Amino lipid compound, method for preparing the same, composition thereof, and use thereof

Abstract

Amino lipid compounds, methods for preparing the same, compositions thereof, and uses thereof. Specifically, amino lipid compounds represented by formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, and their use in preparing lipid nanoparticles for delivering active ingredients, as well as compositions containing amino lipid compounds, particularly lipid nanoparticles, and their use are disclosed. JPEG2025523019000124.jpg24149

Description

Detailed Description of the Invention

[0001] [Technical Field] The present disclosure relates to an amino lipid compound that can be used to prepare lipid nanoparticles for delivering an active ingredient and a method for preparing the same. The present disclosure also relates to a composition containing the amino lipid compound, particularly lipid nanoparticles, and their use.

[0002] [Background Art] Gene therapy agents deliver genes with specific genetic information to target cells by artificial means, and the expressed target proteins interfere with or regulate the expression of related genes to achieve a clinical therapeutic effect. However, it is difficult to directly introduce naked nucleic acids into cells. To achieve gene delivery, an external force or a vector is required. However, the differences in genetic and cell structures require the matching of lipid particles with different properties. Therefore, in order to meet the requirements for delivering gene therapy agents, it is necessary to develop different vectors or adjuvants, particularly amino lipid compounds that can be used to deliver nucleic acid active ingredients, as well as related preparation methods and uses.

[0003] [Summary of the Invention] One aspect of the present disclosure provides an amino lipid compound represented by formula (I): [Chemical Formula] (wherein R1, R2, R3, R4, R5, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, A1, A2, A3, A4, A5, A6 and A7 are each defined as follows).

[0004] Another aspect of the present disclosure provides a method for preparing an amino lipid compound.

[0005] Another aspect of the present disclosure provides the use of an amino lipid compound in the manufacture of a vehicle for an active ingredient.

[0006] Another aspect of the present disclosure provides lipid nanoparticles comprising an amino lipid compound.

[0007] Another aspect of the present disclosure provides a composition comprising an amino lipid compound.

[0008] Another aspect of the present disclosure provides the use of an amino lipid compound, lipid nanoparticles or a composition in the manufacture of a medicament.

[0009] Another aspect of the present disclosure provides the use of an amino lipid compound, lipid nanoparticles or a composition in the manufacture of a medicament for nucleic acid transfection.

[0010] [Mode for Carrying Out the Invention] Definitions Unless otherwise defined herein, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques herein are intended to mean techniques commonly understood in the art including variations or substitutions of equivalent techniques that would be apparent to one of ordinary skill in the art. The following terms are considered to be well understood by one of ordinary skill in the art, but the following definitions are provided to better explain the present disclosure.

[0011] As used herein, the terms "comprising", "including", "having", "containing", or "accompanied by", and other variations thereof, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0012] As used herein, the term "hydrocarbyl" refers to a group remaining after one hydrogen atom has been lost from an aliphatic hydrocarbon, including linear or branched saturated or unsaturated hydrocarbyl groups. Hydrocarbyl groups include alkyl, alkenyl and alkynyl groups. Preferably, the hydrocarbyl group has 1 to 24 carbon atoms (C1-C 24(hydrocarbyl), for example, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (C1, C2, C3, ... C 17 、C 18 、C 19 or C 20 hydrocarbyl). Examples of hydrocarbyl groups include C1-C 20 hydrocarbyl, C1-C 18 hydrocarbyl, C1-C 16 hydrocarbyl, C1-C 12 hydrocarbyl, C1-C 10 hydrocarbyl, C1-C8 hydrocarbyl, C1-C7 hydrocarbyl, C1-C6 hydrocarbyl, C1-C4 hydrocarbyl, C1-C3 hydrocarbyl, C1-C2 hydrocarbyl, C2-C8 hydrocarbyl, C2-C4 hydrocarbyl, C4-C8 hydrocarbyl, C4-C9 hydrocarbyl, C5-C8 hydrocarbyl, C1-C4 hydrocarbyl, C2-C8 hydrocarbyl, C3 hydrocarbyl, C4 hydrocarbyl, C5 hydrocarbyl, C6 hydrocarbyl, C7 hydrocarbyl and C8 hydrocarbyl, but are not limited thereto.

[0013] As used herein, the term "hydrocarbylene" refers to a divalent group remaining after one hydrogen atom is further lost from the hydrocarbyl defined above.

[0014] As used herein, the term "alkyl" is a straight-chain or branched saturated monovalent hydrocarbyl. Preferably, the alkyl group has 1 to 24 carbon atoms (C1-C 24 alkyl), for example, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (C1, C2, C3, ... C 17 、C 18 、C 19 or C 20 alkyl). Examples of alkyl groups include C1-C 20 alkyl, C1-C 18Alkyl, C1-C 16 Alkyl, C1-C 12 Alkyl, C1-C 10 Alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C8 alkyl, C2-C4 alkyl, C4-C8 alkyl, C4-C9 alkyl, C5-C8 alkyl, C1-C4 alkyl, C2-C8 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl and tridecan-7-yl are included, but not limited thereto.

[0015] As used herein, the term "alkylene" refers to a divalent group remaining after one hydrogen atom is further lost from the alkyl defined above.

[0016] As used herein, the term "alkenyl" is a straight-chain or branched monovalent hydrocarbyl containing one or more double bonds (C=C). Preferably, the alkenyl group has 2 to 24 carbon atoms (C2-C 24 alkenyl), for example, having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (C2, C3,...C 17 , C 18 , C 19 or C 20 alkenyl), and has 1, 2, 3, 4 or more double bonds. Examples of alkenyl groups include C2-C 20 alkenyl, C2-C 18 alkenyl, C2-C 16 alkenyl, C2-C 12 alkenyl, C2-C 10Alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, C4-C8 alkenyl, C4-C9 alkenyl, C5-C8 alkenyl are exemplified, but not limited thereto. As some more specific examples, vinyl, propenyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hept-1-enyl, hept-2-enyl, hept-3-enyl, oct-1-enyl, oct-2-enyl, oct-3-enyl, non-1-enyl, non-2-enyl and non-3-enyl are exemplified, but not limited thereto. In some preferred embodiments, the alkenyl group has one double bond.

[0017] As used herein, the term "alkenylene" refers to a divalent group remaining after one hydrogen atom is further lost from the alkenyl defined above.

[0018] As used herein, the term "alkynyl" is a straight-chain or branched monovalent hydrocarbyl group containing one or more triple bonds (C≡C). Preferably, the alkynyl group has 2 to 24 carbon atoms (C2-C 24 alkynyl), for example, having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms (C2, C3,...C 17 , C 18 , C 19 or C 20 alkynyl), and has 1, 2, 3, 4 or more triple bonds. Examples of the alkynyl group include C2-C 20 alkynyl, C2-C 18 alkynyl, C2-C 16 alkynyl, C2-C 12 alkynyl, C2-C 10Examples include, but are not limited to, alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, C4-C8 alkynyl, C4-C9 alkynyl, C5-C8 alkynyl. Some more specific examples include, but are not limited to, ethynyl, propynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hept-1-ynyl, hept-2-ynyl, hept-3-ynyl, oct-1-ynyl, oct-2-ynyl, oct-3-ynyl, non-1-ynyl, non-2-ynyl, and non-3-ynyl. In some preferred embodiments, the alkynyl group has one triple bond.

[0019] As used herein, the term "alkynylene" refers to a divalent group remaining after one hydrogen atom is further lost from the alkynyl defined above.

[0020] As used herein, the terms "cyclohydrocarbyl", "cyclohydrocarbylene", and "hydrocarbon ring" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or unsaturated (i.e., having one or more double bonds (cycloalkenyl) and / or triple bonds (cycloalkynyl) within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3 to 10 (preferably 3 to 8, more preferably 3 to 6, such as 5 to 6 or 5 to 7) ring carbon atoms, including but not limited to cyclopropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclohexenyl(ene)(ring), and the like.

[0021] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (for example, monocyclic ones such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic ones including spirocyclic, fused-ring or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalin). Cycloalkyl has, for example, 3 to 10 carbon atoms such as 3 to 7, 5 to 6 or 5 to 7 carbon atoms.

[0022] As used herein, the terms "heterocycle", "heterocyclyl" or "heterocyclylene" mean a saturated or unsaturated cyclic group having ring heteroatoms selected from N, O and S. Preferably, the heterocycle is an optionally substituted 4- to 10-membered heterocycle having 1, 2, 3, 4, 5 or 6 ring heteroatoms selected from N, O and S. More preferably, the heterocycle is an optionally substituted 4- to 7-membered saturated heterocycle having 1, 2, 3 or 4 ring heteroatoms selected from N, O and S, and still more preferably, an optionally substituted 5- to 7-membered (such as 5- to 6-membered) saturated heterocycle having 1, 2 or 3 ring heteroatoms selected from N, O and S. Examples of heterocycles include, but are not limited to, azetidine, oxetanyl, tetrahydrofuran, pyrrolidine, imidazolidine, pyrazolidine, tetrahydropyran, piperidine, morpholine, thiomorpholine, piperazine, preferably pyrrolidine, piperidine, piperazine and morpholine. The heterocycle may be optionally substituted with one or more substituents, and for the substituents, the definition of "optionally substituted" below is referred to.

[0023] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, "C" 6-14The term "aryl" means an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents.

[0024] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic group having a conjugated π - electron system, the ring atoms of which consist of carbon atoms and at least one heteroatom, and which contains, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and 1, 2, 3, 4 or 5 identical or different heteroatoms independently selected from N, O, S and S(O)2, and having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms. One or more of the ring carbon atoms in the heteroaryl group may be substituted with C(O). The heteroaryl group may be benzo - fused. The heteroaryl group may be optionally substituted with one or more suitable substituents.

[0025] As used herein, the term "optionally substituted" means that one or more hydrogen atoms attached to an atom or group are independently unsubstituted or substituted with one or more (e.g., 1, 2, 3, or 4) substituents. The substituents are independently deuterium (D), halogen, -OH, mercapto, cyano, -CD3, C1-C6 alkyl (preferably C1-C3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl (preferably C3-C8 cycloalkyl), aryl, heterocyclyl (preferably 3- to 8-membered heterocyclyl), heteroaryl, arylC1-C6 alkyl-, heteroarylC1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, OC1-C6 alkylphenyl, C1-C6 alkyl-OH (preferably C1-C4 alkyl-OH), C1-C6 alkyl-SH, C1-C6 alkyl-O-C1-C6 alkyl, OC1-C6 haloalkyl, -NH2, C1-C6 alkyl-NH2 (preferably C1-C3 alkyl-NH2), -N(C1-C6 alkyl)2 (preferably -N(C1-C3 alkyl)2), -NH(C1-C6 alkyl) (preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl (preferably -C(O)OC1-C3 alkyl), -CONRiRii (wherein Ri and Rii are H, D and C1-C6 alkyl, preferably C1-C3 alkyl), -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, -C(O)heteroaryl (preferably -C(O)-5- to 7-membered heteroaryl), -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl (preferably -OC(O)C1-C3 alkyl), -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2,-S(O)2NH(C1-C6 alkyl), -S(O)2NH(phenyl), -NHS(O)2(C1-C6 alkyl), -NHS(O)2(phenyl) and -NHS(O)2(C1-C6 haloalkyl), and each of alkyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl is optionally further substituted with one or more substituents selected from halogen, -OH, -NH2, cycloalkyl, 3- to 8-membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl). When an atom or group is substituted with a plurality of substituents, the plurality of substituents may be the same or different.,

[0026] In certain embodiments, the substituents are halogen (such as chlorine, bromine, fluorine or iodine), deuterium (D), tritium (T), carboxylic acid (such as -C(=O)-OH), oxygen (=O), sulfur (=S), hydroxyl (-OH), ester group (-C(=O)ORiii or -OC(=O)Riii), aldehyde group (-C(=O)H), carbonyl (-C(=O)Riii, etc., or represented by C=O), haloacyl (e.g., -C(=O)X, where X is selected from bromine, fluorine, chlorine or iodine), carbonate ester group (-OC(=O)ORiii), alkoxy (-ORiii), acetal (e.g., -C(ORiii)2Riii, where each ORiii is the same or different and is an alkoxy group), phosphate (P(=O)43- such as thiols (-SH, etc.), sulfoxides (-S(=O)Riii, etc.), sulfinic acids (-S(=O)OH, etc.), sulfonic acids (-S(=O)2OH, etc.), thioaldehydes (-C(=S)H, etc.), sulfates (S(=O)4 2-such as sulfonyl (-S(=O)2Riii etc.), sulfinyl (-S(=O)Riii etc.), amide (-C(=O)N(Riii)2 or -N(Riii)C(=O)Riii etc.), azide (-N3 etc.), nitro (-NO2 etc.), cyano (-CN etc.), isocyano (-NC etc.), acyloxy (-OC(=O)Riii etc.), amino (-N(Riii)2, -N(Riii)H or -NH2 etc.), carbamoyl (-OC(=O)N(Riii)2, -OC(=O)N(Riii)H or -OC(=O)NH2 etc.), sulfonamide (-S(=O)2N(Riii)2, -S(=O)2N(Riii)H, -S(=O)2NH2, -N(Riii)S(=O)2Riii, -N(H)S(=O)2Riii, -N(Riii)S(=O)2H or -N(H)S(=O)2H etc.), alkyl, alkenyl, alkynyl, cyclo hydrocarbyl (such as cycloalkyl, cycloalkenyl or cycloalkynyl etc.), heterocyclo hydrocarbyl (heterocycloalkyl containing one or more heteroatoms selected from S, N and O, or heterocycloalkenyl containing one or more heteroatoms selected from S, N and O etc.), aryl (such as phenyl or fused ring group etc.), heteroaryl (8- to 10-membered bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur etc.), -C(=O)SRiii, -C(=N-CN)N(Riii)2, -C(=N-O-CH3)N(Riii)2, -C(=N-SO2-NH2)N(Riii)2, -C(=CH-NO2)N(Riii)2, -OC(=O)N(Riii)2, -CHN(Riii)N(Riii)2, -C(=O)N(Riii)ORiii, -N(Riii)2C(=O)ORiii, -OP(=O)(ORiii)2, -P(=O)(ORiii)2, -N(ORiii)C(=O)Riii, -N(ORiii)S(=O)2Riii, -N(ORiii)C(=O)ORiii, -N(ORiii)C(=O)N(Riii)2, -N(ORiii)C(=S)N(Riii)2, -N(ORiii)C(NRiii)N(Riii)2, -N(ORiii)C(CHRiii)N(Riii)2, which may be independently selected but are not limited thereto.In each of the above, Riii is hydrogen, or alkyl, or alkenyl, or alkynyl, or heteroalkyl, or heteroalkenyl, or heteroalkynyl as defined herein. In some embodiments, Riii is hydrogen, or C1-C as defined herein. 12 alkyl, or C1-C 12 alkenyl, or C1-C 12 alkynyl, or C1-C 12 heteroalkyl, or C1-C 12 heteroalkenyl, or C1-C 12 heteroalkynyl.

[0027] In certain embodiments, the substituent itself may be further substituted with, for example, one or more substituents as defined herein. For example, a C1-C6 alkyl as a substituent may be further substituted with one or more substituents as defined herein.

[0028] In certain embodiments, the hydrocarbyl, hydrocarbylene, alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cyclo hydrocarbyl, cyclo hydrocarbylene, hydrocarbon ring, cycloalkyl, heterocycle, heterocyclyl, heterocyclylene, aryl and heteroaryl groups described herein may be optionally substituted with one or more substituents.

[0029] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

[0030] As used herein, the groups "C(=O)" and "(C=O)" can be used interchangeably.

Chemical formula

Chemical formula

[0031] As used herein, the term "compound" includes all compounds that are isotopically labeled by substituting one or more atoms with atoms having different atomic weights or mass numbers. "Isotope" refers to atoms having the same atomic number but different mass numbers due to different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0032] The numerical ranges described herein should be understood to include any and all sub-ranges subsumed therein. For example, the range "1 to 10" includes not only the explicitly recited values of 1 and 10, but also any individual values within the range of 1 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, and 9) as well as sub-ranges (e.g., 1 to 2, 1.5 to 2.5, 1 to 3, 1.5 to 3.5, 2.5 to 4, 3 to 4.5, etc.). This principle also applies to ranges that use only one value as the minimum or maximum value.

