.7. Chemical formula: C54H103N3O4

[0856] Lipid 694: 1 1H NMR (500 MHz, CDCl3, ppm): δ 5.34 (m, 4H), 4.13 (br, 1H), 4.05 (m, 2H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.80 (m, 2H), 2.45 (m, 2H), 2.​​​H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,12H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0858] Lipid 766: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,68H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0859] Lipid 767: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6 H),2.24(m,2H),2.09(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,52H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 850.7. Chemical formula: C51H99N3O6

[0860] Lipid 768: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0861] Lipid 769: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0862] Lipid 770: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08 (br,1H),2.45(m,6H),2.24(m,3H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(s,9H),0.88(t,12H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0863] Lipid 771: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(s,9H),0.88(t,12H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0864] Lipid 772: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,54H),1.02(m,12H),0.88(t,9H).MS:m / z 836.7. Chemical formula: C50H97N3O6

[0865] Lipid 773: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(m,12H),0.88(t,9H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0866] Lipid 774: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.2 4(m,2H),2.09(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,50H),1.02(m,12H),0.88(t,6H),0.80(t,3H).MS:m / z 822.7. Chemical formula: C49H95N3O6

[0867] Lipid 775: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(m,12H),0.88(t,9H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0868] Lipid 776: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,4H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.02(m,12H),0.88(t,9H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0869] Lipid 777: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H) ),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.24(m,3H),1.89(m, 1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(m,12H),0.88(t,9H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0870] Lipid 778: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(m,12H),0.88(t,9H).MS:m / z 864.7. Chemical formula: C52H101N3O6

[0871] Lipid 779: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0872] Lipid 780: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,74H),1.02(s,9H),0.88(t,12H).MS:m / z 1004.7. Chemical formula: C62H121N3O6

[0873] Lipid 781: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 2.09 (m, 1H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 58H), 1.02 (s, 9H), 0.88 (t, 9H), 0.80 (t, 3H). MS: m / z 906.7. Chemical formula: C55H107N3O6

[0874] Lipid 782: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 68H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 976.7. Chemical formula: C60H117N3O6

[0875] Lipid 783: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.45 (m, 6H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 70H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 990.7. Chemical formula: C61H119N3O6

[0876] Lipid 784: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,3H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0877] Lipid 785: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,66H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0878] Lipid 786: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,52H),1.02(s,9H),0.88(t,12H).MS:m / z 850.7. Chemical formula: C51H99N3O6

[0879] Lipid 787: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.02(s,9H),0.88(t,12H).MS:m / z 934.7. Chemical formula: C57H111N3O6

[0880] Lipid 788: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,2H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,48H),1.02(s,9H),0.88(t,9H),0.80(t,3H).MS:m / z 836.7. Chemical formula: C50H97N3O6

[0881] Lipid 789: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H) ),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.45(m,6H),2.24(m,2H),2.13(m, 1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,58H),1.02(s,9H),0.88(t,12H).MS:m / z 906.7. Chemical formula: C55H107N3O6

[0882] Lipid 790: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,2H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,2H),2.13(m,1H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0883] Lipid 791: 1 H NMR (500MHz, CDCl3, ppm): δ4.13(br,1H),4.05(m,4H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.4 5(m,6H),2.24(m,3H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,12H).MS:m / z 892.7. Chemical formula: C54H105N3O6

[0884] Lipid 792: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.45(m,6H),2.24(m,2H),2.13(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,56H),1.02(s,9H),0.88(t,12H).MS:m / z 878.7. Chemical formula: C53H103N3O6

[0885] Lipid 793: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 56H), 1.08 (s, 6H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 892.7. Chemical formula: C54H105N3O6

[0886] Lipid 794: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 68H), 1.08 (s, 6H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 976.7. Chemical formula: C60H117N3O6

[0887] Lipid 795: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 3H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 2.09 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 52H), 1.08 (s, 6H), 1.02 (s, 9H), 0.88 (t, 9H), 0.80 (t, 3H). MS: m / z 878.7. Chemical formula: C53H103N3O6

