Ionizable cationic lipid compounds as well as preparation method therefor and use thereof

Abstract

Provided in the present invention are ionizable cationic lipid compounds as well as a preparation method therefor and the use thereof, belonging to the technical field of biological medicines. The ionizable cationic lipid compounds provided by the present invention are compounds of formula (1), or salts, stereoisomers and tautomers thereof, can be used as surfactants for various fields, and particularly can be used for lipid compositions capable of delivering therapeutic agents. Lipid nanoparticle prepared from said compounds can show good effectiveness and safety in cells and in animal bodies.

Description

Ionizable cationic lipid compound and its preparation method and application Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and in particular relates to an ionizable cationic lipid compound and a preparation method and application thereof. Background Art

[0002] Gene therapy uses nucleic acids as functional molecules to activate biological therapeutics. Nucleic acids have garnered significant attention due to global efforts to elucidate the human genome and recent discoveries such as RNA interference (RNAi) and CRISPR-based genome editing. Gene therapy uses genetic material to alter the expression of a target gene or modify the biological properties of living cells to meet therapeutic needs. In recent years, several gene therapy products have been approved by regulatory agencies for various applications, such as the use of mRNA vaccines to combat the COVID-19 pandemic. Gene therapy can be categorized into three main approaches: 1) editing mutant genes using CRISPR-Cas technology; 2) upregulating gene expression by inserting a functional gene copy, using molecules such as DNA plasmids (pDNA), minicircle DNA (mcDNA), synthetic mRNA, circular RNA, and self-amplifying RNA (saRNA); and 3) downregulating gene expression using molecules such as small interfering RNA (siRNA), antisense oligonucleotides (ASOs), short hairpin RNA (shRNA), and microRNA (miRNA).

[0003] Due to their negative charge, high molecular weight, and hydrophilic nature, nucleic acids have poor permeability across cell membranes. Furthermore, nucleic acids have low stability in vivo and are rapidly cleared by the host outside of cells. Therefore, delivering nucleic acids to their active sites within cells is the most challenging aspect of gene therapy. This is particularly true when delivering RNA molecules, as RNA molecules typically have short-term activity, low intracellular retention, and require more frequent dosing. Therefore, the toxicity of the payload and the vector are two very important considerations. The vector itself needs to overcome extracellular and intracellular barriers, provide protection against nuclease activity in the blood, enhance and assist cellular uptake, and promote endosomal escape once inside the cell.

[0004] Commonly used nucleic acid vectors are divided into two categories: viral vectors and non-viral vectors. Viral gene delivery systems have high cell transfection efficiency, but the body produces neutralizing antibodies against the vector or pre-existing antibodies to the viral vector, resulting in rapid clearance of the vector. Furthermore, viral vectors are typically small (usually less than 7 kb). Therefore, lipid-based non-viral gene delivery systems have become the mainstream vector delivery system.

[0005] Ionizable cationic lipids are an important component of lipid non-viral vectors. From a chemical structure perspective, ionizable cationic lipids are amphiphilic molecules whose chemical structure consists of three parts: a head group, a linker, and a tail chain. Generally, the head group contains one or more ionizable sites, so under different pH conditions, the molecule can be neutral or positively charged. Under the premise of being lower than its pKa, ionizable lipids can form lipophilic drug complexes with nucleic acids and anionic small molecules, peptides, proteins, and heparin with opposite charges. Lipids and nucleic acids can form lipid nanoparticles (LNPs) through electrostatic interactions.

[0006] In pharmaceutical products, ionizable cationic lipids have pH-dependent cationic properties, which pose certain safety issues. The first generation of cationic lipids (e.g., DOTMA, DOTAP, etc.) binds to cell membranes and nuclear membranes, triggering the release of degradative enzymes from lysosomes, leading to mitochondrial permeability and dysfunction, generating reactive oxygen species, altering the function of cytoplasmic enzymes, and damaging DNA. In order to address this defect of cationic lipids, around 2001, Acuitas designed a second-generation lipid structure with dimethyl tertiary amine as the head group. Compared with the first-generation lipid structure, the electrical properties of the lipid structure with dimethyl tertiary amine as the head group can be adjusted by pH. Therefore, starting from the second-generation lipid structure, cationic lipids used for nucleic acid carriers are also called ionizable cationic lipids (see CN105873902B, CN107207428A, CN110003066B, CN110325511B, CN110337429B). Common second-generation ionizable cationic lipids include D-Lin-MC3-DMA, DLin-K-DMA, DlinDMA, etc. (CN107922364B, CN108368028B). Second-generation ionizable lipids have been successfully used as carriers for siRNA drugs. For example, Acuitas Therapeutics successfully developed the lipid D-Lin-MC3-DMA, and the siRNA product Onparrto, developed in collaboration with Alnylam, became the world's first nucleic acid drug and was approved for marketing in 2018. Since then, Moderna has developed third-generation lipids with hydroxyl tertiary amine as the head group (CN110520409A, CN114746398A). The third-generation ionizable lipids exhibit positive charges under acidic pH conditions, which is conducive to complexing with nucleic acids and can escape from endosomes after entering cells. Currently, the ionizable cationic lipids with better performance include ALC-0315 (4-hydroxybutyl) azo-2-(hexane-6, 1-diyl) bis(2-hexyldecanoate) and lipid H (SM-102) (9-heptadecanyl-8-{(2-hydroxyethyl)[6-oxo-6-(undecanyloxy)hexyl]amino}octanoate), which are used in the coronavirus (COVID-19) mRNA vaccines BNT 162b and mRNA-1273, respectively.

[0007] At present, the ionizable cationic lipids protected in most patents are based on the tertiary amine group as the central functional group to introduce the head group and the tail chain. Among the three functional groups on the tertiary amine, one is used to introduce the head group and the other two are used to introduce the tail chain. The ionizable cationic lipid compound provided by the present invention (including its stereoisomers, tautomers and the salts corresponding to these lipids) is based on the tetrafunctional compound as the core unit, and the corresponding head group and tail chain are introduced through the terminal functional groups of the tetrafunctional compound. In the present invention, one of the four functional groups is used to introduce the head group, and the other three functional groups are used to introduce the tail chain, as shown in formula (1):

[0008] The ionizable cationic lipid compound provided by the present invention is an amphiphilic lipid compound constructed by using an ionizable cationic compound and its analogues as the ionizable lipid head group, a lipid such as a fatty acid as the tail chain, and a tetrafunctional compound as a linker. The ionizable lipid head group, the tail chain, and the linker are connected by a biodegradable chemical bond (such as an ester bond or an amide bond). When constructing the structure of the ionizable cationic lipid compound, the present invention introduces biodegradable functional groups. Since the biodegradable chemical bonds can be cleaved by various enzymes such as lipases, esterases, and proteases in the body, they are rapidly hydrolyzed into endogenous metabolites, which can reduce cytotoxicity and improve its safety in use.

[0009] Summary of the Invention

[0010] The present invention addresses the problems existing in the prior art and provides an ionizable cationic lipid compound, a preparation method thereof, and an application thereof. The ionizable cationic lipid compound provided by the present invention is an amphiphilic lipid compound constructed by connecting the ionizable lipid head group, the tail chain, and the linker with an ionizable cationic compound and its analogues as the ionizable lipid head group, a lipid such as a fatty acid as the tail chain, and a tetrafunctional compound as the linker through a biodegradable chemical bond (such as an ester bond or an amide bond). The biodegradable chemical bond can be cleaved by a variety of enzymes such as lipases, esterases, and proteases in the body, and is rapidly hydrolyzed into endogenous metabolites with low cytotoxicity.

[0011] To achieve the above objectives, in a first aspect, the present invention provides an ionizable cationic lipid compound, wherein the ionizable cationic lipid compound is a compound of formula (1), or a salt, stereoisomer, or tautomer thereof:

[0012] Wherein, R1, R2, and R3 are independently H, C 5-40 Straight or branched alkyl, C 5-40 Straight-chain or branched alkenyl, C 5-40A straight or branched alkynyl group, a 3-6 membered saturated or partially unsaturated cyclic hydrocarbon group containing 1-3 side chains, or a 6-10 membered aromatic group containing 1-3 side chains; the side chains are independently selected from C 10-30 Straight-chain or branched alkyl, C 10-30 Straight-chain or branched alkenyl, C 10-30 Straight or branched alkynyl; provided that at most one of R1, R2, and R3 is H;

[0013] M is selected from -NR4R5, a saturated or partially unsaturated 3-6 membered heterocyclic group containing at least one nitrogen atom, a 6-10 membered heteroaryl group containing at least one nitrogen atom, wherein the heterocyclic group and the heteroaryl group are unsubstituted or substituted with one or more -OH, carboxyl, amino, oxo or halogen;

[0014] R4 and R5 are independently H, C 1-6 Straight-chain or branched alkyl, C 2-6 Straight-chain or branched alkenyl or C 2-6 Straight chain or branched chain alkynyl, the C 1-6 Straight-chain or branched alkyl, C 2-6 Straight chain or branched alkenyl or C 2-6 The straight-chain or branched alkynyl group is unsubstituted or substituted with one or more -OH, carboxyl, aminoamide, amidino, guanidino or halogen;

[0015] G1, G2, and G3 are independently -O-, -S-, -NR6-, -SS-, -C(=O)-, -C(=S)-, -C(=O)O-, -CH(OH)-, -OC(=O)-, -C(=O)NR6-, -NR6C(=O)-, -OC(=O)O-, -NR6C(=O)O-, -OC(=O)NR6-, -NR6C(=O)NR 13 -, -C(=O)S-, -C(=S)S-, -SC(=S)-, -SC(=O)-, -OC(=O)S-, -SC(=O)O-, -SC(=O)S-, -OS(=O)2O-, -S(=O)2O-, -OS (=O)2-, -S(=O)2-, -S(=O)2-NR6-, -NR6-S(=O)2-, -P(=O)(OR6)O-, -OP(=O)(OR6)- or -OP(=O)(OR6)O-; where each R6, R 13 independently selected from H, hydroxyl, C 1-30 Straight-chain or branched alkyl or cycloalkyl, C 2-30 straight-chain or branched alkenyl;

[0016] L1 is selected from -X1- or -(CR7R8) m-X1-, wherein each X1 is independently selected from -O-, -S-, -NR 14 -, -SS-, -C(=O)-, -C(=S)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 14 -、-NR 14 C(=O)-, -OC(=O)O-, -NR 14 C(=O)O-, -OC(=O)NR 14 -、-NR 14 C(=O)NR 15 -, -C(=O)S-, -C(=S)S-, -SC(=S)-, -SC(=O)-, -OC(=O)S-, -SC(=O)O-, -SC(=O)S-, -OS(=O)2O-, -S(=O)2O-, -OS(=O)2-, -S(=O)2-, -S(=O)2-NR 14 -、-NR 14 -S(=O)2-、-P(=O)(OR 14 )O-、-OP(=O)(OR 14 )-or-OP(=O)(OR 14 )O-; wherein m is an integer from 2 to 6, R 7、 R8 are independently H, hydroxy, halogen, C 1-6 Straight or branched alkyl or cycloalkyl, C 2-6 A straight-chain or branched alkenyl group, each R 14 、R 15 independently selected from H, C 1-30 Straight-chain or branched alkyl or cycloalkyl, C 2-30 straight-chain or branched alkenyl;

[0017] L2 is -(CR9R 10 ) n -or-(CR9R 10 ) n -X2-(CR 11 R 12 ) k -, wherein X2 is selected from -O-, -S-, -NR 16 -, -SS-, -C(=O)-, -C(=S)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 16 -、-NR 16 C(=O)-, -OC(=O)O-, -NR 16 C(=O)O-, -OC(=O)NR 16 -、-NR 16 C(=O)NR 17-, -C(=O)S-, -C(=S)S-, -SC(=S)-, -SC(=O)-, -OC(=O)S-, -SC(=O)O-, -SC(=O)S-, -OS(=O)2O-, -S(=O)2O-, -OS(=O)2-, -S(=O)2-, -S(=O)2-NR 16 -、NR 16 -S(=O)2-、-P(=O)(OR 16 )O-、-OP(=O)(OR 16 )-or-OP(=O)(OR 16 )O-; n is an integer from 1 to 6; k is an integer from 1 to 6; R 9、 R 10、 R 11、 R 12 are independently H, hydroxy, halogen, C 1-6 Straight or branched alkyl or cycloalkyl, C 2-6 A straight-chain or branched alkenyl group, each R 16 、R 17 independently selected from H, C 1-30 Straight-chain or branched alkyl or cycloalkyl, C 2-30 straight-chain or branched alkenyl;

[0018] Where R4 to R 17 The alkyl, cycloalkyl, and alkenyl groups are unsubstituted or substituted by one or more groups selected from hydroxyl, thiol, amino, substituted amino, and halogen;

[0019] The salts do not include quaternary ammonium salts.

[0020] In a preferred embodiment, R1, R2, and R3 are independently the following groups:

[0021] Where Y does not exist or is C 1-30 Straight chain or branched chain alkyl or cycloalkyl, C 2-20 Straight-chain or branched alkenyl, C 2- 20 Straight or branched alkynyl; R1', R2' are independently H, C 1-30 Straight-chain or branched alkyl, C 2-30 Straight-chain or branched alkenyl, C 2-30 The total carbon chain length of Y, R1' and R2' is 8-40.

[0022] In a preferred embodiment, R1, R2, and R3 are independently selected from the following groups:

[0023] Wherein, R1' and R2' are independently H, C 1-30 Straight-chain or branched alkyl, C 2-30 Straight-chain or branched alkenyl, C 2- 30 The total carbon chain length of R1' and R2' is 8-30.

[0024] In a preferred embodiment, R1, R2, and R3 are independently selected from any one of the following groups:

[0025] In a preferred embodiment, G1, G2, and G3 are independently -O-, -S-, -NR6-, -SS-, -C(=O)-, -C(=O)O-, -CH(OH)-, -OC(=O)-, -C(=O)NR6-, -NR6C(=O)-, -OC(=O)O-, -NR6C(=O)O-, -OC(=O)NR6-, -NR6C(=O)NR 13 -, -P(=O)(OR6)O-, -OP(=O)(OR6)- or -OP(=O)(OR6)O-.

[0026] In a preferred embodiment, L1 is selected from -(CR7R8) m -X1-, wherein X1 is selected from -O-, -S-, -NR 14 -, -SS-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 14 -、-NR 14 C(=O)-, -OC(=O)O-, -NR 14 C(=O)O-, -OC(=O)NR 14 -、-NR 14 C(=O)NR 15 -、-P(=O)(OR 14 )O-、-OP(=O)(OR 14 )-or-OP(=O)(OR 14 )O-.

[0027] In a preferred embodiment, L2 is -(CR9R 10 ) n -X2-(CR 11 R 12 ) k -, wherein X2 is selected from -O-, -S-, -NR 16 -, -SS-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 16 -、-NR16 C(=O)-, -OC(=O)O-, -NR 16 C(=O)O-, -OC(=O)NR 16 -、-NR 16 C(=O)NR 17 -、-P(=O)(OR 16 )O-、-OP(=O)(OR 16 )-or-OP(=O)(OR 16 )O-.

[0028] In a preferred embodiment, M is selected from the following structures:

[0029] wherein m' and n' are independently integers of 0-6, R1" and R2" are independently H, C 1-6 Alkyl, C 2-6 The alkenyl, guanidino, amidino, amide, fatty amine, 3-10 membered nitrogen-containing heterocycle; the nitrogen-containing heterocycle is selected from pyrrole, imidazole, pyridine, pyrazole, triazole, oxazole, isoxazole, thiophene, isothiazole, pyridazine, pyrazine, piperazine, indole, benzimidazole, carbazole, quinoline, isoquinoline, purine and pyrimidine and tautomeric forms thereof, which are unsubstituted or optionally substituted with one or more selected from hydroxyl, thiol, amino, substituted amino, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-14 The aromatic group is substituted with an organic group.

[0030] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1A):

[0031] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1B):

[0032] In a preferred embodiment, the compound of formula (1) is selected from the compound of formula (1C):

[0033] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1D):

[0034] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1E)

[0035] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1F):

[0036] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1G):

[0037] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1H):

[0038] In a preferred embodiment, M is selected from any one of the following groups:

[0039] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (II):

[0040] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1J):

[0041] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1K):

[0042] In a preferred embodiment, Y is absent and the compound of formula (1) is selected from the compounds represented by formula (1L):

[0043] In a preferred embodiment, the compound of formula (1) is selected from the compound represented by formula (1M):

[0044] In a preferred embodiment, the compound of formula (1) is selected from:

[0045] In a second aspect, the present invention provides a method for preparing the aforementioned ionizable cationic lipid compound, comprising the steps of reacting a compound of formula (II) with a compound of formula (III):

[0046] Wherein, Xa and Xb are groups containing a leaving group or a nucleophilic group, and Xa and Xb form L1 through a nucleophilic reaction or a condensation reaction.

[0047] In a third aspect, the present invention provides a method for preparing the aforementioned ionizable cationic lipid compound, comprising the steps of reacting a compound of formula (IV) with a compound of formula (V):

[0048] wherein Xc and Xd are groups containing a leaving group or a nucleophilic group, and Xc and Xd form L2 through a nucleophilic reaction or a condensation reaction.

[0049] In a fourth aspect, the present invention provides a method for preparing the aforementioned ionizable cationic lipid compound, comprising the steps of reacting a compound of formula (VI):

[0050] wherein Xe is a group containing a leaving group or a nucleophilic group, Xf is a compound containing a leaving group or a nucleophilic group, and Xe and Xf form M through a nucleophilic reaction or a condensation reaction.

[0051] In a fifth aspect, the present invention provides a method for preparing the aforementioned ionizable cationic lipid compound, comprising the steps of reacting a compound of formula (VII) with a compound of formula (VIII), a compound of formula (IX), and a compound of formula (X) in sequence:

[0052] wherein Xg, Xh, Xi, Xj, Xk, and Xl are groups containing a leaving group or a nucleophilic group, and Xg and Xj form G1 through a nucleophilic reaction or a condensation reaction, Xh and Xk form G2 through a nucleophilic reaction or a condensation reaction, and Xi and Xl form G3 through a nucleophilic reaction or a condensation reaction.

[0053] In a sixth aspect, the present invention provides a method for preparing the aforementioned ionizable cationic lipid compound, comprising the step of reacting a compound of formula (XI) with a compound of formula (XII):

[0054] Steps for reacting the compound of formula (XIII) with the compound of formula (XII):

[0055] wherein Xm is a group containing a nucleophilic group, and Xm and C=CL of the compound of formula (XII) 2a X1-L2 is formed by addition reaction.

[0056] In a preferred embodiment, R1, R2, and R3 are independently of one another the following groups:

[0057] Wherein, Y, R1', and R2' have the same meanings as above;

[0058] It also includes the steps of forming tail chains R1, R2, and R3:

[0059] Wherein X is a leaving group.

[0060] In a preferred embodiment, the raw materials used in the reaction process also contain a protecting group, and the reaction steps include protection and / or deprotection steps.

[0061] Those skilled in the art will recognize that it may be necessary to use protecting groups to protect certain groups from reaction conditions. Protecting groups can also be used to distinguish similar functional groups in molecules. A list of protecting groups and methods for introducing and removing these groups can be found in Wuts, PGM, Greene, TW, Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons: New Jersey, 2007.

[0062] Preferred protecting groups include, but are not limited to, protecting groups for hydroxyl groups, protecting groups for amino or amine groups, protecting groups for carboxyl groups, protecting groups for aldehydes or ketones, protecting groups for thiol groups, and protecting groups for any combination of functional groups such as hydroxyl groups, amino or amine groups, carboxyl groups, aldehydes or ketones, and thiol groups.

