Lipid compound and application thereof

Abstract

The invention provides a novel lipid compound, lipid nanoparticles containing the same and application of the lipid compound in targeted delivery of drugs. Specifically, the invention provides a compound as shown in a general formula I, or pharmaceutically acceptable salt, prodrug or stereoisomer thereof. Further, the invention provides a lipid nanoparticle, which comprises a compound shown in the general formula I or pharmaceutically acceptable salt, prodrug or stereoisomer of the compound, further, the lipid nanoparticles may further comprise a cationic lipid; more further, the lipid nanoparticles may further comprise an adjunct lipid. The composition containing the compound, or the pharmaceutically acceptable salt, prodrug, stereoisomer or lipid nanoparticle thereof can realize the organ targeted delivery function of a therapeutic agent / prophylactic agent. # imgabs0 #

Description

Lipid compounds and their applications

[0001] Cross-references

[0002] This application claims priority to Chinese patent application No. 202210809436.X, filed on July 11, 2022, entitled “Organ-specific delivery composition for nucleic acids,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application relates generally to the field of chemistry. More specifically, it relates to a novel ionizable anionic lipid and a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, a nanoparticle composition comprising the lipid, and the use of the nanoparticle composition in organ-specific delivery of substances such as nucleic acids. Background Art

[0004] Treatment or preventive nucleic acid has the potential to completely change vaccination, gene therapy, protein replacement therapy and other genetic disease therapies. Since the first clinical study of therapeutic nucleic acid began in the 2000s, the design of nucleic acid molecules and the research of their delivery method have made significant progress. However, nucleic acid drugs (comprising therapeutic drugs and preventive drugs) are still faced with several challenges, including that most liposome preparations accumulate by the biological process in the liver, thereby reducing the effectiveness of the composition delivered into the target organ. Similarly, other therapeutic agents such as proteins and small molecule drugs can benefit from organ-specific delivery. Many different types of compounds such as chemicals show significant cytotoxicity. If these compounds can be better directed to be delivered to the desired organ, less off-target effects and side effects will be seen.

[0005] Currently, most lipid nanoparticle delivery systems passively target the liver. To change the target organ of lipid nanoparticles, the common strategy is to adjust the composition of the lipid nanoparticles. According to some reports, lipid nanoparticles composed of one or two lipids can achieve spleen targeting by adjusting the mixing ratio of nucleic acids and nanoparticles (Stephan Grabbe et al., Translating Nanoparticulate-personalized Cancer Vaccines into Clinical Applications: Case Study with RNA-Lipoplexes for the Treatment of Melanoma, 2016). However, this strategy needs to be improved in terms of formulation stability and encapsulation efficiency. In addition, according to some reports (Cheng Qiang et al., Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing, 2020), the addition of permanent anionic lipids to LNPs composed of four components: cationizable lipids, steroids, phospholipids, and PEG lipids can also specifically target the spleen, but at the cost of increased complexity in components and formulation processes. Therefore, lipid nanoparticle delivery systems with high delivery capacity, high stability and low complexity still need to be developed.

[0006] Summary of the Invention

[0007] The present application provides a compound of the following general formula I or a pharmaceutically acceptable salt, prodrug, stereoisomer or deuterated substance thereof:

[0008] Among them, L 1 is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-、-NR a (CH2) x -、-(CH2) x NRa -;;Q 1 is absent or is a C1-C8 linear or branched hydrocarbon group, specifically a C1, C2, C3, C4, C5, C6, C7 or C8 linear or branched hydrocarbon group;

[0009] L 2 is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-;Q 2 is absent or is a C1-C8 linear or branched hydrocarbon group, specifically a C1, C2, C3, C4, C5, C6, C7 or C8 linear or branched hydrocarbon group;

[0010] L 3 is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-;Q 3 is absent or is a C1-C8 linear or branched hydrocarbon group, specifically a C1, C2, C3, C4, C5, C6, C7 or C8 linear or branched hydrocarbon group;

[0011] R a is H or deuterium or a C1-C8 straight or branched hydrocarbon group or a C1-C8 straight or branched hydrocarbon group substituted with a carboxyl group, specifically a C1, C2, C3, C4, C5, C6, C7 or C8 straight or branched hydrocarbon group;

[0012] X is C or N;

[0013] R is Z is C, O, or NR b or S; R b is H or deuterium or a C1-C8 linear or branched hydrocarbon group, specifically a C1, C2, C3, C4, C5, C6, C7 or C8 linear or branched hydrocarbon group;

[0014] Y 1 or Y 2 One of the is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-, and Y 1 or Y 2 The other is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-;

[0015] G 1 and G 2 Each is independently absent or substituted C1-C12 linear or branched hydrocarbon group, specifically C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 linear or branched hydrocarbon group;

[0016] Y 3 or Y 4 One of the is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NRa C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-, and Y 3 or Y 4 The other is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-;

[0017] G 3 and G 4 Each is independently absent or substituted C1-C12 linear or branched hydrocarbon group, specifically C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 linear or branched hydrocarbon group;

[0018] Y 5 or Y 6 One of the is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-, and Y 5 or Y 6 The other is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x-, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-;

[0019] R a is H or deuterium or a C1-C8 straight or branched hydrocarbon group or a C1-C8 straight or branched hydrocarbon group substituted with a carboxyl group, specifically a C1, C2, C3, C4, C5, C6, C7 or C8 straight or branched hydrocarbon group;

[0020] G 5 and G 6 Each is independently absent or substituted C1-C12 linear or branched hydrocarbon group, specifically C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12 linear or branched hydrocarbon group;

[0021] R 1 and R 2 Each is independently a substituted C1-C24 straight or branched hydrocarbon group, specifically a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23 or C24 straight or branched hydrocarbon group;

[0022] x is 0, 1, or 2.

[0023] According to the above general formula, the present application provides specific lipid compounds as shown in Table 1.

[0024] Table 1. Representative structures of lipid compounds

[0025] The present application also provides a lipid nanoparticle that can target different tissues and organs for drug delivery. The lipid nanoparticles provided herein comprise cationic lipids and the lipid compound described herein, or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, wherein the cationic lipid is selected from one or more combinations of permanent cationic lipids and / or ionizable cationic lipids, and wherein the lipid compound is a compound having the structure of general formula I. Preferably, the lipid compound is selected from the compounds shown in Table 1, or a combination thereof. Furthermore, the lipid nanoparticles may also comprise at least one auxiliary lipid, which, after mixing with the drug, enables encapsulation and specific delivery to specific tissues and organs. Tissue and organ specificity is achieved by the lipid compound, or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, in the lipid nanoparticles, preferably by a combination of the lipid compound, or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, and the cationic lipid, and further preferably by a combination of the lipid compound, or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, the cationic lipid, and the auxiliary lipid.

[0026] In some aspects of the present application, there is provided a lipid nanoparticle comprising:

[0027] (1) a lipid compound or a pharmaceutically acceptable salt, prodrug, stereoisomer or deuterated derivative thereof;

[0028] (2) cationic lipids; and

[0029] (3) Auxiliary lipids.

[0030] The lipid nanoparticles preferentially deliver the therapeutic / prophylactic agent to the following target organs: lung, heart, brain, spleen, lymph node, bone, skeletal muscle, stomach, small intestine, large intestine / colorectum, kidney, bladder, breast, testicle, ovary, uterus, thymus, brainstem, cerebellum, cerebrum, spinal cord, eye, ear, tongue or skin. Preferably, the target organ is the spleen.

[0031] The cationic lipid in the lipid nanoparticles comprises an ammonium group that is positively charged at a given pH and contains at least two hydrophobic groups. The cationic lipid is a dendrimer or dendron. The cationic lipid comprises at least two C6-C24 hydrocarbon groups. The cationic lipid can be one or a combination of permanent cationic lipids and / or ionizable cationic lipids. The permanent cationic lipid can be selected from one or more of DOTAP, DODMA, DSTAP, DMTAP, DDA, and DOBAQ, and the ionizable cationic lipid can be selected from one or more of SM-102, Lipid5, A6, DC-chol, C12-200, CKK-E12, 5A2-SC8, G0-C14, OF-2, 306Oi10, OF-Deg-Lin, 92-O17S, OF-C4-Deg-Lin, A18-iso5-2DC18, TT3, FTT5, BAMEA-O16B, Vc-Lipid, C14-4, Lipid 14, 4A3-Cit, and ssPalmO-Phe.

[0032] In the lipid nanoparticles, the molar ratio of the cationic lipid to the lipid compound or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof is 1:1 to 11:1.

[0033] Furthermore, the lipid nanoparticles may further include auxiliary lipids. The auxiliary lipids are optionally one or more of phospholipids, steroids, polymer-conjugated lipids, and modifiable lipids.

[0034] Preferably, the phospholipid is selected from any one of DOPE, DSPC, DPPC, DMPC, DOPC, POPC, SM, or a combination thereof.

[0035] Preferably, the steroid is selected from one or more of cholesterol, sitosterol, stigmasterol and ergosterol.

[0036] Preferably, the polymer-conjugated lipid, wherein the polymer refers to a high molecular weight compound formed by covalently bonding one or more small molecule repeating units; the polymer can be selected from polyethylene glycol, polylactic acid, polyamide, cationic polymer, polysarcosine (pSar), polylactic acid-glycolic acid copolymer (PLGA), polyamino acid, polypeptide, polypeptide, etc.; preferably, the polymer-conjugated lipid is selected from polyethylene glycol-conjugated lipid; further, the polyethylene glycol-conjugated lipid is selected from one or more of PEG1000-DMG, PEG5000-DMG, PEG2000-DMG and PEG2000-DSPE.

[0037] Preferably, the modifiable lipids include lipids modified with small molecule compounds, vitamins, carbohydrates, peptides, proteins, nucleic acids, lipopolysaccharides, inorganic molecules or particles, metal ions or particles, and combinations thereof.

[0038] In the lipid nanoparticles, the molar ratio of the cationic lipid, the lipid compound or its pharmaceutically acceptable salt, prodrug or stereoisomer, and the auxiliary lipid is 1: (0.1-1): (0.5-2).

[0039] In other aspects, the present application provides a composition comprising a therapeutic agent or a prophylactic agent and the above-mentioned lipid nanoparticles.

[0040] In a preferred aspect, the therapeutic / prophylactic agent is a nucleic acid.

[0041] Preferably, the nucleic acid includes any and all forms of nucleic acid molecules, including but not limited to single-stranded DNA, double-stranded DNA, single-stranded RNA, double-stranded RNA, short isomers, plasmid DNA, complementary DNA / cDNA, antisense nucleic acid molecules / ASO, small interfering nucleic acid / siRNA, small activating nucleic acid / saRNA, asymmetric interfering nucleic acid / aiRNA, micronucleic acid / miRNA, miRNA inhibitors (agomir, antagomir), Dicer enzyme substrate nucleic acid, small hairpin nucleic acid (shRNA), transfer RNA (tRNA), messenger RNA / mRNA, circular RNA / circRNA, self-replicating mRNA / samRNA, aptamer / aptamer and other forms of nucleic acid molecules known in the art.

[0042] The nucleic acid molecules may include natural nucleotides, nucleotide mimetics or functional analogs, and chemically modified forms of nucleotides.

[0043] Functional nucleotide analogs include, but are not limited to, locked nucleic acid (LNA), peptide nucleic acid (PNA), or morpholino oligonucleotide nucleic acid mimetics or functional analogs, or a combination of more than one thereof.

[0044] Chemical modifications of nucleotides can be located on the backbone bonds of the nucleic acid molecule. The backbone bonds can be modified by replacing one or more oxygen atoms. Modifications to the backbone bonds can include replacing at least one phosphodiester bond with a phosphorothioate bond.

[0045] The chemical modification of the nucleotide can be located on the nucleoside. The modification on the nucleoside can be located on the sugar and base of the nucleoside. The sugar on the nucleoside can be selected from one or more of the following: 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, hexose.

[0046] The chemically modified form of the nucleotide can be selected from one or more of the following: 5-methylcytosine, pseudouridine, 1-methylpseudouridine, pyridine-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinemethyluridine, 1-taurinemethyl-pseudouridine, 5-taurinemethyl-2-thio-uridine, 1-taurinemethyl-4-thio-uridine, 5-methyl- Uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine Cytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, 2- Aminopurine, 2,6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine, N6-glycylaminoformyladenosine, N6-threonylaminoformyladenosine, 2-methylthio-N6-threonylaminoformyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wyobutosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine and N2,N2-dimethyl-6-thio-guanosine.

[0047] In a preferred embodiment, the nucleic acid is mRNA, which can encode at least one antigen, fragment, or epitope thereof, or a therapeutic protein, wherein the antigen is selected from pathogenic antigens, such as tumor-associated antigens or pathogenic microorganism antigens. The mRNA can be monocistronic or polycistronic.

[0048] The present application also provides the use of the above composition in preparing medicines.

[0049] The present application also provides a drug comprising the above-mentioned composition and pharmaceutically acceptable excipients. Pharmaceutical excipients refer to excipients and additives used in the production of drugs and the preparation of prescriptions; they are substances other than active ingredients that have been reasonably evaluated for safety and are included in pharmaceutical preparations. In addition to providing shape, acting as a carrier, and improving stability, pharmaceutical excipients also have important functions such as solubilization, dissolution assistance, and sustained and controlled release. They are important components that may affect the quality, safety, and effectiveness of drugs. According to their functions and uses, pharmaceutical excipients can be divided into solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc.

[0050] Beneficial effects of this application:

[0051] The present application provides a novel lipid compound or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof. The lipid compound and its derivatives can selectively deliver therapeutic agents / preventive agents to target organs.

[0052] The present application also provides a new lipid nanoparticle that can deliver nucleic acid components to specific organs, especially preferentially to organs other than the liver, providing more options for the delivery of nucleic acid drugs, gene vaccines, etc., and is of great significance for the development and application of nucleic acid preventive and therapeutic agents.

