Polymeric lipid compounds

Abstract

The invention relates to a polymer lipid compound, in particular to a compound as shown in a formula (I), or pharmaceutically acceptable salt, isotope variant, tautomer or stereoisomer thereof. The invention also provides nanoparticle pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions thereof in delivery of loads. The polymer lipid compound can replace PEG lipid and has the advantages of biocompatibility, easiness in decomposition in vivo and no toxicity, so that a novel lipid delivery system is obtained.

Description

Invention Field

[0001] This invention relates to the field of biotechnology, and more specifically to a new class of polymeric lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. The invention also relates to lipid nanoparticles comprising said compounds and pharmaceutical compositions, and the use of said lipid nanoparticles in the delivery of bioactive substances such as nucleic acids (e.g., DNA, RNA, proteins, pharmaceutically active molecules, etc.). Background Technology

[0002] Polyethylene glycol (PEG) possesses advantages such as being non-toxic, non-immunogenic, non-antigenic, and highly water-soluble, making it a widely used polymer material for covalent modification of biopolymers such as proteins and peptides. PEGylation involves covalently binding PEG to drugs to improve their pharmacokinetic, pharmacodynamic, and immunological properties, thereby enhancing their therapeutic effects. Therefore, PEG is frequently used in drug delivery and drug modification technologies, either directly coupled to drugs or encapsulated on drug surfaces within nanomaterials.

[0003] PEG was initially considered a bioinert material, lacking immunogenicity and antigenicity. However, recent reports indicate that long-term administration can lead to PEG accumulation in tissues, potentially causing tissue toxicity and adverse reactions. PEG chains smaller than 400 Da are metabolized in vivo by alcohol dehydrogenases into toxic metabolites, such as related acid metabolites, which may cause dangerous hypercalcemia and acidosis. Free PEG and PEGylated nanocarriers can act as inhibitors of glycogen and cytochrome P450 enzymes, thereby altering the pharmacokinetics of modified drugs. Furthermore, literature reports the existence of anti-PEG antibodies (APAs) that recognize and bind to PEG, including existing and treatment-induced antibodies. As more PEGylated products enter clinical trials, some reports have linked the development of anti-PEG antibodies to reduced therapeutic efficacy, and an increase in reported adverse reactions after repeated administration. A Phase III study (NCT01848106) was reportedly discontinued due to serious adverse events (SAEs), with subjects experiencing SAEs having significantly higher pre-existing APA titers than other subjects. In addition to PEGylated proteins, polyethylene glycol-modified nanoparticles, such as liposomes and micelles, have also been reported to stimulate the production of APA in animal models.

[0004] Therefore, there is an urgent need to develop biocompatible, easily biodegradable, and non-toxic PEG lipid alternatives to obtain a safer new lipid delivery system. Summary of the Invention

[0005] The present invention aims to solve the above problems and provide a new polymer lipid compound that can replace traditional PEG lipids. It has the advantages of good biocompatibility, easy decomposition in vivo, and non-toxicity, thereby obtaining a new lipid delivery system.

[0006] In order to develop polymer lipid compounds with new structures, the inventors attempted to synthesize compounds with different degrees of polymerization by amino acid condensation. They found that using polymerized sarcosine as the head group of lipid molecules resulted in polymer lipids with good biocompatibility, easy decomposition and non-toxicity, which have strong application value in clinical practice.

[0007] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0008]

[0009] Each group is defined as described in this article.

[0010] In another aspect, the present invention provides a lipid composition comprising a polymeric lipid, said polymeric lipid being a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0011] In another aspect, the present invention provides nanoparticle compositions comprising the lipid compositions of the present invention, and optionally comprising a loading agent; preferably, the loading agent is selected from at least one of DNA, RNA, protein, and pharmaceutically active molecules.

[0012] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, or lipid compositions of the present invention, or nanoparticle compositions of the present invention, and pharmaceutically acceptable excipients.

[0013] In another aspect, the present invention provides the use of the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, or lipid compositions of the present invention, or nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention in the preparation of medicaments for treating, diagnosing or preventing diseases.

[0014] In another aspect, the present invention provides the use of the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, or lipid compositions of the present invention, or nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention in the preparation of a delivery-loaded medicament.

[0015] In another aspect, the present invention provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0016] In another aspect, the present invention provides nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention, for the treatment, diagnosis or prevention of diseases.

[0017] In another aspect, the present invention provides a method for delivering a payload into a subject, comprising administering to the subject a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0018] In another aspect, the present invention provides lipid compositions of the present invention, or nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention for delivery of payloads.

[0019] In a specific implementation, the payload is selected from at least one of DNA, RNA, protein, and pharmaceutically active molecules.

[0020] In a more specific embodiment, the RNA is selected from at least one of the following: enable RNA (mRNA), small interfering RNA (siRNA), aiRNA, microRNA (miRNA), double-stranded RNA (dsRNA), antisense RNA (aRNA), long non-coding RNA (lncRNA), short hairpin RNA (shRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme.

[0021] In a more specific embodiment, the protein is selected from at least one of antibodies, enzymes, recombinant proteins, polypeptides, and short peptides.

[0022] definition

[0023] Chemical definition

[0024] The definitions of specific functional groups and chemical terms are described in more detail below.

[0025] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0026] “C 2-18 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 2 to 18 carbon atoms. 1-10 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, the alkyl group is a straight-chain alkyl group.

[0027] “C 4-18 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 4 to 18 carbon atoms and at least one carbon-carbon double bond. 3-12 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 4 to 18 carbon atoms and at least one carbon-carbon double bond. 2-10 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. In some embodiments, C 2-6 Alkenyl groups are preferred, C 2-6Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] “C 2-10 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 The alkynyl group is preferred. In some embodiments, C 2-6 The alkynyl group is preferred, C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0029] “C 1-20 "Alkylene" refers to the removal of C 1-20 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 3-20 Alkylene, C 5-20 Alkylene, C 8-20 Alkylene, C 1-18 Alkylene, C 10-17 Alkylene, C 1-17 Alkylene, C 3-17 Alkylene, C 1-16 Alkylene, C 1-10 Alkylene, C 3-10 Alkylene, C 1-6 Alkylene, C 3-6 Alkylene, C 4-6 Alkylene, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3Alkylenes are preferred. In some embodiments, C6 and C4 alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Exemplary substituted alkylenes, for example, alkylenes 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 propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. In some embodiments, straight-chain alkylene groups are preferred.

[0030] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene", "C" 0-4 "alkylene" refers to chemical bonds and the aforementioned "C" 1-4 Alkylene".

[0031] “C 3-12 "Alkenyl" refers to the group that has been de-carbonied. 3-12 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. "C 2-10 "Alkenyl" refers to the group that has been de-carbonied. 2-10 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-6 imidene group, C 2-4 imide and C 2-3 Alkenyl groups are preferred. In some embodiments, vinylene groups are preferred.

[0032] “C 2-10 "Iso-ynyl group" refers to the group with the C group removed. 2-10 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 2-6 Ethyne group, C 2-4 etyne and C 2-3 The acetylenoid group is preferred. In some embodiments, the acetylenoid group is preferred.

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

[0034] Therefore, "C" 1-10 "Halogenated alkyl" refers to the above "C 1-10 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Halogenated alkyl groups and C 1-3 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 cyclic carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-7 cycloalkyl and C 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl groups also include the aforementioned cycloalkyl ring in which substituents on any non-adjacent carbon atoms are linked to form a bridged ring, together forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups also include the aforementioned cycloalkyl ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] "3-10 membered heterocyclic groups" refer to saturated or unsaturated groups of 3- to 10 membered non-aromatic ring systems having a ring carbon atom and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 1, 2, or 3 double or triple bonds. In heterocyclic groups containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 5-10 membered heterocyclic group is preferred, which is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-7 membered heterocyclic group is preferred, which is a 3-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 5-7 membered heterocyclic group is preferred, which is a 5-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-6 membered heterocyclic group is preferred, which is a 4-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolylyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolylyl, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiohexane, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclic groups also include those that share one or two atoms with a cycloalkyl, heterocyclic, aryl, or heteroaryl group to form a bridged or spirocyclic ring, wherein the shared atom may be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point 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. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] "5-10-membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6, 10, or 14 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In other embodiments, 5-6-membered heteroaryl is particularly preferred, which is a 4n+2 aromatic ring system of a 5-6-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. 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 thiazolyl. 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: pyridinyl or pyridoneyl. 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 tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirmonoheptatrienyl, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0040] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0041] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -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, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0042] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =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 replace;

[0043] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0044] R bb Each is independently selected from: 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. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0045] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups.dd Group substitution;

[0046] R dd Each is independently selected from: 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(=NR) ff )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, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0047] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0048] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0049] R gg Each of these is independently: 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 groups, -NH(OH), -SH, -SC 1-6Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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 groups, -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 group, -P(=O)2(C 1-6Alkyl), -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 ynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0050] Exemplary substituents on the 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, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0051] Other definitions

[0052] It should be understood that all numerical names are preceded by the term "about".

[0053] As used herein, the term “about” should be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. If its meaning is not clear to those skilled in the art based on the context in which the term is applied, then “about” means a deviation of no more than plus or minus 20%, 10%, 5%, 1%, 0.5%, or 0.1% of the specific value or range.

[0054] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise.

[0055] In this document, the terms “comprising,” “having,” “including,” and “containing” should be interpreted as open-ended terms (i.e., meaning “including but not limited to”).

[0056] In this document, “and / or” means and includes any and all possible combinations of one or more of the associated listed items. For example, “the composition contains A and / or B” can be interpreted as the composition contains A, the composition contains B, or the composition contains both A and B.

[0057] "Ionizable lipids" refer to lipid molecules that can exist in a positively charged or neutral form depending on the pH value; they are also known as "ionizable lipids." Ionizable lipids affect the surface charge of lipid nanoparticles under different pH conditions. Common examples include DLin-MC3-DMA, ALC-0315, SM-102, 8-(3-hydroxypropyl)(9,12-dienyl-octadecyl-1)-amino-octanoic acid heptadecano-9-ol ester, bis(2,3-bis(hexyloxy)propyl)8,8'-((2-hydroxyethyl)azonyl)dioctanoate, 2,3-di(hexyloxy)propionyl 12-((8-(2,3-di(hexyloxy))propoxy)-8-oxooctyl)(2-hydroxyethyl)amino)dodecanoate, N,N-dimethyl-2,3-dioleenyloxy)propylamine (DODMA), N,N-dioleenyl-N,N-dimethylammonium chloride (DODAC), and N,N-distearate-N,N-dimethyl... Ammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(2,3-diolenoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) or 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA).

[0058] "Structural lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentane-polyhydrophenanthrene carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coccosterol, rock saponin, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol, or campesterol.

[0059] "Polymer lipids" refer to molecules containing both polymer and lipid moieties, capable of reducing aggregation. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. In some embodiments, the polymer lipid is a compound of the present invention. In some embodiments, the polymer lipid is a combination of a polyethylene glycol (PEG) lipid and a compound of the present invention. Other lipids capable of reducing aggregation, such as products of lipid coupling with compounds having uncharged, hydrophilic, or sterically barrier moieties, may also be used.

[0060] "Lipid nanoparticles" refer to particles containing lipid components and having a nanoscale size.

[0061] As used herein, the term "antibody" should be understood in its broadest sense and includes monoclonal antibodies (including full-length monoclonal antibodies), antibody fragments, and multispecific antibodies (e.g., bispecific antibodies) containing at least two antigen-binding regions. Antibodies may contain additional modifications, such as non-naturally occurring amino acids, mutations in the Fc region, and mutations at glycosylation sites. Antibodies also include post-translational modified antibodies, fusion proteins containing antigenic determinants of antibodies, and immunoglobulin molecules containing any other modifications to antigen recognition sites, provided that these antibodies exhibit the desired biological activity.

[0062] The term "enzyme" as used in this article should be understood in its broadest sense, referring to a protein or RNA that has highly efficient and specific catalytic activity. An enzyme may be a single peptide chain or composed of two or more peptide chains.

[0063] The term "recombinant protein" as used in this article should be understood in its broadest sense, referring to proteins obtained by inserting a target gene fragment into a suitable expression vector using genetic engineering techniques, and then expressing and purifying it in host cells.

[0064] As used herein, the terms “peptide” and “polypeptide” are used interchangeably and should be understood in their broadest sense as a polymer of two or more amino acid subunits, amino acid analogs, or peptide mimics. Both “peptide” and “polypeptide” contain at least two amino acids, and there is no limit to the maximum number of amino acids. As used herein, the term “amino acid” refers to natural and / or non-natural or synthetic amino acids, including D and L optical isomers and amino acid analogs. As used herein, the term “short peptide” refers to a peptide composed of 2 to 10 amino acids.

[0065] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0066] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0067] Pharmaceutically acceptable base addition salts are those 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, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0068] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0069] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0070] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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" are used interchangeably herein.

[0071] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0072] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0073] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0074] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0075] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0076] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation

[0077] The embodiments of the present invention will be described in further detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0078] In this document, “compounds of the present invention” refers to compounds of formula (I), formula (II), formula (III), etc., which are pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers.

[0079] Compounds with asymmetric centers should be understood (unless otherwise stated) to include all optical isomers and mixtures thereof. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0080] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0081]

[0082] in,

[0083] n is an integer between 1 and 100;

[0084] s can be 1, 2, 3, 4, 5, 6, 7, or 8;

[0085] T is selected from chemical bonds, CH, and N;

[0086] R T It is R2-M2-G2-; when T is a chemical bond, R T It does not exist;

[0087] R is selected from H and C. 1-10 Alkyl, C 1-10 Halogenated alkyl groups and R2-M2-G2-;

[0088] R TUnlike R, it is not simultaneously R2-M2-G2-;

[0089] G1, G2, and G3 are independently selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group;

[0090] M1 and M2 are independently selected from chemical bonds, -C(O)-, -C(S)-, and -C(O)NR. b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -O-, -S-, -NR b -、-SS-、-C(S)NR b -、-NR b C(S)- and -OP(O)(OH)-O-;

[0091] R1 and R2 are independently selected from C 1-20 Alkyl groups, optionally marked with 0, 1, 2, 3, 4, or 5 R groups. s The substituted molecule has 0, 1, 2, 3, 4 or 5 unsaturated bonds selected from carbon-carbon double bonds or carbon-carbon triple bonds, and one or more methylene groups are optionally and independently substituted by R*.

[0092] R s Independently selected from H and C 1-20 Alkyl, -L1-OR a -L1-SR a -L1-NR b R c and

[0093] R* is independently selected from -O-, -S-, and -NR. b -;

[0094] R' is independently selected from H and C. 1-10 Alkyl and C 1-10 Halogenated alkyl groups;

[0095] R4 is selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a -C(S)SR a C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L2-C 3-10Cycloalkyl, -L2-3-10-membered heterocyclic group, -L2-C 6-10 Aryl and -L2-5-10 heteroaryl groups;

[0096] L1 is independently selected from chemical bonds and C 1-20 Alkylene;

[0097] L2 is independently selected from chemical bonds and C 1-10 Alkylene;

[0098] R a R b and R c Independently selected from H and C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L2-C 3-10 Cycloalkyl, -L2-3-10-membered heterocyclic group, -L2-C 6-10 aryl and -L2-5-10 heteroaryl; or R b R c Together with the nitrogen atoms attached to them, they form 3 to 10-membered subheterocyclic groups.