[0063] In a preferred embodiment, the protecting group for the hydroxyl group can be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the methyl group and the substituted methyl group can be selected from: methoxymethyl group, methylmercaptomethyl group (phenyldimethylsilyl) methoxymethyl group, benzyloxymethyl group, p-methoxybenzyloxymethyl group, [(3,4-dimethoxybenzyl)oxy]methyl group, p-nitrobenzyloxymethyl group, o-nitrobenzyloxymethyl group, [(R)-1-(2-nitrophenyl)ethoxy]methyl group, (4-methoxyphenoxy)methyl group, o-methoxyphenoxymethyl group, p-phenylphenoxymethyl group, tert-butoxymethyl group, 4-isopentyloxymethyl group, silanyloxymethyl group, 2-methoxyethoxymethyl group, 2-cyanoethoxymethyl group, di(2-chloroethoxy)methyl group, 2,2,2-trichloroethoxymethyl group 1-[[(4-(trimethylsilyl)ethoxy)methyl]-1,4-dimethylsilyl)ethoxy ... (2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1-(4-chlorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxane-2-yl, tetrahydrofuran-2-yl, thiotetrahydrofuran-2-yl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-menthofuran-2-yl.

[0064] In a preferred embodiment, the protecting group for the hydroxyl group may be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the substituted ethyl group may be selected from the group consisting of: 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-hydroxyethyl, 2-bromoethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl, 1,1-di-p-methoxyphenyl- 2,2,2-trichloroethyl, 1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 1-(2-cyanoethoxy)ethyl, 2-trimethylsilylethyl, 2-(benzylmercapto)ethyl, 2-(phenylseleno)ethyl, tert-butyl, cyclohexyl, 1-methyl-1'-cyclopropylmethyl, allyl, isopentyl, cinnamyl, 2-phenylvinyl, propargyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, etc.

[0065] In a preferred embodiment, the protecting group for the hydroxyl group can be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the benzyl group and the methoxy-substituted benzyl group can be selected from the group consisting of p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, pentadienylnitrobenzyl, pentadienyl nitrobenzyl, 2,6-dichlorobenzyl, 2,4-dichlorobenzyl, 2,6-difluorobenzyl, p-cyanobenzyl, fluorobenzyl, 4-fluoroalkoxybenzyl , p-trimethylsilylmethylbenzyl, p-phenylbenzyl, 2-phenyl-2-propyl, p-p-acetamidobenzyl, p-4-azidobenzyl, 4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, p-(methylsulfinyl)benzyl, p-(Si-methyl-cyclotetrasilyl)benzyl, 4-acetoxybenzyl, 4-(2-trimethylsilyl)ethoxymethoxybenzyl, 2-naphthylmethyl, 2-pyridylmethyl, 4-pyridylmethyl, 3-methyl-N-oxy-2-pyridylmethyl, 2-quinolylmethyl, 6-methoxy-2-(4-methylphenyl)-4-quinolyl, 1 -pyrenylmethyl, diphenylmethyl, 4-methoxydiphenylmethyl, 4-phenyldiphenylmethyl, di(p-nitrophenyl)methyl, 5-diphenylcycloheptyl, triphenylmethyl, tri(4-tert-butylphenyl)methyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-benzoyl)phenyldiphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalamidophenyl)methyl, 4,4',4"-tris(levulinyloxyphenyl)methyl, 4,4',4"-tris(benzyloxyphenyl)methyl triphenylmethyl, 4,4'-dimethoxy-3"-[N-(imidazolylmethyl)]triphenylmethyl, 4,4'-dimethoxy-3"-[N-(imidazolylmethyl)aminoacyltriphenylmethyl, di(4-methoxyphenyl)-1'-pyrenylmethyl, 4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4"-dimethoxytriphenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-phenylthioanthenyl, 9-(9-phenyl-10-oxo)anthryl, 4,5-bis(ethoxycarbonyl)-[1,3]-dioxolane-2-yl, S,S-dioxobenzisothiazole, etc.

[0066] In a preferred embodiment, the protecting group for the hydroxyl group can be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the silyl group can be selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl-n-hexylsilyl, 2-norcananedimethylsilyl, tert-butylsilyl, 1-(tert-butyl)-1-pyrenylmethoxysilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl, 1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl, fluoroalkylsilyl, etc.

[0067] In a preferred embodiment, the protecting group for the hydroxyl group may be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the acyl group can form an ester with an alcohol, and may be: formate, benzyloxyformate, ethyl ester, chloroacetate, dichloroacetate, triacetate, trichloroacetimidate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, phenylacetate, p-phenylacetate, diphenylacetate, 3-phenylacetate Propionate, propionate containing two fluorinated alkyl chains, 4-pentenoate, fructose, 4,4-(ethylenedithio)pentanoate, 5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy] fructose, pivalate, 1-adamantanecarboxylic acid, 2-butenoate, 4-methoxy-2-butenoate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate, 4-bromobenzoate, 2,5-difluorobenzoate, p-nitrobenzoate, pyridine-2-carboxylate, nicotinic acid, 2-(azidomethyl)benzoate, 4-azidobutyrate, (2-azidomethyl)benzoate benzoate, 2-{[(triphenylmethylmercapto)oxy]methyl}benzoate, 2-{[(4-methoxytriphenylmethylmercapto)oxy]methyl}benzoate, 2-{[methyl(trityl)amino]methyl}benzoate, 2-{{[(4-methoxytriphenylmethyl)mercapto]methylamino}-methyl}benzoate, 2-(allyloxy)phenylacetate, 2-(isopentenyloxymethyl)benzoate, 6-(fructosyloxymethyl)-3-methoxy-2-nitrobenzoate, 6-(fructosyloxymethyl)-3-methoxy-4-nitrobenzoate, 4-[[(4-methoxytriphenylmethyl)mercapto]methyl]methyl]benzoate -benzyloxybutyrate, 4-triallylsilyloxybutyrate, 4-acetoxy-2,2-dimethylbutyrate, 2,2-dimethyl-4-valerate, 2-iodobenzoate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 4-(methylmercaptomethoxy)butyrate, 2-(methylmercaptomethoxy)benzoate, 2-(chloroacetoxymethyl)benzoate, 2-[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate, 2-[2-(4-methoxybenzyloxy)ethyl]benzoate, etc.;

[0068] In a preferred embodiment, the protecting group for the hydroxyl group can be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the sulfonate, sulfinate or sulfenyl ester, for example, sulfate, allyl sulfonate, methanesulfonate, benzyl sulfonate, p-toluenesulfonate, 2-[(4-nitrophenyl)ethyl]sulfonate, 2-trifluoromethylsulfonate, 4-monomethoxytriphenylmethylsulfenyl ester, 2,4-dinitrophenylsulfenyl ester, 2,2,5,5-tetramethylpyrrolidine-3-one-sulfenyl ester and the like;

[0069] In a preferred embodiment, the protecting group for the hydroxyl group may be borate ester or dimethylphosphorothioate.

[0070] In a preferred embodiment, the protecting group for the hydroxyl group may be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the carbonate group may be: methyl carbonate, methoxymethyl carbonate, 9-fluorenylmethyl carbonate, Ethyl carbonate, bromoethyl carbonate, 2-(methylmercaptomethoxy)ethyl, 2,2,2-trichloroethyl carbonate, 1,1-dimethyl-2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-[dimethyl(2-naphthylmethyl)silyl]ethyl carbonate, 2-(phenylsulfonyloyl)ethyl carbonate, 2-(triphenylphosphino)ethyl carbonate, Cis-[4-[[(-methoxytriphenylmethyl)sulfenyl]oxy]tetrahydrofuran-3-yl]oxy carbonate, isobutyl carbonate, tert-butyl carbonate, vinyl carbonate, allyl carbonate, cinnamyl carbonate, propargyl carbonate, p-chlorophenyl carbonate, p-nitrophenyl carbonate, 4-ethoxy-1-naphthyl carbonate, 6-bromo-7-hydroxycoumarin-4-ylmethyl carbonate esters, benzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, anthraquinone-2-yl methyl carbonate, 2-dansylethyl carbonate, 2-(4-nitrophenyl)ethyl carbonate, 2-(2,4-dinitrophenyl)ethyl carbonate, 2-(2-nitrophenyl)propyl carbonate, 2-(3,4-methylenedioxy-6-nitrophenylpropyl 294 carbonate, 2-cyano-1-phenylethyl carbonate, 2-(2-pyridyl)amino-1-phenylethyl carbonate, 2-[N-methyl-N-(2-pyridyl)]amino-1-phenylethyl carbonate, phenacyl carbonate, 3',5'-dimethoxybenzoinyl carbonate, methyl dithiocarbonate, S-benzylthiocarbonate, etc.;

[0071] In a preferred embodiment, the protecting group for the hydroxyl group can be a substituted methyl group, a substituted ethyl group, a substituted benzyl group, a silyl group, an acyl group, a sulfonyl group, a sulfinyl group, a sulfenyl group, a carbamoyl group, a carbonate group, a borate group and a phosphoryl group, wherein the carbamate can be: N,N-dimethylthiocarbamate, N-phenylcarbamate, N-methyl-N-(o-nitrophenyl)carbamate and the like.

[0072] In a preferred embodiment, the 1,2-diol or 1,3-diol can be protected by forming a cyclic acetal or ketal, a cyclic orthoester, a silane derivative, a cyclic carbonate or a cyclic borate, wherein the protecting group for forming the cyclic acetal or ketal can be: methylene, ethylene, tert-butylmethylene, 1-tert-butylethylene, 1-phenylethylene, 2-(methoxycarbonyl)ethylene, 2-(tert-butylcarbonyl)ethylene, phenylsulfonylethylene, 2,2,2-trichloroethylene, 3-(benzyloxy)propylene, acrolein acetal, acetone (isopropylidene), Cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 1-(4-methoxyphenyl)ethylene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, p-acetoxybenzylidene, 4-(tert-butyldimethylsilyloxy)benzylidene, 2-nitrobenzylidene, 4-nitrobenzylidene, mesitylene, 6-bromo-7-hydroxycoumarin-2-methylene, 1-naphthaldehyde acetal, 2-naphthaldehyde acetal, 9-anthracene acetal, benzophenone ketal, di-(p-anisyl)methylene ketal, xanthene-9-ylidene, 2,7-dimethylxanthene-9-ylidene.

[0073] In a preferred embodiment, 1,2-diol or 1,3-diol can be protected by forming a cyclic acetal or ketal, a cyclic orthoester, a silane derivative, a cyclic carbonate or a cyclic borate, wherein the protecting group for forming a cyclic orthoester can be: methoxymethylene, ethoxymethylene, 2-oxacyclopentylidene, dimethoxymethylene, 1-methoxyethylene, 1-ethoxyethylene, methylene, phthalide, 1,2-dimethoxyethylene, α-methoxybenzylene, 1-(N,N-dimethylamino)ethylene derivatives, α-(N,N-dimethylamino)benzylene derivatives, butane-2,3-diacetal, cyclohexane-1,2-diacetal, dispiroketal, etc.

[0074] In a preferred embodiment, the 1,2-diol or 1,3-diol can be protected by forming a cyclic acetal or ketal, a cyclic orthoester, a silane derivative, a cyclic carbonate or a cyclic borate, wherein the silane derivative protecting group can be: di-tert-butylsilylene, dialkylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxane) derivative, 1,1,3,3-tetra-tert-butoxydisiloxane derivative, methylene-bis-(diisopropylsiloxane)methylene, 1,1,4,4-tetraphenyl-1,4-disilanylidene, o-xylene ether, 3,3'-oxybis(dimethoxytrityl) ether, 1,2-ethylene-3,3-bis(4",4'-dimethoxytrityl) ether.

[0075] In a preferred embodiment, the 1,2-diol or 1,3-diol can be protected by forming a cyclic acetal or ketal, a cyclic orthoester, a silane derivative, a cyclic carbonate or a cyclic boronate, wherein the protecting group for forming the cyclic carbonate can be a formyl group.

[0076] In a preferred embodiment, the 1,2-diol or 1,3-diol can be protected by forming a cyclic acetal or ketal, a cyclic orthoester, a silane derivative, a cyclic carbonate or a cyclic borate, wherein the protecting group forming the cyclic borate can be: methyl borate, ethyl borate, phenyl borate, o-acetamidophenyl borate, etc.

[0077] In a preferred embodiment, the protecting group for the hydroxyl group is preferably selected from the following protecting groups: tetrahydropyranyl (THP), methyl (Me), benzyl (Bn), methoxymethyl (MOM), allyl (All), triphenylmethyl (Trt), acetyl (Ac), pivaloyl (Piv), tert-butyldimethylsilyl (TBDMS), tert-butyldimethylsilyl (TBDPS), trimethylsilyl (TMS), triethylsilyl (TES), phthalimide (Phth), tert-butyloxycarbonate (Boc), benzyloxycarbonate (Cbz), 9-fluorenylmethoxycarbonate (Fmoc).

[0078] In a preferred embodiment, the protecting group for the carboxylic acid can be a substituted methyl ester, a substituted ethyl ester, a phenyl ester or a substituted phenyl ester, a silyl ester, an amino group or a hydrazine group, wherein the substituted methyl ester can be: 9-fluorenylmethyl ester, methoxymethyl ester, 2-methoxyethoxymethyl, methylmercaptomethyl ester, 2-tetrahydropyranyl ester, 2-tetrahydrofuranyl ester, 2-(trimethylsilyl)ethoxymethyl ester, benzyloxymethyl ester, triisopropylsilyloxymethyl ester, pivaloyloxymethyl ester, Phenylacetoxymethyl ester, triisopropylsilylmethyl ester, cyanomethyl ester, acetone alcohol ester, phenacyl ester, p-bromophenacyl ester, α-methylphenacyl ester, p-methoxyphenacyl ester, 3,4,5-trimethoxyphenacyl ester, 2,5-dimethylphenacyl ester, dibenzoyl ester, aminoacyl methyl ester, p-azoanilinoformyl ester, 6-bromo-7-hydroxycoumarin-4-yl methyl ester, N-phthalamidomethyl ester, etc.

[0079] In a preferred embodiment, the protecting group for the carboxylic acid is a substituted ethyl ester, for example: 2,2,2-trichloroethyl ester, 2-haloethyl ester, A-chloroalkyl ester, 2-(trimethylsilyl)ethyl ester, (2-methyl-2-trimethylsilyl)ethyl ester, (2-phenyl-2-trimethylsilyl)ethyl ester, 2-methylthioethyl ester, 1,3-dithiane-2-methyl ester, 2-(p-nitrophenylsulfinyl)ethyl ester, 2-(p-methylphenylsulfonyl)ethyl ester, 2-(2'-pyridyl)ethyl ester, 2-(diphenylphosphino)ethyl ester, (p-methoxyphenyl)ethyl ester, 1-methyl-1-phenylethyl ester, 2-(4-acetyl-2-nitrophenyl)ethyl ester, 1-[2-(2-hydroxyalkyl)phenyl]ethanone, 2-cyanoethyl ester, tert-butyl ester, 3-methyl-3-pentyl ester, dicyclopropyl methyl ester, 2,4-dimethyl-3-pentyl ester, cyclopentyl ester, cyclohexyl ester, allyl ester, methallyl ester, 2-methyl-3-buten-2-yl ester, 3-methyl-2-butenyl ester, 3-butenyl ester, 4-(trimethylsilyl)-2-buten-1-yl ester, cinnamyl ester, α-methylcinnamyl ester, propargyl ester, etc.

[0080] In a preferred embodiment, the protecting group for the carboxylic acid is a phenyl ester or a substituted phenyl ester, for example: phenyl ester, 2,6-dimethylphenyl ester, 2,6-diisopropylphenyl ester, 2,6-di-tert-butyl-4-methylphenyl ester, 2,6-di-tert-butyl-4-methoxyphenyl ester, p-(dimethylthio)phenyl ester, pentafluorophenyl ester, 2-(dimethylamino)-5-nitrophenyl ester, etc.

[0081] In a preferred embodiment, the protecting group for the carboxylic acid is a benzyl ester or a substituted phenyl ester, for example: benzyl ester, triphenylmethyl ester, 2-chlorophenyldiphenylmethyl ester, 2,3,4,4',4",5,6-heptafluorotriphenylmethyl ester, diphenylmethyl ester, di(o-nitrophenyl)methyl, 9-anthrylmethyl ester, 2-(9,10-dioxo)anthrylmethyl ester, 5-dibenzosuberyl ester, 1-pyrenylmethyl ester, 2-(trifluoromethyl)-6-cromolylmethyl ester, 2,4,6-trimethylbenzyl ester, p-bromobenzyl ester, o-nitrobenzyl ester, p-nitrobenzyl ester, p-methoxy Benzyl ester, 2,6-dimethoxybenzyl ester, 4-(methylxanthoyl)benzyl ester, 4-sulfonic acid benzyl ester, 4-azidomethoxybenzyl ester, 4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl ester, piperonyl ester, 4-picolyl ester, polymer-substituted benzyl ester, 2-naphthyl methyl ester, 3-nitro-2-naphthyl methyl ester, 4-quinolyl methyl ester, 8-bromo-7-hydroxyquinolin-2-yl methyl ester, 2-nitro-4,5-dimethoxybenzyl ester, 1,2,3,4-tetrahydro-1-naphthyl ester, and the like.

[0082] In a preferred embodiment, the protecting group for the carboxylic acid can be a silyl ester, for example: trimethylsilyl ester, tri- and silyl ester, tert-butyldimethylsilyl ester, tert-butyldiphenylsilyl ester, isopropyldimethylsilyl ester, phenyldimethylsilyl ester, di-tert-butylmethylsilyl ester, triisopropylsilyl ester, tris(2,6-diphenylbenzyl)silyl ester, and the like.

[0083] In a preferred embodiment, the protecting group for the carboxylic acid can be an amino group or a hydrazine group, for example: N,N-dimethylamino, pyrrolinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilino, N-7-nitroindolyl, N-8-nitro-1,2,3,4-tetrahydroquinolinyl, 2-(2-aminophenyl)acetaldehyde dimethyl acetal, p-polymer-benzenesulfonamide, N-phenylhydrazine, N,N'-dimethylhydrazine, N,N'-diisopropylhydrazine, etc.

[0084] In a preferred embodiment, the protection of carboxylic acid can also be achieved by chemically converting the carboxylic acid group into the following groups: 2-alkyl-1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazoline, 2,2-ditrifluoromethyl-4-alkyl-5-oxo-1,3-oxazoline, 2,2-dimethyl-4-alkyl-2-silan-5-oxo-1,3-oxazoline, 2,2-difluoro-1,3,2-oxazolidin-5-one, 5-alkyl-4-oxo-1,3-dioxolane, dioxanone, orthoester, pentaaminocobalt (III) complex, etc.

[0085] In a preferred embodiment, the protecting group for the carboxyl group is preferably selected from the following protecting groups: tert-butyl ester (t-Bu), benzyl ester (Bn), methyl ester (Me), ethyl ester (Et), allyl ester (All), isopropyl ester (i-Pr), isobutyl ester (i-Bu), triphenylmethyl ester (Trt), methoxymethyl (MOM), tert-butyldisilyl ester (TBDMS), 9-fluorenylmethoxycarbonyl (Fmoc).

[0086] In a preferred embodiment, the protecting group for amino or amine groups can be a carbamate ROC(O)N(R')2 wherein N(R')2 is a protected group and R can be a methyl or substituted methyl group, for example: methyl, 9-fluorenylmethyl, 2,6-di-tert-butyl-9-fluorenylmethyl, 2,7-bis(trimethylsilyl)fluorenylmethyl, 9-(2-sulfonic acid)fluorenylmethyl, 9-(2,7-di- bromo)fluorenylmethyl, 17-tetrabenzo[a,c,g,i]fluorenylmethyl, 2-chloro-3-indenylmethyl, benzo[f]inden-3-ylmethyl, 1,1-dioxobenzo[b]thiophen-2-ylmethyl, 2-methanesulfonyl-3-phenyl-1-prop-2-enoyloxy, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthone)]methyl, and the like.