[0053] Most traditional lipid nanoparticles are targeted for liver delivery. The present application greatly changes the organ targeting by adding the lipid compound of the present application or its pharmaceutically acceptable salt, prodrug or stereoisomer into the lipid nanoparticles. In lipid nanoparticles such as TMF8 and TMF100-TMF109 to which the lipid compound of the present application is added, the distribution (mean fluorescence intensity) ratio of nucleic acid drugs in the spleen and liver is 7 to 99 times (Table 5). In traditional lipid nanoparticles without the addition of the lipid compound of the present application, a higher delivery efficiency is achieved in the liver (Ansell, SM; Du, X. Novel Lipids and Lipid Nanoparticle Formulations for Delivery of Nucleic Acids. WO2017075531 A1).

[0054] Therefore, the lipid compound of the present application and the lipid nanoparticles containing the same play an important role in the organ targeting of delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] One or more embodiments are exemplarily illustrated by the accompanying figures, and these exemplary illustrations do not limit the embodiments. The word "exemplary" is used herein to mean "serving as an example, example, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or preferred over other embodiments.

[0056] Figure 1 shows the NMR of compound 40.

[0057] Figure 2 shows the NMR of compound 44.

[0058] Figure 3 shows the NMR of compound 48.

[0059] Figure 4 shows the NMR of compound 70.

[0060] Figure 5 shows the NMR of compound 130.

[0061] Figure 6 shows the NMR of compound 131.

[0062] Figure 7 shows the NMR of compound 132.

[0063] Figure 8 shows the NMR of compound 133.

[0064] Figure 9 shows the NMR of compound 134.

[0065] Figure 10 shows the NMR of compound 135.

[0066] Figure 11 shows the NMR of compound 136.

[0067] Figure 12 shows the NMR of compound 137.

[0068] Figure 13 shows fluorescence signals in different organs of mice 4 hours after intravenous administration of a sample of luciferase mRNA-encapsulated lipid nanoparticles containing TMF107. As shown in the image, the fluorescence signal is strongest in the spleen, while it is very weak in the liver. This indicates that luciferase mRNA expression in the spleen is higher than that in the liver.

[0069] Figure 14 summarizes the fluorescence intensity ratios of the spleen and liver after delivery of luciferase mRNA by different lipid nanoparticles. DETAILED DESCRIPTION

[0070] A. Chemical and Formulation Definitions

[0071] When used in the context of chemical groups: "hydrogen" refers to -H; "deuterium" refers to 2 H or D; "hydroxy" means -OH; "oxo" means =O; "carbonyl" means -C(=O)-; "carboxy" means -C(=O)OH (also written as -COOH or -CO2H); "halo" independently means -F, -Cl, -Br or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; imino means =NH; "cyano" means -CN; "isocyanate" means -N=C=O; "azido" is refers to -N3; ​​in the context of a monovalent group, "phosphate" refers to -OP(O)(OH)2 or a deprotonated form thereof; in the context of a divalent group, "phosphate" refers to -OP(O)(OH)O- or a deprotonated form thereof; "thiol" refers to -SH; and "thio" refers to =S; "sulfonyl" refers to -S(O)2-; "hydroxysulfonyl" refers to -S(O)2OH; "sulfonamide" refers to -S(O)2NH2; and "sulfinyl" refers to -S(O)-. In the context of a chemical formula, the symbol "-" refers to a single bond, "=" refers to a double bond, and "≡" refers to a triple bond. The symbol "----" represents an optional bond, which, if present, is a single bond or a double bond. When drawn vertically through a bond, the symbol Indicates the point of attachment for this group. It should be noted that attachment points are usually only identified in this way for larger groups to help the reader clearly identify the point of attachment. refers to a single bond where the group attached to the thick end of the wedge "comes out of the page". refers to a single bond where the group attached to the thick end of the wedge "enters the page." The symbol =Referring to a single bond, wherein the geometry (e.g., E or Z) around the double bond is undefined. Therefore, both options and their combinations are contemplated. Any undefined valence on an atom of the structure shown in this application implicitly represents a hydrogen atom bonded to that atom. Bold dots on carbon atoms indicate that the hydrogen attached to that carbon is out of the plane of the paper.

[0072] The term "alkyl" used without the "substituted" modifier means a monovalent saturated aliphatic radical having a carbon atom as the point of attachment, having a straight or branched acyclic structure, and having no atoms other than carbon and hydrogen. The groups -CH3(Me), -CH2CH3(Et), -CH2CH2CH3(n-Pr or propyl), -CH(CH3)2(i-Pr, iPr or isopropyl), -CH2CH2CH2CH3(n-Bu), -CH(CH3)CH2CH3(sec-butyl), -CH2CH(CH3)2(isobutyl), -C(CH3)3(tert-butyl, t-Bu or tBu), and -CH2C(CH3)3(neopentyl) are non-limiting examples of alkyl radicals. The term "alkanediyl," used without the "substituted" modifier, means a divalent saturated aliphatic radical having one or two saturated carbon atoms as points of attachment, having a straight or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CH2-(methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkanediyl radicals. "Alkanes" refers to the class of compounds having the formula HR, in which R is alkyl, as that term is defined above. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have independently been replaced with -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -C02H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "haloalkyl" is a subset of substituted alkyl groups in which the hydrogen atom replacement is limited to halo (i.e., -F, -Cl, -Br, or -I) such that no atoms other than carbon, hydrogen, and halogen are present. The group -CH2Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subset of substituted alkyl groups in which the hydrogen atom replacement is limited to fluoro such that no atoms other than carbon, hydrogen, and fluorine are present. The groups -CH2F, -CF3, and -CH2CF3 are non-limiting examples of fluoroalkyl groups.

[0073] The term "alkenyl" used without the "substituted" modifier means a monovalent unsaturated aliphatic radical having a carbon atom as the point of attachment, a straight or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term "alkenediyl" used without the "substituted" modifier means a divalent unsaturated aliphatic radical having two carbon atoms as the point of attachment, a straight or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are non-limiting examples of alkene diyl groups. It should be noted that although alkene diyl groups are aliphatic, this does not preclude the group from forming part of an aromatic structure once attached at both ends. The terms "alkene" and "alkene" are synonymous and refer to the class of compounds having the formula HR, where R is an alkenyl group, as that term is defined above. Similarly, the terms "terminal alkene" and "α-olefin" are synonymous and refer to an alkene having exactly one carbon-carbon double bond, where the bond is part of a vinyl group at the end of the molecule. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have been independently replaced by -OH, -F, -Cl, -Br, -I, -NH, -NO, -C0H, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH. The groups -CH=CHF, -CH=CHCl, and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

[0074] The term "alkynyl" as used without the "substituted" modifier refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, a straight or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The term alkynyl as used herein does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH3, and -CH2C≡CCH3 are non-limiting examples of alkynyl groups. "Alkynes" refers to the class of compounds having the formula HR, where R is an alkynyl group. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms have independently been replaced with -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -C02H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0075] "Prodrug" refers to a compound, such as a therapeutic agent, that can be converted into a biologically active compound under physiological conditions or by dissolution. Prodrugs are generally rapidly converted in vivo to produce the parent compound, for example by hydrolysis in the blood. Prodrug compounds generally have advantages in solubility, tissue compatibility, or delayed release in mammalian organisms. The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when the prodrug is administered to a mammalian subject. Prodrugs include compounds that have hydroxyl, amino, or sulfhydryl groups bound to any group that, when the prodrug is administered to a mammalian subject, cleaves to form free hydroxyl, free amino, or free sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives or amide derivatives of amine functional groups.

[0076] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are pharmaceutically acceptable as defined above and that possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, Pharmaceutically acceptable salts include hydroxybenzoic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, enanthic acid, caproic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl) benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acid, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, etc. Pharmaceutically acceptable salts also include base addition salts that can form when the acidic protons present can react with inorganic bases or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It will be recognized that the particular anion or cation forming part of any salt of the present disclosure is not critical so long as the salt as a whole is pharmacologically acceptable.

[0077] "Stereoisomers" or "optical isomers" are isomers of a given compound in which the same atoms are bonded to the same other atoms, but in which the three-dimensional configurations of those atoms are different. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like the left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain chiral centers (also called stereocenters or stereocenters), which are any points (although not necessarily atoms) in a molecule that carry multiple groups such that the interchange of any two groups produces stereoisomers. In organic compounds, chiral centers are usually carbon, phosphorus, or sulfur atoms, although other atoms may also serve as stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, resulting in its many stereoisomers. In compounds whose stereoisomerism is attributed to tetrahedral stereocenters (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry often have a number smaller than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be split or separated using techniques known in the art. It is expected that for any stereochemically undefined stereocenter or chiral axis, the stereocenter or chiral axis can exist in its R form, S form, or as a mixture of the R form and S form (including racemic mixtures and non-racemic mixtures). The phrase "substantially free of other stereoisomers" as used herein means that the composition contains ≤15%, more preferably ≤10%, even more preferably ≤5%, or most preferably ≤1% of one or more other stereoisomers.

[0078] deuterium( 2 H (or D) is a stable and non-radioactive isotope of hydrogen, having approximately twice the mass of hydrogen (H) and is the most common isotope of hydrogen.

[0079] "Prevention" or "preventing" includes: (1) inhibiting the onset of a disease in a subject or patient who may be at risk for and / or susceptible to the disease but who does not yet experience or display any or all symptoms or signs of the disease; and / or (2) slowing the onset of symptoms or signs of a disease in a subject or patient who may be at risk for and / or susceptible to the disease but who does not yet experience or display any or all symptoms or signs of the disease.

[0080] "Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease (e.g., arresting further development of the symptoms and / or signs), (2) ameliorating a disease in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease (e.g., reversing the symptoms and / or signs), and / or (3) achieving any measurable reduction in a disease in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease.

