Lipid Nanoparticles

Abstract

To provide a lipid nanoparticle of which lipid ingredient comprises a new class of an ionizable cationic lipid compound, a method of preparing the lipid nanoparticle, a pharmaceutical composition of the lipid nanoparticle, and the use of the lipid nanoparticle or pharmaceutical composition in the delivery of a biologically active substance such as nucleic acid.SOLUTION: The disclosure provides a nanoparticle composition comprising a lipid ingredient, and optionally a load; where the lipid ingredient comprises the following components in the molar percentages: ionizable cationic lipids 20 mol% to 85 mol%; structure lipids 10 mol% to 75 mol%; neutral lipids 1.0 mol% to 30 mol%; polymer lipids 0.25 mol% to 10 mol%, where the ionizable cationic lipid is a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, or tautomer thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Chinese Patent Application No. 202210478559.X filed on April 29, 2022, Chinese Patent Application No. 202210478132.X filed on April 29, 2022, Chinese Patent Application No. 202211319726.2 filed on October 26, 2022, and Chinese Patent Application No. 202211419648.3 filed on November 14, 2022. The above Chinese patent applications are incorporated herein by reference as part of the disclosure of this application.

[0002] The present disclosure relates to novel lipid nanoparticles, the lipid component of which comprises a novel class of ionizable cationic lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. The present disclosure also relates to methods for preparing lipid nanoparticles, pharmaceutical compositions comprising lipid nanoparticles, and the use of lipid nanoparticles or pharmaceutical compositions in the delivery of biologically active substances, such as nucleic acids (e.g., mRNA, miRNA, siRNA, saRNA, ASO, and DNA). [Background technology]

[0003] Gene therapy refers to the introduction of exogenous genes into target cells to correct or correct genetic defects or intracellular abnormalities, so as to achieve the purpose of treatment.In the past few decades, the research related to the treatment of clinical diseases through gene therapy has been increasingly focused.In particular, in recent years, siRNA-related drugs and mRNA vaccines have been approved by the FDA for clinical treatment, which further promotes research and related investment in the field of gene therapy.

[0004] Due to their unique properties, nucleic acid drugs can act on non-druggable targets that are difficult for traditional small molecule chemical drugs, proteins, or antibodies to act on, and have significant application value in the treatment or prevention of diseases such as tumors, infectious diseases, and genetic diseases.

[0005] However, nucleic acid substances are easily degraded by nucleases in living organisms, and because nucleic acid substances themselves are negatively charged, they have difficulty penetrating cell membranes into cells. Therefore, delivery technology is a major challenge in the development of nucleic acid drugs.

[0006] Lipid nanoparticles (LNPs) are one of the most important nucleic acid delivery systems, boasting advantages such as ease of preparation, good biodegradability, non-immunogenicity, and favorable safety. The nucleic acid vaccines developed by Moderna and BioNTech use LNPs as the delivery system, and the main components of LNPs include cationic lipids, cholesterol, neutral lipids, and polyethylene glycol-conjugated lipids. Among these, cationic lipid molecules are the core of the LNP delivery system, and their molecular structure plays a crucial role in the overall delivery efficiency, targeting, and formulation stability of liposomal nanoparticles. Summary of the Invention [Problem to be solved by the invention]

[0007] Due to the different requirements of delivery systems for the delivery of different types of nucleic acid substances and the specific delivery of different targets, further development of new lipid molecules and continuous improvement of LNP technology are needed to obtain new LNP formulations with good nucleic acid delivery efficiency to meet the different needs of gene therapy. [Means for solving the problem]

[0008] The present disclosure develops a new class of lipid nanoparticles that can be used to deliver a variety of bioactive agents with high delivery efficiency.

[0009] In one aspect, the present disclosure provides a nanoparticle composition comprising a lipid component and optionally a load, comprising: The lipid components consist of the following components in mole percentage: ionizable cationic lipids 20 mol% to 85 mol%; structural lipids 10 mol% to 75 mol%; Neutral lipids 1.0mol%~30mol%; Polymer lipids 0.25 mol% to 10 mol% Includes; The ionizable cationic lipid is a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0010] [ka] (In the formula, M1 and M2 are -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS- and -S(O) 0~2 - independently selected from; Q is a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR bC(S)O-, -SS-, -S(O) 0~2 -, phenylene, and pyridylidene, wherein phenylene or pyridylidene is selected from one or more R * optionally substituted with; G5 is a chemical bond or one or more R ** optionally substituted with C 1~8 is alkylene; G 6a and G 6b are independently a chemical bond or one or more R ** optionally substituted with C 1~7 is alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R9, R 10 and R ** are independently H, C 1~8 Alkyl, -L c -OR c , -L c -SR c or -L c -NR c R' c and; G1, G2, G3 and G4 are independently a chemical bond or one or more R s optionally substituted with C 1~13 Alkylene, C 2~13 Alkenylene or C 2~13 is alkynylene; G1 and G2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; G3 and G4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R and R are independently H or one or more R * optionally substituted with C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10Alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C 6~10 aryl or 5- to 14-membered heteroaryl; Alternatively, R3 and R4 together with the N atom to which they are attached form one or more R * forming an optionally substituted 3- to 14-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form one or more R * forming a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl optionally substituted with; R * are independently H, halogen, cyano, C 1~10 Alkyl, C 1~10 Haloalkyl, -L b -OR b , -L b -SR b or -L b -NR b R' b and; R5, R6, R7 and R8 independently represent one or more R * optionally substituted with C 1~8 is alkyl; R and R are independently optionally substituted with one or more R, and one or more methylene units are optionally and independently replaced with -NR''-. 4~20 Alkyl, C 4~20 Alkenyl or C 4~20 is alkynyl; R s are independently H, C 1~14 Alkyl, -L d -OR d , -L d -SR d or -L d -NRdR' d and; R is independently H, C 1~20 Alkyl, -L a -OR a , -L a -SR a or -La -NR a R' a and; R'' is independently H or C 1~20 is alkyl; L a and L e are independently a chemical bond or C 1~20 is alkylene; L b and L f are independently a chemical bond or C 1~10 is alkylene; L c are independently a chemical bond or C 1~8 is alkylene; L d are independently a chemical bond or C 1~14 is alkylene; R a and R' a are independently H, as well as the following substituents: H, C 1~20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e C optionally substituted with one or more of 1~20 independently selected from alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R b and R' b are independently H, as well as the following substituents: H, C 1~10 Alkyl, -L f -OR f , -L f -SR f and -L f -NR f R' f C optionally substituted with one or more of 1~10 independently selected from alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R c and R' c are independently H or C1~8 is alkyl; R d and R' d are independently H or C 1~14 is alkyl; R e and R' e are independently H or C 1~20 is alkyl; R f and R' f are independently H or C 1~10 alkyl) The nanoparticle composition is provided,

[0011] US Patent No. 11246933 discloses that the incorporation of biodegradable group(s) into the tail chain of lipid compound in lipid nanoparticles leads to faster metabolism and lipid removal from the body after delivery of active agent to target area.As a result, these lipids containing biodegradable group have lower toxicity than similar lipids that do not have biodegradable group.The tail chain of the cationic lipid compound of the present disclosure has biodegradable group(s), and therefore has a better toxicity profile than similar lipids that do not have biodegradable group, such as DLin-MC3-DMA.

[0012] In another aspect, the present disclosure provides a method of preparing a nanoparticle composition, the method comprising mixing the components of a lipid component and then mixing with a payload.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising a nanoparticle composition of the present disclosure and, optionally, a pharmaceutically acceptable excipient(s), such as a carrier(s), adjuvant(s), or vehicle(s).

[0014] In another aspect, the present disclosure provides the use of a nanoparticle composition of the present disclosure, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating, diagnosing, or preventing a disease.

[0015] In another aspect, the present disclosure provides use of a nanoparticle composition of the present disclosure, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for delivering a payload.

[0016] In another aspect, the present disclosure provides a method of treating, diagnosing, or preventing a disease in a subject, the method comprising administering to the subject a nanoparticle composition of the present disclosure, or a pharmaceutical composition of the present disclosure.

[0017] In another aspect, the present disclosure provides a nanoparticle composition of the present disclosure, or a pharmaceutical composition of the present disclosure, for use in treating, diagnosing, and / or preventing a disease.

[0018] In another aspect, the present disclosure provides a method of delivering a payload to a subject, the method comprising administering to the subject a nanoparticle composition of the present disclosure, or a pharmaceutical composition of the present disclosure.

[0019] In another aspect, the present disclosure provides a nanoparticle composition of the present disclosure, or a pharmaceutical composition of the present disclosure, for use in delivering a payload.

[0020] In specific embodiments, the payload is selected from one or more of a therapeutic agent, a prophylactic agent, and a diagnostic agent; alternatively, the therapeutic agent, prophylactic agent, or diagnostic agent is a nucleic acid.

[0021] In more specific embodiments, the nucleic acid is selected from one or more of ASO, RNA, and DNA.

[0022] In more specific embodiments, the RNA is selected from one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA) and nucleases, alternatively mRNA, further alternatively modified mRNA.

[0023] Terminology chemical terminology Specific functional group terminology and chemical terminology is explained in more detail below.

[0024] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 It is intended to include alkyl.

[0025] "C 1~28 "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having 1 to 28 carbon atoms. In some embodiments, C 4~28 Alkyl, C 4~24 Alkyl, C 4~20 Alkyl, C 8~10Alkyl, C 2~8 Alkyl, C 7~9 Alkyl, C 4~6 Alkyl, C 1~20 Alkyl, C 1~14 Alkyl, C 2~14 Alkyl, C 1~13 Alkyl, C 1~12 Alkyl, C 1~10 Alkyl, C 1~8 Alkyl, C 1~7 Alkyl, C 2~7 Alkyl, C 1~6 Alkyl, C 1~5 Alkyl, C5 alkyl, C 1~4 Alkyl, C 2~4 Alkyl, C 1~3 Alkyl, C 2~3 Alkyl, C 1~2 Alkyl and Me are alternatives. 1~6 Examples of alkyl include methyl (C1), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). 1~6 The term "alkyl" also includes heteroalkyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0026] "C 2~20 "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms and at least one carbon-carbon double bond.4~28 "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 4 to 28 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4~20 Alkenyl, C 2~13 Alkenyl, C 2~10 Alkenyl, C 2~6 Alkenyl, and C 2~4 Alkenyl is an alternative. 2~6 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 2~6 The term "alkenyl" also includes heteroalkenyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] "C 2~20 "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 4~28 "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 4 to 28 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4~20 Alkynyl, C 2~13 Alkynyl, C 2~10 Alkynyl, C 2~6 Alkynyl, and C 2~4 Alkynyl is an alternative. 2~6 Examples of alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. 2~6The term "alkynyl" also includes heteroalkynyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] "C 1~20 "Alkylene" is C 1~20 refers to a divalent group formed by removing another hydrogen from an alkyl, and may be substituted or unsubstituted. 4~20 Alkylene, C 8~10 Alkylene, C 2~8 Alkylene, C 7~9 Alkylene, C 4~6 Alkylene, C 1~20 Alkylene, C 1~14 Alkylene, C 2~14 Alkylene, C 1~13 Alkylene, C 1~12 Alkylene, C 1~10 Alkylene, C 1~8 Alkylene, C 1~7 Alkylene, C 2~7 Alkylene, C 1~6 Alkylene, C 1~5 Alkylene, C5 alkylene, C 1~4 Alkylene, C 2~4 Alkylene, C 1~3 Alkylene, C 2~3 Alkylene, C 1~2Alkylene and methylene are alternatives. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Examples of substituted alkylene groups, e.g., those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0029] "C 2~13 "Alkenylene" is a divalent radical of alkenylene where another hydrogen is removed to provide the alkenylene radical. 2~13 It refers to an alkenyl group, which may be substituted or unsubstituted. In some embodiments, C 2~10 Alkenyl, C 2~6 Alkenyl, and C 2~4 Alkenylene is further alternative. Exemplary unsubstituted alkenylene groups include, but are not limited to, ethylene (-CH=CH-) and propenylene (e.g., -CH=CHCH-, -CH-CH=CH-). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH)=CH-, -CH=C(CH)-), substituted propylene (e.g., -C(CH)=CHCH-, -CH=C(CH)CH-, -CH=CHCH(CH)-, -CH=CHC(CH)-, -CH(CH)-CH=CH-, -C(CH)-CH=CH-, -CH-C(CH)=CH-, -CH-CH=C(CH)-).

[0030] "C 2~13 "Alkynylene" is a C alkyl group in which another hydrogen is removed to provide a divalent alkynylene radical. 2~13 It refers to an alkynyl group, which may be substituted or unsubstituted. In some embodiments, C 2~10 Alkynylene, C 2~6 Alkynylene, and C 2~4 Alkynylene is a further alternative. Exemplary alkynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), and the like.

[0031] "C 0~6 Alkylene is a chemical bond and the above "C 1~6 "C" refers to "alkylene" 0~4 Alkylene is a chemical bond and the above "C 1~4 It refers to alkylene.

[0032] The phrase "Variable A and Variable B have a total length of x carbon atoms" means that the total number of backbone carbon atoms in the group represented by Variable A and the number of backbone carbon atoms in the group represented by Variable B is x.

[0033] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0034] Therefore, "C 1~10 "Haloalkyl" refers to any of the above "C" groups substituted with one or more halogens. 1~10 In some embodiments, C 1~6 Haloalkyl and C 1~4 Haloalkyl is a further alternative, and C 1~2and haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF, -CHF, -CHFCHF, -CHCHF, -CFCF, -CCl, -CHCl, -CHCl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Haloalkyl can be optionally substituted at any available point of attachment with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] "C 3~14"Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl, and 3- to 6-membered cycloalkyl are further alternatives, with 5- to 7-membered cycloalkyl, 4- to 6-membered cycloalkyl, 5- to 6-membered cycloalkyl, 5-membered cycloalkyl, and 6-membered cycloalkyl being even alternatives. Cycloalkyl also includes ring systems in which the above-described cycloalkyl rings are fused with one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring and, in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the cycloalkyl system. Cycloalkyl further includes the above-described cycloalkyls in which substituents on any non-adjacent carbon atoms are connected to form a bridged ring, together forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl further includes the above cycloalkyls where substituents on the same carbon atom are attached to form a ring, together forming a polycyclic alkane that shares one carbon atom. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), cycloheptyl (C), cycloheptenyl (C), cycloheptadienyl (C), cycloheptatrienyl (C), and the like. Cycloalkyls can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] "C 3~10 "Cycloalkylene" is C 3~10 refers to a divalent radical formed by removing another hydrogen from a cycloalkyl group, and may be substituted or unsubstituted. 3~6 Cycloalkylene and C 3~4Cycloalkylene groups are a particular alternative, especially cyclopropylene.

[0037] "3- to 14-membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, each of which is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. In some embodiments, an alternative is 3-10-membered heterocyclyl, which is a radical of a 3-10-membered non-aromatic ring system having ring carbon atoms and 1-5 heteroatoms; in some embodiments, an alternative is 5-10-membered heterocyclyl, which is a radical of a 5-10-membered non-aromatic ring system having ring carbon atoms and 1-5 ring heteroatoms; in some embodiments, an alternative is 3-8-membered heterocyclyl, which is a radical of a 3-8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms; in some embodiments, an alternative is 3-7-membered heterocyclyl, which is a radical of a 3-7-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms; in some embodiments, an alternative is 3-7-membered heterocyclyl, which is a radical of a 5-7-membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms 5- to 7-membered heterocyclyl is an alternative; 3- to 6-membered heterocyclyl is a radical of a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is an alternative; 4- to 6-membered heterocyclyl is a radical of a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is an alternative; 5- to 6-membered heterocyclyl is a radical of a 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is a further alternative; 5-membered heterocyclyl is a radical of a 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is a further alternative; 6-membered heterocyclyl is a radical of a 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is a further alternative.Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl is fused to one or more cycloalkyl groups, or in which the above-mentioned heterocyclyl is fused to one or more aryl or heteroaryl groups, and in which the above-mentioned heterocyclyl is fused to one or more aryl or heteroaryl groups, and in such cases, the number of ring members continues to represent the number of ring members of the heterocyclyl ring system. Heterocyclyl further includes the above-mentioned heterocyclyl in which substituents on any non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, forming a polycyclic heteroalkane that shares two or more carbon or nitrogen atoms. Heterocyclyl further includes the above-mentioned heterocyclyl in which substituents on the same carbon atom are connected to form a ring, forming a polycyclic heteroalkane that shares one carbon atom. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, pyrazolidyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl further includes, where valence permits, the above heterocyclyls that share one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl to form a bridged or spiro ring, and the shared atoms may be carbon or nitrogen atoms. Heterocyclyl further includes heterocyclyl as defined above optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] "C 6~10 "Aryl" refers to the radical of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6 to 10 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 shared pi electrons in a cyclic arrangement). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl groups also include ring systems in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Aryl may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] "5- to 14-membered heteroaryl" refers to the radical of a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic systems can contain one or more heteroatoms in one or both rings. This includes ring systems in which a heteroaryl or heteroaryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring. In such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5- to 10-membered heteroaryl group is alternatively the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl groups are further alternatives, which are radicals of 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0040] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups.

[0041] "Alkoxy" refers to the oxy ether form of a straight- or branched-chain alkyl group, i.e., an -O-alkyl group. Similarly, "methoxy" refers to -O-CH.

[0042] "Optionally substituted with" means that the group may be substituted or unsubstituted with the specified substituent.

[0043] Divalent radicals formed by removing another hydrogen from groups defined above, such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, are collectively referred to as "ylene." Ring-forming groups, such as cycloalkyl, heterocyclyl, aryl, and heteroaryl, are collectively referred to as "cyclic groups."

[0044] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl as defined herein are optionally substituted groups.

[0045] Exemplary substituents on carbon atoms include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa, -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Alternatively, the two geminal hydrogens on a carbon atom can be =O, =S, or =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is replaced by a group; R aa each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R aa two of the groups are joined to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each of these is hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc)2, independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups joined to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups joined to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each of the following is a halogen: -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NRff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may be linked to form =O or =S; R ee each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ffeach independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups joined to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each of the following is a halogen: -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclyl, C5-C 10 or two geminal R gg The substituents may combine to form =O or =S; X- is the counterion.

[0046] Exemplary substituents on a nitrogen atom include, but are not limited to, hydrogen, —OH, —OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to a nitrogen atom cc groups joined to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with an R aa , R bb , R cc and R dd is as described herein.

[0047] "Nucleic acid" refers to single- or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their heterozygous molecules. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-replicating RNA (saRNA), and antisense oligonucleotides (ASO). Nucleic acids may be further chemically modified, with the chemical modifier selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. mRNA molecules contain a protein-coding region and may further contain expression control sequences. Typical expression control sequences include, but are not limited to, a 5' cap, a 5' untranslated region (5'UTR), a 3' untranslated region (3'UTR), a polyadenylic acid sequence (polyA), and an miRNA binding site.

[0048] "Cationic lipid" refers to a lipid molecule that can be positively charged under physiological pH conditions. In some embodiments, the cationic lipid is an amino lipid.

[0049] "Neutral lipid" refers to a lipid molecule that is uncharged at a specific pH, such as physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3 -phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0050] "Structural lipid" generally refers to a lipid, such as a steroid, that enhances the stability of nanoparticles by filling the interstices between lipids. Steroids are compounds with a perhydrocyclopentanophenanthrene carbon skeleton. In alternative embodiments, the steroid is cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol.

[0051] "Polymer lipid" refers to a molecule containing a polymer portion and a lipid portion. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. Other lipids that can reduce aggregation, such as the product of a compound that has an uncharged, hydrophilic, space-barrier portion coupled to a lipid, can also be used.

[0052] "Lipid nanoparticle" refers to a particle containing lipid components of nanoscale size.

[0053] "Biodegradable group" refers to a functional group containing a biodegradable bond, such as an ester, disulfide bond, amide, and the like. Biodegradation can affect the process of removing a compound from the body. The biodegradable groups of the present disclosure are oriented head-to-tail in an ionizable lipid molecule.

[0054] Other terms The term "treating" as used herein relates to ameliorating, alleviating, or inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The noun "treatment" as used herein refers to the act of treating, which is a verb, as treating is defined.

[0055] As used herein, the term "pharmaceutically acceptable salts" refers to carboxylic acid salts and amino acid addition salts of compounds of the present disclosure that are suitable, within the scope of sound medical judgment, for contact with patient tissues and do not produce undue toxicity, irritation, allergy, etc., that are effective for their intended use, commensurate with a reasonable benefit / risk ratio. The term also includes zwitterionic forms of compounds of the present disclosure, where possible.

[0056] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0057] The base addition salts of acidic compounds can be prepared in a conventional manner by contacting the free acid form with a sufficient amount of the required base to form the salt. The free acid can be regenerated in a conventional manner by contacting the salt form with an acid and then isolating the free acid. The free acid forms differ somewhat from their respective salt forms in physical properties, such as solubility in polar solvents. However, for purposes of this disclosure, the salts are still equivalent to their respective free acids.

[0058] Salts can be prepared from inorganic acids and include sulfate, pyrosulfate, bisulfite, sulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, and iodide. Examples of acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucoheptanate, lactobionate, laurylsulfonate, isethionate, and the like. Salts can also be prepared from organic acids including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, besylate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also included are salts of amino acids such as arginine salts, gluconate salts, galacturonate salts, etc. (See, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, for a review).

[0059] "Subjects" to which administration is contemplated include, but are not limited to, humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human subjects, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" may be used interchangeably herein.

[0060] "Disease," "disorder," and "condition" may be used interchangeably herein.

[0061] Unless otherwise indicated, the term "treatment" as used herein includes an effect on a subject suffering from a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or slows or slows the progression of the disease, disorder, or condition ("therapeutic treatment"). The term also includes an effect that occurs before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0062] Generally, the "effective amount" of a pharmaceutical composition refers to an amount sufficient to induce a target biological response.As will be understood by those skilled in the art, the effective amount of the pharmaceutical composition of the present disclosure can vary depending on the following factors, such as the desired biological endpoint, the pharmacokinetics of the pharmaceutical composition, the disease to be treated, the mode of administration, and the age, health condition and symptoms of the subject.An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0063] Unless otherwise specified, a "therapeutically effective amount" of a pharmaceutical composition as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a pharmaceutical composition refers to the amount of a therapeutic agent that, when used alone or in combination with other treatments, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0064] Unless otherwise indicated, a "prophylactically effective amount" of a pharmaceutical composition as used herein is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a pharmaceutical composition refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention or an amount that enhances the prophylactic effect of another prophylactic agent.

[0065] "Combination" and related terms refer to the simultaneous or sequential administration of a pharmaceutical composition of the present disclosure with another therapeutic agent. For example, the pharmaceutical composition of the present disclosure can be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosages, or simultaneously with the other therapeutic agent in a single unit dosage. DETAILED DESCRIPTION OF THE INVENTION

[0066] As used herein, "compounds of the present disclosure" refers to the following compounds, such as those of Formula (IV), Formula (V), Formula (VI), Formula (VII), pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof.

[0067] In this disclosure, compounds are named using standard nomenclature.For compounds with asymmetric centers, it should be understood that all optical isomers and their mixtures are included unless otherwise stated.In addition, unless otherwise specified, all isomeric compounds and carbon-carbon double bonds included in this disclosure can exist in Z and E forms.One of the compounds that exist in different tautomeric forms is not limited to a specific tautomer, and is intended to cover all tautomeric forms.

[0068] In one embodiment, the present disclosure provides a nanoparticle composition comprising a lipid component and optionally a payload, comprising: The lipid components consist of the following components in mole percentage: ionizable cationic lipids 20 mol% to 85 mol%; structural lipids 10 mol% to 75 mol%; Neutral lipids 1.0mol%~30mol%; Polymer lipids 0.25 mol% to 10 mol% Includes; The ionizable cationic lipid is a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0069] [ka] (In the formula, M1 and M2 are -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR aC(S)O-, -SS- and -S(O) 0~2 - independently selected from; Q is a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, -S(O) 0~2 -, phenylene, and pyridylidene, wherein phenylene or pyridylidene is selected from one or more R * optionally substituted with; G5 is a chemical bond or one or more R ** optionally substituted with C 1~8 is alkylene; G 6a and G 6b are independently a chemical bond or one or more R ** optionally substituted with C 1~7 is alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R9, R 10 and R ** are independently H, C 1~8 Alkyl, -L c -OR c , -L c -SR c or -L c -NR c R' c and; G1, G2, G3 and G4 are independently a chemical bond or one or more R s optionally substituted with C 1~13 Alkylene, C 2~13 Alkenylene or C 2~13 is alkynylene; G1 and G2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; G3 and G4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R and R are independently H or one or more R * optionally substituted with C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C 6~10 aryl or 5- to 14-membered heteroaryl; Alternatively, R3 and R4 together with the N atom to which they are attached form one or more R * forming an optionally substituted 3- to 14-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form one or more R * forming a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl optionally substituted with; R * are independently H, halogen, cyano, C 1~10 Alkyl, C 1~10 Haloalkyl, -L b -OR b , -L b -SR b or -L b -NR b R' b and; R5, R6, R7 and R8 independently represent one or more R * optionally substituted with C 1~8 is alkyl; R and R are independently optionally substituted with one or more R, and one or more methylene units are optionally and independently replaced with -NR''-. 4~20 Alkyl, C 4~20 Alkenyl or C 4~20 is alkynyl; R s are independently H, C 1~14 Alkyl, -L d -OR d , -L d -SR d or -L d -NRdR' d and; R is independently H, C 1~20 Alkyl, -L a -OR a , -L a -SR a or -L a -NR a R' a and; R'' is independently H or C 1~20 is alkyl; L a and L e are independently a chemical bond or C 1~20 is alkylene; L b and L f are independently a chemical bond or C 1~10 is alkylene; L c are independently a chemical bond or C 1~8 is alkylene; L d are independently a chemical bond or C 1~14 is alkylene; R a and R' a is H, as well as the following substituents: H, C 1~20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' eC optionally substituted with one or more of 1~20 independently selected from alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R b and R' b is H, as well as the following substituents: H, C 1~10 Alkyl, -L f -OR f , -L f -SR f and -L f -NR f R' f C optionally substituted with one or more of 1~10 independently selected from alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R c and R' c are independently H or C 1~8 is alkyl; R d and R' d are independently H or C 1~14 is alkyl; R e and R' e are independently H or C 1~20 is alkyl; R f and R' f are independently H or C 1~10 alkyl) The present invention relates to a nanoparticle composition, wherein

[0070] M1 and M2 In one embodiment, M1 is -C(O)O-; in another embodiment, M1 is -O-; in another embodiment, M1 is -SC(O)O-; in another embodiment, M1 is -OC(O)NR a -; in another embodiment, M is -NR a C(O)NR a -; in another embodiment, M1 is -OC(O)S-; in another embodiment, M1 is -OC(O)O-; in another embodiment, M1 is -NR aIn another embodiment, M is -C(O)O-; in another embodiment, M is -OC(O)-; in another embodiment, M is -SC(O)-; in another embodiment, M is -C(O)S-; in another embodiment, M is -NR a -; in another embodiment, M is -C(O)NR a -; in another embodiment, M is -NR a In another embodiment, M is —NR a In another embodiment, M is —SC(O)NR a -; in another embodiment, M1 is -C(O)-; in another embodiment, M1 is -OC(S)-; in another embodiment, M1 is -C(S)O-; in another embodiment, M1 is -OC(S)NR a -; in another embodiment, M is -NR a In another embodiment, M is -C(S)O-; in another embodiment, M is -SS-; in another embodiment, M is -S(O) 0~2 -It is.