[0087] In a preferred embodiment, the protecting group for the amino or amine group can be a carbamate ROC(O)N(R')2 wherein N(R')2 is a protected group and R can be an ethyl or substituted ethyl group, for example: 2,2,2-trichloroethyl, 2-trimethylsilylethyl, (2-phenyl-2-trimethylsilyl)ethyl, 2-phenylethyl, 2-chloroethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 2-(2'-pyridyl)ethyl, 2-(4'-pyridyl)ethyl, 2,2-bis(4'-nitrophenyl)ethyl, 2-[(2-nitrophenyl)dimercapto]-1-phenylethyl, 2-(N,N-dicyclohexylcarbamoyl)ethyl, tert-butyl, Fluorine-substituted Boc, 1-adamantyl, 2-adamantyl, 1-(1-adamantane)-1-methylethyl, 1-methyl-1-(4-biphenyl)ethyl, 1-(3,5-di-tert-butylphenyl)-1-methylethyl, triisopropylsilyl, vinyl, allyl, isopentenyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 3-(3'-pyridyl)prop-2-enyl, hexadienyl, propargyl, but-2-yn-1,4-diyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldisulfide, benzyl, 3,5-di-tert-butylbenzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfenylbenzyl, 4-trifluoromethylbenzyl, fluorobenzyl, 2-naphthylmethyl, 9-anthrylmethyl, diphenylmethyl, and the like.

[0088] In a preferred embodiment, the protecting group for the amino or amine group can be a carbamate ROC(O)N(R')2 wherein N(R')2 is the protected group and R can be the following groups: 4-phenylacetylbenzyl, 4-azidobenzyl, 4-azidomethoxybenzyl, m-chloro-p-acetoxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromanylmethyl, 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, 2-(4-nitrobenzenesulfonyl)ethyl, 2-(2,4-dinitrobenzenesulfonyl)ethyl, 2- (4-trifluoromethylphenylsulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 2-alkylphosphinoethyl, 2-[phenyl(methyl)sulfide]ethyl, 1-methyl-1-(triphenylphosphine)ethyl, 1,1-dimethyl-2-cyanoethyl, 2-dansylethyl, 2-(4-nitrophenyl)ethyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, m-nitrophenyl, 3,5-dimethoxybenzyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, α-methylnitropiperonyl, nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, 3,4-disubstituted-6-nitrobenzyl, Phenyl(o-nitrophenyl)methyl, 2-nitrophenylethyl, 6-nitroveratryl, 4-methoxyphenacyl, 3',5'-dimethoxybenzoinyl, 9-xanthenylmethyl, N-methyl-N-(o-nitrophenyl), N-(2-acetoxyethyl)amino, 1-methyl-1-cyclopropylmethyl, tert-amyl, 1-methylcyclobutyl, 1-methylcyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, isobutyl, isobornyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylformamido)benzyl 1-(4'-pyridyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, p-(p-methoxyphenylazo)benzyl, p-(phenylazo)benzyl, 2,4,6-trimethylbenzyl, isonicotine, 4-(trimethylammonium)benzyl, p-cyanobenzyl, di(2-pyridyl)methyl, 2-furylmethyl, phenyl, 2,4,6-tri-tert-butylphenyl, 1-methyl-1-phenylethyl, benzylthiocarbamate.

[0089] In a preferred embodiment, the protecting group for the amino or amine group can be a urea or thiourea derivative RN(R')2, wherein N(R')2 is the protected group and R can be selected from the following groups: carbamoyl, phenothiazinyl-(10)-carbonyl derivative, N'-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl, 4-hydroxyphenylaminocarbonyl, 3-hydroxytryptaminecarbonyl, N'-phenylaminothiocarbonyl, etc.

[0090] In a preferred embodiment, the protecting group for the amino or amine group can be an amide RN(R')2, wherein N(R')2 is a protected group and R can be selected from the following groups: formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, 3-phenylpropionyl, pent-4-enoyl, pyridylformyl, 3-pyridylformyl, N-benzoylphenylpropanyl derivatives, benzoyl, p-phenylbenzoyl, o-nitrophenylacetyl, 2,2-dimethyl-2-o-nitrophenylacetyl, o-nitrophenoxyacetyl, 3-(o-nitrophenyl)propionyl, 2-methyl-2-(o-nitrophenoxy)propionyl, 3-methyl-3-nitrobutyryl, o-nitrocinnamoyl, o-nitrobenzoyl, 3-(4-tert-butyl-2,6-dinitrophenyl)-2,2-dimethylpropionyl, o-(benzoyloxymethyl)benzoyl, 2-(acetoxymethyl)benzoyl, 2-[(tert-butyldiphenylsilyloxy)methyl]benzoyl, 3-(3',6'-dioxo-2',4',5-trimethylcyclohexa-1,4-diene)-3,3-dimethylpropionyl, o-hydroxytrans-cinnamoyl, 2-methyl-2-(o-phenylazophenoxy)propionyl, 4-chlorobutyryl, acetylacetyl, 3-(p-hydroxyphenyl)propionyl, (N'-dithiobenzyloxycarbonylamino)acetyl, N-acetylmethionine derivatives, and the like.

[0091] In a preferred embodiment, a double protection scheme can be used for the primary amino group, and the protecting group can be selected from the following groups: 4,5-diphenyl-3-oxazolin-2-one, N-phthaloyl, N-dichlorophthaloyl, N-tetrachlorophthaloyl, N-4-nitrophthaloyl, N-thiodiglycol, N-disulfosuccinyl, N-2,3-diphenylmaleyl, N-2,3-dimethylmaleyl, N-2,5-dimethylpyrrolyl, N-2,5- Bis(triisopropylsilyloxy)pyrrole, N-1,1,4,4-tetramethyl-1,4-disilazane-5-azacyclopentane, N-1,1,3,3-tetramethyl-1,3-disilazane isoindoline, N-diphenylsilyldivinyl group, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, 1,3,5-dioxazine.

[0092] In a preferred embodiment, for N-alkyl-substituted and N-aryl-substituted amine groups, the protecting group can be selected from the following groups: N-methyl, N-tert-butyl, N-allyl, N-isoprenyl, N-cinnamyl, N-phenylallyl, N-propynyl, N-methoxymethyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-cyanomethyl, 2-azanorbornene, N-2,4-dinitrophenyl, o-methoxy or p-methoxyphenyl , N-benzyl, N-4-methoxybenzyl, N-2,4-dimethoxybenzyl, N-2-hydroxybenzyl, N-9-phenylfluoroenyl, N-fluorenyl, N-ferrocenylmethyl, N-2-methylpyridinamine N'-oxide, N-7-methoxy-4-ylmethyl, N-diphenylmethyl, N-bis(4-methoxyphenylmethyl), N-5-dibenzophenethyl, N-triphenylmethyl, N-(4-methylphenyl)diphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, etc.

[0093] In a preferred embodiment, the protection of the amino or amine group can be to prepare an imine derivative, such as: N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)methylene]methylene, N-(N',N'-dimethylaminomethylene), N-(N',N'-dibenzylaminomethylene), N-(N'-tert-butylaminomethylene), N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene, N-tert-butylmethylene, etc.

[0094] In a preferred embodiment, the protection of the amino or amine group can be to prepare an enamine derivative, for example: N-(5,5-dimethyl-3-oxo-1-cyclohexenyl), N-2,7-dichloro-9-fluorenylmethylene, N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, N-(1,3-dimethyl-2,4,6-(1H,3H,5H)-trioxopyrimidin-5-ylidene)methyl, N-4,4,4-trifluoro-3-oxo-1-butenyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl).

[0095] In a preferred embodiment, the amino or amine group can be protected by a derivative formed by reacting the nitrogen atom of the amino or amine group with another heteroatom (e.g., N, O, P, Si or S), such as N-nitro, N-nitroso, N-oxide, azide, triazacyclolene, N-trimethylsilylmethyl-N-benzylhydrazine, N-diphenylphosphinamide, dimethyl and diphenylthiophosphinamide, dialkylphosphoramidites, dibenzyl and diphenylphosphoramidites, iminotriphenylphosphane, tritylsilyl, benzenesulfamide, 2-nitrobenzenesulfamide, 2,4-dinitrobenzenesulfamide, pentachlorobenzenesulfamide, 2-nitro-4-methoxybenzenesulfamide, triphenylmethylsulfamide, 1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfamide, N-3-nitro-2-pyridylsulfamide, methanesulfonamide, trifluorosulfonamide, tert-butylsulfonamide, benzylsulfonamide, 2-(trimethylsilyl)sulfonamide Ethylsulfonamide, p-toluenesulfonamide, benzenesulfonamide, anisesulfonamide, 2- or 4-nitrobenzenesulfonamide, 2,4-dinitrobenzenesulfonamide, 2-naphthalenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide), 2-(4-methylphenyl)-6-methoxy-4-methylsulfonamide, 9-anthracenesulfonamide, pyridine-2-sulfonamide, benzothiazole-2-sulfonamide, phenacylmethylsulfonamide, 2,3,6-trimethyl-4-methyl 2,4,6-trimethoxybenzenesulfonamide, 2,6-dimethyl-4-methoxybenzenesulfonamide, pentamethylbenzenesulfonamide, 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide, 4-methoxybenzenesulfonamide, 2,4,6-trimethylbenzenesulfonamide, 2,6-dimethoxy-4-methylbenzenesulfonamide, 3-methoxy-4-tert-butylbenzenesulfonamide, 2,2,5,7,8-pentamethylbenzopyran-6-sulfonamide, and the like.

[0096] In a preferred embodiment, the protection of amino alcohol or amino alcohol can be carried out by converting the amine group or amino group with the hydroxyl group into 2-oxazolidinone or oxazoline.

[0097] In a preferred embodiment, the nitrogen-containing aromatic heterocycles may be selected from the N-sulfonyl derivatives, carbamates, N-alkyl and N-aryl derivatives, N-trialkylsilyl, N-allyl, N-benzyl, amides, aminoacetal derivatives, and protecting groups for amides and yellow amides as described above.

[0098] In a preferred embodiment, the protecting group for the amino group is preferably selected from the following protecting groups: 9-fluorenylmethoxycarbonyl protecting group (Fmoc), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), trichloroethoxycarbonyl (Troc), allyloxycarbonyl (Alloc), methoxycarbonyl (Moc), acetyl (Ac), trifluoroacetyl (TFA), 2,4-dimethoxybenzyl (DMB), benzyl (Bn), trityl (Tr), benzyloxymethyl (Bom), p-toluenesulfonyl (Ts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr) phthalimide (Phth), benzylamine.

[0099] In a preferred embodiment, the protection of the aldehyde or ketone group can be carried out by forming an acetal or ketal, a dithio or monothio acetal or ketal, a geminal nitrile, a substituted hydrazone, an oxime, a 1,2-adduct, or converting the carbonyl group into an enolate, an enol ester, an enamine, or an imine.

[0100] In a preferred embodiment, the protection of the aldehyde group or ketone group can be carried out by forming an acetal or ketal, and the protecting group can be selected from the group consisting of: dimethyl, diisopropyl, bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl), diacetyl, 1,3-dioxane, 5-methylene-1,3-dioxane, 5-trimethylsilyl-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, salicylic acid acetal. , 1,3-dioxolane, 4,4,5,5-tetramethyl-1,3-dioxolane, 4-bromomethyl-1,3-dioxolane, 4-phenylsulfonylmethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(4-methoxyphenyl)-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4-(4-nitrophenyl)-1,3-dioxolane, 4-fluoro-1,3-dioxolane, 4 -[6-bromo-7-hydroxycoumarin-4-yl]-1,3-dioxane, 4-trimethylsilyl-1,3-dioxolane, O,O'-benzenedioxyketal, 1,3-dioxolane, 1,5-dihydro-3H-2,4-benzodioxepane, 7,7-dimethyl-1,2,4-trioxepane, 3,3-dialkyl-6-(1-phenylvinyl)-1,2,4-trioxane, (4R,5R)-diphenyl-1,3-dioxolane, 4,5-dimethyl 1,3-dioxolane, trans-1,2-cyclohexanediol ketal, trans-4,6-dimethyl-1,3-dioxolane, 4,5-bis(dimethylaminocarbonyl)-1,3-dioxolane, 4,5-diformylmethoxy-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, 2,2-dialkyl-4,5-bis(2-nitrophenyl)-1,3-dioxolane, 4,5-bis(2-nitro-4,5-dimethoxyphenyl)-1,3-dioxolane, and the like.

[0101] In a preferred embodiment, the protection of the aldehyde group or ketone group can be carried out by forming a dithioacetal or ketal, and the protecting group can be selected from: S,S'-dimethyl, S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl, S,S'-dipentyl, S,S'-diphenyl, S,S'-dibenzyl, S,S'-diacetyl, 1,3-dithiane, 1,3-dithiocycloalkane, 1,5-dihydro-3H-2,4-dithiocycloheptane, etc.

[0102] In a preferred embodiment, the protection of the aldehyde or ketone group can be carried out by forming a monothioacetal or ketal, and the protecting group can be selected from: O-trimethylsilyl-S-alkyl, O-alkyl-S-alkyl or -S-phenyl, O-methyl-S-2-methylthioethyl, 1,3-oxathiapentane, etc.

[0103] In a preferred embodiment, the protection of the aldehyde or ketone group can be carried out by generating an O-substituted geminal nitrile, and the protecting group can be selected from: O-acetyl, O-methoxycarbonyl, O-trimethylsilyl, O-1-ethoxyethyl, O-tetrahydropyranyl, etc.

[0104] In a preferred embodiment, the protection of the aldehyde or ketone group can be carried out by generating a substituted hydrazone, and the protecting group can be selected from: N,N-dimethyl, phenyl, 2,4-dinitrophenyl, p-toluenesulfonyl, semicarbazone, diphenylmethyl, etc.

[0105] In a preferred embodiment, the protection of the aldehyde group or ketone group can be performed by generating a substituted oxime, and the protecting group can be selected from: O-methyl, O-benzyl or O-thiophenol methyl.

[0106] In a preferred embodiment, the protection of the aldehyde group or ketone group can be carried out by forming a 1,2-adduct, and the protecting group can be selected from: diethylamine adduct, N-methoxy-N-methylamine adduct, pyrrole adduct, 1-methyl-2-(1'-hydroxyalkyl)imidazole, O-silyl imidazolylamine acetal, sodium bisulfite adduct, O-carborane, aminobutyronitrile derivatives, N,N'-dimethylimidazolidine, N,N'-diarylimidazolidine, 2,3-dihydro-1,3-benzothiazole.

[0107] In a preferred embodiment, the protection of the aldehyde or ketone group can be carried out by converting the carbonyl group into an enolate anion, an enol ester, an enamine or an imine, for example: lithium diisopropylamide (LDA), trimethylsilyl enol ether, enamine, imine, substituted methylene derivatives, methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) complex, etc.

[0108] In a preferred embodiment, in a compound containing a dicarbonyl group, one of the carbonyl groups can be selectively protected, wherein for α- or β-diketone, the following protection groups can be selected for protection: enamine, enol acetate, enol ether, methyl, ethyl, isobutyl, methoxyethoxymethyl, methoxymethyl, enamine derivatives, 4-methyl-1,3-dioxolane enol acetate, pyrrolidino enamine, benzyl enol ether, butylthioenol ether, etc.

[0109] In a preferred embodiment, the protecting group for the aldehyde or ketone group is preferably selected from the following protecting groups: O,O-dimethylacetal (ketone), 1,3-dioxane, 1,3-dioxolane, S,S'-dimethylthioacetal (ketone), 1,3-dithiane, 1,3-dithiolane, N,N-dimethylhydrazine (DMH), 2,4-dinitrophenylhydrazine (DNPH), semicarbazide, oxime, trimethylsilyl (TMS), Tollen's reagent (silver ammonia solution), etc.

[0110] In a preferred embodiment, the protection of the sulfhydryl group can be carried out by reacting to form a thioether, a thioester, an asymmetric disulfide bond or a sulfinyl derivative, wherein the thioether protecting group can be: S-alkyl, S-benzyl, S-p-methoxybenzyl, S-o- or S-p-hydroxy or acetoxybenzyl, S-p- and S-o-nitrobenzyl, S-2,4,6-trimethylbenzyl, S-2,4,6-trimethoxybenzyl, S-4-pyridylmethyl, S-2-methylpyridyl N-oxide, S-2-quinolylmethyl, S-9-anthracenylmethyl, S-9-fluorenylmethyl, S-xanthenyl, S-ferrocenylmethyl, S-diphenylmethyl, S-bis(4-methoxyphenyl)methyl, S-5-dibenzosuberyl, S-triphenylmethyl, 4-methoxytrityl, S-diphenyl-4-pyridylmethyl, S-phenyl, S-2,4-dinitrophenyl, S-2-quinolyl, S-tert-butyl, S-1-adamantyl, S-methoxymethyl, S-isobutoxymethyl , S-benzyloxymethyl, S-1-ethoxyethyl, S-2-tetrahydropyranyl, S-benzylthiomethyl, S-phenylthiomethyl, thiazolidine, S-acetylaminomethyl, S-trimethylacetylaminomethyl, S-benzamidomethyl, S-allyloxycarbonylaminomethyl, N[2,3,5,6-tetrafluoro-4-(N'-piperidinyl)phenyl]-N-allyloxycarbonylaminomethyl, phthalimidemethyl, S-phenylacetylaminomethyl, S-acetylmethyl, S-carboxyl methyl, S-cyanomethyl, S-(2-nitro-1-phenyl)ethyl, S-2-(2,4-dinitrophenyl)ethyl, S-2-(4'-pyridyl)ethyl, S-2-cyanoethyl, S-2-(trimethylsilyl)ethyl, S-2,2-bis(carbonylethoxy)ethyl, S-(1-m-nitrophenyl-2-benzoyl)ethyl, S-2-phenylsulfonylethyl, S-1-(4-methylphenylsulfonyl)-2-methylpropyl-2-yl, S-p-hydroxybenzoylmethyl.

[0111] In a preferred embodiment, the protection of the sulfhydryl group can be carried out by reacting to form a thioether, a thioester, an asymmetric disulfide bond or a sulfinyl derivative, wherein the thioester protecting group can be: S-acetyl derivative, S-benzoyl derivative, S-2-methoxyisobutyryl, S-trifluoroacetyl derivative, SN-[[(p-biphenyl)isopropoxy]carbonyl]-N-methyl-γ-aminothiobutyrate, SN-(tert-butoxycarbonyl)-N-methyl-γ-aminothiobutyrate, S-2,2,2-trichloroethoxycarbonyl, S-tert-butoxycarbonyl, S-benzyloxycarbonyl, S-p-methoxybenzyloxycarbonyl, S-fluorenylmethylcarbonyl, S-n-ethylaminocarbonyl, S-(N-methoxymethyl)aminocarbonyl, and the like.

[0112] In a preferred embodiment, the protection of the sulfhydryl group can be achieved by reacting to form a thioether, a thioester, an asymmetric disulfide bond or a sulfinyl derivative, wherein the protecting group for forming the asymmetric disulfide bond can be: S-ethyl, S-tert-butyl or substituted S-phenyl, etc.

[0113] In a preferred embodiment, the protection of the sulfhydryl group can be carried out by reacting to form a thioether, a thioester, an asymmetric disulfide bond or a sulfinyl derivative, wherein the protecting group forming the sulfinyl derivative can be: S-sulfonate derivative, S-thiosulfonate derivative, S-sulfinylthiocarbonate, S-3-nitro-2-pyridylthio, S-[tricarbonyl[1',2,3,4,5-η]-2,4-cyclohexadien-1-yliron, oxathioisopentanone, etc.

[0114] In a preferred embodiment, the dithiol group can be protected by reacting to form a dithioacetal or ketal, and the protecting group can be: S, S'-methylene, S, S'-isopropylidene, S, S'-benzylidene or S, S'-p-methoxybenzylidene, etc.

[0115] In a preferred embodiment, the amino group and the thiol group are present at the same time, and the amino group and the thiol group can be protected simultaneously by reacting to generate thiazoline or ninhydrin.

[0116] In a preferred embodiment, the protecting group for the thiol group is preferably selected from the following protecting groups: diphenylmethyl (Dpm), triphenylmethyl (Trt), monomethoxytrityl (Mmt), benzyl (Bn), p-methylbenzyl, p-methoxybenzyl (Mob), 2,4,6-trimethoxybenzyl (Tmob), 2-nitro-benzyl (oNb), 2-nitro-4,5-dimethoxybenzyl (oNv), tert-butyl (tBu), 1-adamantyl, fluorenylmethyl (Fm), 2,4-dinitrophenethyl (Dnpe), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), acetylaminomethyl (Acm), phenylacetylaminomethyl (Phacm), S-tert-butylthio (StBu), S-2-pyridylthio (S-Pyr), S-3-nitro-2-pyridylthio (Npys), tetrahydropyranyl (Thp), methylsulfonyl, p-toluenesulfonyl, and the like.