[0033] As used herein, "pharmaceutically acceptable salts" refers to acid addition salts or base addition salts of the compounds of the present disclosure that retain the biological effectiveness and properties of the compounds of the present disclosure and are typically not undesirable biologically or otherwise. In many cases, the compounds of the present invention can form acid and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0034] Pharmaceutically acceptable acid addition salts can be formed from the compounds of the present disclosure and inorganic acids and / or organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphanic acid, camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0035] Pharmaceutically acceptable base addition salts can be formed from the compounds of the present disclosure and inorganic and / or organic bases. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include salts of primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins, but are not limited thereto. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0036] The compounds of the present disclosure or pharmaceutically acceptable salts thereof may contain one or more chiral centers and, accordingly, may give rise to enantiomers, diastereomers, and other stereoisomeric forms, such as amino acids, which may be defined as (R)- or (S)-, or (D)- or (L)-, based on absolute stereochemistry. The present invention is intended to include all such possible isomers, as well as racemates and optically pure forms thereof. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using a chiral synthon or chiral reagent or by resolution by conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating a single enantiomer include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compounds include E- and Z-geometric isomers. Similarly, all tautomeric forms are also intended to be encompassed.

[0037] As used herein, the term "stereoisomer" refers to a compound consisting of the same atoms that are bonded through the same bonds but have different three-dimensional structures that are not interchangeable. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of any ratio of a pair of enantiomers may be referred to as a "racemic" mixture. "Diastereomers" are stereoisomers that have at least two chiral atoms and are not mirror images of each other.

[0038] "Stereoisomers" may also include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds described herein are isolated as the E or Z isomer. In other embodiments, the compounds described herein are a mixture of the E and Z isomers.

[0039] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of the isomeric form depends on the environment in which the compound is found and can vary, for example, depending on whether the compound is in the solid state or in an organic or aqueous solution.

[0040] Amino lipid compound In one aspect, the present disclosure provides an amino lipid compound represented by the following formula (I):

Chemical formula

[0041] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A1 and A2 are each independently a C1-C8 hydrocarbylene or a bond, such as a C1-C6 hydrocarbylene or bond, or a C1-C4 hydrocarbylene or bond. In some embodiments, A1 and A2 are each independently a C1-C8 alkylene, a C2-C8 alkenylene or a C2-C8 alkynylene. In some embodiments, A1 and A2 are each independently a C1-C8 alkylene, such as a C1-C6 alkylene, a C1-C4 alkylene, a C2-C4 alkylene or a C1-C3 alkylene. In some embodiments, both A1 and A2 are bonds.

[0042] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A3 is a C1-C 12 hydrocarbylene or a bond. In some embodiments, A3 is a straight-chain C1-C 12 hydrocarbylene. In some embodiments, A3 is a straight-chain C1-C 12 alkylene, a C2-C 12 alkenylene or a C2-C 12 alkynylene. In some embodiments, A3 is a straight-chain C1-C5 alkylene, such as straight-chain C1, C2, C3, C4 or C5 alkylene. In some embodiments, A3 is CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0043] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A4 is a C1-C 12 hydrocarbylene or a bond. In some embodiments, A4 is a straight-chain C1-C 12 hydrocarbylene. In some embodiments, A4 is a straight-chain C1-C 12 alkylene, a C2-C 12An alkenylene or C2-C 12 is an alkynylene. In some embodiments, A4 is a linear C1-C7 alkylene, such as a linear C1, C2, C3, C4, C5, C6, or C7 alkylene. In some embodiments, A4 is a linear C1-C3 alkylene, such as a linear C1, C2, or C3 alkylene. In some embodiments, A4 is -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0044] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A5 is a C1-C8 hydrocarbylene or a bond, such as a C1-C6 hydrocarbylene or a bond, a C1-C4 hydrocarbylene or a bond, or a C1-C3 hydrocarbylene or a bond. In some embodiments, A5 is a C1-C8 alkylene, a C2-C8 alkenylene, or a C2-C8 alkynylene. In some embodiments, A5 is a C1-C8 alkylene, such as a C1-C6 alkylene, a C1-C4 alkylene, a C2-C4 alkylene, or a C1-C3 alkylene. In some embodiments, A5 is a bond.

[0045] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A6 and A7 are each independently a C1-C 12 hydrocarbylene. In some embodiments, A6 and A7 are each independently a linear C1-C 12 hydrocarbylene. In some embodiments, A6 and A7 are each independently a linear C1-C 12 alkylene, a C2-C 12 alkenylene, or a C2-C 12 alkynylene. In some embodiments, A6 and A7 are each independently a linear C1-C 12 alkylene, such as a linear C2-C 12 alkylene, a C4-C 10 alkylene, a C6-C8 alkylene, a C6-C10 It is alkylene or C4-C8 alkylene. In some embodiments, A6 and A7 are each independently a straight-chain C6-C 10 alkylene, for example, straight-chain C6, C7, C8, C9 or C 10 alkylene. In some embodiments, A6 and A7 are each independently -(CH2)6-, -(CH2)7-, -(CH2)8- or -(CH2)9-.

[0046] In some embodiments, R1 and R2 are each independently H, C1-C 18 hydrocarbyl, for example C1-C 16 hydrocarbyl, C1-C 12 hydrocarbyl, C1-C 10 hydrocarbyl, C1-C8 hydrocarbyl, C1-C6 hydrocarbyl or C1-C4 hydrocarbyl, C3-C7 cyclo-hydrocarbyl, for example C3-C6 cyclo-hydrocarbyl or C5-C6 cyclo-hydrocarbyl, phenyl, or a 3- to 7-membered heterocyclic ring, for example a 4- to 6-membered heterocyclic ring, or R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring, for example a 5- to 6-membered heterocyclic ring. The present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0047] In some embodiments, R1 and R2 are each independently H, C1-C 18 alkylene, C2-C 18 alkenylene or C2-C 18 alkynylene. In some embodiments, R1 and R2 are each independently C1-C 18 alkyl, for example C1-C4 alkyl, C3-C6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic ring. In some embodiments, R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring such as pyrrolidine, piperidine, piperazine or morpholine.

[0048] In some embodiments, each of R1 and R2 is independently C1-C4 alkyl, such as C1, C2, C3, or C4 alkyl. In some embodiments, each of R1 and R2 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, each of R1 and R2 is independently C1-C3 alkyl, such as C1, C2, or C3 alkyl. In some embodiments, each of R1 and R2 is independently methyl, ethyl, or n-propyl.

[0049] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is H, C1-C 18 hydrocarbyl, such as C1-C 16 hydrocarbyl, C2-C 12 hydrocarbyl, C4-C 10 hydrocarbyl or C4-C8 hydrocarbyl, C3-C7 cyclo hydrocarbyl, such as C3-C6 cyclo hydrocarbyl or C5-C6 cyclo hydrocarbyl, phenyl, or a 3- to 7-membered heterocyclic ring, such as a 4- to 6-membered heterocyclic ring. In some embodiments, R3 is C1-C 18 alkyl, C2-C 18 alkenyl or C2-C 18 alkynyl. In some embodiments, R3 is C1-C 18 alkyl, such as C2-C 10 alkyl, C4-C8 alkyl, C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic ring. In some embodiments, R3 is straight-chain C4-C8 alkyl, such as straight-chain C4, C5, C6, C7, or C8 alkyl. In some embodiments, R3 is n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl.

[0050] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z1, Z2, Z5, and Z6 are each independently C(=O)-, -O(C=O)-, -O-, or a bond. In some embodiments, Z1, Z2, Z5, and Z6 are each independently a bond.

[0051] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z3 is -C(=O)-.

[0052] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z7 and Z8 are each independently -(C=O)O-, -O(C=O)-, or a bond.

[0053] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one of Z7 or Z8 is -(C=O)O-, -O(C=O)-, or a bond.

[0054] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of Z7 and Z8 is -(C=O)O-. In some embodiments, (C=O) in Z7 is bonded to A6, and (C=O) in Z8 is bonded to A7.

[0055] In some embodiments, the present disclosure provides the amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of Z7 and Z8 is -O(C=O)-. In some embodiments, (C=O) in Z7 is bonded to R4, and (C=O) in Z8 is bonded to R5.

[0056] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one of Z7 or Z8 is a bond. In some embodiments, Z7 is a bond and Z8 is -(C=O)O-. In some embodiments, (C=O) in Z8 is bonded to A7. In some embodiments, Z7 is a bond and Z8 is -O(C=O)-. In some embodiments, (C=O) in Z8 is bonded to R5. In some embodiments, Z8 is a bond and Z7 is -(C=O)O-. In some embodiments, (C=O) in Z7 is bonded to A6. In some embodiments, Z8 is a bond and Z7 is -O(C=O)-. In some embodiments, (C=O) in Z7 is bonded to R4.

[0057] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of Z7 and Z8 is a bond.

[0058] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 and R5 are each independently C1-C 20 hydrocarbyl, C3-C7 cycloalkyl, such as C3-C6 cycloalkyl or C5-C6 cycloalkyl, phenyl, or a 3- to 7-membered heterocyclic ring, such as a 4- to 6-membered heterocyclic ring. In some embodiments, R4 and R5 are each independently C1-C 20 hydrocarbyl, C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic ring.

[0059] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 and R5 are each independently C1-C 20Provided is an amino lipid compound of formula (I) that is a hydrocarbyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0060] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) wherein R4 and R5 are each independently a C1-C 20 alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0061] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) wherein R4 and R5 are each independently a branched C3-C 20 alkyl, such as a branched C5-C 20 alkyl, a branched C7-C 19 alkyl, a branched C9-C 18 alkyl, a branched C 10 -C 18 alkyl, a branched C3-C 10 alkyl, a branched C 11 -C 17 alkyl, or a branched C 18 -C 20 alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, R4 and R5 are each independently a branched C 11 -C 17 alkyl, such as a branched C 11 , C 12 , C 13 , C 14 , C 15 , C 16 or C 17 alkyl. In some embodiments, R4 and R5 are each independently a branched C 11 -C 13 alkyl, such as a branched C 11 , C 12 or C 13 alkyl. In some embodiments, R4 is a branched alkyl group where the branch occurs at the α, β, or γ position relative to Z7, such as

Chemical formula

Chemical formula

[0062] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 and R5 are each independently one of the following structures.

Chemical formula

[0063] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 and R5 are each independently one of the following structures.

Chemical formula

[0064] In some embodiments, the present disclosure is such that R4 and R5 are each independently

Chemical formula

Chemical formula

[0065] In some embodiments, the present disclosure Z3 is -C(=O)-, A4 is C1-C 12 Provided is an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A4 is an alkylene. In some embodiments, A4 is a straight-chain C1-C 12 alkylene, such as a straight-chain C1-C 10 alkylene, C1-C8 alkylene, C1-C6 alkylene, C1-C4 alkylene or C1-C3 alkylene. In some embodiments, A4 is a straight-chain C1-C4 alkylene, such as straight-chain C1, C2, C3 or C4 alkylene. In some embodiments, A4 is -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0066] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z4 is -O-.

[0067] In some embodiments, the present disclosure provides an amino lipid compound of formula (I) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z4 is -CH(OH)-.

[0068] In another aspect, the present disclosure provides an amino lipid compound represented by the following formulas (II) and (III):

Chemical formula

[0069] In some embodiments, the present disclosure provides an amino lipid compound of the above formulas (II) and (III), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Z7 and Z8 are each independently -(C=O)O-, -O(C=O)- or a bond. In some embodiments, each of Z7 and Z8 is -(C=O)O-. In some embodiments, (C=O) in Z7 is bonded to A6 and (C=O) in Z8 is bonded to A7. In some embodiments, each of Z7 and Z8 is -O(C=O)-. In some embodiments, (C=O) in Z7 is bonded to R4 and (C=O) in Z8 is bonded to R5.

[0070] In some embodiments, the present disclosure provides an amino lipid compound of the above formulas (II) and (III), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A3, A4, A6 and A7 are each independently C1-C 12 alkylene. In some embodiments, A3, A4, A6 and A7 are each independently C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 or C 12 alkylene.

[0071] In some embodiments, A3 is a straight-chain C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 and C 11 or C 12 is an alkylene. In some embodiments, A3 is a linear C1, C2, C3, C4 or C5 alkylene. In some embodiments, A3 is a linear C2, C3 or C4 alkylene, such as -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0072] In some embodiments, A4 is a linear C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 and C 11 or C 12 is an alkylene. In some embodiments, A4 is a linear C1, C2, C3 or C4 alkylene, such as -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0073] In some embodiments, A6 and A7 are each independently a linear C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 and C 11 or C 12 is an alkylene. In some embodiments, A6 and A7 are each independently a linear C6, C7, C8, C9 or C 10 alkylene, such as -(CH2)6-, -(CH2)7-, -(CH2)8- or -(CH2)9-.

[0074] In some embodiments, the present disclosure provides that R1 and R2 are each independently a C1-C 18Provided is an amino lipid compound of the above formulas (II) and (III) which is alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, R1 and R2 are each independently C1-C6 alkyl. In some embodiments, R1 and R2 are each independently methyl, ethyl, n-propyl or isopropyl. In some embodiments, R1 and R2 are each independently C1-C4 alkyl, such as C1, C2, C3 or C4 alkyl. In some embodiments, R1 and R2 are each independently methyl.

[0075] In some embodiments, the present disclosure provides an amino lipid compound of the above formulas (II) and (III), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring. In some embodiments, R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring.

[0076] In some embodiments, the present disclosure is such that R3 is C1-C 18 Provided is an amino lipid compound of the above formulas (II) and (III) which is alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, R3 is C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 or C 12 alkyl. In some embodiments, R3 is linear C2, C3, C4, C5, C6, C7, C8, C9 or C 10 alkyl. In some embodiments, R3 is linear C4, C5, C6, C7 or C8 alkyl, such as n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl.

[0077] In some embodiments, the present disclosure is such that R4 and R5 are each independently C1-C 20Provided is a hydrocarbyl amino lipid compound of the above formulas (II) and (III), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0078] In some embodiments, R4 and R5 are each independently C1-C 20 alkyl.

[0079] In some embodiments, R4 and R5 are each independently branched C3-C 20 alkyl, such as branched C5-C 20 alkyl, branched C7-C 19 alkyl, branched C9-C 18 alkyl, branched C 10 -C 18 alkyl, branched C3-C 10 alkyl, branched C 11 -C 17 alkyl or branched C 18 -C 20 alkyl. In some embodiments, R4 and R5 are each independently branched C 11 -C 17 alkyl, such as branched C 11 , C 12 , C 13 , C 14 , C 15 , C 16 or C 17 alkyl. In some embodiments, R4 and R5 are each independently branched C 11 -C 13 alkyl, such as branched C 11 , C 12 or C 13 alkyl. In some embodiments, R4 is a branched alkyl group where the branch occurs at the α, β, or γ position relative to Z7, and R5 is a branched alkyl group where the branch occurs at the α, β, or γ position relative to Z8. In some embodiments, R4 is a branched alkyl group where the branch occurs at the α or β position relative to Z7, and R5 is a branched alkyl group where the branch occurs at the α or β position relative to Z8. In some embodiments, R4 and R5 are each independently one of the following structures. [Chemistry]

[0080] In some embodiments, the present disclosure provides an amino lipid compound of Formula (II) and (III) above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 and R5 are each independently one of the following structures. [Chemistry]

[0081] In some embodiments, the present disclosure provides that R4 and R5 are each independently [Chemistry] or [Chemistry] and provides an amino lipid compound of Formula (II) and (III) above, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0082] In some embodiments, the present disclosure provides that Z7 and Z8 are each independently -(C=O)O- or -O(C=O)-, A3 is a linear C1-C5 alkylene, A4 is a linear C1-C4 alkylene, A6 and A7 are each independently a C5-C 11 alkylene, R1 and R2 are each independently a C1-C4 alkyl, R3 is a linear C2-C 10 alkyl, R4 and R5 are each independently a C1-C 24Provided is an amino lipid compound of the above formulas (II) and (III) which is alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0083] In some embodiments, each of Z7 and Z8 is -(C=O)O-, (C=O) in Z7 is bonded to A6, and (C=O) in Z8 is bonded to A7. In some embodiments, each of Z7 and Z8 is -O(C=O)-, (C=O) in Z7 is bonded to R4, and (C=O) in Z8 is bonded to R5.

[0084] In some embodiments, A3 is a linear C1-C4 alkylene. In some embodiments, A3 is a linear C2-C4 alkylene, such as linear C2, C3 or C4 alkylene. In some embodiments, A3 is CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0085] In some embodiments, A4 is a linear C1-C3 alkylene, such as linear C1, C2 or C3 alkylene. In some embodiments, A4 is -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0086] In some embodiments, A6 and A7 are each independently a linear C5-C 11 alkylene. In some embodiments, A6 and A7 are each independently a linear C6-C 10 alkylene, such as linear C6, C7, C8, C9 or C 10 alkylene. In some embodiments, A6 and A7 are each independently a linear C7, C8 or C9 alkylene, such as -(CH2)7-, -(CH2)8- or -(CH2)9-.

[0087] In some embodiments, R1 and R2 are each independently C1, C2, C3, or C4 alkyl. In some embodiments, R1 and R2 are each independently methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R1 and R2 are each independently methyl.

[0088] In some embodiments, R3 is a straight-chain C4-C8 alkyl, such as straight-chain C4, C5, C6, C7, or C8 alkyl. In some embodiments, R3 is n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl.