[0071] In one embodiment, M2 is -C(O)O-; in another embodiment, M2 is -O-; in another embodiment, M2 is -SC(O)O-; in another embodiment, M2 is -OC(O)NR a -; in another embodiment, M2 is -NR a C(O)NR a -; in another embodiment, M2 is -OC(O)S-; in another embodiment, M2 is -OC(O)O-; in another embodiment, M2 is -NR a In another embodiment, M2 is -C(O)O-; in another embodiment, M2 is -OC(O)-; in another embodiment, M2 is -SC(O)-; in another embodiment, M2 is -C(O)S-; in another embodiment, M2 is -NR a -; in another embodiment, M2 is -C(O)NR a -; in another embodiment, M2 is -NR a In another embodiment, M2 is -NR a In another embodiment, M2 is -SC(O)NR a-; in another embodiment, M2 is -C(O)-; in another embodiment, M2 is -OC(S)-; in another embodiment, M2 is -C(S)O-; in another embodiment, M2 is -OC(S)NR a -; in another embodiment, M2 is -NR a In another embodiment, M2 is -C(S)O-; in another embodiment, M2 is -SS-; in another embodiment, M2 is -S(O) 0~2 -It is.

[0072] In more specific embodiments, M1 and M2 are -C(O)O-, -SC(O)O-, -OC(O)NR a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -C(O)S-, -C(O)NR a -, -NR a C(O)S-, -SC(O)NR a -, -C(S)O-, -OC(S)NR a - and -NR a In another more specific embodiment, M and M are independently selected from -C(O)O-, -C(O)S-, -C(O)NR a -, and -C(S)O-; in another more specific embodiment, M and M are independently selected from -C(O)O-, -C(O)S-, or -C(O)NR a -It is.

[0073] Q In one embodiment, Q is a chemical bond; in another embodiment, Q is —C(O)O—; in another embodiment, Q is —O—; in another embodiment, Q is —SC(O)O—; in another embodiment, Q is —OC(O)NR b -; in another embodiment, Q is -NR b C(O)NR b -; in another embodiment, Q is -OC(O)S-; in another embodiment, Q is -OC(O)O-; in another embodiment, Q is -NR bIn another embodiment, Q is -C(O)O-; in another embodiment, Q is -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR b -; in another embodiment, Q is -C(O)NR b -; in another embodiment, Q is -NR b In another embodiment, Q is —NR b In another embodiment, Q is —SC(O)NR b -; in another embodiment, Q is -C(O)-; in another embodiment, Q is -OC(S)-; in another embodiment, Q is -C(S)O-; in another embodiment, Q is -OC(S)NR b -; in another embodiment, Q is -NR b In another embodiment, Q is -C(S)O-; in another embodiment, Q is -SS-; in another embodiment, Q is -S(O) 0~2 -; in another embodiment, Q is phenylene; in another embodiment, Q is pyridylidene; in another embodiment, phenylene or pyridylidene is selected from the group consisting of one or more R * is optionally replaced by

[0074] In more specific embodiments, Q is a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, and -S(O) 0~2and in another more specific embodiment, Q is selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O-, -NHC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)S-, -SC(O)NH-, -C(O)- , —OC(S)—, —C(S)O—, —OC(S)NH—, and —NHC(S)O—; in another more specific embodiment, Q is selected from —C(O)O—, —O—, —SC(O)O—, —OC(O)NH—, —NHC(O)NH—, —OC(O)S—, —OC(O)O—, and —NHC(O)O—; in another more specific embodiment, Q is —C(O)O—.

[0075] G5 In one embodiment, G5 is a chemical bond; in another embodiment, G5 is C 1~8 alkylene; in another embodiment, G5 is one or more R ** is optionally replaced by

[0076] G 6a and G 6b In one embodiment, G 6a is a chemical bond; in another embodiment, G 6a C 1~7 alkylene; in another embodiment, G 6a C 1~5 alkylene; in another embodiment, G 6a C 1~4 alkylene; in another embodiment, G 6a C 1~4 is a straight chain alkylene; in another embodiment, G 6a is (CH2)2-; in another embodiment, G 6a but one or more R ** and in another embodiment, G 6a but 1, 2, 3 or 4 R ** is optionally replaced by

[0077] In one embodiment, G 6b is a bond; in another embodiment, G 6b C 1~7 alkylene; in another embodiment, G 6b C 1~5 alkylene; in another embodiment, G 6b C 1~2 alkylene; in another embodiment, G 6b is methylene; in another embodiment, G 6b but one or more R ** and in another embodiment, G 6b but 1, 2, 3 or 4 R ** and in another embodiment, G 6b But one or two R ** is optionally replaced by

[0078] In one embodiment, G 6a and G 6b has a total length of 0 carbon atoms; in another embodiment, G 6a and G 6b has a total length of 1 carbon atom; in another embodiment, G 6a and G 6b has a total length of 2 carbon atoms; in another embodiment, G 6a and G 6b has a total length of 3 carbon atoms; in another embodiment, G 6a and G 6b has a total length of 4 carbon atoms; in another embodiment, G 6a and G 6b has a total length of 5 carbon atoms; in another embodiment, G 6a and G 6b has a total length of 6 carbon atoms; in another embodiment, G 6a and G 6b has a total length of 7 carbon atoms.

[0079] In a more specific embodiment, G 6a and G 6b are independently a chemical bond or one, two, three or four R **optionally substituted with C 1~5 alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3, 4 or 5 carbon atoms.

[0080] In another more specific embodiment, G 6a is a chemical bond or 1, 2, 3 or 4 R ** optionally substituted with C 1~4 alkylene; G 6b is a chemical bond or one or two R ** optionally substituted with C 1~2 alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3 or 4 carbon atoms.

[0081] In another more specific embodiment, G 6a is a chemical bond or C 1~4 Alkylene, instead of C 2~4 Alkylene, instead of C 2~3 alkylene, and alternatively -(CH2)2-; G 6b is a chemical bond or methylene; G 6a and G 6b but has a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.

[0082] In another more specific embodiment, G 6a is a chemical bond or C 1~4 Straight chain alkylene, instead of C 2~4 Straight chain alkylene, instead of C 2~3 Linear alkylene, and alternatively -(CH2)2-; G 6b is a chemical bond or methylene; G 6a and G 6b but has a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.

[0083] R9 In one embodiment, R9 is H; in another embodiment, R9 is C 1~8 alkyl; in another embodiment, R is -L c -OR c and in another embodiment, R9 is -L c -SR c and in another embodiment, R9 is -L c -NR c R' c and in another embodiment, R9 is C 1~6 It is alkyl.

[0084] In more specific embodiments, R9 is H, C 1~6 Alkyl, -L c -OR c or -L c -NR c R' c In another more specific embodiment, R9 is H or C 1~6 In another more particular embodiment, R9 is H.

[0085] R 10 In one embodiment, R 10 is H; in another embodiment, R 10 C 1~8 alkyl; in another embodiment, R 10 Ga-L c -OR c and in another embodiment, R 10 Ga-L c -SR c and in another embodiment, R 10 Ga-L c -NR c R' c is.

[0086] In more specific embodiments, R 10 But H, C 1~6 Alkyl, -L c -OR c or -L c -NR c R' cand in another more specific embodiment, R 10 is H.

[0087] R ** In one embodiment, R ** is H; in another embodiment, R ** C 1~8 alkyl; in another embodiment, R ** Ga-L c -OR c and in another embodiment, R ** Ga-L c -SR c and in another embodiment, R ** Ga-L c -NR c R' c and in another embodiment, R ** C 1~6 It is alkyl.

[0088] In more specific embodiments, R ** H, C 1~6 Alkyl, -L c -OR c or -L c -NR c R' c and in another more specific embodiment, R ** is H or C 1~6 alkyl; in another more specific embodiment, R ** is H.

[0089] G1, G2, G3 and G4 In one embodiment, G1 is a chemical bond; in another embodiment, G1 is C 1~13 alkylene; in another embodiment, G is C 2~13 alkenylene; in another embodiment, G is C 2~13 alkynylene; in another embodiment, G is one or more R s is optionally replaced by

[0090] In one embodiment, G2 is a chemical bond; in another embodiment, G2 is C1~13 alkylene; in another embodiment, G2 is C 2~13 alkenylene; in another embodiment, G2 is C 2~13 alkynylene; in another embodiment, G2 is one or more R s is optionally replaced by

[0091] In one embodiment, G1 and G2 have a total length of 3 carbon atoms; in another embodiment, G1 and G2 have a total length of 4 carbon atoms; in another embodiment, G1 and G2 have a total length of 5 carbon atoms; in another embodiment, G1 and G2 have a total length of 6 carbon atoms; in another embodiment, G1 and G2 have a total length of 7 carbon atoms; in another embodiment, G1 and G2 have a total length of 8 carbon atoms; in another embodiment, G1 and G2 have a total length of 9 carbon atoms; in another embodiment, G1 and G2 have a total length of 10 carbon atoms; in another embodiment, G1 and G2 have a total length of 11 carbon atoms; in another embodiment, G1 and G2 have a total length of 12 carbon atoms; in another embodiment, G1 and G2 have a total length of 13 carbon atoms.

[0092] In more specific embodiments, -G1-C(R5R6)-G2- is

[0093] [ka] is.

[0094] In one embodiment, G 1a is a chemical bond; in another embodiment, G 1a C 1~7 alkylene; in another embodiment, G 1a is -CH2-; in another embodiment, G 1a is —(CH)—; in another embodiment, G 1a is —(CH)—; in another embodiment, G 1a is —(CH2)4—; in another embodiment, G 1a is -(CH2)5-; in another embodiment, G1a is -(CH2)6-; in another embodiment, G 1a But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0095] In one embodiment, G 1b is a chemical bond; in another embodiment, G 1b C 1~7 alkylene; in another embodiment, G 1b C 1~3 alkylene; in another embodiment, G 1b is -CH2-; in another embodiment, G 1b is —(CH)—; in another embodiment, G 1b is —(CH)—; in another embodiment, G 1b But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0096] In one embodiment, G 2a is a chemical bond; in another embodiment, G 2a C 1~7 alkylene; in another embodiment, G 2a C 1~3 alkylene; in another embodiment, G 2a But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0097] In one embodiment, G 2b is a chemical bond; in another embodiment, G 2b C 1~7 alkylene; in another embodiment, G 2b C 1~4 alkylene; in another embodiment, G 2b is -CH2-; in another embodiment, G 2b is —(CH)—; in another embodiment, G 2b is —(CH)—; in another embodiment, G 2b But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0098] In a more specific embodiment, G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; in another more specific embodiment, G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0099] In one embodiment, one of L3 and L5 is -(CR s R s In another embodiment, one of L and L is -(CHR s )2- and the other is a chemical bond; in another embodiment, one of L3 and L5 is -CH=CH- and the other is a chemical bond; in another embodiment, one of L3 and L5 is -C≡C- and the other is a chemical bond.

[0100] In one embodiment, G3 is a chemical bond; in another embodiment, G3 is C 1~13 alkylene; in another embodiment, G3 is C 2~13 alkenylene; in another embodiment, G3 is C 2~13 alkynylene; in another embodiment, G3 is one or more R s is optionally replaced by

[0101] In one embodiment, G4 is a chemical bond; in another embodiment, G4 is C 1~13 alkylene; in another embodiment, G4 is C 2~13 alkenylene; in another embodiment, G4 is C 2~13 alkynylene; in another embodiment, G4 is one or more R s is optionally replaced by

[0102] In one embodiment, G3 and G4 have a total length of 3 carbon atoms; in another embodiment, G3 and G4 have a total length of 4 carbon atoms; in another embodiment, G3 and G4 have a total length of 5 carbon atoms; in another embodiment, G3 and G4 have a total length of 6 carbon atoms; in another embodiment, G3 and G4 have a total length of 7 carbon atoms; in another embodiment, G3 and G4 have a total length of 8 carbon atoms; in another embodiment, G3 and G4 have a total length of 9 carbon atoms; in another embodiment, G3 and G4 have a total length of 10 carbon atoms; in another embodiment, G3 and G4 have a total length of 11 carbon atoms; in another embodiment, G3 and G4 have a total length of 12 carbon atoms; in another embodiment, G3 and G4 have a total length of 13 carbon atoms.

[0103] In more specific embodiments, -G3-C(R7R8)-G4- is

[0104] [ka] is.

[0105] In one embodiment, G 3a is a chemical bond; in another embodiment, G 3a C 1~7 alkylene; in another embodiment, G 3a is -CH2-; in another embodiment, G 3a is —(CH)—; in another embodiment, G 3a is —(CH)—; in another embodiment, G 3a is —(CH2)4—; in another embodiment, G 3a is -(CH2)5-; in another embodiment, G 3a is -(CH2)6-; in another embodiment, G 3a But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0106] In one embodiment, G 3b is a chemical bond; in another embodiment, G 3bC 1~7 alkylene; in another embodiment, G 3b C 1~3 alkylene; in another embodiment, G 3b is -CH2-; in another embodiment, G 3b is —(CH)—; in another embodiment, G 3b is —(CH)—; in another embodiment, G 3b But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0107] In one embodiment, G 4a is a chemical bond; in another embodiment, G 4a C 1~7 alkylene; in another embodiment, G 4a C 1~3 alkylene; in another embodiment, G 4a But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0108] In one embodiment, G 4b is a chemical bond; in another embodiment, G 4b C 1~7 alkylene; in another embodiment, G 4b C 1~4 alkylene; in another embodiment, G 4b is -CH2-; in another embodiment, G 4b is —(CH)—; in another embodiment, G 4b is —(CH)—; in another embodiment, G 4b But 1, 2, 3, 4 or 5 R s is optionally replaced by

[0109] In a more specific embodiment, G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5, 6, or 7 carbon atoms; in another more specific embodiment, G 3a , G 3b , G4a and G 4b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0110] In one embodiment, one of L4 and L6 is -(CR s R s In another embodiment, one of L and L is -(CHR s )2- and the other is a chemical bond; in another embodiment, one of L4 and L6 is -CH=CH- and the other is a chemical bond; in another embodiment, one of L4 and L6 is -C≡C- and the other is a chemical bond.

[0111] In more specific embodiments, one of L3 and L5, or one of L4 and L6, is -(CHR s )2-, -CH=CH- or -C≡C-, and the other is a chemical bond; G 1a and G 3a are independently a chemical bond or C 1~7 is alkylene; G 1b and G 3b are independently a chemical bond or C 1~3 is alkylene; G 2a and G 4a are independently a chemical bond or C 1~3 is alkylene; G 2b and G 4b are independently a chemical bond or C 1~4 is alkylene; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms.

[0112] In another more specific embodiment, one of L3 and L5, or one of L4 and L6, is -(CH2)2-, -CH=CH-, or -C≡C-, and the other is a chemical bond; G 1a and G 3a are independently a chemical bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-; G 1b and G 3b is a chemical bond; G 2a and G 4a is a chemical bond; G 2b and G 4b are independently a chemical bond, -CH2-, -(CH2)2-, or -(CH2)3-; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0113] Instead, R s and R s ' independently, H, C 1~10 Alkyl, -L d -OR d or -L d -NR d R' d ; H or C instead 1~6 Alkyl; and also H instead.

[0114] In more specific embodiments, -G 1a -L3-G 1b -or-G 3a -L4-G 3b-- is independently selected from --(CH2)2-, --(CH2)3-, --(CH2)4-, --(CH2)5-, --(CH2)6-, --(CH2)7-, --(CH2)8-, --(CH2)3-CH=CH-, --(CH2)3-C≡C-, --(CH2)2-CH=CH-, and --(CH2)2-C≡C-.

[0115] In more specific embodiments, -G 2a -L5-G 2b -or-G 4a -L6-G 4b - is independently selected from a chemical bond, -CH2-, -(CH2)2-, -(CH2)3-, -CH=CH-CH2-, -C≡C-, and -C≡C-CH2-.

[0116] In a more specific embodiment,

[0117] [ka] but have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms.

[0118] In a more specific embodiment,

[0119] [ka] is -(CH2)3-C(CH3)2-, -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, -(CH2)6-C(CH3)2-, -(CH2)7-C(CH3)2-, -(CH 2)8-C(CH3)2-, -(CH2)3-CH=CH-C(CH3)2-, -(CH2)3-C≡CC(CH3)2-, -(CH2)4-C(CH3)2-CH2-, -(CH2)3-C(CH3)2 and -(CH)-C(CH)-C(CH)-C≡C-CH-, -(CH)-C(CH)-CH=CH-CH-, -(CH)-C(CH)-C≡C-CH-, -(CH)-C(CH)-CH=CH-CH-, -(CH)-C≡CC(CH)-CH-, and -(CH)-C(CH)-C≡C-.

[0120] [ka] is independently selected from —(CH2)4—C(CH3)2—, —(CH2)5—C(CH3)2—, and —(CH2)6—C(CH3)2—; in another more specific embodiment,

[0121] [ka] is -(CH2)5-C(CH3)2-.

[0122] R3 and R4 In one embodiment, R3 is H; in another embodiment, R3 is C 1~10 alkyl; in another embodiment, R3 is C 1~10 haloalkyl; in another embodiment, R is C 2~10 alkenyl; in another embodiment, R is C 2~10 In another embodiment, R3 is alkynyl; in another embodiment, R3 is 3-14 membered cycloalkyl; in another embodiment, R3 is 3-14 membered heterocyclyl; in another embodiment, R3 is C 6~10aryl; in another embodiment, R3 is a 5-14 membered heteroaryl; in another embodiment, R3 is C 1~6 alkyl; in another embodiment, R3 is C 1~6 In another embodiment, R3 is haloalkyl; in another embodiment, R3 is a 3-10 membered cycloalkyl; in another embodiment, R3 is a 3-10 membered heterocyclyl; in another embodiment, R3 is a 3-7 membered cycloalkyl; in another embodiment, R3 is a 3-7 membered heterocyclyl; in another embodiment, R3 is Me; in another embodiment, R3 is -CH2CH3; in another embodiment, R3 is -CH2CH2OH; in another embodiment, R3 is -CH(CH3)2; * In another embodiment, R is substituted with 1, 2, 3, 4, or 5 R * is optionally replaced by

[0123] In one embodiment, R4 is H; in another embodiment, R4 is C 1~10 alkyl; in another embodiment, R4 is C 1~10 haloalkyl; in another embodiment, R4 is C 2~10 alkenyl; in another embodiment, R4 is C 2~10 In another embodiment, R4 is alkynyl; in another embodiment, R4 is 3-14 membered cycloalkyl; in another embodiment, R4 is 3-14 membered heterocyclyl; in another embodiment, R4 is C 6~10 aryl; in another embodiment, R4 is a 5-14 membered heteroaryl; in another embodiment, R4 is C 1~6 alkyl; in another embodiment, R4 is C 1~6 In another embodiment, R4 is haloalkyl; in another embodiment, R4 is 3-10 membered cycloalkyl; in another embodiment, R4 is 3-10 membered heterocyclyl; in another embodiment, R4 is 3-7 membered cycloalkyl; in another embodiment, R4 is 3-7 membered heterocyclyl; in another embodiment, R4 is Me; in another embodiment, R4 is one or more R * In another embodiment, R4 is substituted with 1, 2, 3, 4, or 5 R *is optionally replaced by

[0124] In one embodiment, R3 and R4 together with the N atom to which they are attached form a 3- to 14-membered heterocyclyl; in another embodiment, R3 and R4 together with the N atom to which they are attached form a 3- to 10-membered heterocyclyl; in another embodiment, R3 and R4 together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl; in another embodiment, R3 and R4 together with the N atom to which they are attached form a 5- to 7-membered heterocyclyl; in another embodiment, R3 and R4 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; in another embodiment, R3 and R4 together with the N atom to which they are attached form a 5-membered heterocyclyl; in another embodiment, R3 and R4 together with the N atom to which they are attached

[0125] [ka] In another embodiment, R3 and R4, together with the N atom to which they are attached, form:

[0126] [ka] In another embodiment, R3 and R4, together with the N atom to which they are attached, form:

[0127] [ka] In another embodiment, R3 and R4, together with the N atom to which they are attached, form:

[0128] [ka] In another embodiment, the heterocyclyl formed by R3 and R4 together with the N atom to which they are attached is selected from one or more R *In another embodiment, R and R together with the N atom to which they are attached form a heterocyclyl which is optionally substituted with 1, 2, 3, 4, or 5 R * is optionally replaced by

[0129] In one embodiment, R4 and R9 together with the atom to which they are attached form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl; in another embodiment, R4 and R9 together with the atom to which they are attached form a 3- to 10-membered heterocyclyl; in another embodiment, R4 and R9 together with the atom to which they are attached form a 3- to 7-membered heterocyclyl; in another embodiment, R4 and R9 together with the atom to which they are attached form a 6-membered heterocyclyl; in another embodiment, R4 and R9 together with the atom to which they are attached

[0130] [ka] In another embodiment, the heterocyclyl formed by R and R together with the atoms to which they are attached is selected from one or more R * In another embodiment, R and R together with the atom to which they are attached form a heterocyclyl that is optionally substituted with 1, 2, 3, 4, or 5 R * is optionally replaced by

[0131] In more specific embodiments, R and R are independently H or 1, 2, 3, 4, or 5 R * optionally substituted with C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 10-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3 or 4 R * to form an optionally substituted 3- to 10-membered heterocyclyl.

[0132] In another more specific embodiment, R and R are independently H or 1, 2, 3, 4, or 5 R * optionally substituted with C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocyclyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 7-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3, 4 or 5 R * to form an optionally substituted 3- to 7-membered heterocyclyl.

[0133] In more specific embodiments, R and R are independently 1, 2, 3, 4, or 5 R * optionally substituted with C 1~6 is alkyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * optionally substituted 5- to 7-membered heterocyclyl, alternatively 4- to 6-membered heterocyclyl, and further alternatively 5-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3, 4 or 5 R * to form an optionally substituted 6-membered heterocyclyl.

[0134] In more specific embodiments, R3 is Me, -CH2CH3, -CH2CH2OH or -CH(CH3)2, alternatively Me, -CH2CH3 or -CH(CH3)2, further alternatively Me or -CH2CH3; R4 is Me; Alternatively, R3 and R4 together with the N atom to which they are attached represent:

[0135] [ka] ,instead,

[0136] [ka] , and instead,

[0137] [ka] form; or R4 and R9 together with the atoms to which they are attached represent:

[0138] [ka] Form.

[0139] R * In one embodiment, R * is H; in another embodiment, R * is halogen; in another embodiment, R * is cyano; in another embodiment, R * C 1~10 alkyl; in another embodiment, R * C 1~10 haloalkyl; in another embodiment, R * Ga-L b -OR b and in another embodiment, R * Ga-L b -SR b and in another embodiment, R * Ga-L b -NR b R' b and in another embodiment, R * C 1~6 alkyl; in another embodiment, R* C 1~6 haloalkyl; in another embodiment, R * -OR b is.

[0140] In more specific embodiments, R * are independently H, halogen, cyano, C 1~6 Alkyl, C 1~6 Haloalkyl, -L b -OR b or -L b -NR b R' b and in another more specific embodiment, R * are independent, H, C 1~6 Alkyl, C 1~6 Haloalkyl or -OR b and in another more specific embodiment, R * are independently H, halogen, C 1~6 Alkyl or C 1~6 haloalkyl; in another more specific embodiment, R * are independent, H, C 1~6 Alkyl or C 1~6 haloalkyl; in another more specific embodiment, R * is H, Me, or OH; in another more specific embodiment, R * is H or Me.

[0141] R5, R6, R7 and R8 In one embodiment, R5 is C 1~8 alkyl; in another embodiment, R5 is C 1~6 alkyl; in another embodiment, R5 is C 1~3 In another embodiment, R5 is Me; in another embodiment, R5 is one or more R * In another embodiment, R5 is optionally substituted with 1, 2, 3, 4, or 5 R * is optionally replaced by

[0142] In one embodiment, R6 is C 1~8alkyl; in another embodiment, R6 is C 1~6 alkyl; in another embodiment, R6 is C 1~3 In another embodiment, R6 is Me; in another embodiment, R6 is one or more R * In another embodiment, R6 is optionally substituted with 1, 2, 3, 4, or 5 R * is optionally replaced by

[0143] In one embodiment, R7 is C 1~8 alkyl; in another embodiment, R7 is C 1~6 alkyl; in another embodiment, R7 is C 1~3 In another embodiment, R7 is alkyl; in another embodiment, R7 is Me; in another embodiment, R7 is one or more R * In another embodiment, R7 is optionally substituted with 1, 2, 3, 4, or 5 R * is optionally replaced by

[0144] In one embodiment, R8 is C 1~8 alkyl; in another embodiment, R is C 1~6 alkyl; in another embodiment, R is C 1~3 In another embodiment, R is Me; in another embodiment, R is one or more R * In another embodiment, R is optionally substituted with 1, 2, 3, 4, or 5 R * is optionally replaced by

[0145] R1 and R2 In one embodiment, R is C 4~20 alkyl; in another embodiment, R is C 4~20 alkenyl; in another embodiment, R is C 4~20 alkynyl; in another embodiment, R1 is optionally substituted with one or more R; in another embodiment, one or more methylene units in R1 are optionally and independently replaced by -NR''-.

[0146] In a more specific embodiment, R1 is -G7-L1-G8-H.

[0147] In one embodiment, G7 is a chemical bond; in another embodiment, G7 is C 1~12 alkylene; in another embodiment, G7 is C 1~6 alkylene; in another embodiment, G7 is C 1~5 alkylene; in another embodiment, G7 is C 1~5 In another embodiment, G7 is a straight-chain alkylene; in another embodiment, G7 is -CH2-; in another embodiment, G7 is -(CH2)2-; in another embodiment, G7 is -(CH2)4-; in another embodiment, G7 is -(CH2)5-; in another embodiment, G7 is optionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G7 are optionally and independently substituted with one R; in another embodiment, 1 or 2 methylenes in G7 are optionally and independently substituted with one R; in another embodiment, the methylenes of G7 that are connected to M1 are not substituted with R.

[0148] In one embodiment, G8 is a chemical bond; in another embodiment, G8 is C 1~12 alkylene; in another embodiment, G is C 1~10 alkylene; in another embodiment, G is C 1~8 alkylene; in another embodiment, G is C 1~8 In another embodiment, G8 is a straight-chain alkylene; in another embodiment, G8 is -(CH2)2-; in another embodiment, G8 is -(CH2)4-; in another embodiment, G8 is -(CH2)6-; in another embodiment, G8 is -(CH2)7-; in another embodiment, G8 is -(CH2)8-; in another embodiment, G8 is optionally substituted with 1, 2, 3, 4, 5, or 6 R; in another embodiment, 1, 2, or 3 methylenes in G8 are optionally and independently substituted with one R; in another embodiment, 1 or 2 alkylenes in G8 are optionally and independently substituted with one R.