[0117] The leaving group mentioned above refers to a leaving part in a nucleophilic reaction or a condensation reaction, including but not limited to: H, OH, H2O, halogen (such as F, Cl, Br and I), cyanate anion, inorganic acid (such as nitric acid, sulfuric acid, phosphoric acid), carboxylic acid (such as acetic acid, trifluoroacetic acid and benzoic acid), sulfonic acid (such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and p-nitrobenzenesulfonic acid), carbon dioxide (CO2), nitrogen (N2), imidazole, alkoxy (RO - ), amino (-NHR, wherein R is H, an alkyl or aryl group removed), phenoxy, a tertiary carbon cation (e.g., a tert-butyl cation), a carbon cation stabilized by an unsaturated system or a heteroatom, or the various protecting groups described above.

[0118] The nucleophilic groups mentioned above refer to molecules or ions that can provide electron pairs to form new chemical bonds in chemical reactions. Common nucleophilic groups include: hydroxide (HO - ), ammonia (NH3), hydroxylamine (NH2OH), hydrazine (NH2-NH2), substituted hydrazines, nucleophilic halogens (such as Cl - Br - or I - ), hydrogen ions (H - ), azide anion (N3 - ), cyanate anion (CN - ), alcohol or alkoxy anion (such as alcohol with hydroxyl hydrogen removed), amine group (including primary amine, secondary amine and tertiary amine) or amine anion, carbon anion (such as carbon anion in organometallic reagents such as Grignard reagent, organic lithium reagent, Gilman reagent), sulfhydryl or sulfhydryl anion, sulfide, enol or enol anion, alkenyl ether, enamine, carboxylic acid or carboxylic acid anion, alkyl or aryl phosphine (such as triphenylphosphine), aromatic heterocycle with lone pair electrons (such as pyridine), etc.

[0119] In a preferred embodiment, the synthesis route of the ionizable cationic lipid compound is as follows:

[0120] Wherein, M' is M or M containing a protecting group.

[0121] In a preferred embodiment, the synthesis route of the ionizable cationic lipid compound is as follows:

[0122] Wherein M' is M or M containing a protecting group; A is O, NH or S.

[0123] In a preferred embodiment, the synthesis route of the ionizable cationic lipid compound is as follows:

[0124] Among them, compound 5 is or X' and X are halogen; R4' is R4 or R4 containing a protecting group; R5' is R5 or R5 containing a protecting group.

[0125] In a preferred embodiment, the synthesis route of the ionizable cationic lipid compound is as follows:

[0126] Among them, compound 5 is X' and X are halogen; R4' is R4 or R4 containing a protecting group; R5' is R5 or R5 containing a protecting group.

[0127] In a preferred embodiment, the synthesis route of the ionizable cationic lipid compound is as follows:

[0128] Among them, M pro is M or M containing a protecting group.

[0129] In a seventh aspect, the present invention provides the use of the aforementioned ionizable cationic lipid compound as a surfactant.

[0130] In a preferred embodiment, the ionizable cationic lipid compound is used as an emulsifier, suspending agent, dispersant, solubilizer, lubricant, thickener, bacteriostat or preservative.

[0131] In an eighth aspect, the present invention provides use of the aforementioned ionizable cationic lipid compound in the preparation of a cosmetic composition.

[0132] In a ninth aspect, the present invention provides the use of the aforementioned ionizable cationic lipid compound in the preparation of a lipid composition, wherein the ionizable cationic lipid compound is used as a drug delivery carrier.

[0133] In a tenth aspect, the present invention provides a lipid composition, wherein the lipid component of the lipid composition includes the aforementioned ionizable cationic lipid compound.

[0134] In a preferred embodiment, the lipid component of the lipid composition further comprises other lipids, including phospholipids, structured lipids, and PEG-conjugated lipids; the molar ratio of the ionizable cationic lipid compound to the other lipid components is 1:0.2-5; the active ingredient of the lipid nanoparticle composition includes a therapeutic agent and / or a prophylactic agent; the therapeutic agent and / or prophylactic agent is a vaccine or compound capable of inducing an immune response; and the mass ratio of the lipid component to the active ingredient is 10:1 to 60:1.

[0135] In a preferred embodiment, the phospholipid is selected from 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diondecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0Diether PC), 1-oleoyl-2-cholesteryl hemisuccinyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dialinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0PE), 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-bisdocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoyl at least one of 1-stearoyl-2-oleoyl-stearoylethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoylphosphatidylcholine, lysophosphatidylcholine, and lysophosphatidylethanolamine (LPE).

[0136] In a preferred embodiment, the structured lipid is selected from at least one of cholesterol, coprosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatine, ursolic acid, and α-tocopherol.

[0137] In a preferred embodiment, the PEG lipid is selected from the group consisting of PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol, and mixtures thereof.

[0138] In a preferred embodiment, the therapeutic and / or prophylactic agent is a nucleic acid; the nucleic acid is DNA or RNA.

[0139] In a preferred embodiment, the RNA is selected from at least one of small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer-substrate RNA (dsRNA), small hairpin RNA (shRNA), and messenger RNA (mRNA).

[0140] In an eleventh aspect, the present invention provides the use of the aforementioned lipid composition in a medicament for treating a disease in a mammal, wherein the disease is characterized by dysfunction or abnormal protein or polypeptide activity; the disease is selected from infectious diseases, cancer, proliferative diseases, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardiovascular diseases, renal vascular diseases, and metabolic diseases.

[0141] In a twelfth aspect, the present invention provides a pharmaceutical composition comprising the aforementioned lipid composition and a pharmaceutically acceptable carrier.

[0142] In a preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically active compound selected from the group consisting of anti-inflammatory compounds, steroids, statins, estradiol, BTK inhibitors, S1P1 agonists, glucocorticoid receptor modulators and antihistamines.

[0143] Compared with the prior art, the present invention has the following beneficial effects:

[0144] 1. The present invention provides an ionizable cationic lipid compound having formula (1), or a salt, stereoisomer, or tautomer thereof. The ionizable cationic lipid compound provided by the present invention is an amphiphilic lipid compound constructed by using an ionizable cationic compound or its analog as an ionizable lipid head group, a lipid such as a fatty acid as a tail chain, and a tetrafunctional compound as a linker. The ionizable lipid head group, the tail chain, and the linker are connected by a biodegradable chemical bond (such as an ester bond or an amide bond).

[0145] 2. The ionizable cationic lipid compounds (exemplary compounds) provided herein have a calculated c-pKa (molnetwork) of 5-11. Within a typical pH range of 0-14, the ionization state of the molecule, or the ratio of different ionization states, varies with the ambient pH. Their c-LogP (cLogP driver) ranges from 5-55, indicating good lipophilicity. The ionizable cationic lipid compounds of the present invention are pH-dependent amphiphilic lipid compounds, demonstrating their potential as excellent surfactants and their particular suitability for preparing lipid nanoparticles for use as drug delivery vehicles.

[0146] 3. The ionizable cationic lipid compounds of the present invention can be used to prepare lipid compositions. The mRNA lipid compositions prepared using the exemplary compounds have a Zeta potential of -40 mV to 40 mV, a dispersion coefficient of 0.01-0.5, a particle size of 10-400 nm, and an encapsulation efficiency of >50%.

[0147] 4. Lipid nanoparticles containing mRNA and / or other nucleic acid substances (such as siRNA, microRNA, pDNA, etc.) prepared from the ionizable cationic lipid compounds of the present invention exhibit biological activity in both in vitro cells and in vivo animals, such as expressing proteins encoded by the mRNA sequence. Luciferase mRNA lipid nanoparticles prepared using the exemplary compounds expressed luciferase fluorescence in HEK 293T cells (dose: 100 ng, 96-well plate) with an intensity greater than 10 3 RLU; after injection via tail vein in mice, the average whole-body fluorescence signal was greater than 10 4 p / s / cm 2 The results showed that the luciferase mRNA lipid nanoparticles prepared using the ionizable cationic lipid compound of the present invention exhibited biological activity in both in vitro cells and in vivo animals, with low toxicity. The lipid nanoparticles provided by the present invention have good safety and effectiveness as drug carriers. BRIEF DESCRIPTION OF THE DRAWINGS

[0148] Figure 1 shows the luciferase activity of luciferase mRNA lipid nanoparticles prepared with compound 1005 in HEK293T cells;

[0149] Figure 2 shows whole-body in vivo imaging of mice 3h / 6h after intravenous administration of luciferase mRNA lipid nanoparticles prepared with compound 1008. DETAILED DESCRIPTION

[0150] The synthesis process of the present invention can accommodate multiple functional groups, so a variety of substituted starting materials can be used. These processes generally provide the desired final compound at the end or near the end of the entire process, but in some cases it may be necessary to further convert the compound into a pharmaceutically acceptable salt thereof. The compounds of the present invention can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from easily prepared intermediates by using standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for preparing organic molecules, as well as functional group transformations and manipulations, can be obtained from the relevant scientific literature or from standard textbooks in this field. The following description of the synthetic methods is designed to illustrate, but not to limit, the general procedures for preparing the compounds of the present invention.

[0151] The compounds of the present invention having the various formulas described herein can be prepared according to the processes described in the following general synthetic routes 1, 2, 3, 4 and 5 from commercially available starting materials or starting materials that can be prepared using literature processes. The variables in each general synthetic route (e.g., R1, R2, and R3, etc.) are as defined herein. One of ordinary skill in the art will note that in the reaction procedures and synthetic schemes described herein, the order of certain steps may be varied, such as the introduction and removal of protecting groups.

[0152] In the reaction schemes described herein, a variety of stereoisomers can be produced. When a specific stereoisomer is not indicated, this is understood to include all possible stereoisomers produced by the reaction. One of ordinary skill in the art will recognize that the reaction can be optimized to preferentially obtain a single isomer, or a new scheme can be designed to produce a single isomer. If a mixture is produced, the isomers can be separated using techniques such as preparative thin layer chromatography, preparative HPLC, preparative chiral HPLC, or preparative SFC.

[0153] General synthetic route 1

[0154] Wherein, M' is M or M containing a protecting group.

[0155] As described in the general synthetic route 1 above, Boc-aminotris(hydroxymethyl)methane reacts with an acid (Compound 2) to form Compound 3. Step 1 can be carried out in an organic solvent (e.g., dichloromethane (DCM)) in the presence of, for example, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) and 4-dimethylaminopyridine (DMAP). Step 1 can be carried out at room temperature for 24 hours.

[0156] Next, the Boc protecting group of compound 3 is removed to generate compound 4. Step 2 can be carried out in an organic solvent (eg, DCM) under the catalysis of an acid (eg, trifluoroacetic acid).

[0157] Next, compound 4 and compound 5 undergo condensation reaction to obtain compound 6. Step 3 can be carried out in an organic solvent (such as DCM or DMF) using EDCl and DMAP or dicyclohexylcarbodiimide (DCC) as a catalyst.

[0158] If the M' group of compound 6 contains the aforementioned protecting group, the protecting group is removed to obtain the target lipid compound. Step 4 is carried out under the selected protecting group removal reaction conditions.

[0159] General synthetic route 2

[0160] Wherein M' is M or M containing a protecting group; A is O, NH or S.

[0161] As described in the above general synthetic route 2, compound 1 and compound 2 undergo condensation reaction to give compound 3. Step 1 can be carried out in an organic solvent (eg, DCM) in the presence of EDCl and DMAP.

[0162] Next, the tert-butyloxy protecting group of compound 3 is removed to obtain compound 4. Step 2 can be carried out in an organic solvent (eg, DCM) in the presence of an acid (eg, trifluoroacetic acid) and a positive ion scavenger (eg, triisopropylsilane (TiPS)).

[0163] Next, compound 4 undergoes a condensation reaction with a compound 5 to obtain compound 6. Step 3 can be carried out in an organic solvent (such as DCM or DMF) in the presence of EDCl and DMAP or DCC.

[0164] If the M' group of compound 6 contains the above-mentioned protecting group, the protecting group is removed to obtain the target lipid compound. Step 4 is carried out under the deprotection reaction conditions of the selected protecting group.

[0165] General synthetic route 3

[0166] Among them, compound 5 is or X' and X are halogen, such as Cl, Br or I; R4' is R4 or R4 containing a protecting group; R5' is R5 or R5 containing a protecting group.

[0167] As described in the general synthetic route 3 above, Boc-aminotris(hydroxymethyl)methane undergoes a condensation reaction with compound 2 to produce compound 3. Step 1 can be carried out in an organic solvent (e.g., DCM) in the presence of, for example, EDCl and DMAP. Step 1 can be carried out at room temperature for 24 hours.

[0168] Next, the Boc protecting group of compound 3 is removed to generate compound 4. Step 2 can be carried out in an organic solvent (eg, DCM) under the catalysis of an acid (eg, trifluoroacetic acid).

[0169] Next, compound 4 is reacted with a halogen-substituted aldehyde (compound 5) through condensation and reduction to obtain compound 6. Step 3 can be carried out in an organic solvent (such as dichloroethane (DCE)) in the presence of a reducing agent (such as sodium triacetylborohydride (NaBH(OAc)3)).

[0170] Next, compound 6 reacts with an amine (compound 7) to produce compound 8. Step 4 can be carried out in an organic solvent (such as DMF) in the presence of a base (such as a non-nucleophilic organic base (e.g., triethylamine, iPr2EtN) or an inorganic base (e.g., K2CO3)) and a catalyst (KI or NaI).

[0171] If the R4' and / or R5' groups of compound 8 contain the aforementioned protecting groups, the protecting groups are removed to obtain the target lipid compound. Step 5 is carried out under the deprotection reaction conditions of the selected protecting groups.

[0172] General synthetic route 4

[0173] Among them, compound 5 is X' and X are halogen, such as Cl, Br or I; R4' is R4 or R4 containing a protecting group; R5' is R5 or R5 containing a protecting group.

[0174] As described in the general synthetic route 4 above, Boc-aminotris(hydroxymethyl)methane undergoes a condensation reaction with compound 2 to produce compound 3. Step 1 can be carried out in an organic solvent (e.g., DCM) in the presence of, for example, EDCl and DMAP. Step 1 can be carried out at room temperature for 24 hours.

[0175] Next, the Boc protecting group of compound 3 is removed to generate compound 4. Step 2 can be carried out in an organic solvent (eg, DCM) under the catalysis of an acid (eg, trifluoroacetic acid).

[0176] Next, compound 4 undergoes a condensation reaction with a halogen-substituted compound 5 to obtain compound 6. Step 3 can be carried out in an organic solvent such as DCM or DMF using EDCl and DMAP or DCC as catalyst.

[0177] Next, compound 6 reacts with an amine (compound 7) to form compound 8. Step 4 can be carried out in an organic solvent (e.g., DMF) in the presence of a base (e.g., a non-nucleophilic organic base (e.g., triethylamine, iPr2EtN) or an inorganic base (e.g., K2CO3)) and a catalyst (KI or NaI).

[0178] If the R4' and / or R5' groups of compound 8 contain the aforementioned protecting groups, the protecting groups are removed to obtain the target lipid compound. Step 5 is carried out under the deprotection reaction conditions of the selected protecting groups.

[0179] General synthetic route 5

[0180] Among them, M pro is M or M containing a protecting group.

[0181] As described in the general synthetic route 5 above, Boc-aminotris(hydroxymethyl)methane undergoes a condensation reaction with compound 2 to produce compound 3. Step 1 can be carried out in an organic solvent (e.g., DCM) in the presence of, for example, EDCl and DMAP. Step 1 can be carried out at room temperature for 24 hours.

[0182] Next, the Boc protecting group of compound 3 is removed to generate compound 4. Step 2 can be carried out in an organic solvent (eg, DCM) under the catalysis of an acid (eg, trifluoroacetic acid).

[0183] Next, compound 4 and compound 5 are subjected to condensation and reduction reaction to obtain compound 6. Step 3 can be carried out in an organic solvent (such as dichloroethane (DCE)) in the presence of a reducing agent (such as sodium triacetylborohydride (NaBH(OAc)3)).

[0184] If the M of compound 6 pro If the group contains the above-mentioned protecting group, the protecting group is removed to obtain the target lipid compound. Step 4 is carried out under the deprotection reaction conditions of the selected protecting group.

[0185] Furthermore, it is to be understood that any particular embodiment of the present invention that is within the prior art may be expressly excluded from any one or more claims. Such embodiments may be excluded because they are deemed to be known to one of ordinary skill in the art, even if such exclusion is not expressly stated herein.

[0186] All cited sources, such as references, publications, databases, database entries, and techniques cited herein, are incorporated herein by reference, even if not explicitly stated in the citation. In the event of a conflict between a cited source and the present application, the present application shall prevail.

[0187] Example 1: Synthesis of compounds according to formula (1), (1A), (1B), (1C), (1D), (1E), (1F), (1G), (1H), (1I), (1J), (1K), (1L), or (1M)

[0188] A. General considerations

[0189] It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0190] The process routes described below can be used to synthesize compounds 1001-3422 of the present invention.

[0191] This article uses the following abbreviations:

[0192] THF: Tetrahydrofuran

[0193] MeCN: acetonitrile

[0194] MeOH: methanol

[0195] PE: Petroleum ether

[0196] EA: ethyl acetate

[0197] DMF: N,N-dimethylformamide

[0198] EDCl: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0199] LAH: lithium aluminum hydride

[0200] DCM: dichloromethane

[0201] DMAP: 4-dimethylaminopyridine

[0202] LDA: lithium diisopropylamide

[0203] rt: room temperature

[0204] DCE: 1,2-dichloroethane

[0205] n-BuLi: n-butyllithium

[0206] i-Pr2EtN:N,N-diisopropylethylamine

[0207] B. Intermediate Synthesis

[0208] Intermediate A:

[0209] Intermediate A is obtained by the following synthetic process:

[0210] Tris(hydroxymethyl)aminomethane (50.0 g) and di-tert-butyl carbonic anhydride (Boc2O) (99.1 g) were dissolved in a methanol (300 mL) / H2O (30 mL) mixed solvent and reacted at room temperature for 72 h. The mixture was purified by silica gel column chromatography (DCM:MeOH = 20:1-10:1) to obtain a white solid compound intermediate A (N-Boc-aminotrihydroxymethylmethane) (75.0 g). LCMS (ESI) calculation for C9H 19 NO 5， [M+H] + m / z 222.13, found 222.25.

[0211] Intermediate B:

[0212] Intermediate B is obtained by the following synthetic process:

[0213] To a single-necked flask, diethyl 2-ethyl-1,3-propanedioate (29.0 g), THF (90 mL), and DMF (30 mL) were added, and NaH (3.7 g) was added under ice bath. The mixture was stirred at room temperature for 30 min under nitrogen protection; pentadecane bromide (15.0 g) was added, and the mixture was reacted at 80° C. for 2 h under nitrogen protection; THF was concentrated under reduced pressure to remove THF, and the reaction solution was added dropwise to ice water. Ethyl acetate was added and stirred, and the mixture was filtered through diatomaceous earth. The organic phase was collected and then separated. The organic phase was washed with saturated brine, separated, and purified by silica gel column chromatography (PE:EA=100:1-50:1) to obtain the compound diethyl 2-ethyl-2-pentadecylamealate (16.5 g). To diethyl 2-ethyl-2-pentadecylmaleate (8.0 g) was added EtOH (50 mL), H2O (50 mL), and KOH (11.3 g), and the mixture was reacted at 90°C for 12 h; the EtOH was removed by concentration under reduced pressure, and the reaction system was adjusted to pH 4-5 by adding dilute hydrochloric acid. Water and ethyl acetate were added, stirred, and separated, and the organic phase was washed with saturated brine, separated, and purified by column chromatography (PE:EA=5:1-1:1) to obtain 2-ethyl-2-pentadecylmaleic acid (5.2 g). 2-ethyl-2-pentadecylmaleic acid (10.0 g) was reacted at 170°C for 6 h under open conditions, cooled to room temperature, and water and ethyl acetate were added, stirred, separated, and the organic phase was washed with saturated brine, separated, concentrated, and purified by column chromatography (DCM:MeOH=20:1-10:1) to obtain intermediate B (2-ethylheptadecanoic acid) (8.2 g). 1H NMR (400MHz, CDCl3) δ2.31 (tt, J = 8.6, 5.3Hz, 1H), 1.71–1.46 (m, 4H), 1.28 (s, 26H), 0.96 (t, J = 7.4Hz, 3H), 0.90 (t, J = 6.7Hz, 3H).