[0089] In some embodiments, R4 and R5 are each independently branched C3-C 20 alkyl, such as branched C5-C 20 alkyl, branched C7-C 19 alkyl, branched C9-C 18 alkyl, branched C 10 -C 18 alkyl, branched C3-C 10 alkyl, branched C 11 -C 17 alkyl, or branched C 18 -C 20 alkyl. In some embodiments, R4 and R5 are each independently branched C 11 -C 17 alkyl, such as branched C 11 、C 12 、C 13 、C 14 、C 15 、C 16 or C 17 alkyl. In some embodiments, R4 and R5 are each independently branched C 11 -C 13 alkyl, such as branched C 11 、C 12 or C 13It is alkyl. In some embodiments, R4 is a branched alkyl group where the branching occurs at the α, β, or γ position relative to Z7, and R5 is a branched alkyl group where the branching occurs at the α, β, or γ position relative to Z8. In some embodiments, R4 is a branched alkyl group where the branching occurs at the α or β position relative to Z7, and R5 is a branched alkyl group where the branching occurs at the α or β position relative to Z8.

[0090] In some embodiments, R4 and R5 are each independently one of the following structures.

Chemical formula

[0091] In some embodiments, R4 and R5 are each independently one of the following structures.

Chemical formula

[0092] In some embodiments, R4 and R5 are each independently

Chemical formula

Chemical formula

[0093] In various embodiments, the present disclosure provides an amino lipid compound of formula (I), (II), or (III) above, or a pharmaceutically acceptable salt or stereoisomer thereof, and the amino lipid compound has one of the structures shown in Table 1 below.

Table 1

[0094] All amino lipid compounds of the present disclosure have hydrophobic properties due to the presence of long nonpolar residues and at the same time hydrophilic properties due to amino groups. Due to these amphiphilic properties, lipid nanoparticles, such as lipid bilayers, micelles, liposomes, etc., can be formed using the amino lipid compounds of the present disclosure.

[0095] In the context of the present disclosure, the term "lipid nanoparticle" means a nanometer-sized material produced by introducing an amino lipid compound into an aqueous solution. The particles are in particular lipid nanoparticles, lipid bilayer vesicles (liposomes), multilamellar vesicles or micelles.

[0096] In some preferred embodiments, the lipid nanoparticles are liposomes containing the amino lipid compounds of the present disclosure. Within the scope of the present disclosure, a liposome is a microvesicle consisting of a bilayer of lipid amphiphilic molecules enclosing an aqueous compartment.

[0097] Liposome formation is not a spontaneous process. When lipids are introduced into water, lipid vesicles are first formed, and thus bilayers or a series of bilayers separated by water molecules are formed. Liposomes can be formed by sonication of lipid vesicles in water.

[0098] In the context of the present disclosure, the term "lipid bilayer" means a thin film formed by two layers of lipid molecules. The term "micelle" means an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in an aqueous solution forms a hydrophilic head region in contact with water and chelates the hydrophobic single tail region at the center of the micelle.

[0099] In one aspect, the present disclosure provides the use of the amino lipid compounds of the present disclosure for the manufacture of a vehicle for an active ingredient. In some embodiments, the vehicle is in the form of lipid nanoparticles such as lipid bilayers, micelles, liposomes.

[0100] Lipid nanoparticles In another aspect, the present disclosure provides lipid nanoparticles containing the amino lipid compounds of the present disclosure.

[0101] In some embodiments, the lipid nanoparticles further contain a pharmaceutically acceptable carrier, diluent or excipient.

[0102] In some embodiments, the lipid nanoparticles further contain one or more of helper lipids, structural lipids and PEG-lipids (polyethylene glycol-lipids).

[0103] In some further embodiments, the lipid nanoparticles further contain helper lipids, structural lipids and PEG-lipids.

[0104] In some embodiments, the lipid nanoparticles comprise the amino lipid compound in an amount (mole percent) of about 25.0% to 75.0%, such as about 25.0% to 28.0%, 28.0% to 32.0%, 32.0% to 35.0%, 35.0% to 40.0%, 40.0% to 42.0%, 42.0% to 45.0%, 45.0% to 48.0%, 48.0% to 55.0%, 55.0% to 65.0%, 65.0% to 75.0%, 45.0% to 46.3%, 46.3% to 48.0%, 48.0% to 49.5%, 49.5% to 50.0%, 50.0% to 55.0% or 60.0% to 65.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid.

[0105] In some embodiments, the lipid nanoparticles comprise the helper lipid in an amount (mole percent) of about 5.0% to 45.0%, such as about 5.0% to 10.0%, 10.0% to 16.0%, 16.0% to 25.0%, 25.0% to 33.5%, 33.5% to 37.0%, 37.0% to 40.0%, 40.0% to 42.0%, 42.0% to 45.0%, 5.0% to 9.0%, 9.0% to 9.4%, 9.4% to 10.0%, 10.0% to 10.5%, 10.5% to 11.0%, 11.0% to 15.0%, 15.0% to 16.0%, 16.0% to 18.0%, 18.0% to 20.0% or 20.0% to 25.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid.

[0106] In some embodiments, the lipid nanoparticles contain the structural lipid in an amount (mol percent) of about 0.0% to 50.0%, such as about 0.0% to 10.0%, 10.0% to 15.5%, 15.5% to 22.5%, 22.5% to 35.0%, 35.0% to 36.5%, 36.5% to 39.5%, 39.5% to 40.5%, 40.5% to 41.5%, 41.5% to 45.0%, 45.0% to 46.5%, 46.5% to 50.0%, 15.5% to 18.5%, 18.5% to 22.5%, 22.5% to 23.5%, 23.5% to 28.5%, 28.5% to 33.5%, 33.5% to 35.0%, 36.5% to 38.0%, 38.0% to 38.5%, 38.5% to 39.0%, 39.0% to 39.5%, 41.5% to 42.5%, 42.5% to 42.7%, 42.7% to 43.0%, 43.0% to 43.5%, 43.5% to 45.0% or 46.5% to 48.5% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid. In some embodiments, the lipid nanoparticles contain the structural lipid in an amount (mol percent) of about 50.0% to 55.0%, such as about 50.0% to 51.5%, 51.5% to 53.5% or 53.5% to 55.0%.

[0107] In some embodiments, the lipid nanoparticles contain the PEG-lipid in an amount (mol percent) of about 0.5% to 5.0%, such as about 0.5% to 1.0%, 1.0% to 1.5%, 1.5% to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, 4.5% to 5.0%, 1.5% to 1.6% or 1.6% to 2.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid.

[0108] In some of the above embodiments, the helper lipid is a phospholipid. Phospholipids are generally semi-synthetic and may be of natural origin or chemically modified. Examples of phospholipids include, but are not limited to, DSPC (distearoylphosphatidylcholine), DOPE (dioleoylphosphatidylethanolamine), DOPC (dioleoyl lecithin), DOPS (dioleoylphosphatidylserine), DSPG (1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol)), DPPG (dipalmitoyl phosphatidylglycerol), DPPC (dipalmitoylphosphatidylcholine), DGTS (1,2-dipalmitoyl-sn-glycero-3-O-4'-(N,N,N-trimethyl)homoserine), lysophospholipids, etc. Preferably, the helper lipid is one or more selected from the group consisting of DSPC, DOPE, DOPC, and DOPS. In some embodiments, the helper lipid is DSPC and / or DOPE.

[0109] In some embodiments, the structural lipid is a sterol including, but not limited to, cholesterol, cholesterol ester, steroid hormone, steroid vitamin, bile acid, cholesterin, ergosterol, β-sitosterol, oxidized cholesterol derivative, etc. Preferably, the structural lipid is at least one selected from cholesterol, cholesteryl ester, steroid hormone, steroid vitamin, and bile acid. In some embodiments, the structural lipid is cholesterol, preferably high-purity cholesterol, particularly injection-grade high-purity cholesterol such as CHO-HP (AVT).

[0110] As used herein, the term PEG-lipid (polyethylene glycol-lipid) is a conjugate of polyethylene glycol and a lipid structure. Preferably, the PEG-lipid is selected from PEG-DMG and PEG-distearoyl phosphatidylethanolamine (PEG-DSPE), preferably PEG-DMG. Preferably, PEG-DMG is a polyethylene glycol (PEG) derivative of 1,2-dimyristoyl-sn-glycerol. Preferably, PEG has an average molecular weight of about 2,000 to 5,000, preferably about 2,000, such as PEG2000-DMG.

[0111] In some of the above embodiments, in the lipid nanoparticles, the molar ratio of the amino lipid compound: helper lipid: structural lipid: PEG-lipid of the present disclosure is about 45:11:41.5:2.5, or 42.0:10.5:45.0:2.5, or 42.0:16.0:39.5:2.5, or 40.0:16.0:41.5:2.5, or 40.0:18.0:39.5:2.5, or 35.0:16.0:46.5:2.5, or 35.0:25.0:36.5:3.5, or 28.0:33.5:35.0:3.5, or 32.0:37.0:40.5:0.5, or 35.0:40.0:22.5:2.5, or 40.0:42.0:15.5:2.5, or 45:10:42.5:2.5, or 40.0:20.0:38.5:1.5, or 45.0:15.0:38.5:1.5, or 55.0:5.0:38.5:1.5, or 60.0:5.0:33.5:1.5, or 45.0:20.0:33.5:1.5, or 50.0:20.0:28.5:1.5, or 55.0:20.0:23.5:1.5, or 60.0:20.0:18.5:1.5, or 40.0:15.0:43.5:1.5, or 50.0:15.0:33.5:1.5, or 55.0:15.0:28.5:1.5, or 60.0:15.0:23.5:1.5, or 40.0:10.0:48.5:1.5, or 45.0:10.0:43.5:1.5, or 55.0:10.0:33.5:1.5, or 40.0:5.0:53.5:1.5, or 45.0:5.0:48.5:1.5, or 50.0:5.0:43.5:1.5. In some such embodiments, the helper lipid is DOPE and the structural lipid is CHO-HP.

[0112] In the above other embodiments, in the lipid nanoparticles, the molar ratio of the amino lipid compound:helper lipid:structural lipid:PEG-lipid of the present disclosure is about 48.0:10.0:40.5:1.5, or 50.0:10.0:38.5:1.5, or 50.0:9.0:38.0:3.0, or 49.5:10.0:39.0:1.5, or 46.3:9.4:42.7:1.6, or 45.0:9.0:43.0:3.0, or 45.0:11.0:41.5:2.5, or 42.0:10.5:45.0:2.5, or 42.0:16.0:39.5:2.5, or 40.0:16.0:41.5:2.5, or 40.0:18.0:39.5:2.5, or 35.0:40.0:22.5:2.5, or 40.0:20.0:38.5:1.5, or 45.0:15.0:38.5:1.5, or 55.0:5.0:38.5:1.5, or 60.0:5.0:33.5:1.5, or 45.0:20.0:33.5:1.5, or 50.0:20.0:28.5:1.5, or 55.0:20.0:23.5:1.5, or 60.0:20.0:18.5:1.5, or 40.0:15.0:43.5:1.5, or 50.0:15.0:33.5:1.5, or 55.0:15.0:28.5:1.5, or 60.0:15.0:23.5:1.5, or 40.0:10.0:48.5:1.5, or 45.0:10.0:43.5:1.5, or 55.0:10.0:33.5:1.5, or 40.0:5.0:53.5:1.5, or 45.0:5.0:48.5:1.5, or 50.0:5.0:43.5:1.5. In some such embodiments, the helper lipid is DSPC and the structural lipid is CHO-HP.

[0113] In some embodiments, the lipid nanoparticles have the amino lipid compound, helper lipid, structural lipid, and PEG-lipid of the present disclosure in mole percent (%) as shown in Numbers 1 to 12 and Numbers 13 to 24 in Table 2 below, based on the total amount of the amino lipid compound, helper lipid, structural lipid, and PEG-lipid:

Table 2

[0114] In some embodiments, the active ingredient includes a therapeutic agent and / or a prophylactic agent.

[0115] The term "therapeutic agent" or "prophylactic agent" refers to any agent that has a therapeutic effect, a diagnostic effect, and / or a prophylactic effect and / or induces a desired biological and / or pharmacological effect when administered to a subject.

[0116] "Effective amount" or "therapeutically effective amount" refers to the amount of the amino lipid compound of the present disclosure or the lipid nanoparticles containing the amino lipid compound of the present disclosure that is sufficient to effect treatment in a mammal (preferably a human) when administered to the mammal (preferably a human). The amount of the lipid nanoparticles of the present disclosure that constitutes a "therapeutically effective amount" depends on the amino lipid compound, the condition and its severity, the mode of administration, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art in light of their own knowledge and the present disclosure.

[0117] In some embodiments, the active ingredient is a pharmaceutically active ingredient including, but not limited to, anti-neoplastic agents, antibiotics, immunomodulators, anti-inflammatory agents, agents acting on the central nervous system, antigens or fragments thereof, proteins, peptides, polypeptides, polypeptides, vaccines, and small molecules, and mixtures thereof. Preferably, the pharmaceutically active ingredient is a biologically active ingredient.

[0118] In the context of the present disclosure, a biologically active component is a substance that has a biological effect when introduced into a cell or a host, for example, by stimulating an immune response or an inflammatory response, by exerting enzyme activity, by complementing a mutation, etc. Examples of biologically active components include, but are not limited to, nucleic acids, antigens or fragments thereof, proteins, peptides, polypeptides, polypeptoids, antibodies, vaccines, and small molecules, as well as mixtures thereof.

[0119] When lipid nanoparticles encapsulate an active component in their internal aqueous space, they may be referred to as "lipid nanoparticle drugs".

[0120] In the context of the present disclosure, the term "cell" is a general term and includes individual cells, tissues, organs, insect cells, avian cells, fish cells, amphibian cells, mammalian cells, primary cells, continuous cell lines, stem cells, and / or cultures of genetically engineered cells (e.g., recombinant cells that express a heterologous polypeptide or protein). Examples of recombinant cells include cells that express a heterologous polypeptide or protein (such as a growth factor or a blood factor).

[0121] In some preferred embodiments, the biologically active component is a nucleic acid.

[0122] In some of the above embodiments, the lipid nanoparticles of the present disclosure further contain a nucleic acid.

[0123] In some embodiments, the mass ratio of the amino lipid compound of the present disclosure to the nucleic acid in the lipid nanoparticles is about (5 - 30):1, for example, about (5 - 10):1, (10 - 15):1, (15 - 20):1, (20 - 25):1, or (25 - 30):1, preferably about 10:1.

[0124] In some embodiments, the nucleic acid is selected from the group consisting of RNA, antisense oligonucleotides, and DNA.

[0125] In some embodiments, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA), small nuclear RNA (snRNA), short hairpin RNA (shRNA), single guide RNA (sgRNA), Cas9 mRNA, or mixtures thereof.

[0126] In some embodiments, the messenger RNA (mRNA) encodes a polypeptide and / or protein of interest. Any natural or non-natural or other modified polypeptide is included. In some embodiments, the polypeptide and / or protein encoded by the mRNA may have a therapeutic and / or prophylactic effect when expressed in a cell.

[0127] In some embodiments, the RNA is siRNA that can selectively reduce the expression of a gene of interest or down-regulate the expression of that gene. For example, the siRNA can be selected such that when a lipid nanoparticle containing the siRNA is administered to a subject in need thereof, the gene associated with a particular disease, disorder, or condition is silenced. The siRNA can include a sequence complementary to the mRNA sequence encoding the gene or protein of interest. In some embodiments, the siRNA can be an immunomodulatory siRNA.

[0128] In certain embodiments, the RNA is sgRNA and / or cas9 mRNA. The sgRNA and / or cas9 mRNA can be used as a gene editing tool. For example, the sgRNA-Cas9 complex can affect the mRNA translation of cellular genes.

[0129] In some embodiments, the RNA is shRNA or a vector or plasmid encoding the same. The shRNA can be produced inside the target cell after delivery of an appropriate construct to the nucleus. The constructs and mechanisms associated with shRNA are well known in the relevant art.

[0130] In some embodiments, the DNA is a plasmid.

[0131] In some embodiments, the lipid nanoparticles are used to deliver nucleic acids. In some embodiments, the lipid nanoparticles can be used, for example, in gene therapy, gene vaccination, protein replacement therapy, antisense therapy or therapy with interfering RNA.

[0132] Composition In another aspect, the present disclosure provides a composition comprising the lipid nanoparticles described above and a pharmaceutically acceptable carrier, diluent or excipient.

[0133] In some embodiments, the composition further comprises a buffer solution. In some such embodiments, the buffer solution is selected from phosphate buffer and Tris buffer, preferably phosphate buffer. In some embodiments, the buffer solution has a concentration of about 5 mmol / L to about 30 mmol / L, preferably about 10 mmol / L. In some embodiments, the buffer solution has a pH of about 6 to 8, preferably about 7 to 8, more preferably about 7 to 7.5.