[0081] "Protein", "polypeptide" or "peptide" refers to a polymer of amino acid residues and includes a wide range of protein molecules such as cytokines, chemokines, interleukins, interferons, growth factors, coagulation factors, anticoagulants, blood factors, bone morphogenic proteins, immunoglobulins and enzymes. Some non-limiting examples of therapeutic proteins include the following therapeutic proteins or fragments, variants or derivatives thereof: therapeutic proteins for the treatment of metabolic or endocrine disorders, including acid sphingomyelinase, Adipotide, Agalsidase-β, Alglucosidase, α-galactosidase A, α-glucosidase, α-L-iduronidase, α-N-acetylglucosidase, amphiregulin, angiopoietin (Ang1, Ang2, Ang3, Ang4, ANGPTL2, ANGPTL3, ANGPTL4, ANGPTL5, ANGPTL6, ANGPTL7), beta-cellulose , β-glucuronidase, bone morphogenetic proteins BMPs (BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP15), CLN6 protein, epidermal growth factor (EGF), Epigen, epidermal regulin, fibroblast growth factors (FGF, FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, FGF-15, FGF FGF-16, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21, FGF-22, FGF-23), Galsulphase, Glucocerebrosidase, GM-CSF, Heparin-binding EGF-like growth factor (HB-EGF), Hepatocyte growth factor (HGF), Hepcidin, Human albumin, Increased albumin loss, Iduronate sulfatase (iduronate-2-sulfatase), Integrins αVβ3, αVβ5, and α5β1, Iduronate sulfatase, Laronease, N-acetylgalactosamine-4-sulfatase (rhASB; galsulf ase, arylsulfatase A (ARSA), arylsulfatase B (ARSB)), N-acetylglucosamine-6-sulfatase, nerve growth factor (NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin 4 / 5 (NT-4 / 5), neuregulin (NRG1, NRG2, NRG3, NRG4), neuropilin (NRP-1, NRP-2), obestatin, platelet-derived growth factor (PDGF (PDFF-A, PDGF-B, PDGF-C, PDGF-D), TGFβ receptors (endothelin, TGF-β1 receptor,TGF-β2 receptor, TGF-β3 receptor), thrombopoietin (THPO) (megakaryocyte growth and development factor (MGDF)), transforming growth factor (TGF (TGF-a, TGF-β (TGFβ1, TGFβ2, and TGFβ3))), VEGF (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PIGF), nesiritide, trypsin, adrenocorticotropic hormone (ACTH), atrial natriuretic peptide (ANP), cholecystokinin, gastrin, leptin, oxytocin, somatostatin, vasopressin (antidiuretic hormone), calcitonin, exenatide, growth hormone (GH), somatropin, insulin, insulin-like growth factor 1 IGF-1, mecasermin rinfabate, an IGF-1 analog, mecasermin, an IGF-1 analog, pegvisomant, pramlintide, teriparatide (human parathyroid hormone residues 1-34), becaplermin, dibotermin-α (bone morphogenetic protein 2), histrelin acetate (gonadotropin-releasing hormone; GnRH), octreotide, and palifermin (keratinocyte growth factor; KGF); for the treatment of blood disorders, circulatory system diseases, respiratory system diseases, cancer or tumor diseases, infectious diseases, or immunodeficiency Therapeutic proteins, including alteplase (tissue plasminogen activator; tPA), anistreplase, antithrombin III (AT-III), bivalirudin, darbepoietin alfa, drotrexone alfa (activated protein C, erythropoietin, epoetin alfa, erythropoietin, erythropoietin, factor IX, factor VIIa, factor VIII, lepirudin, protein C concentrate, reteplase (a deletion mutant of tPA), streptokinase, tenecteplase, urokinase, angiostatin, anti-CD22 immunotoxin , denileukin-toxin conjugate, Immunocyanin, MPS (Metallopanstimulin), Aflibercept, Endostatin, Collagenase, Human deoxyribonuclease I, Dornase, Hyaluronidase, Papain, L-asparaginase, Peg-asparaginase, Rasburicase, Human chronic gonadotropin (HCG), Human follicle-stimulating hormone (FSH), Luteinizing hormone-alpha, Prolactin, Alpha-1 proteinase inhibitor, Lactase, Pancreatic enzymes (lipase, amylase) enzyme, protease), adenosine deaminase (bovine pegastatin, PEG-ADA), abatacept, alefacept, anakinra, etanercept, interleukin-1 (IL-1) receptor antagonist, thymosin, TNF-α antagonist, enfuvirtide, and thymosin α1; therapeutic proteins selected from adjuvants or immunostimulatory proteins, including: human adjuvant proteins, in particular pattern recognition receptors TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10,TLR11; NOD1, NOD2, NOD3, NOD4, NOD5, NALP1, NALP2, NALP3, NALP4, NALP5, NALP6, NALP7, NALP8, NALP9, NALP10, NALP11, NALP12, NALP13, NALP14, 1IPAF, NAIP, CIITA, RIG-I, MDA5 and LGP2, signal transducers of TLR signaling, including adaptor proteins, including, for example, Trif and Cardif; components of small-GTPase signaling (RhoA, Ras, Rac1, Cdc42, Rab, etc.), components of PIP signaling (PI3K, Src-kinase, etc.), components of MyD88-dependent signaling (MyD88, IRAK1, IRAK2, IRAK4, TIRAP, TRAF6, etc.), components of MyD88-independent signaling (TICAM1, T Activated kinases include, for example, Akt, MEKK1, MKK1, MKK3, MKK4, MKK6, MKK7, ERK1, ERK2, GSK3, PKC kinase, PKD kinase, GSK3 kinase, JNK, p38 MAPK, TAK1, IKK and TAK1; activated transcription factors include, for example, NF-κB, c-Fos, c -Jun, c-Myc, CREB, AP-1, Elk-1, ATF2, IRF-3, IRF-7, heat shock proteins such as HSP10, HSP60, HSP65, HSP70, HSP75 and HSP90, gp96, fibrinogen, TypIII repeat extra domain A of fibronectin; or components of the complement system, including C1q, MBL, C1r, C1s, C2b, Bb, D, MASP-1, MASP-2, C4b, C3b, C5a, C3a, C4a, C5b, C6, C7, C8, C9, CR1, CR2, CR3, CR4, C1qR, C1INH, C4bp, MCP, DAF, H, I, P and CD59, or induced target genes including, for example, beta-defensins, cell surface proteins; or human adjuvant proteins including trif, flt-3 ligand, Gp96 or fibronectin, cells that induce or enhance innate immune responses Cytokines, including IL-1α, IL1β, IL-2, IL-6, IL-7, IL-8, IL-9, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL -21, IL-23, TNFα, IFNα, IFNβ, IFNγ, GM-CSF, G-CSF, M-CSF; chemokines, including IL-8, IP-10, MCP-1, MIP-1α,RANTES, eotaxin, CCL21; cytokines released by macrophages, including IL-1, IL-6, IL-8, IL-12, and TNF-α; as well as IL-1R1 and IL-1α; bacterial (adjuvant) proteins, particularly bacterial heat shock proteins or chaperones, including Hsp60, Hsp70, Hsp90, Hsp100; OmpA (outer membrane protein) from Gram-negative bacteria; bacterial porins, including OmpF; bacterial toxins, including those from Bordetella pertussis pertussis toxin (PT), pertussis adenylate cyclase toxins CyaA and CyaC from Bordetella pertussis, PT-9K / 129G mutant from pertussis toxin, tetanus toxin, cholera toxin (CT), cholera toxin B-subunit, CTK63 mutant from cholera toxin, CTE112K mutant from CT, Escherichia coli heat-labile enterotoxin (LT), B subunit (LTB) from heat-labile enterotoxin, Escherichia coli heat-labile enterotoxin mutants with reduced toxicity, including LTK63, LTR72; phenol-soluble regulatory protein; neutrophil-activating protein (HP-NAP) from Helicobacter pylori; surfactant protein D; outer surface protein A lipoprotein from Borrelia burgdorferi, lipoprotein B from Mycobacterium tuberculosis. tuberculosis; proteins from bacterial fimbriae; enterotoxin CT from Vibrio cholerae, fimbriae proteins from fimbriae of Gram-negative bacteria, and surfactant protein A and bacterial flagellin, protozoan (adjuvant) proteins, in particular Tc52 from Trypanosoma cruzi, PFTG from Trypanosoma gondii, protozoan heat shock proteins, LeIF from Leishmania spp., LeIF from Toxoplasma gondii ... gondii), viral (adjuvant) proteins, in particular respiratory syncytial virus fusion glycoprotein (F-protein), envelope proteins from MMT virus, murine leukemia virus proteins, hemagglutinin protein of wild-type measles virus, fungal (adjuvant) proteins, in particular fungal immunomodulatory protein (FIP; LZ-8); and keyhole limpet hemocyanin (KLH), OspA; therapeutic proteins for hormone replacement therapy, in particular estrogens, progesterone or progesterone, and testosterone; therapeutic proteins for reprogramming somatic cells into pluripotent or totipotent stem cells, in particular Oct-3 / 4,Sox gene family (Sox1, Sox2, Sox3 and Sox15), Klf family (Klf1, Klf2, Klf4 and Klf5), Myc family (c-myc, L-myc and N-myc), Nanog and LIN28; and therapeutic antibodies selected from antibodies for the treatment of cancer or tumor diseases, in particular 131T-Tositumomab, 3F8, 8H9, Abafuzumab, Adelimumab, Afutuzumab, Alacizumab pegol, Alemtuzumab, Amatuximab, AME-133v, AMG102, Maanimumab (Maanatumomab), Apolizumab, Batumuximab, Betumumab, Belimumab, Bevacizumab, Bivalve-DM1, Blinatumomab, Brentuximab vedotin, Cantuzumab, Mecanizumab, Cantuzumab ravtansine, Carlosomab pendetide, Carlumab, Catuzumab, Cetuximab, Citatuzumab bogatox, Cixutumumab, Clivatuzumab tetraxetan, CNTO328, CNTO 95, Conatumumab, Dacetuzumab, Dalotuzumab, Desutuzumab, Desutuzumab, Drozitumab, Ecomeximab, Edelecomab, Elotuzumab, Elsilimomab, Enavatuzumab, Ensituximab, Epratuzumab, Ertumaxomab, Etaracizumab, Farletuzumab, FBTA05, Ficlatuzumab, Figitumumab, Flanvotumab, Galiximab, Galiximab, Ganitumab, GC1008, Gemtuzumab, Gemtuzumab Ozogacin, Girentuximab, Glemnbatumumab vedotin, GS6624, HuC242-DM4, HuHMFG1, HuN901-DM1, Ibritumomab Tiuxetan, Icrucumab, ID09C3, Indatuximab ravtansine, Inotuzumab ozogamicin, Intetumumab, Ipilimumab, Iratumumab, Labetuzumab, Lexitumab, Lintuzumab, Lorvotuzumab mertansine, Lucatumumab, Ruximab, Mapatumumab, Matuzumab, MDX-060, MEDI 522, Mitumomab, Mogamulizumab, MORab-003,MORab-009, Moxetumomab pasudotox, MT103, Tarceva, Naptumomab estafenatox, Narnatumab, Necitumumab, Nimotuzumab, Olaratumab, Onartuzumab, Oportuzumab monatox, Oregovomab, PAM4, Panitumab, Patritumab, Pemtumomab, Pertuzumab, Pliximab, Racotumomab, Radretumab, Ramucirumab, Rilotumumab, Rituximab, Robatumumab, Samalizumab, SGN-30, SGN-40, Silobuzumab, Siltuximab, Tabalumab, Tacatuzumab Tetraxetan, Palatatumomab, Tenatumomab, Teprotumumab, TGN1412, Ticilimumab (= tremelimumab), Tigatuzumab, TNX-650, Tositumomab, Trastuzumab, TRBS07, Tremelimumab, Tucotuzumab celmoleukin, Ublituximab, Urelumab, Veltuzumab, Veltuzumab (IMMU-106), Volociximab, Futumomab, WX-G250, zalutumumab and Talizumab; antibodies for the treatment of immune disorders, particularly Efalizumab, Epratuzumab, Etrolizumab, Fontolizumab, Ixekizumab, Mepolizumab, Milatuzumab, pooled immunoglobulins, Priliximab, Rituximab, Rontalizumab, Lulizumab, Sarilumab, Vedolizumab, Visilizumab, Reslizumab, Adalimumab, Ase lizumab, Atinumab, Atlizumab, Belimumab, Besilesomab, BMS-945429, Briakinumab, Brodalumab, Canakinumab, Becerolizumab, Erlizumab, Fezakinumab, Golimumab, Gomiliximab, Infliximab, Mavrilimumab, Natalizumab, Ocrelizumab, Odomumab, Ofatumumab, Ozoralizumab, Pexelizumab, Rovizumab, SBI-087, Secukinumab, Sirukumab, Talizumab, Tocilizumab, Toralizumab, TRU-015,TRU-016, Ustekinumab, Vepramumab, Azotumomab, Sifalimumab, Ruximab, and Rho(D) immune globulin; antibodies for the treatment of infectious diseases, particularly Afelimomab, CR6261, Ebalizumab, Efungumab, Avelumab, Felvelumab, Foravirumab, Ibalizumab, Libivirumab, Motavizumab, Nebacumab, Tuvirumab, and Ubiquinolone , Baciximab, Pagibaximab, Palivizumab, Panobacumab, PRO140, Refavirux, Raxibacumab, Rigavir, Sevir, Suvizumab, and Tilatuzumab; Antibodies for the treatment of blood disorders, particularly abciximab, adalimumab, eculizumab, mepolizumab, and milatuzumab; Antibodies for immunomodulation, particularly antithymocyte globulin, basiliximab, cilizumab, daclizumab Antibodies for the treatment of diabetes, in particular Gevokizumab, Otelixizumab and Teplizumab; Antibodies for the treatment of Alzheimer's disease, in particular Bapineuzumab, Crenezumab, Gantenerumab, Ponezumab, R1450 and Solanezumab; Antibodies for the treatment of asthma, in particular Benralizumab, Enokizumab, Keliximab, Lebrikizumab, Omalizumab, Oxelumab, Pascolizumab and Tralokinumab; Antibodies for the treatment of various conditions, in particular Blosozumab, CaroRx, Fresolimumab, Fulranumab, Romosozumab, Siplizumab,Tanezumab and ranibizumab; erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), α-galactosidase A, α-L-iduronidase, thyrotropin α, N-acetylgalactosamine-4-sulfatase (rhASB), dornase alfa, tissue-type plasminogen activator (TPA) activase, glucocerebrosidase, interferon (IF) β-1α, interferon β-1b, interferon γ, interferon α, TNF-α, IL-1 to IL-36, human growth hormone (rHGH), human insulin (BHI), human chorionic gonadotropin α, darbepoetin α, follicle-stimulating hormone (FSH), and factor VIII, antibodies and antibody derivatives such as bispecific antibodies, multispecific antibodies, and ADCs, all used to treat various conditions. Peptides are compounds formed by α-amino acids linked together by peptide bonds and are also intermediate products of protein hydrolysis. Generally, the number of amino acids contained in a peptide is from two to nine. Depending on the number of amino acids in the peptide, peptides are called different names: dipeptides, tripeptides, tetrapeptides, pentapeptides, etc. Peptides composed of three or more amino acid molecules are called polypeptides. Their molecular weight is less than 10,000 Da, they can pass through semipermeable membranes, and are not precipitated by trichloroacetic acid and ammonium sulfate. There are also literatures that call peptides composed of 2 to 10 amino acids oligopeptides (small molecule peptides); peptides composed of 10 to 50 amino acids are called polypeptides; peptides composed of more than 50 amino acids are called proteins. In other words, proteins are sometimes also called polypeptides.