[0149] In one embodiment, G7 and G8 have a total length of 4 carbon atoms; in another embodiment, G7 and G8 have a total length of 5 carbon atoms; in another embodiment, G7 and G8 have a total length of 6 carbon atoms; in another embodiment, G7 and G8 have a total length of 7 carbon atoms; in another embodiment, G7 and G8 have a total length of 8 carbon atoms; in another embodiment, G7 and G8 have a total length of 9 carbon atoms; in another embodiment, G7 and G8 have a total length of 10 carbon atoms; in another embodiment, G7 and G8 have a total length of 11 carbon atoms; in another embodiment, G7 and G8 have a total length of 12 carbon atoms.

[0150] In more specific embodiments, G7 and G8 have a total length of 6, 7, 8, 9 or 10 carbon atoms.

[0151] In more specific embodiments, G7 and G8 have a total length of 6, 7 or 8 carbon atoms.

[0152] In one embodiment, L1 is -(CRR')2-; in another embodiment, L1 is -CH=CH-; in another embodiment, L1 is -C≡C-; in another embodiment, L1 is -NR''-; in another embodiment, L1 is -(CHR)2-.

[0153] In one embodiment, R2 is C 4~20 alkyl; in another embodiment, R2 is C 4~20 alkenyl; in another embodiment, R2 is C 4~20 alkynyl; in another embodiment, R2 is optionally substituted with one or more R; in another embodiment, one or more methylene units in R2 are optionally and independently replaced by -NR''-.

[0154] In more specific embodiments, R2 is -G9-L2-G 10 -H.

[0155] In one embodiment, G9 is a chemical bond; in another embodiment, G9 is C 1~12 alkylene; in another embodiment, G is C 1~6 alkylene; in another embodiment, G is C 1~5 alkylene; in another embodiment, G is C 1~5 In another embodiment, G9 is a straight-chain alkylene; in another embodiment, G9 is -CH2-; in another embodiment, G9 is -(CH2)2-; in another embodiment, G9 is -(CH2)4-; in another embodiment, G9 is -(CH2)5-; in another embodiment, G9 is optionally substituted with 1, 2, 3, 4, 5 or 6 R; in another embodiment, 1, 2 or 3 methylenes in G9 are optionally and independently substituted with one R; in another embodiment, 1 or 2 methylenes in G9 are optionally and independently substituted with one R; in another embodiment, the methylenes of G9 that are attached to M2 are not substituted with R.

[0156] In one embodiment, G 10 is a chemical bond; in another embodiment, G 10 C 1~12 alkylene; in another embodiment, G 10 C 1~10 alkylene; in another embodiment, G 10 C 1~8 alkylene; in another embodiment, G 10 C 1~8 is a straight chain alkylene; in another embodiment, G 10 is —(CH)—; in another embodiment, G 10 is —(CH2)4—; in another embodiment, G 10 is -(CH2)6-; in another embodiment, G 10 is -(CH2)7-; in another embodiment, G 10 is -(CH2)8-; in another embodiment, G 10 is optionally substituted with 1, 2, 3, 4, 5, or 6 R; in another embodiment, G 10wherein one, two, or three methylenes are optionally and independently substituted with one R; in another embodiment, G 10 wherein one or two methylenes are optionally and independently substituted with one R.

[0157] In one embodiment, G9 and G 10 has a total length of 4 carbon atoms; in another embodiment, G and G 10 has a total length of 5 carbon atoms; in another embodiment, G and G 10 has a total length of 6 carbon atoms; in another embodiment, G and G 10 has a total length of 7 carbon atoms; in another embodiment, G and G 10 has a total length of 8 carbon atoms; in another embodiment, G and G 10 has a total length of 9 carbon atoms; in another embodiment, G and G 10 has a total length of 10 carbon atoms; in another embodiment, G and G 10 has a total length of 11 carbon atoms; in another embodiment, G and G 10 has a total length of 12 carbon atoms.

[0158] In a more specific embodiment, G9 and G 10 but have a total length of 6, 7, 8, 9 or 10 carbon atoms.

[0159] In a more specific embodiment, G9 and G 10 but have a total length of 6, 7 or 8 carbon atoms.

[0160] In one embodiment, L2 is -(CRR')2-; in another embodiment, L2 is -CH=CH-; in another embodiment, L2 is -C≡C-; in another embodiment, L2 is -NR''-; in another embodiment, L1 is -(CHR)2-.

[0161] In more specific embodiments, L1 and L2 are independently -(CRR')2-, -CH=CH-, -C≡C-, or -NR''-; G7, G8, G9 and G 10 are independently a chemical bond or C optionally substituted with 1, 2, 3, 4, 5, or 6 R 1~12 is alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R' is independently H, C 1~20 Alkyl, -L a -OR a or -L a -NR a R' a is.

[0162] In another more specific embodiment, L and L are independently -(CHR)-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond or C 1~6 is alkylene; G8 and G 10 independently, C 1~10 is alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with one R.

[0163] In another more specific embodiment, L and L are independently -(CHR)-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond or C 1~5Alkylene, instead of a chemical bond or C 1~5 is a straight chain alkylene; G8 and G 10 independently, C 1~8 Alkylene, instead of C 1~8 is a straight chain alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; G9 and G 10 but have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, instead of 6, 7, 8, 9, 10 carbon atoms; G7, G8, G9 or G 10 wherein one or two methylenes are optionally and independently substituted with one R.

[0164] Instead, the methylenes that connect M1 and M2 are not substituted with R.

[0165] In another more specific embodiment, L and L are independently -(CHR)-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond, -CH2-, -(CH2)2-, -(CH2)4-, or -(CH2)5-; G8 and G 10 are independently -(CH2)2-, -(CH2)4-, -(CH2)6-, -(CH2)7-, or -(CH2)8-; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; G9 and G 10 but have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, instead of 6, 7, 8, 9, 10 carbon atoms; G7, G8, G9 or G 10 wherein one or two methylenes are optionally and independently substituted with one R.

[0166] Instead, the methylenes that connect M1 and M2 are not substituted with R.

[0167] In another more specific embodiment, -G7-L1-G8-H or -G9-L2-G 10 -H is -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0168] [ka] are independently selected from

[0169] R s In one embodiment, R s is H; in another embodiment, R s C 1~14 alkyl; in another embodiment, R s Ga-L d -OR d and in another embodiment, R s Ga-L d -SR d and in another embodiment, R s Ga-L d -NR d R' d and in another embodiment, R s C 1~10 alkyl; in another embodiment, R s C 1~6 It is alkyl.

[0170] In more specific embodiments, R s H, C 1~10Alkyl, -L d -OR d or -L d -NR d R' d and in another more specific embodiment, R s is H or C 1~6 It is alkyl.

[0171] R In one embodiment, R is H; in another embodiment, R is C 1~20 alkyl; in another embodiment, R is -L a -OR a and in another embodiment, R is -L a -SR a and in another embodiment, R is -L a -NR a R' a and in another embodiment, R is C 1~10 alkyl; in another embodiment, R is C 1~8 alkyl; in another embodiment, R is C 1~8 It is a straight chain alkyl.

[0172] In more specific embodiments, R is H, Me, —(CH2)3CH3, —(CH2)4CH3, —(CH2)5CH3, —(CH2)6CH3, or —(CH2)7CH3.

[0173] R'' In one embodiment, R" is H; in another embodiment, R" is C 1~20 alkyl; in another embodiment, R″ is C 1~14 alkyl; in another embodiment, R″ is C 1~10 alkyl; in another embodiment, R″ is C 7~9 alkyl; in another embodiment, R'' is -(CH2)7CH3.

[0174] L a and L e In one embodiment, L a and L eare independently a chemical bond; in another embodiment, L a and L e independently, C 1~20 alkylene; in another embodiment, L a and L e independently, C 1~14 alkylene; in another embodiment, L a and L e independently, C 1~10 It is alkylene.

[0175] L b and L f In one embodiment, L b and L f are independently a chemical bond; in another embodiment, L b and L f independently, C 1~10 alkylene; in another embodiment, L b and L f independently, C 1~6 It is alkylene.

[0176] L c In one embodiment, L c is a chemical bond; in another embodiment, L c C 1~8 alkylene; in another embodiment, L c C 1~6 It is alkylene.

[0177] L d In one embodiment, L d is a chemical bond; in another embodiment, L d C 1~14 alkylene; in another embodiment, L d C 1~10 It is alkylene.

[0178] R a and R' a In one embodiment, R a is H; in another embodiment, Ra C 1~20 alkyl; in another embodiment, R a is 3- to 14-membered cycloalkyl; in another embodiment, R a is 3- to 14-membered heterocyclyl; in another embodiment, R a C 1~14 alkyl; in another embodiment, R a C 1~10 alkyl; in another embodiment, R a C 8~10 alkyl; in another embodiment, R a C 8~10 is a straight chain alkyl; in another embodiment, R a is -(CH2)8CH3; in another embodiment, R a but with the following substituents: H, C 1~20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e Optionally substituted with one or more of:

[0179] In one embodiment, R' a is H; in another embodiment, R' a C 1~20 alkyl; in another embodiment, R' a is a 3- to 14-membered cycloalkyl; in another embodiment, R' a is 3- to 14-membered heterocyclyl; in another embodiment, R' a C 1~14 alkyl; in another embodiment, R' a C 1~10 alkyl; in another embodiment, R' a C 8~10 alkyl; in another embodiment, R' a C 8~10 In another embodiment, R' is a straight chain alkyl; a is —(CH 2 ) 8 CH 3 ; in another embodiment, R′ a but with the following substituents: H, C 1~20Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e Optionally substituted with one or more of:

[0180] R b and R' b In one embodiment, R b is H; in another embodiment, R b C 1~10 alkyl; in another embodiment, R b is 3- to 14-membered cycloalkyl; in another embodiment, R b is 3- to 14-membered heterocyclyl; in another embodiment, R b C 1~6 alkyl; in another embodiment, R b is 3-10 membered cycloalkyl; in another embodiment, R b is 3-10 membered heterocyclyl; in another embodiment, R b but with the following substituents: H, C 1~10 Alkyl, -L f -OR f , -L f -SR f and -L f -NR f R' f Optionally substituted with one or more of:

[0181] In one embodiment, R' b is H; in another embodiment, R' b C 1~10 alkyl; in another embodiment, R' b is a 3- to 14-membered cycloalkyl; in another embodiment, R' b is 3- to 14-membered heterocyclyl; in another embodiment, R' b C 1~6 alkyl; in another embodiment, R' b is a 3- to 10-membered cycloalkyl; in another embodiment, R'b is 3-10 membered heterocyclyl; in another embodiment, R b but with the following substituents: H, C 1~10 Alkyl, -L f -OR f , -L f -SR f and -L f -NR f R' f Optionally substituted with one or more of:

[0182] R c and R' c In one embodiment, R c is H; in another embodiment, R c C 1~8 alkyl; in another embodiment, R c C 1~6 It is alkyl.

[0183] In one embodiment, R' c is H; in another embodiment, R' c C 1~8 alkyl; in another embodiment, R' c C 1~6 It is alkyl.

[0184] R d and R' d In one embodiment, R d is H; in another embodiment, R d C 1~14 alkyl; in another embodiment, R d C 1~10 In one embodiment, R' is alkyl. d is H; in another embodiment, R' d C 1~14 alkyl; in another embodiment, R' d C 1~10 It is alkyl.

[0185] R e and R' e In one embodiment, R e is H; in another embodiment, R e C 1~20 It is alkyl.

[0186] In one embodiment, R' e is H; in another embodiment, R' e C 1~20 It is alkyl.

[0187] R f and R' f In one embodiment, R f is H; in another embodiment, R f C 1~10 It is alkyl.

[0188] In one embodiment, R' f is H; in another embodiment, R' f C 1~10 It is alkyl.

[0189] Any of the above technical solutions in any specific embodiment or any combination thereof can be combined with any of the technical solutions in other specific embodiments or any combination thereof. For example, any of the technical solutions of Q or any combination thereof can be combined with M1, M2, G5, G 6a , G 6b , R9, R 10 , R ** , G1, G2, G3, G4, R1, R2, R3, R4, R5, R6, R7, R8, R, R'', R s , Ar2, L a , L e , L b , L f , L c , L d , R a , R' a , R b , R' b , R c , R' c , R d , R' d , R e , R' e , Rf and R' f The present disclosure is intended to include all of these combinations of technical solutions, but space limitations prevent their enumeration.

[0190] Technical Solution 1: In a more specific embodiment, the present disclosure provides a nanoparticle composition comprising a lipid component and optionally a payload, comprising: The lipid components consist of the following components in mole percentage: ionizable cationic lipids 20 mol% to 85 mol%; structural lipids 10 mol% to 75 mol%; Neutral lipids 1.0mol%~30mol%; Polymer lipids 0.25 mol% to 10 mol% Includes; The ionizable cationic lipid is a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0191] [ka] (In the formula, M1 and M2 are -C(O)O-, -O-, -SC(O)O-, and -OC(O)NR a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS- and -S(O) 0~2 - independently selected from; Q is a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, -S(O) 0~2 -, phenylene, and pyridylidene, wherein phenylene or pyridylidene is selected from one or more R * optionally substituted with; G5 is a chemical bond or one or more R ** optionally substituted with C 1~8 is alkylene; G 6a and G 6b are independently a chemical bond or one or more R ** optionally substituted with C 1~7 is alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R9, R 10 and R ** are independently H, C 1~8 Alkyl, -L c -OR c , -L c -SR c or -L c -NR c R' c and; G1, G2, G3 and G4 are independently a chemical bond or one or more R s optionally substituted with C 1~13 Alkylene, C2~13 Alkenylene or C 2~13 is alkynylene; G1 and G2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; G3 and G4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R and R are independently H or one or more R * optionally substituted with C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C 6~10 aryl or 5- to 14-membered heteroaryl; Alternatively, R3 and R4 together with the N atom to which they are attached form one or more R * forming an optionally substituted 3- to 14-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form one or more R * forming a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl optionally substituted with; R * are independently H, halogen, cyano, C 1~10 Alkyl, C 1~10 Haloalkyl, -L b -OR b , -L b -SR b or -L b -NR b R' b and; R5, R6, R7 and R8 independently represent one or more R * optionally substituted with C 1~8 is alkyl; R and R are independently optionally substituted with one or more R, and one or more methylene units are optionally and independently replaced with -NR''-. 4~20 Alkyl, C4~20 Alkenyl or C 4~20 is alkynyl; R s are independently H, C 1~14 Alkyl, -L d -OR d , -L d -SR d or -L d -NRdR' d and; R is independently H, C 1~20 Alkyl, -L a -OR a , -L a -SR a or -L a -NR a R' a and; R'' is independently H or C 1~20 is alkyl; L a and L e are independently a chemical bond or C 1~20 is alkylene; L b and L f are independently a chemical bond or C 1~10 is alkylene; L c are independently a chemical bond or C 1~8 is alkylene; L d are independently a chemical bond or C 1~14 is alkylene; R a and R' a is H, as well as the following substituents: H, C 1~20 Alkyl, -L e -OR e , -L e -SR e and -L e -NR e R' e C optionally substituted with one or more of 1~20 independently selected from alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R b and R'b is H, as well as the following substituents: H, C 1~10 Alkyl, -L f -OR f , -L f -SR f and -L f -NR f R' f C optionally substituted with one or more of 1~10 independently selected from alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R c and R' c are independently H or C 1~8 is alkyl; R d and R' d are independently H or C 1~14 is alkyl; R e and R' e are independently H or C 1~20 is alkyl; R f and R' f are independently H or C 1~10 alkyl) The nanoparticle composition is provided,

[0192] Technical Solution 2: In a more specific embodiment, the present disclosure provides a lipid composition comprising the following components in molar percentage: ionizable cationic lipids 25 mol% to 65 mol%; Structural lipids 25mol%~70mol%; Neutral lipids 1mol%~25mol%; Polymer lipids 0.5 mol% to 8 mol% The nanoparticle composition as described above is provided, comprising:

[0193] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 30 mol% to 60 mol%; structural lipids 27.5 mol% to 66 mol%; Neutral lipids 1.5mol%~20mol%; Polymer lipid 1mol%~5mol% Includes.

[0194] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 30 mol% to 50 mol%; structural lipids 30.5 mol% to 66 mol%; Neutral lipids 1.5mol%~20mol%; Polymer lipid 1mol%~5mol% Includes.

[0195] Technical Solution 3: In a more specific embodiment, the present disclosure provides a compound of formula (IV), wherein M1 and M2 are -C(O)O-, -SC(O)O-, -OC(O)NR a -, -NR a C(O)NR a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -C(O)S-, -C(O)NR a -, -NR a C(O)S-, -SC(O)NR a -, -C(S)O-, -OC(S)NR a - and -NR a C(S)O-; alternatively -C(O)O-, -C(O)S-, -C(O)NR a -, and -C(S)O-; alternatively -C(O)O-, -C(O)S- and -C(O)NR a - Independently selected from the following nanoparticle compositions:

[0196] Technical Solution 4: In a more specific embodiment, the present disclosure provides a compound of formula (IV), wherein Q is a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR bC(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, and -S(O) 0~2 -; alternatively selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O-, -NHC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)S-, -SC(O)NH-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NH- and -NHC(S)O-; alternatively -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O- and -NHC(O)O-; and further alternatively -C(O)O-.

[0197] Technical Solution 5: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein in the compound of formula (IV), G5 is a chemical bond.

[0198] Technical Solution 6: In a more specific embodiment, the present disclosure provides a compound of formula (IV): G 6a and G 6b are independently a chemical bond or one, two, three or four R ** optionally substituted with C 1~5 is alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3, 4 or 5 carbon atoms; The above nanoparticle composition is provided.

[0199] Instead, G 6a is a chemical bond or 1, 2, 3 or 4 R ** optionally substituted with C 1~4 is alkylene; G6b is a chemical bond, or one or two R ** optionally substituted with C 1~2 is alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3 or 4 carbon atoms.

[0200] Instead, G 6a is a chemical bond or C 1~4 Alkylene, instead of C 2~4 Alkylene, instead of C 2~3 alkylene, and alternatively -(CH2)2-; G 6b is a chemical bond or methylene; G 6a and G 6b but has a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.

[0201] Instead, G 6a is a chemical bond or C 1~4 Straight chain alkylene, instead of C 2~4 Straight chain alkylene, instead of C 2~3 straight chain alkylene, further alternatively -(CH2)2-; G 6b is a chemical bond or methylene; G 6a and G 6b but has a total length of 0, 1, 2, 3 or 4 carbon atoms, alternatively 1, 2, 3 or 4 carbon atoms, alternatively 2 or 3 carbon atoms.

[0202] Technical Solution 7: In a more specific embodiment, the present disclosure provides a compound of formula (IV) in which R and R ** are independent, H, C 1~6 Alkyl, -L c -OR c or -L c -NR c R' c and R 10is H.

[0203] Instead, R9 and R ** are independently H or C 1~6 alkyl, and R 10 is H.

[0204] Instead, R9, R ** and R 10 is H.

[0205] Technical Solution 8: In a more specific embodiment, the present disclosure provides a compound of formula (IV): -G1-C(R5R6)-G2-

[0206] [ka] and -G3-C(R7R8)-G4- is

[0207] [ka] and; Either L3 and L5, or either L4 and L6, is -(CR s R s ')2-, -CH=CH- or -C≡C-, and the other is a chemical bond; G 1a , G 1b , G 2a , G 2b , G 3a , G 3b , G 4a and G 4b are independently a chemical bond or 1, 2, 3, 4 or 5 R s optionally substituted with C 1~7 is alkylene; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G 3a , G 3b, G 4a and G 4b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R s ' independently, H, C 1~14 Alkyl, -L d -OR d or -L d -NR d R' d is; Alternatively, either L3 and L5, or either L4 and L6, may be -(CHR s )2-, -CH=CH- or -C≡C-, and the other is a chemical bond; G 1a and G 3a are independently a chemical bond or C 1~7 is alkylene; G 1b and G 3b are independently a chemical bond or C 1~3 is alkylene; G 2a and G 4a are independently a chemical bond or C 1~3 is alkylene; G 2b and G 4b are independently a chemical bond or C 1~4 is alkylene; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; The above nanoparticle composition is provided.

[0208] Alternatively, one of L3 and L5, or one of L4 and L6, is -(CH2)2-, -CH=CH-, or -C≡C-, and the other is a chemical bond; G 1a and G3a are independently a chemical bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-; G 1b and G 3b is a chemical bond; G 2a and G 4a is a chemical bond; G 2b and G 4b are independently a chemical bond, -CH2-, -(CH2)2-, or -(CH2)3-; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0209] Instead, R s and R s ' independently, H, C 1~10 Alkyl, -L d -OR d or -L d -NR d R' d ; H or C instead 1~6 Alkyl; and alternatively H; Instead -G 1a -L3-G 1b -or-G 3a -L4-G 3b is selected from the group: -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)3-CH=CH-, -(CH2)3-C≡C-, -(CH2)2-CH=CH- and -(CH2)2-C≡C- are independently selected from; -G 2a -L5-G 2b -or-G4a -L6-G 4b is selected from the group: Chemical bonds: -CH2-, -(CH2)2-, -(CH2)3-, -CH=CH-CH2-, -C≡C-, and -C≡C-CH2- are independently selected from;

[0210] [ka] but have a total length of 4, 5, 6, 7, 8 or 9 carbon atoms.

[0211] instead,

[0212] [ka] However, the following groups: -(CH2)3-C(CH3)2-, -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, -(CH2)6-C(CH3)2-, -(CH2)7-C(CH3)2-, -(CH2)8-C(CH3)2-, -(C H2)3-CH=CH-C(CH3)2-, -(CH2)3-C≡CC(CH3)2-, -(CH2)4-C(CH3)2-CH2-, -(CH2)3-C(CH3)2-(CH2)2-, -(CH2)2-C(CH3)2-(CH2 )3-, -(CH2)2-CH=CH-C(CH3)2-CH2-, -(CH2)2-C(CH3)2-C≡C-CH2-, -(CH2)2-C(CH3)2-CH=CH-CH2-, -(CH2)2-C≡CC(CH3)2-CH2- and -(CH2)3-C(CH3)2-C≡C-, alternatively -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2- and -(CH2)6-C(CH3)2-, further alternatively -(CH2)5-C(CH3)2- are independently selected from

[0213] Technical Solution 9: In a more specific embodiment, the present disclosure provides a compound of formula (IV): R3 and R4 are independently H or 1, 2, 3, 4 or 5 R *optionally substituted with C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 10-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3 or 4 R * to form an optionally substituted 3- to 10-membered heterocyclyl.

[0214] Alternatively, R3 and R4 may independently be H or 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocyclyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 7-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3, 4 or 5 R * to form an optionally substituted 3- to 7-membered heterocyclyl.

[0215] Alternatively, R3 and R4 may independently be 1, 2, 3, 4, or 5 R * optionally substituted with C 1~6 Alkyl, instead of C 1~3 is alkyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * optionally substituted 5- to 7-membered heterocyclyl, alternatively 4- to 6-membered heterocyclyl, and further alternatively 5-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3, 4 or 5 R * to form an optionally substituted 6-membered heterocyclyl.

[0216] Instead, R * are independently H, halogen, cyano, C 1~6 Alkyl, C 1~6 Haloalkyl, -L b -OR b or -L b -NR b R' b ;H,C instead 1~6 Alkyl, C 1~6 Haloalkyl or -OR b ;H, halogen, C instead 1~6 Alkyl or C 1~6 Haloalkyl; instead of H, C 1~6 Alkyl or C 1~6 haloalkyl; alternatively, independently, H, Me, or OH; further alternatively, H or Me.

[0217] Alternatively, R3 is Me, -CH2CH3, -CH2CH2OH or -CH(CH3)2, alternatively Me, -CH2CH3 or -CH(CH3)2, further alternatively Me or -CH2CH3; R4 is Me; Alternatively, R3 and R4 together with the N atom to which they are attached represent:

[0218] [ka] ,instead

[0219] [ka] , and even instead

[0220] [ka] form; or R4 and R9 together with the atoms to which they are attached represent:

[0221] [ka] Form.

[0222] Technical Solution 10: In a more specific embodiment, the present disclosure provides a compound of formula (IV), wherein R5, R6, R7 and R8 are independently selected from the group consisting of C 1~6 Alkyl; instead of C 1~3 alkyl; and further alternatively, Me.

[0223] Alternatively, R5, R6, R7 and R8 may be 1, 2, 3, 4 or 5 R * is optionally replaced by

[0224] Technical Solution 11: In a more specific embodiment, the present disclosure provides a compound of formula (IV): R1 is -G7-L1-G8-H and R2 is -G9-L2-G 10 -H, L1 and L2 are independently -(CRR')2-, -CH=CH-, -C≡C-, or -NR''-; G7, G8, G9 and G 10 are independently a chemical bond or C optionally substituted with 1, 2, 3, 4, 5, or 6 R 1~12 is alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R' is independently H, C 1~20 Alkyl, -L a -OR a or -L a-NR a R' a That is, The above nanoparticle composition is provided.

[0225] Alternatively, L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond or C 1~6 is alkylene; G8 and G 10 independently, C 1~10 is alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with one R.

[0226] Alternatively, L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond or C 1~5 Alkylene, instead of a chemical bond or C 1~5 is a straight chain alkylene; G8 and G 10 independently, C 1~8 Alkylene, instead of C 1~8 is a straight chain alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; G9 and G 10 but have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, instead of 6, 7, 8, 9, 10 carbon atoms; G7, G8, G9 or G 10 wherein one or two methylenes are optionally and independently substituted with one R.

[0227] Alternatively, L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond, -CH2-, -(CH2)2-, -(CH2)4-, or -(CH2)5-; G8 and G 10 are independently -(CH2)2-, -(CH2)4-, -(CH2)6-, -(CH2)7-, or -(CH2)8-; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, alternatively 6, 7, 8, 9, 10 carbon atoms; G9 and G 10 but have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms, instead of 6, 7, 8, 9, 10 carbon atoms; G7, G8, G9 or G 10 wherein one or two methylenes are optionally and independently substituted with one R.

[0228] Alternatively, R and R' may independently be H, C 1~14 Alkyl, -L a -OR a or -L a -NR a R' a ; H or C instead 1~10 Alkyl; instead H or C 1~8 Alkyl; instead H or C 1~7 Alkyl; instead H or C 1~6 Alkyl; instead H or C 1~8 Straight chain alkyl; H or C instead 1~7 Straight chain alkyl; H or C instead 1~6 Straight chain alkyl; alternatively H, Me, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3 or -(CH2)7CH3; alternatively H, Me, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3 or -(CH2)6CH3; further alternatively H, Me, -(CH2)3CH3, -(CH2)4CH3 or -(CH2)5CH3.

[0229] Alternatively, R'' may be H or C 1~14 Alkyl; instead H or C 1~10 Alkyl; instead H or C 7~9 Alkyl; instead H or C 7~9 A straight chain alkyl; a further alternative is -(CH2)7CH3.