[0134] In some embodiments, the composition further comprises a cryoprotectant. In some such embodiments, the cryoprotectant is selected from sucrose and trehalose, preferably sucrose. In some embodiments, the cryoprotectant has a concentration of about 50 mg / ml to 100 mg / ml.

[0135] In some of the above embodiments, the composition further comprises a cryoprotectant. In some such embodiments, the cryoprotectant is selected from sucrose and trehalose, preferably sucrose. In some embodiments, the cryoprotectant has a concentration of about 50 mg / ml to 100 mg / ml.

[0136] In some embodiments, the composition is a pharmaceutical composition.

[0137] Use The lipid nanoparticles of the present disclosure have excellent properties for encapsulating bioactive components. Lipid nanoparticles containing bioactive components can be used to transfer any of various therapeutic agents into cells. The present disclosure includes the use of the above lipid nanoparticles for transferring bioactive components into cells. The present disclosure also provides a method for transferring a bioactive component into a cell, which includes contacting a cell with a lipid nanoparticle of the present disclosure containing the bioactive component.

[0138] The lipid nanoparticles of the present disclosure can be used to transfect multicellular tissues or organs. Accordingly, the present disclosure also provides a method for transfecting a cell, a multicellular tissue or an organ, which includes contacting a lipid nanoparticle of the present disclosure containing a nucleic acid with the cell, the tissue or the organ. This provides the possibility of new therapeutic treatments for a subject.

[0139] In some embodiments, the cell is a mammalian cell, and more preferably, the mammalian cell is in a mammal.

[0140] In some embodiments, the tissue or organ is selected from the group consisting of spleen, liver, kidney, lung, femur, eye tissue, vascular endothelium in blood vessels, lymph, and tumor tissue.

[0141] As used herein, the subject can preferably be any mammal selected from the group consisting of mice, rats, pigs, cats, dogs, horses, goats, cows, monkeys, etc. In some preferred embodiments, the subject is a human.

[0142] In another aspect, the present disclosure provides a method for producing a polypeptide and / or protein of interest in a mammalian cell, which includes contacting a lipid nanoparticle containing mRNA encoding the polypeptide and / or protein of interest with the cell when the cell is contacted with the lipid nanoparticle, wherein the mRNA can be taken up by the cell and translated to produce the polypeptide and / or protein of interest.

[0143] In yet another aspect, the present disclosure provides for the use of the amino lipid compounds, lipid nanoparticles or compositions of the present disclosure in the manufacture of a medicament. In yet another aspect, the present disclosure provides for the lipid nanoparticles or compositions of the present disclosure for use as a medicament. In yet another aspect, the present disclosure provides for a medicament comprising the lipid nanoparticles or compositions of the present disclosure. In some embodiments, the medicament is used for the treatment and / or prevention of a disease. In some embodiments, the disease is selected from the group consisting of rare diseases, infectious diseases, cancer, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardiovascular diseases, renal vascular diseases and metabolic diseases. In some embodiments, the medicament is used, for example, for gene therapy, gene vaccination, protein replacement therapy, antisense therapy or therapy by interfering RNA. Preferably, the gene therapy is for use in the treatment of cancer and genetic diseases. In some embodiments, the cancer is selected from one or more of lung cancer, gastric cancer, liver cancer, esophageal cancer, colon cancer, pancreatic cancer, brain cancer, lymphoma, blood cancer or prostate cancer. In some embodiments, the genetic disorder is one or more selected from hemophilia, thalassemia and Gaucher's disease. In some embodiments, the gene vaccine is preferably for vaccination for the treatment of cancer, allergy, toxicity and pathogen infection. In some embodiments, the pathogen is selected from one or more of a virus, a bacterium or a fungus.

[0144] In yet another aspect, the present disclosure provides a method of treating a disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the above lipid nanoparticles.

[0145] Preferably, the disease or disorder is selected from the group consisting of rare diseases, infectious diseases, cancer, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardiovascular diseases, renal vascular diseases and metabolic diseases.

[0146] In yet another aspect, the present disclosure provides for the use of the disclosed amino lipid compounds, lipid nanoparticles or compositions in the manufacture of a medicament for nucleic acid transfection. In yet another aspect, the present disclosure provides the disclosed lipid nanoparticles or compositions for use as a medicament for nucleic acid transfection. In yet another aspect, the present disclosure provides a medicament comprising the disclosed lipid nanoparticles or compositions for nucleic acid transfection. In some embodiments, the nucleic acid is selected from the group consisting of RNA, antisense oligonucleotides and DNA. In some embodiments, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA) and small nuclear RNA (snRNA). In some embodiments, the DNA is a plasmid.

[0147] Preparation method In another aspect, the present disclosure also provides a general synthetic process for preparing the amino lipid compounds of formula (II) of the present disclosure as follows:

Chemical formula

[0148] Specifically, the method comprises Step 1: subjecting a compound of formula DTN and a compound of formula di-N to a reductive amination reaction to obtain a compound of formula F; and Step 2: reacting a compound of formula F with a compound of formula G to obtain an amino lipid compound of formula (II).

[0149] In some embodiments, the reductive amination reaction in Step 1 is carried out in an organic solvent (e.g., C1-C3 alcohol, preferably ethanol). In some embodiments, the reductive amination reaction is carried out in a hydrogen atmosphere in the presence of a catalyst (e.g., palladium on carbon). In some embodiments, the reductive amination reaction is carried out at high pressure (e.g., about 2-8 or about 4-6 MPa) and high temperature (e.g., about 50-90 or about 60-80 °C).

[0150] In some embodiments, the reaction in Step 2 is carried out in the presence of a base (e.g., pyridine or DMAP).

[0151] In yet another aspect, the present disclosure also provides a general synthetic process for preparing the amino lipid compounds of formula (III) of the present disclosure as follows:

Chemical formula

[0152] Specifically, the method comprises Step 1: subjecting a compound of formula DTN and a compound of formula di-N to a reductive amination reaction to obtain a compound of formula F; Step 2: reacting the compound of formula F with a compound of formula H to obtain an amino lipid compound of formula (III).

[0153] In some embodiments, the reductive amination reaction in Step 1 is carried out in an organic solvent (e.g., C1-C3 alcohol, preferably ethanol). In some embodiments, the reductive amination reaction is carried out in a hydrogen atmosphere in the presence of a catalyst (e.g., palladium on carbon). In some embodiments, the reductive amination reaction is carried out at high pressure (e.g., about 2-8 or about 4-6 MPa) and high temperature (e.g., about 50-90 or about 60-80 °C).

[0154] In yet another aspect, the lipid nanoparticles or compositions of the present disclosure can be prepared according to methods known in the art. For example, the method can include the following steps.

[0155] (1) Formulation: Formulating a suitable aqueous phase and formulating an organic phase containing the amino lipid compound of the present disclosure and optionally a helper lipid, a structural lipid, and / or a PEG-lipid. (2) Encapsulation: Mixing a suitable amount of the aqueous phase with the organic phase. (3) Dialysis: Optionally, dialyzing the mixture of step (2), and (4) Sterilization: Optionally, sterilizing the product of step (3) with a sterilizing filter such as a 0.22 μm microporous membrane.

[0156] In yet another aspect, the lipid nanoparticles or compositions of the present disclosure containing a nucleic acid, particularly mRNA, can be prepared by a method comprising the following steps.

[0157] (1) Formulation: Formulating an aqueous phase containing a nucleic acid and formulating an organic phase (e.g., an ethanol phase) containing the amino lipid compound of the present disclosure and optionally a helper lipid, a structural lipid, and / or a PEG-lipid. (2) Encapsulation: Mixing a suitable amount of the aqueous phase with the organic phase. (3) Dialysis: Optionally, dialyzing the mixture of step (2). (4) Sterilization: Optionally, sterilizing the product of step (3) with a sterilizing filter such as a 0.22 μm microporous membrane.

[0158] The present disclosure also includes the following embodiments.

[0159] Embodiment 1. An amino lipid compound having the structure of formula (I): [Chemical formula] (wherein, Z1, Z2, Z5, Z6, Z7 and Z8 are each independently C(=O)-, -CH(OH)-, -C=C-, -C≡C-, -O-, -(C=O)O-, -O(C=O)-, -C(=O)S-, -SC(=O)-, -S-S- or a bond, Z3 is -C(=O)- or a bond, Z4 is -O- or -CH(OH)-, A1, A2, A3, A4, A5, A6 and A7 are each independently a C1-C 12 hydrocarbylene, cyclo hydrocarbyl, phenyl, heterocycle or a bond, R1 and R2 are each independently H or a C1-C 18 hydrocarbyl or cyclo hydrocarbyl, phenyl, heterocycle, or R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, R3 is H or a C1-C 18 hydrocarbyl or cyclo hydrocarbyl, phenyl, heterocycle, R4 and R5 are each independently a C1-C 24 hydrocarbyl or cyclo hydrocarbyl, phenyl, heterocycle, preferably, A5, Z5 and Z6 are bonds) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0160] Embodiment 2. The amino lipid compound according to Embodiment 1, wherein Z7 and Z8 are each independently -(C=O)O-, -O(C=O)- or a bond.

[0161] Embodiment 3. The amino lipid compound according to Embodiment 1, wherein one of Z7 or Z8 is -(C=O)O-, -O(C=O)- or a bond.

[0162] Embodiment 4. The amino lipid compound according to Embodiment 1, wherein each of Z7 and Z8 is -(C=O)O-.

[0163] The amino lipid compound according to Embodiment 1, wherein one of Z7 and Z8 is a bond.

[0164] The amino lipid compound according to Embodiment 1, wherein each of Z7 and Z8 is a bond.

[0165] Embodiment 7. R4 and R5 are each independently C1-C 20 hydrocarbyl, the amino lipid compound according to Embodiment 1.

[0166] Embodiment 8. R4 and R5 are each independently C1-C 20 alkyl, the amino lipid compound according to Embodiment 1.

[0167] Embodiment 9. R4 and R5 are each independently branched C3-C 20 alkyl, the amino lipid compound according to Embodiment 1.

[0168] Embodiment 10. R4 and R5 are each independently

Chemical formula

[0169] Embodiment 11. An amino lipid compound having the structure of formula (II):

Chemical formula

[0170] Embodiment 12. The amino lipid compound according to Embodiment 11, wherein Z7 and Z8 are each independently -(C=O)O- or -O(C=O)-.

[0171] Embodiment 13. The amino lipid compound according to Embodiment 11, wherein A3, A4, A6 and A7 are each independently C1-C 12 alkylene.

[0172] Embodiment 14. The amino lipid compound according to Embodiment 11, wherein R1 and R2 are each independently C1-C 18 alkyl.

[0173] Embodiment 15. The amino lipid compound according to Embodiment 14, wherein R1 and R2 are each independently C1-C6 alkyl.

[0174] Embodiment 16. The amino lipid compound according to Embodiment 14, wherein R1 and R2 are each independently methyl, ethyl, n-propyl or isopropyl.

[0175] Embodiment 17. The amino lipid compound according to Embodiment 11, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring.

[0176] Amino lipid compound according to Embodiment 17, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring.

[0177] Embodiment 19. R3 is C1-C 18 alkyl, and the amino lipid compound according to Embodiment 11.

[0178] Embodiment 20. R4 and R5 are each independently C1-C 20 hydrocarbyl, and the amino lipid compound according to Embodiment 11.

[0179] Embodiment 21. R4 and R5 are each independently C1-C 20 alkyl, and the amino lipid compound according to Embodiment 11.

[0180] Embodiment 22. R4 and R5 are each independently branched C3-C 18 alkyl, and the amino lipid compound according to Embodiment 11.

[0181] Embodiment 23. R4 and R5 are each independently

Chemical formula

[0182] Embodiment 24. An amino lipid compound having the structure of formula (III):

Chemical formula

[0183] Embodiment 25. The amino lipid compound according to Embodiment 24, wherein Z7 and Z8 are each independently -(C=O)O- or -O(C=O)-.

[0184] Embodiment 26. The amino lipid compound according to Embodiment 24, wherein A3, A4, A6 and A7 are each independently C1-C 12 alkylene.

[0185] Embodiment 27. The amino lipid compound according to Embodiment 24, wherein R1 and R2 are each independently C1-C 18 alkyl.

[0186] Embodiment 28. The amino lipid compound according to Embodiment 27, wherein R1 and R2 are each independently C1-C6 alkyl.

[0187] Embodiment 29. The amino lipid compound according to Embodiment 28, wherein R1 and R2 are each independently methyl, ethyl, n-propyl or isopropyl.

[0188] Embodiment 30. The amino lipid compound according to Embodiment 24, wherein R1 and R2, together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclic ring.

[0189] Embodiment 31. The amino lipid compound according to Embodiment 24, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring.

[0190] Embodiment 32. The amino lipid compound according to Embodiment 24, wherein R3 is a C1-C 18 alkyl.

[0191] Embodiment 33. The amino lipid compound according to Embodiment 24, wherein R4 and R5 are each independently a C1-C 20 hydrocarbyl.

[0192] Embodiment 34. The amino lipid compound according to Embodiment 24, wherein R4 and R5 are each independently a C1-C 20 alkyl.

[0193] Embodiment 35. The amino lipid compound according to Embodiment 24, wherein R4 and R5 are each independently a branched C3-C 18 alkyl.

[0194] Embodiment 36. R4 and R5 are each independently

Chemical formula

[0195] Embodiment 37. A lipid nanoparticle comprising the amino lipid compound according to any one of Embodiments 1 to 36 and optionally a pharmaceutically acceptable carrier, diluent or excipient.

[0196] Embodiment 38. Further comprising one or more of helper lipid, structural lipid and PEG-lipid, and further, the lipid nanoparticle according to Embodiment 37, wherein the lipid nanoparticle comprises a helper lipid, a structural lipid and a PEG-lipid.

[0197] Embodiment 39. The lipid nanoparticles contain the amino lipid compound according to any one of Embodiments 1 to 36 in an amount (mol%) of about 25.0% to 75.0%, for example, about 25.0% to 28.0%, 28.0% to 32.0%, 32.0% to 35.0%, 35.0% to 40.0%, 40.0% to 42.0%, 42.0% to 45.0%, 45.0% to 48.0%, 48.0% to 55.0%, 55.0% to 65.0% or 65.0% to 75.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid according to any one of Embodiments 1 to 36. The lipid nanoparticles according to Embodiment 38.

[0198] Embodiment 40. The lipid nanoparticles contain the helper lipid in an amount (mol%) of about 5.0% to 45.0%, for example, about 5.0% to 10.0%, 10.0% to 16.0%, 16.0% to 25.0%, 25.0% to 33.5%, 33.5% to 37.0%, 37.0% to 40.0%, 40.0% to 42.0% or 42.0% to 45.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid according to any one of Embodiments 1 to 36. The lipid nanoparticles according to Embodiment 38 or 39.

[0199] Embodiment 41. The lipid nanoparticles contain the structural lipid in an amount (mol%) of about 0.0% to 50.0%, for example, about 0.0% to 10.0%, 10.0% to 15.5%, 15.5% to 22.5%, 22.5% to 35.0%, 35.0% to 36.5%, 36.5% to 39.5%, 39.5% to 40.5%, 40.5% to 41.5%, 41.5% to 45.0%, 45.0% to 46.5% or 46.5% to 50.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid according to any one of Embodiments 1 to 36. The lipid nanoparticles according to any one of Embodiments 38 to 40.

[0200] Embodiment 42. The lipid nanoparticles contain PEG-lipid in an amount (mol percent) of about 0.5% to 5.0%, such as about 0.5% to 1.0%, 1.0% to 1.5%, 1.5% to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5% or 4.5% to 5.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid and PEG-lipid described in any one of Embodiments 1 to 36. The lipid nanoparticles according to any one of Embodiments 38 to 41.

[0201] Embodiment 43. The helper lipid is one or more selected from the group consisting of DSPC, DOPE, DOPC, DOPS, DSPG, DPPG, DPPC, DGTS and lysophospholipids, preferably one or more selected from the group consisting of DSPC, DOPE, DOPC and DOPS, more preferably DSPC and / or DOPE. The lipid nanoparticles according to any one of Embodiments 38 to 42.

[0202] Embodiment 44. The structural lipid is at least one selected from the group consisting of cholesterol, cholesterol ester, steroid hormone, steroid vitamin, bile acid, cholesterin, ergosterol, β-sitosterol and oxidized cholesterol derivative, preferably at least one selected from the group consisting of cholesterol, cholesterol ester, steroid hormone, steroid vitamin and bile acid, more preferably cholesterol, still more preferably high-purity cholesterol, particularly injection-grade high-purity cholesterol such as CHO-HP. The lipid nanoparticles according to any one of Embodiments 38 to 43.