[0099] In another embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (II) or (III):

[0100]

[0101] in,

[0102] p is 0, 1, 2, 3, 4, 5 or 6;

[0103] q can be 0, 1, 2, 3, 4, 5, or 6;

[0104] r can be 0, 1, 2, 3, 4, 5, or 6;

[0105] s can be 1, 2, 3, 4, 5, or 6;

[0106] The remaining groups are as defined in this invention.

[0107] n

[0108] In one embodiment, n is an integer between 1 and 100; in another embodiment, n is an integer between 5 and 70; in another embodiment, n is an integer between 5 and 60; in another embodiment, n is an integer between 10 and 50; in another embodiment, n is an integer between 10 and 45; in another embodiment, n is an integer between 20 and 50; in another embodiment, n is an integer between 25 and 50; in another embodiment, n is an integer between 10 and 15; in another embodiment, n is an integer between 25 and 30; in another embodiment, n is an integer between 30 and 35; in another embodiment, n is an integer between 35 and 40; in another embodiment, n is an integer between 40 and 45; in another embodiment, n is an integer between 45 and 50.

[0109] In one specific implementation, n is an integer between 10 and 45, such as 10-15, 25-30, 35-40, or 40-45, such as 25-30, 35-40, or 40-45; in another specific implementation, n is an integer between 25 and 50, such as 25-30, 30-35, or 45-50.

[0110] s

[0111] In one implementation, s is 1; in another implementation, s is 2; in another implementation, s is 3; in another implementation, s is 4; in another implementation, s is 5; in another implementation, s is 6; in another implementation, s is 7; in another implementation, s is 8.

[0112] In one specific implementation, s is 1, 2, 3, 4, 5, or 6; in another specific implementation, s is 1, 2, or 3; in yet another specific implementation, s is 1 or 2.

[0113] In one embodiment, T is a chemical bond; in another embodiment, T is CH; in yet another embodiment, T is N.

[0114] In one specific implementation, T is selected from chemical bonds and CH.

[0115] R

[0116] In one embodiment, R is selected from H; in another embodiment, R is selected from C. 1-10 Alkyl; in another embodiment, R is selected from C 1-10 Haloalkyl; in another embodiment, R is selected from R2-M2-G2-.

[0117] In one specific implementation plan, R is selected from H and C. 1-10 Alkyl, C 1-10 Halogenated alkyl group and R2-M2-G2-; in another specific embodiment, R is selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another specific embodiment, R is selected from H, C 1-4 Alkyl and C 1-4 Halogenated alkyl; in another specific embodiment, R is H.

[0118] In one specific implementation plan, R T R is R2-M2-G2-, and R is not R2-M2-G2-; in another specific embodiment, R is R2-M2-G2-, T is a chemical bond, and R T It does not exist; in another specific implementation, R is not R2-M2-G2-, T is a chemical bond, and R T It does not exist; in another specific implementation, R is H.

[0119] G1, G2 and G3

[0120] In one embodiment, G1 is a chemical bond; in another embodiment, G1 is a C bond. 1-10 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene; in another embodiment, G1 is C 2-10 Alkenyl group, preferably C 2-6 Alkenyl group, preferably C 2-3 alkenyl; in another embodiment, G1 is C 2-10 Alynyl group, preferably C 2-6 Alynyl group, preferably C 2-3 Alynyl group.

[0121] In one embodiment, G2 is a chemical bond; in another embodiment, G2 is a C bond. 1-10 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene; in another embodiment, G2 is C 2-10 Alkenyl group, preferably C 2-6 Alkenyl group, preferably C 2-3 alkenyl; in another embodiment, G2 is C 2-10 Alynyl group, preferably C 2-6 Alynyl group, preferably C 2-3 Alynyl group.

[0122] In one embodiment, G3 is a chemical bond; in another embodiment, G3 is a C bond. 1-10 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene; in another embodiment, G3 is C 2-10 Alkenyl group, preferably C 2-6 Alkenyl group, preferably C 2-3 alkenyl; in another embodiment, G3 is C 2-10 Alynyl group, preferably C 2-6 Alynyl group, preferably C 2-3 Alynyl group.

[0123] In one specific implementation scheme, G1 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; in another specific embodiment, G1 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; in another specific embodiment, G1 is selected from chemical bonds and C 1-6 Alkylene; in another specific embodiment, G1 is selected from chemical bonds and C 1-3 Alkylene; in another specific embodiment, G1 is not a chemical bond.

[0124] In one specific implementation scheme, G2 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; in another specific embodiment, G2 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group; in another specific embodiment, G2 is selected from chemical bonds and C 1-6 Alkylene; in another specific embodiment, G2 is selected from chemical bonds and C 1-3 Alkylene.

[0125] In one specific implementation scheme, G3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; in another specific embodiment, G3 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; in another specific embodiment, G3 is selected from chemical bonds and C 1-6 Alkylene; in another specific embodiment, G3 is selected from chemical bonds and C1-3 Alkylene.

[0126] M1 and M2

[0127] In one embodiment, M1 is a chemical bond; in another embodiment, M1 is -C(O)-; in yet another embodiment, M1 is -C(S)-; in still another embodiment, M1 is -C(O)NR. b -; In another implementation, M1 is -NR b C(O)-; In another embodiment, M1 is -C(O)O-; In another embodiment, M1 is -OC(O)-; In another embodiment, M1 is -C(O)S-; In another embodiment, M1 is -SC(O)-; In another embodiment, M1 is -C(S)O-; In another embodiment, M1 is -OC(S)-; In another embodiment, M1 is -C(S)S-; In another embodiment, M1 is -SC(S)-; In another embodiment, M1 is -O-; In another embodiment, M1 is -S-; In another embodiment, M1 is -NR b -; In another embodiment, M1 is -SS-; In another embodiment, M1 is -C(S)NR b -; In another implementation, M1 is -NR b C(S)-; In another embodiment, M1 is -OP(O)(OH)-O-.

[0128] In one embodiment, M2 is a chemical bond; in another embodiment, M2 is -C(O)-; in yet another embodiment, M2 is -C(S)-; in still another embodiment, M2 is -C(O)NR. b -; In another implementation, M2 is -NR b C(O)-; In another embodiment, M2 is -C(O)O-; In another embodiment, M2 is -OC(O)-; In another embodiment, M2 is -C(O)S-; In another embodiment, M2 is -SC(O)-; In another embodiment, M2 is -C(S)O-; In another embodiment, M2 is -OC(S)-; In another embodiment, M2 is -C(S)S-; In another embodiment, M2 is -SC(S)-; In another embodiment, M2 is -O-; In another embodiment, M2 is -S-; In another embodiment, M2 is -NR b -; In another embodiment, M2 is -SS-; In another embodiment, M2 is -C(S)NR b-; In another implementation, M2 is -NR b C(S)-; In another embodiment, M2 is -OP(O)(OH)-O-.

[0129] In one specific implementation, M1 and M2 are independently selected from chemical bonds, -C(O)-, -C(S)-, and -C(O)NR. b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -O-, -S-, -NR b -, -SS- and -OP(O)(OH)-O-; in another specific embodiment, M1 and M2 are independently selected from chemical bonds, -C(O)-, -C(S)-, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -O-, -S-, and -NR b -

[0130] In one specific implementation, M1 and M2 are independently selected from chemical bonds, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -NR b -, -O- and -S-; in another specific implementation, M1 and M2 are independently selected from -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, and -SC(O)-; in another specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -O-, and -S-; in another specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, and -SC(O)-; In another specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -O-; in another specific embodiment, M1 and M2 are independently selected from -C(O)O- and -OC(O)-; preferably, M1 is selected from -C(O)O- and -O-, more preferably -C(O)O-; M2 is selected from -C(O)O-, -OC(O)- and -O-, more preferably -C(O)O- and -OC(O)-.

[0131] In one specific embodiment, M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -O-, and -S-; in another specific embodiment, M1 and M2 are independently selected from chemical bonds, -C(O)O-, -C(O)S-, -O-, and -S-; in another specific embodiment, M1 and M2 are independently selected from -O- and -S-; in another specific embodiment, M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)-, and -O-; in another specific embodiment, M1 and M2 are independently selected from chemical bonds, -C(O)O-, and -O-; in another specific embodiment, M1 and M2 are -O-.

[0132] R1 and R2

[0133] In one implementation, R1 is C 1-20 Alkyl, preferably C 4-20 Alkyl, preferably C 10-20 Alkyl, preferably C 10-18 Alkyl, preferably C 13-18 Alkyl, preferably C 13-16 Alkyl, such as C 13 Straight-chain alkyl groups, such as C 14 Straight-chain alkyl groups, such as C 16 Straight-chain alkyl groups, such as C 18 Straight-chain alkyl; in another embodiment, R1 is optionally replaced by 0, 1, 2, 3, 4 or 5 (preferably 0, 1, 2 or 3, preferably 0 or 1) R s In another embodiment, R1 is not substituted; in another embodiment, R1 optionally has 0, 1, 2, 3, 4 or 5 (preferably 0, 1, 2 or 3) unsaturated bonds selected from carbon-carbon double bonds or carbon-carbon triple bonds; in another embodiment, R1 optionally has 0, 1, 2 or 3 (preferably 0, 1 or 2) carbon-carbon double bonds, for example, R1 is... For example, R1 is In another embodiment, R1 does not have unsaturated bonds; in another embodiment, one or more (preferably 1, 2, 3, 4 or 5, preferably 1, 2 or 3, preferably 0, 1 or 2, preferably 0 or 1) methylene groups in R1 are optionally and independently replaced by R*; in another embodiment, one or more methylene groups in R1 are not replaced by R*.

[0134] In one implementation, R2 is C 1-20 Alkyl, preferably C 4-20 Alkyl, preferably C 10-20 Alkyl, preferably C 10-18 Alkyl, preferably C 13-18 Alkyl, preferably C13-16 Alkyl, such as C 13 Straight-chain alkyl groups, such as C 14 Straight-chain alkyl groups, such as C 16 Straight-chain alkyl groups, such as C 18 Straight-chain alkyl; in another embodiment, R2 is optionally replaced by 0, 1, 2, 3, 4 or 5 (preferably 0, 1, 2 or 3, preferably 0 or 1) R s In another embodiment, R2 is not substituted; in another embodiment, R2 optionally has 0, 1, 2, 3, 4 or 5 (preferably 0, 1, 2 or 3) unsaturated bonds selected from carbon-carbon double bonds or carbon-carbon triple bonds; in another embodiment, R2 optionally has 0, 1, 2 or 3 (preferably 0, 1 or 2) carbon-carbon double bonds, for example, R2 is... For example, R2 is In another embodiment, R2 does not have unsaturated bonds; in another embodiment, one or more (preferably 1, 2, 3, 4 or 5, preferably 1, 2 or 3, preferably 0, 1 or 2, preferably 0 or 1) methylene groups in R2 are optionally and independently replaced by R*; in another embodiment, one or more methylene groups in R2 are not replaced by R*.

[0135] In one specific implementation, when R1 has two carbon-carbon double bonds, these two carbon-carbon double bonds are separated by one methylene group, resulting in the following structure:

[0136] In one specific implementation, when R2 has two carbon-carbon double bonds, these two carbon-carbon double bonds are separated by one methylene group, resulting in the following structure:

[0137] In one specific embodiment, at least one of R1 and R2 does not have an unsaturated bond; in another specific embodiment, at least one of R1 and R2 does not have a carbon-carbon double bond.

[0138] In one specific implementation, R1 and R2 are independently selected from C. 13 straight-chain alkyl, C 14 straight-chain alkyl, C 16 straight-chain alkyl, C 18 straight-chain alkyl, In another specific implementation, R1 and R2 are independently selected from C. 13 straight-chain alkyl, C 14 straight-chain alkyl and C 16 Straight-chain alkyl; in another specific embodiment, R1 and R2 are independently selected from C 13 straight-chain alkyl, C 16 straight-chain alkyl, C18 straight-chain alkyl,

[0139] In a specific implementation scheme, R1 is Preferred

[0140] R s

[0141] In one implementation, R s H; in another embodiment, R s C 1-20 Alkyl; in another embodiment, R s -L1-OR a In another implementation, R s -L1-SR a In another implementation, R s -L1-NR b R c In another implementation, R s for Preferred

[0142] In one specific implementation plan, R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 Alkyl), -L1-OR a -L1-SR a -L1-NR b R c In another specific implementation scheme, R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 alkyl).

[0143] R*

[0144] In one implementation, R* is -O-; in another implementation, R* is -S-; in yet another implementation, R* is -NR. b -

[0145] In one specific implementation, R* is independently selected from -O-, -S-, and -NR. b -; In another specific implementation, R* is independently selected from -O- and -S-.

[0146] R'

[0147] In one implementation, R' is H; in another implementation, R' is C. 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, such as methyl; in another embodiment, R' is C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-4 Halogenated alkyl groups.

[0148] In one specific implementation scheme, R' is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; in another specific embodiment, R' is independently selected from H, C 1-4 Alkyl and C 1-4 Halogenated alkyl; in another specific embodiment, R' is independently selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0149] R4

[0150] In one embodiment, R4 is H; in another embodiment, R4 is -C(O)R a For example, -C(O)Me; in another embodiment, R4 is -C(S)R a In another embodiment, R4 is -C(O)OR a In another embodiment, R4 is -C(O)SR a In another implementation, R4 is -C(S)OR a In another embodiment, R4 is -C(S)SR a In another embodiment, R4 is C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R4 is C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-4 Halogenated alkyl; in another embodiment, R4 is -L2-C 3-10 Cycloalkyl, preferably -L2-C 3-7 Cycloalkyl; in another embodiment, R4 is a -L2-3-10-membered heterocyclic group, preferably a -L2-3-7-membered heterocyclic group; in another embodiment, R4 is a -L2-C 6-10 Aryl, preferably -L2-phenyl; in another embodiment, R4 is -L2-5-10 heteroaryl, preferably -L2-5-6 heteroaryl.

[0151] In one specific implementation, R4 is selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a -C(S)SR a C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L2-C 3-7 Cycloalkyl, -L2-3-7-membered heterocyclic, -L2-phenyl, and -L2-5-6-membered heteroaryl; in another specific embodiment, R4 is selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another specific embodiment, R4 is selected from H, -C(O)R a -C(O)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another specific embodiment, R4 is selected from H, -C(O)R a C 1-4 Alkyl and C 1-4 Halogenated alkyl; in another specific embodiment, R4 is selected from H and -C(O)R a For example, H or -C(O)Me.

[0152] L1

[0153] In one embodiment, L1 is a chemical bond; in another embodiment, L1 is a C 1-20 Alkylene, preferably C 1-18 Alkylene, preferably C 1-16 Alkylene.