[0082] "Small molecule compounds" include 7-methoxypteridine, 7-methylpteridine, abacavir, abafungin, abarelix, acebutolol, acenaphthene, acetaminophen, acetanilide, acetazolamide, acetohexamide, acitretin, acrivastine, adenine, adenosine, alafloxacin, albendazole, salbutamol, alclofenac, aldesleukin, alemtuzumab, alfuzosin, alitretinoin, alobarbital, allopurinol, all-trans retinoic acid (ATRA), aloprin, alprazolam, alprenolol, hexamethylenetetramine, amifostine, amiloride, aminoglutethimide, aminopyrine, amiodarone hydrochloride, amitriptyline, amlodipine, amobarbital, amodiaquine, amoxapine, amphetamine, amphetamine, amphetamine, amphetamine B, ampicillin, and amprenavir , amsacrine, amyl nitrate, amobarbital, anastrozole, amrinone, anthracene, anthracycline antibiotics, aprobital, arsenic trioxide, asparaginase, aspirin, astemizole, atenolol, atorvastatin, atovaquone, atrazine, atropine, azathioprine atropine, auranofin, azacitidine, azapropazone, azathioprine, azintamide, azithromycin, aztreonam, baclofen, barbiturates, live BCG, beclomethasone, bendroflumethiazide, benezepril, benidipine, benoyl ester, benzyl alcohol, benzazepam, benzamide, benzanthracene, benzathine penicillin, benzhexyphenidyl hydrochloride, benznidazole, benzodiazepines, benzoic acid, hydroxynaphthyphenidin, benzyl alcohol Tamethasone, bevacizumab (atorvastatin), bexarotene, bezafibrate, bicalutamide, bifonazole, biperiden, bisacodyl, bisantrene, bleomycin, bleomycin, bortezomib, brinzolamide, bromazepam, bromocriptine mesylate, bromperidol, brotizolam, budesonide, bumetanide, bupropion, busulfan, butalbital, butamben, butenafine hydrochloride, butalbital, butalbital (n-butalbital), butoconazole, butoconazole nitrate, butylparaben, caffeine, calcifediol, calciprotriene, calcitriol, captestosterone, cambendazole, camphor, camptothecin, camptothecin analogs, candesartan, capecitabine, capsaicin, captopril, carbamazepine, carboplatin Bimazole, chloramphenicol, carboplatin, carbimazole, carimazole, carmustine, cefamandole, cefazolin, cefixime, ceftazidime, cefuroxime axetil, celecoxib, cephradine, cerivastatin, cetrizine, cetuximab, chlorambucil, chloramphenicol, chlordiazepoxide, clomethiazole, chloroquine, chlorothiazide, chlorpheniramine, chlorproguanil hydrochloride, chlorpromazine, chlorsulfuronamide, chlorprothixene, chlorpyrifos, chlortetracycline, chlorthalidone, chlorzoxazone, cholecalciferol, cilostazol, cimetidine, cinnarizine, cinoxacin, ciprofibrate, ciprofloxacin hydrochloride, cisapride, cisplatin, citalopram, cladribine, clarithromycin, clemastine fumarate, clioquinol, clobazam, clofarabine, clofazimine, clofibrate,Clomiphene citrate, clomipramine, clonazepam, clopidogrel, clotiazepam, clotrimazole, clotrimazole, cloxacillin, clozapine, cocaine, codeine, colchicine, colistin, conjugated estrogens, corticosterone, cortisone, cortisone acetate, cyclizine, cyclohexane-spirobarbital, cyclobenzaprine, cyclobutane-spirobarbiturate, cyclohexane-spirobarbiturate, cycloheptane-spirobarbiturate, cyclohexane-spirobarbiturate, cyclopentane-spirobarbiturate, cyclophosphamide, cyclopropane-spirobarbiturate, cycloserine, cyclosporine, cyproheptadine, cyproheptadine hydrochloride, cytarabine, cytosine, dacarbazine, dactinomycin, Danazol, danthron, dantrolene sodium, dapsone, erythropoietin alfa, darodipine, daunorubicin, decoquinate, dehydroepiandrosterone, delavirdine, demethylchlorocycline, denileukin, deoxycorticosterone, desoximetasone, dexamethasone, dextroamphetamine, dexchlorpheniramine, dexfenfluramine, dexrazoxane, dextropropoxyphene, heroin, diatrizoate, diazepam, diazoxide, dichlorophen, 2,4-dichlorprop, diclofenac, dicoumarol, didanosine, diflunisal, digitoxin, digoxin, dihydrocodeine, dihydroequilin, dihydroergotamine mesylate, diiodohydroxyquinoline, diltiazem hydrochloride, diloxanide furoate, diphenhydramine Amine, desmopramine, dinitolamide, diosgenin, diphenoxylate hydrochloride, biphenyl, dipyridamole, dirithromycin, disopyramide, disulfiram, diuron, docetaxel, domperidone, donepezil, doxazosin, doxazosin hydrochloride, doxorubicin (neutral), doxorubicin hydrochloride, doxycycline, drostanolone propionate, droperidol, diprophylline, echinocandins, econazole, econazole nitrate, efavirenz, elitizine, enalapril, emtamol, enoximone, epinephrine, epipodophyllotoxin derivatives, epirubicin, epoetin alfa, iprosartan (eposartan), dehydroequilin, equilin , ergocalciferol, ergotamine tartrate, erlotinib, erythromycin, estradiol, estramustine, estriol, estrone, ethacrynic acid, ethambutol, ethinyl amine, ethionamide, profenamide hydrochloride, ethyl 4-aminobenzoate (benzocaine), ethyl parahydroxybenzoate, ethinyl estradiol, etodolac, etomidate, etoposide, acitretin, exemestane, felbamate, felodipine, fenbendazole, fenbuconazole, fenbufen, fenfluramine, fenclorac, fenfluramine, fenofibrate, fenoldepam, fenoprofen calcium, fenoxycarb, fenpiclonil, Fentanyl, fenticonazole, fexofenadine, filgrastim, finasteride, flecainide acetate, floxuridine, fludarabine, fluconazole, fluconazole, flucytosine, fludioxonil, fludrocortisone, fludrocortisone acetate, flufenamic acid, fluanisone, flunarizine hydrochloride, flunisolide, flunitrazepam, fluocortolone, flumethuron, fluorene, fluorouracil, fluoxetine hydrochloride, fluoxymesterone, flupentixol decanoate,Fluphenthixol decanoate, flurazepam, flurbiprofen, fluticasone propionate, fluvastatin, folic acid, fosenopril, fosphenytoin sodium, frovatriptan, furosemide, fulvestrant, furazolidone, gabapentin, G-BHC (lindane), gefitinib, gemcitabine, gemfibrozil, gemtuzumab, glafenine, glyburide, gliclazide, glimepiride, glipizide, glutethimide, glyburide, glyceryl trinitrate (nitroglycerin), goserelin acetate, grepafloxacin, griseofulvin, guaifenesin, guanabenzyl acetate, guanine, halofantrine hydrochloride, haloperidol, hydrochlorothiazide, helbutal, heroin, hesperetin, hexachlorobenzene, hexobarbital, histrelin acetate, hydrocortisone, hydroflumethiazide, hydroxyurea, hyoscine Polamine, hypoxanthine, ibritumomab tiuxetan, ibuprofen, idarubicin, allyl butalbital, ifosfamide, ihydroequilenin, imatinib mesylate, imipenem, indapamide, indinavir, indomethacin, indoprofen, interferon alfa-2a, interferon alfa-2b, iodamide, iopanoic acid, iprodione, irbesartan, irinotecan, isavuconazole, isocarboxazid, isoconazole, isoguanine, isoniazid, isopropyl barbiturate, isoproturon, isosorbide dinitrate, isosorbide mononitrate, isradipine, itraconazole, itraconazole (Itra), ivermectin, ketoconazole, ketoprofen, ketorolac, kaeline, labetalol, lamivudine, lamotrigine, lansoside C, lansotrafenone lanosprazole, L-DOPA, leflunomide, lenalidomide, letrozole, folinic acid, leuprolide acetate, levamisole, levofloxacin, lidocaine, linduron, lisinopril, lomefloxacin, lomustine, loperamide, loratadine, lorazepam, lorefloxacin, lormetazepam, losartan mesylate, lovastatin, lisuride maleate, maprotiline hydrochloride, mazindol, mebendazole, meclizine hydrochloride, meclofenamic acid, medazepam, methyldigoxin, medroxyprogesterone acetate, mefenamic acid, mefloquine hydrochloride, megestrol acetate, melphalan, mepentate bromide, meprobamate, meptazinol, mercaptopurine, mesalamine, mesna, mesoridazine, Mestranol, methadone, methaqualone, methocarbamol, mephenytoin, methotrexate, methoxsalen, methsuximide, methylclothiazide, methylphenidate, methylphenobarbital, methylparaben, methylprednisolone, methyltestosterone, methysergide maleate, metoclopramide, metolazone, metoprolol, metronidazole, mianserin hydrochloride, miconazole, midazolam, mifepristone, miglitol, minocycline, minoxidil, mitomycin C, mitotane, mitoxantrone, mycophenolate mofetil, molinone, montelukast, morphine, moxifloxacin hydrochloride, nabumetone, nadolol, nalbuphine, nalidixic acid, nandrolone, tetracene, naphthalene, naproxen, naratriptan hydrochloride, natamycin, nelarabine, nelfinavir, nevirapine, nicardipine hydrochloride,Nicotinamide, niacin, acenocoumarol, nifedipine, nilutamide, nimodipine, nimozole, nisoldipine, nitrazepam, nitrofurantoin, nitrofurazone, nizatidine, novofloxacin, norethindrone, norfloxacin, norgestrel, nortriptyline hydrochloride, nystatin, estradiol, ofloxacin, olanzapine, omeprazole, omoconazole, ondansetron hydrochloride, oprelvekin, ornidazole, oxaliplatin, oxaliplatin, oxaproz ... Oxcarbazepine, oxfendazole, oxiconazole, oxprenolol, hydroxybutazone, hydroxybenzylamine hydrochloride, paclitaxel, palifermin, pamidronate, para-aminosalicylic acid, pantoprazole, mefenacet, paroxetine hydrochloride, pegaspargase, pegfilgrastim, pemetrexed disodium, penicillamine, pentaerythritol tetranitrate, pentazocine, pentobarbital l), pentobarbital, pentostatin, pentoxifylline, perphenazine, perphenazine pimozide, perylene, phenylacetylurea, phenacetin, phenanthren, phenindione, phenobarbital, phenolbarbital, phenolphthalein, phenoxybenzamine, phenoxybenzamine hydrochloride, phenoxymethylpenicillin, phensuximide, phenylbutazone, phenytoin, pindolol, pioglitazone, pipobroman, piroxicam, pizotifen maleate, platinum compounds, plicamycin, polyene, polymyxin B, porfibril sodium, posaconazole (Posa), pramipexole, prasterone, pravastatin, praziquantel, prazosin, prazosin hydrochloride, prednisolone, prednisone, primidone, probarbital, probenecid, probucol, procarbazine, prochlorperazine, progesterone, proguanil hydrochloride, promethazine, propofol, propoxur, propranolol, propylparaben, propylthiouracil, prostaglandin, pseudoephedrine, pteridine-2-methyl-thiol, pteridine-2-thiol, pteridine-4-methyl-thiol, pteridine-4-thiol, pteridine-7-methyl alkyl-thiol, pteridine-7-thiol, pyrantel pamoate, pyrazinamide, pyrene, pyridostigmine, pyrimethamine, quetiapine, imipenem, quinapril, quinidine, quinidine sulfate, quinine, quinine sulfate, rabeprazole sodium, ranitidine hydrochloride, rasburicase, ravuconazole, repaglinide, dicyclopental, reserpine, retinoids, rifabutin, rifampicin, rifapentine, rimexolone, risperidone, ritonavir, rituximab, rizatriptan benzoate, rofecoxib, ropinirole hydrochloride , rosiglitazone, saccharin, salbutamol, salicylamide, salicylic acid, saquinavir, sargramostim, butabarbital, secobarbital, sertaconazole, sertindole, sertraline hydrochloride, simvastatin, sirolimus, sorafenib, sparfloxacin, spiramycin, spironolactone, dihydrotestosterone, stanozolol, stavudine, diethylstilbestrol, streptozocin, strychnine, sulconazole, sulconazole nitrate, sulfacetamide, sulfadiazine, sulfamethazine, sulfamethazine, sulfamethoxazole, sulfa, sulfathiazole, sulindac,Sulfadiazine, sulfacetamide, sulfadiazine, sulfadoxine, sulfisoxazole, sulfamerazine, sulfa-methoxazole, sulfapyridine, sulfasalazine, sulfinpyridine, sulphapyridine, sulfathiazide, sulpiride, thiothiazide, sumatriptan succinate, sunitinib maleate, tacrine, tacrolimus, talbutal, tamoxifen citrate, tamsulosin, targretin, taxane, tazarotene, telmisartan, temazepam, temozolomide, teniposide, tenoxicam, terazosin, terazosin hydrochloride, terazosin hydrochloride Terbinafine, terbutaline sulfate, terconazole, terfenadine, testosterone, testosterone, tetracycline, tetrahydrocannabinol, tetraoxoprene, thalidomide, thebaine, theobromine, theophylline, thiabendazole, thiamphenicol, thioguanine, thioridazine, thiotepa, ethotoin, thymidine, tiagabine hydrochloride, tibolone, ticlopidine, tinidazole, tioconazole, tirofiban , tizanidine hydrochloride, tolazamide, tolbutamide, tolcapone, topiramate, topotecan, toremifene, tositumomab, tramadol, trastuzumab, trazodone hydrochloride, tretinoin, triamcinolone, triamterene, triazolam, triazoles, triflupromazine, trimethoprim, trimipramine maleate, benzyl alcohol, troglitazone, tromethamine, tropicamide, trovafloxacin, tadalafil, Ubidecarenone (coenzyme Q10), undecylenic acid, uracil, uracil mustard, uric acid, valproic acid, valrubicin, valsartan, vancomycin, venlafaxine hydrochloride, vigabatrin, pentobarbital, vinblastine, vincristine, vinorelbine, voriconazole, xanthine, zafirlukast, zidovudine, zileuton, zoledronic acid, zolmitriptan, zolpidem, and zopiclone.

[0083] An antigen (Ag) is any substance that triggers the production of antibodies and is considered to be any substance capable of inducing an immune response. Foreign molecules can be recognized by immunoglobulins on B cells or processed by antigen-presenting cells, where they bind to the major histocompatibility complex (MHC), forming complexes that reactivate T cells and trigger a continuous immune response.

[0084] Epitopes, also known as antigenic determinants, can be composed of a continuous sequence (protein primary structure) or a discontinuous three-dimensional protein structure, and are specific chemical groups that determine antigenicity. Most epitopes are found on the surface of antigenic substances, while some are found internally and are exposed only after enzymatic or other treatment. A natural antigen can have multiple determinants. The larger the antigen molecule, the greater the number of epitopes.

[0085] Tumor-associated antigens (TAAs) are antigenic molecules present on both tumor cells and normal cells. These include embryonic proteins, glycoprotein antigens, and squamous cell antigens, and are commonly used in clinical tumor diagnosis. TAAs are not unique to tumor cells; they are synthesized in trace amounts by normal cells and highly expressed during tumor cell proliferation, hence the term "associated antigens." Tumors originating from the same tissue type may harbor the same TAAs in different individuals.

[0086] Pathogens are microorganisms that can invade the human body and cause infection or even infectious diseases. Among pathogens, bacteria and viruses are the most harmful. Pathogens include prions, fungi, bacteria, spirochetes, mycoplasmas, rickettsiae, chlamydiae, and viruses. Pathogen antigens are substances derived from pathogens that have the ability to trigger an immune response.

[0087] "Lipid encapsulation" refers to lipid nanoparticles that provide active or therapeutic agents (e.g., nucleic acids (e.g., mRNA)), with full encapsulation, partial encapsulation, or intermediate between the two. In some embodiments, the nucleic acid (e.g., mRNA) is completely encapsulated in the lipid nanoparticles.