[0214] Intermediate C:

[0215] Intermediate C is obtained by the following synthetic process:

[0216] To a three-necked flask, add decanoic acid (50 g) and THF (500 mL). After cooling the system to 0°C, slowly add NaH (23.22 g). After stirring at 0°C under nitrogen for 1 hour, slowly add LDA (62.19 g) dropwise. Stirring at 0°C under nitrogen for another 1 hour is then continued. Finally, add iodonane (88.52 g) dropwise, warm to room temperature, stir overnight, then dilute with 1 L of DCM and wash with saturated NH4Cl solution and water, respectively. The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated. Purify by silica gel chromatography (PE:EA = 50:1) to obtain intermediate C (2-octylundecanoic acid) (11 g). 1H NMR (400MHz, Chloroform-d) δ2.37(tt,J=8.7,5.1Hz,1H),1.71–1.58(m,2H),1.48(dt,J=13.3,6.7Hz,2H),1.29(d,J=9.4Hz,25H),0.90(t,J=6.8Hz,6H).

[0217] Intermediate D:

[0218] Intermediate D is obtained by the following synthetic route:

[0219] Tridecanoic acid (79.5 g) and THF (800 mL) were added to a three-necked flask. The temperature was lowered to 0°C, and NaH (22.25 g) was slowly added. The reaction mixture was stirred at 0°C under nitrogen for 1 hour. LDA (317.87 g) was then slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 0°C under nitrogen for another 1 hour. After adding n-hexyl iodide (94.3 g) dropwise, the mixture was warmed to room temperature and stirred overnight. The reaction mixture was then diluted with 1 L of DCM and washed with saturated NH4Cl solution and then water. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 50:1) to yield intermediate D (2-hexyltridecanoic acid) (26 g). 1H NMR(400MHz,Chloroform-d)δ2.36(tt,J=8.7,5.4Hz,1H),1.63(ddd,J=14.3,8.7,5.5 Hz, 2H), 1.49 (dq, J = 13.5, 6.6 Hz, 2H), 1.29 (d, J = 10.1 Hz, 26H), 0.90 (t, J = 6.6 Hz, 6H).

[0220] Intermediate E:

[0221] Intermediate E is obtained by the following synthetic process:

[0222] Tris(hydroxymethyl)aminomethane (10.0 g) and tert-butyl acrylate (21.1 1) were dissolved in EtOH (150 mL) and reacted at 45°C under nitrogen for 30 h. The EtOH was then concentrated under reduced pressure to remove the EtOH. Three 100 mL portions of (PE:EA=20:1) were added for slurrying, and the mixture was filtered to obtain Intermediate E (11.5 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.60 (s, 6H), 2.84 (t, J=5.9 Hz, 2H), 2.47 (t, J=5.8 Hz, 2H), 1.48 (s, 9H).

[0223] Intermediate F:

[0224] Intermediate F is obtained by the following synthetic route:

[0225] To a single-necked flask, tert-butyl (2-aminoethyl)carbamate (2.7 g), MeCN (90 mL), benzyl 2-bromoethyl ether (7.99 g), and K2CO3 (11.65 g) were added. After reacting at 80°C overnight, water and ethyl acetate were added and stirred for separation. The organic phase was washed with saturated brine, separated, concentrated, and purified by silica gel column chromatography (PE:EA=10:1-5:1) to obtain compound 2 (5.5 g). Dioxane (30 mL) and dioxane hydrochloride solution (30 mL) were added to compound 2, stirred at room temperature for 3 h, and then concentrated under reduced pressure to obtain compound 3, intermediate F (6 g). LCMS (ESI) calculated for C 20 H 28 N2O2,[M+H] + m / z 329.22, found 329.24.

[0226] Intermediate G:

[0227] Intermediate G is obtained by the following synthetic process:

[0228] Compound 1 (3.0 g), MeCN (90 mL), 3-benzyloxypropane bromide (9.45 g), and K2CO3 (12.94 g) were added to a single-necked flask and reacted overnight at 80°C. Water and ethyl acetate were then added for separation by stirring. The organic phase was washed with saturated brine, separated, concentrated, and purified by column chromatography (PE:EA=10:1-5:1) to obtain compound 2 (6.9 g). Dioxane (30 mL) and dioxane hydrochloride solution (30 mL) were added to compound 2 (6.9 g). After stirring at room temperature for 3 h, the mixture was concentrated under reduced pressure to obtain intermediate G (7.5 g). LCMS (ESI) calculated for C 22 H 32 N2O2,[M+H] + m / z 357.25, found 357.51.

[0229] Intermediate H:

[0230] Intermediate H is obtained using the following synthetic process:

[0231] Compound 1 (1.5 g), MeCN (90 mL), 4-bromobutyl benzyl ether (5.02 g), and K2CO3 (6.47 g) were added to a single-necked flask and reacted overnight at 80°C. Water and ethyl acetate were then added and stirred for separation. The organic phase was washed with saturated brine, separated, concentrated, and purified by column chromatography (PE:EA = 20:1-10:1) to obtain compound 2 (4.1 g). Dioxane (30 mL) and dioxane hydrochloride solution (30 mL) were added to compound 2 (4.1 g). After stirring at room temperature for 3 h, the mixture was concentrated under reduced pressure to obtain intermediate H (4.9 g). LCMS (ESI) calculated for C 24 H 36 N2O2, [M+H] + m / z 385.28, found 385.56.

[0232] Intermediate I:

[0233] Intermediate I is obtained by the following synthetic route:

[0234] Compound 1 (3.9 g), MeCN (90 mL), benzyl 2-bromoethyl ether (5.78 g), and K2CO3 (15.46 g) were added to a single-necked flask and reacted overnight at 80°C. Water and ethyl acetate were then added for separation by stirring. The organic phase was washed with saturated brine, separated, concentrated, and purified by column chromatography (PE:EA=20:1-10:1) to obtain compound 2 (6.8 g). Dioxane (30 mL) and dioxane hydrochloride solution (30 mL) were added to compound 2 (6.8 g). After stirring at room temperature for 3 h, the mixture was concentrated under reduced pressure to obtain intermediate I (6.5 g). LCMS (ESI) calculated for C 12 H 20 N2O, [M+H] + m / z 209.16, found 209.31.

[0235] Intermediate J:

[0236] Intermediate J is obtained using the following synthetic route:

[0237] Butyric acid (5.0 g) and THF (100 mL) were added to a single-necked flask. NaH (2.73 g) was added at 0°C, and LDA (56.8 ml) was slowly added dropwise. The mixture was reacted at room temperature for 30 min. 1-Bromotridecane was added and the reaction was continued at room temperature overnight. Ice water and ethyl acetate were added and stirred for separation. The organic phase was washed with saturated brine, separated, concentrated, and purified by column chromatography (PE:EA = 10:1-5:1) to obtain intermediate J (5.0 g). LCMS (ESI) calculated for C 17 H 34 O2, [M+H] + m / z 271.26, found 271.46.

[0238] Intermediate K:

[0239] Intermediate K is obtained by the following synthetic process:

[0240] Reactant 1 (24 g), imidazole (19.00 g), and DCM (200 mL) were added to a three-necked flask. The temperature was lowered to 0°C, and then TBDMSCI (38.57 g) was slowly added. After stirring at 25°C for 4 h, the mixture was diluted with 300 mL of DCM. The organic phase was washed twice with 1 L of water and dried over anhydrous Na2SO4. After filtration and concentration, silica gel was added and column chromatography with 1:20 DCM:MeOH was performed. The sample was collected and concentrated to yield intermediate K (28.00 g). 1H NMR (400 MHz, CDCl3) δ 4.89 (s, 1H), 3.58 (t, J = 6.1 Hz, 2H), 2.66 (t, J = 7.3 Hz, 2H), 2.45 (s, 3H), 1.67–1.40 (m, 4H), 0.84 (s, 9H).

[0241] Intermediate L:

[0242] Intermediate L is obtained by the following synthetic process:

[0243] Compound DMSO (3.58 g) and anhydrous solvent DCM (30 mL) were added to a three-necked flask. The system was cooled to -78°C and oxalyl chloride (2.91 g) was slowly added. The reaction solution was stirred at -78°C under N2 protection for 10 minutes, and compound 1 (3 g) was slowly added dropwise. Stirring was continued at -78°C under N2 protection for 1 hour. Finally, TEA (9.28 g) was added dropwise. Stirring was continued at -78°C under N2 protection for 0.5 hour, and the mixture was diluted with 100 mL of DCM and washed with saturated NH4Cl solution and water, respectively. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain intermediate L (3.0 g). LCMS (ESI) calculated for C 11 H 14 O3, [M+H] + m / z 195.09, found 195.23.

[0244] Intermediate M:

[0245] Intermediate M is obtained by the following synthetic process:

[0246] To a sealed tube, intermediate K (2.0 g), compound 1 (1.79 g), and ACN (20 mL) were added. The reactants, KCO (3.81 g) and KI (1.52 g), were then added. The mixture was stirred overnight at 70°C under N2 protection, then diluted with 100 mL of EA and washed with saturated NH4Cl solution and water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was then added to a silica gel column and filtered with 15:1 DCM:MeOH. The sample was collected and concentrated to yield compound 2 (2.0 g). Reactant 2 (1.80 g) and solvent DCM (20 mL) were added to a three-necked flask. The system was purged with nitrogen and the temperature was lowered to -78°C. DIBAL-H (1.00 g) was then added dropwise. After stirring at -78°C for 4 h, methanol and sodium carbonate solution were added dropwise to the reaction solution to quench the mixture. The mixture was then extracted with DCM (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate M (1.36 g). LCMS (ESI) calculated for C 15 H 33 NO2Si,[M+H] + m / z 288.52, found 288.23.

[0247] Intermediate N:

[0248] Intermediate N is obtained by the following synthetic process:

[0249] To a single-necked flask, add reactant 20651-71-2 (20 g). Add concentrated sulfuric acid (350 mL) and stir to dissolve. Then add NBS (22 g) and stir to mix. The mixture is allowed to react overnight at room temperature. The reaction solution is slowly poured into 1 L of water for dilution. The aqueous phase is then extracted twice with 1 L of ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated to yield product 1 (28 g). 1H NMR (400MHz, CDCl3) δ8.29(d,J=1.7Hz,1H),7.98(dd,J=8.0,1.8Hz,1H),7.34(d,J=8.0Hz,1H),2. 87-2.78(m,2H),1.64(tt,J=7.8,6.4Hz,2H),1.43(dp,J=13.4,6.8Hz,2H),0.99(t,J=7.3Hz,3H).

[0250] Product 1 (28 g) was added to a single-necked flask. Ethanol (400 mL) was added and stirred to dissolve. Concentrated sulfuric acid (200 mL) was slowly added and stirred to mix. The reaction solution was refluxed at 85°C for 18 h. The reaction solution was slowly poured into 1 L of water for dilution. The aqueous phase was then extracted twice with 1 L of ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated to obtain product 2 (30 g). 1H NMR (400MHz, CDCl3) δ8.22 (d, J=1.8Hz, 1H), 7.91 (dd, J=7.9, 1.7Hz, 1H), 7.30 (s, 1H), 4.39 (q, J = 7.1Hz, 2H), 2.85-2.74 (m, 2H), 1.62 (tt, J = 7.9, 6.4Hz, 2H), 1.42 (dt, J = 9.7, 7.3Hz, 4H), 0.98 (t, J = 7.3Hz, 3H).

[0251] To a 25 mL three-necked flask under nitrogen, add product 2 (2.4 g) and triphenylphosphine (0.66 g), stir and dissolve in anhydrous DMF (20 mL). Palladium acetate (0.19 g) and cuprous iodide (0.27 g) are then added and stirred. Finally, triethylamine (4.26 g) and 26186-02-7 (1.82 g) are added. The reaction mixture is heated to 90°C and allowed to react overnight. After cooling to room temperature, it is slowly poured into 200 L of water for dilution. The aqueous phase is then extracted twice with 1 L of ethyl acetate. Drying over anhydrous Na2SO4, filtration, and concentration are performed. Purification by silica gel column chromatography (PE:EA = 50:1) affords product 3 (2.5 g). Product 3 (3.8 g) and Pd / C (0.66 g) were added to a three-necked flask under hydrogen protection. MeOH (20 mL) and EA (20 mL) were added and stirred. The mixture was stirred at room temperature for 4 h, filtered, and concentrated to obtain crude compound 4 (3.7 g). Crude compound 4 (3.9 g) was added to a single-necked flask, and EtOH (20 mL) was added and stirred to dissolve. 1 M aqueous NaOH (20 mL) was then added and the reaction mixture was stirred at room temperature for 2 h. 1 M dilute hydrochloric acid was slowly added dropwise to adjust the pH of the reaction mixture to 6-7. The mixture was then extracted twice with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by silica gel column chromatography (PE:EA = 10:1) to obtain intermediate N (1.5 g). 1H NMR (400MHz, CDCl3) δ7.93(d,J=2.0Hz,1H),7.89(dd,J=7.9,1.8Hz,1H),7.26(d,J=8.0Hz,1H),2.69(q,J=7.3 Hz, 4H), 1.70-1.55 (m, 4H), 1.45 (h, J = 7.3Hz, 4H), 1.30 (s, 18H), 0.99 (t, J = 7.3Hz, 3H), 0.91 (t, J = 6.7Hz, 3H).

[0252] Intermediate O:

[0253] Intermediate O is obtained by the following synthetic process:

[0254] The reactant 150349-36-3 (3 g) was added to a single-necked flask, and DMF (20 mL) was added and stirred to dissolve. Potassium carbonate (4.4 g) was then added and stirred to mix. The reaction system was cooled to 0°C, and the reactant CbzCl (3.3 g) was added. The reaction was allowed to return to room temperature and react overnight. The mixture was diluted with 100 mL of DCM and the organic phase was washed with water, dried, filtered, and concentrated. Silica gel was added and the mixture was filtered through a column with 20:1 DCM:MeOH. The sample was collected and concentrated to obtain the product 1 (3.8 g). LCMS (ESI) calculated for: C 17 H 26 N2O4,[M+Na] + 345.18,found 345.22.

[0255] Product 1 (3.7 g) and DCM (20 mL) were added to a three-necked flask and stirred. A 4M dioxane hydrochloride solution (28.7 mL) was then added and stirred overnight at 25°C. The mixture was diluted with DCM (100 mL), and the organic phase was washed with saturated NaHCO₃ solution and water, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford product 2 (2.4 g). LCMS (ESI) calculated for: C₁₂H₁₈N₂O₂, [M+H]+ 223.15, found 223.14 + .

[0256] Product 2 (2.3 g) was added to a single-necked flask, and DMF (20 mL) was added and stirred to dissolve. Potassium carbonate (2.9 g) was added and stirred to mix. Then, 4-bromo-1-butanol (2.1 g) was added as the reactant and the reaction was allowed to proceed overnight at room temperature. After dilution with 100 mL of DCM, the organic phase was washed with water. It was dried over anhydrous Na2SO4, filtered and concentrated. After adding silica gel, it was passed through a column with 20:1 DCM:MeOH. The sample was collected and concentrated to obtain product 3 (1.2 g). LCMS (ESI) calculated for: C 16 H 26 N2O3,[M+H] + 295.20,found 295.20.

[0257] Product 3 (1.1 g) was added to a single-necked flask, and DCM (20 mL) was added and stirred to dissolve. Imidazole (0.32 g) was added and stirred to mix. The reaction system was cooled to 0°C, and then TBSCl (0.89 g) was added. The reaction solution was gradually restored to room temperature and reacted for 4 hours. After dilution with 100 mL of DCM, the organic phase was washed with water, dried over anhydrous Na2SO4, filtered and concentrated. Silica gel was added and column chromatography with 20:1 DCM:MeOH was performed. The sample was collected and concentrated to obtain product 4 (1.2 g). LCMS (ESI) calculated for: C 22 H 40 N2O3Si,[M+H] + =409.29,found 409.30.

[0258] Product 4 (1.1 g) was added to a three-necked flask protected by hydrogen, and MeOH (20 mL) was added and stirred to dissolve. Pd / C (0.89 g) was added and stirred to mix. The mixture was reacted overnight at room temperature under a hydrogen atmosphere, filtered, and the filtrate was concentrated to obtain intermediate O (0.8 g). LCMS (ESI) calculated for: C 14 H 34 N2OSi,[M+H] + =275.25,found 275.26 + .

[0259] Intermediate P:

[0260] Intermediate P is obtained by the following synthetic process:

[0261] Compound 1 (5.3 g) was added to a nitrogen-protected three-necked flask at room temperature. Anhydrous dioaxne (100 mL) was added and stirred, followed by pyridine (0.24 mL) and SOCl2 (4.3 mL). The mixture was reacted at 100°C for 3 h. The mixture was cooled to room temperature, filtered to remove the solid, and the filtrate was rinsed twice with DCM. The filtrate was concentrated and purified to obtain product 2 (5 g). LCMS (ESI) calculated for C7H8ClN5, + [M+H] + m / z 198.06, found 198.1. To a single-necked flask, product 2 (0.8 g), 122734-32-1 (15.3 g), and K2CO3 (12.2 g) were added, followed by dioxane (100 mL), stirred, and reacted at 100°C overnight. The reaction solution was cooled to room temperature, filtered, concentrated, and purified to obtain product 3 (5 g). LCMS (ESI) calculated for C 15 H25 N7O2, + [M+H] + m / z 336.21, found 336.2. Product 3 (1 g) and 4 M dioxane hydrochloride solution (7.5 mL) were added to a single-necked bottle, stirred, and reacted overnight at room temperature; concentrated and purified to obtain intermediate P (0.3 g). LCMS (ESI) calculated for C 10 H 17 N7, + [M+H] + m / z 236.16, found 236.1.

[0262] Intermediate Q:

[0263] Intermediate Q is obtained using the following synthetic process:

[0264] At 0°C, compound 4097-88-5 (5 g) was added to a single-necked flask, followed by DCM (100 mL) and stirring. Boc anhydride (0.24 mL) was then added and stirred. The mixture was allowed to react overnight at room temperature. The mixture was diluted with DCM, stirred, and separated by adding water. The aqueous phase was extracted twice with DCM, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification (DCM:MeOH = 10:1) afforded intermediate Q (4 g). LCMS (ESI) calculation for C 10 H 23 N3O2, + [M+H] + m / z 218.19, found 218.2.

[0265] Intermediate R:

[0266] Intermediate R is obtained by the following synthetic process:

[0267] To a single-necked flask, 121492-06-6 (5.0 g), CbzCl (5.87 g), and DMF (50 mL) were added and stirred. KCO (5.95 g) was then added. After stirring overnight at room temperature, the mixture was diluted with 100 mL of EA and washed with saturated NHCl solution and water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. Silica gel was added and column-filtered with DCM:MeOH (20:1). The sample was collected and concentrated to yield product 2 (5.1 g). Product 2 (5 g) and DCM (50 mL) were added to a single-necked flask and stirred to dissolve. A 4M solution of dioxane hydrochloride (40 mL) was then added and the mixture was allowed to react overnight at room temperature. The solvent was then removed by concentration to yield product 3 (4 g). Product 3 (1.05 g), 89043-32-3 (0.9 g), and DMF (10 mL) were added to a single-necked flask and stirred. KCO (2.3 g) was added and stirred overnight at room temperature. The mixture was diluted with 100 mL of EA and washed with saturated NHCl solution and water. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. Silica gel was added and column-filtered with DCM:MeOH (20:1). The sample was collected and concentrated to yield product 4 (1.1 g). Product 4 (1 g) and MeOH (10 mL) were added to a single-necked flask and stirred. Pd / C was added and stirred. The reaction system was reacted under a hydrogen atmosphere for 2 h. The filtrate was filtered through celite and concentrated to yield intermediate R (600 mg).