[0154] In one specific implementation, L1 is independently selected from chemical bonds and C. 1-18 Alkylene; in another specific embodiment, L1 is independently selected from chemical bonds and C 1-16 Alkylene.

[0155] L2

[0156] In one embodiment, L2 is a chemical bond; in another embodiment, L2 is C. 1-10 Alkylene.

[0157] In one specific implementation, L2 is independently selected from chemical bonds and C. 1-6 Alkylene; in another specific embodiment, L2 is independently selected from chemical bonds and C 1-4 Alkylene.

[0158] R a R b and R c

[0159] In one implementation, R a H; in another embodiment, R a C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R a C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-4 Halogenated alkyl; in another embodiment, R a -L2-C 3-10 Cycloalkyl, preferably -L2-C 3-7 cycloalkyl; in another embodiment, R a It is a -L2-3-10-membered heterocyclic group, preferably a -L2-3-7-membered heterocyclic group; in another embodiment, R a -L2-C 6-10 aryl, preferably -L2-phenyl; in another embodiment, R a It is a -L2-5-10 heteroaryl group, preferably a -L2-5-6 heteroaryl group.

[0160] In one implementation, R b H; in another embodiment, R b C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R b C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-4 Halogenated alkyl; in another embodiment, R b -L2-C 3-10 Cycloalkyl, preferably -L2-C 3-7 cycloalkyl; in another embodiment, R b It is a -L2-3-10-membered heterocyclic group, preferably a -L2-3-7-membered heterocyclic group; in another embodiment, R b -L2-C 6-10aryl, preferably -L2-phenyl; in another embodiment, R b It is a -L2-5-10 heteroaryl group, preferably a -L2-5-6 heteroaryl group.

[0161] In one implementation, R c H; in another embodiment, R c C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R c C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-4 Halogenated alkyl; in another embodiment, R c -L2-C 3-10 Cycloalkyl, preferably -L2-C 3-7 cycloalkyl; in another embodiment, R c It is a -L2-3-10-membered heterocyclic group, preferably a -L2-3-7-membered heterocyclic group; in another embodiment, R c -L2-C 6-10 aryl, preferably -L2-phenyl; in another embodiment, R c It is a -L2-5-10 heteroaryl group, preferably a -L2-5-6 heteroaryl group.

[0162] In one specific implementation plan, R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L2-C 3-7 Cycloalkyl, -L2-3-7-membered heterocyclic, -L2-phenyl and -L2-5-6-membered heteroaryl; in another specific embodiment, R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl; in another specific embodiment, R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0163] In one implementation, R b R cTogether with the nitrogen atoms attached to them, they form 3 to 10-membered subheterocyclic groups, preferably 3 to 7-membered subheterocyclic groups; in another embodiment, R b R c The nitrogen atoms bonded to them do not form rings.

[0164] p

[0165] In one implementation, p is 0; in another implementation, p is 1; in another implementation, p is 2; in another implementation, p is 3; in another implementation, p is 4; in another implementation, p is 5; in another implementation, p is 6.

[0166] In one specific implementation, p is 0, 1, 2, or 3; in another specific implementation, p is 0, 1, or 2; in yet another specific implementation, p is not 0.

[0167] q

[0168] In one implementation, q is 0; in another implementation, q is 1; in another implementation, q is 2; in another implementation, q is 3; in another implementation, q is 4; in another implementation, q is 5; in another implementation, q is 6.

[0169] In one specific implementation, q is 0, 1, 2, or 3; in another specific implementation, q is 0, 1, or 2; in yet another specific implementation, q is 0 or 1.

[0170] r

[0171] In one implementation, r is 0; in another implementation, r is 1; in another implementation, r is 2; in another implementation, r is 3; in another implementation, r is 4; in another implementation, r is 5; in another implementation, r is 6.

[0172] In one specific implementation, r is 0, 1, 2, or 3; in another specific implementation, r is 0, 1, or 2; in yet another specific implementation, r is 0 or 1.

[0173] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of n can be combined with s, T, R. T ,R,G1,G2,G3,M1,M2,R1,R2,R s ,R*,R4,L1,L2,p,q,r,R a Rb and R c This invention involves combining any of the technical solutions or any combination thereof. The present invention aims to include combinations of all these technical solutions; however, due to space limitations, they will not be listed individually.

[0174] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0175]

[0176] in,

[0177] n is an integer between 1 and 100;

[0178] s can be 1, 2, 3, 4, 5, 6, 7, or 8;

[0179] T is selected from chemical bonds, CH, and N;

[0180] R T It is R2-M2-G2-; when T is a chemical bond, R T It does not exist;

[0181] R is selected from H and C. 1-10 Alkyl, C 1-10 Halogenated alkyl groups and R2-M2-G2-;

[0182] R T Unlike R, it is not simultaneously R2-M2-G2-;

[0183] G1, G2, and G3 are independently selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group;

[0184] M1 and M2 are independently selected from chemical bonds, -C(O)-, -C(S)-, and -C(O)NR. b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -O-, -S-, -NR b -、-SS-、-C(S)NR b -、-NR b C(S)- and -OP(O)(OH)-O-;

[0185] R1 and R2 are independently selected from C 1-20 Alkyl groups, optionally marked with 0, 1, 2, 3, 4, or 5 R groups. sThe substituted molecule has 0, 1, 2, 3, 4 or 5 unsaturated bonds selected from carbon-carbon double bonds or carbon-carbon triple bonds, and one or more methylene groups are optionally and independently substituted by R*.

[0186] R s Independently selected from H and C 1-20 Alkyl, -L1-OR a -L1-SR a -L1-NR b R c and

[0187] R* is independently selected from -O-, -S-, and -NR. b -;

[0188] R' is independently selected from H and C. 1-10 Alkyl and C 1-10 Halogenated alkyl groups;

[0189] R4 is selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a -C(S)SR a C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L2-C 3-10 Cycloalkyl, -L2-3-10-membered heterocyclic group, -L2-C 6-10 Aryl and -L2-5-10 heteroaryl groups;

[0190] L1 is independently selected from chemical bonds and C 1-20 Alkylene;

[0191] L2 is independently selected from chemical bonds and C 1-10 Alkylene;

[0192] R a R b and R c Independently selected from H and C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L2-C 3-10 Cycloalkyl, -L2-3-10-membered heterocyclic group, -L2-C 6-10 aryl and -L2-5-10 heteroaryl; or R b R c Together with the nitrogen atoms attached to them, they form 3 to 10-membered subheterocyclic groups.

[0193] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein n is an integer between 5 and 70; preferably an integer between 5 and 60; preferably an integer between 10 and 50; preferably an integer between 10 and 45, such as an integer between 10 and 15, 25 and 30, 35 and 40 or 40 and 45, preferably an integer between 25 and 30, preferably an integer between 35 and 40, preferably an integer between 40 and 45; preferably an integer between 20 and 50, preferably an integer between 25 and 50, such as an integer between 25 and 30, 30 and 35 or 45 and 50.

[0194] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein s is 1, 2, 3, 4, 5 or 6; preferably 1, 2 or 3; preferably 1.

[0195] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein T is selected from chemical bonds and CH; preferably CH; preferably chemical bonds.

[0196] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R is selected from H, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups and R2-M2-G2-; preferably selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and C 1-4 Alkyl and C 1-4 Halogenated alkyl group; preferably H.

[0197] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R T R is R2-M2-G2-, and R is not R2-M2-G2-; preferably, R is R2-M2-G2-, T is a chemical bond, and R T It does not exist; preferably, R is not R2-M2-G2-, T is a chemical bond, and R T It does not exist; preferably, R is H.

[0198] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein G1, G2, and G3 are independently selected from chemical bonds, C1-10 Alkylene, C 2-10 imide and C 2-10 Alynyl group; preferably selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group; preferably selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-3 Alkylene; preferably G1 is not chemically bonded.

[0199] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein M1 and M2 are independently selected from chemical bonds, -C(O)-, -C(S)-, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -O-, -S-, -NR b -, -SS- and -OP(O)(OH)-O-; preferably selected from chemical bonds, -C(O)-, -C(S)-, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -O-, -S-, and -NR b -

[0200] In a more specific implementation, M1 and M2 are independently selected from chemical bonds, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -NR b -, -O- and -S-; preferably selected from -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S- and -SC(O)-; preferably selected from -C(O)O-, -OC(O)-, -C(O)S-, -SC(O-, -O- and -S-; preferably selected from -C(O)O-, -OC(O-, -C(O)S- and -SC(O-); preferably selected from -C(O)O-, -OC(O- and -O-, more preferably selected from -C(O)O- and -OC(O-); preferably, M1 is selected from -C(O)O- and -O-, more preferably -C(O)O-; M2 is selected from -C(O)O-, -OC(O- and -O-, more preferably selected from -C(O)O- and -OC(O)-.

[0201] In a more specific embodiment, M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -O- and -S-, preferably selected from chemical bonds, -C(O)O-, -C(O)S-, -O- and -S-, more preferably selected from -O- and -S-; preferably selected from chemical bonds, -C(O)O-, -OC(O)- and -O-, more preferably selected from chemical bonds, -C(O)O- and -O-, most preferably -O-.

[0202] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R1 and R2 are independently selected from C 4-20 Alkyl, preferably C 10-20 Alkyl, preferably C 10-18 Alkyl, preferably C 13-18 Alkyl, preferably C 13-16 alkyl.

[0203] In a more specific implementation, R1 and R2 are independently and optionally represented by 0, 1, 2, 3, 4, or 5 (preferably 0, 1, 2, or 3, preferably 0 or 1) R s replace.

[0204] In a more specific embodiment, R1 and R2 independently optionally have 0, 1, 2, 3, 4 or 5 (preferably 0, 1, 2 or 3) unsaturated bonds selected from carbon-carbon double bonds or carbon-carbon triple bonds; preferably optionally have 0, 1, 2 or 3 carbon-carbon double bonds; preferably optionally have 0, 1 or 2 carbon-carbon double bonds; preferably, when R1 or R2 has 2 carbon-carbon double bonds, these 2 carbon-carbon double bonds are separated by 1 methylene group.

[0205] In a more specific embodiment, at least one of R1 and R2 does not have an unsaturated bond; preferably, at least one of R1 and R2 does not have a carbon-carbon double bond.

[0206] In a more specific embodiment, 1, 2, 3, 4 or 5 (preferably 1, 2 or 3, preferably 0, 1 or 2, preferably 0 or 1) methylene groups in R1 or R2 are optionally and independently replaced by R*.

[0207] In a more specific implementation, R1 and R2 are independently selected from C. 13 straight-chain alkyl, C 14 straight-chain alkyl, C 16 straight-chain alkyl, C 18 straight-chain alkyl,

[0208] In a more specific implementation plan, R1 is Preferred

[0209] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 Alkyl), -L1-OR a -L1-SR a -L1-NR b R c Preferred ingredients are H and C. 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 alkyl).

[0210] In a more specific implementation plan, R s for Preferred

[0211] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R* is independently selected from -O- and -S-; preferably -O-.

[0212] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R' is independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably C 1-4 Alkyl groups, such as methyl groups.

[0213] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R4 is selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a -C(S)SR a C 1-6 Alkyl, C 1-6Halogenated alkyl, -L2-C 3-7 Cycloalkyl, -L2-3-7-membered heterocyclic, -L2-phenyl and -L2-5-6-membered heteroaryl; preferably selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H, -C(O)R a -C(O)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H, -C(O)R a C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from H and -C(O)R a For example, H or -C(O)Me; preferably -C(O)R a For example, -C(O)Me.

[0214] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein L1 is independently selected from chemical bonds and C. 1-18 Alkylene; preferably selected from chemical bonds and C 1-16 Alkylene.

[0215] In a more specific implementation, L2 is independently selected from chemical bonds and C. 1-6 Alkylene; preferably selected from chemical bonds and C 1-4 Alkylene.

[0216] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L2-C 3-7 Cycloalkyl, -L2-3-7-membered heterocyclic, -L2-phenyl and -L2-5-6-membered heteroaryl; preferably selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl; preferably selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0217] Or R b R c Together with the nitrogen atoms attached to them, they form 3 to 7-membered subheterocyclic groups.

[0218] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II) or (III):

[0219]

[0220] in,

[0221] p is 0, 1, 2, 3, 4, 5 or 6;

[0222] q can be 0, 1, 2, 3, 4, 5, or 6;

[0223] r can be 0, 1, 2, 3, 4, 5, or 6;

[0224] The remaining groups are as defined in this invention.

[0225] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II):

[0226]

[0227] in,

[0228] n is an integer between 5 and 70;

[0229] p is 0, 1, 2, 3, 4, 5 or 6;

[0230] q can be 0, 1, 2, 3, 4, 5, or 6;

[0231] r can be 0, 1, 2, 3, 4, 5, or 6;

[0232] s can be 1, 2, 3, 4, 5, or 6;

[0233] M1 and M2 are independently selected from chemical bonds, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -NR b -, -O- and -S-; preferably selected from -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, and -SC(O)-;

[0234] R1 and R2 are independently selected from C 4-20 Alkyl groups, optionally surrounded by 0, 1, 2 or 3 (preferably 0 or 1) R groups. s The carbon-carbon double bond is replaced by, and optionally has 0, 1, 2, 3, 4 or 5 unsaturated bonds selected from carbon-carbon double bonds and carbon-carbon triple bonds; preferably, at least one of R1 and R2 does not have unsaturated bonds.

[0235] R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 Alkyl), -L1-OR a -L1-SR a -L1-NR b R c Preferred ingredients are H and C. 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 alkyl);

[0236] R is selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0237] R' is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0238] R4 is selected from H, -C(O)R a -C(O)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0239] L1 is independently selected from chemical bonds and C 1-20 Alkylene (preferably C) 1-18 Alkylene, preferably C 1-16 Alkylene);

[0240] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0241] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (II), wherein...

[0242] n is an integer between 5 and 60, preferably an integer between 10 and 50;

[0243] p is 0, 1, 2 or 3, preferably 0, 1 or 2;

[0244] q can be 0, 1, 2 or 3, preferably 0, 1 or 2;

[0245] r can be 0, 1, 2 or 3, preferably 0, 1 or 2;

[0246] s is 1, 2 or 3,

[0247] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, -SC(O-), -O- and -S-; preferably selected from -C(O)O-, -OC(O)-, -C(O)S- and -SC(O-);

[0248] R1 and R2 are independently selected from C 10-20 Alkyl, preferably C 10-18 Alkyl groups, which optionally have 0, 1, 2 or 3 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond;

[0249] R is selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0250] R' is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0251] R4 is selected from H, -C(O)R a C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from H and -C(O)R a Preferred -C(O)R a ;

[0252] R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0253] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (II), wherein...