[0088] In various embodiments, the lipid nanoparticles have an average diameter of about 90 nm to about 600 nm, about 100 nm to about 550 nm, about 150 nm to about 500 nm, about 200 nm to about 400 nm, about 250 nm to about 300 nm, about 200 nm to about 300 nm, and are substantially non-toxic.

[0089] B. Lipid compounds

[0090] In some aspects, the lipid compound disclosed in the present disclosure causes the selective delivery of the lipid nanoparticle comprising it to a specific organ. The lipid compound is preferably one or more of ionizable anionic lipids. In some embodiments, the lipid compound is present in the composition in a mol ratio of about 5%, 10%, 15%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 45%, to about 50% or any range that can be derived therefrom. In some embodiments, the lipid compound can exist in a mol ratio of about 5% to about 50%, about 5% to about 45%, about 10% to about 40%, or about 20% to about 35%, or about 20% to about 30%.

[0091] In some embodiments, the lipid compound is selected from ionizable anionic lipids. Ionizable anionic lipids are small molecules with two or more C6-C24 alkyl or alkenyl or alkynyl chains. In some aspects, the present disclosure provides one or more lipids with one or more hydrophobic components and ionizable anionic groups. The ionizable anionic groups that can be used in ionizable anionic lipids are carboxylate groups, sulfonate groups, or phosphate groups. The ionizable anionic groups can be carboxylate groups. The carboxylate groups can be compounds with negative charges at pHs lower than 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. The hydrophobic components can be one or more C6-C24 alkyl or alkenyl or alkynyl groups. The compound can have one hydrophobic group, two hydrophobic groups, or three hydrophobic groups.

[0092] C. Helper lipids

[0093] In some aspects of the present disclosure, a composition containing one or more auxiliary lipids is mixed with a cationic lipid and a lipid compound of the present application to produce lipid nanoparticles. In some embodiments, the cationic lipid and the lipid compound of the present application are mixed with 1, 2, 3, 4 or 5 different types of auxiliary lipids. It is contemplated that cationic lipids and the lipid compound of the present application can be mixed with a variety of different auxiliary lipids of a single type. In some embodiments, the auxiliary lipid includes but is not limited to one or more of a phospholipid, a steroid or steroid derivative, a polymer-conjugated lipid and a modified lipid.

[0094] "Phospholipid" refers to any lipid that contains a phosphate group. In some embodiments, the phospholipid is a structure containing one or two long-chain C6-C24 alkyl or alkenyl groups, glycerol or sphingosine, one or two phosphate groups, and an optional small organic molecule. In some embodiments, the small organic molecule is an amino acid, a sugar, or an amino-substituted alkoxy group, such as choline or ethanolamine. In some embodiments, the phospholipid is phosphatidylcholine. In some embodiments, the phospholipid is DOPE, DSPC, DPPC, DMPC, DOPC, POPC, or SM. In some embodiments, the phospholipid is distearoylphosphatidylcholine or dioleoylphosphatidylethanolamine.

[0095] "Steroids and steroid derivatives" include any steroid or steroid derivative. As used herein, in some embodiments, the term "steroid" is a class of compounds with a tetracyclic 17-carbon ring structure, which may further include one or more substitutions, including alkyl, alkoxy, hydroxyl, oxo, acyl, or a double bond between two or more carbon atoms. In one aspect, the ring structure of a steroid includes three fused cyclohexyl rings and a fused cyclopentyl ring. In some embodiments, a steroid derivative includes the above-mentioned ring structure substituted with one or more non-alkyl groups. In some embodiments, a steroid or a steroid derivative is a sterol. In some embodiments of the present disclosure, the steroid or steroid derivative is cholestane or a cholestane derivative. As mentioned above, a cholestane derivative includes the non-alkyl substitution of one or more of the above-mentioned ring systems. In some embodiments, the cholestane or cholestane derivative is cholestene or a cholestene derivative or a sterol or a sterol derivative. In other embodiments, the cholestane or cholestane derivative is cholestene and a sterol or a derivative thereof.

[0096] "Polymer-conjugated lipids" refer to lipids that inhibit aggregation of lipid nanoparticles or improve lipid nanoparticle stability or change immune responses or change circulation time in the body. The polymer-conjugated lipids include, but are not limited to, polyethylene glycol-conjugated lipids, polylactic acid-conjugated lipids, polyamide-conjugated lipids, cationic polymer-conjugated lipids, polysarcosine (pSar)-conjugated lipids, polylactic acid-co-glycolic acid (PLGA)-conjugated lipids, polyamino acids-conjugated lipids, polypeptides-conjugated lipids, poly-peptide-conjugated lipids or mixtures thereof. In some embodiments, the "polyethylene glycol-conjugated lipids" refer to any lipid to which a PEG group has been attached. In some embodiments, the PEG lipid is a diglyceride, which also includes a PEG chain connected to a glycerol group. In other embodiments, the PEG lipid is a compound containing one or more C6-C24 long-chain alkyl or alkenyl groups or C6-C24 fatty acid groups connected to a linker group with a PEG chain. Some non-limiting examples of PEG lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-conjugated ceramides, PEG-modified dialkylamines and PEG-modified 1,2-diacyloxypropane-3-amines, PEG-modified diacylglycerols and dialkylglycerols. In some embodiments, PEG-modified distearoyl phosphatidylethanolamine or PEG-modified dimyristoyl-sn-glycerol. In some embodiments, PEG modification is measured by the molecular weight of the PEG component of the lipid. In some embodiments, the molecular weight of the PEG used for modification is about 100 to about 15,000. In some embodiments, the molecular weight is about 200 to about 500, about 400 to about 5000, about 500 to about 3000, or about 1200 to about 3000. The molecular weight of PEG used for modification is about 100, 200, 400, 500, 600, 800, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000, 10000, 12500 to about 15000. "Modified lipids" include lipids modified with small molecule compounds, vitamins, carbohydrates, peptides, proteins, nucleic acids, lipopolysaccharides, inorganic molecules or particles, metal ions or particles, and combinations thereof.

[0097] List of English abbreviations

[0098] Example

[0099] In order to more clearly describe the purpose, features and advantages of the present application, the present application will be described in detail below with reference to the accompanying drawings and specific implementation methods. However, the implementation methods of the present application described in detail below are only for the purpose of illustrating the contents of the present application and do not constitute any limitation to the present application.

[0100] Example 1. Compound Synthesis

[0101] The following reagents used for compound synthesis were all from Shanghai Titan Technology Co., Ltd., AR grade.

[0102] The synthesis method of compound 40 is as follows:

[0103] To a 50 mL flask, add succinic anhydride (151.4 mg, 1.51 mmol), DMAP (18.5 mg, 0.15 mmol), DLin-MeOH (400 mg, 0.76 mmol), and DCM (2 mL). Stir at room temperature overnight. TLC (5% MeOH / DCM) is used to monitor the reaction progress. Upon completion, wash with 2 mL of water and 2 mL of saturated sodium chloride solution, dry over anhydrous NaSO, filter, and concentrate the organic phase to yield approximately 500 mg of crude product. The pure product, compound 40, 190 mg, was isolated and purified using a flash column (20 g silica gel, mobile phases: 300 mL of n-heptane; 100 mL of 1% EtOAc + 99% n-heptane; 100 mL of 2% EtOAc + 98% n-heptane; 100 mL of 5% EtOAc + 95% n-heptane; 300 mL of 8% EtOAc + 92% n-heptane).

[0104] The NMR results of compound 40 are shown in Figure 1. 1 H NMR (400MHz, CDCl3): δ5.41-5.29(m,8H),4.91-4.86(m,1H),2.77(t,J=8Hz,4H),2.69-2. 58(m,4H),2.07-2.02(m,8H),1.53-1.48(m,4H),1.39-1.25(m,40H),0.89(t,J=8Hz,6H).

[0105] The synthesis method of compound 43 is as follows:

[0106] To a 100 mL flask, add DLin-MeOH (1.5 g, 2.8 mmol), glutaric anhydride (485.5 mg, 4.3 mmol), DMAP (346.5 mg, 2.8 mmol), and DCM (5 mL). Stir at room temperature overnight. TLC (20% EtOAc / n-heptane) is used to monitor the reaction progress. Upon completion, the mixture is washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous NaSO, filtered, and the organic phase concentrated to yield approximately 1.3 g of crude product. The pure product was isolated and purified using a flash column (100 g silica gel, loaded with 200 mL of n-heptane; the mobile phases were: 200 mL of n-heptane; 200 mL of 0.3% EtOAc + 99.7% of n-heptane; 200 mL of 0.5% EtOAc + 99.5% of n-heptane; 200 mL of 1% EtOAc + 99% of n-heptane; 200 mL of 2% EtOAc + 98% of n-heptane; 800 mL of 3% EtOAc + 97% of n-heptane), 43,900 mg, with a yield of 50%.

[0107] The synthesis method of compound 44 is as follows:

[0108] Step 1: Synthesis of compound 44-1

[0109] A 50 mL flask was charged with BOC-glycine (33 mg, 0.19 mmol), DMAP (3.4 mg, 0.028 mmol), DCC (57.8 mg, 0.28 mmol), DCM (0.75 mL), and THF (0.75 mL). The mixture was stirred for 30 min, and DLin-MeOH (150 mg, 0.28 mmol) was added to the solution. The mixture was stirred overnight at room temperature. The reaction progress was monitored by TLC (10% THF / n-heptane). After completion of the reaction, the mixture was diluted with 10 mL of DCM, washed with 3 mL of water and 3 mL of saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and the organic phase was concentrated. 2 mL of n-heptane was added for pulping, filtered, and the filtrate was concentrated to dryness to obtain the product, 44-1, 50 mg, in a 26% yield.

[0110] Step 2: Synthesis of compound 44-2

[0111] To a 10 mL flask, 44-1 (120 mg, 0.175 mmol) was added and dissolved in DCM (2.0 mL), followed by the addition of TFA (0.4 mL). After stirring at room temperature for 2 h, the reaction was monitored by TLC (20% EtOAc / n-heptane). After completion of the reaction, the reaction solution was concentrated to yield 230 mg of crude product. Purification by flash column (8 g silica gel, mobile phases: 100 mL of DCM; 100 mL of 1% MeOH + 99% DCM; 100 mL of 1.5% MeOH + 95% DCM; 300 mL of 10% MeOH + 90% DCM) afforded the pure product, 44-2, 80 mg, in a yield of 78%.

[0112] Step 3: Synthesis of compound 44

[0113] Succinic anhydride (28 mg, 0.28 mmol), DMAP (1.7 mg, 0.014 mmol), and DCM (2 ml) were added to a 50 mL flask. The mixture was stirred at room temperature for 30 min, and 44-2 (80 mg, 0.14 mmol) was added to the reaction solution. The reaction progress was monitored by TLC (30% EtOAc / n-heptane). After completion of the reaction, the mixture was diluted with 10 mL of DCM, washed with 3 mL of water and 3 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and the organic phase concentrated to yield approximately 160 mg of crude product. Purification was performed using a flash column (20 g silica gel, mobile phases: 100 mL of n-heptane; 100 mL of 1% EtOAc + 99% n-heptane; 100 mL of 2% EtOAc + 98% n-heptane; 300 mL of 5% EtOAc + 95% n-heptane) to obtain the pure product, compound 44, 60 mg, in a 62% yield.

[0114] The NMR results of compound 44 are shown in Figure 2. 1 H NMR (400MHz, d6-DMSO): δ12.07 (s, 1H), 8.26 (t, J = 8Hz, 1H), 5.37-5.26 (m, 8H), 4.80-4.73 (m, 1H), 3.78 (d, J = 4Hz, 2H), 2.73(t,J=8Hz,4H),2.43-2.35(m,4H),2.04-1.99(m,8H),1.47-1.45(m,4H),1.35-1.23(m,40H),0.86(t,J=8Hz,6H).

[0115] The synthesis method of compound 48 is as follows:

[0116] Step 1: Synthesis of compound 48-1

[0117] To a 100 mL flask, add DLin-MeOH (750 mg, 1.4 mmol), triethylamine (287 mg, 2.8 mmol), and DCM (20 mL). Place in an ice bath at 0-5°C, and add dropwise methanesulfonic anhydride (365.8 mg, 2.1 mmol). Stir at 0-5°C for 2 h after addition, then slowly warm to room temperature and stir overnight. Monitor the reaction progress by TLC (5% EtOAc / n-heptane). Upon completion, wash with 5 mL of water and 5 mL of saturated brine, dry over anhydrous Na2SO4, filter, and concentrate the organic phase to yield approximately 1.3 g of crude product. The pure product, 48-1, 600 mg, was isolated and obtained by purification using a flash column (100 g silica gel, loaded with 200 mL of n-heptane; the mobile phases were: 200 mL of n-heptane; 200 mL of 0.3% EtOAc + 99.7% of n-heptane; 200 mL of 1% EtOAc + 99% of n-heptane; 600 mL of 2% EtOAc + 98% of n-heptane). The yield was 71%.

[0118] Step 2: Synthesis of compound 48-2

[0119] A 100 mL flask was charged with 48-1 (1.0 g, 1.6 mmol), potassium phthalimide (0.44 g, 2.4 mmol), and DMF (15 mL). The mixture was heated at 90°C and stirred for 16 h. The reaction progress was monitored by TLC (10% EtOAc / n-heptane). After completion of the reaction, 15 mL of water was added and the aqueous layer was extracted with 20 mL of ethyl acetate (3 times). The combined organic phases were washed with 5 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield approximately 1.6 g of crude product. Purification was performed using a flash column (120 g silica gel, loaded with 200 mL of n-heptane; mobile phases were: 300 mL of n-heptane; 300 mL of 0.5% THF + 99.5% n-heptane; 600 mL of 1% THF + 99% n-heptane) to obtain the pure product, 48-2, 800 mg, in a 76% yield.