[0203] Embodiment 45. The PEG-lipid is selected from PEG-DMG and PEG-DSPE, preferably PEG-DMG. Preferably, PEG-DMG is a polyethylene glycol (PEG) derivative of 1,2-dimyristoyl-sn-glycerol. Preferably, the lipid nanoparticles according to any one of Embodiments 38 to 44, wherein the PEG has an average molecular weight of about 2,000 to 5,000, preferably about 2,000.

[0204] Embodiment 46. The lipid nanoparticles according to any one of Embodiments 38 to 45, wherein the molar ratio of the amino lipid compound: helper lipid: structural lipid: PEG-lipid according to any one of Embodiments 1 to 36 is about 45:11:41.5:2.5, or 42.0:10.5:45.0:2.5, or 42.0:16.0:39.5:2.5, or 40.0:16.0:41.5:2.5, or 40.0:18.0:39.5:2.5, or 35.0:16.0:46.5:2.5, or 35.0:25.0:36.5:3.5, or 28.0:33.5:35.0:3.5, or 32.0:37.0:40.5:0.5, or 35.0:40.0:22.5:2.5, or 40.0:42.0:15.5:2.5.

[0205] Embodiment 47. The lipid nanoparticles according to Embodiment 46, wherein the helper lipid is DOPE and the structural lipid is CHO-HP.

[0206] Embodiment 48. The lipid nanoparticles according to any one of Embodiments 38 to 45, wherein the molar ratio of the amino lipid compound: helper lipid: structural lipid: PEG-lipid according to any one of Embodiments 1 to 36 is about 48.0:10.0:40.5:1.5.

[0207] Embodiment 49. The lipid nanoparticles according to Embodiment 48, wherein the helper lipid is DSPC and the structural lipid is CHO-HP.

[0208] Embodiment 50. The lipid nanoparticles according to any one of Embodiments 37 to 49, further comprising a nucleic acid.

[0209] Embodiment 51. The lipid nanoparticles according to Embodiment 50, wherein the mass ratio of the amino lipid compound and the nucleic acid according to any one of Embodiments 1 to 36 is about (5 to 30):1, for example, about (5 to 10):1, (10 to 15):1, (15 to 20):1, (20 to 25):1 or (25 to 30):1, preferably about 10:1.

[0210] Embodiment 52. The nucleic acid is selected from the group consisting of RNA, antisense oligonucleotides, and DNA. Preferably, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA), and small nuclear RNA (snRNA). Preferably, the DNA is a plasmid. The lipid nanoparticles according to Embodiment 50 or 51.

[0211] Embodiment 53. A composition comprising the amino lipid compound according to any one of Embodiments 1 to 36 and a pharmaceutically acceptable carrier, diluent, or excipient.

[0212] Embodiment 54. Further comprising one or more of a helper lipid, a structural lipid, and a PEG-lipid. Furthermore, the composition according to Embodiment 53, wherein the composition further comprises a helper lipid, a structural lipid, and a PEG-lipid.

[0213] Embodiment 55. The composition according to Embodiment 54, wherein the composition comprises the amino lipid compound according to any one of Embodiments 1 to 36 in an amount (mole percent) of about 25.0% to 75.0%, for example, about 25.0% to 28.0%, 28.0% to 32.0%, 32.0% to 35.0%, 35.0% to 40.0%, 40.0% to 42.0%, 42.0% to 45.0%, 45.0% to 48.0%, 48.0% to 55.0%, 55.0% to 65.0%, or 65.0% to 75.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid, and PEG-lipid according to any one of Embodiments 1 to 36.

[0214] Embodiment 56. The composition contains helper lipid in an amount (mole percent) of about 5.0% to 45.0%, for example about 5.0% to 10.0%, 10.0% to 16.0%, 16.0% to 25.0%, 25.0% to 33.5%, 33.5% to 37.0%, 37.0% to 40.0%, 40.0% to 42.0%, or 42.0% to 45.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid, and PEG-lipid described in any one of Embodiments 1 to 36, and is the composition described in Embodiment 54 or 55.

[0215] Embodiment 57. The composition contains structural lipid in an amount (mole percent) of about 0.0% to 50.0%, for example about 0.0% to 10.0%, 10.0% to 15.5%, 15.5% to 22.5%, 22.5% to 35.0%, 35.0% to 36.5%, 36.5% to 39.5%, 39.5% to 40.5%, 40.5% to 41.5%, 41.5% to 45.0%, 45.0% to 46.5%, or 46.5% to 50.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid, and PEG-lipid described in any one of Embodiments 1 to 36, and is the composition described in any one of Embodiments 54 to 56.

[0216] Embodiment 58. The composition contains PEG-lipid in an amount (mole percent) of about 0.5% to 5.0%, for example about 0.5% to 1.0%, 1.0% to 1.5%, 1.5% to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, or 4.5% to 5.0% based on the total amount of the amino lipid compound, helper lipid, structural lipid, and PEG-lipid described in any one of Embodiments 1 to 36, and is the composition described in any one of Embodiments 54 to 57.

[0217] Embodiment 59. The composition according to any one of Embodiments 54 to 58, wherein the helper lipid is one or more selected from the group consisting of DSPC, DOPE, DOPC, DOPS, DSPG, DPPG, DPPC, DGTS and lysophospholipids, preferably one or more selected from the group consisting of DSPC, DOPE, DOPC and DOPS, more preferably DSPC and / or DOPE.

[0218] Embodiment 60. The composition according to any one of Embodiments 54 to 58, wherein the structural lipid is at least one selected from the group consisting of cholesterol, cholesterol ester, steroid hormone, steroid vitamin, bile acid, cholesterin, ergosterol, β-sitosterol and oxidized cholesterol derivative, preferably at least one selected from the group consisting of cholesterol, cholesterol ester, steroid hormone, steroid vitamin and bile acid, more preferably cholesterol, even more preferably high-purity cholesterol, particularly high-purity cholesterol of injection grade such as CHO-HP.

[0219] Embodiment 61. The PEG-lipid is selected from PEG-DMG and PEG-DSPE, preferably PEG-DMG. Preferably, PEG-DMG is a polyethylene glycol (PEG) derivative of 1,2-dimyristoyl-sn-glycerol. Preferably, PEG has an average molecular weight of about 2,000 to 5,000, preferably about 2,000. The composition according to any one of Embodiments 54 to 58.

[0220] The composition according to any one of Embodiments 54 to 61, wherein the molar ratio of the amino lipid compound:helper lipid:structural lipid:PEG-lipid described in any one of Embodiments 1 to 36 is about 45:11:41.5:2.5, or 42.0:10.5:45.0:2.5, or 42.0:16.0:39.5:2.5, or 40.0:16.0:41.5:2.5, or 40.0:18.0:39.5:2.5, or 35.0:16.0:46.5:2.5, or 35.0:25.0:36.5:3.5, or 28.0:33.5:35.0:3.5, or 32.0:37.0:40.5:0.5, or 35.0:40.0:22.5:2.5, or 40.0:42.0:15.5:2.5.

[0221] The composition according to Embodiment 62, wherein the helper lipid is DOPE and the structural lipid is CHO-HP.

[0222] The composition according to any one of Embodiments 54 to 61, wherein the molar ratio of the amino lipid compound:helper lipid:structural lipid:PEG-lipid described in any one of Embodiments 1 to 36 is about 48.0:10.0:40.5:1.5.

[0223] The composition according to Embodiment 64, wherein the helper lipid is DSPC and the structural lipid is CHO-HP.

[0224] The composition according to any one of Embodiments 53 to 65, further comprising a nucleic acid.

[0225] The composition according to Embodiment 66, wherein the mass ratio of the amino lipid compound described in any one of Embodiments 1 to 36 to the nucleic acid is about (5 to 30):1, for example, about (5 to 10):1, (10 to 15):1, (15 to 20):1, (20 to 25):1 or (25 to 30):1, preferably about 10:1.

[0226] The nucleic acid is selected from the group consisting of RNA, antisense oligonucleotides and DNA. Preferably, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA), and small nuclear RNA (snRNA), The composition according to embodiment 66 or 67, wherein preferably the DNA is a plasmid.

[0227] Embodiment 69. Further comprising a buffer, Preferably, the buffer is selected from phosphate buffer and Tris buffer, preferably phosphate buffer, and / or Preferably, the buffer has a concentration of about 5 mmol / L to 30 mmol / L, preferably about 10 mmol / L, and / or Preferably, the buffer has a pH of about 6 to 8, preferably about 7 to 8, more preferably about 7 to 7.5, the composition according to any one of embodiments 53 to 68.

[0228] Embodiment 70. Further comprising a cryoprotectant, Preferably, the cryoprotectant is selected from sucrose and trehalose, preferably sucrose, and / or Preferably, the cryoprotectant has a concentration of about 50 mg / ml to 100 mg / ml, the composition according to any one of embodiments 53 to 68.

[0229] Embodiment 71. Use of the amino lipid compound according to any one of embodiments 1 to 36 in the manufacture of a vehicle for an active ingredient.

[0230] Embodiment 72. The vehicle is a lipid nanoparticle according to any one of embodiments 37 to 52, and / or The active ingredient is a pharmaceutical active ingredient, preferably a nucleic acid, and / or Preferably, the nucleic acid is selected from the group consisting of RNA, antisense oligonucleotides, and DNA, Preferably, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA), and small nuclear RNA (snRNA). Use according to embodiment 71, wherein preferably the DNA is a plasmid.

[0231] Embodiment 73. Use of an amino lipid compound according to any one of embodiments 1 to 36, a lipid nanoparticle according to any one of embodiments 37 to 52, or a composition according to any one of embodiments 53 to 70 in the manufacture of a pharmaceutical.

[0232] Embodiment 74. Use according to embodiment 73, wherein the pharmaceutical is for use in gene therapy, gene vaccination, protein replacement therapy, antisense therapy, or therapy with interfering RNA.

[0233] Embodiment 75. Use according to embodiment 74, wherein the gene therapy is for use in the treatment of cancer and genetic diseases.

[0234] Embodiment 76. Use according to embodiment 75, wherein the cancer is one or more selected from the group consisting of lung cancer, gastric cancer, liver cancer, esophageal cancer, colon cancer, pancreatic cancer, brain cancer, lymphoma, blood cancer, or prostate cancer, and the genetic disease is one or more selected from the group consisting of hemophilia, thalassemia, and Gaucher disease.

[0235] Embodiment 77. Use according to embodiment 75, wherein the gene vaccination is for use in the treatment of cancer, allergy, toxicity, and pathogen infection.

[0236] Embodiment 78. Use according to embodiment 77, wherein the pathogen is one or more selected from the group consisting of viruses, bacteria, or fungi.

[0237] Use of the amino lipid compound according to any one of Embodiments 1 to 36, the lipid nanoparticle according to any one of Embodiments 37 to 52 or the composition according to any one of Embodiments 53 to 70 in the manufacture of a medicament for nucleic acid transfer.

[0238] Embodiment 80. The nucleic acid is selected from the group consisting of RNA, antisense oligonucleotides and DNA, preferably, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA) and small nuclear RNA (snRNA), preferably, the DNA is a plasmid, the use according to Embodiment 79.

[0239] Beneficial effects The amino lipid compound of the present disclosure can form vehicles such as lipid nanoparticles having excellent properties of encapsulating biologically active components, and can deliver biologically active components, particularly water-insoluble drugs or active components (such as nucleic acids) that are easily decomposed or degraded, and its biological availability and effectiveness, or immunological activity, or transfection efficiency (in the case of nucleic acids), or safety, or preference for specific organs or tissues. In particular, lipid nanoparticles containing the amino lipid compound of the present disclosure have a clear delivery preference for the spleen.

[0240] Lipid nanoparticles containing the amino lipid compound of the present disclosure have a clear delivery preference for immune cells in different tissues and organs, and examples of the tissues and organs include the spleen, lymph, peripheral blood, bone marrow, lung, liver, etc., and examples of the immune cells include neutrophils, NK cells - NK T cells, macrophages - monocytes, dendritic cells, B cells, T cells, CD4 T cells, etc.

[0241] Figures 1A to 1F show the delivery efficiency of lipid nanoparticles containing different amino lipid compounds to immune cell populations in different tissues and organs.

Brief Description of the Drawings

[0242]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 1F

[0243] To make the objectives, technical solutions, and advantages of the present disclosure clearer, the present disclosure will be described below with reference to specific examples. The following examples are merely illustrative of the present disclosure and are not intended to be limiting.

[0244] Examples The following examples are provided for illustrative purposes only and not for limitation.

[0245] In the examples, experimental methods for which specific conditions are not specified are generally conventional conditions or conditions recommended by the manufacturers of raw materials or products, and reagents of unspecified origin are generally commercially available conventional reagents.

[0246] The abbreviations used in the examples have the following meanings.

[0247] Pd / C palladium / carbon, EA ethyl acetate, DCM dichloromethane, MPa megapascal, DMF N,N-dimethylformamide, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DMAP 4-dimethylaminopyridine, TEMPO 2,2,6,6-tetramethylpiperidinooxy, Sodium dichloroisocyanurate (NaDCC), h hours, min minutes.

[0248] Example 1: Synthesis of amino lipid compound 125 (1) Synthesis of compound 1522F-1

Chemical formula

[0249] (2) Synthesis of compound 125-G

Chemical formula

[0250] 17 g of 125G-1 (116.2 mmol), 100 ml of DCM, 0.54 g of TEMPO, 23.3 g of KHCO₃ and 1.2 g of NaBr were added to a 1000 mL round-bottom flask, and while stirring, 38.34 g of an aqueous NaDCC solution was added. The reaction was carried out with stirring at room temperature for 15 hours and then filtered. The organic phase was separated from the filtrate, and the aqueous phase was extracted twice with 100 ml of DCM. The organic phases were combined and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography and eluted with EA:n-hexane = 1:8 to obtain 11 g of 125-G in a yield of 64.7%. 1 H NMR in (CDCl₃) δ 3.71 - 3.69 (m, 2H), 3.47 - 3.44 (m, 2H), 2.64 - 2.61 (m, 2H), 1.57 - 1.54 (m, 2H), 1.34 - 1.25 (m, 6H), 0.89 - 0.87 (m, 3H).

[0251] (3) Synthesis of amino lipid compound 125

Chemical formula

[0252] Example 2: Synthesis of Amino Lipid Compound 120

Chemical Structure

[0253] Example 3: Synthesis of Amino Lipid Compound 130

Chemical Structure

[0254] Example 4: Synthesis of Amino Lipid Compound 144

Chemical Structure

[0255] Example 5: Synthesis of Amino Lipid Compound 149

Chemical Structure

[0256] Example 6: Synthesis of Amino Lipid Compound 154

Chemical Structure

[0257] Example 7: Synthesis of Amino Lipid Compound 166

Chemical Structure

[0258] Example 8: Synthesis of Amino Lipid Compound 172

Chemical Structure

[0259] Example 9: Synthesis of Amino Lipid Compound 176

Chemical Structure

[0260] Example 10: Synthesis of Amino Lipid Compound 119

Chemical Structure

[0261] Example 11: Synthesis of Amino Lipid Compound 121

Chemical Structure

[0262] Example 12: Synthesis of Amino Lipid Compound 124

Chemical Structure

[0263] Example 13: Synthesis of Amino Lipid Compound 129

Chemical Structure

[0264] Example 14: Synthesis of Amino Lipid Compound 131

Chemical Structure

[0265] Example 15: Synthesis of Amino Lipid Compound 132

Chemical Structure

[0266] Example 16: Synthesis of amino lipid compound 133

Chemical Structure

[0267] Example 17: Synthesis of amino lipid compound 036 [Chemical formula] According to the general synthesis process, amino lipid compound 036 (1.1 g) was prepared from compound 1522F-4 (3.0 g, 4.07 mmol) and 0.93 g of 130-G as a pale yellow oily substance with a purity of 96.18% and a yield of 30.3%. 1 H NMR (600 MHz, CDCl3) δ 4.95 - 4.85 (m, 2H), 3.73 - 3.63 (m, 1H), 3.48 (t, J = 6.2 Hz, 2H), 3.41 (t, J = 6.7 Hz, 2H), 3.17 - 3.11 (m, 2H), 2.45 (t, J = 7.3 Hz, 1H), 2.41 (t, J = 7.3 Hz, 1H), 2.34 - 2.28 (m, 6H), 2.24 (m, 6H), 2.04 - 1.86 (m, 4H), 1.79 - 1.70 (m, 2H), 1.65 - 1.43 (m, 16H), 1.38 - 1.10 (m, 48H), 0.96 - 0.84 (m, 15H). LC-MS (ESI): (M + H) 893.9.