[0254] n is an integer between 10 and 45, such as 10-15, 25-30, 35-40 or 40-45, preferably an integer between 25-30, preferably an integer between 35-40, and preferably an integer between 40-45;

[0255] p is 1;

[0256] q can be 0 or 1, preferably 1;

[0257] r is 0 or 1, preferably 0;

[0258] s is 1,

[0259] M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -O-, preferably from -C(O)O- and -OC(O-); preferably, M1 is selected from -C(O)O- and -O-, preferably from -C(O)O-; M2 is selected from -C(O)O-, -OC(O)- and -O-, preferably from -C(O)O- and -OC(O-);

[0260] R1 and R2 are independently selected from C 13-16 Alkyl groups, which optionally have 0, 1 or 2 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond;

[0261] R is H;

[0262] R' is C 1-4 Alkyl groups, preferably methyl groups;

[0263] R4 is H or -C(O)Me, preferably -C(O)Me.

[0264] In a more specific implementation, when R1 or R2 has two carbon-carbon double bonds, these two carbon-carbon double bonds are separated by one methylene group.

[0265] In a more specific implementation, R1 and R2 are independently selected from C. 13 straight-chain alkyl, C 14 straight-chain alkyl and C 16 Straight-chain alkyl groups.

[0266] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (III):

[0267]

[0268] in,

[0269] n is an integer between 5 and 70;

[0270] p is 0, 1, 2, 3, 4, 5 or 6;

[0271] q can be 0, 1, 2, 3, 4, 5, or 6;

[0272] s can be 1, 2, 3, 4, 5, or 6;

[0273] M1 and M2 are independently selected from chemical bonds, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -NR b -、-O- and -S-;

[0274] R1 and R2 are independently selected from C 4-20 Alkyl groups, optionally surrounded by 0, 1, 2 or 3 (preferably 0 or 1) R groups. s The carbon-carbon double bond is replaced by, and optionally has 0, 1, 2, 3, 4 or 5 unsaturated bonds selected from carbon-carbon double bonds and carbon-carbon triple bonds; preferably, at least one of R1 and R2 does not have unsaturated bonds.

[0275] R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 Alkyl), -L1-OR a -L1-SR a -L1-NR b R c Preferred ingredients are H and C. 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 alkyl);

[0276] R' is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0277] R4 is selected from H, -C(O)R a -C(O)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0278] L1 is independently selected from chemical bonds and C 1-20 Alkylene (preferably C) 1-18 Alkylene, preferably C 1-16 Alkylene);

[0279] R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0280] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (III), wherein...

[0281] n is an integer between 5 and 60, preferably an integer between 10 and 50, and even more preferably an integer between 20 and 50;

[0282] p is 0, 1, 2 or 3, preferably 0, 1 or 2;

[0283] q can be 0, 1, 2 or 3, preferably 0, 1 or 2;

[0284] s is 1, 2, or 3;

[0285] M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O-), -O- and -S-, preferably selected from chemical bonds, -C(O)O-, -C(O)S-, -O- and -S-, and more preferably selected from -O- and -S-;

[0286] R1 and R2 are independently selected from C 10-20 Alkyl, preferably C 10-18 Alkyl groups, which optionally have 0, 1, 2 or 3 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond;

[0287] R' is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0288] R4 is selected from H, -C(O)R a C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from H and -C(O)R a Preferred -C(O)R a ;

[0289] R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0290] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (III), wherein...

[0291] n is an integer between 25 and 50, such as an integer between 25 and 30, 30 and 35, or 45 and 50.

[0292] p is 0, 1 or 2, preferably 2;

[0293] q can be 0, 1, or 2, preferably 2;

[0294] s is 1;

[0295] M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)- and -O-, preferably selected from chemical bonds, -C(O)O- and -O-, and most preferably -O-;

[0296] R1 and R2 are independently selected from C 13-18 Alkyl groups, preferably selected from C 13-16 Alkyl groups, which optionally have 0, 1 or 2 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond;

[0297] R' is C 1-4 Alkyl groups, preferably methyl groups;

[0298] R4 is -C(O)Me.

[0299] In a more specific implementation, when R1 or R2 has two carbon-carbon double bonds, these two carbon-carbon double bonds are separated by one methylene group;

[0300] In a more specific implementation, R1 and R2 are independently selected from C. 13 straight-chain alkyl, C 16 straight-chain alkyl, C 18 straight-chain alkyl,

[0301] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from the following:

[0302]

[0303]

[0304]

[0305] In a more specific embodiment, the present invention also provides a lipid composition comprising a polymeric lipid, wherein the polymeric lipid is a compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0306] In a more specific embodiment, the present invention provides the above-described lipid composition, wherein the lipid composition comprises ionizable lipids, polymeric lipids, and structural lipids.

[0307] In a more specific embodiment, the present invention provides the above-described lipid composition, wherein it comprises the following components in molar percentages:

[0308] The ionizable lipid content is approximately 20%-80%, preferably approximately 28%-70%;

[0309] The polymer lipid content is approximately 1%-10%, preferably approximately 1%-8%;

[0310] Structural lipids comprise approximately 14%-70%, preferably approximately 25%-70%;

[0311] Preferably,

[0312] The lipid composition comprises the following components in molar percentage:

[0313] The ionizable lipids are approximately 35%-65%, preferably approximately 40%-60%;

[0314] Polymer lipids comprise approximately 1.5%-6%;

[0315] The structural lipids comprise approximately 33.5%-63.5%, preferably approximately 38.5%-58.5%;

[0316] Preferably,

[0317] The lipid composition comprises the following components in molar percentage:

[0318] The ionizable lipid content is approximately 40%-50%, preferably approximately 42%-48%, and most preferably approximately 45%.

[0319] The polymer lipid content is approximately 1.5%-7%, preferably approximately 2.5%-6%, more preferably approximately 1.5%-4%, and even more preferably approximately 2.5%-3%.

[0320] The structural lipids comprise approximately 45%-55%, preferably approximately 49%-52.5%, more preferably approximately 50%-55%, and most preferably approximately 52%-52.5%.

[0321] In a more specific embodiment, the present invention provides the above-described lipid composition, wherein the ionizable lipid is selected from the structures shown in formulas (i)-(v):

[0322]

[0323] in,

[0324] R'1 is independently selected from -R”1-X;

[0325] R”1 is -(CH2) 0-6 -, X represents amino, hydroxyl, ethynyl, cyano, or -C(O)(CH2). 1-3 NR'a R' b -C(O)O(CH2) 1-3 NR' a R' b -OC(O)(CH2) 1-3 NR' a R' b -C(O)NH(CH2) 1-3 NR' a R' b -NHC(O)(CH2) 1-3 NR' a R' b -NHC(O)CH(NR' a R' b (CH2) 1-3 NR' a R' b C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10-membered heteroaryl group, preferably amino, hydroxyl, or cyano, preferably hydroxyl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more (preferably 1, 2, or 3) groups selected from the following: -(CH2) 1-3 OH, -(CH2) 1-3 NR' a R' b -(CH2) 1-3 C(O)NR' a R' b Or X is:

[0326]

[0327] R' a 、R' b Each is independently selected from H and C. 1-3 Alkyl group, -(CH2) 1-3 NH2、-(CH2) 1-3 NH(CH2) 1-3 NH2; or R' a and R' b Together with the nitrogen atom to which it is attached, it forms a 5-10 membered heterocycle (preferably a 5-7 membered heterocycle) comprising 1-3 heteroatoms selected from N, O, or S, wherein the heterocycle is optionally substituted by one or more (preferably 1, 2, or 3) groups selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino;

[0328] R'2 and R'3 are independently selected from H and C. 2-18 Alkyl, C 4-18 alkenyl or Preferably selected from H, C 2-18 Alkyl or C 4-18 alkenyl;

[0329] Each M is independently selected from -CH2-, -CH=CH-, -NH-, -C(O)-, -O-, -C(O)O-, -OC(O-, -C(O)NH- or -NHC(O-), preferably selected from -C(O)O-, -OC(O-, -C(O)NH- or -NHC(O-), more preferably -C(O)O- or -C(O)NH-, and most preferably -C(O)O-;

[0330] Each R'6 is independently selected from H, -R'5, -OR'4, or -L'OR'4;

[0331] Each R'5 is selected from C. 1-10 Alkyl or C 3-12 alkenyl;

[0332] Each R'4 is selected from C 1-10 Alkyl or C 3-12 alkenyl;

[0333] L' is independently selected from C 1-10 Alkylene or C 3-12 alkenyl;

[0334] m1 and m2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0335] m3 and m4 are each independently selected from 0, 1, 2 or 3, preferably 0 or 1.

[0336] In some embodiments, the ionizable lipid is selected from at least one of the following:

[0337]

[0338] In a more specific embodiment, the present invention provides the above-described lipid composition, wherein the ionizable lipid is selected from at least one of the following: DLin-MC3-DMA, ALC-0315, SM-102, 8-(3-hydroxypropyl)(9,12-dienyl-octadecyl-1)-amino-octanoic acid heptadecano-9-ol ester, bis(2,3-bis(hexyloxy)propyl)8,8'-((2-hydroxyethyl)azonyl)dioctanoate, 2,3-di(hexyloxy)propionyl 12-((8-(2,3-di(hexyloxy))propoxy)-8-oxooctyl)(2-hydroxyethyl)amino)dodecanoate, N,N-dimethyl-2,3-dioleenyloxy)propylamine (DODMA), N,N-dioleenyl-N,N-dimethylammonium chloride (DODMA). DAC), N,N-distearate-N,N-dimethylammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(2,3-dioleenoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) and 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-KDMA).

[0339] In some embodiments, the ionizable lipid is SM-102.

[0340] In a more specific embodiment, the present invention provides the above-described lipid composition, wherein the polymeric lipid further comprises a polyethylene glycol-modified lipid selected from at least one of PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol.

[0341] In a more specific embodiment, 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, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000, preferably DMG-PEG2000.

[0342] In a more specific embodiment, the present invention provides the above-described lipid composition, wherein the molar ratio of the polyethylene glycol-modified lipid to the compound of the present invention is (0.5–3):(0.5–3), preferably (0.5–2):(0.5–2), preferably (0.5–1.5):(0.5–1.5), preferably (0.7–1.3):(0.7–1.3), and preferably 1:1.

[0343] In a more specific embodiment, the present invention provides the above-described lipid composition, wherein the structural lipid is selected from steroids; preferably, the steroid is selected from at least one of cholesterol, coprosterol, sitosterol, ergosterol, campesterol, stigmasterol, rapeseed sterol, tomatine, ursolic acid, α-tocopherol, rock saponin, alfalfa sterol and ergocalciferol; preferably cholesterol.

[0344] In a more specific embodiment, the present invention also provides a nanoparticle composition comprising the lipid composition of the present invention, and optionally comprising a loading agent; preferably, the loading agent is selected from at least one of DNA, RNA, protein, and pharmaceutically active molecules.

[0345] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the RNA is selected from at least one of the following: messenger RNA (mRNA), small interfering RNA (siRNA), aiRNA, microRNA (miRNA), double-stranded RNA (dsRNA), antisense RNA (aRNA), long non-coding RNA (lncRNA), short hairpin RNA (shRNA), small activating RNA (saRNA), polymer-encoding nucleic acid (MCNA), polymer-encoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme.

[0346] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the protein is selected from at least one of antibodies, enzymes, recombinant proteins, polypeptides, and short peptides.

[0347] In a more specific embodiment, the present invention also provides a pharmaceutical composition comprising the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, or lipid compositions of the present invention, or nanoparticle compositions of the present invention, and pharmaceutically acceptable excipients.

[0348] In more specific embodiments, the present invention also provides the use of the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, or lipid compositions of the present invention, or nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention in the preparation of medicaments for treating, diagnosing or preventing diseases.

[0349] In more specific embodiments, the present invention also provides the use of the compounds of the present invention, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, or lipid compositions of the present invention, or nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention in the preparation of a delivery-loaded medicament.

[0350] In a more specific embodiment, the present invention also provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering the nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention, to the subject.

[0351] In more specific embodiments, the present invention also provides nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention, for the treatment, diagnosis or prevention of diseases.

[0352] In a more specific embodiment, the present invention also provides a method for delivering a payload into a subject, comprising administering the nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention, to the subject.

[0353] In more specific embodiments, the present invention also provides lipid compositions of the present invention, or nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention for delivery of payloads.

[0354] In a more specific embodiment, the payload is selected from at least one of DNA, RNA, protein, and pharmaceutically active molecules.

[0355] In a more specific implementation, the RNA is selected from at least one of the following: messenger RNA (mRNA), small interfering RNA (siRNA), aiRNA, microRNA (miRNA), double-stranded RNA (dsRNA), antisense RNA (aRNA), long non-coding RNA (lncRNA), short hairpin RNA (shRNA), small activating RNA (saRNA), polymer-encoding nucleic acid (MCNA), polymer-encoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme.

[0356] In a more specific embodiment, the protein is selected from at least one of antibodies, enzymes, recombinant proteins, polypeptides, and short peptides.

[0357] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0358] The compounds of this invention can exist in tautomer form. Tautomers are functional group isomers that occur when an atom in a molecule rapidly moves between two positions. Tautomers are a special type of functional group isomer. A pair of tautomers can interconvert, but usually the more stable isomer is the dominant form.

[0359] Pharmaceutical compositions, formulations and kits

[0360] This invention provides pharmaceutical compositions comprising a compound or conjugate of the invention (also referred to as the "active component") and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active component. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active component. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the active component.

[0361] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds or conjugates formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, 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 substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0362] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0363] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0364] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0365] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0366] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0367] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus dose delivered directly to a vein (e.g., via IV infusion) allows for a more rapid delivery, causing the concentration of the active ingredient in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0368] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0369] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0370] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0371] The above-described components for use in compositions intended for injection or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0372] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0373] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water.

[0374] Drug combination

[0375] The compounds or conjugates of the present invention described herein may be combined with one or more other active ingredients in pharmaceutical compositions or methods to treat the diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or pharmaceuticals that mitigate adverse effects against the intended disease target. Such combinations may be used to increase efficacy, improve other disease symptoms, reduce one or more side effects, or reduce the required dosage of the compounds of the present invention. Additional active ingredients may be formulated into pharmaceutical compositions separate from the compounds of the present invention or may be included with the compounds of the present invention in a single pharmaceutical composition. Additional active ingredients may be administered concurrently with, before, or after the administration of the compounds of the present invention.

[0376] Combination pharmaceutical agents include active ingredients known or observed to be effective in treating the diseases and conditions described herein, including those effective against another target associated with the disease. For example, the compositions and formulations of the present invention, as well as the methods of treatment, may further comprise other pharmaceutical agents, such as other agents that can be used to treat or alleviate the target disease or related symptoms or conditions. The pharmaceutical compositions of the present invention may additionally comprise one or more of the said active agents, and the methods of treatment may additionally comprise an effective amount of one or more of the said active agents. Attached Figure Description

[0377] Figure 1 Results of hEPO mRNA expression of hEPO protein in mice;

[0378] Figure 2 The graph shows the results of total IgG antibody titer in mice after a first immunization.

[0379] Figure 3 This is a graph showing the results of total IgG antibody titers in mice after a second immunization.

[0380] Figure 4 This figure shows the results of inducing an immune response in mice after administration of the S protein mRNA vaccine.