[0230] Instead, -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0231] [ka] are independently selected from

[0232] Technical Solution 12: In a more specific embodiment, the present disclosure provides a compound of formula (IV) having the following structural formula:

[0233] [ka] (In the formula, a, a', b and g are independently 0, 1, 2, 3, 4 or 5, and a' and b are not simultaneously 0; a'+g=0, 1, 2, 3, 4 or 5; c and e are independently 3, 4, 5, 6, 7, 8, or 9; d and f are independently 0, 1, 2, 3, or 4; c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9;

[0234] [ka] The methylene in the 1~6 and optionally and independently substituted with alkyl. The nanoparticle composition as described above is provided, having:

[0235] The remaining groups are defined as any one of the above.

[0236] Technical Solution 13: In a more specific embodiment, the present disclosure provides a compound of formula (V): Q is -C(O)O-, -O-, -SC(O)O-, -OC(O)NR b -, -NR b C(O)NR b -, -OC(O)S-, -OC(O)O-, -NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)S-, -SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR b C(S)O-, -SS-, and -S(O) 0~2 -Selected from; G 6a and G 6b are independently a chemical bond or one, two, three or four R ** optionally substituted with C 1~5 is alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3, 4 or 5 carbon atoms; R9 and R** are independent, H, C 1~6 Alkyl, -L c -OR c or -L c -NR c R' c and; Either L3 and L5, or either L4 and L6, is -(CR s R s ')2-, -CH=CH-, or -C≡C-, and the other is a chemical bond; G 1a , G 1b , G 2a , G 2b , G 3a , G 3b , G 4a and G 4b are independently a chemical bond or 1, 2, 3, 4 or 5 R s optionally substituted with C 1~7 is alkylene; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R3 and R4 are independently H or 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 10-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3 or 4 R * forming an optionally substituted 3- to 10-membered heterocyclyl; R * are independently H, halogen, cyano, C 1~6 Alkyl, C 1~6 Haloalkyl, -L b -OR b or -L b -NR b R' b and; R5, R6, R7 and R8 are independently 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 is alkyl; Y1 and Y2 are independently O, S, or NR a and; L1 and L2 are independently -(CRR')2-, -CH=CH-, -C≡C-, or -NR''-; G7, G8, G9 and G 10 are independently a chemical bond or C optionally substituted with 1, 2, 3, 4, 5, or 6 R 1~12 is alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R s and R s ' independently, H, C 1~10 Alkyl, -L d -OR d or -L d -NR d R' d and; R and R' are independently H, C 1~14 Alkyl, -L a -OR a or -L a -NR a R' a and; R'' is independently H or C1~14 is alkyl; L a are independently a chemical bond or C 1~14 is alkylene; L b are independently a chemical bond or C 1~6 is alkylene; L c are independently a chemical bond or C 1~6 is alkylene; L d are independently a chemical bond or C 1~10 is alkylene; R a and R' a are independent, H, C 1~14 alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R b and R' b are independent, H, C 1~6 alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R c and R' c are independently H or C 1~6 is alkyl; R d and R' d are independently H or C 1~10 is alkyl, The above nanoparticle composition is provided.

[0237] Technical Solution 14: In a more specific embodiment, the present disclosure provides a compound of formula (V): Q is selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O-, -NHC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)S-, -SC(O)NH-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NH- and -NHC(S)O-; G 6a is a chemical bond or 1, 2, 3 or 4 R **optionally substituted with C 1~4 is alkylene; G 6b is a chemical bond or one or two R ** optionally substituted with C 1~2 is alkylene; G 6a and G 6b has a total length of 0, 1, 2, 3 or 4 carbon atoms; R9 and R ** are independently H or C 1~6 is alkyl; Either L3 and L5, or either L4 and L6, is -(CHR s )2-, -CH=CH- or -C≡C-, and the other is a chemical bond; G 1a and G 3a are independently a chemical bond or C 1~7 is alkylene; G 1b and G 3b are independently a chemical bond or C 1~3 is alkylene; G 2a and G 4a are independently a chemical bond or C 1~3 is alkylene; G 2b and G 4b are independently a chemical bond or C 1~4 is alkylene; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R3 and R4 are independently H or 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 Alkyl, C 1~6haloalkyl, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocyclyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 7-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 7-membered heterocyclyl; R * are independently H, halogen, cyano, C 1~6 Alkyl, C 1~6 Haloalkyl, -L b -OR b or -L b -NR b R' b and; R5, R6, R7 and R8 are independently C 1~6 is alkyl; Y1 and Y2 are independently O, S, or NR a and; L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond or C 1~6 is alkylene; G8 and G 10 independently, C 1~10 is alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R s are independently H or C 1~6 is alkyl; R is independently H or C 1~10 is alkyl; R'' is independently H or C 1~10 is alkyl; L b are independently a chemical bond or C 1~6 is alkylene; R a are independently H or C 1~10 is alkyl; R b and R' b are independently H or C 1~6 is alkyl, The above nanoparticle composition is provided.

[0238] Technical Solution 15: In a more specific embodiment, the present disclosure provides a compound of formula (V): Q is -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O- or -NHC(O)O-; G 6a is a chemical bond or C 1~4 Alkylene, instead of a chemical bond or C 1~4 is a straight chain alkylene; G 6b is a chemical bond or methylene; G 6a and G 6b has a total length of 0, 1, 2, 3 or 4 carbon atoms; R9 is H; one of L3 and L5, or one of L4 and L6, is -(CH2)2-, -CH=CH-, or -C≡C-, and the other is a chemical bond; G 1a and G 3a are independently a chemical bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-; G 1b and G 3b is a chemical bond; G 2a and G 4a is a chemical bond; G 2b and G4b are independently a chemical bond, -CH2-, -(CH2)2-, or -(CH2)3-; G 1a , G 1b , G 2a and G 2b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; G 3a , G 3b , G 4a and G 4b has a total length of 1, 2, 3, 4, 5 or 6 carbon atoms; R3 and R4 are independently 1, 2, or 3 R * optionally substituted with C 1~6 is alkyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 5- to 7-membered heterocyclyl; Alternatively, R4 and R9 together with the atoms to which they are attached may form 1, 2, 3, 4 or 5 R * forming an optionally substituted 6-membered heterocyclyl; R * are independent, H, C 1~6 Alkyl, C 1~6 Haloalkyl or -OR b and; R5, R6, R7 and R8 are independently C 1~3 is alkyl; Y1 and Y2 are independently O, S, or NR a , instead of O or S; L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond or C 1~5 Alkylene, instead of a chemical bond or C 1~5 is a straight chain alkylene; G8 and G 10 independently, C 1~8 Alkylene, instead of C 1~8 is a straight chain alkylene; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9, or 10 carbon atoms; G7, G8, G9 or G 10 wherein one or two methylenes are optionally and independently replaced with one R; R is independently H or C 1~8 Alkyl, instead of H or C 1~8 is a straight chain alkyl; R'' is independently H or C 7~9 Alkyl, instead of H or C 7~9 is a straight chain alkyl; R a are independently H or C 8~10 Alkyl, instead of H or C 8~10 is a straight chain alkyl; R b are independently H or C 1~6 alkyl, instead of H, The above nanoparticle composition is provided.

[0239] Technical Solution 16: In a more specific embodiment, the present disclosure provides a compound of formula (V): Q is -C(O)O-, -O-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -OC(O)S-, -OC(O)O- or -NHC(O)O-; G 6a is a chemical bond, -CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-; G 6b is a chemical bond or methylene; G 6a and G 6b has a total length of 0, 1, 2, 3 or 4 carbon atoms; R9 is H; -G 1a -L3-G 1b -or-G 3a -L4-G 3b is selected from the group: -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)3-CH=CH-, -(CH2)3-C≡C-, -(CH2)2-CH=CH- and -(CH2)2-C≡C- are independently selected from; -G 2a -L5-G 2b -or-G 4a -L6-G 4b is selected from the group: Chemical bonds: -CH2-, -(CH2)2-, -(CH2)3-, -CH=CH-CH2-, -C≡C-, and -C≡C-CH2- are independently selected from;

[0240] [ka] has a total length of 4, 5, 6, 7, 8 or 9 carbon atoms; R3 is Me, -CH2CH3, -CH2CH2OH, or -CH(CH3)2; R4 is Me; Alternatively, R3 and R4 together with the N atom to which they are attached represent:

[0241] [ka] form; or R4 and R9 together with the atoms to which they are attached represent:

[0242] [ka] Forming; R5, R6, R7 and R8 are Me; Y1 and Y2 are independently O, S, or NR a and; L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-; G7 and G9 are independently a chemical bond, -CH2-, -(CH2)2-, -(CH2)4-, or -(CH2)5-; G8 and G 10 are independently -(CH2)2-, -(CH2)4-, -(CH2)6-, -(CH2)7-, or -(CH2)8-; G7 and G8 have a total length of 4, 5, 6, 7, 8, 9, 10 carbon atoms; G9 and G 10 has a total length of 4, 5, 6, 7, 8, 9, or 10 carbon atoms; G7, G8, G9 or G 10 wherein one or two methylenes are optionally and independently replaced with one R; R is independently H, Me, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3, or -(CH2)7CH3; R'' is -(CH2)7CH3; R a are independently H or -(CH2)8CH3; The above nanoparticle composition is provided.

[0243] instead,

[0244] [ka] However, the following groups: -(CH2)3-C(CH3)2-, -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, -(CH2)6-C(CH3)2-, -(CH2)7-C(CH3)2- , -(CH2)8-C(CH3)2-, -(CH2)3-CH=CH-C(CH3)2-, -(CH2)3-C≡CC(CH3)2-, -(CH2)4-C(CH3)2-CH2-, -(C H2)3-C(CH3)2-(CH2)2-, -(CH2)2-C(CH3)2-(CH2)3-, -(CH2)2-CH=CH-C(CH3)2-CH2-, -(CH2)2-C(CH3 )2-C≡C-CH2-, -(CH2)2-C(CH3)2-CH=CH-CH2-, -(CH2)2-C≡CC(CH3)2-CH2- and -(CH2)3-C(CH3)2-C≡C- are independently selected from; -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0245] [ka] are independently selected from

[0246] Technical Solution 17: In a more specific embodiment, the present disclosure provides a compound of formula (VI) or formula (VII): a, a', b and g are independently 0, 1, 2, 3, 4 or 5, and a' and b are not simultaneously 0; a'+g=0, 1, 2, 3, 4 or 5; c and e are independently 3, 4, 5, 6, 7, 8, or 9; d and f are independently 0, 1, 2, 3, or 4; c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9;

[0247] [ka] The methylene in 1~6 optionally and independently substituted with alkyl; R3 and R4 are independently H or 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 Alkyl, C 1~6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; Alternatively, R3 and R4 together with the N atom to which they are attached form 1, 2, 3, 4 or 5 R * forming an optionally substituted 3- to 10-membered heterocyclyl; R * are independently H, halogen, cyano, C 1~6 Alkyl, C 1~6 Haloalkyl, -L b -OR b or -L b -NR b R' b and; R5, R6, R7 and R8 are independently 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 is alkyl; Y1 and Y2 are independently O, S, or NR a and; L1 and L2 are independently -(CRR')2-, -CH=CH-, -C≡C-, or -NR''-; G7, G8, G9 and G 10are independently a chemical bond or C optionally substituted with 1, 2, 3, 4, 5, or 6 R 1~12 is alkylene; G7 and G8 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G9 and G 10 has a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R and R' are independently H, C 1~14 Alkyl, -L a -OR a or -L a -NR a R' a and; L a are independently a chemical bond or C 1~14 is alkylene; L b are independently a chemical bond or C 1~6 is alkylene; R a and R' a are independent, H, C 1~14 alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R b and R' b are independent, H, C 1~6 alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R'' is independently H or C 1~14 is alkyl, The above nanoparticle composition is provided.

[0248] Technical Solution 18: In a more specific embodiment, the present disclosure provides a compound of formula (VI) or formula (VII): a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; a' and b are independently 0, 1, 2, 3 or 4, alternatively 2; g is 0, 1 or 2, alternatively 0 or 1; a'+g=0, 1, 2, 3, 4 or 5, alternatively a'+g=2 or 3; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6;

[0249] [ka] The methylene in 1~6 optionally and independently substituted with alkyl;

[0250] [ka] The methylene in 1~6 optionally and independently substituted with alkyl; R3 and R4 are independently 1, 2, or 3 R * optionally substituted with C 1~6 is alkyl; R * are independent, H, C 1~6 Alkyl, C 1~6 Haloalkyl or -OR b is; Alternatively, R3 and R4 together with the N atom to which they are attached form one, two or three R * optionally substituted 3- to 7-membered heterocyclyl, alternatively forming a 5-membered heterocyclyl; R5, R6, R7 and R8 are independently 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 is alkyl; Y1 and Y2 are independently O, S, or NR a , instead of O or S; L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-, alternatively -(CHR)2-, -CH=CH-, or -C≡C-; G7 and G9 are independently a chemical bond or C 1~6 is alkylene; G8 and G 10 independently, C 1~10 is alkylene; G7 and G8 have a total length of 6, 7, 8, 9 or 10 carbon atoms; G9 and G 10 has a total length of 6, 7, 8, 9 or 10 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with one R, and alternatively, the methylenes joining Y1 and Y2 are not substituted with R; R is independently H or C 1~8 is alkyl; R'' is independently H or C 1~10 is alkyl; R a are independently H or C 1~10 is alkyl; R b are independently H or C 1~6 alkyl, instead of H, The above nanoparticle composition is provided.

[0251] Technical Solution 19: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; R3 and R4 are independently C 1~6 is alkyl; Alternatively, R3 and R4 together with the N atom to which they are attached form one, two or three R * optionally substituted 4- to 6-membered heterocyclyl, alternatively forming a 5-membered heterocyclyl; R * are independent, H, C 1~6 Alkyl or C 1~6 is haloalkyl; R5, R6, R7 and R8 are independently 1, 2, 3, 4 or 5 R * optionally substituted with C 1~6 Alkyl, instead of C 1~3 is alkyl; Y1 and Y2 are independently O, S, or NR a , instead of O or S; L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C-, or -NR''-, alternatively -(CHR)2-, -CH=CH-, or -C≡C-; G7 and G9 are independently a chemical bond or C 1~5 Alkylene, instead of a chemical bond or C 1~5 is a straight chain alkylene; G8 and G 10 independently, C 1~8 Alkylene, instead of C 1~8 is a straight chain alkylene; G7 and G8 have a total length of 6, 7, 8, 9 or 10 carbon atoms; G9 and G 10 has a total length of 6, 7, 8, 9 or 10 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with one R, and alternatively, the methylenes joining Y1 and Y2 are not substituted with R; R is independently H or C 1~8 Alkyl, instead of H or C 1~7 Alkyl, instead of H or C 1~6 is alkyl; R'' is independently H or C 7~9 is alkyl; R a are independently H or C 8~10 is alkyl, The above nanoparticle composition is provided.

[0252] Alternatively, R may be independently H or C. 1~8 Straight chain alkyl, instead of H or C 1~7 Straight chain alkyl, instead of H or C 1~6 It is a straight chain alkyl.

[0253] Alternatively, R'' may be independently H or C 7~9 It is a straight chain alkyl.

[0254] Instead, R a are independently H or C 8~10 It is a straight chain alkyl.

[0255] Technical Solution 20: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; instead,

[0256] [ka] are independently -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, -(CH2)6-C(CH3)2-, -(CH2)4-C(CH3)2-CH2-, or -(CH2)3-C(CH3)2-(CH2)2-; R3 and R4 are independently C 1~6 alkyl, instead of Me; Alternatively, R3 and R4 together with the N atom to which they are attached represent:

[0257] [ka] ,instead

[0258] [ka] Forming; R5, R6, R7 and R8 are Me; Y1 and Y2 are independently O, S, or NR a , instead of O or S; L1 and L2 are independently -(CHR)2-, -CH=CH-, -C≡C- or -NR''-, alternatively -(CHR)2-, -CH=CH- or -C≡C-; G7 and G9 are independently a chemical bond, -CH2-, -(CH2)2-, -(CH2)4-, or -(CH2)5-; G8 and G 10 are independently -(CH2)2-, -(CH2)4-, -(CH2)6-, -(CH2)7-, or -(CH2)8-; G7 and G8 have overall lengths of 6, 7, 8, 9, 10 carbon atoms; G9 and G 10 but have a total length of 6, 7, 8, 9, or 10 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with one R, and alternatively, the methylenes joining Y1 and Y2 are not substituted with R; R is independently H, Me, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -(CH2)6CH3 or -(CH2)7CH3, alternatively H, Me, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3 or -(CH2)6CH3, alternatively H, Me, -(CH2)3CH3, -(CH2)4CH3 or -(CH2)5CH3; R a are independently H or -(CH2)8CH3; R'' is -(CH2)7CH3, The above nanoparticle composition is provided.

[0259] Instead, -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -C H2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0260] [ka] , are selected independently from

[0261] [ka] isn't it.

[0262] Technical Solution 21: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2, 3, or 4; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; R3 and R4 are independently C 1~6 Alkyl, instead of C 1~3 is alkyl; R5, R6, R7 and R8 are independently C 1~6 Alkyl, instead of C 1~3 is alkyl; Y1 and Y2 are independently O or S; L1 and L2 are independently -(CHR)2-, -CH=CH-, or -C≡C-; G7 and G9 independently 1~4 Alkylene, instead of C 1~4 is a straight chain alkylene; G8 and G 10 independently, C 2~7 Alkylene, instead of C 2~7 is a straight chain alkylene; G7 and G8 have a total length of 6, 7 or 8 carbon atoms; G9 and G 10 has a total length of 6, 7 or 8 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H or C 1~7 Alkyl, instead of H or C 1~7 is a straight chain alkyl; However, if L1 is -C≡C-, G7 is C 1~2 Alkylene, instead of C 1~2 is a straight chain alkylene; when L2 is -C≡C-, G9 is C 1~2 Alkylene, instead of C 1~2 is a straight chain alkylene; The above nanoparticle composition is provided.

[0263] Instead, the methylene groups at Y1 and Y2 are not substituted with R.

[0264] Technical Solution 22: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2, 3, or 4; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; instead,

[0265] [ka] are independently -(CH2)4-C(CH3)2-, -(CH2)5-C(CH3)2-, -(CH2)6-C(CH3)2-, -(CH2)4-C(CH3)2-CH2-, or -(CH2)3-C(CH3)2-(CH2)2-; R3 and R4 are independently C 1~6 alkyl, instead of Me; R5, R6, R7 and R8 are independently C 1~6 alkyl, instead of Me; Y1 and Y2 are independently O or S; L1 and L2 are independently -(CHR)2-, -CH=CH-, or -C≡C-; G7 and G9 are independently -CH2-, -(CH2)2-, or -(CH2)4-; G8 and G 10 are independently -(CH2)4-, -(CH2)6-, or -(CH2)7-; G7 and G8 have a total length of 6, 7 or 8 carbon atoms; G9 and G 10 has a total length of 6, 7 or 8 carbon atoms; G7, G8, G9 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H, Me, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, or -(CH2)6CH3; provided that when L1 is -C≡C-, G7 is -CH2- or -(CH2)2-, and when L2 is -C≡C-, G9 is -CH2- or -(CH2)2-; Instead, -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡ C-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3,

[0266] [ka] are independently selected from The above nanoparticle composition is provided.

[0267] Technical Solution 23: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2, 3 or 4, instead 2 or 3; c and e are independently 4, 5, or 6; d and f are 0; R3 and R4 are independently C 1~6 Alkyl, instead of C 1~3 is alkyl; R5, R6, R7 and R8 are independently C 1~6 Alkyl, instead of C 1~3 is alkyl; Y1 and Y2 are O; L1 and L2 are independently -(CHR)2- or -CH=CH-; G7 and G9 are independently -CH2- or -CH2CHR-; G8 and G 10 are independently -(CH2)6- or -(CH2)7-; G7 and G8 have a total length of 7 or 8 carbon atoms; G9 and G 10 has a total length of 7 or 8 carbon atoms; G8 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H or C4~6 alkyl, alternatively H or C5 alkyl; Instead -G7-L1-G8-H and -G9-L2-G 10 -H is not simultaneously -(CH2)9CH3, The above nanoparticle composition is provided.

[0268] Alternatively, R may be independently H or C. 4~6 Straight chain alkyl, alternatively H or C5 straight chain alkyl.

[0269] Technical Solution 24: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2, 3 or 4, instead 2 or 3; c and e are independently 4, 5, or 6; d and f are 0; R3 and R4 are Me; R5, R6, R7 and R8 are Me; Y1 and Y2 are O; -G7-L1-G8-H and -G9-L2-G 10 -H is one of the following groups: -(CH2)8CH3, -(CH2)9CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3,

[0270] [ka] ;instead of -(CH2)8CH3, -(CH2)9CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3 and

[0271] [ka] independently selected from; alternatively -G7-L1-G8-H and -G9-L2-G 10 -H is not simultaneously -(CH2)9CH3, The above nanoparticle composition is provided.

[0272] Technical Solution 25: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 3; c and e are independently 5 or 6, alternatively 6; d and f are 0; R3 and R4 are independently C 1~3 is alkyl; R5, R6, R7 and R8 are independently C 1~3 is alkyl; Y1 and Y2 are O; L1 and L2 are independently -(CHR)2- or -CH=CH, alternatively -(CHR)2-; G7 and G9 are independently -CH2- or -CH2CHR-; G8 and G 10 are independently -(CH2)6- or -(CH2)7-; G7 and G8 have a total length of 7 or 8 carbon atoms, alternatively 7 carbon atoms; G9 and G 10 but having a total length of 7 or 8 carbon atoms, alternatively 7 carbon atoms; G8 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H or C 4~6 alkyl, alternatively H or C5 alkyl; The above nanoparticle composition is provided.

[0273] Alternatively, R may be independently H or C. 4~6 Straight chain alkyl, alternatively H or C5 straight chain alkyl.

[0274] Technical Solution 26: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 3; c and e are 6; d and f are 0; R3 and R4 are Me; R5, R6, R7 and R8 are Me; Y1 and Y2 are O; -G7-L1-G8-H and -G9-L2-G 10 -H is one of the following groups: -(CH2)8CH3,

[0275] [ka] ;instead of -(CH2)8CH3 and

[0276] [ka] are independently selected from The above nanoparticle composition is provided.

[0277] Technical Solution 27: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2 or 3, instead it is 2; c and e are independently 4, 5, or 6, alternatively 5; d and f are 0; R3 and R4 are independently C 1~3 is alkyl; R5, R6, R7 and R8 are independently C 1~3 is alkyl; one of Y1 and Y2 is O and the other is S; L1 and L2 are independently -(CHR)2- or -CH=CH, alternatively -(CHR)2-; G7 and G9 are independently -CH2- or -CH2CHR-; G8 and G 10 are independently -(CH2)5- or -(CH2)6-; G7 and G8 have a total length of 7 carbon atoms; G9 and G 10 has a total length of 7 carbon atoms; G8 or G 10wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H or C 4~6 alkyl, alternatively H or C5 alkyl; The above nanoparticle composition is provided.

[0278] Alternatively, R may be independently H or C. 4~6 Straight chain alkyl, alternatively H or C5 straight chain alkyl.

[0279] Technical Solution 28: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are 5; d and f are 0; R3 and R4 are Me; R5, R6, R7 and R8 are Me; one of Y1 and Y2 is O and the other is S; -G7-L1-G8-H and -G9-L2-G 10 -H is one of the following groups: -(CH2)8CH3,

[0280] [ka] ;instead of -(CH2)8CH3 are independently selected from The above nanoparticle composition is provided.

[0281] Technical Solution 29: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are independently 4, 5, or 6, alternatively 5; d and f are 0; R3 and R4 are independently C 1~6 Alkyl, instead of C 1~3 is alkyl; R5, R6, R7 and R8 are independently C 1~6Alkyl, instead of C 1~3 is alkyl; Y1 and Y2 are independently O or S; one of L1 and L2 is -C≡C- and the other is -(CHR)2-, or both L1 and L2 are -C≡C-; alternatively one of L1 and L2 is -C≡C- and the other is -(CHR)2-; G7 and G9 are -CH2-; G8 and G 10 are independently -(CH2)6- or -(CH2)7-; G or G optionally and independently substituted by one R 10 , instead of G8 and G 10 wherein one methylene is independently -CHR-(CH2)5-, -CHR-(CH2)6-, -CH2-CHR-(CH2)4-, or -(CH2)2-CHR-(CH2)4-; R is independently H or C 4~6 alkyl, alternatively H or C5 alkyl; However, -G7-L1-G8-H and -G9-L2-G 10 only one of the -H is substituted with one non-hydrogen R substituent, and the other is unsubstituted; The above nanoparticle composition is provided.

[0282] Alternatively, R may be independently H or C. 4~6 Straight chain alkyl, alternatively H or C5 straight chain alkyl.

[0283] Technical Solution 30: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are 5; d and f are 0; R3 and R4 are Me; R5, R6, R7 and R8 are Me; Y1 and Y2 are independently O or S; -G7-L1-G8-H and -G9-L2-G 10 -H is one of the following groups: -(CH2)8CH3, -(CH2)9CH3, -CH2-C≡C-(CH2)6CH3,

[0284] [ka] are independently selected from; However, -G7-L1-G8-H and -G9-L2-G 10 At least one of the -Hs contains an alkynyl, and one of the two has a substituent and the other has no substituent; The above nanoparticle composition is provided.

[0285] Technical Solution 31: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are independently 4, 5, or 6, alternatively 5; d and f are 0; R3 and R4 are independently C 1~3 alkyl, instead of Me; R5, R6, R7 and R8 are independently C 1~3 alkyl, instead of Me; Y1 and Y2 are independently O or S, instead O; Both L1 and L2 are -C≡C-; G7 and G9 are -CH2-; G8 and G 10 are independently -(CH2)6- or -(CH2)7-, alternatively -(CH2)7-; The above nanoparticle composition is provided.

[0286] Technical Solution 32: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are 3; d and f are 2; R3 and R4 are independently C 1~3 alkyl, instead of Me; R5, R6, R7 and R8 are independently C 1~3 is alkyl; Y1 and Y2 are independently O or S, instead O; L1 and L2 are -(CHR)2-; G7 and G9 are independently -CH2- or -CH2CHR-; G8 and G 10 are independently -(CH2)5-, -(CH2)6-, or -(CH2)7-; G7 and G8 have a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms; G9 and G 10 but having a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms; G8 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H or C 1~7 Alkyl, instead of H or C 1~6 alkyl, instead of Me, The above nanoparticle composition is provided.

[0287] Alternatively, R may be independently H or C. 1~7 Straight chain alkyl, instead of H or C 1~6 Straight chain alkyl, instead Me.

[0288] Technical Solution 33: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are 3; d and f are 2; R3 and R4 are Me; R5, R6, R7 and R8 are Me; Y1 and Y2 are independently O or S, instead O; -G7-L1-G8-H and -G9-L2-G 10 -H is one of the following groups:

[0289] [ka] ,instead

[0290] [ka] ,instead

[0291] [ka] are independently selected from The above nanoparticle composition is provided.