[0888] Lipid 796: 1H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.68(m,4H ),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,62H),1.08(s,6H),1.02(s,9H),0.88(t,12H).MS:m / z 948.7. Chemical formula: C58H113N3O6

[0889] Lipid 797: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,3H),4.13(br,1H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H),2.68(m,4H ),2.24(m,2H),1.89(m,1H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,64H),1.08(s,6H),1.02(s,9H),0.88(t,12H).MS:m / z 962.7. Chemical formula: C59H115N3O6

[0890] Lipid 798: 1 H NMR (500MHz, CDCl3, ppm): δ4.89(m,1H),4.13(br,1H),4.05(m,2H),3.73(br,1H),3.47(br,1H),3.22(br,1H),3.08(br,1H ),2.68(m,4H),2.24(m,3H),1.72(m,6H),1.60(m,2H),1.51-1.18(m,60H),1.08(s,6H),1.02(s,9H),0.88(t,12H).MS:m / z 920.7. Chemical formula: C56H109N3O6

[0891] Lipid 799: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 2H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 60H), 1.08 (s, 6H), 1.02 (s, 9H), 0.88 (t, 12H). MS: m / z 920.7. Chemical formula: C56H109N3O6

[0892] Lipid 800: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 3H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 54H), 1.08 (s, 6H), 1.02 (m, 12H), 0.88 (t, 9H). MS: m / z 864.7. Chemical formula: C52H101N3O6

[0893] Lipid 801: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 3H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 66H), 1.08 (s, 6H), 1.02 (m, 12H), 0.88 (t, 9H). MS: m / z 920.7. Chemical formula: C56H109N3O6

[0894] Lipid 802: 11H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 2.09 (m, 1H), 1.89 (m, 1H), 1.72 (m, 6H), 1.60 (m, 2H), 1.51 - 1.18 (m, 50H), 1.08 (s, 6H), 1.02 (m, 12H), 0.88 (t, 6H), 0.80 (t, 3H). MS: m / z 850.7. Chemical formula: C51H99N3O6

[0895] Lipid 803: 1 1H NMR (500 MHz, CDCl3, ppm): δ 4.89 (m, 4H), 4.13 (br, 1H), 3.73 (br, 1H), 3.47 (br, 1H), 3.22 (br, 1H), 3.08 (br, 1H), 2.68 (m, 4H), 2.24 (m, 2H), 1.89 (m, 2H), 1.72 (m, 6H), 1.60 (m, 2H)...