[0381] Example

[0382] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0383] Example 1 – Synthesis of P1

[0384] Synthesis route:

[0385]

[0386] Synthesis steps:

[0387] 1. Synthesis of PS-2

[0388] PS-1 (20.0 g) and Et3N (66 g, 3 eq) were added to anhydrous methanol (500 mL), stirred for 10 min, and then Boc2O (72 g, 1.5 eq) was added. The mixture was heated to 50 °C and stirred to react. After the reaction was complete, the mixture was cooled to room temperature, concentrated to remove the solvent, loaded onto silica gel, and purified by chromatography (methanol:dichloromethane = 8%) to obtain PS-2.

[0389] 2. The synthesis of PS-3

[0390] PS-2 (21.0 g), dichloromethane (500 mL), DMAP (29 g, 2.2 eq), and myristic acid (75 g, 3 eq) were added, followed by dropwise addition of DIC (44.3 g, 3.2 eq). The mixture was stirred at room temperature for 4 h. The dichloromethane was removed by concentration, and 500 mL of ethyl acetate was added. The mixture was filtered, and the filtrate was collected. The filtrate was washed, extracted, and separated. The filtrate was washed with 1 M HCl and saturated sodium chloride solution. The organic phase was collected, concentrated to dryness under reduced pressure, and purified by chromatography to obtain compound PS-3.

[0391] 3. PS-4 Synthesis

[0392] PS-3 (24g) was dissolved in ethyl acetate (100mL), and hydrochloric acid / ethyl acetate solution (100mL, 2mol / L) was added. The reaction was carried out at room temperature. After the reaction was complete, the mixture was filtered to obtain a white powder. Saturated sodium bicarbonate solution (200mL) was added to adjust the pH to 7-8. Dichloromethane (500mL) solvent was added, and the mixture was extracted and separated. The organic phase was dried and concentrated to obtain PS-4.

[0393] 4. Synthesis of NCA

[0394] Creatine (20.0 g) was dissolved in anhydrous tetrahydrofuran (200 mL), and phosgene (17 mL) was slowly added dropwise while heating to 50 °C. The reaction was carried out under reflux until complete. The solvent was removed by concentration, and the mixture was crystallized at low temperature using tetrahydrofuran / n-hexane. The crystals were then filtered to obtain NCA.

[0395] 5. The synthesis of PS-5

[0396] PS-4 (2.2g) was dissolved in anhydrous DFM (100mL), NCA (5.6g, 10eq) was added, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed by concentration, ethyl acetate was added and the mixture was stirred and filtered to obtain the product PS-5.

[0397] 6. Synthesis of P1

[0398] PS-5 (5g) was dissolved in anhydrous dichloromethane (50mL), and triethylamine (1.17g, 3eq) and acetic anhydride (1.17g, 3eq) were added. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by concentration, and the product was dissolved in deionized water. The mixture was then dialyzed through a membrane, the solvent was removed by concentration, and ethyl acetate was added to make a slurry. The mixture was then filtered to obtain product P1 (4.2g, white powder, yield 80%, n=10-15).

[0399] 1 H NMR(500MHz,MeOD)δ5.15(d,J=26.5Hz,1H),3.46–3.93(m,26H),3.51–3.41(m,1H),3.36(d,J=6.0Hz,1H),3.12–2.61(m,3 6H), 2.29 (q, J=7.6Hz, 4H), 2.15–1.86 (m, 3H), 1.57 (d, J=5.6Hz, 4H), 1.27 (dd, J=14.0, 6.5Hz, 40H), 0.86 (t, J=6.8Hz, 6H).

[0400] MS(ESI): m / z(M+H) + 1406.55.10, (M+Na) + 1428.55

[0401] Example 2 – Synthesis of P2

[0402] Product P2 (4.2 g, white powder, yield 80%, n = 25-30) was prepared according to the method in Example 1.

[0403] 1H NMR(500MHz,MeOD)δ5.27–5.09(m,1H),4.62–3.90(m,58H),3.49(td,J=27.6,12.5Hz,1H),3.38(dd,J=13.5,6.6Hz,1H), 3.22–2.79(m,84H),2.33(q,J=7.3Hz,4H),2.15–1.95(m,3H),1.61(d,J=5.3Hz,4H),1.29(s,40H),0.90(t,J=6.8Hz,6H).

[0404] MS(ESI): m / z(M+H) + 2542.55.(M+Na) + 2564.55

[0405] Example 3 – Synthesis of P3

[0406] Product P3 (4.2 g, white powder, yield 80%, n = 40-45) was prepared according to the method in Example 1. 1 HNMR(500MHz,MeOD)δ5.18(d,J=21.6Hz,1H),4.49–3.98(m,90H),3.48(t,J=14.5Hz,1H),3.40(d,J=6.6Hz,1H),3.20(dd,J=17.4,10.1Hz,1H),3.15–2 .85(m,135H),2.33(dd,J=14.9,7.4Hz,4H),2.13(d,J=3.4Hz,2H),2.06–1. 88(m,3H),1.61(d,J=5.6Hz,4H),1.39–1.21(m,40H),0.90(t,J=6.8Hz,6H).

[0407] MS(ESI): m / z(M+H) + 3749.55(M+Na) + 3771.55

[0408] Example 4 – Synthesis of P4

[0409] Synthesis route:

[0410]

[0411] Synthesis steps:

[0412] 1. PS-7 synthesis

[0413] PS-6 (26.8 g) was added to dichloromethane (100 mL) and triphenylphosphine (27.7 g, 1.06 eq), stirred for 10 min, and NBS (20.6 g, 1.16 eq) was slowly added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated, and hexane was added to slurry the mixture. The mixture was filtered, and the filtrate was concentrated and purified by chromatography (ethyl acetate: hexane = 2%) to obtain PS-7.

[0414] 2. The synthesis of PS-9

[0415] PS-7 (10 g), acetonitrile (100 mL), sodium carbonate (6.4 g, 2 eq), potassium iodide (0.5 g, 0.1 eq), and PS-8 (8.21 g, 1 eq) were added. The mixture was heated under reflux with stirring until complete. The solvent was removed by concentration, and the mixture was washed and extracted with dichloromethane. The organic phase was collected and concentrated to dryness under reduced pressure. The mixture was then purified by chromatography (methanol:dichloromethane = 5%) to give compound PS-9.

[0416] 3. The synthesis of PS-10

[0417] PS-9 (0.69 g) was dissolved in dichloromethane (50 mL), NCA (3.1 g, 20 eq) was added, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed by concentration, and ethyl acetate was added to make a pulp and filtered to obtain the product PS-10.

[0418] 4. Synthesis of P4

[0419] PS-10 (2.2 g) was dissolved in anhydrous dichloromethane (30 mL), and triethylamine (0.5 g, 3 eq) and acetic anhydride (0.5 g, 3 eq) were added. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by concentration, and the product was dissolved in deionized water. The mixture was then dialyzed through a membrane, the solvent was removed by concentration, and ethyl acetate was added to form a slurry. The slurry was filtered to obtain product P4 (2 g, white powder, yield 85%, n = 25-30).

[0420] 1 H NMR (500MHz, CDCl3) δ5.44–5.26(m,4H),4.46–3.83(m,50H),3.55(dq,J=14.4,7.2Hz,2H),3.29(dd,J=18.1,10.6Hz,2H),3.16(t,J=16.6Hz,2H ),3.13–2.82(m,75H),2.77(t,J=6.2Hz,2H),2.11(d,J=23.0Hz,7H),1.54(d,J=36.7Hz,4H),1.38–1.08(m,44H),0.88(dd,J=12.0,6.7Hz,6H).

[0421] MS(ESI): m / z(M+H) + 2335.65, (M+Na) + 2357.65

[0422] Example 5 – Synthesis of P5

[0423] Synthesis route:

[0424]

[0425] Synthesis steps:

[0426] Product P5 (1g, white powder, yield 80%, n=35-40) was prepared according to the method in Example 1.

[0427] 1 H NMR(500MHz, CDCl3)δ6.65(s,1H),4.56–3.78(m,72H),3.51(s,2H),3.30–2.70(m,10 2H),2.44(d,J=26.7Hz,4H),1.59(s,4H),1.32–1.17(m,41H),0.88(t,J=6.8Hz,6H).

[0428] MS(ESI): m / z(M+H) + 2926.54, (M+Na) + 2948.54

[0429] Example 6 – Synthesis of P6

[0430] Synthesis route:

[0431]

[0432] Synthesis steps:

[0433] Product P6 (2g, white powder, yield 80%, n=35-40) was prepared according to the method in Example 1.

[0434] 1 H NMR(500MHz, CDCl3)δ6.64(s,1H),4.55–3.83(m,78H),3.25–2.74(m,111H),2 .35–2.18(m,7H),1.59(s,4H),1.26(d,J=7.2Hz,42H),0.88(t,J=6.8Hz,6H).

[0435] MS(ESI): m / z(M+H) + 3181.55, (M+Na) +3203.55

[0436] Example 7 – Synthesis of P7

[0437] Synthesis route:

[0438]

[0439] Synthesis steps:

[0440] Product P7 (2.1 g, white powder, yield 85%, n = 45-50) was prepared according to the method in Example 1.

[0441] 1 H NMR (500MHz, CDCl3) δ4.41–3.87(m,102H),3.57(t,J=17.1Hz,4H),3.21–2.82(m,147H),2.30(ddd,J=24.1 ,15.8,8.1Hz,4H),2.07(dd,J=38.6,17.0Hz,3H),1.60(s,4H),1.36–1.20(m,40H),0.88(t,J=6.8Hz,6H).

[0442] MS(ESI): m / z(M+H) + 4047.56, (M+Na) + 4069.56

[0443] Example 8 – Synthesis of P8

[0444] Synthesis route:

[0445]

[0446] Synthesis steps:

[0447] 1. The synthesis of PS-21

[0448] PS-16 (13.5 g), toluene (100 mL), PS-20 (46 g, 2.3 eq), and TBAB (20%, 1.0 g) were added, and the mixture was stirred at room temperature for 10 min. Then, 100 mL of NaOH (50% aqueous solution) was added, and the mixture was heated to 70 °C. After the reaction was complete, the mixture was cooled to room temperature, and the organic layer was separated, washed with saturated sodium chloride, dried, concentrated, and purified by chromatography to obtain compound PS-21.

[0449] 3. The synthesis of PS-22

[0450] PS-21 (8.3g) was dissolved in ethyl acetate (50mL), and hydrochloric acid / ethyl acetate solution (50mL, 2mol / L) was added. The reaction was carried out at room temperature. After the reaction was complete, the mixture was filtered to obtain a white powder. Saturated sodium bicarbonate solution (200mL) was added to adjust the pH to 7-8. Dichloromethane (500mL) solvent was added, and the mixture was extracted and separated. The organic phase was dried and concentrated to obtain PS-22.

[0451] 4. Synthesis of PS-23

[0452] PS-22 (1.0 g) was dissolved in anhydrous dichloromethane (50 mL), NCA (4.4 g, 20 eq) was added, and the mixture was reacted at room temperature for 18 h (the reaction was initiated and a large amount of carbon dioxide was generated). After the reaction was complete, the solvent was removed by concentration, and ethyl acetate was added to make a slurry and filtered to obtain the product PS-23.

[0453] 5. Synthesis of P08

[0454] PS-23 (2.3 g) was dissolved in anhydrous dichloromethane (30 mL), and triethylamine (0.51 g, 3 eq) and acetic anhydride (0.51 g, 3 eq) were added. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by concentration, and the product was dissolved in deionized water. The mixture was then dialyzed through a membrane, concentrated to remove the solvent, and slurried with ethyl acetate. The mixture was filtered to obtain product P08 (2 g, white powder, yield 83%, n = 30-35).

[0455] 1 H NMR (500MHz, CDCl3) δ4.43–3.85 (m, 64H), 3.45 (ddd, J = 27.9, 22.4, 9.2Hz, 12H), 3.15 –2.81(m,96H),2.16–1.97(m,3H),1.53(s,4H),1.26(s,52H),0.88(t,J=6.8Hz,6H).

[0456] MS(ESI): m / z(M+H) + 2868.67, (M+Na) + 2890.67

[0457] Example 9 – Synthesis of P09

[0458] Synthesis route:

[0459]

[0460] Synthesis steps:

[0461] Product P9 (2g, white powder, yield 80%, n=25-30) was prepared according to the method in Example 1.

[0462] 1 H NMR (500MHz, CDCl3) δ6.67 (s, 1H), 4.51–3.81 (m, 58H), 3.55 (t, J = 5.8Hz, 1H), 3.21–2.80 (m, 81 H),2.29(t,J=7.4Hz,4H),2.16–1.94(m,3H),1.58(s,4H),1.24(s,40H),0.86(t,J=6.8Hz,6H).

[0463] MS(ESI): m / z(M+H) + 2471.55, (M+Na) + 2493.55

[0464] Example 10 – Synthesis of P10

[0465] Synthesis route:

[0466]

[0467] Synthesis steps:

[0468] Product P10 (2g, white powder, yield 82%, n=25-30) was prepared according to the method in Example 8.

[0469] 1 H NMR(500MHz, CDCl3)δ6.40(s,1H),4.45–3.82(m,50H),3.67–3.23(m,9H),3.21–2.79(m,75H),2.11 (d,J=23.6Hz,3H),1.54(s,4H),1.27(d,J=13.4Hz,52H),0.88(t,J=6.8Hz,6H).MS(ESI):m / z(M+H) + 2357.65, (M+Na) + 2379.65

[0470] Example 11 – Synthesis of P11

[0471] Synthesis route:

[0472]

[0473] Synthesis steps:

[0474] P11 was prepared according to the method in Example 8, yielding a product (4.3 g, white powder, yield 85%, n = 20-25).

[0475] 1H NMR(500MHz, CDCl3)δ6.25(d,J=53.2Hz,1H),4.37–3.86(m,45H),3.61–3.34(m,8H),3.22–2.79(m,66H),2.28–2 .02(m,3H),1.52(d,J=6.2Hz,4H),1.41(t,J=7.3Hz,2H),1.26(s,50H),0.88(t,J=6.9Hz,6H).MS(ESI):m / z(M+H) + 2144.65, (M+Na) + 2166.65

[0476] Example 12 – Synthesis of P12

[0477]

[0478] Synthesis steps:

[0479] Product P12 (2g, white powder, yield 81%, n=25-30) was prepared according to the method in Example 4.

[0480] 1 H NMR (500MHz, CDCl3) δ5.42–5.30(m,2H),4.47–3.80(m,50H),3.55(dd,J=12.8,5.6Hz,1H),3.28(dd,J=17.9,10.4Hz,2H),3.18(d,J=7.1Hz,2H) ,3.12–2.78(m,75H),2.31–2.01(m,6H),1.54(d,J=36.9Hz,4H),1.41(t,J=7.3Hz,3H),1.26(s,46H),0.88(t,J=6.8Hz,6H).MS(ESI): m / z(M+H) + 2309.63, (M+Na) + 2331.63

[0481] Example 13 – Synthesis of P13

[0482] Synthesis route:

[0483]

[0484] Synthesis steps:

[0485] Product P13 (1.8 g, white powder, yield 79%, n = 25-30) was prepared according to the method in Example 4.