[0268] C. Compound 1003 was synthesized according to general synthetic route 1

[0269] Structural formula:

[0270] Chemical formula: C 63 H 122 N2O7

[0271] Molecular weight: 1019.68

[0272] Step 1: Synthesis of compound 3 in general synthetic route 1

[0273] Compound 1 (intermediate A) (1.0 g), DCM (20 mL), DMAP (2.2 g), and EDCI (3.4 g) were added to compound 2 (intermediate B) (4.3 g). The mixture was stirred at room temperature for 12 h under nitrogen protection, and then water and dichloromethane were added for stirring and separation. The organic phase was washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated. The organic phase was purified by silica gel column chromatography (PE:EA=40:1-30:1) to give compound 3 (2.6 g).

[0274] Step 2: Synthesis of compound 4 in general synthetic route 1

[0275] DCM (15 mL) and TFA (5 mL) were added to compound 3 (2.6 g), and the mixture was stirred at room temperature for 3 h, concentrated, and purified by silica gel column chromatography (PE:EA=10:1-5:1) to give compound 4 (3.2 g).

[0276] Step 3: Synthesis of compound 6 in general synthetic route 1

[0277] To compound 4 (3.2 g) were added DCM (20 mL), Boc-glycine (compound 5, 578 mg), and DCC (6.8 g). The mixture was stirred at room temperature under nitrogen for 12 h, and then water and ethyl acetate were added for stirring and separation. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=5:1-2:1) to give compound 6 (2.2 g).

[0278] Step 4: Compound 1003

[0279] To compound 6 (2.2 g) were added DCM (15 mL) and TFA (5 mL), and the mixture was stirred at room temperature for 12 h and concentrated. The mixture was purified by column chromatography (DCM:MeOH=30:1-20:1) to give compound 1003 (1.3 g). 1 H NMR (400MHz, CDCl3) δ4.49 (d, J=2.6Hz, 6H), 3.28 (s, 2H), 2.32 (tt, J=8.6, 5. 5Hz, 3H), 1.62 (q, J = 7.1Hz, 12H), 1.27 (d, J = 3.4Hz, 78H), 0.94-0.86 (m, 18H).

[0280] D. Compound 1002 was synthesized according to general synthetic route 1

[0281] Structural formula:

[0282] Chemical formula: C 60 H 116 N2O7

[0283] Molecular weight: 977.60

[0284] The compound was synthesized according to the general synthetic route 1, which is similar to the synthetic process of compound 1003, except that intermediate C was used as compound 2 in the general synthetic route 1. 1H NMR (400MHz, CDCl3) δ4.48 (s, 6H), 3.27 (s, 2H), 2.37 (tt, J = 8.5, 5.5Hz, 3H), 1 .64(d,J=6.9Hz,6H),1.50-1.42(m,6H),1.27(s,72H),0.90(t,J=6.7Hz,18H).

[0285] E. Compound 1004 was synthesized according to general synthetic route 1

[0286] Structural formula:

[0287] Chemical formula: C 54 H 104 N2O7

[0288] Molecular weight: 893.43

[0289] The compound was synthesized according to the general synthetic route 1, which is similar to the synthetic process of compound 1003, except that palmitic acid was used as compound 2 in the general synthetic route 1. 1 H NMR (400MHz, CDCl3) δ7.55 (s, 1H), 4.45 (s, 6H), 3.74 (s, 2H), 2.35 (t, J = 7.6Hz, 6H), 1.60 (p, J = 6.9Hz, 6H), 1.27 (s, 72H), 0.90 (t, J = 6.7Hz, 9H).

[0290] F. Compound 1001 was synthesized according to general synthetic route 1

[0291] Structural formula:

[0292] Chemical formula: C 59 H 108 N2O7

[0293] Molecular weight: 957.52

[0294] The product was synthesized according to the general synthetic route 1, which is similar to the synthetic process of compound 1003, except that (9Z)-9-hexadecenoic acid was used as compound 2 in the general synthetic route 1, and 5-(N,N-dimethylamino)pentanoic acid was used as compound 5 in the general synthetic route 1. 1H NMR (400MHz, CDCl3) δ5.42-5.30(m,6H),4.51-4.38(m,6H),3.19(dt,J=11.3,5 .6Hz,2H),2.97(t,J=5.9Hz,6H),2.46(t,J=6.6Hz,1H),2.35(td,J=7.6,3.1Hz, 5H),2.20(t,J=7.6Hz,2H),2.03(d,J=6.2Hz,12H),1.89-1.81(m,3H),1.74(q, J=7.8Hz,2H),1.67-1.51(m,6H),1.31(d,J=7.8Hz,48H),0.90(t,J=6.7Hz,9H).

[0295] G. Compound 1014 was synthesized according to general synthetic route 2

[0296] Structural formula:

[0297] Chemical formula: C 70 H 137 N3O9

[0298] Molecular weight: 1164.88

[0299] Step 1: Synthesis of Intermediate 3 in General Synthesis Route 2

[0300] Intermediate 3 was synthesized according to the method shown in step 1 of general synthetic route 1, except that intermediate E was used as compound 1 in general synthetic route 1.

[0301] Step 2: Synthesis of compound 4 of general synthetic route 2

[0302] DCM (15 mL), TFA (12 mL), and TiPS (3 mL) were added to compound 3 (4.8 g). After reacting at room temperature for 12 h, water and dichloromethane were added for stirring and separation. The organic phase was washed with saturated brine, separated, concentrated, and purified by silica gel column chromatography (DCM:MeOH=20:1-10:1) to give compound 4 (3.3 g).

[0303] Step 3: Synthesis of compound 6 of general synthetic route 2

[0304] Compound 4 (4.0 g), DCM (80 mL), EDCI (1.1 g), 1-hydroxybenzotriazole (HOBt) (0.78 g), and DIEA (2.5 g) were added to compound 5 (1.9 g). After stirring at room temperature for 12 h, water and dichloromethane were added, stirred and separated, and the organic phase was washed with saturated brine. The organic phase was separated and concentrated, and purified by silica gel column chromatography (DCM:MeOH=30:1-20:1) to give compound 6 (4.0 g).

[0305] Step 4: Compound 1014

[0306] To compound 6 (4.0 g) were added MeOH (30 mL), DCM (10 mL), and Pd / C (4.73 g (10%)). The mixture was stirred at room temperature overnight under hydrogen atmosphere, filtered through celite, concentrated, and purified by silica gel column chromatography (DCM:MeOH 30:1-15:1) to give compound 1014 (2 g). 1 H(400MHz, CDCl3)δ7.38(t,J=5.8Hz,1H),4.14-4.05(m,6H),3.58(t,J=4.9Hz,4H),3.31(q,J=5.7Hz,2H),2.89(t,J=6.3Hz, 2H), 2.64 (q, J=5.2Hz, 6H), 2.29 (dq, J=10.8, 4.4Hz, 6H), 1.66-1.37 (m, 12H), 1.24 (d, J=4.3Hz, 78H), 0.87 (t, J=7.1Hz, 18H).

[0307] H. Compound 1015 was synthesized according to general synthetic route 2

[0308] Structural formula:

[0309] Chemical formula: C 72 H 141 N3O9

[0310] Molecular weight: 1192.93

[0311] The compound was synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate G was used as compound 5 in general synthetic route 2. 1H(400MHz, CDCl3)δ7.58(t,J=5.7Hz,1H),4.15-4.01(m,6H),3.70(t,J=5.4Hz,4H),3.39(q,J=5.7Hz,2H),2.86(t,J=6.2Hz,2H),2 .57(dt,J=20.5,5.8Hz,6H),2.36-2.22(m,5H),1.76-1.67(m,4H),1.62-1.35(m,13H),1.23(d,J=4.6Hz,78H),0.92-0.80(m,18H).

[0312] I. Compound 1020, synthesized according to general synthetic route 2

[0313] Structural formula:

[0314] Chemical formula: C 74 H 145 N3O9

[0315] Molecular weight: 1220.99

[0316] The compound was synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate H was used as compound 5 in general synthetic route 2.

[0317] J. Compound 1025 was synthesized according to general synthetic route 2

[0318] Structural formula:

[0319] Chemical formula: C 69 H 135 N3O8

[0320] Molecular weight: 1134.85

[0321] The compound was synthesized according to the general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate I was used as compound 5 in the general synthetic route 2. 1 H(400MHz, CDCl3)δ6.98(t,J=5.7Hz,1H),4.10(m,J=3.8Hz,6H),3.63(t,J=5.2Hz,2H),3.35(q,J=5.8Hz,2H),2.89(t,J=6.1Hz,2 H), 2.57 (q, J = 5.3Hz, 4H), 2.32 (s, 3H), 2.28 (q, J = 4.1Hz, 5H), 1.65-1.41 (m, 13H), 1.24 (d, J = 4.4Hz, 78H), 0.87 (t, J = 7.1Hz, 18H).

[0322] K. Compound 1005, synthesized according to general synthetic route 2

[0323] Structural formula:

[0324] Chemical formula: C 68 H 133 N3O7

[0325] Molecular weight: 1104.83

[0326] The compound 5 was synthesized according to the general synthetic route 2, which is similar to the synthetic process of compound 1014, except that N,N-dimethylethylenediamine was used as compound 5 in the general synthetic route 2. 1 H NMR (400MHz, CDCl3) δ4.19-4.07(m,6H),3.40(d,J=5.7Hz,2H),2.95-2.87(m,2H),2.82(s,4H),2.64-2.55(m,2H),2.38 (s, 6H), 2.33-2.29 (m, 3H), 1.63-1.55 (m, 6H), 1.49-1.44 (m, 2H), 1.26 (d, J = 5.4Hz, 78H), 0.89 (td, J = 7.0, 2.8Hz, 18H).

[0327] L. Compound 1006 was synthesized according to general synthetic route 2

[0328] Structural formula:

[0329] Chemical formula: C 53 H 103 N3O7

[0330] Molecular weight: 894.42

[0331] The compound was synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that tetradecanoic acid was used as compound 2 in general synthetic route 2 and N,N-dimethylethylenediamine was used as compound 5 in general synthetic route 2. 1 H NMR (400MHz, CDCl3) δ7.99(t,J=5.8Hz,1H),4.13(s,6H),3.60(q,J=5.3Hz,2H),3.38-3.34(m,2H),3.00(s,6H),2.94(t, J=5.8Hz,2H),2.45(t,J=5.8Hz,2H),2.35(t,J=7.6Hz,6H),1.66-1.56(m,6H),1.33-1.23(m,60H),0.90(t,J=6.8Hz,9H).

[0332] M. Compound 1007, synthesized according to general synthetic route 2

[0333] Structural formula:

[0334] Chemical formula: C 68 H 133 N3O7

[0335] Molecular weight: 1104.83

[0336] The compound was synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate D was used as compound 2 in general synthetic route 2 and N,N-dimethylethylenediamine was used as compound 5 in general synthetic route 2. 1 H NMR (400MHz, Chloroform-d) δ7.13(t,J=5.0Hz,1H),4.13(s,6H),3.33(q,J=5.6Hz,2H),2.92(t,J=6.0Hz,2H),2.47-2.28(m,7H ), 2.24 (s, 6H), 1.60 (dq, J = 14.7, 7.2Hz, 6H), 1.47 (dd, J = 14.2, 6.7Hz, 6H), 1.27 (d, J = 3.4Hz, 78H), 0.89 (td, J = 6.7, 2.5Hz, 18H).

[0337] N. Compound 1008, synthesized according to general synthetic route 2

[0338] Structural formula:

[0339] Chemical formula: C 68 H 133 N3O7

[0340] Molecular weight: 1104.01

[0341] The compound was synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate C was used as compound 2 in general synthetic route 2 and N,N-dimethylethylenediamine was used as compound 5 in general synthetic route 2. 1H NMR(400MHz,Chloroform-d)δ4.13(s,6H),3.33(q,J=5.6Hz,2H),2.92(t,J=5.9Hz,2H),2.51-2.26(m,7H),2.24 (s, 6H), 1.59 (ddt, J = 14.8, 10.9, 6.4Hz, 6H), 1.47 (tq, J = 11.0, 5.4Hz, 6H), 1.26 (s, 77H), 0.89 (t, J = 6.7Hz, 18H).

[0342] O. Compound 1009, synthesized according to general synthetic route 2

[0343] Structural formula:

[0344] Chemical formula: C 62 H 121 N3O7

[0345] Molecular weight: 1020.66

[0346] The compound was synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate J was used as compound 2 in general synthetic route 2 and N,N-dimethylethylenediamine was used as compound 5 in general synthetic route 2. 1 H(400MHz, CDCl3)δ7.04(t,J=5.0Hz,1H),4.12(m,J=3.3Hz,6H),3.30(q,J=5.6Hz,2H),2.91(t,J=6.0Hz,2H),2.39 (t,J=6.0Hz,2H),2.33-2.25(m,5H),2.22(s,6H),1.76-1.54(m,12H),1.24(m,J=3.7Hz,66H),0.90-0.84(m,18H).

[0347] P. Compound 1011 was synthesized according to general synthetic route 2

[0348] Structural formula:

[0349] Chemical formula: C 70 H 137 N3O7

[0350] Molecular weight: 1132.88

[0351] The compound 5 was synthesized according to the general synthetic route 2, which is similar to the synthetic process of compound 1014, except that N,N-diethylethylenediamine was used as compound 5 in the general synthetic route 2. 1H NMR (400MHz, CDCl3) δ4.19-4.08(m,6H),3.31(q,J=5.8Hz,2H),2.92(t,2H),2.57(t,J=6.9Hz,6H),2.37-2.26( m,5H),1.62(ddd,J=18.3,9.0,4.3Hz,12H),1.27(d,J=4.7Hz,78H),1.04(t,J=7.1Hz,6H),0.94-0.86(m,18H).

[0352] Q. Compound 1012, synthesized according to general synthetic route 2

[0353] Structural formula:

[0354] Chemical formula: C 72 H 141 N3O7

[0355] Molecular weight: 1160.93

[0356] The compound 5 was synthesized according to the general synthetic route 2, which is similar to the synthetic process of compound 1014, except that N,N-diethylethylenediamine was used as compound 5 in the general synthetic route 2. 1 H NMR (400MHz, CDCl3) δ6.59 (s, 1H), 4.18-4.07 (m, 6H), 3.29 (q, J = 5.7Hz, 2H), 2.91 (t, J = 6.2Hz, 2H), 2.54 (t, J = 6.1 Hz, 2H), 2.40 (t, J = 7.5Hz, 4H), 2.35-2.27 (m, 5H), 1.63-1.42 (m, 16H), 1.27 (m, J = 4.5Hz, 78H), 0.93-0.85 (m, 24H).

[0357] R. Compound 1013, synthesized according to general synthetic route 2

[0358] Structural formula:

[0359] Chemical formula: C 74 H 145 N3O7

[0360] Molecular weight: 1188.99

[0361] The compound 5 was synthesized according to the general synthetic route 2, which is similar to the synthetic process of compound 1014, except that N,N-diethylethylenediamine was used as compound 5 in the general synthetic route 2. 1H NMR (400MHz, CDCl3) δ4.10(d,J=4.1Hz,6H),3.26(q,J=5.8Hz,2H),2.89(t,J=6.2Hz,2H),2.52(d,J=6.6Hz,2H) ,2.41(t,J=7.4Hz,4H),2.33-2.25(m,5H),1.60(d,J=11.8Hz,16H),1.24(d,J=4.5Hz,82H),0.96-0.79(m,24H).

[0362] S. Compound 1029, synthesized according to general synthetic route 2

[0363] Structural formula:

[0364] Chemical formula: C 68 H 132 N2O8

[0365] Molecular weight: 1105.81

[0366] The compound 5 was synthesized according to the general synthetic route 2, which is similar to the synthetic process of compound 1014, except that N,N-diethyl-2-hydroxyethylamine was used as compound 5 in the general synthetic route 2. 1 H NMR (400MHz, CDCl3) δ4.16(t,J=5.8Hz,2H),4.13-4.05(m,6H),2.86(t,J=6.3Hz,2H),2.55(t,J=5.8Hz,2H) ,2.44(t,J=6.3Hz,2H),2.35-2.20(m,9H),1.60-1.39(m,11H),1.24(d,J=4.5Hz,80H),1.02-0.79(m,18H).

[0367] T. Compound 1111, synthesized according to general synthetic route 2

[0368] Structural formula:

[0369] Chemical formula: C 70 H 136 N4O7

[0370] Molecular weight: 1145.88

[0371] The product was synthesized according to general synthetic route 2, which was similar to the synthetic process of compound 1014, except that intermediate C was used as compound 2 in general synthetic route 2 and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate was used as compound 5 in general synthetic route 2. 1H NMR (400 MHz, Chloroform-d) δ 4.28 (s, 6H), 3.41 (s, 2H), 3.31 (s, 4H), 3.22 (s, 3H), 2.97-2.80 (m, 5H), 2.70 (s, 5H), 2.46-2.32 (m, 4H), 1.60 (t, J = 7.1 Hz, 6H), 1.54-1.40 (m, 6H), 1.27 (s, 78H), 0.89 (t, J = 6.7 Hz, 18H).

[0372] U. Compound 1118, synthesized according to general synthetic route 2

[0373] Structural formula:

[0374] Chemical formula: C 71 H 139 N3O8

[0375] Molecular weight: 1162.91

[0376] The compound was synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate C was used as compound 2 in general synthetic route 2 and intermediate K was used as compound 5 in general synthetic route 2. 1 HNMR(400MHz,Chloroform-d)δ4.11(s,6H),3.61(s,2H),3.42(d,J=33.5Hz,2H),2.91(t,J=6.2Hz,3 H), 2.36 (dd, J = 9.2, 3.6Hz, 6H), 1.47 (dd, J = 13.9, 6.2Hz, 14H), 1.27 (s, 71H), 0.90 (t, J = 6.7Hz, 18H).

[0377] U1. Compound 1132, synthesized according to general synthetic route 2

[0378] Structural formula:

[0379] Molecular weight: 1363.15

[0380] The product was synthesized according to the general synthetic route 2, which was similar to the synthetic process of compound 1014, except that intermediate N was used as compound 2 in the general synthetic route 2 and intermediate O was used as compound 5 in the general synthetic route 2. LCMS (ESI) calculated for: C87H147N3O8, [M+H]+=1363.13, found 682.4 (half peak). 1H NMR (400 MHz, Chloroform-d) δ7.82 (d, J=1.9 Hz, 3H), 7.77 (dd, J=8.0,1.9 Hz, 3H), 7.18 (d, J=8.0 Hz, 3H), 4.57 (s, 6H), 3.66 (t, J=5.4 Hz, 2H), 3.23 (q, J=6.1 Hz, 2H), 3.11 (t, J=6.0 Hz, 2H), 2.82 (d,J=17.6Hz,0H),2.71-2.50(m,16H),2.42(t,J=5.9Hz,2H),1.87(p,J=7.2Hz,5H),1.72-1.63 (m,2H),1.63-1.49(m,13H),1.48-1.17(m,53H),0.97(t,J=7.3Hz,10H),0.90(t,J=6.7Hz,9H).

[0381] U2. Compound 1139, synthesized according to general synthetic route 2

[0382] Structural formula:

[0383] Molecular weight: 1251.97

[0384] Synthesized according to general synthetic route 2, which is similar to the synthetic process of compound 1014, except that intermediate C was used as compound 2 in general synthetic route 2 and intermediate P was used as compound 5 in general synthetic route 2. LCMS (ESI) calculated for C 74 H 138 N8O7, + [M+H] +m / z 1252.08, found 626.8 (half peak).1H NMR (400MHz, Chloroform-d) δ8.38 (s, 1H), 7.90 (s, 1H), 6.25 (t, J = 5.2Hz, 1H), 5.71 (s, 2H),4.31(t,J=5.9Hz,2H),4.15(s,6H),3.20(q,J=5.7Hz,2H),2.86(dt,J=15.6,6.1Hz ,4H),2.51(t,J=5.9Hz,2H),2.37(ddd,J=8.4,5.7,2.7Hz,3H),2.32(s,3H),2.20(t,J= 6.3Hz, 2H), 1.60 (q, J = 7.8Hz, 6H), 1.51-1.43 (m, 6H), 1.26 (s, 78H), 0.92-0.86 (m, 18H).