[0120] Step 3: Synthesis of compound 48-3

[0121] To a 100 mL flask, add 48-2 (100 mg, 0.15 mmol), hydrazine hydrate (23.8 mg, 0.38 mmol), and anhydrous ethanol (0.5 mL). Heat to 80-85°C and stir for 4 h. Monitor the reaction progress by TLC (10% THF / n-heptane). After completion, purify by Pre-TLC (n-heptane / THF = 10 / 1) to obtain the product, 48-3, 60 mg, in an 80% yield.

[0122] Step 4: Synthesis of compound 48

[0123] Succinic anhydride (40.1 mg, 0.4 mmol), DMAP (4.8 mg, 0.04 mmol), and DCM (1 mL) were added to a 50 mL flask. Stir at room temperature for 30 min, and then 48-3 (100 mg, 0.2 mmol) was added to the reaction mixture. The reaction progress was monitored by TLC (30% EtOAc / n-heptane). Upon completion of the reaction, the mixture was diluted with 10 mL of DCM, washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous NaSO, filtered, and the organic phase concentrated to yield approximately 100 mg of crude product. The pure product, compound 48, 60 mg, was isolated and obtained using a flash column (20 g silica gel, mobile phases: 100 mL of n-heptane; 100 mL of 1% EtOAc + 99% n-heptane; 100 mL of 2% EtOAc + 98% n-heptane; 100 mL of 5% EtOAc + 95% n-heptane; 300 mL of 8% EtOAc + 92% n-heptane).

[0124] The NMR results of compound 48 are shown in Figure 3. 1 H NMR (400MHz, d6-DMSO): δ12.01(s,1H),7.49(d,J=8Hz,1H),5.37-5.27(m,8H),3.63(m,1H),2.73(t,J=8Hz ,4H),2.40(t,J=8Hz,2H),2.28(t,J=8Hz,2H),2.04-1.95(m,8H),1.33-1.22(m,47H),0.86(t,J=8Hz,6H).

[0125] The synthesis method of compound 70 is as follows:

[0126] Step 1: Synthesis of compound 70-1

[0127] To a 100 mL flask, add 60% sodium hydride (25.8 mg, 0.64 mmol), slowly add ethylene glycol (1 mL) dropwise, and then add a mixture of 48-1 (100 mg, 0.16 mmol) and ethylene glycol (0.5 mL) dropwise. Heat to 65°C and stir for 2 h. Add 2 mL of DMF and continue heating at 90°C and stirring for 16 h. Monitor the reaction progress by TLC (20% EtOAc / n-heptane). After the reaction is complete, add 5 mL of water and extract the aqueous layer with 10 mL of ethyl acetate (3 times). Combine the organic phases, wash with 5 mL of saturated brine, dry over anhydrous Na2SO4, filter, and concentrate the organic phase to yield approximately 300 mg of crude product. The pure product was isolated and purified using a flash column (20 g silica gel, loaded with 100 mL of n-heptane; the mobile phases were: 100 mL of n-heptane; 100 mL of 1% EtOAc + 99% of n-heptane; 100 mL of 3% EtOAc + 97% of n-heptane; 100 mL of 5% EtOAc + 95% of n-heptane; 500 mL of 10% EtOAc + 90% of n-heptane) to obtain 70-1.60 mg of the product with a yield of 66%.

[0128] Step 2: Synthesis of compound 70

[0129] To a 50 mL flask, add succinic anhydride (63.3 mg, 0.62 mmol), DMAP (7.6 mg, 0.062 mmol), and DCM (2 mL). Stir at room temperature for 30 min, then add 70-1 (180 mg, 0.31 mmol). Monitor the reaction progress by TLC (30% EtOAc / n-heptane). Upon completion, dilute with 10 mL of DCM, wash with 5 mL of water and 5 mL of saturated brine, dry over anhydrous NaSO, filter, and concentrate the organic phase to yield approximately 180 mg of crude product. The pure product, compound 70, 100 mg, was isolated and obtained by purification using a flash column (20 g silica gel, mobile phases: 100 mL of n-heptane; 100 mL of 1% EtOAc + 99% n-heptane; 100 mL of 2% EtOAc + 98% n-heptane; 100 mL of 5% EtOAc + 95% n-heptane; 300 mL of 8% EtOAc + 92% n-heptane).

[0130] The NMR results of compound 70 are shown in Figure 4. 1H NMR (400MHz, CDCl3): δ5.41-5.30(m,8H),4.22(t,J=8Hz,2H),3.63(t,J=8Hz,2H),3.27-3.21(m,1H),2.77(t, J=8Hz,4H),2.72-2.63(m,4H),2.08-1.98(m,8H),1.47-1.42(m,4H),1.37-1.21(m,40H),0.89(t,J=8Hz,6H).

[0131] The synthesis method of compound 130 is as follows:

[0132] To a 25 mL flask, 130-1 (200 mg, 0.28 mmol, 1.0 eq), DMAP (6.89 mg, 0.056 mmol, 0.2 eq), and succinic anhydride (56.44 mg, 0.56 mmol, 2.0 eq) were dissolved in DCM (2 mL) and stirred at room temperature overnight. The reaction progress was monitored by TLC (35% EtOAc / n-heptane). Upon completion, the reaction was washed with 2 mL of water and 2 mL of saturated brine. The organic phase was dried over anhydrous NaSO, filtered, and concentrated to yield approximately 500 mg of crude product. The pure product, compound 130, was isolated and purified using a flash column (30 g silica gel, loaded with 100 mL of n-heptane; the mobile phases were: 100 mL of n-heptane; 100 mL of 1% EtOAc + 99% n-heptane; 100 mL of 2% EtOAc + 98% n-heptane; 100 mL of 3% EtOAc + 97% n-heptane; 300 mL of 10% EtOAc + 90% n-heptane). 30 mg of compound 130 was obtained in a 13% yield.

[0133] The NMR results of compound 130 are shown in Figure 5. 1 H NMR (400MHz, CDCl3): δ4.91-4.88(m,1H),4.06(t,J=8Hz,1H),2.69-2.58(m,4H) ,2.34-1.27(m,2H),1.64-1.25(m,68H),1.65-0.85(m,48H),0.89-0.83(m,12H).

[0134] The synthesis method of compound 131 is as follows:

[0135] Step 1: Synthesis of compound 131-2

[0136] To a 50 mL flask, 131-1 (746.3 mg, 1.1 mmol) was dissolved in DCM (10 mL). DMAP (57.7 mg, 0.47 mmol) and DCC (234.1 mg, 1.1 mmol) were added. After stirring at room temperature for 30 min, Dlin-MEOH (500 mg, 0.95 mmol) was added to the solution and stirred at room temperature overnight. The reaction progress was monitored by TLC (10% MeOH / DCM). After completion of the reaction, the reaction mixture was filtered to remove solids. The filtrate was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and the organic phase concentrated to yield approximately 800 mg of crude product. The pure product 131-2 was separated and purified using a flash column (12 g silica gel, mobile phases: 300 mL of n-heptane; 200 mL of 1% EtOAc + 99% n-heptane; 200 mL of 5% EtOAc + 95% n-heptane; 300 mL of 8% EtOAc + 92% n-heptane) to obtain 550 mg of the product with a yield of 50%.

[0137] Step 2: Synthesis of compound 131

[0138] To a 50 mL flask, 131-2 (550 mg, 0.47 mmol) was dissolved in DCM (5 mL), and TFA (2 mL) was added. After stirring at room temperature for 2 h, the reaction was monitored by TLC (20% EtOAc / n-heptane). After completion of the reaction, the reaction solution was concentrated and dissolved in MTBE (20 mL). The solution was then adjusted to pH 8-9 with 10% NaHCO₃ solution and pH 1-2 with 1 M dilute hydrochloric acid. The mixture was stirred for 20 min, separated, and the aqueous phase was extracted with 20 mL of MTBE. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield 300 mg of a crude product. The pure product, compound 131, 100 mg, was isolated and obtained by purification using a flash column (8 g silica gel, mobile phases: 200 mL of n-heptane; 100 mL of 5% EtOAc + 95% of n-heptane; 100 mL of 10% EtOAc + 90% of n-heptane; 100 mL of 20% EtOAc + 80% of n-heptane; 200 mL of 30% EtOAc + 70% of n-heptane). The yield was 19%.

[0139] The NMR results of compound 131 are shown in Figure 6. 1H NMR (400MHz, CDCl3): δ5.41-5.29(m,9H),4.88-4.81(m,1H),4.67-4.62(m,1H),4.17(s,1H),4.06(s,1H),3.74(t,1H,J=8Hz),3.63(t,1H, J=4Hz),2.79-2.63(m,9H),2.51(t,1H,J=8Hz),2.34-2.33(m,2H),2.07-1.94(m,10H),1.88-1.80(m,3H),1.61-0.85(m,77H),0.67(s,3H).

[0140] The synthesis method of compound 132 is as follows:

[0141] Step 1: Synthesis of compound 132-2

[0142] To a 50 mL flask, 131-1 (762.2 mg, 1.1 mmol) was dissolved in DCM (10 mL). DMAP (57.7 mg, 0.47 mmol) and DCC (234.1 mg, 1.1 mmol) were added. After stirring at room temperature for 30 min, Dlin-MEOH (500 mg, 0.95 mmol) was added to the solution and stirred at room temperature overnight. The reaction progress was monitored by TLC (10% MeOH / DCM). After completion of the reaction, the reaction mixture was filtered to remove solids. The filtrate was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and the organic phase concentrated to yield approximately 930 mg of crude product. The pure product 132-2 was isolated and purified using a flash column (12 g silica gel, mobile phases: 300 mL of n-heptane; 200 mL of 1% EtOAc + 99% n-heptane; 200 mL of 5% EtOAc + 95% n-heptane; 300 mL of 8% EtOAc + 92% n-heptane). The yield was 60%.

[0143] Step 2: Synthesis of compound 132

[0144] To a 50 mL flask, 132-2 (610 mg, 0.52 mmol) was dissolved in DCM (7 mL), and TFA (3 mL) was added. After stirring at room temperature for 2 h, the reaction was monitored by TLC (60% EtOAc / n-heptane). Upon completion of the reaction, the reaction solution was concentrated and dissolved in MTBE (20 mL). The solution was then adjusted to pH 8-9 with 10% NaHCO₃ solution and pH 1-2 with 1 M dilute hydrochloric acid. The mixture was stirred for 20 min, separated, and the aqueous phase was extracted with 20 mL of MTBE. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield 300 mg of a crude product. The pure product, compound 132, 110 mg, was isolated and obtained in an 18% yield by purification using a flash column (8 g silica gel, mobile phases: 200 mL of n-heptane; 100 mL of 5% EtOAc + 95% n-heptane; 100 mL of 10% EtOAc + 90% n-heptane; 100 mL of 20% EtOAc + 80% n-heptane; 200 mL of 30% EtOAc + 70% n-heptane; 200 mL of 50% EtOAc + 50% n-heptane).

[0145] The NMR results of compound 132 are shown in Figure 7. 1 H NMR (400MHz, CDCl3): δ5.41-5.29(m,9H),4.88-4.81(m,1H),4.67-4.62(m,1H),4.17(s,1H),4.06(s,1H),3.74(t,1H,J=8Hz),3.63(t,1H, J=8Hz),2.79-2.63(m,9H),2.50(t,1H,J=4Hz),2.34-2.33(m,2H),2.07-1.94(m,10H),1.88-1.78(m,3H),1.64-0.85(m,79H),0.67(s,3H).

[0146] The synthesis method of compound 133 is as follows:

[0147] Step 1: Synthesis of compound 133-2

[0148] To a 50 mL flask, 133-1 (526 mg, 0.78 mmol) was dissolved in DCM (5 mL). DMAP (39.7 mg, 0.33 mmol) and DCC (160.9 mg, 0.78 mmol) were added. After stirring at room temperature for 30 min, ALC-0315 (500 mg, 0.65 mmol) was added to the solution and stirred overnight at room temperature. The reaction progress was monitored by TLC (20% MeOH / DCM). After completion of the reaction, the reaction mixture was filtered to remove solids. The filtrate was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous NaSO, filtered, and the organic phase concentrated to yield approximately 820 mg of crude product. The pure product, 133-2, 500 mg, was isolated and obtained by purification using a Flash column (15 g silica gel, mobile phases: 300 mL of DCM; 200 mL of 1% MeOH + 99% of DCM; 200 mL of 1.5% MeOH + 98.5% of DCM; 200 mL of 2% MeOH + 98% of DCM; 200 mL of 3% MeOH + 97% of DCM). The yield was 54%.

[0149] Step 2: Synthesis of compound 133

[0150] To a 50 mL flask, 133-2 (500 mg, 0.35 mmol) was dissolved in DCM (9 mL), and TFA (4 mL) was added. After stirring at room temperature for 2 h, the reaction progress was monitored by TLC (20% MeOH / DCM). Upon completion of the reaction, the reaction solution was concentrated and then dissolved in MTBE (20 mL). The pH was then adjusted to 8-9 with 10% NaHCO₃ solution and then to 1-2 with 1 M dilute hydrochloric acid. The mixture was stirred for 20 min, separated, and the aqueous phase was extracted with 20 mL of MTBE. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield 480 mg of the crude product. The pure product, compound 133, 200 mg, was isolated and obtained in a yield of 42% by purification using a flash column (8 g silica gel, mobile phases: 300 mL of DCM; 200 mL of 1% MeOH + 99% DCM; 200 mL of 1.5% MeOH + 98.5% DCM; 200 mL of 2% MeOH + 98% DCM; 200 mL of 3% MeOH + 97% DCM; 200 mL of 5% MeOH + 95% DCM).

[0151] The NMR results of compound 133 are shown in Figure 8. 1H NMR (400MHz, CDCl3): δ5.37-5.34(m,1H),4.14-4.04(m,10H),2.41-2.29( m,7H),2.01(s,2H),2.06-1.98(m,5H),1.85-0.85(m,121H),0.67(s,3H).