[0486] 1H NMR (500MHz, CDCl3) δ5.47–5.23(m,6H),4.49–3.82(m,60H),3.64–3.44(m,1H),3.37–3.21(m,2H),3.18(d,J=7.5Hz,2H),3.13–2 .81(m,90H),2.77(t,J=6.1Hz,2H),2.23–1.88(m,11H),1.54(d,J=37.2Hz,4H),1.37–1.13(m,32H),0.88(dd,J=11.7,6.7Hz,6H).

[0487] MS(ESI): m / z(M+H) + 2688.63, (M+Na) + 2710.63

[0488] Example 14 – Synthesis of P14

[0489] Synthesis route:

[0490]

[0491] Synthesis steps:

[0492] 1. The synthesis of PS-39

[0493] PS-38 (20.0 g) was added to anhydrous DMF (150 mL) and imidazole (20 g, 3.2 eq), stirred for 10 min, and then TBDMSCl (19.7 g, 1.4 eq) was added. The mixture was stirred at room temperature until the reaction was complete. The solvent was removed by concentration, and the mixture was dissolved in ethyl acetate, washed with 1 M HCl, and then washed with saturated sodium chloride solution. The organic layer was dried, mixed with silica gel, and purified by chromatography (ethyl acetate: n-hexane = 50%) to obtain PS-39.

[0494] 2. The synthesis of PS-41

[0495] PS-39 (11.8 g), dichloromethane (300 mL), DMAP (4.5 g, 1 eq), and tetradecyl alcohol (7.92 g, 1 eq) were added. DIC (5.6 g, 1.2 eq) was added dropwise, and the mixture was stirred at room temperature until complete. The reaction mixture was then concentrated to remove dichloromethane. 500 mL of ethyl acetate was added, and the mixture was filtered. The filtrate was collected, washed, extracted, and separated. The filtrate was washed with 1 M HCl and saturated sodium chloride solution, and the organic phase was collected. The solution was concentrated to dryness under reduced pressure and purified by chromatography (ethyl acetate: n-hexane = 5%) to give compound PS-41.

[0496] 3. The synthesis of PS-42

[0497] PS-41 (13.6 g) was dissolved in tetrahydrofuran (100 mL), TBAF (10.2 g, 1.2 eq) was added, and the reaction was carried out at room temperature. The solvent was removed by concentration, ethyl acetate was added to dissolve the mixture, saturated sodium chloride solution (200 mL) was added to wash the mixture, the mixture was extracted and separated, the organic phase was dried, and the mixture was concentrated and purified by chromatography to obtain PS-42.

[0498] 4. The synthesis of PS-43

[0499] PS-42 (11.6 g), dichloromethane (300 mL), DMAP (3.5 g, 1 eq), and myristic acid (7.26 g, 1.1 eq) were reacted with DIC (4.73 g, 1.3 eq) dropwise. The mixture was stirred at room temperature until complete. After the reaction was completed, the dichloromethane was removed by concentration. 500 mL of ethyl acetate was added, and the mixture was filtered. The filtrate was collected, washed, extracted, and separated. The filtrate was washed with 1 M HCl and saturated sodium chloride solution, and the organic phase was collected. The mixture was concentrated to dryness under reduced pressure and purified by chromatography (ethyl acetate: n-hexane = 10%) to give compound PS-43.

[0500] 5. The synthesis of PS-44

[0501] PS-43 (7.3g) was dissolved in ethyl acetate (50mL), and hydrochloric acid / ethyl acetate solution (50mL, 2mol / L) was added. The reaction was carried out at room temperature. After the reaction was complete, the mixture was filtered to obtain a white powder. Saturated sodium bicarbonate solution (200mL) was added to adjust the pH to 7-8. Dichloromethane (500mL) solvent was added, and the mixture was extracted and separated. The organic phase was dried and concentrated to obtain PS-44.

[0502] 6. The synthesis of PS-45

[0503] PS-44 (1.32 g) was dissolved in anhydrous DFM (100 mL), NCA (6 g, 20 eq) was added, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed by concentration, and ethyl acetate was added to slurry and filtered to obtain product PS-45.

[0504] 7. Synthesis of P14

[0505] PS-45 (5g) was dissolved in anhydrous dichloromethane (100mL), and triethylamine (1.1g, 3eq) and acetic anhydride (1.1g, 3eq) were added. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by concentration, and the product was dissolved in deionized water. The mixture was then dialyzed through a membrane, the solvent was removed by concentration, and ethyl acetate was added to make a slurry. The mixture was then filtered to obtain product P14 (4.2g, white powder, yield 82%, n=25-30).

[0506] 1H NMR (500MHz, CDCl3) δ6.87(s,1H),4.77(s,1H),4.59–3.80(m,57H),3.61–3.44(m,1H),3.22–2.77(m,81H),2.24(ddd, J=34.2,20.3,12.8Hz,3H),2.18–1.94(m,7H),1.60(d,J=28.6Hz,4H),1.28(d,J=20.4Hz,40H),0.88(t,J=6.8Hz,6H).

[0507] MS(ESI): m / z(M+H) + 2471.55, (M+Na) + 2493.55

[0508] Example 15 – Synthesis of P15

[0509]

[0510] Synthesis steps:

[0511] 1. The synthesis of PS-46

[0512] PS-45 (50g) was added to anhydrous Py (150mL) and p-toluenesulfonyl chloride (51.6g, 2eq), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed by concentration, and the mixture was stirred and slurried with water, then stirred and slurried with acetonitrile, and filtered to obtain PS-46.

[0513] 2. The synthesis of PS-47

[0514] PS-46 (66g), 1,4-dioxane (300mL), and tetraethylene glycol (237g, 10eq) were heated under reflux and stirred until complete. The solvent was removed by concentration, and 500mL of dichloromethane was added. The mixture was washed with saturated sodium chloride, filtered, extracted, and the organic phase was collected. The organic phase was concentrated to dryness under reduced pressure and purified by chromatography to obtain compound (ethyl acetate: n-hexane = 90%) PS-47.

[0515] 3. The synthesis of PS-48

[0516] PS-47 (25g) was added to anhydrous Py (100mL) and p-toluenesulfonyl chloride (12.6g, 1.5eq), and the mixture was stirred at room temperature. After the reaction was complete, the solvent was removed by concentration, dichloromethane was added, and the mixture was washed with saturated sodium chloride aqueous solution. The mixture was separated, the organic layer was dried and concentrated, and purified by chromatography to obtain PS-48.

[0517] 4. The synthesis of PS-49

[0518] PS-48 (9g), DMF (80mL), and NaN3 (1.22g, 1.5eq) were reacted at room temperature with stirring. After the reaction was complete, ethyl acetate was added for dilution, and the mixture was washed with saturated sodium chloride. The organic layer was dried and concentrated under reduced pressure to dryness, and purified by chromatography to obtain compound PS-49.

[0519] 5. The synthesis of PS-50

[0520] PS-49 (3.2 g) was dissolved in tetrahydrofuran (50 mL), and triphenylphosphine (2.15 g, 1.5 eq) was added. The mixture was reacted at room temperature for 2 h, and water (10 mL) was added. The reaction was continued at room temperature until the reaction was complete. The solvent was removed by concentration, and dichloromethane was added. The mixture was washed with saturated sodium chloride solution (200 mL), extracted, and separated. The organic phase was dried and purified by concentration and chromatography to obtain compound (methanol: dichloromethane 20%) PS-50.

[0521] 6. The synthesis of PS-51

[0522] PS-50 (1.25g) was dissolved in anhydrous DCM (50mL), and NCA (6.5g, 20eq) was added. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by concentration, and ethyl acetate was added to make a slurry. The mixture was then filtered to obtain the product PS-51.

[0523] 7. Synthesis of P15

[0524] PS-51 (5g) was dissolved in anhydrous dichloromethane (100mL), and triethylamine (1.1g, 3eq) and acetic anhydride (1.1g, 3eq) were added. The mixture was reacted at room temperature. After the reaction was complete, the solvent was removed by concentration, and the product was dissolved in deionized water. The mixture was then dialyzed through a membrane, the solvent was removed by concentration, and ethyl acetate was added to make a slurry. The mixture was then filtered to obtain product P15 (4.5g, white powder, yield 87%, n=20-25).

[0525] 1 H NMR(500MHz,CDCl3)δ5.27(s,1H),4.34–3.81(m,42H),3.75–3.30(m,15H),3.21–3.04(m,2H),3.06–2.68(m,60H),2.29(d,J=11.9Hz,1H),2.20– 1.68(m,10H),1.58–1.31(m,9H),1.23–1.11(m,4H),1.12–0.95(m,6H), 0.94(d,J=18.3Hz,5H), 0.82(ddd,J=12.1,8.3,6.6Hz,9H), 0.61(s,3H).

[0526] MS(ESI): m / z(M+H) + 2024.56, (M+Na)+ 2046.56

[0527] Synthesis Example 1 – Synthesis of A1

[0528] Synthesis route:

[0529]

[0530] Synthesis steps:

[0531] 1. Synthesis of ((2,3-bis(hexyloxy)propoxy)methyl)benzene

[0532] Add 50 mL of n-hexane, 10.0 g of 1-benzyloxy-2,3-propanediol, and 0.88 g of tetrabutylammonium bromide, stir for 10 min, then add sodium hydroxide solution (18 mol / L) and 36.2 g of bromohexane, and heat and stir the reaction mixture. After the reaction is complete, cool to room temperature, allow to stand and separate the layers, collect the organic layer and wash and extract, then purify the organic layer by column chromatography (n-heptane: ethyl acetate = 5%) to obtain ((2,3-bis(hexyloxy)propoxy)methyl)benzene.

[0533] 2. Synthesis of 2,3-bis(hexyloxy)-1-propanol

[0534] Add ((2,3-bis(hexyloxy)propoxy)methyl)benzene (15.0 g), ethyl acetate (50 ml), glacial acetic acid (3.75 ml), and carbohydrate-impregnated palladium hydroxide (20%, 1.0 g), and stir with hydrogen at room temperature. After the reaction is complete, filter, collect the filtrate, wash the filtrate, extract and separate the liquid, and collect the organic phase. Concentrate to dryness under reduced pressure to give compound 2,3-bis(hexyloxy)-1-propanol.

[0535] 3. Synthesis of 2,3-bis(hexyloxy)propyl-8-bromooctanoate

[0536] 10.3 g of 8-bromooctanoic acid was dissolved in 100 ml of dichloromethane, and DCC (10.3 g), DMAP (6.1 g), and 2,3-bis(hexyloxy)-1-propanol (10 g) were added. The mixture was stirred at room temperature. After the reaction was complete, the dichloromethane solvent was removed by concentration, the mixture was extracted and separated, the organic phase was dried, concentrated to dryness, and the crude product was purified by column chromatography (PE:EA = 20:1) to give 2,3-bis(hexyloxy)propyl-8-bromooctanoic acid ester.

[0537] 4. Synthesis of 2,3-bis(hexyloxy)propyl-8-((2-hydroxyethyl)amino)octanoate

[0538] 5.0 g of 2,3-bis(hexyloxy)propyl-8-bromooctanoate was dissolved in 50 ml of anhydrous ethanol, and 2.2 g of sodium carbonate, 0.17 g of KI, and 20 g of ethanolamine were added. The mixture was stirred at room temperature. After the reaction was complete, the solvent was removed by concentration, and the mixture was washed, extracted, and separated. The organic phase was dried, filtered, and concentrated to dryness. The crude product was purified by column chromatography (MeOH:DCM = 3%) to give 2,3-bis(hexyloxy)propyl-8-((2-hydroxyethyl)amino)octanoate.

[0539] 5. Synthesis of A1

[0540] 1,3-bis(hexyloxy)-2-propanol-8-bromooctanoate (2.08 g) and 2,3-bis(hexyloxy)propyl-8-((2-hydroxyethyl)amino)octanoate (2.0 g) were dissolved in anhydrous ethanol (20 ml), and sodium carbonate (0.95 g) and KI (0.15 g) were added. The mixture was refluxed. After the reaction was complete, the solvent was removed by concentration, and the mixture was washed, extracted, and separated. The organic phase was dried, filtered, and concentrated to dryness. The crude product was purified by column chromatography (MeOH:DCM = 3%) to obtain an oily product A1 (2.1 g). 1 H NMR (500MHz, CDCl3) δ (ppm) = 5.05 (p, J = 5.1Hz, 1H), 4.15 (dd, J = 11.6, 4.1Hz, 1H), 4.03 (dd,J=11.6,5.8Hz,1H),3.55(dt,J=10.4,5.4Hz,1H),3.49(m,8H),3.43–3.30(m,8H), 2.53(t,J=5.1Hz,2H),2.43-2.35(m,4H),2.25(t,J=7.5Hz,4H),1.60-1.52(m,4H),1. 48(m,8H),1.38(m,4H),1.31-1.15(m,36H),0.82(t,J=6.8Hz,12H).MS(ESI):m / z(M+H) + 832.10, (M+Na) + 853.2.

[0541] Synthesis Example 2 – Synthesis of A2

[0542] Synthesis route:

[0543]

[0544] A2 was prepared according to the method in Example 1, yielding an oily product (4.01 g). 1H NMR (500MHz, CDCl3) δ (ppm) = 4.15 (dd, J = 11.6, 4.1Hz, 2H), 4.02 (dd, J = 11.6, 5.8Hz, 2 H),3.54(m,2H),3.48(t,J=6.6Hz,6H),3.42–3.34(m,8H),2.54(t,J=5.0Hz,2H),2.4 4–2.36(t,4H),2.25(t,J=7.5Hz,4H),1.59–1.52(m,4H),1.52–1.44(m,8H),1.39(dd ,J=14.0,7.3Hz,4H),1.32–1.17(m,36H),0.82(t,J=6.8Hz,12H).MS(ESI):m / z(M+H) + 831.92.

[0545] Synthesis Example 3 – Synthesis of A11

[0546] Synthesis route:

[0547]

[0548] A11 was prepared according to the method in Example 1, yielding an oily product (0.9 g). 1 H NMR (500MHz, CDCl3) δ (ppm) = 4.22 (dd, J = 11.6, 4.0Hz, 2H), 4.09 (dd, J = 11.6, 5.9Hz, 2H), 3.64–3.58 (m, 2H), 3.57–3.50 (t, J = 6.6Hz, 6H), 3.49–3.40 ( m,8H),2.60(t,J=4.8Hz,2H),2.51–2.43(t,4H),2.31(t,J=7.5Hz,4H),1. 57–1.45(m,16H),1.31(m,44H),0.88(t,J=6.8Hz,12H).MS(ESI):m / z(M+H) + 887.62.