[0292] Technical Solution 34: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are 4, 5 or 6, instead of 5; d and f are 0; R3 and R4 are independently C 1~6 Alkyl, instead of C 1~3 is alkyl; R5, R6, R7 and R8 are independently C 1~6 Alkyl, instead of C 1~3 is alkyl; Y1 and Y2 are S; L1 and L2 are -(CHR)2-; G7 and G9 are independently -CH2- or -CH2CHR-; G8 and G 10 are independently -(CH2)5-, -(CH2)6-, or -(CH2)7-; G7 and G8 have a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms; G9 and G 10 but having a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms; G8 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H or C 4~6alkyl, alternatively H or C5 alkyl; The above nanoparticle composition is provided.

[0293] Alternatively, R may be independently H or C. 4~6 Straight chain alkyl, alternatively H or C5 straight chain alkyl.

[0294] Technical Solution 35: In a more specific embodiment, the present disclosure provides a compound of formula (VI): a is 2; c and e are 5; d and f are 0; R3 and R4 are independently Me; R5, R6, R7 and R8 are independently Me; Y1 and Y2 are S; -G7-L1-G8-H and -G9-L2-G 10 -H is: -(CH2)8CH3, -(CH2)9CH3,

[0295] [ka] , instead of -(CH2)8CH3 or -(CH2)9CH3, instead of -(CH2)9CH3 are independently selected from The above nanoparticle composition is provided.

[0296] Technical Solution 36: In a more specific embodiment, the present disclosure provides a compound of formula (VII): a' and b are 2; g is 0 or 1; c and e are 5; d and f are 0; R3 can be 1, 2 or 3 R * optionally substituted with C 1~6 is alkyl; R * are independent, H, C 1~6 Alkyl, C 1~6 Haloalkyl or -ORb , instead of H, C 1~6 Alkyl or C 1~6 is haloalkyl; R5, R6, R7 and R8 are independently C 1~3 is alkyl; Y1 and Y2 are independently O or S; L1 and L2 are -(CHR)2-; G7 and G9 are independently -CH2- or -CH2CHR-; G8 and G 10 are independently -(CH2)5-, -(CH2)6-, or -(CH2)7-; G7 and G8 have a total length of 6, 7 or 8 carbon atoms; G9 and G 10 has a total length of 6, 7 or 8 carbon atoms; G8 or G 10 wherein 1, 2, or 3 methylenes are optionally and independently substituted with 1 R; R is independently H or C 4~6 is alkyl; R b are independently H or C 1~6 alkyl, instead of H, The above nanoparticle composition is provided.

[0297] Alternatively, R may be independently H or C. 4~6 It is a straight chain alkyl.

[0298] Technical Solution 37: In a more specific embodiment, the present disclosure provides a compound of formula (VII): a' and b are 2; g is 0 or 1; c and e are 5; d and f are 0; R3 is Me, -CH2CH3, -CH2CH2OH or -CH(CH3)2, alternatively Me, -CH2CH3 or -CH(CH3)2; R5, R6, R7 and R8 are independently Me; Y1 and Y2 are independently O or S; -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[0299] [ka] ;instead of -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3 and

[0300] [ka] are independently selected from The above nanoparticle composition is provided.

[0301] Technical Solution 38: In a more specific embodiment, the present disclosure provides a compound of formula (VII): R3 is Me or -CH2CH3, instead Me; both Y1 and Y2 are O; G7 and G8 have a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms; G9 and G 10 but having a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms, The above nanoparticle composition is provided.

[0302] Technical Solution 39: In a more specific embodiment, the present disclosure provides a compound of formula (VII): a' and b are 2; g is 0 or 1; c and e are 5; d and f are 0; R3 is Me or -CH2CH3, instead Me; R5, R6, R7 and R8 are independently Me; both Y1 and Y2 are O; -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)7CH3, -(CH2)8CH3,

[0303] [ka] ;Instead of -(CH2)7CH3, -(CH2)8CH3 and

[0304] [ka] are independently selected from; instead of -(CH2)7CH3, The above nanoparticle composition is provided.

[0305] Technical Solution 40: In a more specific embodiment, the present disclosure provides a compound of formula (VII): R3 is Me or -CH2CH3; Y1 and Y2 are independently O or S, provided that Y1 and Y2 are not both O; G7 and G8 have a total length of 6, 7 or 8 carbon atoms; G9 and G 10 has a total length of 6, 7 or 8 carbon atoms; The above nanoparticle composition is provided.

[0306] Technical Solution 41: In a more specific embodiment, the present disclosure provides a compound of formula (VII): g is 0 or 1, alternatively 1; R3 is Me or -CH2CH3, instead Me; one of Y1 and Y2 is O and the other is S; G7 and G8 have a total length of 7 carbon atoms; G9 and G 10 has a total length of 7 carbon atoms, The above nanoparticle composition is provided.

[0307] Technical Solution 42: In a more specific embodiment, the present disclosure provides a compound of formula (VII), a' and b are 2; g is 0 or 1, alternatively 1; c and e are 5; d and f are 0; R3 is Me or -CH2CH3, instead Me; R5, R6, R7 and R8 are independently Me; one of Y1 and Y2 is O and the other is S; -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)8CH3,

[0308] [ka] ;instead of -(CH2)8CH3 and

[0309] [ka] are independently selected from The above nanoparticle composition is provided.

[0310] Technical Solution 43: In a more specific embodiment, the present disclosure provides a compound of formula (VII), g is 0 or 1, alternatively 0; R3 is Me or -CH2CH3; both Y1 and Y2 are S; G7 and G8 have a total length of 7 or 8 carbon atoms; G9 and G 10 has a total length of 7 or 8 carbon atoms, The above nanoparticle composition is provided.

[0311] Technical Solution 44: In a more specific embodiment, the present disclosure provides a compound of formula (VII), a' and b are 2; g is 0 or 1, alternatively 0; c and e are 5; d and f are 0; R3 is Me or -CH2CH3; R5, R6, R7 and R8 are independently Me; both Y1 and Y2 are S; -G7-L1-G8-H or -G9-L2-G 10 -H is one of the following groups: -(CH2)8CH3, -(CH2)9CH3,

[0312] [ka] ;Instead of -(CH2)8CH3, -(CH2)9CH3 and

[0313] [ka] are independently selected from The above nanoparticle composition is provided.

[0314] Technical Solution 45: In a more specific embodiment, the present disclosure provides a compound of formula (IV) comprising:

[0315] [ka]

[0316] [ka]

[0317] [ka] The nanoparticle composition is provided as above, wherein the nanoparticle composition is selected from:

[0318] Technical Solution 46: In a more specific embodiment, the present disclosure provides a nanoparticle composition as described above, wherein the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1-15:1, alternatively 3-12:1, alternatively 3-7:1, alternatively 6-12:1, and further alternatively 3-6:1.

[0319] In some specific embodiments, the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1-10:1, alternatively 3-6:1, and further alternatively 3-5:1.

[0320] In some specific embodiments, the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1-15:1, alternatively 3-12:1, and further alternatively 6-12:1.

[0321] In some specific embodiments, the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1-10:1, alternatively 3-7:1, and further alternatively 5:1.

[0322] Technical Solution 47: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the particle size is 65 to 200 nm, alternatively 65 to 180 nm, alternatively 70 to 170 nm, or further alternatively 70 to 130 nm.

[0323] In some specific embodiments, the particles have a size of 70-180 nm, alternatively 80-180 nm, alternatively 90-180 nm, and further alternatively 100-135 nm.

[0324] In some specific embodiments, the particles have a size between 65 and 160 nm, alternatively between 65 and 150 nm, alternatively between 70 and 150 nm, alternatively between 90 and 130 nm, and further alternatively between 90 and 115 nm.

[0325] In some specific embodiments, the particles have a size of 65-140 nm, alternatively 65-130 nm, alternatively 70-130 nm, and further alternatively 65-75 nm.

[0326] Technical Solution 48: In a more specific embodiment, the present disclosure provides a lipid composition comprising, in molar percentage, the following components: ionizable cationic lipids 30mol%-55mol%, alternatively 32.5mol%-50mol%; structural lipids 28mol%-64mol%, alternatively 30.6mol%-61mol%; Neutral lipids 5mol%~20mol%; Polymer lipid 1mol%~3mol%, alternatively 1mol%~2mol% Includes; The ionizable cationic lipid is as described in any one of technical solutions 12 to 45, alternatively as described in technical solution 23, alternatively

[0327] [ka] is, most instead

[0328] [ka] The nanoparticle composition is provided as described above, wherein

[0329] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 40mol%-52.5mol%, alternatively 42.5mol%-50mol%; structural lipids 28mol%-54mol%, alternatively 30.6mol%-51mol%; Neutral lipids 5mol%~20mol%; Polymer lipid 1mol%~3mol%, alternatively 1mol%~2mol% Includes; The ionizable cationic lipid is as described in any one of technical solutions 12 to 45, alternatively as described in technical solution 23, alternatively

[0330] [ka] is, most instead

[0331] [ka] is.

[0332] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 45mol%-52.5mol%, alternatively 47.5mol%-50mol%; structural lipids 28mol%-43mol%, alternatively 30.6mol%-40.5mol%; Neutral lipids 10mol%~20mol%; Polymer lipid 1.4mol%~2mol% Includes; The ionizable cationic lipid is as described in any one of technical solutions 12 to 45, alternatively as described in technical solution 23, alternatively

[0333] [ka] is, most instead

[0334] [ka] is.

[0335] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 45mol%-50mol%, instead 47mol%-48mol%, instead 47.6mol%; structural lipids 28 mol%-40.5 mol%, alternatively 30.6 mol%-38.1 mol%; Neutral lipids 12.5mol%~20mol%; Polymer lipid 1.8mol%~2mol% Includes; The ionizable cationic lipid is as described in any one of technical solutions 12 to 45, alternatively as described in technical solution 23, alternatively

[0336] [ka] is, most instead

[0337] [ka] is.

[0338] Technical Solution 49: In more specific embodiments, the present disclosure provides a method for preparing a lipid-rich lipid mixture in which the molar ratio of ionizable cationic lipid:structural lipid:neutral lipid:polymeric lipid is 32.5:61:5:1.5, 32.5:51.5:15:1, 42.5:49:7.5:1, 42.5:51:5:1.5, 47.6:38.1:12.5:1.8, 47.6:30.6:20:1.8, 47.5:40.5:10:2, 47.6:32.9:17.5:2, 47.6:36:15:1.4 or 50:38.5:10:1.5; instead: 42.5:49:7.5:1, 42.5:51:5:1.5, 47.6:38.1:12.5:1. or alternatively: 47.6:38.1:12.5:1.8, 47.6:30.6:20:1.8, 47.5:40.5:10:2, 47.6:32.9:17.5:2, 47.6:36:15:1.4 or 50:38.5:10:1.5; or further alternatively: 47.6:38.1:12.5:1.8, 47.6:30.6:20:1.8 or 47.6:32.9:17.5:2.

[0339] Technical Solution 50: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1-10:1, alternatively 3-6:1, further alternatively 3-5:1.

[0340] Technical Solution 51: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the particle size is 70 to 180 nm, alternatively 80 to 180 nm, alternatively 90 to 180 nm, and further alternatively 100 to 135 nm.

[0341] Technical Solution 52: In a more specific embodiment, the present disclosure provides a lipid composition comprising, in molar percentage, the following components: ionizable cationic lipids 30 mol% to 60 mol%; structural lipids 27.5 mol% to 66 mol%; Neutral lipids 1.5mol%~20mol%; Polymer lipid 1.5mol%~5mol% Includes; The ionizable cationic lipid is as described in any one of Technical Solutions 12-45, or

[0342] [ka] Alternatively, as described in Technical Solution 23,

[0343] [ka] is, most instead

[0344] [ka] The nanoparticle composition is provided as described above, wherein

[0345] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 30 mol% to 50 mol%; structural lipids 35 mol% to 66 mol%; Neutral lipids 1.5mol%~20mol%; Polymer lipid 1.5mol%~5mol% Includes; The ionizable cationic lipid is as described in any one of Technical Solutions 12-45, or

[0346] [ka] Alternatively, as described in Technical Solution 23,

[0347] [ka] is, most instead

[0348] [ka] is.

[0349] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 30 mol% to 50 mol%; Structural lipids 38.5mol%~63.5mol%; Neutral lipids 1.5mol%~10mol%; Polymer lipid 1.5mol%~4mol%, alternatively 1.5mol%~3.5mol% Includes; The ionizable cationic lipid is as described in any one of Technical Solutions 12-45, or

[0350] [ka] Alternatively, as described in Technical Solution 23,

[0351] [ka] is, most instead

[0352] [ka] is.

[0353] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 30mol%-50mol%, alternatively 30mol%-48.5mol%; structural lipids 43 mol%–60 mol%, alternatively 45.5 mol%–57.5 mol%; Neutral lipids 1.5mol%~10mol%; Polymer lipid 1.5mol%~4mol%, alternatively 1.5mol%~3.5mol% Includes; The ionizable cationic lipid is as described in any one of Technical Solutions 12-45, or

[0354] [ka] Alternatively, as described in Technical Solution 23,

[0355] [ka] is, most instead

[0356] [ka] is.

[0357] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 46mol%-50mol%, instead 48mol%-49mol%, instead 48.5mol%; structural lipids 43mol%-50mol%, alternatively 45.5mol%-47.5mol%; neutral lipids 1.5mol%-3.5mol%, alternatively 1.5mol%-2.5mol%; Polymer lipids 2 mol% to 4 mol%, alternatively 2.5 mol% to 3.5 mol% Includes; The ionizable cationic lipid is as described in any one of Technical Solutions 12-45, or

[0358] [ka] Alternatively, as described in Technical Solution 23,

[0359] [ka] is, most instead

[0360] [ka] is.

[0361] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 46mol%-50mol%, instead 48mol%-49mol%, instead 48.5mol%; structural lipids 43mol%-49mol%, alternatively 45.5mol%-46.5mol%; neutral lipids 1.5mol%-3.5mol%, alternatively 1.5mol%-2.5mol%; Polymer lipids 3 mol% to 4 mol%, alternatively 3.5 mol% Includes; The ionizable cationic lipid is as described in any one of Technical Solutions 12-45, or

[0362] [ka] as described in Technical Solution 9, instead

[0363] [ka] is, most instead

[0364] [ka] is.

[0365] Technical Solution 53: In a more specific embodiment, the present disclosure provides a method for preparing lipids containing ionizable cationic lipids:structural lipids:neutral lipids:polymeric lipids in a molar ratio of 40:35:20:5, 40:48.5:10:1.5, 30:66:2.5:1.5, 40:53.5:5:1.5, 30:63.5:5:1.5, 40:55:2.5:2.5, 3 0:62.5:5:2.5, 30:57.5:10:2.5, 48.5:47.5:1.5:2.5, 48.5:46.5:2.5:2.5, 48.5:45.5:2.5:3.5, 48.5:46.5:1.5:3.5, 50:42.5:5:2.5, 60:27.5:10:2.5 or 50:38.5:10:1.5; Instead: 40:35:20:5, 40:48.5:10:1.5, 30:66:2.5:1.5, 40:53.5:5:1.5, 30:63.5:5:1.5, 40:55:2.5:2.5, 30:62.5:5:2.5, 30:57.5:10:2.5, 48.5:47.5:1.5:2.5, 48.5:46.5:2.5:2.5, 48.5:45.5:2.5:3.5, 48.5:46.5:1.5:3.5, 50:42.5:5:2.5 or 50:38.5:10:1.5; Instead: 40:48.5:10:1.5, 40:53.5:5:1.5, 30:63.5:5:1.5, 40:55:2.5:2.5, 30:62.5:5:2.5, 30:57.5:10:2.5, 48.5:47.5:1.5:2.5, 48.5:46.5:2.5:2.5, 48.5:45.5:2.5:3.5, 48.5:46.5:1.5:3.5, 50:42.5:5:2.5 or 50:38.5:10:1.5; Instead: 40:48.5:10:1.5, 40:53.5:5:1.5, 40:55:2.5:2.5, 30:57.5:10:2.5, 48.5:47.5:1.5:2.5, 48.5:46.5:2.5:2.5, 48.5:45.5:2.5:3.5 or 48.5:46.5:1.5:3.5; Alternatively, the nanoparticle composition is: 48.5:47.5:1.5:2.5, 48.5:46.5:2.5:2.5, 48.5:45.5:2.5:3.5 or 48.5:46.5:1.5:3.5; alternatively, the nanoparticle composition is: 48.5:45.5:2.5:3.5 or 48.5:46.5:1.5:3.5.

[0366] Technical Solution 54: In a more specific embodiment, the present disclosure provides a nanoparticle composition as described above, wherein the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1-15:1, alternatively 3-12:1, further alternatively 6-12:1.

[0367] Technical Solution 55: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the particle size is 65 to 160 nm, alternatively 65 to 150 nm, alternatively 75 to 150 nm, alternatively 90 to 130 nm, or further alternatively 90 to 115 nm.

[0368] Technical Solution 56: In a more specific embodiment, the present disclosure provides a lipid composition comprising, in molar percentage, the following components: ionizable cationic lipids 27.5mol%-55mol%, alternatively 30mol%-50mol%; structural lipids 35mol%-68.5mol%, alternatively 38.5mol%-66mol%; Neutral lipids 1.5mol%-20mol%, alternatively 2.5mol%-15mol%; Polymer lipids 1 mol% to 5 mol%, alternatively 1.5 mol% to 3.5 mol% Includes; Alternatively, the ionizable cationic lipid is as described in Technical Solution 23.

[0369] [ka] is, most instead

[0370] [ka] The nanoparticle composition is provided as described above, wherein

[0371] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 27.5mol%-42.5mol%, alternatively 30mol%-40mol%; structural lipids 41 mol%–68.5 mol%, alternatively 43.5 mol%–66 mol%; Neutral lipids 2mol%-18mol%, alternatively 2.5mol%-15mol%; Polymer lipids 1 mol% to 4 mol%, alternatively 1.5 mol% to 3.5 mol% Includes; Alternatively, the ionizable cationic lipid is as described in Technical Solution 23.

[0372] [ka] is, most instead

[0373] [ka] is.

[0374] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 37.5 mol% to 42.5 mol%, instead 40 mol%; structural lipids 41 mol%–58.5 mol%, alternatively 43.5 mol%–56 mol%; Neutral lipids 2mol%-18mol%, alternatively 2.5mol%-15mol%; Polymer lipids 1 mol% to 4 mol%, alternatively 1.5 mol% to 3.5 mol% Includes; Alternatively, the ionizable cationic lipid is as described in Technical Solution 23.

[0375] [ka] is, most instead

[0376] [ka] is.

[0377] Alternatively, the lipid component may comprise, in mole percentage, the following components: ionizable cationic lipids 27.5 mol% to 32.5 mol%, instead 30 mol%; structural lipids 63.5 mol% to 68.5 mol%, instead 66 mol%; Neutral lipids 2mol%-3mol%, instead 2.5mol%; Polymer lipid 1 mol% to 2 mol%, alternatively 1.5 mol% Includes; Alternatively, the ionizable cationic lipid is as described in Technical Solution 23.

[0378] [ka] is, most instead

[0379] [ka] is.

[0380] Technical Solution 57: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the molar ratio of ionizable cationic lipid:structural lipid:neutral lipid:polymeric lipid is 40:44:12.5:3.5, 40:53.5:5:1.5, 40:43.5:15:1.5, 30:66:2.5:1.5, 40:56:2.5:1.5, 40:51:7.5:1.5 or 50:38.5:10:1.5; alternatively: 40:44:12.5:3.5, 40:53.5:5:1.5, 40:43.5:15:1.5, 30:66:2.5:1.5, 40:56:2.5:1.5 or 40:51:7.5:1.5; alternatively: 30:66:2.5:1.5.

[0381] Technical Solution 58: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1-10:1, alternatively 3-7:1, further alternatively 5:1.

[0382] Technical Solution 59: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the particle size is 65 to 140 nm, alternatively 65 to 130 nm, alternatively 70 to 130 nm, and further alternatively 65 to 75 nm.

[0383] Technical Solution 60: In a more specific embodiment, the present disclosure provides a nanoparticle composition as described above, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE and DPPE, alternatively DSPC and / or DOPE.

[0384] Technical Solution 61: In a more specific embodiment, the present disclosure provides a nanoparticle composition as described above, wherein the structural lipid is selected from one or more of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campesterol, alternatively cholesterol and / or β-sitosterol, further alternatively cholesterol.

[0385] Technical Solution 62: In a more specific embodiment, the present disclosure provides the above nanoparticle composition, wherein the polymeric lipid is a PEGylated lipid.

[0386] Optionally, the pegylated lipid is selected from one or more of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, and a PEG-modified dialkylglycerol.

[0387] Alternatively, the pegylated lipid contains a PEG moiety of from about 1000 Da to about 20 kDa, alternatively from about 1000 Da to about 5000 Da.

[0388] Alternatively, the pegylated lipid is selected from one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, azide-PEG2000, DSPE-PEG2000-mannose, ceramide-PEG5000, and DSPE-PEG5000, alternatively DMG-PEG2000.

[0389] Technical Solution 63: In a more specific embodiment, the present disclosure provides a method for detecting a payload, wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent, and a diagnostic agent; Alternatively, the therapeutic, prophylactic or diagnostic agent is a nucleic acid; Alternatively, the nucleic acid is selected from one or more of ASO, RNA and DNA; Alternatively, the RNA is selected from one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA) and nucleases; alternatively, mRNA; further alternatively, modified mRNA; The above nanoparticle composition is provided.

[0390] Technical Solution 64: In a more specific embodiment, the present disclosure provides a method for preparing the above nanoparticle composition, comprising the steps of mixing the components of the lipid component and then with a payload; Alternatively, mixing each component of the lipid component with a solvent and then a solution of the payload. Includes; Alternatively, the solvent is an organic solvent, instead an alcoholic solvent, instead ethanol; Alternatively, the payload is a sodium acetate solution, alternatively a nucleic acid dissolved in a 20-30 mmol / L sodium acetate solution; A method is provided.

[0391] Technical Solution 65: In a more specific embodiment, the present disclosure provides a method for preparing the above nanoparticle composition, further comprising the step of removing impurities; alternatively by ultrafiltration; alternatively using a 30 kDa ultrafiltration tube for ultrafiltration.

[0392] Technical Solution 66: In a more specific embodiment, the present disclosure provides a method for preparing the above nanoparticle composition, further comprising a sterilization step; alternatively, a step of using a sterile filtration membrane for filtration and sterilization; alternatively, the sterile filtration membrane has a pore size of 0.2 μm.

[0393] Technical Solution 67: In a more specific embodiment, the present disclosure also provides a compound having the structure of general formula (I):

[0394] [ka] (In the formula, G1, G2, G3, or G4 each independently represent a bond, C 1~20 Alkylene, C 2~20 Alkenylene or C 2~20 is alkynylene; G5 or G6 each independently represent a bond or C 1~8 is alkylene; M1 or M2 are each independently a biodegradable group; Q is a bond or a biodegradable group; R1 or R2 are each independently C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 is alkynyl; R3 or R4 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R3 and R4 together with the N atom to which they are attached form a 3- to 14-membered heterocyclyl; R5, R6, R7 or R8 are each independently C 1~8 is alkyl; each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each independently and optionally further substituted. and a pharmaceutically acceptable salt or stereoisomer thereof.

[0395] Furthermore, the lipid compound has the structure of general formula (I)

[0396] [ka] (In the formula, G1, G2, G3, or G4 each independently represent a bond, C 1~20 Alkylene, C 2~20 Alkenylene or C 2~20 Alkynylene; C 1~20 Alkylene, C 2~20 Alkenylene or C 2~20 The alkynylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; G5 or G6 each independently represent a bond or C 1~6 alkylene; C 1~6 The alkylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; M1 or M2 is -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -O-, -OC(O)O-, -SC(O)O-, -OC(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -OC(O)NR a -, -NR a C(O)S-, -SC(O)NR a -, -NR a C(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS- and -S(O) m - each independently selected from; Q is a bond, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -O-, -OC(O)O-, -SC(O)O-, -OC(O)S-, or -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)O-, -OC(O)NR b -, -NR b C(O)S-, -SC(O)NR b -, -NR b C(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR a C(S)O-, -SS-, -S(O) n -, phenylene and pyridylidene; wherein the phenylene or pyridylidene group is optionally substituted with one or more substituents selected from H, hydroxy, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl and alkoxy; R1 or R2 are each independently C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 Alkynyl; C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 alkynyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; R3 and R4 are each independently H or C 1~20 Alkyl; C 1~20 The alkyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; or R3 and R4, together with the N atom to which they are attached, form a 3- to 14-membered heterocyclyl; the 3- to 14-membered heterocyclyl is optionally further substituted with substituents selected from halogen, cyano, OH, alkyl, hydroxyalkyl, haloalkyl, alkoxy, amino, alkylamino, and dialkylamino; R5, R6, R7 or R8 are each independently C 1~8 is alkyl; R a or R b each independently represents H, C 1~28 Alkyl or C 3~14 is cycloalkyl; C 1~28 Alkyl or C 3~14 cycloalkyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; m and n are each independently 0, 1, or 2. It has.

[0397] Furthermore, both G1 and G3 are C 2~8 alkylene and G2 and G4 are both a bond; alternatively, G1 and G3 are both C5 alkylene and G2 and G4 are both a bond.

[0398] Additionally, G5 is a bond.

[0399] Furthermore, G6 is a bond or C 1~6 It is alkylene.

[0400] Furthermore, each of M1 and M2 independently represents -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, or -NR a C(O)- or -C(O)NR a - and R a is H or C 4~24 Alternatively, each M1 or M2 is independently -C(O)O- or -C(O)S-.

[0401] Further, Q is a bond, -O-, -OC(O)-, -C(O)O-, -OC(O)O-, or -OC(O)NH-, -NHC(O)O-, -NHC(O)NH-, -OC(O)S-, or -SC(O)O-; alternatively Q is -C(O)O-.

[0402] Further, R1 or R2 may each independently be C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 Alkynyl, C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 Alkynyl is a group consisting of one or more substituents H, hydroxyl or C 2~14 Alternatively, R1 or R2 may each independently be C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 It is alkynyl.

[0403] Additionally, R3 or R4 may each independently be C 1~6 alkyl or hydroxyethyl; alternatively, R3 or R4 are both methyl.

[0404] Further, R5, R6, R7 or R8 each independently represent C 1~3 Alternatively, R5, R6, R7 or R8 are both methyl.

[0405] Furthermore, the lipid compound may be a compound of general formula (II) or general formula (III):

[0406] [ka] wherein the substituents are defined as described in general formula (I). is.

[0407] Technical Solution 68: The present disclosure provides a compound comprising:

[0408] [ka]

[0409] [ka] The present invention provides a lipid compound selected from the group consisting of:

[0410] Technical Solution 69: The present disclosure provides a composition comprising a biologically active substance and a lipid compound of the present disclosure.

[0411] Additionally, the biologically active substance is DNA or RNA.

[0412] Additionally, the composition further comprises a neutral lipid, a structured lipid, and a polymeric lipid.