Claims

A lipid compound of formula (I), or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, in, X is O or NH; Y is O or S; Z is absent or is O, NH or S; R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms; R I 、R II 、R III and R IV Each independently selected from group (A) comprising a group containing at least one ionizable tertiary amine structure, group (B) comprising a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, and group (C) comprising a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, provided that: (1) when R I 、R II 、R III and R IV when any one of the three is a group containing at least one ionizable tertiary amine structure, any two of the remaining three are the same or different substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl groups having less than 11 carbon atoms, and the other is a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11-30 carbon atoms, or any two of the remaining three are the same or different substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11-30 carbon atoms, and the other is a substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl group having less than 11 carbon atoms; or (2) when R I 、R II 、R III and R IV When any two of the groups are the same or different groups containing at least one ionizable tertiary amine structure, one of the remaining two is a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, and the other is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that R I 、R II 、R III and R IV Only one of the groups is a group containing at least one ionizable tertiary amine structure. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 1 or 2, characterized in that R II ' is hydrogen or a substituted or unsubstituted hydrocarbon group having 1 to 11 carbon atoms, such as a C1-C4 alkyl group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, Group A includes a group comprising at least one ionizable tertiary amine structure, wherein the group comprising at least one ionizable tertiary amine structure has 3 to 11 carbon atoms and is represented by the following general formula, Among them, R a is a C1-C6 substituted or unsubstituted alkylene group; R b 、R c are each independently C1-C6 substituted or unsubstituted alkyl, C2-C6 substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, which may be optionally substituted by 1, 2 or 3 selected from -OH, -SH, -NR d R d' or substituted by a phenyl group, wherein R d 、R d' are each independently hydrogen or C1-C3 alkyl; or R b 、R c Together with the nitrogen atom to which it is attached, it forms a 5-12 membered heterocyclic or heteroaromatic ring, the 5-12 membered heterocyclic or heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, and the 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6 alkylene, the 5-12 membered heterocyclic ring 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6 alkylene is optionally substituted with 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 heterocyclic or heteroaromatic ring optionally substituted with C1-C6 alkylene, the 5-12 membered heterocyclic or heteroaromatic ring optionally substituted with C1-C6 alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, the 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 (=O); Group B includes substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups with 11-30 carbon atoms, wherein the substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups with 11-30 carbon atoms optionally contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms 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)- groups, wherein R m 、R n 、R o and R p are each independently substituted or unsubstituted C1-C 14 and Group C includes substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heteroaryl groups having 1 to 11 carbon atoms, wherein the substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups or substituted or unsubstituted heteroaryl groups having 1 to 11 carbon atoms optionally contain 1, 2, 3, 4 or 5 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)- groups, wherein R m '、R n '、R o ' and R p ' are each independently substituted or unsubstituted C1-C 14 wherein the hydrocarbon group, heterohydrocarbon group, aryl group or heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH, R I 、R II 、R III and R IV The following conditions are met: R I Selected from Group A, R II and R III Selected from Group B, and R IV Selected from Group C; or R I Selected from Group A, R II and R IV Selected from Group B, and R III Selected from Group C; or R I Selected from Group A, R III and R IV Selected from Group B, and R II Selected from Group C; or R II Selected from Group A, R I and R III Selected from Group B, and R IV Selected from Group C; or R II Selected from Group A, R I and R IV Selected from Group B, and R III Selected from Group C; or R II Selected from Group A, R III and R IV Selected from Group B, and R I Selected from Group C; or R III Selected from Group A, R I and R II Selected from Group B, and R IV Selected from Group C; or R III Selected from Group A, R I and R IV Selected from Group B, and R II Selected from Group C; or R III Selected from Group A, R II and R IV Selected from Group B, and R I Selected from Group C; or R IV Selected from Group A, R I and R II Selected from Group B, and R III Selected from Group C; or R IV Selected from Group A, R I and R III Selected from Group B, and R II Selected from Group C; or R IV Selected from Group A, R II and R III Selected from Group B, and R I Selected from Group C. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that R I 、R II 、R III and R IV Each independently further optionally comprises at least one degradable group, preferably R I 、R II 、R III and R IV When each is independently selected from Group B, it optionally further comprises at least one degradable group. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 4, characterized in that wherein the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SS-, -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-, where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 are each independently substituted or unsubstituted C1-C 14 aliphatic hydrocarbon group. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 5, characterized in that When R III and R IV When selected from Group B, R III and R IV Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms; when R II and R IV When selected from Group B, R II and R IV Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms; when R I and R IV When selected from Group B, R I and R IV Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms; when R I and R II When selected from Group B, R I and R II Any one of has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms; and / or when R I and R III When selected from Group B, R I and R III Any one of them has 16 to 30 carbon atoms, and the other has 11 to 25 carbon atoms. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 6, characterized in that When R III and R IV When selected from Group B, R III and R IV Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms; when R II and R IV When selected from Group B, R II and R IV Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms; when R I and R IV When selected from Group B, R I and R IV Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms; when R I and R II When selected from Group B, R I and R II Any one of has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms; and / or when R I and R III When selected from Group B, R I and R III Any one of them has 16 to 25 carbon atoms, and the other has 11 to 16 carbon atoms. The lipid compound or its N-oxide, isomer or pharmaceutically acceptable salt according to any one of claims 1 to 7, characterized in that When R III and R IV When selected from Group B, R III and R IV At least one of contains at least one degradable group; when R II and R IV When selected from Group B, R II and R IV At least one of contains at least one degradable group; when R I and R IV When selected from Group B, R I and R IV At least one of contains at least one degradable group; when R I and R II When selected from Group B, R I and R II At least one of contains at least one degradable group; and / or when R I and R III When selected from Group B, R I and R III At least one of the comprises at least one degradable group. The lipid compound or its N-oxide, isomer or pharmaceutically acceptable salt according to any one of claims 1 to 8, characterized in that When R III and R IV When selected from Group B, R III and R IV Only one of them contains a degradable group; when R II and R IV When selected from Group B, R II and R IV Only one of them contains a degradable group; when R I and R IV When selected from Group B, R I and R IV Only one of them contains a degradable group; when R I and R II When selected from Group B, R I and R II contains a degradable group; and / or when R I and R III When selected from Group B, R I and R III Only one of the 5′-aminobutyric acid molecules contains a degradable group. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that The group A includes the groups shown in the following structures: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 10, characterized in that The group B includes the groups shown in the following structures: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 11, characterized in that The group C includes the groups shown in the following structure: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 12, characterized in that The lipid compound has the following general structural formula (I A ) The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 13, characterized in that R II ' is hydrogen, or a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having 1 to 11 carbon atoms; R III Selected from Group A, R I and R IV Selected from Group B, and R II Selected from Group C. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 13 or 14, characterized in that R II ' is hydrogen or a C1-C6 alkyl group. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 15, characterized in that R III The group selected from Group A, which contains at least one ionizable tertiary amine structure, is a group having the following general formula: Among them, R a is a C1-C6, for example, a C1-C4, substituted or unsubstituted alkylene group; R b 、R c Each is independently C1-C6 such as C1-C4 substituted or unsubstituted alkyl, C2-C6 such as C2-C4 substituted or unsubstituted alkenyl, C2-C6 such as C2-C4 substituted or unsubstituted alkynyl, which may be optionally substituted by 1, 2 or 3 selected from -OH, -SH, -NR d R d' or substituted by a phenyl group, wherein R d 、R d' are each 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 heterocyclic or heteroaromatic ring, the 5-12 membered heterocyclic or heteroaromatic ring contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic or heteroaromatic ring is optionally substituted with one or more C1-C6, such as C1-C4, 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6, for example, C1-C4 alkylene, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more C1-C6, for example, C1-C4 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 heterocyclic ring or heteroaromatic ring optionally substituted with C1-C6, for example, C1-C4 alkylene, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene contains 1, 2 or 3 heteroatoms independently selected from N, O, and S, wherein at least one heteroatom is N, the 5-12 membered heterocyclic ring or heteroaromatic ring optionally substituted with alkylene is optionally substituted with one or more C1-C6, for example, C1-C4 alkyl, or oxo (=O). The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 16, characterized in that R III Selected from Group A, Group A includes a group containing at least one ionizable tertiary amine structure represented by the following structure: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 17, characterized in that R I and R IV Each is independently selected from Group B, wherein the substituted or unsubstituted aliphatic group selected from Group B has 11-30 carbon atoms, and the substituted or unsubstituted heteroaliphatic group selected from Group B has 11-30 atoms including carbon atoms and heteroatoms such as N, O, and S. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 18, characterized in that R I and R IV Each is independently selected from Group B, which includes substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic groups having 11 to 30 carbon atoms as shown in the following structure: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 19, characterized in that R I and R IV At least one of the compounds comprises at least one degradable group, optionally, the degradable group is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SS-, -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-, where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 are each independently substituted or unsubstituted C1-C 14 The aliphatic hydrocarbon group is preferably an ester group, that is, -C(O)O- or -OC(O)-; or the degradable group includes an ester bond. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 20, characterized in that R I and R IV Each contains at least one degradable group, for example, the degradable group is an ester group, ie, -C(O)O- or -OC(O)-; or the degradable group includes an ester bond. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 21, characterized in that R I and R IV Any one of them contains 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 includes an ester bond; and the other does not contain a degradable group. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 22, characterized in that When R I and / or R IV When no degradable group is included, R I and / or R IV A group selected from the following structures: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 23, characterized in that When R I and / or R IV When containing a degradable group, R I and / or R IV A group selected from the following structures: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 23, characterized in that When R I and / or R IV When containing a degradable group, R I and / or R IV Has the following structure: Among them, R d is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene having 1 to 11 carbon atoms, wherein the alkylene or heteroalkylene is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH, R e There is no or is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene having 1 to 4 carbon atoms, the alkylene or heteroalkylene being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH, R f and R g Each is independently a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted heterohydrocarbon group having 1 to 11 carbon atoms, wherein the hydrocarbon group or heterohydrocarbon group is optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 23, characterized in that When R I and / or R IV When containing a degradable group, R I and / or R IV are each independently selected from the group consisting of: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 26, characterized in that R II The substituted or unsubstituted hydrocarbon, substituted or unsubstituted heterohydrocarbon, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl group selected from Group C has 1 to 11 carbon atoms. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 27, characterized in that R II Selected from Group C, which includes substituted or unsubstituted hydrocarbon groups, substituted or unsubstituted heterohydrocarbon groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups having less than 11 carbon atoms as shown in the following structures: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 28, characterized in that The lipid compound has the following general structural formula (I A-1 ) The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 13 to 28, characterized in that The lipid compound has the following general structural formula (I A-2 ) The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 12, characterized in that The lipid compound has the following general structural formula (I B ) The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 31, characterized in that R II ' is hydrogen; R II is selected from group C, such as C1-C6 alkyl, C1-C4 alkyl, and tert-butyl; R III Selected from group A, for example, a group having the following general formula: Among them, R a 、R b 、R c Each is independently C1-C6, such as C1-C4, substituted or unsubstituted alkyl, which may be optionally substituted by 1, 2 or 3 groups selected from -OH, -SH, -NR d R d' or substituted by a phenyl group, wherein R d 、R d' are each independently hydrogen or C1-C3 alkyl; and R I and R IV Each independently selected from Group B, R I and R IV At least one of them contains a degradable group, such as an ester group, i.e., -C(O)O- or -OC(O)-; or the degradable group includes an ester bond, preferably, for example, a group selected from the following structures: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that The lipid compound is selected from the lipid compounds shown below: The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that The lipid compound is selected from the lipid compounds shown in Table 1 to Table 8: lipid numbers 1-1075. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that The lipid compound is selected from the following lipid compounds: lipid number 16, 30, 60, 108, 113, 157, 158, 159, 160, 161, 162, 163, 166, 170, 173, 174, 175, 176, 188, 189, 194, 195, 223, 226, 227, 229, 230, 232, 233, 234, 235, 236, 237, 238, 239, 240, 284, 285, 286, 287, 292, 293, 294, 295, 304, 325, 326, 327, 401, 402, 406, 407, 408, 409 , 420, 424, 431, 445, 446, 447, 583, 595, 598, 607, 613, 641, 675, 685, 914, 915, 920, 921, 922, 923, 924, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 949, 950, 951, 952, 954, 955, 958, 959, 960, 961, 962, 963, 964, 966-1051, and 1053-1057. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that The lipid compound is selected from the lipid compounds shown below: lipid numbers 317 and 1058-1075. The lipid compound or its N-oxide, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 36, 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. The lipid compound according to any one of claims 1 to 37, or its N-oxide, stereoisomer or pharmaceutically acceptable salt, characterized in that it is used for nucleic acid delivery. Use of a lipid compound according to any one of claims 1 to 38 or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof in the preparation of liposomes and / or lipid nanoparticles. A liposome, characterized in that The liposome comprises the lipid compound according to any one of claims 1 to 37 or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof. The liposome according to claim 40, characterized in that Based on the total molar amount of the components constituting the liposome, the lipid compound accounts for about 10 mol% to about 90 mol%, preferably the lipid compound accounts for about 10 mol% to about 70 mol%, and more preferably the lipid compound accounts for about 20 mol% to about 50 mol%. The liposome according to claim 40 or 41, characterized in that The liposomes also contain phospholipids and cholesterol. The liposome according to claim 42, wherein The phospholipid accounts for about 0 mol % to about 20 mol % based on the total molar amount of the components constituting the liposome, or a range of any value between about 0 mol % and about 20 mol %. The liposome according to claim 42 or 43, characterized in that The cholesterol accounts for about 30 mol% to about 50 mol% based on the total molar amount of the components constituting the liposome, or a range of any value between about 30 mol% and about 50 mol%. A lipid nanoparticle, characterized in that The lipid nanoparticle comprises the lipid compound according to any one of claims 1 to 37 or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof. The lipid nanoparticle according to claim 45, characterized in that Based on the total molar amount of the components constituting the lipid nanoparticles, the lipid compound accounts for about 10 mol% to about 90 mol%, preferably the lipid compound accounts for about 10 mol% to about 70 mol%, and more preferably the lipid compound accounts for about 20 mol% to about 50 mol%. The lipid nanoparticle according to claim 45 or 46, characterized in that The lipid nanoparticles further comprise phospholipids, structural lipids and PEG lipids. The lipid nanoparticle according to claim 47, characterized in that The phospholipid accounts for about 0 mol% to about 20 mol% based on the total molar amount of the components constituting the lipid nanoparticles. The lipid nanoparticle according to claim 47 or 48, characterized in that Wherein, based on the total molar amount of components constituting the lipid nanoparticles, the structural lipid accounts for about 30 mol% to about 50 mol%. The lipid nanoparticle according to any one of claims 47 to 49, characterized in that The PEG lipid accounts for about 0 mol% to about 10 mol% based on the total molar amount of the components constituting the lipid nanoparticles. The lipid nanoparticle according to any one of claims 47 to 50, characterized in that The lipid nanoparticles also include plasmids or nucleic acids. The lipid nanoparticle according to claim 51, characterized in that The N / P ratio of the lipid compound to the nucleic acid is about 1.1:1 to 10:

1. The lipid nanoparticle according to claim 51 or 52, characterized in that The nucleic acid is RNA. Use of the liposome according to any one of claims 40 to 44 or the lipid nanoparticle according to any one of claims 45 to 50 as a delivery vehicle. The use according to claim 54, characterized in that The delivery vector is used to deliver plasmids or nucleic acids. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the lipid compound according to any one of claims 1 to 37, the liposome according to any one of claims 40 to 44, or the lipid nanoparticle according to any one of claims 45 to 50, and a pharmaceutically acceptable carrier or excipient. A lipid compound of formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, in, R A is selected from substituted or unsubstituted aliphatic and heteroaliphatic groups, R A Optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; R B is a degradable group containing a degradable bond selected from the following group: Where a represents the A The connected position, b represents the connection with R C Connected position, R B1 and R B2 are each independently selected from H and substituted or unsubstituted C 1-6 Alkyl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; R C is selected from substituted or unsubstituted aliphatic and heteroaliphatic groups, R C optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH; and R D Selected from -NC or -COOH. The lipid compound of formula (II) according to claim 57, or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that (i)R A (ii) R A Selected from the group consisting of A ) is a substituted or unsubstituted branched aliphatic group or a substituted or unsubstituted branched heteroaliphatic group: Among them, R A1 Not present or selected from substituted or unsubstituted C 1-4 Alkyl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; a branched central group R T Selected from the group consisting of: Where a represents the A1 Connected position, or R A1 If it does not exist, it is directly compared with R B Connected position; R A2 and R A3 are each independently selected from a substituted or unsubstituted aliphatic group and a substituted or unsubstituted heteroaliphatic group having 1 to 12 carbon atoms, the aliphatic group and the heteroaliphatic group being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH; R A4 R is absent or selected from hydrogen, substituted or unsubstituted aliphatic groups having 1 to 12 carbon atoms, and substituted or unsubstituted heteroaliphatic groups, which are optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH; A2 The number of carbon atoms n A2 、R A3 The number of carbon atoms n A3 and R A4 The number of carbon atoms n A4 The sum is in the range of 2-24. The lipid compound of formula (II) according to claim 57 or 58, or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that (i)R C is selected from a substituted or unsubstituted straight-chain aliphatic group having 2 to 18 carbon atoms and a substituted or unsubstituted straight-chain heteroaliphatic group having 2 to 18 carbon atoms, the straight-chain aliphatic group and the straight-chain heteroaliphatic group being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH, and R D is attached to the terminal end of the straight-chain aliphatic group or straight-chain heteroaliphatic group; or (ii) R C Selected from the group consisting of B ) is a substituted or unsubstituted branched aliphatic group or a substituted or unsubstituted branched heteroaliphatic group: Among them, R C1 Not present or selected from substituted or unsubstituted C 1-4 Alkyl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; a branched central group R T’ Selected from the group consisting of: Where a represents the C1 Connected position, or R C1 If it does not exist, it is directly compared with R B Connected position; R C2 and R C3 are each independently selected from a substituted or unsubstituted aliphatic group and a substituted or unsubstituted heteroaliphatic group having 1 to 12 carbon atoms, the aliphatic group and the heteroaliphatic group being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH; R C4 R is absent or selected from hydrogen, substituted or unsubstituted aliphatic groups having 1 to 12 carbon atoms, and substituted or unsubstituted heteroaliphatic groups, which are optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2, and -OH; C2 The number of carbon atoms n C2 、R C3 The number of carbon atoms n C3 and R C4 The number of carbon atoms n C4 The sum is in the range of 2-24; R D With R C2 、R C3 and R C4 Any and only one end of the group is connected. The lipid compound of formula (II) according to any one of claims 57 to 59, or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that R A is selected from a substituted or unsubstituted straight-chain aliphatic group having 6 to 20 carbon atoms, the straight-chain aliphatic group being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH; or R A Selected from the group consisting of A’ ) is a substituted or unsubstituted branched aliphatic group or a substituted or unsubstituted branched heteroaliphatic group: Among them, R A1 Not present or selected from substituted or unsubstituted C 1-2 Alkyl, optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; a branched central group R T yes Where a represents the A1 Connected position, or R A1 If it does not exist, it is directly compared with R B Connected position; R A2 and R A3 are each independently selected from a substituted or unsubstituted aliphatic group having 3 to 12 carbon atoms, the aliphatic group being optionally substituted with one or more substituents selected from the following group: deuterium, halogen, -NO2 and -OH; R A2 The number of carbon atoms n A2 and R A3 The number of carbon atoms n A3 The sum is in the range of 6-18; R B is a degradable group containing a degradable bond selected from the following group: Where a represents the A The connected position, b represents the connection