[0268] Example 18: Synthesis of amino lipid compound 037 [Chemical formula] According to the general synthesis process, amino lipid compound 037 (0.25 g) was prepared from compound 1522F-5 (0.60 g, 0.75 mmol) and 0.27 g of 130-G as a pale yellow oily substance with a purity of 95.17% and a yield of 35.4%. 11H NMR (600 MHz, CDCl3) δ 4.08 (m, 4H), 3.73 - 3.64 (m, 1H), 3.48 (t, J = 6.1 Hz, 2H), 3.42 (t, J = 6.7 Hz, 2H), 3.15 (m, 2H), 2.45 (t, J = 7.3 Hz, 1H), 2.42 (t, J = 7.3 Hz, 1H), 2.36 - 2.28 (m, 4H), 2.25 (m, 6H), 1.98 - 1.87 (m, 4H), 1.78 - 1.71 (m, 2H), 1.66 - 1.55 (m, 10H), 1.52 - 1.42 (m, 6H), 1.39 - 1.20 (m, 56H), 0.94 - 0.84 (m, 15H). LC - MS (ESI): (M + H) 950.0.

[0269] Example 19: Synthesis of Amino Lipid Compound 038

Chem.

[0270] Example 20: Synthesis of Amino Lipid Compound 039

Chem.

[0271] Example 21: Synthesis of amino lipid compound 040

Chemical formula

[0272] Example 22: Synthesis of Amino Lipid Compound 041

Chemical formula

[0273] Example 23: Synthesis of Amino Lipid Compound 042

Chemical formula

[0274] Example 24: Synthesis of amino lipid compound 044

Chemical formula

[0275] Example 25: Synthesis of Amino Lipid Compound 045

Chemical Structure

[0276] Example 26: Synthesis of Amino Lipid Compound 046

Chemical Structure

[0277] Example 27: Synthesis of Amino Lipid Compound 047

Chemical Structure

[0278] Example 28: Synthesis of Amino Lipid Compound 048 [Chemical formula] According to a general process, amino lipid compound 048 (0.276 g) was prepared as a pale yellow oily substance with a purity of 95.01% and a yield of 40.7% from compound 1522F - 15 (0.56 g, 0.76 mmol) and 0.17 g of 130 - G. 1 1H NMR (600 MHz, CDCl3) δ 4.07 (t, J = 6.8 Hz, 4H), 3.71 - 3.62 (m, 1H), 3.48 - 3.46 (t, J = 6.2 Hz, 2H), 3.42 - 3.40 (t, J = 6.7 Hz, 2H), 3.16 - 3.12 (m, 2H), 2.46 - 2.43 (t, J = 7.2 Hz, 1H), 2.42 - 2.40 (t, J = 7.3 Hz, 1H), 2.33 - 2.28 (m, 6H), 2.24 (s, 6H), 2.01 - 1.89 (m, 2H), 1.77 - 1.69 (m, 2H), 1.67 - 1.55 (m, 10H), 1.47 - 1.46 (m, 4H), 1.40 - 1.21 (m, 56H), 0.93 - 0.89 (m, 9H). LC - MS (ESI): (M + H) 893.9.

[0279] Example 29: Synthesis of Amino Lipid Compound 049

Chemical Structure

[0280] Example 30: Synthesis of Amino Lipid Compound 122

Chemical Structure

[0281] Example 31: Synthesis of Amino Lipid Compound 123

Chem.

[0282] Example 32: Synthesis of Amino Lipid Compound 126

Chem.

[0283] Example 33: Synthesis of Amino Lipid Compound 127 [Chemical Formula] According to the general synthesis process, amino lipid compound 127 (0.75 g) was prepared as a pale yellow oil with a purity of 95.58% and a yield of 48% from compound 1522F-1 (1.3 g, 1.64 mmol) and 0.46 g of 127-G. 1 1H NMR in CDCl3 δ 4.88 - 4.84 (m, 2H), 3.75 - 3.72 (m, 2H), 3.62 (m, 1H), 3.44 - 3.40 (m, 2H), 3.14 - 3.09 (m, 2H), 2.61 - 2.59 (m, 2H), 2.30 - 2.24 (m, 6H), 2.21 (s, 6H), 1.70 - 1.25 (m, 80H), 0.88 - 0.86 (m, 15H). LC-MS (ESI): (M + H) 964.4.

[0284] Example 34: Synthesis of Amino Lipid Compound 128 [Chemical Formula] According to the general synthesis process, amino lipid compound 128 (0.76 mg) was prepared as a pale yellow oil with a purity of 94.70% and a yield of 47% from compound 1522F-1 (1.3 g, 1.64 mmol) and 0.49 g of 128-G. 1 1H NMR in CDCl3 δ 4.88 - 4.84 (m, 2H), 3.75 - 3.72 (m, 2H), 3.62 (m, 1H), 3.44 - 3.40 (m, 2H), 3.15 - 3.09 (m, 2H), 2.61 - 2.59 (m, 2H), 2.29 - 2.25 (m, 6H), 2.21 (s, 6H), 1.71 - 1.43 (m, 20H), 1.27 - 1.25 (m, 62H), 0.88 - 0.86 (m, 15H). LC-MS (ESI): (M + H) 978.4.

[0285] Example 35: Synthesis of Amino Lipid Compound 145 [Chemistry] According to the general synthesis process, amino lipid compound 145 (0.24 g) was prepared from compound 1522F-2 (1 g, 1.28 mmol) and 0.28 g of 120-G as a pale yellow oily substance with a purity of 90.77% and a yield of 20%. 1 H NMR (600 MHz, CDCl3) δ 4.89 - 4.82 (m, 2H), 4.12 (d, J = 34.5 Hz, 2H), 3.59 - 3.44 (m, 3H), 3.32 - 3.20 (m, 2H), 2.43 (dd, J = 36.8, 28.9 Hz, 2H), 2.32 (s, 4H), 2.26 (td, J = 7.6, 3.5 Hz, 6H), 1.60 (dd, J = 11.6, 6.9 Hz, 6H), 1.54 - 1.40 (m, 12H), 1.36 - 1.12 (m, 56H), 0.88 (dt, J = 17.2, 7.0 Hz, 15H). LC-MS (ESI): (M + H) 908.3

[0286] Example 36: Synthesis of amino lipid compound 146 [Chemistry] According to the general synthesis process, amino lipid compound 146 (0.55 g) was prepared from compound 1522F-2 (1 g, 1.28 mmol) and 0.31 g of 121-G as a pale yellow oily substance with a purity of 97.28% and a yield of 47%. 1 H NMR (600 MHz, CDCl3) δ 4.86 (p, J = 6.5 Hz, 2H), 4.12 (d, J = 34.8 Hz, 2H), 3.59 - 3.45 (m, 3H), 3.25 (dd, J = 14.6, 5.8 Hz, 2H), 2.52 - 2.37 (m, 2H), 2.33 - 2.22 (m, 10H), 1.65 - 1.55 (m, 6H), 1.55 - 1.39 (m, 12H), 1.38 - 1.14 (m, 58H), 0.91 - 0.83 (m, 15H). LC-MS (ESI): (M + H) 922.3.

[0287] Example 37: Synthesis of Amino Lipid Compound 147

Chem.

[0288] Example 38: Synthesis of Amino Lipid Compound 148

Chem.

[0289] Example 39: Synthesis of Amino Lipid Compound 150

Chemical Structure

[0290] Example 40: Synthesis of Amino Lipid Compound 151

Chemical Structure

[0291] Example 41: Synthesis of Amino Lipid Compound 152

Chemical formula

[0292] Example 42: Synthesis of Amino Lipid Compound 153 [Chemical formula] According to a general synthesis process, amino lipid compound 153 (1.07 g) was prepared as a pale yellow oily substance with a purity of 93.89% and a yield of 58% from compound 152 2F-2 (1.5 g, 1.92 mmol) and 0.58 g of 128-G. 1 H NMR (600 MHz, CDCl3) δ 4.90 - 4.82 (m, 2H), 3.77 - 3.70 (m, 2H), 3.65 - 3.57 (m, 1H), 3.47 - 3.38 (m, 2H), 3.25 (dd, J = 9.5, 5.8 Hz, 2H), 2.59 (dd, J = 9.2, 5.5 Hz, 2H), 2.51 - 2.40 (m, 2H), 2.31 (s, 4H), 2.26 (dt, J = 11.7, 3.6 Hz, 6H), 1.64 - 1.36 (m, 18H), 1.26 (d, J = 12.4 Hz, 62H), 0.87 (t, J = 6.8 Hz, 15H). LC-MS (ESI): (M + H) 964.4.

[0293] Example 43: Synthesis of amino lipid compound 155 [Chemical formula] According to a general synthesis process, amino lipid compound 155 (1.0 g) was prepared as a pale yellow oily substance with a purity of 93.39% and a yield of 64% from compound 152 2F-2 (1.3 g, 1.67 mmol) and 0.44 g of 130-G. 1 H NMR (600 MHz, CDCl3) δ 4.89 - 4.82 (m, 2H), 3.64 (p, J = 6.6 Hz, 1H), 3.43 (q, J = 6.0 Hz, 2H), 3.38 (t, J = 6.7 Hz, 2H), 3.28 - 3.18 (m, 2H), 2.52 - 2.34 (m, 4H), 2.34 - 2.21 (m, 10H), 1.96 - 1.84 (m, 2H), 1.52 (ddt, J = 21.3, 13.8, 6.6 Hz, 18H), 1.35 - 1.07 (m, 56H), 0.87 (dt, J = 7.2, 6.2 Hz, 15H). LC-MS (ESI): (M + H) 936.4.

[0294] Example 44: Synthesis of Amino Lipid Compound 156

Chemical Structure

[0295] Example 45: Synthesis of Amino Lipid Compound 157

Chemical Structure

[0296] Example 46: Synthesis of Amino Lipid Compound 158

Chemical Structure

[0297] Example 47: Synthesis of Amino Lipid Compound 167

Chemical Structure

[0298] Example 48: Synthesis of Amino Lipid Compound 168

Chemical Structure

[0299] Example 49: Synthesis of Amino Lipid Compound 169

Chemical Structure

[0300] Example 50: Synthesis of Amino Lipid Compound 170

Chemical Structure

[0301] Example 51: Synthesis of Amino Lipid Compound 171

Chemical Structure

[0302] Example 52: Synthesis of Amino Lipid Compound 173

Chemical Structure

[0303] Example 53: Synthesis of Amino Lipid Compound 174

Chemical Structure

[0304] Example 54: Synthesis of amino lipid compound 175

Chemical formula

[0305] Example 55: Synthesis of Amino Lipid Compound 177 [Chemical formula] According to the general synthesis process, amino lipid compound 177 (0.6 g) was prepared as a pale yellow oil with a purity of 92.65% and a yield of 39% from compound 1522F-3 (1.3 g, 1.61 mmol) and 0.42 g of 130-G. 1 H NMR (600 MHz, CDCl3) δ 4.94 - 4.80 (m, 2H), 3.69 - 3.56 (m, 1H), 3.48 - 3.41 (m, 2H), 3.41 - 3.35 (m, 2H), 3.07 (t, J = 7.0 Hz, 2H), 2.46 - 2.35 (m, 3H), 2.33 - 2.23 (m, 11H), 1.96 - 1.87 (m, 2H), 1.68 - 1.38 (m, 24H), 1.36 - 1.14 (m, 54H), 0.96 - 0.85 (m, 15H). LC-MS (ESI): (M + H) 964.2.

[0306] Example 56: Synthesis of Amino Lipid Compound 178 [Chemical formula] According to the general synthesis process, amino lipid compound 178 (0.43 g) was prepared as a pale yellow oil with a purity of 94.43% and a yield of 27% from compound 1522F-3 (1.3 g, 1.61 mmol) and 0.42 g of 131-G. 1 H NMR (600 MHz, CDCl3) δ 4.90 - 4.84 (m, 2H), 3.70 - 3.58 (m, 1H), 3.48 - 3.43 (m, 2H), 3.43 - 3.38 (m, 2H), 3.08 (t, J = 7.0 Hz, 2H), 2.46 - 2.35 (m, 3H), 2.33 - 2.23 (m, 11H), 1.96 - 1.85 (m, 2H), 1.66 - 1.39 (m, 24H), 1.36 - 1.10 (m, 56H), 0.92 - 0.83 (m, 15H). LC-MS (ESI): (M + H) 978.2.

[0307] Comparative Example 1: Synthesis of Compound 118 [Chemical Formula] According to the general synthesis process, Compound 118 (0.85 g) was prepared as a colorless oil with a purity of 90.77% and a yield of 57% from 1.3 g of Compound 1522F-1 (1.3 g, 1.64 mmol) and 0.31 g of 118-G. 1 H NMR in (CDCl3) δ 4.86 - 4.85 (m, 2H), 3.62 (m, 1H), 3.11 - 3.09 (m, 2H), 2.30 - 2.26 (m, 8H), 2.22 (s, 6H), 1.70 - 1.44 (m, 20H), 1.25 (m, 60H), 0.88 - 0.86 (m, 15H). LC-MS (ESI): (M + H) 920.5.

[0308] Biological Tests Compounds 118 and 1004 used in the biological tests of the present disclosure have the following structures: [Chemical Formula]

[0309] Compound 118 can be prepared according to the synthesis method of Compound 10 (Example 9) described in Comparative Example 1 or the specification of Chinese Patent No. 107922364A, and Compound 1004 can be prepared according to the synthesis method of Compound 7 (Example 7) in the specification of Chinese Patent No. 114127044A.

[0310] Experimental Example 1: Preparation of Lipid Nanoparticles Encapsulating Luciferase mRNA (Fluc mRNA)

[0311] (1) Formulation: A specified amount of the Fluc mRNA stock solution, 0.2 M sodium acetate buffer, and DEPC water were added to a container and mixed well to obtain an aqueous phase. The amino lipid compound, helper lipid, structural lipid, and PEG-lipid of the present disclosure were separately dissolved in absolute ethanol at concentrations of 20 mg / mL, 10 mg / mL, 20 mg / mL, and 25 mg / mL, respectively, to prepare each solution. The above four solutions were pipetted at a molar ratio of amino lipid compound:DSPC:CHO-HP:PEG2000-DMG of 48:10:40.5:1.5 and mixed well to prepare an alcohol phase.

[0312] (2) Encapsulation: Using a microfluidic preparation device (MPE-L2), it was injected into a microfluidic chip at a flow rate of aqueous phase:alcohol phase = 12 mL / min:4 mL / min, and encapsulation was performed at a flow rate of aqueous phase:alcohol phase = 9 mL / min:3 mL / min to obtain mRNA-encapsulated lipid nanoparticles (mRNA-LNP).

[0313] (3) Dialysis: The product of step (2) was placed in a dialysis bag and put into a Tris buffer-8% sucrose solution for exchange to remove components such as residual ethanol and unorganized lipids. Dialysis was carried out for 2 hours at room temperature while protecting from light and stirring magnetically (the dialysis solution was exchanged every hour).

[0314] (4) The product of step (3) was sterilized by passing through a 0.22 μm microporous membrane and then packaged. A lipid nanoparticle preparation encapsulating Fluc mRNA was prepared at a concentration of 0.2 μg / μL of Fluc mRNA, a mass ratio of Fluc mRNA to lipid of 1:10, a particle size of 80 - 130 nm, and an encapsulation efficiency of 80% or more.

[0315] Experimental Example 2: Performance evaluation of in vivo delivery of lipid nanoparticles Preparation of animals: Female BALB / c mice aged 6 - 8 weeks were selected and bred in an SPF-grade breeding room. Animal tests were strictly carried out in accordance with national medical institution guidelines and animal ethics requirements.

[0316] In vivo delivery: Before injecting the test LNP formulation, the LNP formulation was gently and repeatedly inverted to thoroughly mix the formulation sample. The corresponding amount of the formulation sample was aspirated with a 1 ml insulin syringe, and the LNP formulation was injected by tail vein injection (IV), and two mice were injected in triplicate for each formulation. 75 μL of the luciferase mRNA (Fluc mRNA)-encapsulating lipid nanoparticle formulation prepared in Experimental Example 1 was injected into each mouse.

[0317] Six hours after injection of the LNP formulation, 200 μL of D-luciferin luciferase expression substrate (catalog number 122799, manufacturer, Perkin Elmer) was injected into the mice. After injecting the substrate, the mice were anesthetized by injecting 200 μl of 2.5% avertin, and the injection time of the luciferase expression substrate was recorded. Ten minutes after substrate injection, the animals were placed in the supine position, and the signal distribution and expression intensity of luciferase in the body and organs of the animals were observed using an In Vivo Imaging System (IVIS).

[0318] Table 4 shows the fluorescence expression intensities induced by lipid nanoparticles encapsulating luciferase mRNA (Fluc mRNA) with representative amino lipid compounds, with amino lipid compound 118 as a control.