[0385] U3. Compound 1140, synthesized according to general synthetic route 2

[0386] Structural formula:

[0387] Molecular weight: 1175.91

[0388] Synthesized according to general synthetic route 2, similar to the synthetic process of compound 1014, except that intermediate B was used as compound 2 in general synthetic route 2 and intermediate Q was used as compound 5 in general synthetic route 2, and intermediate 1140 was synthesized first. LCMS (ESI) calculated for C 69 H 136 N4O7, + [M+H] + m / z 1134.05, found 1134.25. Then, intermediate 1140 (520 mg), CH3CN (10 mL), 4023-02-3 (101 mg), and DIPEA (355 mg) were added to a single-necked flask and reacted at room temperature for 12 h. Water and dichloromethane were added, stirred, and separated. The organic phase was washed with saturated brine, separated, concentrated, and purified to obtain compound 1140 (300 mg). LCMS (ESI) calculated for C 70 H 138 N6O7, + [M+H] +m / z 1176.07, found 1176.22.1H NMR(400MHz,Chloroform-d)δ4.23-4.04(m,6H),3.42-3.20(m,4H),2.91(t,J=6.1Hz,2H),2.71-2.51(m,4H), 2.43(t,J=6.0Hz,2H),2.36-2.23(m,6H),1.76-1.40(m,11H),1.27(d,J=4.0Hz,75H),0.90(t,J=7.1Hz,18H).

[0389] V. Compound 1010, synthesized according to general synthetic route 3

[0390] Structural formula:

[0391] Chemical formula: C 67 H 133 N3O6

[0392] Molecular weight: 1076.82

[0393] Step 1 and Step 2: Synthesis of Compound 3 and Compound 4 of General Synthesis Route 3

[0394] According to steps 1 and 2 of general synthetic route 1, the synthesis process is the same as that of compound 1003.

[0395] Step 3: Synthesis of compound 6 of general synthetic route 3

[0396] Compound 4 (600 mg), chloroacetaldehyde (compound 5, 242 mg (40%)), and NaBH(OAc)3 (394 mg) were added to DCE (60 mL). After reacting at room temperature overnight, water and dichloromethane were added, stirred, and the liquids were separated. The organic phase was washed with saturated brine, separated, and concentrated. Compound 6 (270 mg) was obtained by silica gel column chromatography (DCM:MeOH=30:1-15:1).

[0397] Step 4: Synthesis of Compound 1010

[0398] MeCN (20 mL), N,N-dimethylethylenediamine (compound 7, 229 mg), KI (43 mg), and K2CO3 (179 mg) were added to compound 6 (270 mg). The mixture was reacted at 70°C under nitrogen protection overnight, and then silica gel column chromatography was used to obtain compound 1010 (16 mg). 1H(400MHz, CDCl3)δ4.10(m,J=2.9Hz,6H),2.76-2.64(m,6H),2.40(t,J=6.2Hz,2H),2.29(ddd,J=8.5,5.6 ,2.9Hz,3H),2.22(s,6H),1.97(s,6H),1.50-1.41(m,6H),1.24(d,J=4.2Hz,78H),0.87(t,J=7.1Hz,18H).

[0399] W. Compound 1059, synthesized according to general synthetic route 3

[0400] Structural formula:

[0401] Chemical formula: C 67 H 132 N2O7

[0402] Molecular weight: 1077.80

[0403] The synthesis was carried out according to the general synthetic route 3, which is similar to the synthesis process of compound 1010, except that intermediate C and intermediate L were used as compound 2 and compound 5 in the general synthetic route 3, respectively. In addition, compound 6 in the general synthetic route 3 was subjected to the following process steps for functional group transformation:

[0404] To intermediate 6a (1.5 g) was added MeOH (5 mL) and THF (5 mL), and the reactants Pd(OH)2 / C (10%) (0.46 g) and Pd / C (10%) (0.35 g) were added. The mixture was reacted under H2 at 25°C overnight, filtered through celite, and the filtrate was concentrated and chromatographed on a silica gel column (PE:EA 30:1 to 10:1) to afford intermediate 6b (520 mg). To intermediate 6b (470 mg) was added DCM (5 mL), and SOCl2 (1064.26 mg, 8.946 mmol) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 3 hours, and then the reaction mixture was extracted with water and DCM. The organic phase was concentrated and chromatographed on a silica gel column (PE:EA 20:1) to afford intermediate 6c (181 mg). To intermediate 6c (170 mg) were added dimethylamine (143.39 mg) and DMF (2 mL), potassium carbonate (43.96 mg) and potassium iodide (26.39 mg). The reaction solution was stirred at 70°C, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH 20:1) to give compound 1059 (91 mg, 53.22% yield). 1H NMR(400MHz,Chloroform-d)δ4.11(s,6H),3.51(dt,J=18.3,5.6Hz,4H),2.81(dd,J=10.3,5.1Hz,2 H),2.50(t,J=6.0Hz,2H),2.42-2.32(m,3H),2.28(s,6H),2.08-1.98(m,1H),1.53-1.38(m,7H),1.27(s,77H),0.90(t,J=6.7Hz,18H).

[0405] X. Compound 1112, synthesized according to general synthetic route 3

[0406] Structural formula:

[0407] Chemical formula: C 69 H 136 N2O6

[0408] Molecular weight: 1089.85

[0409] The compound was synthesized according to the general synthetic route 3, which is similar to the synthetic process of compound 1010, except that intermediate C and 6-bromohexanal were used to synthesize compound 2 and compound 5 in the general synthetic route 3, respectively. 1 H NMR(400MHz,Chloroform-d)δ4.11(s,6H),3.11(s,1H),2.57(t,J=6.8Hz,2H),2.44-2.19 (m,12H),2.04(q,J=6.5Hz,2H),1.53-1.38(m,13H),1.27(s,92H),0.90(t,J=6.7Hz,20H).

[0410] X1. Compound 3424, synthesized according to general synthetic route 3

[0411] Structural formula:

[0412] Molecular weight: 1091.83

[0413] The synthesis was carried out according to the general synthetic route 3, which was similar to the synthetic process of compound 1010, except that intermediate B, 2-chloroacetaldehyde and 4-(methylamino)butan-1-ol were used as compound 2, compound 5 and compound 7 in the general synthetic route 3, respectively. LCMS (ESI) calculated for: C 68 H 134 N2O7,[M+H] + =1091.02,found 1091.92 +.1H NMR (400MHz, CDCl3) δ4.13(d,J=2.1Hz,6H),3.60(d,J=5.4Hz,2H),2.79(s,2H),2.55-2.38(m,4H),2 .31(ddt,J=16.3,13.3,6.6Hz,6H),1.69-1.43(m,18H),1.27(d,J=4.0Hz,78H),0.94-0.86(m,18H).

[0414] X2. Compound 3425, synthesized according to general synthetic route 3

[0415] Structural formula:

[0416] Molecular weight: 1091.83

[0417] The synthesis was carried out according to the general synthetic route 3, which was similar to the synthetic process of compound 1010, except that intermediate C, 2-chloroacetaldehyde and 4-(methylamino)butan-1-ol were used as compound 2, compound 5 and compound 7 in the general synthetic route 3, respectively. LCMS (ESI) calculated for: C 68 H 134 N2O7,[M+H] + =1091.02,found 1091.83 + .1H NMR (400MHz, CDCl3) δ4.12(s,6H),3.60(d,J=5.2Hz,2H),2.79(s,2H),2.50(s,2H),2.37(tt,J=8.5,5.6Hz,4H),2 .28(s,2H),1.67(t,J=3.7Hz,4H),1.59(p,J=7.2Hz,6H),1.51-1.41(m,6H),1.27(s,78H),0.90(t,J=6.7Hz,18H).

[0418] X3. Compound 3426, synthesized according to general synthetic route 3

[0419] Structural formula:

[0420] Molecular weight: 1147.94

[0421] The synthesis was carried out according to the general synthetic route 3, which was similar to the synthetic process of compound 1010, except that intermediate B, 6-bromohexanal and 4-(methylamino)butan-1-ol were used as compound 2, compound 5 and compound 7 in the general synthetic route 3, respectively. LCMS (ESI) calculated for: C 72 H142 N2O7,[M+H] + =1148.08,found 1149.22 + .1H NMR (400MHz, CDCl3) δ4.16-4.06(m,6H),3.59(dd,J=6.1,3.4Hz,2H),2.97(dd,J=29.3,22.5Hz,1H),2.57(t,J=6.9Hz,2H),2.46( dt,J=7.9,5.2Hz,4H),2.35-2.27(m,6H),1.76-1.66(m,4H),1.65-1.38(m,16H),1.27(d,J=4.1Hz,78H),0.90(t,J=7.1Hz,18H).

[0422] Y. Compound 1113, synthesized according to general synthetic route 4

[0423] Structural formula:

[0424] Chemical formula: C 71 H 138 N2O8

[0425] Molecular weight: 1147.89

[0426] Step 1 and Step 2: Synthesis of Compound 3 and Compound 4 of General Synthesis Route 4

[0427] According to steps 1 and 2 of general synthetic route 1, the synthesis process is the same as that of compound 1003.

[0428] Step 3: Synthesis of compound 6 of general synthetic route 4

[0429] DIEA (0.30 g) and DCM (20 mL) were added to compound 4. Under nitrogen, the temperature was cooled to 0°C, and 5-bromovaleryl chloride (compound 5, 0.27 g) was added. The mixture was stirred at 25°C for 2 h. After dilution with 100 mL of DCM, the organic phase was washed twice with 100 mL of water. The organic phase was dried over anhydrous NaSO, filtered, concentrated, and then purified by silica gel column chromatography (PE:EA 20:1) to obtain compound 6 (800 mg).

[0430] Step 4: Synthesis of compound 8 of general synthetic route 4

[0431] Compound 6 (750.00 mg), intermediate K (compound 7, 217.31 mg), and DMF (20 mL) were added to a three-necked flask. KCO (184.16 mg) and KI (110.60 mg) were then added and stirred at 25°C for 16 h. The temperature was then raised to 100°C and stirred for 3 h. The reaction solution was diluted with 200 mL of EA, and the organic phase was washed twice with 300 mL of saturated brine. The organic phase was dried over anhydrous NaSO, filtered, and concentrated. Silica gel was added and the mixture was filtered through a column using 20:1 DCM:MeOH. The sample was collected and concentrated to yield compound 8 (700.00 mg).

[0432] Step 5: Synthesis of Compound 1113

[0433] Compound 8 (700.00 mg) and THF (5 mL) were added to a three-necked flask, followed by a 1 M dioxane hydrochloride solution (5.55 mL). The reaction mixture was stirred at 25°C for 2 h, diluted with 50 mL of EA, and the organic phase was washed with a saturated NaHCO solution and water. The organic phase was dried over anhydrous NaSO, filtered, concentrated, and then purified by silica gel column chromatography (MeOH:DCM 1:20) to afford compound 1113 (201.1 mg, 31.59% yield). 1 H NMR (400MHz, CDCl3) δ4.50-4.39(m,6H),3.59(t,J=4.6Hz,2H),2.49(s,3H),2.35-2.26(m,6H),2.14 (t,J=7.5Hz,2H),1.75-1.69(m,4H),1.66-1.43(m,17H),1.27(d,J=3.7Hz,78H),0.94-0.87(m,18H).

[0434] Z. Compound 1115, synthesized according to general synthetic route 4

[0435] Structural formula:

[0436] Chemical formula: C 67 H 131 N3O7

[0437] Molecular weight: 1090.80

[0438] The compound was synthesized according to general synthetic route 4, which is similar to the synthetic process of compound 1010, except that 2-bromoacetyl chloride and N,N-dimethylethylenediamine were used to synthesize compound 5 and compound 7 in general synthetic route 4, respectively. 1H NMR(400MHz, CDCl3)δ7.42(s,1H),4.48(tt,J=11.9,5.7Hz,6H),3.27(s,2H),3.13(s,2H),3.01(s,2H),2.83(s,6 H), 2.38-2.25 (m, 3H), 1.55 (dtt, J = 36.3, 14.1, 7.3Hz, 12H), 1.27 (d, J = 3.3Hz, 78H), 0.90 (td, J = 7.2, 3.4Hz, 18H).

[0439] Z1. Compound 3427, synthesized according to general synthetic route 4

[0440] Structural formula:

[0441] Molecular weight: 1148.88

[0442] The synthesis was carried out according to the general synthetic route 4, which was similar to the synthetic process of compound 1010, except that 2-bromoacetyl chloride and intermediate R were used to synthesize compound 5 and compound 7 in the general synthetic route 4, respectively. LCMS (ESI) calculated for: C 70 H 137 N3O8,[M+H] + =1148.88,found 1148.97 + .1H NMR (400MHz, CDCl3) δ7.74(s,1H),4.53-4.40(m,6H),3.60(d,J=4.8Hz,2H),3.20(s,2H),2.72(dd,J=6.6,4.9Hz,2H),2.54(t,J=5.7Hz ,2H),2.43(d,J=5.2Hz,2H),2.34-2.23(m,6H),1.70(p,J=2.4Hz,4H),1.66-1.40(m,12H),1.26(d,J=3.9Hz,78H),0.95-0.84(m,18H).

[0443] Z2. Compound 3423, synthesized according to general synthetic route 4

[0444] Structural formula:

[0445] Molecular weight: 1148.88

[0446] The synthesis was carried out according to the general synthetic route 4, which was similar to the synthetic process of compound 1010, except that intermediate C, 2-bromoacetyl chloride and intermediate R were used as compound 2, compound 5 and compound 7 in the general synthetic route 4, respectively. LCMS (ESI) calculated for: C 70 H 137 N3O8,[M+H] + =1148.88,found 1149.28 + .1H NMR(400MHz, CDCl3)δ7.72(s,1H),4.45(s,6H),3.62(d,J=5.2Hz,2H),3.20(s,2H),2.73(d,J=6.3Hz,2H),2.59(s,2H),2.47( s,2H),2.41-2.24(m,6H),1.59(dp,J=10.9,6.4Hz,6H),1.52-1.40(m,6H),1.27(s,78H),0.90(t,J=6.7Hz,18H).

[0447] AA. Compound 1114, synthesized according to general synthetic route 5

[0448] Structural formula:

[0449] Chemical formula: C 70 H 138 N2O7

[0450] Molecular weight: 1119.88

[0451] Step 1 and Step 2: Synthesis of Compound 3 and Compound 4 of General Synthesis Route 5

[0452] According to steps 1 and 2 of general synthetic route 1, the synthesis process is the same as that of compound 1003.

[0453] Step 3: Synthesis of compound 6 of general synthetic route 5

[0454] Compound 4 (500 mg), intermediate M (compound 5, 298.68 mg), reactant STAB (328.68 mg) and DCE (10 ml) were added to a three-necked flask. The reaction solution was stirred under N2 at 25°C for 16 h. Then, 100 mL of water was added to the reaction solution, and the mixture was extracted twice with EA (100 ml). The organic phases were combined and concentrated. Silica gel was added and the mixture was passed through a column with 1:20 DCM:MeOH. The sample was collected and concentrated to give compound 6 (500 mg).

[0455] Step 4: Synthesis of Compound 1114

[0456] Compound 6 (450 mg) and THF (5 mL) were added to a three-necked flask, followed by a 1 M dioxane hydrochloride solution (3.65 mL). The mixture was stirred at 25°C for 2 h, diluted with 50 mL of EA, and the organic phase was washed with 50 mL of saturated NaHCO solution and water. The organic layer was dried over anhydrous NaSO, filtered, concentrated, and then purified by silica gel column chromatography (MeOH:DCM 1:20) to afford compound 1114 (107 mg, 24.84% yield). 1 H NMR (400MHz, CDCl3) δ4.16-4.07(m,6H),3.60(t,J=4.8Hz,2H),2.62(t,J=7.0Hz,2H),2.49(s,3H),2.31(tt, J=8.4,5.5Hz,6H),1.70(d,J=4.6Hz,3H),1.64-1.39(m,18H),1.27(d,J=4.0Hz,78H),0.90(t,J=7.1Hz,18H).

[0457] AA-1. Compound 1120, synthesized according to general synthetic route 5

[0458] Structural formula:

[0459] Chemical formula: C 72 H 142 N2O7

[0460] Molecular weight: 1147.90

[0461] The product was synthesized according to general synthetic route 5, which was similar to the synthetic process of compound 1114, except that intermediate C and 6-bromohexanal were used to synthesize compound 2 and compound 5 in general synthetic route 5, respectively. 1H NMR (400 MHz, Chloroform-d) δ4.11 (s, 6H), 3.63 (s, 2H), 2.57 (t, J = 6.8 Hz, 4H), 2.37 (ddd, J = 8.5, 7.1, 4.3 Hz, 5H), 1.67-1.41 (m, 24H), 1.27 (s, 79H), 0.90 (t, J = 6.7 Hz, 18H).

[0462] AA-2. Compound 3428, synthesized according to general synthetic route 5

[0463] Structural formula:

[0464] Molecular weight: 1119.88

[0465] The synthesis was carried out according to the general synthetic route 5, which was similar to the synthesis process of compound 1114, except that intermediate C was used as compound 2 in the general synthetic route 5.

[0466] LCMS (ESI) calculated for: C 70 H 138 N2O7,[M+H] + =1119.88,found 1119.98 + .

[0467] 1 H NMR (400MHz, CDCl3) δ4.10 (s, 6H), 3.59 (d, J = 4.7Hz, 2H), 2.61 (t, J = 7.1Hz, 2H), 2.45 (d, J = 7.0Hz, 4H) ,2.36(tt,J=8.5,5.4Hz,4H),2.28(s,3H),1.69-1.42(m,18H),1.27(s,79H),0.90(t,J=6.7Hz,18H).

[0468] Example 2: Exemplary compounds and their properties

[0469] The exemplary compounds of the present invention and their properties are listed in Table 1, which were synthesized according to the process routes in Example 1.

[0470] The calculated c-pKa (molnetwork), LogP (cLogP driver) of the exemplary compounds of the present invention, c-pKa and cLogP values ​​were generated by the ChemDraw module of Chemoffice.

[0471] Table 1 Properties of exemplary compounds

[0472] The above properties of the exemplary compounds of the present invention indicate that they can serve as excellent surfactants and are particularly suitable for preparing lipid nanoparticles for use as drug delivery carriers.

[0473] Example 3: Preparation of Nanoparticles

[0474] Luciferase mRNA was diluted in 10-100 mM sodium citrate buffer solution (pH 4.0) to a concentration of 135 μg / ml. A lipid mixed ethanol solution was prepared according to the molar ratio of 50:10:38.5:1.5 of ionizable cationic lipid compound (each exemplary compound): DSPC: cholesterol: 2-[(polyethylene glycol)-2000]-N,N-diisodecanoylacetamide (ALC-0159). The mRNA solution and the lipid mixed solution were mixed in a nanomedicine preparation device at a volume ratio of 3:1, and then ultrafiltration was performed to obtain luciferase mRNA lipid nanoparticles.

[0475] Example 4: Apparent pKa determination

[0476] The apparent pKa of lipid nanoparticles is related to the effectiveness of lipid nanoparticles in delivering nucleic acids (see Jayaraman et al., Angewandte Chemie, International Edition (2012), 51(34), 8529-8533; Semple et al., Nature Biotechnology 28, 172-176 (2010)). The apparent pKa of nanoparticles prepared from different lipid compounds was determined using a fluorescence probe based on 2-(p-tolylamino)-6-naphthalenesulfonic acid (TNS), which is non-fluorescent in water but becomes slightly fluorescent when bound to lipid membranes. Blank lipid nanoparticles were prepared according to a molar ratio of 50:10:38.5:1.5 of ionizable cationic lipid compound (each exemplary compound): DSPC: cholesterol: 2-[(polyethylene glycol)-2000]-N,N-tetracosylacetamide (ALC-0159). They were diluted in different pH buffers ranging from pH 2 to 11, mixed with TNS aqueous solution, and then added to a 96-well plate (black bottom). The excitation wavelength was 325 nm, the emission wavelength was 435 nm, and top detection was performed. Each well was measured 10 times, the fluorescence intensity was recorded, and the pH-fluorescence intensity curve was plotted to determine the apparent pKa. The apparent pKa data of lipid nanoparticles prepared from each exemplary compound are shown in Table 2.