[0413] Further, the neutral lipid is DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE.

[0414] Additionally, the structural lipid is selected from one or a combination of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, and campesterol.

[0415] Further, the polymeric lipid is selected from one or a combination of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, azide-PEG2000, DSPE-PEG2000-mannose, ceramide-PEG5000, and DSPE-PEG5000.

[0416] Technical Solution 70: The present disclosure provides lipid nanoparticles comprising the lipid compound of the present disclosure or the composition of the present disclosure.

[0417] Technical Solution 71: The present disclosure provides a pharmaceutical composition comprising a lipid compound of the present disclosure, a composition of the present disclosure, or a lipid nanoparticle of the present disclosure, and a pharmaceutically acceptable excipient(s).

[0418] Technical Solution 72: The present disclosure provides use of a lipid compound of the present disclosure, a composition of the present disclosure, a lipid nanoparticle of the present disclosure, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating or preventing a disease.

[0419] Technical Solution 73: The present disclosure provides a method for preparing a compound of general formula (II), comprising:

[0420] [ka] reacting a compound of general formula (IIb) with a compound of general formula (IIc) to obtain a compound of general formula (II) wherein the substituents are defined as described in general formula (I). The present invention provides a method comprising:

[0421] Technical Solution 74: The present disclosure provides a compound having a structure of general formula (IIa) or general formula (IIb):

[0422] [ka] wherein the substituents are defined as described in general formula (I). and a pharmaceutically acceptable salt or stereoisomer thereof.

[0423] When a degradable group in a compound is changed, a compound of the corresponding structure can be prepared by conventional methods in the art, such as esterification and amide condensation.

[0424] Technical Solution 75: The present disclosure provides the use of a compound having a structure of general formula (IIa) or general formula (IIb), a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a cationic lipid.

[0425] Technical Solution 76: The present disclosure also provides a compound having a structure of general formula (I'):

[0426] [ka] (In the formula, Ring A is C 3~14 Cycloalkyl, 3-14 membered heterocyclyl, C 6~14 aryl or 5-14 membered heteroaryl; Ring A is connected to the parent structure by a C atom on the ring; Ring A is optionally further substituted; G1, G2, G3, or G4 each independently represent a bond, C 1~20 Alkylene, C 2~20 Alkenylene or C 2~20 is alkynylene; G5 or G6 each independently represent a bond or C 1~8 is alkylene; M1 or M2 are each independently a biodegradable group; Q is a bond or a biodegradable group; R1 or R2 are each independently C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 is alkynyl; R'3, R'4, R'5 or R'6 each independently represent C 1~8 is alkyl; each of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each independently and optionally further substituted. or a pharmaceutically acceptable salt or stereoisomer thereof.

[0427] Furthermore, the lipid compound has the structure of general formula (I')

[0428] [ka] (In the formula, Ring A is C 3~14 Cycloalkyl, 3-14 membered heterocyclyl, C 6~14 aryl or 5-14 membered heteroaryl; Ring A is connected to the parent structure by a C atom on the ring; Ring A is optionally further substituted; G1, G2, G3, or G4 each independently represent a bond, C 1~20 Alkylene, C 2~20 Alkenylene or C 2~20 Alkynylene; C 1~20 Alkylene, C 2~20 Alkenylene or C 2~20 The alkynylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; G5 or G6 each independently represent a bond or C 1~6 alkylene; C 1~6 The alkylene is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; M1 or M2 is -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -O-, -OC(O)O-, -SC(O)O-, -OC(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -OC(O)NR a -, -NR a C(O)S-, -SC(O)NR a -, -NR a C(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -SS- and -S(O)m - each independently selected from; Q is a bond, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -O-, -OC(O)O-, -SC(O)O-, -OC(O)S-, or -NR b -, -C(O)NR b -, -NR b C(O)-, -NR b C(O)O-, -OC(O)NR b -, -NR b C(O)S-, -SC(O)NR b -, -NR b C(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -, -NR a C(S)O-, -SS-, -S(O) n -, phenylene and pyridylidene; wherein the phenylene or pyridylidene group is optionally substituted with one or more substituents selected from H, hydroxy, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl and alkoxy; R1 or R2 are each independently C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 Alkynyl; C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 alkynyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; R'3, R'4, R'5 or R'6 each independently represent C 1~8 is alkyl; R a or R b each independently represents H, C 1~28 Alkyl or C 3~14 is cycloalkyl; C 1~28 Alkyl or C 3~14cycloalkyl is optionally substituted with one or more substituents selected from H, OH, alkyl, hydroxyalkyl, alkoxy, amino, alkylamino, and dialkylamino; m and n are each independently 0, 1, or 2. It has.

[0429] Furthermore, both G1 and G3 are C 2~8 alkylene and G2 and G4 are both bonds; alternatively, G1 and G3 are both C5 alkylene and G2 and G4 are both bonds.

[0430] Additionally, G5 is a bond.

[0431] Furthermore, G6 is bonded or C 1~6 It is alkylene.

[0432] Furthermore, M1 and M2 each independently represent -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, or -NR a C(O)- or -C(O)NR a - and R a is H or C 4~24 Alternatively, M1 or M2 are each independently -C(O)O- or -C(O)S-.

[0433] Additionally, Q is a bond, -O-, -OC(O)-, -C(O)O-, -OC(O)O-, or -OC(O)NH-, -NHC(O)-O-, -NHC(O)NH-, -OC(O)S-, -SC(O)O-; alternatively Q is -C(O)O-.

[0434] Additionally, ring A is a 3- to 8-membered heterocyclyl, and ring A is optionally substituted with one or more R7; alternatively, ring A is

[0435] [ka] is.

[0436] Furthermore, R1 or R2 may each independently be C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 Alkynyl, C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 Alkynyl may be substituted with one or more substituents H, hydroxyl or C 2~14 Alternatively, R1 or R2 may each independently be C 4~28 Alkyl, C 4~28 Alkenyl or C 4~28 It is alkynyl.

[0437] Further, R'3, R'4, R'5, or R'6 are each independently selected from the group consisting of C 1~3 Alternatively, R'3, R'4, R'5 or R'6 are both methyl.

[0438] Further, each R'7 is independently H, halogen, cyano, OH, oxo, C 1~6 Alkyl, C 1~6 Alkoxy, -NH2, -NHC 1~6 Alkyl, or -N(C 1~6 alkyl)2; C 1~6 Alkyl is halogen, cyano, OH, oxo, -NH2, -NHC 1~6 Alkyl, and -N(C 1~6 alkyl)2; alternatively, R'7 is C 1~3 It is alkyl.

[0439] Technical Solution 77: Furthermore, the lipid compound is a compound of general formula (II'):

[0440] [ka] (wherein the substituents are defined as described in general formula (I')). is.

[0441] Technical Solution 78: The present disclosure provides:

[0442] [ka] The present invention provides a lipid compound selected from the group consisting of:

[0443] Technical Solution 79: The present disclosure provides a composition comprising a biologically active substance and a lipid compound of the present disclosure.

[0444] Additionally, the biologically active substance is DNA or RNA.

[0445] Additionally, the composition further comprises a neutral lipid, a structured lipid, and a polymeric lipid.

[0446] Further, the neutral lipid is DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE.

[0447] Additionally, the structural lipid is selected from one or a combination of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, and campesterol.

[0448] Further, the polymeric lipid is selected from one of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, azide-PEG2000, DSPE-PEG2000-mannose, ceramide-PEG5000, and DSPE-PEG5000, or a combination thereof.

[0449] Technical Solution 80: The present disclosure provides lipid nanoparticles comprising the lipid compound of the present disclosure or the composition of the present disclosure.

[0450] Technical Solution 81: The present disclosure provides a pharmaceutical composition comprising a lipid compound of the present disclosure, a composition of the present disclosure, or a lipid nanoparticle of the present disclosure, and a pharmaceutically acceptable excipient(s).

[0451] Technical Solution 82: The present disclosure provides use of a lipid compound of the present disclosure, a composition of the present disclosure, a lipid nanoparticle of the present disclosure, or a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating or preventing a disease.

[0452] Technical Solution 83: The present disclosure provides a method for preparing a compound of general formula (II'),

[0453] [ka] reacting a compound of general formula (II'a) with a compound of general formula (II'b) to obtain a compound of general formula (II'); (wherein the substituents are defined as described in general formula (I')). The present invention provides a method comprising:

[0454] The compounds of the present disclosure contain one or more asymmetric centers, and therefore can exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the compounds of the present disclosure can be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis- and trans-isomers), or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; Alternatively, isomers can be prepared by asymmetric synthesis.

[0455] The compounds of the present disclosure can exist in tautomeric forms.Tautomers are functional group isomers that arise from the rapid movement of atoms between two positions in a molecule.Tautomers are special functional group isomers, and tautomer pairs can be converted into each other, but usually exist in the relatively stable isomer as their main form.The most important example is enol and keto tautomers.

[0456] The present disclosure also includes isotopically labeled compounds (isotopic variants) equivalent to those described in formula (IV), but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that of the atoms common in nature. Examples of isotopes that can be introduced into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Compounds of the present disclosure, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or prodrugs that contain the above isotopes and / or other isotopes of other atoms are all within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, such as compounds containing radioactive isotopes (e.g., 3 H and 14 C) can be used to measure drug and / or substrate distribution in tissues. 3 H, tritium, and 14 The C isotope, carbon-14, is a further alternative as it is easy to prepare and detect. 2Substitution of H with a heavier isotope, such as deuterium, may confer therapeutic benefits due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus may be an alternative in some cases. Isotopically labeled compounds of formula (I) of the present disclosure, and prodrugs thereof, may generally be prepared by using readily available isotopically labeled reagents to substitute for non-isotopically labeled reagents in the following schemes and / or procedures disclosed in the Examples and Preparative Examples.

[0457] The present disclosure also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (VI), or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof, all of which forms are within the present disclosure.

[0458] Pharmaceutical Compositions and Kits In another aspect, the present disclosure provides a pharmaceutical composition comprising a nanoparticle composition of the present disclosure and a pharmaceutically acceptable excipient(s), wherein the nanoparticle composition comprises a compound of the present disclosure.

[0459] Pharmaceutically acceptable excipients for use in the present disclosure refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound that is formulated together.The pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present disclosure include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum protein (for example, human serum albumin), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

[0460] The present disclosure also includes kits (e.g., pharmaceutical packs). The provided kits may include a nanoparticle composition of the present disclosure, another therapeutic, diagnostic, or prophylactic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersion packages or other materials) containing the nanoparticle composition of the present disclosure or another therapeutic, diagnostic, or prophylactic agent. In some embodiments, the provided kits may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the nanoparticle composition of the present disclosure and / or another therapeutic, diagnostic, or prophylactic agent. In some embodiments, the nanoparticle composition of the present disclosure provided in the first container and the other therapeutic, diagnostic, or prophylactic agent provided in the second container are combined to form a unit dosage form.

[0461] Administration The pharmaceutical compositions provided by the present disclosure can be administered by a variety of routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, oral, vaginal, by implant or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraventricular, intralesional, and intracranial injection or infusion techniques.

[0462] Generally, the pharmaceutical compositions provided herein are administered in effective amounts. The amount of pharmaceutical composition actually administered is typically determined by a physician in light of the relevant circumstances, including the condition to be treated or prevented, the selected route of administration, the actual pharmaceutical composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0463] When used to prevent the disorders disclosed herein, the pharmaceutical compositions provided herein are typically administered to the subject at risk of developing the condition at the dosage level described above, under the advice and supervision of a doctor.The subject at risk of developing a particular condition generally includes the subject with a family history of the condition, or the subject identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0464] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound or a pharmaceutical composition thereof for an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continued indefinitely, for example, for the remainder of the subject's life. In certain embodiments, chronic administration is intended to, for example, provide a constant level of the compound in the blood within the therapeutic window for an extended period of time.

[0465] The pharmaceutical composition of the present disclosure can be further delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus administration depends on the systemic level of the desired active ingredient in the body; for example, intramuscular or subcutaneous bolus administration allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., via IV drip) allows for a much faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV drip, to maintain a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition can be initially administered as a bolus administration, followed by a continuous infusion.

[0466] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary administration for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in combination with appropriate pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the active ingredient is usually a minor component (about 0.1 to about 50% by weight, or alternatively about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0467] A typical oral administration regimen is 1 to 5 times, particularly 2 to 4 times, and typically 3 times per day. Using these dosing patterns, each dose provides about 0.001 mg / kg to about 10 mg / kg of therapeutic, diagnostic, or prophylactic agent, with alternate doses providing about 0.1 mg / kg to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0468] Transdermal administrations are generally selected to result in blood levels similar to or lower than those achieved using injection administration, generally in amounts ranging from about 0.01 to about 20% by weight, alternatively from about 0.1 to about 20% by weight, alternatively from about 0.1 to about 10% by weight, and further alternatively from about 0.5 to about 15% by weight.

[0469] Injection dosage levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human subject.

[0470] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0471] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable vehicles known in the art. As noted above, the active compound in such compositions is typically a minor component, usually about 0.05-10% by weight, with the remainder being the injectable vehicle and the like.

[0472] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s).When formulated as an ointment, active ingredient is typically combined with a paraffinic or water-miscible ointment base.Alternatively, active ingredient can be formulated into a cream, for example, with an oil-in-water cream base.Such transdermal formulations are well known in the art and generally contain additional ingredients to enhance the stable transdermal penetration of active ingredient or formulation.All such known transdermal formulations and ingredients are included within the scope provided herein.

[0473] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0474] The above ingredients for oral, injectable, or topical compositions are merely representative. Other materials, processing techniques, and the like are set forth in Remington's Pharmaceutical Sciences, Volume 8, 17th Edition, 1985, Mack Publishing Company, Easton, PA, which is incorporated herein by reference.

[0475] The nanoparticle compositions of the present disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0476] The present disclosure also relates to pharmaceutically acceptable formulations of the compounds of the present disclosure. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the attached sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water). [Example]

[0477] In order to make the technical solutions of the present disclosure clearer and more explicit, the present disclosure will be further described in detail through the following examples. The following examples are merely used to illustrate specific embodiments of the present disclosure so that those skilled in the art can understand the present disclosure, and are not intended to limit the scope of protection of the present disclosure. Technical means or methods not specifically described in the specific embodiments of the present disclosure are conventional technical means or methods in the art, etc. Unless otherwise specified, materials, reagents, etc. used in the examples are commercially available.

[0478] [Table 1]

[0479] Example 1: Synthesis of Compound 1

[0480] [ka]

[0481] A solution of compound 1-1 (100 g, 979 mmol) in tetrahydrofuran (800 mL) was cooled to -40 °C. LDA (2 M, 490 mL) was slowly added dropwise to the solution, and after the addition was complete, the mixture was stirred for another 1 h. A solution of 1-2 (315 g, 1.37 mol) in tetrahydrofuran (100 mL) was added dropwise to the reaction at the same temperature, and the reaction was stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column to obtain compound 1-3 (115 g).

[0482]

number

[0483] A solution of compound 1-3 (100 g, 398 mmol), TsCHCN (38.9 g, 199 mmol), and TBAI (14.7 g, 39.8 mmol) in dimethyl sulfoxide (800 mL) was cooled to 0 °C, and sodium hydride (20.7 g, 517 mmol) was added slowly in batches. The mixture was allowed to react at room temperature overnight. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give 115 g of crude compound 1-4, which was used directly in the next reaction without isolation or purification.

[0484] To a solution of crude compound 1-4 (110 g, 205 mmol) in dichloromethane (880 mL), 330 mL of concentrated hydrochloric acid was added, and the mixture was allowed to react at room temperature for 2 hours. Complete reaction of the substrate was monitored by TLC. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column to obtain compound 1-5 (30.0 g, 80.9 mmol, 39.4% yield).

[0485] TMSOK (11.0 g, 86.4 mmol) was added to a solution of compound 1-5 (8.0 g, 21.6 mmol) in tetrahydrofuran (35.0 mL) at room temperature, and the reaction was heated to 70 °C with stirring. Complete consumption of the reactants was monitored by TLC. The reaction solution was cooled to room temperature, and the organic solvent was removed by rotary evaporation. The crude product was added to 20 mL of water and extracted with dichloromethane. The aqueous layer was collected, and the solution was adjusted to pH < 5 with 1 M hydrochloric acid. The solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give compound 1-6 (7.0 g).

[0486]

number

[0487] Potassium carbonate (482 mg, 3.48 mmol) was added to a solution of compound 1-6 (294 mg, 0.87 mmol) and 1-7 (771 mg, 3.48 mmol) in DMF, and the reaction was then warmed to 60 °C for 6 h. Complete disappearance of reactant 1-6 was monitored. The mixture was cooled to room temperature. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel column to give compound 1-8 (325 mg).

[0488] Compound 1-8 (325 mg) was dissolved in 4.0 mL of methanol, and sodium borohydride (30 mg, 0.84 mmol) was added to the reaction mixture. The mixture was allowed to react at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 1-9 (260 mg), which was used directly in the next reaction without purification.

[0489] Crude compound 1-9 (260 mg, 0.42 mmol), 1-10 (73.1 mg, 0.63 mmol), EDCI (238 mg, 1.26 mmol), triethylamine (0.17 mL, 1.26 mmol), and DMAP (51 mg, 0.42 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed using a rotary evaporator to obtain the crude product, which was purified by preparative high-performance liquid chromatography to obtain compound 1 (130 mg).

[0490]

number

[0491] Example 2: Synthesis of Compound 2

[0492] [ka]

[0493] Compound 2 was prepared as an oily product: 25.7 mg, according to the method of Example 1.

[0494]

number

[0495] Example 3: Synthesis of Compound 3

[0496] [ka]

[0497] Compound 3 was prepared as an oily product: 31.2 mg, according to the method of Example 1.

[0498]

number

[0499] Example 4: Synthesis of Compound 4

[0500] [ka]

[0501] Compound 4 was prepared as an oily product: 32 mg, according to the method of Example 1.

[0502]

number

[0503] Example 5: Synthesis of Compound 5

[0504] [ka]

[0505] Compound 5 was prepared as an oily product: 31.4 mg, according to the method of Example 1.

[0506]

number

[0507] Example 6: Synthesis of Compound 6

[0508] [ka]

[0509] Compound 6 was prepared as an oily product: 30.7 mg, according to the method of Example 1.

[0510]

number

[0511] Example 7: Synthesis of Compound 7

[0512] [ka]

[0513] Compound 1-6 (548 mg, 1.5 mmol) was dissolved in 5.0 mL of dichloromethane, and the reaction mixture was cooled to 0 °C in an ice bath. DMF (12 μL, 0.15 mmol) was added, and oxalyl chloride (0.47 mL, 6.0 mmol) was added dropwise to the reaction solution. The ice bath was removed, and the mixture was stirred at room temperature for 1 h. The solvent was removed using a rotary evaporator to give the crude acyl chloride (458 mg) as an oil, which was used directly in the next reaction step.

[0514] The crude acyl chloride product (458 mg) obtained above was dissolved in 3.0 mL of 1,2-dichloroethane, and then compound 7-1 (429 mg, 3.0 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was completely reacted. The solvent was removed using a rotary evaporator to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 7-2 (540 mg).

[0515] Then, compound 7 was prepared as an oily product: 33.2 mg, according to the method of Example 1.

[0516]

number

[0517] Example 8: Synthesis of Compound 8

[0518] [ka]

[0519] Compound 1-6 (548 mg, 1.5 mmol) was dissolved in 5.0 mL of dichloromethane and the reaction mixture was cooled in an ice bath. DMF (12 μL, 0.15 mmol) was added, and oxalyl chloride (0.47 mL, 6.0 mmol) was added dropwise to the reaction solution. The ice bath was removed, and the mixture was stirred at room temperature for 1 h. The solvent was removed using a rotary evaporator to give the crude acyl chloride (458 mg) as an oil, which was used directly in the next reaction step.

[0520] 458 mg of the crude acyl chloride obtained above was dissolved in 3.0 mL of 1,2-dichloroethane, and then compound 8-1 (472 mg, 3.0 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was completely reacted. The solvent was removed using a rotary evaporator to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 8-2 (518 mg).

[0521] 518 mg of compound 8-2 was dissolved in 5.0 mL of methanol, and sodium borohydride (48 mg, 1.25 mmol) was added to the reaction mixture. The mixture was allowed to react at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction mixture was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give 473 mg of crude compound 8-3, which was used directly in the next reaction without purification.

[0522] Crude compound 8-3 (270 mg, 0.43 mmol), 1-10 (76.1 mg, 0.65 mmol), EDCI (248 mg, 1.3 mmol), triethylamine (0.18 mL, 1.3 mmol), and DMAP (53 mg, 0.43 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous sodium chloride and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed using a rotary evaporator to give the crude product, which was purified by preparative high-performance liquid chromatography to give compound 8 (39 mg).

[0523]

number

[0524] Example 9: Synthesis of Compound 9

[0525] [ka]

[0526] Compound 9 (73 mg) was prepared with reference to the method of Example 8.

[0527]

number

[0528] Example 10: Synthesis of Compound 10

[0529] [ka]

[0530] Compound 10 (31.2 mg) was prepared with reference to the method of Example 8.

[0531]

number

[0532] Example 11: Synthesis of Compound 11

[0533] [ka]

[0534] Compound 11 (48.1 mg) was prepared with reference to the method of Example 8.

[0535]

number

[0536] Example 12: Synthesis of Compound 12

[0537] [ka]

[0538] Compound 12 (52 mg) was prepared with reference to the method of Example 8.

[0539]

number

[0540] Example 13: Synthesis of Compound 13

[0541] [ka]

[0542] Compound 13 (32 mg) was prepared with reference to the method of Example 8.

[0543]

number

[0544] Example 14: Synthesis of Compound 14

[0545] [ka]

[0546] Compound 14 (18 mg) was prepared with reference to the method of Example 8.

[0547]

number

[0548] Example 15: Synthesis of Compound 15

[0549] [ka]

[0550] A solution of compound 15-1 (400 mg, 1.4 mmol) in dichloromethane (3.0 mL) was cooled to 0 °C, and then a solution of SOCl (0.12 mL, 1.68 mmol) in dichloromethane (2.0 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for an additional 1 h. After the reaction was complete, the reaction was quenched by adding saturated sodium bicarbonate solution to the reaction, and the reaction was extracted with dichloromethane. The organic phases were combined, and the organic solvent was removed to give crude compound 15-2, which was used directly in the next reaction without purification.

[0551] Compound 1-6 (223, 0.65 mmol), 15-2 (496 mg, 1.63 mmol), and potassium carbonate (361 mg, 2.6 mmol) were dissolved in 5.0 mL of DMF, and the reaction solution was heated to 70 °C for 6 hours. The reaction solution was cooled to room temperature, and then saturated sodium chloride solution was added to the reaction system to quench the reaction. The reaction system was extracted with dichloromethane. The organic phases were combined, and the organic solvent was removed to obtain the crude product. The crude product was purified using a silica gel column to obtain compound 15-3.

[0552] Then, compound 15 (40 mg) was prepared with reference to the method of Example 1.

[0553]

number

[0554] Example 16: Synthesis of Compound 16

[0555] [ka]

[0556] DMF (11 μL, 0.14 mmol) was added to a solution of compound 1-6 (460 mg, 1.34 mmol) in dichloromethane (5.0 mL) under ice bath conditions, and then oxalyl chloride (0.47 mL, 5.37 mmol) was added dropwise to the reaction solution. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The solvent was removed using a rotary evaporator to give 255 mg of crude acyl chloride as an oil, which was used directly in the next reaction step.

[0557] The crude acyl chloride product (255 mg, 0.67 mmol) obtained above was dissolved in 3.0 mL of 1,2-dichloroethane, and then compound 16-1 (384 mg, 1.68 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was completely reacted. The solvent was removed using a rotary evaporator to obtain the crude product, which was purified by silica gel column chromatography to obtain 300 mg of compound 16-2.

[0558]

number

[0559] Compound 16-2 (300 mg, 0.39 mmol) was dissolved in 4.0 mL of methanol. Then, NaBH4 (45 mg, 1.17 mmol) was slowly added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, and the organic solvent was removed to give 300 mg of crude compound 16-3, which was used directly in the next reaction without purification.

[0560] Crude compound 16-3 (300 mg, 0.39 mmol) was dissolved in 2.0 mL of DMF, and then 1-10 (69 mg, 0.59 mmol), EDCI (225 mg, 1.17 mmol), triethylamine (119 mg, 1.17 mmol), and DMAP (48 mg, 0.39 mmol) were added. The mixture was stirred at room temperature until the reactants were completely reacted. The reaction solution was quenched with saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain compound 16 (32.5 mg).

[0561]

number

[0562] Example 17: Synthesis of Compound 17

[0563] [ka]

[0564] Compound 17 was prepared as an oily product: 41.3 mg, according to the method of Example 1.

[0565]

number

[0566] Example 18: Synthesis of Compound 18

[0567] [ka]

[0568] Compound 18 was prepared as an oily product: 35.4 mg, according to the method of Example 1.

[0569]

number

[0570] Example 19: Synthesis of Compound 19

[0571] [ka]

[0572] Compound 19 was prepared as an oily product: 33.1 mg, according to the method of Example 1.

[0573]

number

[0574] Example 20: Synthesis of Compound 20

[0575] [ka]

[0576] Compound 20 was prepared as an oily product: 302 mg, according to the method of Example 1.

[0577]

number

[0578] Example 21: Synthesis of Compound 21

[0579] [ka]

[0580] Compound 21 was prepared as an oily product: 31.2 mg, according to the method of Example 1.

[0581]

number

[0582] Example 22: Synthesis of Compound 22

[0583] [ka]

[0584] Compound 22 was prepared as an oily product: 31.8 mg, following the method of Example 1.

[0585]

number

[0586] Example 23: Synthesis of Compound 23

[0587] [ka]

[0588] Compound 23 was prepared as an oily product: 31.0 mg, following the method of Example 7.

[0589]

number

[0590] Example 24: Synthesis of Compound 24

[0591] [ka]

[0592] Compound 24 was prepared as an oily product: 31.0 mg, following the method of Example 7.

[0593]

number

[0594] Example 25: Synthesis of Compound 25

[0595] [ka]

[0596] Compound 25 was prepared as an oily product: 32.1 mg, following the method of Example 7.

[0597]

number

[0598] Example 26: Synthesis of Compound 26

[0599] [ka]

[0600] Compound 23 (300 mg, 0.41 mmol) and quinoline (106 mg, 0.82 mmol) were dissolved in 3.0 mL of ethyl acetate. The air in the reaction system was replaced with nitrogen at room temperature for 2–3 minutes, and then Lindlar's catalyst (16.9 mg) was added. Hydrogen gas was introduced into the reaction solution, and the air was replaced with hydrogen for 2–3 minutes. The reaction system was maintained under a hydrogen atmosphere (15 psi) at room temperature for 30 minutes. The complete disappearance of the reactants was monitored by LC-MS. The reaction solution was filtered, and the filter cake was rinsed 3–4 times with ethyl acetate. The combined ethyl acetate was collected, and the organic solvent was removed using a rotary evaporator to obtain the crude product, which was purified by preparative high-performance liquid chromatography to give compound 26 (31.3 mg).