Table 4

Table 5

[0319] Experimental Example 3: Evaluation of the Delivery Efficiency of Lipid Nanoparticles to Immune Cell Populations in Different Tissues and Organs C57BL / 6 mice (3 mice per group) were intravenously injected with eGFP mRNA encapsulated in LNP. After 6 hours, the mice were sacrificed, and the spleen, axillary lymph nodes, peripheral blood, bone marrow, lungs, and liver were collected to prepare single-cell suspensions of various tissues and organs. After blocking with an Fc blocking antibody and surface staining with a fluorescently labeled antibody, sample analysis was performed by flow cytometry to analyze the expression levels of eGFP in various immune cell populations and confirm the delivery efficiency of lipid nanoparticles containing different amino lipid compounds to immune cell populations in different tissues and organs.

[0320] The test results are shown in FIGS. 1A to 1F. As can be seen from the drawings, lipid nanoparticles containing amino lipid compounds 130, 131, and 133 have an obvious delivery preference for immune cells in various tissues and organs.

[0321] In addition to what is described in this disclosure, various modifications to this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be included within the scope of the appended claims.

Claims

1. An amino lipid compound having the structure of formula (I): 【Chemical 1】 (wherein, Z １ , Z ２ , Z ５ , Z ６ , Z ７ and Z ８ are each independently, -C(=O)-, -CH(OH)-, -C=C-, -C≡C-, -O-, -(C=O)O-, -O(C=O)-, -C(=O)S-, -SC(=O)-, -S-S- or a bond, Z ３ is -C(=O)- or a bond, Z ４ is -O- or -CH(OH)-, A １ 、 A ２ 、 A ３ 、 A ４ 、 A ５ 、 A ６ and A ７ are each independently C １ -C １２ hydrocarbylene, cycloalkyl, phenyl, heterocyclic ring or a bond, R １ and R ２ are each independently H or C １ -C １８ hydrocarbyl or cyclo hydrocarbyl, phenyl, a heterocyclic ring, or R １ and R ２ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring, R ３ is H or C １ -C １８ is hydrocarbyl or cyclo hydrocarbyl, phenyl, or heterocycle R ４ and R ５ are each independently C １ -C ２４ hydrocarbyl or cyclo hydrocarbyl, phenyl, heterocyclic ring, Preferably, A ５ , Z ５ and Z ６ are bonds.) or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A １ and A ２ each independently is C １ -C ８ hydrocarbylene or a bond, for example C １ -C ６ hydrocarbylene or a bond, or C １ -C ４ hydrocarbylene or a bond, and Preferably, A １ and A ２ are each independently C １ -C ８ alkylene, C ２ -C ８ alkenylene or C ２ -C ８ alkynylene, and Preferably, A １ and A ２ are each independently C １ -C ８ alkylene, for example C １ -C ６ alkylene, C １ -C ４ alkylene, C ２ -C ４ alkylene or C １ -C ３ alkylene, and Preferably, A １ and A ２ are both bonds, and / or Said A ３ is C １ -C １２ a hydrocarbylene or a bond, Preferably, A ３ is a linear C １ -C １２ hydrocarbylene, Preferably, A ３ is linear C １ -C １２ alkylene, C ２ -C １２ alkenylene or C ２ -C １２ alkynylene, and Preferably, said A ３ is linear C １ -C ５ alkylene, for example linear C １ , C ２ , C ３ , C ４ or C ５ alkylene, and Preferably, said A ３ is -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, or -CH ２ CH ２ CH ２ CH ２ -. and / or A ４ is C １ -C １２ hydrocarbylene or a bond, and Preferably, A ４ is a linear C １ -C １２ hydrocarbylene, Preferably, A ４ is a linear C １ -C １２ alkylene, C ２ -C １２ alkenylene or C ２ -C １２ alkynylene, and Preferably, A ４ is a linear C １ -C ７ alkylene, for example linear C １ , C ２ , C ３ , C ４ , C ５ , C ６ or C ７ alkylene, and Preferably, A ４ is a linear C １ -C ３ alkylene, for example linear C １ , C ２ or C ３ alkylene, and Preferably, A ４ is -CH ２ -, -CH ２ CH ２ - or -CH ２ CH ２ CH ２ -, and and / or A ５ is C １ -C ８ hydrocarbylene or bond, for example C １ -C ６ hydrocarbylene or bond, C １ -C ４ hydrocarbylene or bond, or C １ -C ３ hydrocarbylene or bond, and Preferably, A ５ is C １ -C ８ alkylene, C ２ -C ８ alkenylene or C ２ -C ８ alkynylene, and Preferably, A ５ is C １ -C ８ alkylene, for example C １ -C ８ alkylene, C １ -C ６ alkylene, C １ -C ４ alkylene, C ２ -C ４ alkylene or C １ -C ３ alkylene, and Preferably, A ５ is a bond, and / or A ６ and A ７ are each independently a C １ -C １２ hydrocarbylene, Preferably, A ６ and A ７ are each independently a linear C １ -C １２ hydrocarbylene, Preferably, A ６ and A ７ are each independently a linear C １ -C １２ alkylene, C ２ -C １２ alkenylene or C ２ -C １２ alkynylene, and Preferably, A ６ and A ７ are each independently a linear C １ -C １２ alkylene, for example linear C ２ -C １２ alkylene, C ４ -C １０ alkylene, C ６ -C ８ alkylene, C ６ -C １０ alkylene or C ４ -C ８ alkylene, and Preferably, A ６ and A ７ are each independently a linear C ６ -C １０ alkylene, for example linear C ６ , C ７ , C ８ , C ９ or C １０ alkylene, and Preferably, A ６ and A ７ are each independently, -(CH ２ ), ６ -(CH ２ ), ７ -(CH ２ ), ８ - or -(CH ２ ), ９ - and and / or R １ and R ２ are each independently H, C １ -C １８ hydrocarbyl, e.g., C １ -C １６ hydrocarbyl, C １ -C １２ hydrocarbyl, C １ -C １０ hydrocarbyl, C １ -C ８ hydrocarbyl, C １ -C ６ hydrocarbyl or C １ -C ４ hydrocarbyl, C ３ -C ７ cyclohydrocarbyl, e.g., C ３ -C ６ cyclohydrocarbyl or C ５ -C ６ cyclohydrocarbyl, phenyl, or a 3- to 7-membered heterocyclic ring, e.g., a 4- to 6-membered heterocyclic ring, or R １ and R ２ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring, e.g., a 5- to 6-membered heterocyclic ring, Preferably, R １ and R ２ are each independently H, C １ -C １８ alkylene, C ２ -C １８ alkenylene or C ２ -C １８ alkynylene, and Preferably, R １ and R ２ are each independently C １ -C １８ alkyl, such as C １ -C ４ alkyl, C ３ -C ６ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic ring, or R １ and R ２ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring such as pyrrolidine, piperidine, piperazine or morpholine, Preferably, R １ and R ２ are each independently C １ -C ４ alkyl, such as C １ , C ２ , C ３ or C ４ alkyl, and Preferably, R １ and R ２ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, Preferably, R １ and R ２ are each independently C １ -C ３ alkyl, for example C １ , C ２ or C ３ alkyl, and Preferably, R １ and R ２ are each independently methyl, ethyl or n-propyl, and / or R ３ is H, C １ -C １８ hydrocarbyl, e.g., C １ -C １６ hydrocarbyl, C ２ -C １２ hydrocarbyl, C ４ -C １０ hydrocarbyl or C ４ -C ８ hydrocarbyl, C ３ -C ７ cyclohydrocarbyl, e.g., C ３ -C ６ cyclohydrocarbyl or C ５ -C ６ cyclohydrocarbyl, phenyl, or a 3- to 7-membered heterocyclic ring, e.g., a 4- to 6-membered heterocyclic ring, and Preferably, R ３ is C １ -C １８ alkyl, C ２ -C １８ alkenyl or C ２ -C １８ alkynyl, and Preferably, R ３ is C １ -C １８ alkyl, such as C ２ -C １０ alkyl, C ４ -C ８ alkyl, C ３ -C ６ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic ring, Preferably, R ３ is a linear C ４ -C ８ alkyl, for example linear C ４ , C ５ , C ６ , C ７ or C ８ alkyl, and Preferably, R ３ is n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl, and and / or Z １ , Z ２ , Z ５ and Z ６ each independently represents -C(=O)-, -O(C=O)-, -O- or a bond, Preferably, Z １ , Z ２ , Z ５ and Z ６ are each independently a bond, and / or Z ３ is -C(=O)-, and / or Z ４ is -O-, or Z ４ is -CH(OH)-, and / or Z ７ and Z ８ is each independently, —(C═O)O—, —O(C═O)— or a bond, the amino lipid compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. Z ７ or Z ８ The amino lipid compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein one of them is -(C=O)O-, -O(C=O)- or a bond.

4. Z ７ and Z ８ each of which is —(C=O)O—, Preferably, Z ７ in which (C=O) is bonded to A ６ , and Z ８ in which (C=O) is bonded to A ７ , the amino lipid compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

5. Z ７ and Z ８ each of which is -(C=O)-, Preferably, (C=O) in Z ７ is bonded to R ４ , and (C=O) in Z ８ is bonded to R ５ . The amino lipid compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. Z ７ or Z ８ one of which is a bond, Preferably, Z ７ is a bond, and Z ８ is -(C=O)O-, and preferably, the (C=O) in Z ８ is bonded to the A ７ or Z ７ is a bond, and Z ８ is -O(C=O)-, and preferably, (C=O) in Z ８ is bonded to the said R ５ or Z ８ is a bond, and Z ７ is -(C=O)O-, and preferably, the (C=O) in Z ７ is bonded to the said A ６ or Z ８ is a bond, and Z ７ is -O(C=O)-, and preferably, the (C=O) in Z ７ is bonded to R ４ The amino lipid compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

7. Z ７ and Z ８ The amino lipid compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of them is a bond.

8. R ４ and R ５ are each independently C １ -C ２０ hydrocarbyl, C ３ -C ７ cyclohydrocarbyl, e.g., C ３ -C ６ cyclohydrocarbyl or C ５ -C ６ cyclohydrocarbyl, phenyl, or a 3- to 7-membered heterocyclic ring, e.g., a 4- to 6-membered heterocyclic ring, Preferably, R ４ and R ５ are each independently C １ -C ２０ hydrocarbyl, C ３ -C ６ cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, phenyl, or a 5- to 6-membered heterocyclic ring, Preferably, R ４ and R ５ are each independently C １ -C ２０ hydrocarbyl, the amino lipid compound according to any one of claims 1 to 7.

9. R ４ and R ５ are each independently C １ -C ２０ alkyl, the amino lipid compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. R ４ and R ５ are each independently a branched C ３ -C ２０ alkyl, Preferably, R ４ and R ５ are each independently a branched C ５ -C ２０ alkyl, a branched C ７ -C １９ alkyl, a branched C ９ -C １８ alkyl, a branched C １０ -C １８ alkyl, a branched C ３ -C １０ alkyl, a branched C １１ -C １７ alkyl or a branched C １８ -C ２０ alkyl, and Preferably, R ４ and R ５ are each independently a branched C １１ -C １７ alkyl, for example a branched C １１ , C １２ , C １３ , C １４ , C １５ , C １６ or C １７ alkyl, and Preferably, R ４ and R ５ are each independently a branched C １１ -C １３ alkyl, for example branched C １１ , C １２ or C １３ alkyl, and Preferably, R ４ is a branched alkyl group in which the branching occurs at the α, β or γ position relative to Z ７ and R ５ is a branched alkyl group in which the branching occurs at the α, β or γ position relative to Z ８ and Preferably, R ４ is a branched alkyl group in which the branching occurs at the α or β position relative to Z ７ and R ５ is a branched alkyl group in which the branching occurs at the α or β position relative to Z ８ and Preferably, R ４ and R ５ are each independently one of the following structures, the amino lipid compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Chemical Formula 2】

11. R ４ and R ５ each independently is one of the following structures, the amino lipid compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Chemical Formula 3】

12. R ４ and R ５ are each independently 【Chemical Formula 4】 or 【Chemical Formula 5】 is, the amino lipid compound according to any one of Claims 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

13. Z ３ is -C(=O)-, A ４ is C １ -C １２ is alkylene, Preferably, A ４ is a linear C １ -C １２ alkylene, for example linear C １ -C １０ alkylene, C １ -C ８ alkylene, C １ -C ６ alkylene, C １ -C ４ alkylene, or C １ -C ３ alkylene, and Preferably, A ４ is a linear C １ -C ４ alkylene, for example, linear C １ , C ２ , C ３ or C ４ alkylene, and Preferably, A ４ is -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, or -CH ２ CH ２ CH ２ CH ２ -, and and / or Z ４ is -O-, or Z ４ is -CH(OH)-, the amino lipid compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. An amino lipid compound according to any one of Claims 1 to 13, having the structure of formula (II) or formula (III): [Chemical Formula 6] (wherein, Z ７ and Z ８ are each independently —C(=O)—, —CH(OH)—, —C═C—, —C≡C—, —O—, —(C=O)O—, —O(C=O)—, —C(=O)S—, —SC(=O)—, —S—S—, or a bond, A ３ 、 A ４ 、 A ６ and A ７ are each independently, C １ -C １２ hydrocarbylene, cycloalkyl, phenyl, heterocyclic ring or a bond, R １ and R ２ are each independently H or C １ -C １８ hydrocarbyl or cyclo hydrocarbyl, phenyl, a heterocyclic ring, or R １ and R ２ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring, R ３ is H or C １ -C １８ is hydrocarbyl, or cyclo-hydrocarbyl, phenyl, or heterocyclic ring, R ４ and R ５ are each independently C １ -C ２４ hydrocarbyl or cyclo hydrocarbyl, phenyl, a heterocyclic ring.) or a pharmaceutically acceptable salt or stereoisomer thereof.

15. Z ７ and Z ８ are each independently —(C═O)O— or —O(C═O)—, Preferably, Z ７ and Z ８ each is —(C═O)O—, and preferably, (C═O) in Z ７ is bonded to A ６ , and (C═O) in Z ８ is bonded to A ７ ​ or Z ７ and Z ８ each of which is —O(C═O)—, and preferably, (C═O) in Z ７ is bonded to R ４ , and (C═O) in Z ８ is bonded to R ５ The amino lipid compound according to claim 14, or a pharmaceutically acceptable salt or stereoisomer thereof.

16. A ３ 、 A ４ 、 A ６ and A ７ are each independently C １ -C １２ alkylene, Preferably, A ３ , A ４ , A ６ and A ７ are each independently C １ , C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , C １０ , C １１ or C １２ is alkylene, Preferably, A ３ is a linear C １ , C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , C １０ , C １１ or C １２ alkylene, Preferably, A ３ is a linear C １ , C ２ , C ３ , C ４ or C ５ alkylene, and Preferably, A ３ is a linear C ２ , C ３ or C ４ alkylene, for example -CH ２ CH ２ -, -CH ２ CH ２ CH ２ - or -CH ２ CH ２ CH ２ CH ２ -, and and / or Preferably, A ４ is linear C １ , C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , C １０ , C １１ or C １２ is alkylene, Preferably, A ４ is a linear C １ , C ２ , C ３ or C ４ alkylene, for example -CH ２ -, -CH ２ CH ２ - or -CH ２ CH ２ CH ２ -, and and / or Preferably, A ６ and A ７ are each independently a linear C １ C ２ C ３ C ４ C ５ C ６ C ７ C ８ C ９ C １０ C １１ or C １２ alkylene, Preferably, A ６ and A ７ are each independently a linear C ６ , C ７ , C ８ , C ９ or C １０ alkylene, for example -(CH ２ ) ６ -, -(CH ２ ) ７ -, -(CH ２ ) ８ - or -(CH ２ ) ９ -, the amino lipid compound according to any one of claims 14 or 15, or a pharmaceutically acceptable salt or stereoisomer thereof.