[0477] Example 5: Determination of particle size, zeta potential and encapsulation efficiency of nanoparticles

[0478] 1. Particle Size and Polydispersity Index (PDI) Determination: The average particle size and PDI of the nanoparticle sample solutions in the examples were determined by dynamic light scattering using a Malvern ZetaSizer Nano ZS90. The measurement angle was 90°, the refractive index of the dispersant was 1.330, and the test temperature was 25°C.

[0479] 2. Zeta potential: The zeta potential of the nanoparticle sample solution in the examples was measured using a Malvern ZetaSizer Nano ZS90 based on electrophoretic light scattering (ELS) technology. The refractive index of the dispersant was 1.330 and the test temperature was 25°C.

[0480] 3. Encapsulation efficiency: The luciferase mRNA encapsulation efficiency in lipid nanoparticles was determined using the Quant-it Ribogreen RNA Quantification Assay Kit (ThermoFisher Scientific, UK) according to the manufacturer's instructions.

[0481] The average particle size, PDI, Zeta potential and encapsulation efficiency of lipid nanoparticles prepared from each exemplary compound are shown in Table 2.

[0482] Table 2 Summary of apparent pKa, particle size, PDI, Zeta potential and encapsulation efficiency of lipid nanoparticles prepared by compounds

[0483] Example 6: In vitro cell activity evaluation of lipid nanoparticles

[0484] The in vitro transfection efficiency of lipid nanoparticle compositions prepared with each exemplary compound was evaluated using HEK-293T cells. HEK293T cells were routinely cultured in DMEM + 10% FBS medium to ensure that the cells were in the logarithmic growth phase. The day before transfection, the cells were seeded at an appropriate cell density in 96-well culture plates and grown overnight. During transfection, the cell confluence was 70-90%. The lipid nanoparticle compositions prepared with each exemplary compound were diluted in DMEM to four different dose concentrations and added to 96-well cell culture plates, with concentrations of 400 ng, 200 ng, 100 ng, and 50 ng per well, respectively. A luciferase plasmid was transfected using Lipofectamine 2000 as a positive control (PC). After incubation for 24 h at 37°C in a 5% CO2 incubator, substrate was added to the wells and luciferase activity was measured using a microplate reader. The results are shown in Table 3. It can be seen that the fluorescence intensity of luciferase expressed by luciferase mRNA lipid nanoparticles prepared using the exemplary compounds in HEK 293T cells (dose: 100 ng, 96-well plate) is >10 3RLU, indicating that the luciferase mRNA lipid nanoparticles prepared using the ionizable cationic lipid compound of the present invention exhibit biological activity in cells in vitro and have low cytotoxicity. The luciferase activity of the luciferase mRNA lipid nanoparticles prepared using compound 1005 in HEK293T cells is shown in Figure 1. It can be seen that at different doses (50-400 ng), the fluorescence intensity of the luciferase mRNA lipid nanoparticles expressed in HEK 293T cells is greater than 10 7 RLU, and the fluorescence intensity increased with the increase of dose, indicating that the expression of luciferase increased accordingly with the increase of dose, and the prepared lipid nanoparticles had good mRNA delivery ability and safety.

[0485] Example 7: In vivo activity evaluation of lipid nanoparticles

[0486] The in vivo transfection efficiency and safety evaluation of the lipid nanoparticle compositions prepared by each exemplary compound were performed using female Balb / c mice aged 6-8 weeks. The lipid nanoparticles prepared by each exemplary compound were administered by tail vein injection at a single dose of 0.3 mpk. At specific time points (e.g., 3 h, 6 h) after administration, the animals were imaged in vivo using a PerkinElmer small animal imaging system to measure the bioluminescent signal. The results are shown in Table 3. The whole-body live imaging of mice 3 h / 6 h after intravenous administration of luciferase mRNA lipid nanoparticles prepared by compound 1008 is shown in Figure 2. As can be seen from Table 3, 6 h after administration of the lipid nanoparticles prepared by each exemplary compound, the average whole-body fluorescence signal of the mice was greater than 10 4 p / s / cm 2 / sr, indicating that luciferase mRNA lipid nanoparticles containing the exemplary compounds induced effective expression of luciferase in vivo. Furthermore, mice administered lipid nanoparticles prepared with each exemplary compound showed no toxic reactions such as abnormal activity. This demonstrates that luciferase mRNA lipid nanoparticles prepared using the ionizable cationic lipid compounds of the present invention exhibit biological activity in animals and have low toxicity.

[0487] Table 3 Summary of in vivo / in vitro activity evaluation of lipid nanoparticles prepared by compounds

[0488] The present invention is not limited to the technical means disclosed above, but also includes technical solutions composed of any combination of the above technical features. The above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. An ionizable cationic lipid compound, characterized in that The ionizable cationic lipid compound is a compound of formula (1), or a salt, stereoisomer, or tautomer thereof: Wherein, R1, R2, and R3 are independently H, C 5-40 Straight or branched alkyl, C 5-40 Straight-chain or branched alkenyl, C 5-40 A straight or branched alkynyl group, a 3-6 membered saturated or partially unsaturated cyclic hydrocarbon group containing 1-3 side chains, or a 6-10 membered aromatic group containing 1-3 side chains; the side chains are independently selected from C 10-30 Straight or branched alkyl, C 10-30 Straight or branched alkenyl, C 10-30 Straight or branched alkynyl; provided that at most one of R1, R2, and R3 is H; M is selected from -NR4R5, a saturated or partially unsaturated 3-6-membered heterocyclic group containing at least one nitrogen atom, a 6-10-membered heteroaryl group containing at least one nitrogen atom, wherein the heterocyclic group and the heteroaryl group are unsubstituted or substituted by one or more -OH, carboxyl, amino, oxo or halogen; R4 and R5 are independently H, C 1-6 Straight or branched alkyl, C 2-6 Straight or branched alkenyl or C 2-6 A straight chain or branched chain alkynyl group, the C 1-6 Straight or branched alkyl, C 2-6 Straight or branched alkenyl or C 2-6 The straight-chain or branched alkynyl group is unsubstituted or substituted with one or more -OH, carboxyl, amino, amide, amidino, guanidino or halogen; G1, G2, and G3 are independently -O-, -S-, -NR6-, -SS-, -C(=O)-, -C(=S)-, -C(=O)O-, -CH(OH)-, -OC(=O)-, -C(=O)NR6-, -NR6C(=O)-, -OC(=O)O-, -NR6C(=O)O-, -OC(=O)NR6-, -NR6C(=O)NR 13 -, -C(=O)S-, -C(=S)S-, -SC(=S)-, -SC(=O)-, -OC(=O)S-, -SC(=O)O-, -SC(=O)S-, -OS(=O)2O-, -S(=O)2O-, -OS (=O)2-, -S(=O)2-, -S(=O)2-NR6-, -NR6-S(=O)2-, -P(=O)(OR6)O-, -OP(=O)(OR6)- or -OP(=O)(OR6)O-; where each R6, R 13 are independently selected from H, hydroxyl, C 1-30 Straight or branched chain alkyl or cycloalkyl, C 2-30 Straight-chain or branched alkenyl; L1 is selected from -X1- or -(CR7R8) m -X1-, wherein each X1 is independently selected from -O-, -S-, -NR 14 -, -SS-, -C(=O)-, -C(=S)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 14 -、-NR 14 C(=O)-, -OC(=O)O-, -NR 14 C(=O)O-、-OC(=O)NR 14 -、-NR 14 C(=O)NR 15 -, -C(=O)S-, -C(=S)S-, -SC(=S)-, -SC(=O)-, -OC(=O)S-, -SC(=O)O-, -SC(=O)S-, -OS(=O)2O-, -S(=O)2O-, -OS(=O)2-, -S(=O)2-, -S(=O)2-NR 14 -、-NR 14 -S(=O)2-、-P(=O)(OR 14 )O-、-OP(=O)(OR 14 )-or- OP(=O)(OR 14 )O-; wherein m is an integer from 2 to 6, R 7、 R8 are independently H, hydroxy, halogen, C 1-6 A straight or branched alkyl or cycloalkyl group, C 2-6 A straight-chain or branched alkenyl group, each R 14 , R 15 are independently selected from H, C 1-30 Straight or branched chain alkyl or cycloalkyl, C 2-30 Straight-chain or branched alkenyl; L2 is -(CR9R 10 ) n -or-(CR9R 10 ) n -X2-(CR 11 R 12 ) k -, wherein X2 is selected from -O-, -S-, -NR 16 -, -SS-, -C(=O)-, -C(=S)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 16 -、-NR 16 C(=O)-, -OC(=O)O-, -NR 16 C(=O)O-、-OC(=O)NR 16 -、-NR 16 C(=O)NR 17 -, -C(=O)S-, -C(=S)S-, -SC(=S)-, -SC(=O)-, -OC(=O)S-, -SC(=O)O-, -SC(=O)S-, -OS(=O)2O-, -S(=O)2O-, -OS(=O)2-, -S(=O)2-, -S(=O)2-NR 16 -、NR 16 -S(=O)2-、-P(=O)(OR 16 )O-、-OP(=O)(OR 16 )-OR-OP(=O)(OR 16 )O-; n is an integer from 1 to 6; k is an integer from 1 to 6; R 9、 R 10、 R 11、 R 12 are independently H, hydroxyl, halogen, C 1-6 A straight or branched alkyl or cycloalkyl group, C 2-6 A straight-chain or branched alkenyl group, each R 16 , R 17 are independently selected from H, C 1-30 Straight or branched chain alkyl or cycloalkyl, C 2-30 Straight-chain or branched alkenyl; Where R4 to R 17 The alkyl, cycloalkyl, alkenyl described in is unsubstituted or substituted by one or more groups selected from hydroxyl, thiol, amino, substituted amino, halogen; The salts do not include quaternary ammonium salts.

2. The ionizable cationic lipid compound according to claim 1, characterized in that The R1, R2, and R3 are independently the following groups: Where Y does not exist or is C 1-30 Straight or branched alkyl or cycloalkyl, C 2-20 Straight or branched alkenyl, C 2- 20 Straight or branched alkynyl; R1', R2' are independently H, C 1-30 Straight or branched alkyl, C 2-30 Straight or branched alkenyl, C 2-30 A straight chain or branched alkynyl group, and the total carbon chain length of Y, R1' and R2' is 8-40.

3. The ionizable cationic lipid compound according to claim 1, characterized in that The R1, R2, and R3 are independently selected from the following groups: Wherein, R1' and R2' are independently H, C 1-30 Straight or branched alkyl, C 2-30 Straight or branched alkenyl, C 2- 30 The total carbon chain length of R1' and R2' is 8-30.

4. The ionizable cationic lipid compound according to claim 1, characterized in that R1, R2, and R3 are independently selected from any one of the following groups:

5. The ionizable cationic lipid compound according to claim 1, characterized in that G1, G2, and G3 are independently -O-, -S-, -NR6-, -SS-, -C(=O)-, -C(=O)O-, -CH(OH)-, -OC(=O)-, -C(=O)NR6-, -NR6C(=O)-, -OC(=O)O-, -NR6C(=O)O-, -OC(=O)NR6-, -NR6C(=O)NR 13 -, -P(=O)(OR6)O-, -OP(=O)(OR6)- or -OP(=O)(OR6)O-.

6. The ionizable cationic lipid compound according to claim 1, characterized in that L1 is selected from -(CR7R8) m -X1-, wherein X1 is selected from -O-, -S-, -NR 14 -, -SS-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 14 -、-NR 14 C(=O)-, -OC(=O)O-, -NR 14 C(=O)O-、-OC(=O)NR 14 -、-NR 14 C(=O)NR 15 -、-P(=O)(OR 14 )O-、-OP(=O)(OR 14 )-OR-OP(=O)(OR 14 )O-.

7. The ionizable cationic lipid compound according to claim 1, characterized in that L2 is -(CR9R 10 ) n -X2-(CR 11 R 12 ) k -, wherein X2 is selected from -O-, -S-, -NR 16 -, -SS-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR 16 -、-NR 16 C(=O)-, -OC(=O)O-, -NR 16 C(=O)O-、-OC(=O)NR 16 -、-NR 16 C(=O)NR 17 -、-P(=O)(OR 16 )O-、-OP(=O)(OR 16 )-OR-OP(=O)(OR 16 )O-.

8. The ionizable cationic lipid compound according to claim 1, characterized in that M is selected from the following structures: wherein m' and n' are independently integers of 0-6, R1" and R2" are independently H, C 1-6 Alkyl, C 2-6 The alkenyl, guanidino, amidino, amide, fatty amine, 3-10 membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocyclic ring is selected from pyrrole, imidazole, pyridine, pyrazole, triazole, oxazole, isoxazole, thiophene, isothiazole, pyridazine, pyrazine, piperazine, indole, benzimidazole, carbazole, quinoline, isoquinoline, purine and pyrimidine and tautomeric forms thereof, which are unsubstituted or optionally substituted with one or more selected from hydroxyl, thiol, amino, substituted amino, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-14 The aromatic group is substituted with an organic group.

9. The ionizable cationic lipid compound according to claim 1, characterized in that The compound of formula (1) is selected from the compound represented by formula (1A):

10. The ionizable cationic lipid compound according to claim 1, characterized in that The compound of formula (1) is selected from the compound represented by formula (1B):

11. The ionizable cationic lipid compound according to claim 1, characterized in that The compound of formula (1) is selected from the compound represented by formula (1C):

12. The ionizable cationic lipid compound according to claim 10, characterized in that The compound of formula (1) is selected from the compound represented by formula (1D):

13. The ionizable cationic lipid compound according to claim 12, wherein The compound of formula (1) is selected from the compound represented by formula (1E) 14. The ionizable cationic lipid compound according to claim 13, wherein The compound of formula (1) is selected from the compound represented by formula (1F):

15. The ionizable cationic lipid compound according to claim 14, characterized in that The compound of formula (1) is selected from the compound represented by formula (1G):

16. The ionizable cationic lipid compound according to claim 14, wherein The compound of formula (1) is selected from the compound represented by formula (1H):

17. The ionizable cationic lipid compound according to claim 1, wherein The structure of the ionizable cationic lipid compound is a compound shown in formula (II):

18. The ionizable cationic lipid compound according to claim 10, wherein The compound of formula (1) is selected from the compound represented by formula (1J):

19. The ionizable cationic lipid compound according to claim 17, wherein The compound of formula (1) is selected from the compounds represented by formula (1K):

20. The ionizable cationic lipid compound according to claim 2, characterized in that Y does not exist, and the compound of formula (1) is selected from the compounds represented by formula (1L): Wherein R1' and R2' are independently selected from H, C 1-30 Straight or branched alkyl, C 2-30 Straight or branched alkenyl, C 2-30 The total carbon chain length of R1' and R2' is 8-40.

21. The ionizable cationic lipid compound according to claim 2, characterized in that The compound of formula (1) is selected from the compounds represented by formula (1M):

22. The ionizable cationic lipid compound according to claim 1, wherein The compound of formula (1) is selected from:

23. The method for preparing an ionizable cationic lipid compound according to any one of claims 1 to 22, characterized in that: The method comprises the steps of reacting a compound of formula (II) with a compound of formula (III): Wherein, Xa and Xb are groups containing a leaving group or a nucleophilic group, and Xa and Xb form L1 through a nucleophilic reaction or a condensation reaction.

24. The method for preparing an ionizable cationic lipid compound according to any one of claims 1 to 22, characterized in that: The method comprises the steps of reacting a compound of formula (IV) with a compound of formula (V): Wherein Xc and Xd are groups containing a leaving group or a nucleophilic group, and Xc and Xd form L2 through a nucleophilic reaction or a condensation reaction.

25. The method for preparing an ionizable cationic lipid compound according to any one of claims 1 to 22, characterized in that: The method comprises the steps of reacting a compound of formula (VI): Wherein Xe is a group containing a leaving group or a nucleophilic group, Xf is a compound containing a leaving group or a nucleophilic group, and Xe and Xf form M through a nucleophilic reaction or a condensation reaction.

26. The method for preparing an ionizable cationic lipid compound according to any one of claims 1 to 22, characterized in that: The method comprises the steps of reacting a compound of formula (VII) with a compound of formula (VIII), a compound of formula (IX), and a compound of formula (X) in sequence: Wherein Xg, Xh, Xi, Xj, Xk, and Xl are groups containing leaving groups or nucleophilic groups, and Xg and Xj form G1 through nucleophilic reaction or condensation reaction, Xh and Xk form G2 through nucleophilic reaction or condensation reaction, and Xi and Xl form G3 through nucleophilic reaction or condensation reaction.

27. The method for preparing an ionizable cationic lipid compound according to any one of claims 1 to 22, characterized in that: The method comprises the steps of reacting a compound of formula (XI) with a compound of formula (XII): Steps for reacting a compound of formula (XIII) with a compound of formula (XII): Wherein Xm is a group containing a nucleophilic group, and Xm and C=CL of the compound of formula (XII) 2a X1-L2 is formed by addition reaction.

28. The preparation method according to any one of claims 23 to 27, characterized in that The R1, R2, and R3 are independently the following groups: Wherein, Y, R1', and R2' have the same meanings as in claim 2; It also includes the steps of forming tail chains R1, R2, and R3: Wherein X is a leaving group.

29. The preparation method according to any one of claims 23 to 27, characterized in that: The raw materials used in the reaction process also contain protecting groups, and the reaction steps include protecting and / or deprotecting steps.

30. Use of the ionizable cationic lipid compound according to any one of claims 1 to 22 as a surfactant.

31. The use according to claim 30, characterized in that The ionizable cationic lipid compound is used as an emulsifier, suspending agent, dispersant, solubilizer, lubricant, thickener, antibacterial agent or preservative.

32. Use of the ionizable cationic lipid compound according to any one of claims 1 to 22 in the preparation of a cosmetic composition.

33. Use of the ionizable cationic lipid compound according to any one of claims 1 to 22 in the preparation of a lipid composition, characterized in that: The ionizable cationic lipid compound is used as a drug delivery carrier.

34. A lipid composition, characterized in that The lipid component of the lipid composition comprises the ionizable cationic lipid compound of any one of claims 1-22.

35. The lipid composition of claim 34, wherein The lipid component of the lipid composition also contains other lipids, which include phospholipids, structural lipids, and PEG-conjugated lipids; the molar ratio of the ionizable cationic lipid compound to the other lipid components is 1:0.2-5; the active ingredients of the lipid nanoparticle composition include therapeutic agents and / or preventive agents; the therapeutic agents and / or preventive agents are vaccines or compounds that can induce an immune response; the mass ratio of the lipid component to the active ingredient is 10:1 to 60:

1.

36. The lipid composition of claim 35, wherein The therapeutic and / or preventive agent is a nucleic acid; the nucleic acid is DNA or RNA.

37. Use of the lipid composition according to any one of claims 34 to 36 in a drug for treating a disease in a mammal, characterized in that: The disease is characterized by dysfunctional or abnormal protein or polypeptide activity; the disease is selected from infectious diseases, cancer, proliferative diseases, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardiovascular diseases, renal vascular diseases, and metabolic diseases.

38. A pharmaceutical composition, characterized in that Comprising the lipid composition of any one of claims 34-36 and a pharmaceutically acceptable carrier.

39. The pharmaceutical composition according to claim 38, characterized in that The pharmaceutical composition further comprises a pharmaceutically active compound selected from the group consisting of anti-inflammatory compounds, steroids, statins, estradiol, BTK inhibitors, S1P1 agonists, glucocorticoid receptor modulators and antihistamines.

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