[0152] The synthesis method of compound 134 is as follows:

[0153] Step 1: Synthesis of compound 134-2

[0154] To a 50 mL flask, 134-1 (500 mg, 0.74 mmol) was dissolved in DCM (5 mL). DMAP (18.2 mg, 0.15 mmol) and DCC (230.3 mg, 1.12 mmol) were added. After stirring at room temperature for 30 min, Dlin-MeOH (393.6 mg, 0.74 mmol) was added to the solution and stirred at room temperature overnight. The reaction progress was monitored by TLC (10% MeOH / DCM). After completion of the reaction, the reaction mixture was filtered to remove solids. The filtrate was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and the organic phase concentrated to yield approximately 700 mg of crude product. The pure product 134-2 was isolated and purified using a flash column (12 g silica gel, mobile phases: 300 mL of n-heptane; 200 mL of 1% EtOAc + 99% n-heptane; 200 mL of 5% EtOAc + 95% n-heptane; 300 mL of 8% EtOAc + 92% n-heptane) to obtain 500 mg of the product with a yield of 57%. 1 H NMR (400MHz, CDCl3): δ5.41-5.29(m,8H),4.86-4.83(m,1H),4.72-4.60(m,1H),4.13-4.03(m,4 H),2.79-2.75(m,4H),2.39-2.32(m,6H),1.07-1.78(m,16H),1.65-0.85(m,92H),0.68(s,3H).

[0155] Step 2: Synthesis of compound 134

[0156] To a 50 mL flask, 134-2 (500 mg, 0.42 mmol) was dissolved in DCM (12 mL), and TFA (4 mL) was added. After stirring at room temperature for 2 h, the reaction was monitored by TLC (20% EtOAc / n-heptane). Upon completion of the reaction, the reaction solution was concentrated and dissolved in MTBE (20 mL). The pH was then adjusted to 8-9 with 10% NaHCO₃ solution and then to 1-2 with 1 M dilute hydrochloric acid. The mixture was stirred for 20 min, separated, and the aqueous phase was extracted with MTBE (20 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield 410 mg of the crude product. The pure product, compound 134, was isolated and purified using a flash column (8 g silica gel, mobile phases: 200 mL of n-heptane; 100 mL of 5% EtOAc + 95% n-heptane; 100 mL of 10% EtOAc + 90% n-heptane; 100 mL of 20% EtOAc + 80% n-heptane; 200 mL of 50% EtOAc + 50% n-heptane). The yield was 42%.

[0157] The NMR results of compound 134 are shown in Figure 9. 1 H NMR (400MHz, CDCl3): δ5.41-5.29(m,8H),4.86-4.83(m,1H),4.72-4.68(m,1H),4.19-4.15(m,4 H),2.79-2,72(m,4H),2.41-2.33(m,6H),2.07-1.85(m,16H),1.58-0.86(m,83H),0.68(s,3H).

[0158] The synthesis method of compound 135 is as follows:

[0159] Step 1: Synthesis of compound 135-1

[0160] In a 250mL flask, DMAP (2.5g, 20.1mmol), DCC (4.1g, 20.1mmol), and DCM (50mL) were added, stirred to clarify, and 2-hexyldecanoic acid (5.13g, 20.1mmol) was added. The mixture was stirred at room temperature for 30min. Then, tert-butyl 6-hydroxyhexanoate (3.6g, 19.1mmol) was added at once and stirred at room temperature overnight. TLC (30% n-heptane / DCM) was used to detect the degree of reaction. After the reaction was complete, the reaction solution was filtered to remove solids. The filtrate was washed with 15mL of water and 15mL of saturated common salt water, dried over anhydrous Na2SO4, filtered, and the concentrated organic phase gave approximately 9.3g of crude product. The pure product 135-1 was separated and purified using a Flash column (80 g silica gel, loaded with 100 mL PE; mobile phases: 300 mL n-heptane; 300 mL 10% DCM + 90% n-heptane; 300 mL 20% DCM + 60% n-heptane) to obtain 7 g of the product with a yield of 86%.

[0161] Step 2: Synthesis of compound 135

[0162] To a 50 mL flask, 135-1 (600 mg, 9.7 mmol) was dissolved in DCM (12 mL), and TFA (4 mL) was added. After stirring at room temperature for 2 h, the reaction was monitored by TLC (0.5% MeOH / DCM). Upon completion of the reaction, the reaction solution was concentrated and then dissolved in MTBE (20 mL). The solution was then adjusted to pH 8-9 with 10% NaHCO₃ solution and pH 1-2 with 1 M dilute hydrochloric acid. The mixture was stirred for 20 min, separated, and the aqueous phase was extracted with 20 mL of MTBE. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield 620 mg of the crude product. The pure product, compound 135, 410 mg, was isolated and obtained by purification using a flash column (10 g silica gel, loaded with 50 mL DCM; the mobile phases were: 100 mL DCM; 100 mL 1% MeOH + 99% DCM; 100 mL 2% MeOH + 98% DCM; 100 mL 3% MeOH + 97% DCM; 100 mL 4% MeOH + 96% DCM). The yield was 78%.

[0163] The NMR results of compound 135 are shown in Figure 10. 1 H NMR (400MHz, CDCl3): δ4.07(t,J=8Hz,2H),2.36(t,J=8Hz,2H),2.33-2,28(m,1H ),1,71-1.53(m,6H),1.46-1.36(m,4H),1.33-1.20(m,20H),0.87(t,J=8Hz,6H).

[0164] The synthesis method of compound 136 is as follows:

[0165] To a 100 mL flask, add pentadecan-7-ol (1.9 g, 8.32 mmol), DMAP (1.02 g, 8.32 mmol), and DCM (19 mL). Stirring allowed to settle. Add adipic anhydride (1.6 g, 12.5 mmol) and stir at room temperature for 2 h. Monitor the reaction progress by TLC (30% EtOAc / PE). Upon completion, wash with 5 mL of water and 5 mL of saturated sodium chloride solution, dry over anhydrous NaSO, filter, and concentrate the organic phase to yield approximately 3.1 g of crude product. The pure product, compound 136, 1.2 g, was isolated and obtained using a flash column (60 g silica gel, loaded with 200 mL PE; the mobile phases were: 300 mL 1% EtOAc + 99% n-heptane; 300 mL 2% EtOAc + 98% n-heptane; 300 mL 5% EtOAc + 95% n-heptane; 1000 mL 10% EtOAc + 90% n-heptane).

[0166] The NMR results of compound 136 are shown in Figure 11. 1 H NMR (400MHz, CDCl3): δ4.89-4.85(m,1H),2.41-2.29(m,4H),1.72-1.63(m,4H),1.52-1.48(m,4H),1.32-1.25(m,20H),0.87(t,J=4Hz,6H).

[0167] The synthesis method of compound 137 is as follows:

[0168] Step 1: Synthesis of compound 137-1

[0169] A 250 mL flask was charged with DMAP (500.2 mg, 4.1 mmol), DCC (1.69 g, 8.2 mmol), and DCM (20 mL). After stirring, the mixture was clarified. 8-(tert-butoxy)-8-oxooctanoic acid (1.9 g, 8.2 mmol) was added and stirred at room temperature for 30 min. Then, 9-heptadecanol (2.1 g, 8.2 mmol) was added all at once and stirred at room temperature overnight. The reaction progress was monitored by TLC (10% EtOAc / n-heptane). After completion of the reaction, the reaction mixture was filtered to remove solids. The filtrate was washed with 5 mL of water and 5 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and the organic phase concentrated to yield approximately 3.2 g of crude product. The pure product 137-1 was isolated and purified using a flash column (30 g silica gel, loaded with 200 mL n-heptane; the mobile phases were: 200 mL 0.5% EtOAc + 99.5% n-heptane; 200 mL 1% EtOAc + 99% n-heptane; 1000 mL 2% EtOAc + 98% n-heptane). The product was 2.1 g (yield 55%).

[0170] Step 2: Synthesis of compound 137

[0171] To a 100 mL flask, 137-1 (1.2 g, 2.56 mmol) was dissolved in DCM (8 mL), and TFA (4 mL) was added. After stirring at room temperature for 2 h, the reaction was monitored by TLC (5% MeOH / DCM). Upon completion, the reaction solution was concentrated and dissolved in MTBE (20 mL). The pH was then adjusted to 8-9 with 10% NaHCO₃ solution and then to 1-2 with 1 M dilute hydrochloric acid. The mixture was stirred for 20 min, separated, and the aqueous phase was extracted with 50 mL of MTBE. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to yield 1.5 g of a crude product. The pure product, compound 137, was isolated and purified using a flash column (100 g silica gel, loaded with 50 mL of n-heptane; the mobile phases were: 300 mL of 1% EtOAc + 99% n-heptane; 200 mL of 1.5% EtOAc + 98.5% n-heptane; and 1000 mL of 2% EtOAc + 98% n-heptane) to obtain 800 mg of compound 137 in an 80% yield.

[0172] The NMR results of compound 137 are shown in Figure 12. 1 H NMR (400MHz, CDCl3): δ4.89-4.83(m,1H),2.34(t,J=8Hz,2H),2.28(t,J=8Hz,2H),1.67-1 .59(m,4H),1.52-1.47(m,4H),1.40-1.32(m,4H),1.31-1.19(m,24H),0.87(t,J=8Hz,6H).

[0173] DODMA, DSPC, cholesterol, PEG2000-DMG, etc. used in the following examples were all obtained from Avituo (Shanghai) Pharmaceutical Technology Co., Ltd., and Luc-mRNA (luciferase mRNA) was obtained from Shanghai Zhaowei Technology Development Co., Ltd.

[0174] Example 2. Preparation of lipid nanoparticles TMF7 (containing 20% ​​compound 40)

[0175] 1. Dissolve DODMA (cationic lipid), DSPC (auxiliary lipid), cholesterol (auxiliary lipid), PEG2000-DMG (auxiliary lipid) and compound 40 (lipid compound of the present application) in ethanol to obtain oil phase (ethanol phase) stock solutions with molar ratios of 37.0%, 7.5%, 34.2%, 1.3% and 20.0%, respectively.

[0176] 2. Dilute the luciferase-expressing mRNA stock solution to 0.09 mg / mL using pH 4 citric acid buffer to obtain an aqueous phase.

[0177] 3. The oil phase (ethanol phase) containing the five lipid mixtures and the mRNA-containing aqueous phase were quickly mixed at a volume ratio of 1:3 to prepare TMF7 with a total lipid to mRNA weight ratio of 25.9:1. The sample was then concentrated using an ultrafiltration tube with a molecular weight cutoff of 100 kd, followed by elution with pH 7.4 PBS buffer, and finally replaced with 120 mg / mL sucrose PBS buffer to obtain the final sample.

[0178] Example 3. Preparation of lipid nanoparticles TMF8 (containing 20% ​​compound 44)

[0179] 1. DODMA (cationic lipid), DSPC (auxiliary lipid), cholesterol (auxiliary lipid), PEG2000-DMG (auxiliary lipid) and compound 44 (lipid compound of the present application) were dissolved in ethanol to obtain oil phase (ethanol phase) stock solutions with molar ratios of 37.0%, 7.5%, 34.2%, 1.3% and 20.0%, respectively.

[0180] 2. Dilute the luciferase-expressing mRNA stock solution to 0.09 mg / mL using pH 4 citric acid buffer to obtain an aqueous phase.

[0181] 3. The oil phase (ethanol phase) containing the five lipid mixtures and the mRNA-containing aqueous phase were rapidly mixed at a volume ratio of 1:3 to prepare TMF8 with a total lipid to mRNA weight ratio of 26.3:1. The sample was then concentrated using an ultrafiltration tube with a molecular weight cutoff of 100 kd, followed by elution with pH 7.4 PBS buffer, and finally exchanged with 120 mg / mL sucrose PBS buffer to obtain the final sample.

[0182] Example 4. Preparation of lipid nanoparticles TMF9 (containing 20% ​​compound 70)

[0183] 1. Dissolve DODMA (cationic lipid), DSPC (auxiliary lipid), cholesterol (auxiliary lipid), PEG2000-DMG (auxiliary lipid) and compound 70 (lipid compound of the present application) in ethanol to obtain oil phase (ethanol phase) stock solutions with molar ratios of 37.0%, 7.5%, 34.2%, 1.3% and 20.0%, respectively

[0184] 2. Dilute the luciferase-expressing mRNA stock solution to 0.09 mg / mL using pH 4 citric acid buffer to obtain an aqueous phase.

[0185] 3. The oil phase (ethanol phase) containing the five lipid mixtures and the mRNA-containing aqueous phase were rapidly mixed at a volume ratio of 1:3 to prepare TMF9 with a total lipid to mRNA weight ratio of 26.3:1. The sample was then concentrated using an ultrafiltration tube with a molecular weight cutoff of 100 kd, followed by elution with pH 7.4 PBS buffer, and finally exchanged with 120 mg / mL sucrose PBS buffer to obtain the final sample.

[0186] Example 5. Preparation of lipid nanoparticles TMF100 (containing 38.5% compound 40)

[0187] 1. Dissolve DODMA (cationic lipid), DSPC (auxiliary lipid), compound 40 (lipid compound of the present application) and PEG2000-DMG (auxiliary lipid) in ethanol to obtain oil phase (ethanol phase) stock solutions with molar ratios of 50%, 10%, 38.5% and 1.5%

[0188] 2. Dilute the luciferase-expressing mRNA stock solution to 0.3 mg / mL using pH 4 citric acid buffer to obtain an aqueous phase.

[0189] 3. The oil phase (ethanol phase) containing the four lipid mixtures and the mRNA-containing aqueous phase were rapidly mixed at a volume ratio of 1:3 to prepare TMF100 with a total lipid to mRNA weight ratio of 27.1:1. The sample was then concentrated using an ultrafiltration tube with a molecular weight cutoff of 100 kd, followed by elution with pH 7.4 PBS buffer, and finally exchanged with 120 mg / mL sucrose PBS buffer to obtain the final sample.