with R C Connected position; R C is selected from a substituted or unsubstituted straight-chain aliphatic group having 2 to 18 carbon atoms, the straight-chain aliphatic group being optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, -NO2 and -OH; and R D Selected from -NC or -COOH. The lipid compound of formula (II) according to any one of claims 57 to 60, or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that The lipid compound is selected from the lipid compounds shown below: The method for preparing the lipid compound of formula (II) according to claim 60 or 61, or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that The preparation method includes the following synthetic route: D When -NC is selected, When R D When selected from -COOH, Use of a lipid compound of formula (II) according to any one of claims 57 to 61, or a stereoisomer or pharmaceutically acceptable salt thereof in the preparation of an ionizable lipid. The use according to claim 63, characterized in that The ionizable lipid is a lipid compound of formula (I) according to any one of claims 1-37. The use according to claim 64, characterized in that The preparation includes the following Ugi reaction synthesis route: Among them, R I 、R II 、R II '、R III and R IV As defined in any one of claims 1 to 37, and R I -NC and R IV -COOH is each independently selected from the lipid compound of formula (II) according to any one of claims 57 to 61. The use according to claim 63, characterized in that The ionizable lipid is a lipid compound of formula (III): R I 、R II and R IV are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, and (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, provided that: R I 、R II and R IV There is only one group containing at least one ionizable tertiary amine structure. The use according to claim 66, characterized in that The preparation comprises the following Passerini reaction synthesis route: Among them, R I -NC and R IV -COOH is each independently selected from the lipid compound of formula (II) according to any one of claims 57 to 61. The use according to claim 66, characterized in that The preparation comprises the following reaction synthesis route: Among them, R I -NC and R IV -COOH is each independently selected from the lipid compound of formula (II) according to any one of claims 57 to 61. The use according to claim 63, characterized in that The ionizable lipid is a lipid compound of formula (IV): R I 、R II and R III are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, and (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, provided that: R I 、R II and R III There is only one group containing at least one ionizable tertiary amine structure. The use according to claim 69, characterized in that The preparation includes the following Ugi-Smiles reaction synthesis route: Among them, R I -NC is selected from the lipid compounds of formula (II) according to any one of claims 57 to 61. The use according to claim 63, characterized in that The ionizable lipid is a lipid compound of formula (V): R1 V 、R2 V 、R3 V and R4 V are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, and (C) a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, provided that: R1 V 、R2 V 、R3 V and R4 V There is only one group containing at least one ionizable tertiary amine structure. The use according to claim 71, characterized in that The preparation comprises the following reaction synthesis route: Among them, R1 V -NC is selected from the lipid compounds of formula (II) according to any one of claims 57 to 61. The use according to claim 63, characterized in that The ionizable lipid is a lipid compound of formula (VI): R1 VI 、R2 VI and R3 VI are each independently selected from (A) a group containing at least one ionizable tertiary amine structure, (B) a substituted or unsubstituted aliphatic or substituted or unsubstituted heteroaliphatic group having 11 to 30 carbon atoms, and (C) a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterohydrocarbon group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group having less than 11 carbon atoms, provided that: R1 VI 、R2 VI and R3 VI There is only one group containing at least one ionizable tertiary amine structure. The use according to claim 73, characterized in that The preparation comprises the following reaction synthesis route: in, Each is independently selected from the lipid compound of formula (II) according to any one of claims 57 to 61. A lipid compound of formula (III), (IV), (V) or (VI) or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that it is used for nucleic acid delivery. Use of a lipid compound of formula (III), (IV), (V) or (VI) or an N-oxide, stereoisomer or pharmaceutically acceptable salt thereof in preparing liposomes and / or lipid nanoparticles. A liposome, characterized in that The liposomes include a lipid compound of formula (III), (IV), (V) or (VI). The liposome according to claim 77, wherein The liposomes also contain phospholipids and cholesterol. A lipid nanoparticle, characterized in that The lipid nanoparticles include a lipid compound of formula (III), (IV), (V) or (VI). The lipid nanoparticle according to claim 79, characterized in that The lipid nanoparticles further include phospholipids, structural lipids, and PEG lipids. The lipid nanoparticle according to claim 80, characterized in that The lipid nanoparticles also include plasmids or nucleic acids. Use of the liposome according to claim 77 or 78 or the lipid nanoparticle according to any one of claims 79 to 81 as a delivery vehicle. The use according to claim 82, characterized in that The delivery vector is used to deliver plasmids or nucleic acids. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a lipid compound of formula (III), (IV), (V) or (VI), a liposome according to claim 77 or 78 or a lipid nanoparticle according to any one of claims 79 to 81, and a pharmaceutically acceptable carrier or excipient.

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