[0601]

number

[0602] Example 27: Synthesis of Compound 27

[0603] [ka]

[0604] Compound 27 was prepared as an oily product: 35.0 mg, following the method of Example 26.

[0605]

number

[0606] Example 28: Synthesis of Compound 28

[0607] [ka]

[0608] Compound 28 was prepared as an oily product: 31.8 mg, following the method of Example 26.

[0609]

number

[0610] Example 30: Synthesis of Compound 30

[0611] [ka]

[0612] Compound 30 was prepared as an oily product: 33.0 mg, following the method of Example 1.

[0613]

number

[0614] Example 32: Synthesis of Compound 32

[0615] [ka]

[0616] Compound 32 was prepared as an oily product: 31.1 mg, following the method of Example 1.

[0617]

number

[0618] Example 33: Synthesis of Compound 33

[0619] [ka]

[0620] Compound 1-6 (448 mg, 1.3 mmol) was dissolved in 5.0 mL of dichloromethane, and the reaction mixture was cooled to 0 °C in an ice bath. DMF (10 μL, 0.13 mmol) was added, followed by the dropwise addition of oxalyl chloride (0.44 mL, 5.2 mmol). After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 h. The solvent was removed using a rotary evaporator to give the crude acyl chloride (330 mg) as an oil, which was used directly in the next reaction step.

[0621] 1-Decanethiol 33-1 (455 mg, 2.61 mmol) was added to a solution of crude acyl chloride (330 mg, 0.87 mmol) in DCE (3.0 mL), and the reaction was heated to 70 °C overnight. The reaction solution was cooled to room temperature, and the solvent was removed using a rotary evaporator to give the crude product, which was purified by silica gel column chromatography to give compound 33-2 (400 mg).

[0622]

number

[0623] Compound 33-2 (300 mg, 0.46 mmol) was dissolved in 3.0 mL of methanol, and NaBH4 (52.5 mg, 1.38 mmol) was added in batches. The reaction solution was stirred under a nitrogen atmosphere at room temperature for 2 hours. The complete disappearance of the reactants was monitored by TLC. The reaction solution was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give 300 mg of crude compound 33-3, which was used directly in the next reaction step without further purification.

[0624] Crude compound 33-3 (150 mg, 0.23 mmol) was dissolved in 3.0 mL of dichloromethane, and 1-10 (80.2 mg, 0.69 mmol), EDCI (131 mg, 0.69 mmol), triethylamine (0.1 mL, 0.69 mmol), and DMAP (28 mg, 0.23 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched by adding saturated ammonium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give the crude product, which was then passed through preparative high-performance liquid chromatography to give compound 33 (28.6 mg).

[0625]

number

[0626] Example 34: Synthesis of Compound 34

[0627] [ka]

[0628] Compound 34 was prepared as an oily product: 105.2 mg, following the method of Example 33.

[0629]

number

[0630] Example 36: Synthesis of Compound 36

[0631] [ka]

[0632] Compound 36 was prepared as an oily product: 33.4 mg, following the method of Example 33.

[0633]

number

[0634] Example 37: Synthesis of Compound 37

[0635] [ka]

[0636] Compound 37 was prepared as an oily product: 33.2 mg, following the method of Example 33.

[0637]

number

[0638] Example 39: Synthesis of Compound 39

[0639] [ka]

[0640] Compound 39 was prepared as an oily product: 30.7 mg, following the method of Example 33.

[0641]

number

[0642] Example 40: Synthesis of Compound 40

[0643] [ka]

[0644] Potassium carbonate (1.55 g, 11.2 mmol, 4.0 equiv) was added to a solution of compound 1-6 (959 mg, 2.8 mmol, 1.0 equiv) and 3-1 (638 mg, 3.08 mmol, 1.1 equiv) in DMF. The reaction was then heated to 60 °C for 4 hours. The reaction was cooled to room temperature. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column to give compound 40-1 (682 mg).

[0645] Compound 40-1 (324 mg, 0.69 mmol, 1.0 equiv) was dissolved in 5.0 mL of dichloromethane, and the reaction mixture was cooled to 0 °C in an ice bath. Two drops of DMF were added, and then oxalyl chloride (0.24 mL, 2.8 mmol, 4.0 equiv) was added dropwise to the reaction solution. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 h. The solvent was removed using a rotary evaporator to give the crude acyl chloride (309 mg) as an oil, which was used directly in the next reaction step.

[0646] 1-Decanethiol 33-1 (331 mg, 1.9 mmol, 3.0 equiv.) was added to a solution of crude acyl chloride (309 mg) in DCE (3.0 mL), and the reaction was heated to 70 °C overnight. The reaction solution was cooled to room temperature, and the solvent was removed using a rotary evaporator to give the crude product, which was purified by silica gel column chromatography to give compound 40-2 (274 mg).

[0647] Then, compound 40 was prepared as an oily product: 34.2 mg, by referring to the method of Example 1.

[0648]

number

[0649] Example 41: Synthesis of Compound 41

[0650] [ka]

[0651] Compound 41 was prepared as an oily product: 31.1 mg, following the method of Example 40.

[0652]

number

[0653] Example 42: Synthesis of Compound 42

[0654] [ka]

[0655] Compound 42 was prepared as an oily product: 30.9 mg, following the method of Example 40.

[0656]

number

[0657] Example 43: Synthesis of Compound 43

[0658] [ka]

[0659] Compound 43 was prepared as an oily product: 31.3 mg, following the method of Example 26.

[0660]

number

[0661] Example 44: Synthesis of Compound 44

[0662] [ka]

[0663] Compound 44 was prepared as an oily product: 33.1 mg, following the method of Example 40.

[0664]

number

[0665] Example 45: Synthesis of Compound 45

[0666] [ka]

[0667] n-Nonanoic acid (3.0 g, 19 mmol) was added to 50 mL of anhydrous tetrahydrofuran, and the reaction solution was cooled to 0° C. in an ice bath. Sodium hydride (836 mg, 20.9 mmol) and LDA (49.4 mL, 24.7 mmol) were added to the reaction solution, and the reaction solution was stirred at 0° C. for 1 hour. 1-Iodoheptane was then added dropwise to the reaction system. The ice bath was removed, and the mixture was then reacted at room temperature for 12 hours. The reaction solution was quenched by pouring it into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to remove the solvent to obtain a crude product, which was purified by silica gel column to obtain 2.0 g of compound 2-heptylnonanoic acid.

[0668] 2-Heptylnonanoic acid (2.0 g, 7.8 mmol) obtained in the previous step was dissolved in 30 mL of anhydrous tetrahydrofuran, and lithium tetrahydroaluminum (593 mg, 15.6 mmol) was added to the reaction solution. The reaction was heated to 80 °C for 2 hours. The reaction solution was cooled to room temperature and quenched by pouring the reaction solution into saturated ammonium chloride solution and extracting with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to remove the solvent to obtain the crude product, which was purified by silica gel column chromatography to obtain 1.3 g of compound 45-1.

[0669] Then, compound 45 was prepared as an oily product: 31.6 mg, following the method of Example 40.

[0670]

number

[0671] Example 46: Synthesis of Compound 46

[0672] [ka]

[0673] Compound 46 was prepared as an oily product: 32.6 mg, following the method of Example 40.

[0674]

number

[0675] Example 47: Synthesis of Compound 47

[0676] [ka]

[0677] Compound 47 was prepared as an oily product: 33.1 mg, following the method of Example 7.

[0678]

number

[0679] Example 48: Synthesis of Compound 48

[0680] [ka]

[0681] Compound 48 was prepared as an oily product: 34.8 mg, following the method of Example 7.

[0682]

number

[0683] The compounds in Table 2 were synthesized using the corresponding intermediates using the methods in the above examples or similar methods.

[0684] [Table 2-1]

[0685] [Table 2-2]

[0686] [Table 2-3]

[0687] Example 90: Synthesis of Compound 90

[0688] [ka]

[0689] Compound 90 was prepared as an oily product: 40.5 mg, following the method of Example 1.

[0690]

number

[0691] Example 91: Synthesis of Compound 91

[0692] [ka]

[0693] Compound 91 was prepared as an oily product: 32.2 mg, following the method of Example 1.

[0694]

number

[0695] Example 92: Synthesis of Compound 92

[0696] [ka]

[0697] Compound 92 was prepared as an oily product: 32 mg, following the method of Example 1.

[0698]

number

[0699] Example 93: Synthesis of Compound 93

[0700] [ka]

[0701] 3-Bromopropanol (20 g, 144 mmol), trifluoromethanesulfonic anhydride (26.6 mL, 158 mmol), and pyridine (14.0 mL, 173 mmol) were added to a round-bottom flask containing 500 mL of dichloromethane. The mixture was stirred at room temperature until the reactants were completely consumed, as monitored by TLC. The reaction solution was quenched with 1 M hydrochloric acid solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. The filtrate was collected. The solvent was removed using a rotary evaporator to give 25 g of crude compound 93-2, which was used directly in the subsequent reaction without further purification.

[0702] 3-3 (6.0 g, 10 mmol) and crude compound 93-2 (3.0 g, 11 mmol) were added to a round-bottom flask containing 50 mL of nitromethane, and then 2,6-di-tert-butylpyridine (3.37 mL, 15 mmol) was added to the reaction solution. The reaction solution was heated to 95 °C overnight to react. The reaction solution was cooled to room temperature. The solvent was removed using a rotary evaporator to obtain a crude product. The crude product was then dissolved in dichloromethane and extracted after adding saturated ammonium chloride. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and filtered to remove sodium sulfate. The filtrate was collected. The solvent was removed using a rotary evaporator, and then purified by silica gel column to obtain compound 93-3 (2.3 g).

[0703] Compound 93-3 (251 mg, 0.35 mmol) and 2-ethylpiperidine (71 μL, 0.53 mmol) were dissolved in 3.0 mL of anhydrous acetonitrile, and anhydrous potassium carbonate (73 mg, 0.53 mmol) was added to the reaction solution. The mixture was heated to 80 °C for 6 hours. The reaction solution was cooled to room temperature, quenched by adding saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and filtered to remove sodium sulfate. The filtrate was collected. The solvent was removed using a rotary evaporator, and then purified by preparative high-performance liquid chromatography to obtain compound 93 (82 mg).

[0704]

number

[0705] Example 94: Synthesis of Compound 94

[0706] [ka]

[0707] Compound 94 was prepared as an oily product: 79.2 mg, following the method of Example 93.

[0708]

number

[0709] The compounds in Table 3 were synthesized using the corresponding intermediates using the methods in the above examples or similar methods.

[0710] [Table 3]

[0711] Example 97: Synthesis of Compound 97

[0712] [ka]

[0713] To a round-bottom flask, CuCl (989 mg, 9.99 mmol) and 160 mL of THF were added, and the reaction was cooled to -30 °C. 3-Butenyl magnesium bromide (1 M, 299 mL) was then added. 160 mL of a solution of compound 97-1 (40.0 g, 199 mmol) in tetrahydrofuran was slowly added to the reaction. After the dropwise addition was complete, the reaction was warmed to room temperature and stirred for an additional 2 hours. After the complete reaction of reactant 97-1 as monitored by TLC, the reaction solution was quenched with 300 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 97-2 (45.0 g).

[0714] Compound 97-2 (42.0 g, 164 mmol) was dissolved in 400 mL of DMSO, and 4 mL of water and LiCl (27.8 g, 655 mmol) were added to the reaction solution. The reaction was then heated to 180 ° C and stirred until the reactant 97-2 was completely reacted as monitored by TLC. The reaction was cooled to room temperature and then poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain crude product 97-3 (31.0 g), which was used directly in the next reaction without further purification.

[0715] The crude product 97-3 (30.0 g, 163 mmol) was dissolved in 240 mL of tetrahydrofuran, and BH3·THF (1 M, 244 mL) was added dropwise to the reaction solution in an ice bath. The mixture was then warmed to room temperature and stirred for 2 h. The reaction was then cooled to 0 °C in an ice bath, and methanol (13.2 mL, 325 mmol), Br2 (8.39 mL, 163 mmol), and sodium methoxide (43.9 g, 244 mmol) were added sequentially. The mixture was warmed to room temperature and stirred for an additional 1 h. The reaction solution was quenched with cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column chromatography to give compound 97-4 (14.0 g).

[0716] Then, compound 97 was prepared as an oily product: 31.6 mg, according to the method of Example 1.

[0717]

number

[0718] Example 98: Synthesis of Compound 98

[0719] [ka]

[0720] Compound 98 was prepared as an oily product: 31.0 mg, following the method of Example 97.

[0721]

number

[0722] Example 99: Synthesis of Compound 99

[0723] [ka]

[0724] A solution of compound 1-1 (100 g, 979 mmol) in tetrahydrofuran (800 mL) was cooled to -40 °C. LDA (2 M, 490 mL) was slowly added dropwise to the solution, and after the addition was complete, the mixture was stirred for another 1 h. A solution of 1-2 (315 g, 1.37 mol) in tetrahydrofuran (100 mL) was added dropwise to the reaction at the same temperature, and the reaction was stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column to obtain compound 1-3 (115 g).

[0725]

number

[0726] A solution of compound 1-3 (100 g, 398 mmol), TsCHCN (38.9 g, 199 mmol), and TBAI (14.7 g, 39.8 mmol) in dimethyl sulfoxide (800 mL) was cooled to 0 °C, and sodium hydride (20.7 g, 517 mmol, 60% purity) was added slowly in batches. The mixture was allowed to react at room temperature overnight. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give 115 g of crude compound 1-4, which was used directly in the next reaction without isolation or purification.

[0727] To a solution of crude compound 1-4 (110 g, 205 mmol) in dichloromethane (880 mL), 330 mL of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. Complete reaction of the substrate was monitored by TLC. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column to obtain compound 1-5 (30.0 g, 80.9 mmol, 39.4%).

[0728] TMSOK (11.0 g, 86.4 mmol) was added to a solution of compound 1-5 (8.0 g, 21.6 mmol) in tetrahydrofuran (35.0 mL) at room temperature, and the reaction was heated to 70 °C with stirring. Complete consumption of the reactants was monitored by TLC. The reaction solution was cooled to room temperature, and the organic solvent was removed by rotary evaporation. The crude product was added to 20 mL of water and extracted with dichloromethane. The aqueous layer was collected, and the solution was adjusted to pH < 5 with 1 M hydrochloric acid. The solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give compound 1-6 (7.0 g).

[0729]

number

[0730] Potassium carbonate (482 mg, 3.48 mmol) was added to a solution of compound 1-6 (294 mg, 0.87 mmol) and 1-7 (771 mg, 3.48 mmol) in DMF, and the reaction was then warmed to 60 °C for 6 h. Complete disappearance of reactant 1-6 was monitored. The mixture was cooled to room temperature. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product. The crude product was purified by silica gel column to give compound 1-8 (325 mg).

[0731] Compound 1-8 (325 mg) was dissolved in 4.0 mL of methanol, and sodium borohydride (30 mg, 0.84 mmol) was added to the reaction mixture. The mixture was allowed to react at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 1-9 (260 mg), which was used directly in the next reaction without purification.

[0732] Crude compound 1-9 (250 mg, 0.40 mmol), 1-11 (35.9 mg, 0.60 mmol), EDCI (230 mg, 1.20 mmol), triethylamine (0.17 mL, 1.20 mmol), and DMAP (49 mg, 0.40 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed using a rotary evaporator to obtain the crude product, which was purified by preparative high-performance liquid chromatography to obtain compound 99 (31.6 mg).

[0733]

number

[0734] Example 100: Synthesis of Compound 100

[0735] [ka]

[0736] Compound 100 was prepared as an oily product: 33.5 mg, following the method of Example 99.

[0737]

number

[0738] Example 101: Synthesis of Compound 101

[0739] [ka]

[0740] Compound 101 was prepared as an oily product: 30.8 mg, following the method of Example 99.

[0741]

number

[0742] Example 102: Synthesis of Compound 102

[0743] [ka]

[0744] Compound 102 was prepared with reference to the method of Example 99 as an oily product: 32.4 mg.

[0745]

number

[0746] Example 103: Synthesis of Compound 103

[0747] [ka]

[0748] Compound 103 was prepared as an oily product: 32.8 mg, following the method of Example 99.

[0749]

number

[0750] Example 104: Synthesis of Compound 104

[0751] [ka]

[0752] Compound 1-6 (448 mg, 1.3 mmol) was dissolved in 5.0 mL of dichloromethane, and the reaction mixture was cooled to 0 °C in an ice bath. DMF (10 μL, 0.13 mmol) was added, followed by the dropwise addition of oxalyl chloride (0.44 mL, 5.2 mmol). After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 h. The solvent was removed using a rotary evaporator to give the crude acyl chloride (330 mg) as an oil, which was used directly in the next reaction step.

[0753] 1-Decanethiol 33-1 (455 mg, 2.61 mmol) was added to a solution of crude acyl chloride (330 mg, 0.87 mmol) in DCE (3.0 mL), and the reaction was heated to 70 °C overnight. The reaction solution was cooled to room temperature, and the solvent was removed using a rotary evaporator to give the crude product, which was purified by silica gel column chromatography to give compound 33-2 (400 mg).

[0754]

number

[0755] Compound 33-2 (300 mg, 0.46 mmol) was dissolved in 3.0 mL of methanol, and NaBH4 (52.5 mg, 1.38 mmol) was added in batches. The reaction solution was stirred under a nitrogen atmosphere at room temperature for 2 hours. The complete disappearance of the reactants was monitored by TLC. The reaction solution was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give 300 mg of crude compound 33-3, which was used directly in the next reaction step without further purification.

[0756] Crude compound 33-3 (300 mg, 0.46 mmol), 1-11 (98.8 mg, 0.69 mmol), EDCI (264.5 mg, 1.38 mmol), triethylamine (0.19 mL, 1.38 mmol), and DMAP (56.2 mg, 0.46 mmol) were dissolved in 8.0 mL of dichloromethane, and the reaction solution was stirred at room temperature until the reactant 33-3 was completely consumed. The reaction solution was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phases were collected, and the organic solvent was removed using a rotary evaporator. The crude product was purified by preparative high-performance liquid chromatography to give compound 104 (67.3 mg).

[0757]

number

[0758] Example 105: Synthesis of Compound 105

[0759] [ka]

[0760] Compound 105 was prepared as an oily product: 27.1 mg, following the method of Example 104.

[0761]

number

[0762] Example 106: Synthesis of Compound 106

[0763] [ka]

[0764] Compound 106 was prepared by following the method of Example 104 as an oily product: 38.4 mg.

[0765]

number

[0766] Example 107: Synthesis of Compound 107

[0767] [ka]

[0768] Compound 107 was prepared as an oily product: 39 mg, following the method of Example 104.

[0769]

number

[0770] Example 108: Synthesis of Compound 108

[0771] [ka]

[0772] Compound 108 was prepared as an oily product: 43.8 mg, following the method of Example 104.

[0773]

number

[0774] Example 109: Synthesis of Compound 109

[0775] [ka]

[0776] Compound 109 was prepared as an oily product: 44.8 mg, following the method of Example 104.

[0777]

number

[0778] Example 110: Synthesis of Compound 110

[0779] [ka]

[0780] Compound 110 was prepared with reference to the method of Example 104 as an oily product: 34.4 mg.

[0781]

number

[0782] Example 111: Synthesis of Compound 111

[0783] [ka]

[0784] Compound 111 was prepared as an oily product: 31.4 mg, following the method of Example 104.

[0785]

number

[0786] Example 112: Synthesis of Compound 112

[0787] [ka]

[0788] Compound 112 was prepared as an oily product: 24.4 mg, following the method of Example 104.

[0789]

number

[0790] Example 113: Synthesis of Compound 113

[0791] [ka]

[0792] Compound 113 was prepared by following the method of Example 110 as an oily product: 31.1 mg.

[0793]

number

[0794] Example 114: Synthesis of Compound 114

[0795] [ka]

[0796] Compound 114 was prepared as an oily product: 32.7 mg, following the method of Example 110.

[0797]

number

[0798] Example 115: Synthesis of Compound 115

[0799] [ka]

[0800] Compound 115 was prepared as an oily product: 31.0 mg, following the method of Example 104.

[0801]

number

[0802] Example 116: Synthesis of Compound 116

[0803] [ka]

[0804] Compound 116 was prepared with reference to the method of Example 104 as an oily product: 31.3 mg.

[0805]

number

[0806] Example 117: Synthesis of Compound 117

[0807] [ka]

[0808] Compound 117 was prepared as an oily product: 35.9 mg, following the method of Example 104.

[0809]

number

[0810] Example 118: Synthesis of Compound 118

[0811] [ka]

[0812] Compound 118 was prepared as an oily product: 32.0 mg, following the method of Example 104.

[0813]

number

[0814] Example 119: Synthesis of Compound 119

[0815] [ka]

[0816] Compound 119 was prepared as an oily product: 34.8 mg, following the method of Example 104.

[0817]

number

[0818] Example 120: Synthesis of Compound 120

[0819] [ka]

[0820] Compound 120 was prepared as an oily product: 34.5 mg, following the method of Example 104.

[0821]

number

[0822] Example 121: Synthesis of Compound 121

[0823] [ka]

[0824] Compound 121 was prepared as an oily product: 33.8 mg, following the method of Example 104.

[0825]

number

[0826] Example 122: Synthesis of Compound 122

[0827] [ka]

[0828] Compound 122 was prepared as an oily product: 33.7 mg, following the method of Example 104.

[0829]

number

[0830] Example 123: Synthesis of Compound 123

[0831] [ka]

[0832] Compound 123 was prepared as an oily product: 35.2 mg, following the method of Example 104.

[0833]

number

[0834] Example 124: Synthesis of Compound 124

[0835] [ka]

[0836] Compound 124 was prepared by following the method of Example 104 as an oily product: 33.4 mg.

[0837]

number

[0838] Example 125: Synthesis of Compound 125

[0839] [ka]

[0840] Compound 125 was prepared as an oily product: 31.1 mg, following the method of Example 104.

[0841]

number

[0842] Example 126: Synthesis of Compound 126

[0843] [ka]

[0844] Compound 126 was prepared as an oily product: 35.1 mg, following the method of Example 104.

[0845]

number

[0846] Example 127: Synthesis of Compound 127

[0847] [ka]

[0848] A solution of compound 127-1 (100 g, 552.4 mmol) in anhydrous ether (800 mL) was cooled to 0 °C in an ice bath, and methylmagnesium bromide (3 M in ether, 737 mL) was slowly added dropwise to the solution. After the addition was completed, the ice bath was removed, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ether. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column to obtain compound 127-2 (100 g).

[0849] Compound 127-2 (42g, 232mmol), Compound 127-3 (30.3mL, 278mmol), Cp * TiCl3 (5.09 g, 23.2 mmol), zinc powder (45.5 g, 696 mmol), and triethylchlorosilane (116.8 mL, 696 mmol) were added to a round-bottom flask. Anhydrous tetrahydrofuran (1200 mL) was then added to the reaction system, and the reaction was carried out under argon gas protection. The reaction system was heated to 60 °C and stirred for 1 hour. The reaction system was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude product 1-4, which was purified by silica gel column to give compound 127-4 (21 g).

[0850] Compound TosMIC (7.03 g, 36 mmol) was dissolved in DMSO (200 mL), and NaH (4.32 g, 60%, 108 mmol) was added to the reaction mixture in batches under ice bath conditions. After the addition was complete, the ice bath was removed, and the mixture was allowed to react at room temperature for another 1 h. Compound 127-4 (21 g, 79 mmol) and TBAI (1.33 g, 3.6 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 127-5 (21.9 g), which was used directly in the next reaction step without purification.

[0851] To a solution of crude compound 127-5 (21.9 g, 38.8 mmol) in dichloromethane (350 mL), 200 mL of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. The complete reaction of the substrate was monitored by TLC. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column to give compound 127-6 (12.5 g).

[0852] Compound 127-6 (12.5 g, 31.4 mmol) was dissolved in ethanol (20 mL) and water (40 mL), and NaOH (3.77 g, 94.2 mmol) was added to the mixture in batches under ice bath conditions. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature. Complete consumption of the reactants was monitored by TLC. The organic solvent was removed by rotary evaporation, and the residue was extracted with dichloromethane. The aqueous layer was collected, and the solution was adjusted to pH <5 with 1 M hydrochloric acid. The solution was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated to give compound 127-7 (9.7 g).

[0853] DMF (17 μL, 0.22 mmol) was added to a solution of compound 127-7 (750 mg, 2.19 mmol) in dichloromethane (10.0 mL) under ice bath conditions, and then oxalyl chloride (0.77 mL, 8.76 mmol) was added dropwise to the reaction solution. The ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The solvent was removed using a rotary evaporator to give the crude acyl chloride, which was used directly in the next reaction step.

[0854] The crude acyl chloride product obtained above was dissolved in 10.0 mL of 1,2-dichloroethane, and then compound 127-8 (693 mg, 4.38 mmol) was added to the reaction solution. The mixture was stirred at room temperature until the substrate was completely reacted. The solvent was removed using a rotary evaporator. The crude product was purified by silica gel column chromatography to give compound 127-9 (800 mg).

[0855] Compound 127-9 (800 mg, 1.29 mmol) was dissolved in 5.0 mL of methanol, and sodium borohydride (146 mg, 3.87 mmol) was added to the reaction mixture. The mixture was allowed to react at room temperature. The complete disappearance of the reactants was monitored by TLC. The reaction was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to give crude compound 127-10 (800 mg), which was used directly in the next reaction without purification.

[0856] Crude compound 127-10 (300 mg, 0.48 mmol), 4-dimethylaminobutyric acid (94.4 mg, 0.72 mmol), EDCI (276 mg, 1.44 mmol), triethylamine (0.21 mL, 1.44 mmol), and DMAP (59 mg, 0.48 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phases were collected, and the organic solvent was removed using a rotary evaporator. The crude product was purified by preparative high-performance liquid chromatography to give compound 127 (43.6 mg).

[0857]

number

[0858] Example 128: Synthesis of Compound 128

[0859] [ka]

[0860] Following the method of Example 127, compound 128 was obtained as an oily product: 64.2 mg.

[0861]

number

[0862] Example 129: Synthesis of Compound 129

[0863] [ka]

[0864] Compound 129 was prepared as an oily product: 67.0 mg, following the method of Example 127.

[0865]

number

[0866] Comparative Example Synthesis of comparative compound 1 (D1) D1 was prepared according to the method of Example 20, [M+H] + :654.6.

[0867]

number

[0868] [ka]

[0869] Synthesis of comparative compound 2 (D2)

[0870] [ka]

[0871] D2 was prepared according to the method of Example 46, [M+H] + :724.6.

[0872]

number

[0873] Pharmacological assays Assay Example 1: Preparation of Nanoparticles The materials used for lipid nanoparticle assemblies include: (1) ionizable lipid compounds, such as the ionizable lipids designed and synthesized in this disclosure or DLin-MC3-DMA (purchased from AVT) as a control; (2) structural lipids, such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids, such as DSPC, i.e., 1,2-distearoyl-SN-glycero-3-phosphocholine (distearoylphosphatidylcholine, purchased from AVT); (4) PEGylated lipids, such as DMG-PEG2000, i.e., dimyristoylglycero-polyethylene glycol 2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, purchased from AVT); and (5) nucleic acid fragment active ingredients, such as luciferase mRNA, siRNA, CRISPR Cas9 mRNA, etc. (produced in-house). The names of the materials for lipid nanoparticle assemblies and their structural formulas are detailed in Table 4.