17. R １ and R ２ are each independently C １ -C １８ alkyl, Preferably, R １ and R ２ are each independently C １ -C ６ alkyl, Preferably, R １ and R ２ are each independently methyl, ethyl, n-propyl or isopropyl, Preferably, R １ and R ２ are each independently C １ -C ４ alkyl, for example C １ , C ２ , C ３ or C ４ alkyl, and Preferably, R １ and R ２ are each independently methyl, or R １ and R ２ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring, Preferably, R １ and R ２ together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic ring, the amino lipid compound according to any one of claims 14 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. R ３ is C １ -C １８ alkyl, Preferably, R ３ is C １ , C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , C １０ , C １１ or C １２ is alkyl, Preferably, R ３ is a linear C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ or C １０ alkyl, and Preferably, R ３ is a linear C ４ , C ５ , C ６ , C ７ or C ８ alkyl, for example n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl, the amino lipid compound according to any one of claims 14 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. R ４ and R ５ each independently is C １ -C ２０ hydrocarbyl, Preferably, R ４ and R ５ are each independently C １ -C ２０ alkyl, Preferably, R ４ and R ５ are each independently a branched C ３ -C ２０ alkyl, Preferably, R ４ and R ５ are each independently a branched C ５ -C ２０ alkyl, a branched C ７ -C １９ alkyl, a branched C ９ -C １８ alkyl, a branched C １０ -C １８ alkyl, a branched C ３ -C １０ alkyl, a branched C １１ -C １７ alkyl or a branched C １８ -C ２０ alkyl, and Preferably, R ４ and R ５ are each independently a branched C １１ -C １７ alkyl, for example branched C １１ , C １２ , C １３ , C １４ , C １５ , C １６ or C １７ alkyl, and Preferably, R ４ and R ５ are each independently a branched C １１ -C １３ alkyl, for example a branched C １１ , C １２ or C １３ alkyl, and Preferably, R ４ is a branched alkyl group in which the branch occurs at the α, β or γ position relative to Z ７ and R ５ is a branched alkyl group in which the branch occurs at the α, β or γ position relative to Z ８ and Preferably, R ４ is a branched alkyl group in which the branching occurs at the α or β position relative to Z ７ and R ５ is a branched alkyl group in which the branching occurs at the α or β position relative to said Z ８ and Preferably, R ４ and R ５ each independently is one of the following structures, the amino lipid compound according to any one of claims 14 to 18, or a pharmaceutically acceptable salt or stereoisomer thereof. [Chemical Formula 7]

20. R ４ and R ５ each independently is one of the following structures, the amino lipid compound according to any one of claims 14 to 19, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. [Chemical Formula 8]

21. R ４ and R ５ are each independently 【Chemical Formula 9】 or 【Chemical 10】 is, the amino lipid compound according to any one of Claims 14 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof.

22. Z ７ and Z ８ are each independently —(C=O)O— or —O(C=O)—, A ３ is a linear C １ -C ５ alkylene, and A ４ is a linear C １ -C ４ alkylene, and A ６ and A ７ are each independently C ５ -C １１ alkylene, R １ and R ２ are each independently C １ -C ４ alkyl, R ３ is a linear C ２ -C １０ alkyl, R ４ and R ５ are each independently C １ -C ２４ alkyl, the amino lipid compound according to any one of claims 14 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof.

23. Z ７ and Z ８ each is -(C=O)O-, and the (C=O) in Z ７ is bonded to A ６ and the (C=O) in Z ８ is bonded to A ７ or each of Z ７ and Z ８ is -O(C=O)-, and the (C=O) in Z ７ is bonded to R ４ and the (C=O) in Z ８ is bonded to R ５ and and / or A ３ is a linear C １ -C ４ alkylene, and Preferably, A ３ is a linear C ２ -C ４ alkylene, for example linear C ２ , C ３ or C ４ alkylene, and Preferably, A ３ is -CH ２ CH ２ -, -CH ２ CH ２ CH ２ - or -CH ２ CH ２ CH ２ CH ２ -, and and / or A ４ is a linear C １ -C ３ alkylene, for example linear C １ , C ２ or C ３ alkylene, and Preferably, A ４ is -CH ２ -, -CH ２ CH ２ - or -CH ２ CH ２ CH ２ -, and and / or Preferably, A ６ and A ７ are each independently a linear C ５ -C １１ alkylene, Preferably, A ６ and A ７ are each independently a linear C ６ -C １０ alkylene, for example linear C ６ , C ７ , C ８ , C ９ or C １０ alkylene, and Preferably, A ６ and A ７ are each independently a linear C ７ C ８ or C ９ alkylene, for example -(CH ２ ) ７ -, -(CH ２ ) ８ - or -(CH ２ ) ９ -, and and / or R １ and R ２ are each independently C １ C ２ C ３ or C ４ alkyl, Preferably, R １ and R ２ are each independently methyl, ethyl, n-propyl or isopropyl, Preferably, R １ and R ２ are each independently methyl, and / or R ３ is a linear C ４ -C ８ alkyl, for example C ４ , C ５ , C ６ , C ７ or C ８ alkyl, and Preferably, R ３ is n-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl, and and / or R ４ and R ５ are each independently a branched C ３ -C ２０ alkyl, for example a branched C ５ -C ２０ alkyl, a branched C ７ -C １９ alkyl, a branched C ９ -C １８ alkyl, a branched C １０ -C １８ alkyl, a branched C ３ -C １０ alkyl, a branched C １１ -C １７ alkyl or a branched C １８ -C ２０ alkyl, and Preferably, R ４ and R ５ are each independently a branched C １１ -C １７ alkyl, for example branched C １１ , C １２ , C １３ , C １４ , C １５ , C １６ or C １７ alkyl, and Preferably, R ４ and R ５ are each independently a branched C １１ -C １３ alkyl, for example a branched C １１ , C １２ or C １３ alkyl, and Preferably, R ４ is a branched C ７ -C ３ alkyl group that occurs at the α, β, or γ position relative to Z ２０ and R ５ is a branched C ８ -C ３ alkyl group that occurs at the α, β, or γ position relative to Z ２０ and Preferably, R ４ is a branched C ７ -C ３ -C ２０ alkyl group that occurs at the α or β position relative to Z ５ is a branched C ８ -C ３ -C ２０ alkyl group that occurs at the α or β position relative to Z, and Preferably, R ４ and R ５ are each independently one of the following structures, 【Chemical Formula 11】 Preferably, R ４ and R ５ are each independently one of the following structures, 【Chemical Formula 12】 Preferably, R ４ and R ５ are each independently 【Chemical 13】 or 【Chemical 14】 is, the amino lipid compound according to Claim 22, or a pharmaceutically acceptable salt or stereoisomer thereof.

24. The amino lipid compound according to any one of Claims 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the amino lipid compound has one of the following structures. 【Table 1】

25. Lipid nanoparticles comprising the amino lipid compound according to any one of Claims 1 to 24.

26. The lipid nanoparticles further comprise one or more of helper lipid, structural lipid and PEG-lipid, Furthermore, the lipid nanoparticles according to Claim 25, wherein the lipid nanoparticles further comprise the helper lipid, the structural lipid and the PEG-lipid.

27. The lipid nanoparticles are based on the total amount of the amino lipid compound according to any one of Claims 1 to 24, the helper lipid, the structural lipid and the PEG-lipid, in an amount (mole percent) of about 25.0% to 75.0%, such as about 25.0% to 28.0%, 28.0% to 32.0%, 32.0% to 35.0%, 35.0% to 40.0%, 40.0% to 42.0%, 42.0% to 45.0%, 45.0% to 48.0%, 48.0% to 55.0%, 55.0% to 65.0%, 65.0% to 75.0%, 45.0% to 46.3%, 46.3% to 48.0%, 48.0% to 49.5%, 49.5% to 50.0%, 50.0% to 55.0% or 60.0% to 65.0% of the amino lipid compound according to any one of claims 1 to 24, and / or in an amount (mole percent) of about 5.0% to 45.0%, such as about 5.0% to 10.0%, 10.0% to 16.0%, 16.0% to 25.0%, 25.0% to 33.5%, 33.5% to 37.0%, 37.0% to 40.0%, 40.0% to 42.0%, 42.0% to 45.0%, 5.0% to 9.0%, 9.0% to 9.4%, 9.4% to 10.0%, 10.0% to 10.5%, 10.5% to 11.0%, 11.0% to 15.0%, 15.0% to 16.0%, 16.0% to 18.0%, 18.0% to 20.0% or 20.0% to 25.0% of the helper lipid, and / or in an amount (mole percent) of about 0.0% to 50.0%, such as about 0.0% to 10.0%, 10.0% to 15.5%, 15.5% to 22.5%, 22.5% to 35.0%, 35.0% to 36.5%, 36.5% to 39.5%, 39.5% to 40.5%, 40.5% to 41.5%, 41.5% to 45.0%, 45.0% to 46.5%, 46.5% to 50.0%, 15.5% to 18.5%, 18.5% to 22.5%, 22.5% to 23.5%, 23.5% to 28.5%, 28.5% to 33.5%, 33.5% to 35.0%, 36.5% to 38.0%, 38.0% to 38.5%, 38.5% to 39.0%, 39.0% to 39.5%, 41.5% to 42.5%, 42.5% to 42.7%, 42.7% to 43.0%, 43.0% to 43.5%, 43.5% to 45.0% or 46.5% to 48.5%, or in an amount (mole percent) of about 50.0% to 55.0%, such as about 50.0% to 51.5%, 51.5% to 53.5% or 53.5% to 55.0% of the structural lipid, and / or The lipid nanoparticles according to claim 26, comprising the PEG-lipid in an amount (mole percent) of about 0.5% to 5.0%, such as about 0.5% to 1.0%, 1.0% to 1.5%, 1.5% to 2.0%, 2.0% to 2.5%, 2.5% to 3.0%, 3.0% to 3.5%, 3.5% to 4.0%, 4.0% to 4.5%, 4.5% to 5.0%, 1.5% to 1.6% or 1.6% to 2.0%.

28. The helper lipid is a phospholipid, preferably, the helper lipid is one or more selected from the group consisting of DSPC, DOPE, DOPC, DOPS, DSPG, DPPG, DPPC, DGTS and lysophospholipids, preferably, the helper lipid is one or more selected from the group consisting of DSPC, DOPE, DOPC and DOPS, preferably, the helper lipid is DSPC and / or DOPE, and / or the structural lipid is a sterol, preferably, the structural lipid is at least one selected from the group consisting of cholesterol, cholesterol ester, steroid hormone, steroid vitamin, bile acid, cholesterin, ergosterol, β-sitosterol and oxidized cholesterol derivative, preferably, the structural lipid is at least one selected from the group consisting of cholesterol, cholesteryl ester, sterol hormone, sterol vitamin and bile acid, preferably, the structural lipid is cholesterol, more preferably high-purity cholesterol, especially injection-grade high-purity cholesterol such as CHO-HP, and / or the PEG-lipid is a conjugate of polyethylene glycol and a lipid structure, preferably, the PEG-lipid is selected from the group consisting of PEG-DMG and PEG-DSPE, preferably PEG-DMG, preferably, the PEG-DMG is a polyethylene glycol (PEG) derivative of 1,2-dimyristoyl-sn-glycerol, preferably, the PEG has an average molecular weight of about 2,000 to 5,000, preferably about 2,000, such as PEG2000-DMG, the lipid nanoparticles according to claim 26 or 27.

29. The amino lipid compound according to any one of claims 1 to 24: wherein the molar ratio of the helper lipid: the structural lipid: the PEG-lipid is about 45:11:41.5:2.5, or 42.0:10.5:45.0:2.5, or 42.0:16.0:39.5:2.5, or 40.0:16.0:41.5:2.5, or 40.0:18.0:39.5:2.5, or 35.0:16.0:46.5:2.5, or 35.0:25.0:36.5:3.5, or 28.0:33.5:35.0:3.5, or 32.0:37.0:40.5:0.5, or 35.0:40.0:22.5:2.5, or 40.0:42.0:15.5:2.5, or 45:10:42.5:2.5, or 40.0:20.0:38.5:1.5, or 45.0:15.0:38.5:1.5, or 55.0:5.0:38.5:1.5, or 60.0:5.0:33.5:1.5, or 45.0:20.0:33.5:1.5, or 50.0:20.0:28.5:1.5, or 55.0:20.0:23.5:1.5, or 60.0:20.0:18.5:1.5, or 40.0:15.0:43.5:1.5, or 50.0:15.0:33.5:1.5, or 55.0:15.0:28.5:1.5, or 60.0:15.0:23.5:1.5, or 40.0:10.0:48.5:1.5, or 45.0:10.0:43.5:1.5, or 55.0:10.0:33.5:1.5, or 40.0:5.0:53.5:1.5, or 45.0:5.0:48.5:1.5, or 50.0:5.0:43.5:1.5; Preferably, the helper lipid is DOPE and the structural lipid is CHO-HP. The lipid nanoparticles according to any one of claims 26 to 28.

30. The amino lipid compound according to any one of claims 1 to 24: the molar ratio of the helper lipid: the structural lipid: the PEG-lipid is about 48.0:10.0:40.5:1.5, or 50.0:10.0:38.5:1.5, or 50.0:9.0:38.0:3.0, or 49.5:10.0:39.0:1.5, or 46.3:9.4:42.7:1.6, or 45.0:9.0:43.0:3.0, or 45.0:11.0:41.5:2.5, or 42.0:10.5:45.0:2.5, or 42.0:16.0:39.5:2.5, or 40.0:16.0:41.5:2.5, or 40.0:18.0:39.5:2.5, or 35.0:40.0:22.5:2.5, or 40.0:20.0:38.5:1.5, or 45.0:15.0:38.5:1.5, or 55.0:5.0:38.5:1.5, or 60.0:5.0:33.5:1.5, or 45.0:20.0:33.5:1.5, or 50.0:20.0:28.5:1.5, or 55.0:20.0:23.5:1.5, or 60.0:20.0:18.5:1.5, or 40.0:15.0:43.5:1.5, or 50.0:15.0:33.5:1.5, or 55.0:15.0:28.5:1.5, or 60.0:15.0:23.5:1.5, or 40.0:10.0:48.5:1.5, or 45.0:10.0:43.5:1.5, or 55.0:10.0:33.5:1.5, or 40.0:5.0:53.5:1.5, or 45.0:5.0:48.5:1.5, or 50.0:5.0:43.5:1.5, and Preferably, the helper lipid is DSPC and the structural lipid is CHO-HP. The lipid nanoparticles according to any one of claims 26 to 28.

31. Further comprising a nucleic acid, Preferably, the mass ratio of the amino lipid compound according to any one of claims 1 to 24 to the nucleic acid is about (5 to 30):1, for example about (5 to 10):1, (10 to 15):1, (15 to 20):1, (20 to 25):1 or (25 to 30):1, preferably about 10:1, and / or Preferably, the nucleic acid is selected from the group consisting of RNA, antisense oligonucleotide and DNA. Preferably, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA), small nuclear RNA (snRNA), small hairpin RNA (shRNA), single guide RNA (sgRNA), Cas9 mRNA, or a mixture thereof, and / or Preferably, the DNA is a plasmid, the lipid nanoparticle according to any one of claims 25 to 30.

32. An amino lipid compound according to any one of claims 1 to 24 or a lipid nanoparticle according to any one of claims 25 to 31, and a pharmaceutically acceptable carrier, diluent or excipient.

33. The composition further comprises a buffer solution, Preferably, the buffer solution is selected from phosphate buffer solution and Tris buffer solution, preferably phosphate buffer solution, and / or Preferably, the buffer solution has a concentration of about 5 mmol / L to about 30 mmol / L, preferably about 10 mmol / L, and / or Preferably, the buffer solution has a pH of about 6 to 8, preferably about 7 to 8, more preferably about 7 to 7.5, and / or The composition further comprises a cryoprotectant, Preferably, the cryoprotectant is selected from sucrose and trehalose, preferably sucrose, and / or Preferably, the cryoprotectant has a concentration of about 50 mg / ml to 100 mg / ml, the composition according to claim 32.

34. The composition according to claim 32 or 33, which is a pharmaceutical composition.

35. Preferably, the vehicle is a lipid nanoparticle according to any one of claims 25 to 31, and / or the active ingredient is a pharmaceutical active ingredient, preferably a nucleic acid, and / or Preferably, the nucleic acid is selected from the group consisting of RNA, antisense oligonucleotide and DNA, Preferably, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA) and small nuclear RNA (snRNA), and / or Use of a compound according to any one of claims 1 to 24 in the manufacture of a vehicle for an active ingredient, preferably wherein the DNA is a plasmid.

36. Preferably, the pharmaceutical is for use in gene therapy, gene vaccination or protein replacement therapy, antisense therapy, or therapy with interfering RNA, more preferably, the gene therapy is for use in the treatment of cancer and genetic diseases, the cancer is preferably one or more selected from the group consisting of lung cancer, gastric cancer, liver cancer, esophageal cancer, colon cancer, pancreatic cancer, brain cancer, lymphoma, blood cancer and prostate cancer, and / or the genetic disease is preferably one or more selected from the group consisting of hemophilia, thalassemia and Gaucher's disease, and / or the gene vaccination is for use in the treatment of cancer, allergy, toxicity and pathogen infection, the pathogen is preferably one or more selected from the group consisting of virus, bacterium or fungus, use of a compound according to any one of claims 1 to 24, a lipid nanoparticle according to any one of claims 25 to 31 or a composition according to any one of claims 32 to 34 in the manufacture of the pharmaceutical.

37. Preferably, the nucleic acid is selected from the group consisting of RNA, antisense oligonucleotide and DNA, preferably, the RNA is selected from the group consisting of messenger RNA (mRNA), ribosomal RNA (rRNA), microRNA (miRNA), transfer RNA (tRNA), small interfering RNA (siRNA) and small nuclear RNA (snRNA), and / or preferably, the DNA is a plasmid, use of a compound according to any one of claims 1 to 24, a lipid nanoparticle according to any one of claims 25 to 31 or a composition according to any one of claims 32 to 34 in the manufacture of a pharmaceutical for nucleic acid transfer.

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