[0190] Example 6. Preparation of lipid nanoparticles TMF107 (containing 38.5% compound 134)

[0191] 1. Dissolve DODMA (cationic lipid), DSPC (auxiliary lipid), compound 134 (lipid compound of the present application) and PEG2000-DMG (auxiliary lipid) in ethanol to obtain oil phase (ethanol phase) stock solutions with molar ratios of 50%, 10%, 38.5% and 1.5% respectively.

[0192] 2. Dilute the luciferase-expressing mRNA stock solution to 0.3 mg / mL using pH 4 citric acid buffer to obtain an aqueous phase.

[0193] 3. The oil phase (ethanol phase) containing the four lipid mixtures and the mRNA-containing aqueous phase were rapidly mixed at a volume ratio of 1:3 to prepare TMF107 with a total lipid to mRNA weight ratio of 34.9:1. The sample was then concentrated using an ultrafiltration tube with a molecular weight cutoff of 100 kd, followed by elution with pH 7.4 PBS buffer, and finally exchanged with 120 mg / mL sucrose PBS buffer to obtain the final sample.

[0194] Lipid nanoparticles TMF101-106 and TMF108-109 were prepared in a similar manner to lipid nanoparticles TMF100 and TMF107 using the corresponding starting materials. Detailed information on the lipid nanoparticle components is shown in Table 2.

[0195] Table 2. List of components of lipid nanoparticles prepared from representative GOLD lipid compounds

[0196] Example 7. Detection of lipid nanoparticles

[0197] The size and polydispersity index (PDI) of the lipid nanoparticles were determined using dynamic light scattering (DLS) at a 90° side scattering angle using a NanoBrook 90plus PLAS (Brookhaven Instruments, US). The results are shown in Tables 3 and 4. The content and encapsulation efficiency of the lipid nanoparticles were determined using the Qubit RNA HS Quantification Kit (ThermoFisher Scientific, UK) according to the manufacturer's instructions. The results are shown in Tables 3 and 4.

[0198] Table 3. Characterization data of lipid nanoparticles prepared from representative lipid compounds

[0199] Table 4. Characterization data of lipid nanoparticles prepared from representative lipid compounds

[0200] Example 8. Detection of organ distribution of lipid nanoparticles delivered

[0201] At a dose of 0.5 mg / kg, liposomes prepared in Examples 1, 2, 3, 4, and 5 were injected into female ICR mice aged 6-8 weeks through the epicanthal venous plexus of the fundus. Four hours after administration, 15 mg / mL of D-luciferin potassium salt was injected intraperitoneally at a dose of 150 mg / kg. Ten minutes after the injection of the luciferase substrate, the mice were placed under an in vivo imaging system (IVIS Lumina XRMS Series III, PerkinElmer) to observe the fluorescence intensity and distribution in the mice. The mice were then sacrificed, and the organs (heart, liver, spleen, lungs, and kidneys) were isolated and imaged in vitro to observe the fluorescence intensity and distribution in different organs. The organ distribution of Luc-mRNA delivered by representative lipid compounds is shown in Table 5 and Figure 13. The selectivity data of spleen and liver are summarized as shown in Figure 14, and as long as the ratio of spleen to liver is higher than 1, it is shown that the selectivity of spleen is better, and the effect of spleen targeting can be achieved, and the higher the ratio, the better the spleen targeting effect, wherein the lipid nanoparticles TMF105, TMF104, TMF109 and TMF107 spleen and liver have the highest selectivity, and 4 hours after intravenous administration to mice, the ratio of the mean fluorescence intensity of TMF105, TMF104, TMF109 and TMF107 in spleen and liver (spleen / liver) is 32.1, 43.1, 57.6 and 98.5 respectively. The mean fluorescence intensity in different organs represents the delivery efficiency of the corresponding delivery system in different organs, and the lipid nanoparticles of the present application can successfully deliver nucleic acid molecules to the spleen and express them, and the delivery efficiency for the spleen is significantly higher than the delivery efficiency for the liver and other tissues / organs.

[0202] Table 5. Expression intensity of Luc-mRNA delivered by lipid nanoparticles prepared from representative lipid compounds

[0203] The above detailed description of the present application is intended to enable persons familiar with the technology in this field to understand the mechanism and content of the present application and implement it. It does not limit the scope of protection of the present application. Any equivalent changes or modifications made according to the spirit of the present application should be included in the scope of protection of the present application. Industrial Applicability

[0204] The lipid compounds and their derivatives provided in this application can selectively deliver therapeutic agents / preventive agents to target organs, and lipid nanoparticles containing them can deliver nucleic acid components to specific organs, especially preferentially to organs other than the liver, providing more options for the delivery of nucleic acid drugs, gene vaccines, etc., and are of great significance to the development and application of nucleic acid preventive and therapeutic agents.

Claims

1. A lipid compound of formula I or a pharmaceutically acceptable salt, prodrug, stereoisomer or deuterated derivative thereof, wherein: Among them, L 1 is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-、-NR a (CH2) x -、-(CH2) x NR a -;;Q 1 is absent or is a C1-C8 straight or branched hydrocarbon group; L 2 is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-;Q 2 is absent or is a C1-C8 straight or branched hydrocarbon group; L 3 is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-;Q 3 is absent or is a C1-C8 straight or branched hydrocarbon group; R a is H or deuterium or a C1-C8 straight or branched hydrocarbon group or a C1-C8 straight or branched hydrocarbon group substituted with a carboxyl group; X is C or N; R is Z is C, O, or NR b or S; R b is H or deuterium or a C1-C8 straight or branched hydrocarbon group; Y 1 or Y 2 One of the is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-, and Y 1 or Y 2 The other is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-; G 1 and G 2 Each is independently absent or substituted C1-C12 straight or branched hydrocarbon group; Y 3 or Y 4 One of the is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-, and Y 3 or Y 4 The other is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-; G 3 and G 4 Each is independently absent or substituted C1-C12 straight or branched hydrocarbon group; Y 5 or Y 6 One of the is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-, and Y 5 or Y 6 The other is absent, a carbon-carbon single bond, a carbon-carbon double bond, a carbon-carbon triple bond, or -O(C=O)-, -C(OH)-, -(C=O)O-, -C(=O)-, -O(C=O)O-, -O-, -S(O) x -, -SS-, -C(=O)S-, -SC(=O)-, -NR a C(=O)-, -C(=O)NR a -、-NR a C(=O)NR a -、-OC(=O)NR a -or-NR a C(=O)O-; R a is H or deuterium or a C1-C8 straight or branched hydrocarbon group or a C1-C8 straight or branched hydrocarbon group substituted with a carboxyl group; G 5 and G 6 Each is independently absent or substituted C1-C12 straight or branched hydrocarbon group; R 1 and R 2 Each is independently a substituted C1-C24 straight or branched hydrocarbon group; x is 0, 1, or 2.

2. A lipid compound of Table 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer or deuterated form thereof.

3. A lipid nanoparticle comprising the compound according to any one of claims 1 or 2 and one or more cationic lipids.

4. The lipid nanoparticle of claim 3, further comprising one or more auxiliary lipids.

5. The lipid nanoparticle according to claim 3, characterized in that The cationic lipid is selected from one or more combinations of permanent cationic lipids and / or ionizable cationic lipids.

6. The lipid nanoparticle according to claim 5, characterized in that The permanent cationic lipid is selected from one or a combination of more than one of DOTAP, DODMA, DSTAP, DMTAP, DDA, and DOBAQ.

7. The lipid nanoparticle according to claim 5, characterized in that The ionizable cationic lipid is selected from one or more of SM-102, Lipid 5, A6, DC-chol, C12-200, CKK-E12, 5A2-SC8, G0-C14, OF-2, 306Oi10, OF-Deg-Lin, 92-O17S, OF-C4-Deg-Lin, A18-iso5-2DC18, TT3, FTT5, BAMEA-O16B, Vc-Lipid, C14-4, Lipid 14, 4A3-Cit, and ssPalmO-Phe.

8. The lipid nanoparticle according to claim 4, wherein the auxiliary lipid is selected from one or more combinations of phospholipids and / or steroids and / or polymer-conjugated lipids and / or modified lipids.

9. The lipid nanoparticle according to claim 8, characterized in that The phospholipid is selected from one or a combination of more than one of DOPE, DSPC, DPPC, DMPC, DOPC, POPC, and SM.

10. The lipid nanoparticle according to claim 8, characterized in that The steroid is selected from any one or a combination of more than one of cholesterol, sitosterol, stigmasterol and ergosterol.

11. The lipid nanoparticle according to claim 8, characterized in that The polymer-conjugated lipid is selected from one or more of polyethylene glycol-conjugated lipids, polylactic acid-conjugated lipids, polyamide-conjugated lipids, cationic polymer-conjugated lipids, polysarcosine pSar-conjugated lipids, polylactic acid-glycolic acid copolymer PLGA-conjugated lipids, polyamino acid-conjugated lipids, polypeptide-conjugated lipids, and poly-peptide-conjugated lipids.

12. The lipid nanoparticle according to claim 8, characterized in that The polyethylene glycol-conjugated lipid is selected from any one or a combination of more than one of PEG1000-DMG, PEG5000-DMG, PEG2000-DMG and PEG2000-DSPE.

13. The lipid nanoparticle according to claim 8, characterized in that The modified lipid is selected from lipids modified by any one or a combination of small molecule compounds, vitamins, carbohydrates, peptides, proteins, nucleic acid lipopolysaccharides, inorganic molecules or particles, metal ions or particles.

14. The lipid nanoparticle according to claim 4, characterized in that The lipid compound or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, the auxiliary lipid and the cationic lipid have a molar ratio of (0.1-1): (0.5-2):

1.

15. A composition comprising the lipid nanoparticle of any one of claims 3 to 14 and a therapeutic or preventive agent.

16. The composition according to claim 15, characterized in that The composition is targeted to the following organs: lung, heart, brain, spleen, lymph node, bone, skeletal muscle, stomach, small intestine, large intestine / colorectum, kidney, bladder, breast, testicle, ovary, uterus, thymus, brainstem, cerebellum, cerebrum, spinal cord, eye, ear, tongue or skin, preferably to the spleen.

17. The composition according to claim 15, characterized in that The preventive or therapeutic agent is selected from any one of nucleic acids, proteins, polypeptides, small molecule compounds, and cells, or a combination of more than one of them.

18. The composition according to claim 15, characterized in that The mass ratio of lipid nanoparticles to the preventive or therapeutic agent is 10:1 to 100:

1.

19. The composition according to claim 15, characterized in that The average particle size of the composition is 20 nm to 600 nm.

20. The composition according to claim 15, characterized in that The polydispersity index PDI of the composition is from 0.001 to 0.

5.

21. The composition according to claim 17, characterized in that The nucleic acid is selected from single-stranded DNA, double-stranded DNA, single-stranded RNA, double-stranded RNA, short isomers, plasmid DNA, complementary DNA / cDNA, antisense nucleic acid molecules / ASO, small interfering nucleic acid / siRNA, small activating nucleic acid / saRNA, asymmetric interfering nucleic acid / aiRNA, micronucleic acid / miRNA, micronucleic acid agonist / miRNA agomir, micronucleic acid inhibitor / miRNA antagomir, Dicer enzyme substrate nucleic acid / dsRNA, small hairpin nucleic acid / shRNA, transfer RNA / tRNA, messenger RNA / mRNA, circular RNA / circRNA, self-replicating mRNA / samRNA, and aptamer / aptamer.

22. The composition of claim 15, wherein the therapeutic or prophylactic agent comprises at least one mRNA encoding an antigen or a fragment thereof or an epitope thereof, or an mRNA encoding a therapeutic protein.

23. The composition of claim 22, wherein the mRNA is selected from a monocistronic mRNA or a polycistronic mRNA.

24. The composition of claim 22, wherein the mRNA comprises one or more functional nucleotide analogs or nucleotide chemical modifications.

25. The composition according to claim 24, wherein the functional nucleotide analogue is selected from one or more combinations of locked nucleic acid (LNA), peptide nucleic acid (PNA), or morpholino oligonucleotide nucleic acid mimetics or functional analogues.

26. The composition of claim 24, wherein the nucleotide chemical modifications are selected from one or more of the following modifications: Modification of the backbone connecting nucleotides in the nucleotide sequence of the nucleic acid molecule; modification of the ribose sugar in the nucleotide sequence of the nucleic acid molecule; Modification of the bases in the nucleotide sequence of the nucleic acid molecule.

27. The composition of claim 26, wherein the backbone modification is a phosphorothioate bond.

28. The composition according to claim 26, wherein the modification of the ribose is selected from one or more of 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose.

29. The composition of claim 26, wherein the nucleotide chemical modification is selected from the group consisting of 5-methylcytosine, pseudouridine, 1-methylpseudouridine, pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1- Methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, 5-azacytidine, pseudoisocytidine , 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebulin (zebulin) arine), 5-aza-zabularine, 5-methyl-zabularine, 5-aza-2-thio-zabularine, 2-thio-zabularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, 2-aminopurine, 2,6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza- 8-Aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine, N6-glycylaminoformyladenosine, N6-threonylaminoformyladenosine, 2-methylthio-N6-threonylaminoformyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wyosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio-guanosine, or a combination of more than one thereof.

30. The composition of claim 22, wherein the antigen is a pathogenic antigen.

31. The composition according to claim 30, wherein the pathogenic antigen is selected from any one or a combination of more than one of tumor-associated antigens or pathogenic microorganism antigens.

32. Use of the composition according to any one of claims 15 to 31 in the preparation of a medicament.

33. A drug, characterized in that Comprising the composition according to any one of claims 15 to 31 and pharmaceutically acceptable excipients.

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