[0874] [Table 4]

[0875] (1) Dissolve and mix 50%, 38.5%, 10%, and 1.5% (by mole) of ionizable lipid compounds, cholesterol, phospholipids, and polyethylene glycolated lipids in ethanol; (2) Dissolve the mRNA active ingredient in 25 mM sodium acetate solution (pH = 4.5); (3) Using an automated high-throughput microfluidic system, mix the organic phase containing the lipid mixture and the aqueous phase containing the mRNA component at a flow rate ranging from 1:1 to 1:4 at a mixing speed of 10 mL / min to 18 mL / min; (4) Dilute the prepared lipid nanoparticles (N / P ratio 6) with phosphate buffer and ultrafilter the nanoparticle solution to the original preparation volume using an ultrafiltration tube with a 30 kDa molecular weight cutoff (purchased from Millipore); (5) Filter the obtained nanoparticles through a sterile 0.2 μm filtration membrane and then store them in sealed glass vials at low temperature.

[0876] Methods for preparing lipid nanoparticles include, but are not limited to, microfluidic mixing systems, including T-mixers and ethanol injection methods.

[0877] Assay Example 2: Characterization of the physical properties of lipid nanoparticles The particle size and particle size dispersity index (PDI) of the prepared lipid nanoparticles were measured using Zetasizer Pro (purchased from Malvern Instruments Ltd.) and DynaPro NanoStar (purchased from Wyatt). The degree of RNA encapsulation by lipid nanoparticles was characterized by the % encapsulation efficiency, which reflects the degree of binding of lipid nanoparticles to RNA fragments. This parameter was measured by the Quant-it™ RiboGreen RNA Assay (purchased from Invitrogen). Lipid nanoparticle samples were diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH = 7.5). A portion of the sample solution was removed, 0.5% Triton (Triton X-100) was added, and the mixture was then allowed to stand at 37°C for 30 minutes. Immediately after addition of the RIBOGREEN® reaction solution, fluorescence values ​​were read on a Varioskan LUX multifunction microplate reader (purchased from Thermofisher) at 485 nm for absorbance and 528 nm for emission to obtain encapsulation efficiency values.

[0878] Assay Example 3: Animal Experiments The delivery efficacy and safety of nanoparticles encapsulating luciferase mRNA (Trilink, L-7202) in mice were evaluated. Test mice were female SPF-grade C57BL / 6 mice, 6-8 weeks old and weighing 18-22 g, purchased from SPF (Beijing) Biotechnology Co., Ltd. All animals were acclimated for 7 days before the experiment and had free access to food and water during the experiment. The conditions included a 12 / 12-hour alternating light / dark cycle, a room temperature of 20-26°C, and a humidity of 40-70%. Mice were randomly assigned to groups. The luciferase mRNA-encapsulated lipid nanoparticles prepared above were intravenously injected into mice at a single dose of 0.5 mg / kg mRNA. Six hours after administration, the mice were subjected to in vivo bioluminescence assays using a Small Animal In Vivo Imaging System (IVIS LUMINA III, purchased from PerkinElmer). The assay was performed as follows: D-luciferin solution was prepared in saline at a concentration of 15 mg / mL, and each mouse was given the substrate via intraperitoneal injection. Ten minutes after substrate administration, the mouse was anesthetized with 2.5% isoflurane in an anesthesia chamber. The anesthetized mouse was placed in an IVIS for fluorescence imaging, and data acquisition and analysis were performed on the concentrated fluorescence distribution area.

[0879] The in vivo delivery efficiency of lipid nanoparticle carriers was expressed as the average fluorescence intensity and total photon count in different animals in the same subject group, as shown in Table 5. High fluorescence intensity and total photon count values ​​indicate high in vivo delivery efficiency of this mRNA fragment by lipid nanoparticles. Lipid nanoparticles containing cationic lipids of the present disclosure have good in vivo delivery efficiency. Unexpectedly, compared with molecules without tetramethyl groups, the corresponding lipid nanoparticles of the present disclosure have significantly increased in vivo delivery efficiency, for example, compound 20 vs. D1, compound 46 vs. D2.

[0880] [Table 5-1]

[0881] [Table 5-2]

[0882] Assay Example 4: Evaluation of delivery efficiency and safety in vitro The delivery efficacy and safety of luciferase mRNA-loaded nanoparticles were evaluated at the cellular level in vitro. Human embryonic kidney 293 (HEK293T) cells were cultured in Dulbecco's modified Eagle's medium (DMEM) (purchased from Thermo Fisher Scientific) containing 10% fetal bovine serum and 5% penicillin-streptomycin dual antibiotics at 37°C and 5% CO2. The cells were uniformly dispersed and spread in a 48-well plate and incubated in an incubator for 24 hours. A solution of luciferase mRNA-loaded lipid nanoparticles was then added. After 24 hours, the cells were lysed, and the intracellular expression intensity and relative light units (RLU) of luciferase in each type of lipid nanoparticle were measured using a luciferase detection reagent (purchased from Promega). Higher expression intensity indicates higher cellular delivery efficiency of the lipid material. Meanwhile, after 24 hours, CCK-8 reagent (purchased from DOJINDO) was used for a cytotoxicity test on parallel lipid nanoparticle-treated cell groups. In this test, a cell group treated with PBS alone was used as a negative control. The procedure was as follows: after adding the CCK-8 solution, the cells were placed in an incubator at 37°C for 4 hours. The absorbance values ​​were read at 450 nm using a multifunctional microplate reader. The ratio of the absorbance value of the nanoparticle-treated cells to that of the negative control was used as a characterization parameter for cell viability.

[0883] In vitro cellular level nanoparticle delivery efficacy and toxicity data are shown in Table 6.

[0884] [Table 6]

[0885] Assay Example 5: Characterization of the physical properties of lipid nanoparticles of different formulations The lipid nanoparticles of formulations 1 to 39 were prepared using the same method as used in the assay examples, where the ionizable cationic lipid in formulations 1 to 9 was compound 46, the ionizable cationic lipid in formulations 10 to 31 was compound 20, and the ionizable cationic lipid in formulations 32 to 39 was compound 26. Specific formulation information can be found in Tables 10 to 12. The formulations for DLin-MC3-DMA and SM-102 used as controls are as follows: MC3 formulation: MC3: cholesterol:DSPC:DMG-PEG = 50:38.5:10:1.5, N / P ratio 6; SM102 formulation: SM102: cholesterol: DSPC: DMG-PEG = 50: 38.5: 10: 1.5, N / P ratio 6.

[0886] The particle size and particle size dispersity index (PDI) of the prepared lipid nanoparticles were measured using Zetasizer Pro (purchased from Malvern Instruments Ltd.) and DynaPro NanoStar (purchased from Wyatt). The degree of RNA encapsulation by lipid nanoparticles was characterized by the % encapsulation efficiency, which reflects the degree of binding of lipid nanoparticles to RNA fragments. This parameter was measured by the Quant-it™ RiboGreen RNA Assay (purchased from Invitrogen). Lipid nanoparticle samples were diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH = 7.5). A portion of the sample solution was removed, 0.5% Triton (Triton X-100) was added, and the mixture was then allowed to stand at 37°C for 30 minutes. Immediately after addition of the RIBOGREEN® reaction solution, fluorescence values ​​were read on a Varioskan LUX multifunction microplate reader (purchased from Thermofisher) at 485 nm for absorbance and 528 nm for emission to obtain encapsulation efficiency values.

[0887] [Table 7]

[0888] [Table 8]

[0889] [Table 9]

[0890] Assay Example 6: Animal studies with different formulations The in vivo delivery efficacy and safety of nanoparticles encapsulating luciferase mRNA (Trilink, L-7202) in mice were evaluated. Test mice were female SPF-grade C57BL / 6 mice, 6-8 weeks old and weighing 18-22 g, purchased from SPF (Beijing) Biotechnology Co., Ltd. All animals were acclimated for 7 days before the experiment and had free access to food and water during the experiment. The conditions included a 12 / 12-hour alternating light / dark cycle, a room temperature of 20-26°C, and a humidity of 40-70%. Mice were randomly divided into groups. The luciferase mRNA-encapsulated lipid nanoparticles prepared above were intravenously injected into mice at a single dose of 0.5 mg / kg mRNA. Six hours after administration, the mice were subjected to in vivo bioluminescence assays using a Small Animal In Vivo Imaging System (IVIS LUMINA III, purchased from PerkinElmer). The assay was performed as follows: D-luciferin solution was prepared in saline at a concentration of 15 mg / mL, and each mouse was given the substrate via intraperitoneal injection. Ten minutes after substrate administration, the mouse was anesthetized with 2.5% isoflurane in an anesthesia chamber. The anesthetized mouse was placed in an IVIS for fluorescence imaging, and data acquisition and analysis were performed on the concentrated fluorescence distribution area.

[0891] The in vivo delivery efficiency of lipid nanoparticle carriers was expressed as the average fluorescence intensity and total photon count in different animals within the same subject group. Higher values ​​of fluorescence intensity and total photon count indicate higher in vivo delivery efficiency of this mRNA fragment by lipid nanoparticles. The MC3 fold and SM102 fold in Tables 10-12 indicate the fold improvement of the LNPs of the present disclosure compared to MC3 LNPs or SM102 LNPs, respectively.

[0892] The LNPs of the present disclosure have good in vivo delivery efficiency (Tables 10-12), and are expressed up to 35-fold more efficiently in vivo than MC3 or SM102 when delivering luciferase mRNA.

[0893] [Table 10]

[0894] [Table 11]

[0895] [Table 12]

[0896] Although the present disclosure has been fully described by its embodiments, it is to be noted that various changes and modifications will be apparent to those skilled in the art, and all such changes and modifications are intended to be included within the scope of the claims appended hereto.

Claims

1. 1. A nanoparticle composition comprising a lipid component and optionally a payload, comprising: The lipid components comprise, in mole percentage, the following components: 20 mol % to 85 mol % ionizable cationic lipid; 10 mol% to 75 mol% of structured lipids; Neutral lipid 1.0 mol% to 30 mol%; Polymer lipid 0.25 mol% to 10 mol% Including; The ionizable cationic lipid is a compound of formula (IV) or a pharma- ceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: 【Chemistry 1】 (In the formula, M １ and M. ２ is -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -C(O)NR ａ - and -NR ａ C(O)—; Q is -C(O)O-; G ５ is a chemical bond; G ６ａ and G ６ｂ are independently a chemical bond, or C １～７ is alkylene; G ６ａ and G ６ｂ has a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R ９ and R １０ are independently H or C １～８ is alkyl; G １ , G ２ , G ３ and G ４ are independently a chemical bond or one or more R ｓ C optionally substituted with １～１３ Alkylene, C ２～１３ Alkenylene or C ２～１３ alkynylene; G １ and G ２ has a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; G ３ and G ４ has a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R ３ and R ４ are independently H, or one or more R ＊ C optionally substituted with １～１０ Alkyl, C １～１０ Haloalkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C ６～１０ aryl or 5-14 membered heteroaryl; Or, R ３ and R ４ together with the N atom to which they are attached, represent one or more R ＊ forming a 3- to 14-membered heterocyclyl optionally substituted with Or, R ４ and R ９ together with the atoms to which they are attached, represent one or more R ＊ forming a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl optionally substituted with R ＊ are independently H, halogen, cyano, C １～１０ Alkyl, C １～１０ Haloalkyl, -L ｂ -OR ｂ , -L ｂ -SR ｂ Or -L ｂ -NR ｂ R' ｂ and R ５ , R ６ , R ７ and R ８ is independent, C １～２ is alkyl; R １ and R ２ is independently optionally substituted with one or more R, and one or more methylene units are optionally and independently replaced with -NR''-; ４～２０ Alkyl, C ４～２０ Alkenyl or C ４～２０ alkynyl; R ｓ are independently H, C １～１４ Alkyl, -L ｄ -OR ｄ , -L ｄ -SR ｄ Or -L ｄ -NR ｄ R' ｄ and R is independently H, C １～２０ Alkyl, -L ａ -OR ａ , -L ａ -SR ａ Or -L ａ -NR ａ R' ａ and R″ is independently H or C １～２０ is alkyl; L ａ and L ｅ are independently a chemical bond or C １～２０ is alkylene; L ｂ and L ｆ are independently a chemical bond or C １～１０ is alkylene; L ｄ are independently a chemical bond or C １～１４ is alkylene; R ａ and R' ａ are independently H, as well as the following substituents: H, C １～２０ Alkyl, -L ｅ -OR ｅ , -L ｅ -SR ｅ and -L ｅ -NR ｅ R' ｅ C optionally substituted with one or more of １～２０ alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R ｂ and R' ｂ are independently H, as well as the following substituents: H, C １～１０ Alkyl, -L ｆ -OR ｆ , -L ｆ -SR ｆ and -L ｆ -NR ｆ R' ｆ C optionally substituted with one or more of １～１０ alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl; R ｄ and R' ｄ are independently H or C １～１４ is alkyl; R ｅ and R' ｅ are independently H or C １～２０ is alkyl; R ｆ and R' ｆ are independently H or C １～１０ is alkyl) is; Nanoparticle compositions.

2. Said M １ and M. ２ is independently selected from -C(O)O- and -OC(O)-; The nanoparticle composition of claim 1.

3. The lipid components comprise, in mole percentage, the following components: 25 mol% to 65 mol% ionizable cationic lipid; Structured lipid 25 mol% to 70 mol%; Neutral lipid 1 mol% to 25 mol%; Polymer lipid 0.5mol% to 8mol% Including, The nanoparticle composition of claim 1.

4. The lipid components comprise, in mole percentage, the following components: 30 mol% to 60 mol% of ionizable cationic lipid; structural lipids 27.5 mol% to 66 mol%; Neutral lipid 1.5 mol% to 20 mol%; Polymer lipid 1mol% to 5mol% Including, The nanoparticle composition of claim 1.

5. The lipid components comprise, in mole percentage, the following components: 30 mol% to 50 mol% of an ionizable cationic lipid; Structured lipids 30.5 mol% to 66 mol%; Neutral lipid 1.5 mol% to 20 mol%; Polymer lipid 1mol% to 5mol% Including, The nanoparticle composition of claim 1.

6. The compound of formula (IV) has the structure of formula (V): 【Chemistry 2】 (In the formula, Q is -C(O)O-; G ６ａ and G ６ｂ are independently a chemical bond, or C １～５ is alkylene; G ６ａ and G ６ｂ has a total length of 0, 1, 2, 3, 4 or 5 carbon atoms; R ９ is H and C １～６ alkyl; L ３ and L ５ Either one of or L ４ and L ６ One of the two is -(CR ｓ R ｓ ') ２ is selected from -, -CH=CH-, and -C≡C-, the other being a chemical bond; G １ａ , G １ｂ , G ２ａ , G ２ｂ , G ３ａ , G ３ｂ , G ４ａ and G ４ｂ are independently a chemical bond or 1, 2, 3, 4 or 5 R ｓ C optionally substituted with １～７ is alkylene; G １ａ , G １ｂ , G ２ａ and G ２ｂ has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; G ３ａ , G ３ｂ , G ４ａ and G ４ｂ has a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R ３ and R ４ are independently H or 1, 2, 3, 4 or 5 R ＊ C optionally substituted with １～６ Alkyl, C １～６ haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; Or, R ３ and R ４ may be, together with the N atom to which they are attached, one, two, three, four or five R ＊ forming a 3- to 10-membered heterocyclyl optionally substituted with Or, R ４ and R ９ may be, together with the atoms to which they are attached, one, two, three, four or five R ＊ forming a 3- to 10-membered heterocyclyl optionally substituted with; R ＊ are independently H, halogen, cyano, C １～６ Alkyl, C １～６ Haloalkyl, -L ｂ -OR ｂ Or -L ｂ -NR ｂ R' ｂ and R ５ , R ６ , R ７ and R ８ is independent, C １～２ is alkyl; Y １ and Y ２ are independently O, S or NR ａ and L １ and L ２ are independently -(CRR') ２ -, -CH=CH-, -C≡C- or -NR''-; G ７ , G ８ , G ９ and G １０ is independently a chemical bond or C optionally substituted with 1, 2, 3, 4, 5, or 6 R １～１２ is alkylene; G ７ and G ８ has a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G ９ and G １０ has a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; R ｓ and R ｓ ' is independently H, C １～１０ Alkyl, -L ｄ -OR ｄ Or -L ｄ -NR ｄ R' ｄ and R and R′ are independently H, C １～１４ Alkyl, -L ａ -OR ａ Or -L ａ -NR ａ R' ａ and R″ is independently H or C １～１４ is alkyl; L ａ are independently a chemical bond or C １～１４ is alkylene; L ｂ are independently a chemical bond or C １～６ is alkylene; L ｄ are independently a chemical bond or C １～１０ is alkylene; R ａ and R' ａ are independently H, C １～１４ alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R ｂ and R' ｂ are independently H, C １～６ alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R ｄ and R' ｄ are independently H or C １～１０ is alkyl) having The nanoparticle composition of claim 1.

7. The compound of formula (IV) has the structure of formula (VI) or formula (VII): 【Chemistry 5】 (In the formula, a, a', b and g are independently 0, 1, 2, 3, 4 or 5, and a' and b are not simultaneously 0; a'+g=0, 1, 2, 3, 4 or 5; c and e are independently 3, 4, 5, 6, 7, 8, or 9; d and f are independently 0, 1, 2, 3 or 4; c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9; 【Chemistry 6】 The methylene in the １～６ optionally and independently substituted with alkyl; R ３ and R ４ are independently H or 1, 2, 3, 4 or 5 R ＊ C optionally substituted with １～６ Alkyl, C １～６ haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl; Or, R ３ and R ４ may be, together with the N atom to which they are attached, one, two, three, four or five R ＊ forming a 3- to 10-membered heterocyclyl optionally substituted with; R ＊ are independently H, halogen, cyano, C １～６ Alkyl, C １～６ Haloalkyl, -L ｂ -OR ｂ Or -L ｂ -NR ｂ R' ｂ and R ５ , R ６ , R ７ and R ８ is independent, C １～２ is alkyl; Y １ and Y ２ are independently O, S or NR ａ and L １ and L ２ are independently -(CRR') ２ -, -CH=CH-, -C≡C- or -NR''-; G ７ , G ８ , G ９ and G １０ is independently a chemical bond or C optionally substituted with 1, 2, 3, 4, 5, or 6 R １～１２ is alkylene; G ７ and G ８ has a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; G ９ and G １０ has a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms; R and R′ are independently H, C １～１４ Alkyl, -L ａ -OR ａ Or -L ａ -NR ａ R' ａ and L ａ are independently a chemical bond or C １～１４ is alkylene; L ｂ are independently a chemical bond or C １～６ is alkylene; R ａ and R' ａ are independently H, C １～１４ alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R ｂ and R' ｂ are independently H, C １～６ alkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl; R″ is independently H or C １～１４ is alkyl) having The nanoparticle composition of claim 1.

8. In the compound of formula (VI) or (VII), a is 0, 1, 2, 3 or 4; a' and b are independently 0, 1, 2, 3 or 4; g is 0, 1 or 2; a'+g=0, 1, 2, 3, 4 or 5; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; 【Chemistry 7】 The methylene in the １～６ optionally and independently substituted with alkyl; 【Chemistry 8】 The methylene in the １～６ optionally and independently substituted with alkyl; R ３ and R ４ are independently 1, 2 or 3 R ＊ C optionally substituted with １～６ is alkyl; R ＊ are independent, H, C １～６ Alkyl, C １～６ Haloalkyl or -OR ｂ is; Or, R ３ and R ４ together with the N atom to which they are attached, form one, two or three R ＊ forming a 3- to 7-membered heterocyclyl optionally substituted with; R ５ , R ６ , R ７ and R ８ became independent and C １～２ is alkyl; Y １ and Y ２ are independently O, S or NR ａ and L １ and L ２ are independently -(CHR) ２ -, -CH=CH-, -C≡C- or -NR''-; G ７ and G ９ are independently a chemical bond or C １～６ is alkylene; G ８ and G １０ became independent and C １～１０ is alkylene; G ７ and G ８ has a total length of 6, 7, 8, 9 or 10 carbon atoms; G ９ and G １０ has a total length of 6, 7, 8, 9 or 10 carbon atoms; G ７ , G ８ , G ９ or G １０ wherein one, two or three methylenes are optionally and independently substituted with one R; R is independently H or C １～８ is alkyl; R″ is independently H or C １～１０ is alkyl; R ａ are independently H or C １～１０ is alkyl; R ｂ are independently H or C １～６ is alkyl, The nanoparticle composition of claim 7.

9. In the compound of formula (VI), a is 0, 1, 2, 3 or 4; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; R ３ and R ４ became independent and C １～６ is alkyl, Or, R ３ and R ４ together with the N atom to which they are attached, form one, two or three R ＊ forming a 4-6 membered heterocyclyl optionally substituted with; R ＊ are independent, H, C １～６ Alkyl or C １～６ haloalkyl; R ５ , R ６ , R ７ and R ８ became independent and C １～２ is alkyl; Y １ and Y ２ are independently O, S or NR ａ and L １ and L ２ are independently -(CHR) ２ -, -CH=CH-, -C≡C- or -NR''-; G ７ and G ９ are independently a chemical bond or C １～５ is alkylene; G ８ and G １０ became independent and C １～８ is alkylene; G ７ and G ８ has a total length of 6, 7, 8, 9 or 10 carbon atoms; G ９ and G １０ has a total length of 6, 7, 8, 9 or 10 carbon atoms; G ７ , G ８ , G ９ or G １０ wherein one, two or three methylenes are optionally and independently substituted with one R; R is independently H or C １～８ is alkyl; R″ is independently H or C ７～９ is alkyl; R ａ are independently H or C ８～１０ is alkyl, The nanoparticle composition of claim 7.

10. In the compound of formula (VI), a is 2, 3 or 4; c and e are independently 3, 4, 5, or 6; d and f are independently 0, 1 or 2; c+d=4, 5 or 6, e+f=4, 5 or 6; R ３ and R ４ became independent and C １～６ is alkyl; R ５ , R ６ , R ７ and R ８ became independent and C １～２ is alkyl; Y １ and Y ２ is independently O or S; L １ and L ２ are independently -(CHR) ２ -, -CH=CH- or -C≡C-; G ７ and G ９ became independent and C １～４ is alkylene; G ８ and G １０ became independent and C ２～７ is alkylene; G ７ and G ８ has a total length of 6, 7 or 8 carbon atoms; G ９ and G １０ has a total length of 6, 7 or 8 carbon atoms; G ７ , G ８ , G ９ or G １０ wherein one, two or three methylenes are optionally and independently substituted with one R; R is independently H or C １～７ is alkyl; However, L １ When -C≡C-, G ７ C １～２ alkylene, or L ２ When -C≡C-, G ９ C １～２ is alkylene, The nanoparticle composition of claim 9.

11. In the compound of formula (VI), a is 2, 3 or 4; c and e are independently 4, 5 or 6; d and f are 0; R ３ and R ４ became independent and C １～６ is alkyl; R ５ , R ６ , R ７ and R ８ became independent and C １～２ is alkyl; Y １ and Y ２ is O; L １ and L ２ are independently -(CHR) ２ - or -CH=CH-; G ７ and G ９ are independently -CH ２ - or -CH ２ CHR-; G ８ and G １０ are independently -(CH ２ ) ６ - or - (CH ２ ) ７ - and G ７ and G ８ has a total length of 7 or 8 carbon atoms; G ９ and G １０ has a total length of 7 or 8 carbon atoms; G ８ or G １０ wherein one, two or three methylenes are optionally and independently substituted with one R; R is independently H or C ４～６ Alkyl, instead H or C ５ is alkyl, The nanoparticle composition of claim 9.

12. In the compound of formula (VI), a is 2 or 3; The nanoparticle composition of claim 11.

13. In the compound of formula (VI), -G ７ -L １ -G ８ -H and -G ９ -L ２ -G １０ -H is simultaneously -(CH ２ ) ９ CH ３ isn't it, The nanoparticle composition of claim 11.

14. In the compound of formula (VI), a is 2; c and e are 3; d and f are 2; R ３ and R ４ became independent and C １～３ is alkyl; R ５ , R ６ , R ７ and R ８ became independent and C １～２ is alkyl; Y １ and Y ２ is independently O or S; L １ and L ２ Ga-(CHR) ２ - and G ７ and G ９ are independently -CH ２ - or -CH ２ CHR-; G ８ and G １０ are independently -(CH ２ ) ５ -, -(CH ２ ) ６ - or - (CH ２ ) ７ - and G ７ and G ８ has a total length of 6, 7 or 8 carbon atoms; G ９ and G １０ has a total length of 6, 7 or 8 carbon atoms; G ８ or G １０ wherein one, two or three methylenes are optionally and independently substituted with one R; R is independently H or C １～７ is alkyl, The nanoparticle composition of claim 9.

15. In the compound of formula (VI), R is independently H or C １～６ is alkyl, 15. The nanoparticle composition of claim 14.

16. In the compound of formula (VI), R is independently Me; 15. The nanoparticle composition of claim 14.

17. The ionizable cationic lipid is selected from the group consisting of: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 The nanoparticle composition of claim 1 , wherein the nanoparticle composition is selected from:

18. The payload is a nucleic acid, and the N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 1 to 15:1; The nanoparticle composition of claim 1.

19. The N:P molar ratio of N atoms in the ionizable cationic lipid to P atoms in the payload molecule is 3 to 12:

1.

20. The nanoparticle composition of claim 18.

20. The particle size is 65 to 200 nm; The nanoparticle composition of claim 1.

21. The neutral lipid is one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE and DPPE; The nanoparticle composition of claim 1.

22. The structural lipid is one or more of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campesterol; The nanoparticle composition of claim 1.

23. The polymer lipid is a polyethylene glycol-containing lipid. The nanoparticle composition of claim 1.

24. the pegylated lipid is one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, azide-PEG2000, DSPE-PEG2000-mannose, ceramide-PEG5000, and DSPE-PEG5000; 24. The nanoparticle composition of claim 23.

25. the payload is selected from one or more of a therapeutic agent, a prophylactic agent, and a diagnostic agent; The nanoparticle composition of claim 1.

26. A pharmaceutical composition comprising the nanoparticle composition of any one of claims 1 to 25 and a pharma- ceutically acceptable excipient(s).

27. A pharmaceutical composition for treating, diagnosing or preventing a disease or for delivering a payload, comprising a nanoparticle composition according to any one of claims 1 to 24, wherein the payload is one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

28. 26. The nanoparticle composition of claim 25, wherein the therapeutic, prophylactic or diagnostic agent is a nucleic acid.

29. 28. The pharmaceutical composition of claim 27, wherein the therapeutic, prophylactic or diagnostic agent is a nucleic acid.

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