[0549] Biological Experiment

[0550] Effect of Component Ratio Changes on the Properties of Lipid Nanoparticles in Experiment Example 1

[0551] The lipid nanoparticles include (1) ionizable lipid compounds, which are commercially available or prepared in-house, such as MC3 (purchased from Avanti), SM-102 (purchased from Avanti), A18, A2, and A11 (prepared in-house; A18 is referenced in Chinese Patent Application 202110617445.4; A2 and A11 were synthesized in Examples 2 and 3, respectively); (2) polymeric lipids, such as DMG-PEG-2000 (purchased from Avanti, hereinafter referred to as PEG), and P1 to P15 were prepared in-house (see Examples 1-15); (3) structural lipids (such as cholesterol, purchased from Sigma-Aldrich); and (4) active ingredients (such as Luciferase mRNA, siRNA, SARS-CoV-2S protein mRNA, Cas 9 mRNA, etc.). In this experimental example, luciferase mRNA was used.

[0552] Preparation and encapsulation method: (1) Ionizable lipid compounds, polymer lipids and structural lipids are generally dissolved and mixed in ethanol at 40-60%, 1-10% and 30-55% (molar) respectively to obtain an organic phase; (2) The active ingredients are diluted to a concentration of 0.3-0.7 mg / ml with buffer such as Citrate or TRIS to obtain an aqueous phase; (3) The organic phase and aqueous phase are uniformly mixed in a ratio of 1:1 to 1:3 using a microfluidic chip or T-type mixer to obtain lipid nanoparticles.

[0553] After diluting the encapsulated lipid nanoparticles with PBS or Tris dialysis buffer, they were dialyzed using 10–100 kDa dialysis bags at 2–8°C. The dialysate was then collected and sent for analysis to assess the lipid nanoparticle performance, including encapsulation efficiency, particle size, and transfection efficiency. Encapsulation efficiency reflects the degree of encapsulation of the material; a higher encapsulation efficiency indicates that the encapsulated material is less likely to be degraded during in vivo delivery. Transfection efficiency is reflected by in vivo imaging data of the lipid nanoparticles. Fluorescence intensity and total photon count reflect the transfection efficiency of LNPs; higher values ​​indicate a higher efficiency in delivering the encapsulated material into cells.

[0554] Experimental method for transfection efficiency: Quarantined, SPF-grade female BALB / c mice (purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd.) were selected and randomly divided into groups of 3 mice each, based on their body weight. All animals were acclimatized for at least 7 days before the experiment. During the experiment, they had free access to food and water, with alternating light and dark cycles of 12 / 12 hours. The indoor temperature was 20–26℃, and the humidity was 40–70%. Mice were administered LNP-encapsulated luciferase mRNA via intramuscular injection (tibialis anterior muscle of the right leg), tail vein injection, or intraperitoneal injection, with only one administration method used per group of mice. A blank control group was also included, consisting of PBS solution composed of 137 mM NaCl, 2.7 mM KCl, 8 mM Na2HPO4, and 2 mM KH2PO4. Bioluminescence detection was performed using a small animal in vivo imaging system (Brand: Bruker, Model: XTREME) at 6 h, 24 h, 48 h, and 72 h post-administration (time points were adjusted based on results). The specific procedures were as follows: Substrate preparation: An appropriate amount of substrate Luciferin (Brand: Promega) was added to physiological saline to prepare a 10 mg / mL solution, which was stored in the dark. The test substance dose was 5 μg / mouse. At each time point, mice in each group were given the substrate and allowed free movement for 5-10 min, after which they were anesthetized in an anesthesia box using 2.5% isoflurane. Anesthetized mice were placed in the machine, bioluminescence parameters were set, and images were taken. After image acquisition, the upper and lower limits of the image values ​​were adjusted according to the fluorescence intensity of different groups. Data (e.g., fluorescence intensity, average photon count, and total photon count) were collected from areas of concentrated fluorescence distribution, and the data were processed. Statistical analysis: In vivo imaging results were expressed as the mean of fluorescence intensity or total photon count among different animals within the same test group, thereby determining the fluorescence intensity or total photon count of different LNP-encapsulated luciferase mRNAs.

[0555] Table 1 Encapsulation data of lipid nanoparticles

[0556]

[0557]

[0558] Table 2. Encapsulation data of lipid nanoparticles

[0559] Serial Number Package Number Composition and proportion Particle size (nm) PDI Encapsulation rate 1 AC1 A18:PEG:Cholesterol = 35%:1.5%:63.5% 118 0.34 84％ 2 AC2 A18:PEG:Cholesterol = 40%:1.5%:58.5% 122 0.33 87％ 3 AC3 A18:PEG:Cholesterol = 45%:1.5%:53.5% 163 0.42 90％ 4 AC4 A18:PEG:Cholesterol = 50%:1.5%:48.5% 102 0.15 94％ 5 AC5 A18:PEG:Cholesterol = 55%:1.5%:43.5% 109 0.19 87％ 6 AC6 A18:PEG:Cholesterol = 60%:1.5%:38.5% 134 0.08 88％ 7 AC7 A18:PEG:Cholesterol = 65%:1.5%:33.5% 171 0.19 70％ 8 L11 A18:P3:Cholesterol = 35%:1.5%:63.5% 275 0.55 62％ 9 L12 A18:P3:Cholesterol = 40%:1.5%:58.5% 140 0.39 87％ 10 L13 A18:P3:Cholesterol = 45%:1.5%:53.5% 111 0.23 92％ 11 L14 A18:P3:Cholesterol = 50%:1.5%:48.5% 92 0.1 97％ 12 L15 A18:P3:Cholesterol = 55%:1.5%:43.5% 104 0.19 88％ 13 L16 A18:P3:Cholesterol = 60%:1.5%:38.5% 155 0.08 81％ 14 L17 A18:P3:Cholesterol = 65%:1.5%:33.5% 147 0.03 68％

[0560] Effect of component changes on the properties of lipid nanoparticles in Experiment Example 2

[0561] Following the method in Experimental Example 1, lipid nanoparticles were prepared and their properties were tested.

[0562] Table 3. Encapsulation data of lipid nanoparticles

[0563]

[0564]

[0565] Table 4. Induction of luciferase expression in lipid nanoparticle formulations (6 h)

[0566]

[0567] Note: The symbol " / " indicates that it has not been tested.

[0568] Table 5. Encapsulation data of lipid nanoparticles

[0569]

[0570]

[0571] Table 6. Induction of luciferase expression in lipid nanoparticle formulations (6 h)

[0572]

[0573]

[0574] Note: The symbol " / " indicates that it has not been tested.

[0575] Table 7. Encapsulation data of lipid nanoparticles

[0576]

[0577] Table 8. Encapsulation data of lipid nanoparticles

[0578] Serial Number Package Number Composition and proportion Particle size (nm) PDI Encapsulation rate 1 AC11 A11:PEG:Cholesterol = 45%:4%:51% 54 0.21 95％ 2 L40 A11:P2:Cholesterol = 45%:6%:49% 49 0.18 99％ 3 L41 A11:P3:Cholesterol = 45%:2.5%:52.5% 56 0.04 99％ 4 L42 A11:P5:Cholesterol = 45%:2.5%:52.5% 77 0.24 98％ 5 L43 A11:P6:Cholesterol = 45%:2.5%:52.5% 59 0.11 98％ 6 L44 A11:P9:Cholesterol = 45%:6%:49% 52 0.15 99％

[0579] Table 9. Induction of luciferase expression in lipid nanoparticle formulations (6 h)

[0580]

[0581]

[0582] Note: The symbol " / " indicates that it has not been tested.

[0583] Table 10. Encapsulation data of lipid nanoparticles

[0584]

[0585]

[0586] Table 11. Induction of luciferase expression in lipid nanoparticle formulations (6 h)

[0587]

[0588]

[0589] Note: The symbol " / " indicates that it has not been tested.

[0590] Table 12. Encapsulation data of lipid nanoparticles

[0591] Serial Number Package Number Composition and proportion Particle size (nm) PDI Encapsulation rate 1 AC13 A18:PEG:Cholesterol = 45%:4%:51% 65 0.13 92％ 2 L55 A18:P12:Cholesterol = 45%:6%:49% 64 0.12 96％ 3 L56 A18:P13:Cholesterol = 45%:6%:49% 63 0.06 81％ 4 L57 A18:P14:Cholesterol = 45%:6%:49% 70 0.12 58％ 5 L58 A18:P15:Cholesterol = 45%:6%:49% 44 0.21 99％ 6 AC14 SM-102:PEG:Cholesterol = 45%:4%:51% 43 0.19 93％ 7 L59 SM-102:P12:Cholesterol = 45%:6%:49% 41 0.09 99％ 8 L60 SM-102:P13:Cholesterol = 45%:6%:49% 45 0.22 98％ 9 L61 SM-102:P14:Cholesterol = 45%:6%:49% 42 0.15 97％ 10 L62 SM-102:P15:Cholesterol = 45%:6%:49% 69 0.09 97％ 11 AC15 A2:PEG:Cholesterol = 45%:4%:51% 71 0.24 95％ 12 L63 A2:P12:Cholesterol = 45%:6%:49% 55 0.09 98％ 13 L64 A2:P13:Cholesterol = 45%:6%:49% 56 0.08 95％ 14 L65 A2:P14:Cholesterol = 45%:6%:49% 57 0.1 96％ 15 L66 A2:P15:Cholesterol = 45%:6%:49% 60 0.07 98％

[0592] Table 13. Induction of luciferase expression in lipid nanoparticle formulations (6 h)

[0593]

[0594]

[0595] Note: The symbol " / " indicates that it has not been tested.

[0596] As can be seen from the above data, the polymer lipid compounds of the present invention with different structures and different ionizable lipids, in different proportions, can all produce new LNPs with effects at least comparable to those of traditional PEG formulations, and can effectively deliver drugs through different injection routes.

[0597] Experimental Example 3: Efficacy of a single dose of hEPO mRNA

[0598] Lipid nanoparticles were prepared and their performance and efficacy were tested, following the guidelines of Experiment 1. The difference from Experiment 1 is that this experiment encapsulated hEPO mRNA, and also included a PBS group (PBS), an LNP empty vector group (L67), and an hEPO recombinant protein group (L68). The composition and ratio of L67 were: A18:PEG:Cholesterol = 45%:1.5%:53.5%; L68 was purchased from MCE. Mice were randomly divided into groups of 5 mice each according to their body weight, and administered different test substances intraperitoneally once. The dosage was 10 μg / mouse, and the administration volume was 0.2 mL / mouse.

[0599] (1) Before administration and at 6, 24, 48, 72 and 96 hours after administration, blood was collected from the orbit of each group (to avoid hemolysis), serum was separated, and the EPO content in the serum was detected by ELISA; (2) On Day 0, 3, 5, 7, 10 and 15, blood was collected from the tail vein of each group (anticoagulated blood, 0.5 μL of 0.2 mol / L EDTA was added to every 5 μL of blood), and the proportion of reticulocytes was detected by flow cytometry.

[0600] hEPO mRNA sequence (SEQ ID NO.1):

[0601]

[0602]

[0603] Table 14. Encapsulation data of lipid nanoparticles

[0604]

[0605] according to Figure 1 The results showed that the serum Hepo content in the PBS and L67 groups was almost zero, while other experimental groups showed significant hEPO protein expression 24-96 hours after drug administration, indicating that the LNP formed by the polymer lipid compound of the present invention can effectively achieve drug delivery.

[0606] Experiment 4: Immunogenic effect of SARS-CoV-2 mRNA

[0607] Lipid nanoparticles were prepared and their performance and efficacy were tested, referring to Experiment Example 1. The difference from Experiment Example 1 is that this experiment encapsulated SARS-CoV-2 mRNA and included a PBS group (PBS) and a control group (AC17). The composition and ratio of the lipid nanoparticles used in AC17 were (on a molar basis): A18:DSPC:cholesterol:PEG = 50%:10%:38.5%:1.5%. Mice were randomly divided into groups of 6 mice each according to their body weight. The mice were administered the drug twice, with each dose being either 1 μg / mouse or 20 μg / mouse, and each administration volume being 0.2 mL / mouse.

[0608] SARS-CoV-2mRNA sequence (SEQ ID NO.2):

[0609]

[0610]

[0611]

[0612]

[0613] Table 14. Encapsulation data of lipid nanoparticles

[0614]

[0615] 1. Immunization regimen

[0616] Table 15

[0617]

[0618] 2. ELISA detection of IgG antibodies

[0619] 2.1 Samples: Serum from mice 14 days after primary immunization, and serum from mice 14 days after secondary immunization.

[0620] 2.2 Antigen protein: SARS-CoV-2 Spike Trimer Protein, His Tag (EG.5.1 / Omicron) (ACROBiosystems, Cat#SPN-C524v)

[0621] 2.3 Antigen protein coating: 2 ng / μL, 100 μL / well

[0622] 2.4 Secondary antibody: Goat anti-mouse IgG (H+L), HRP conjugate 1:1000 dilution

[0623] 2.5 Results

[0624] (1) Immunization for 2 weeks IgG

[0625] Table 16. IgG antibody test results 2 weeks after primary immunization

[0626]

[0627]

[0628] (2) Second immunization 2 weeks IgG

[0629] Table 17. IgG antibody test results 2 weeks after second immunization

[0630] Package Number Dosage Mean IgG antibody titer PBS - 75 AC17 1μg 94000 AC17 20μg 8192000 L71 1μg 1536000 L71 20μg 13107200

[0631] According to Table 16, Table 17, Figure 2 and Figure 3 The results show that the LNP prepared by the polymer lipid compound of the present invention can effectively deliver mRNA and exert its function.

[0632] 3. ELISPOT detection of cytokines

[0633] 3.1 Samples: Spleens were collected from mice 2 weeks after the second immunization, and splenic lymphocytes were isolated;

[0634] 3.2 Antigen protein: SARS-CoV-2 Spike Trimer, His Tag (BA.2.75.2 / Omicron) (ACROBiosystems, Cat#SPN-C522r);

[0635] 3.3 Cell count: 2.5 x 10⁻⁶ 5 1 / well;

[0636] 3.4 Cytokine markers: IFN-γ, IL-4;

[0637] 3.5 Results are shown in Figure 4 .

[0638] The above experimental results demonstrate that the present invention has developed a biocompatible, easily decomposed in vivo, and non-toxic polymer lipid material that can replace traditional PEG polymer lipids, thus providing a new lipid delivery system.

[0639] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: in, n is an integer between 1 and 100; s can be 1, 2, 3, 4, 5, 6, 7, or 8; T is selected from chemical bonds, CH, and N; R T It is R2-M2-G2-; when T is a chemical bond, R T It does not exist; R is selected from H and C. 1-10 Alkyl, C 1-10 Haloalkyl groups and R2-M2-G2-; R T Unlike R, it is not simultaneously R2-M2-G2-; G1, G2, and G3 are independently selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; M1 and M2 are independently selected from chemical bonds, -C(O)-, -C(S)-, and -C(O)NR. b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -O-, -S-, -NR b -、-SS-、-C(S)NR b -、-NR b C(S)- and -OP(O)(OH)-O-; R1 and R2 are independently selected from C 1-20 Alkyl groups, optionally marked with 0, 1, 2, 3, 4, or 5 R groups. s The substituted molecule has 0, 1, 2, 3, 4 or 5 unsaturated bonds selected from carbon-carbon double bonds or carbon-carbon triple bonds, and one or more methylene groups are optionally and independently substituted by R*. R s Independently selected from H and C 1-20 Alkyl, -L1-OR a -L1-SR a -L1-NR b R c and R* is independently selected from -O-, -S-, and -NR. b -; R' is independently selected from H and C. 1-10 Alkyl and C 1-10 Halogenated alkyl groups; R4 is selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a -C(S)SR a C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L2-C 3-10 Cycloalkyl, -L2-3-10-membered heterocyclic group, -L2-C 6-10 Aryl and -L2-5-10 heteroaryl groups; L1 is independently selected from chemical bonds and C 1-20 Alkylene; L2 is independently selected from chemical bonds and C 1-10 Alkylene; R a R b and R c Independently selected from H and C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L2-C 3-10 Cycloalkyl, -L2-3-10-membered heterocyclic group, -L2-C 6-10 aryl and -L2-5-10 heteroaryl; or R b R c Together with the nitrogen atoms attached to them, they form 3 to 10-membered subheterocyclic groups.

2. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, n is an integer between 5 and 70; preferably an integer between 5 and 60; preferably an integer between 10 and 50; preferably an integer between 10 and 45, such as 10-15, 25-30, 35-40 or 40-45, preferably an integer between 25 and 30, preferably an integer between 35 and 40, preferably an integer between 40 and 45; preferably an integer between 20 and 50, preferably an integer between 25 and 50, such as 25-30, 30-35 or 45-50.

3. The compound of formula (I) of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, s can be 1, 2, 3, 4, 5 or 6; preferably 1, 2 or 3; preferably 1.

4. The compound of formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, T is selected from chemical bonds and CH; preferably CH; preferably chemical bonds.

5. The compound of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R is selected from H and C. 1-10 Alkyl, C 1-10 Halogenated alkyl groups and R2-M2-G2-; preferably selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and C 1-4 Alkyl and C 1-4 Halogenated alkyl group; preferably H.

6. The compound of formula (I) according to any one of claims 1-5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R T R is R2-M2-G2-, and R is not R2-M2-G2-; preferably, R is R2-M2-G2-, T is a chemical bond, and R T It does not exist; preferably, R is not R2-M2-G2-, T is a chemical bond, and R T It does not exist; preferably, R is H.

7. The compound of formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, G1, G2, and G3 are independently selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Alynyl group; preferably selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group; preferably selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-3 Alkylene; preferably G1 is not chemically bonded.

8. The compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, M1 and M2 are independently selected from chemical bonds, -C(O)-, -C(S)-, and -C(O)NR. b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -O-, -S-, -NR b -, -SS- and -OP(O)(OH)-O-; preferably selected from chemical bonds, -C(O)-, -C(S)-, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -O-, -S-, and -NR b -; Preferably, M1 and M2 are independently selected from chemical bonds, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -NR b -, -O- and -S-; preferably selected from -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S- and -SC(O)-; preferably selected from -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -O- and -S-; preferably selected from -C(O)O-, -OC(O)-, -C(O)S- and -SC(O)-; preferably selected from -C(O)O-, -OC(O)- and -O-, more preferably selected from -C(O)O- and -OC(O)-; preferably, M1 is selected from -C(O)O- and -O-, more preferably -C(O)O-; M2 is selected from -C(O)O-, -OC(O)- and -O-, more preferably selected from -C(O)O- and -OC(O)-; Preferably, M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -O- and -S-, more preferably selected from chemical bonds, -C(O)O-, -C(O)S-, -O- and -S-, more preferably selected from -O- and -S-; more preferably selected from chemical bonds, -C(O)O-, -OC(O)- and -O-, more preferably selected from chemical bonds, -C(O)O- and -O-, and most preferably -O-.

9. The compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R1 and R2 are independently selected from C 4-20 Alkyl, preferably C 10-20 Alkyl, preferably C 10-18 Alkyl, preferably C 13-18 Alkyl, preferably C 13-16 alkyl; Preferably, R1 and R2 are independently and optionally represented by 0, 1, 2, 3, 4 or 5 (preferably 0, 1, 2 or 3, preferably 0 or 1) R s replace; Preferably, R1 and R2 independently optionally have 0, 1, 2, 3, 4 or 5 (preferably 0, 1, 2 or 3) unsaturated bonds selected from carbon-carbon double bonds or carbon-carbon triple bonds; preferably optionally have 0, 1, 2 or 3 carbon-carbon double bonds; preferably optionally have 0, 1 or 2 carbon-carbon double bonds; preferably, when R1 or R2 has 2 carbon-carbon double bonds, these 2 carbon-carbon double bonds are separated by 1 methylene group; Preferably, at least one of R1 and R2 does not have an unsaturated bond; more preferably, at least one of R1 and R2 does not have a carbon-carbon double bond. Preferably, 1, 2, 3, 4 or 5 (preferably 1, 2 or 3, preferably 0, 1 or 2, preferably 0 or 1) methylene groups in R1 or R2 are optionally and independently replaced by R*; Preferably, R1 and R2 are independently selected from C 13 straight-chain alkyl, C 14 straight-chain alkyl, C 16 straight-chain alkyl, C 18 straight-chain alkyl, and Preferably, R1 is Preferred 10. The compound of formula (I) of any one of claims 1-9, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 Alkyl), -L1-OR a -L1-SR a -L1-NR b R c Preferred ingredients are H and C. 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 alkyl); Preferably, R s for Preferred 11. The compound of formula (I) according to any one of claims 1-10, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R* is independently selected from -O- and -S-; -O- is preferred.

12. The compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R' is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl; preferably C 1-4 Alkyl groups, such as methyl groups.

13. The compound of formula (I) of any one of claims 1-12, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R4 is selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a -C(S)SR a C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L2-C 3-7 Cycloalkyl, -L2-3-7-membered heterocyclic, -L2-phenyl and -L2-5-6-membered heteroaryl; preferably selected from H, -C(O)R a -C(S)R a -C(O)OR a -C(O)SR a -C(S)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H, -C(O)R a -C(O)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H, -C(O)R a C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from H and -C(O)R a For example, H or -C(O)Me; preferably -C(O)R a For example, -C(O)Me.

14. The compound of formula (I) according to any one of claims 1-13, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, L1 is independently selected from chemical bonds and C 1-18 Alkylene; preferably selected from chemical bonds and C 1-16 Alkylene; Preferably, L2 is independently selected from chemical bonds and C. 1-6 Alkylene; preferably selected from chemical bonds and C 1-4 Alkylene.

15. The compound of formula (I) according to any one of claims 1-14, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L2-C 3-7 Cycloalkyl, -L2-3-7-membered heterocyclic, -L2-phenyl and -L2-5-6-membered heteroaryl; preferably selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7-membered heterocyclic, phenyl, and 5-6-membered heteroaryl; preferably selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Or R b R c Together with the nitrogen atoms attached to them, they form 3 to 7-membered subheterocyclic groups.

16. The compound of formula (I) of any one of claims 1-15, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II) or (III): in, p is 0, 1, 2, 3, 4, 5 or 6; q can be 0, 1, 2, 3, 4, 5, or 6; r can be 0, 1, 2, 3, 4, 5, or 6; The remaining groups are as defined in any one of claims 1-15.

17. The compound of formula (I) of claim 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II): in, n is an integer between 5 and 70; p is 0, 1, 2, 3, 4, 5 or 6; q can be 0, 1, 2, 3, 4, 5, or 6; r can be 0, 1, 2, 3, 4, 5, or 6; s can be 1, 2, 3, 4, 5, or 6; M1 and M2 are independently selected from chemical bonds, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -NR b -, -O- and -S-; preferably selected from -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, and -SC(O)-; R1 and R2 are independently selected from C 4-20 Alkyl groups, optionally surrounded by 0, 1, 2 or 3 (preferably 0 or 1) R groups. s The carbon-carbon double bond is replaced by, and optionally has 0, 1, 2, 3, 4 or 5 unsaturated bonds selected from carbon-carbon double bonds and carbon-carbon triple bonds; preferably, at least one of R1 and R2 does not have unsaturated bonds. R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 Alkyl), -L1-OR a -L1-SR a -L1-NR b R c Preferred ingredients are H and C. 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 alkyl); R is selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R' is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R4 is selected from H, -C(O)R a -C(O)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; L1 is independently selected from chemical bonds and C 1-20 Alkylene (preferably C) 1-18 Alkylene, preferably C 1-16 Alkylene); R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

18. The compound of formula (I) of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (II), wherein, n is an integer between 5 and 60, preferably an integer between 10 and 50; p is 0, 1, 2 or 3, preferably 0, 1 or 2; q can be 0, 1, 2 or 3, preferably 0, 1 or 2; r can be 0, 1, 2 or 3, preferably 0, 1 or 2; s is 1, 2 or 3, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, -SC(O-), -O- and -S-; preferably selected from -C(O)O-, -OC(O)-, -C(O)S- and -SC(O-); R1 and R2 are independently selected from C 10-20 Alkyl, preferably C 10-18 Alkyl groups, which optionally have 0, 1, 2 or 3 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond; R is selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R' is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R4 is selected from H, -C(O)R a C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from H and -C(O)R a Preferred -C(O)R a ; R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

19. The compound of formula (I) of claim 17 or 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II), wherein, n is an integer between 10 and 45, such as 10-15, 25-30, 35-40 or 40-45, preferably an integer between 25-30, preferably an integer between 35-40, and preferably an integer between 40-45; p is 1; q can be 0 or 1, preferably 1; r is 0 or 1, preferably 0; s is 1, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -O-, preferably from -C(O)O- and -OC(O-); preferably, M1 is selected from -C(O)O- and -O-, preferably from -C(O)O-; M2 is selected from -C(O)O-, -OC(O)- and -O-, preferably from -C(O)O- and -OC(O-); R1 and R2 are independently selected from C 13-16 Alkyl groups, which optionally have 0, 1 or 2 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond; R is H; R' is C 1-4 Alkyl groups, preferably methyl groups; R4 is H or -C(O)Me, preferably -C(O)Me; Preferably, when R1 or R2 has two carbon-carbon double bonds, there is a methylene group between the two carbon-carbon double bonds; Preferably, R1 and R2 are independently selected from C 13 straight-chain alkyl, C 14 Straight-chain alkyl and C 16 Straight-chain alkyl groups.

20. The compound of formula (I) of claim 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (III): in, n is an integer between 5 and 70; p is 0, 1, 2, 3, 4, 5 or 6; q can be 0, 1, 2, 3, 4, 5, or 6; s can be 1, 2, 3, 4, 5, or 6; M1 and M2 are independently selected from chemical bonds, -C(O)NR b -、-NR b C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -NR b -、-O- and -S-; R1 and R2 are independently selected from C 4-20 Alkyl groups, optionally surrounded by 0, 1, 2 or 3 (preferably 0 or 1) R groups. s The carbon-carbon double bond is replaced by, and optionally has 0, 1, 2, 3, 4 or 5 unsaturated bonds selected from carbon-carbon double bonds and carbon-carbon triple bonds; preferably, at least one of R1 and R2 does not have unsaturated bonds. R s Independently selected from H and C 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 Alkyl), -L1-OR a -L1-SR a -L1-NR b R c Preferred ingredients are H and C. 1-20 Alkyl (preferably C) 1-18 Alkyl, preferably C 1-16 alkyl); R' is independently selected from H and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R4 is selected from H, -C(O)R a -C(O)OR a C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; L1 is independently selected from chemical bonds and C 1-20 Alkylene (preferably C) 1-18 Alkylene, preferably C 1-16 Alkylene); R a R b and R c Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

21. The compound of formula (I) of claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (III), wherein, n is an integer between 5 and 60, preferably an integer between 10 and 50, and even more preferably an integer between 20 and 50; p is 0, 1, 2 or 3, preferably 0, 1 or 2; q can be 0, 1, 2 or 3, preferably 0, 1 or 2; s is 1, 2, or 3; M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O-), -O- and -S-, preferably selected from chemical bonds, -C(O)O-, -C(O)S-, -O- and -S-, and more preferably selected from -O- and -S-; R1 and R2 are independently selected from C 10-20 Alkyl, preferably C 10-18 Alkyl groups, which optionally have 0, 1, 2 or 3 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond; R' is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R4 is selected from H, -C(O)R a C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; preferably selected from H and -C(O)R a Preferred -C(O)R a ; R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

22. The compound of formula (I) of claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (III), wherein, n is an integer between 25 and 50, such as an integer between 25 and 30, 30 and 35, or 45 and 50. p is 0, 1 or 2, preferably 2; q can be 0, 1, or 2, preferably 2; s is 1; M1 and M2 are independently selected from chemical bonds, -C(O)O-, -OC(O)- and -O-, preferably selected from chemical bonds, -C(O)O- and -O-, and most preferably -O-; R1 and R2 are independently selected from C 13-18 Alkyl groups, preferably selected from C 13-16 Alkyl groups, which optionally have 0, 1 or 2 carbon-carbon double bonds; preferably at least one of R1 and R2 does not have a carbon-carbon double bond; R' is C 1-4 Alkyl groups, preferably methyl groups; R4 is -C(O)Me; Preferably, when R1 or R2 has two carbon-carbon double bonds, there is a methylene group between the two carbon-carbon double bonds; Preferably, R1 and R2 are independently selected from C 13 straight-chain alkyl, C 16 straight-chain alkyl, C 18 straight-chain alkyl, 23. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, The compound is selected from the following:

24. A lipid composition, wherein, The lipid composition comprises a polymeric lipid, which is a compound of any one of claims 1-23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

25. The lipid composition of claim 24, wherein, This includes ionizable lipids, polymeric lipids, and structural lipids.

26. The lipid composition of claim 25, wherein, Components containing the following molar percentages: The ionizable lipid content is approximately 20%-80%, preferably approximately 28%-70%; The polymer lipid content is approximately 1%-10%, preferably approximately 1%-8%; Structural lipids comprise approximately 14%-70%, preferably approximately 25%-70%; Preferably, The lipid composition comprises the following components in molar percentage: The ionizable lipids are approximately 35%-65%, preferably approximately 40%-60%; Polymer lipids comprise approximately 1.5%-6%; The structural lipids comprise approximately 33.5%-63.5%, preferably approximately 38.5%-58.5%; Preferably, The lipid composition comprises the following components in molar percentage: The ionizable lipid content is approximately 40%-50%, preferably approximately 42%-48%, and most preferably approximately 45%. The polymer lipid content is approximately 1.5%-7%, preferably approximately 2.5%-6%, more preferably approximately 1.5%-4%, and even more preferably approximately 2.5%-3%. The structural lipids comprise approximately 45%-55%, preferably approximately 49%-52.5%, more preferably approximately 50%-55%, and most preferably approximately 52%-52.5%.

27. The lipid composition of claim 25 or 26, wherein, The ionizable lipid is selected from the structures shown in formulas (i)-(v): in, R'1 is independently selected from -R”1-X; R”1 is -(CH2) 0-6 -, X represents amino, hydroxyl, ethynyl, cyano, or -C(O)(CH2). 1-3 NR' a R' b -C(O)O(CH2) 1- 3NR' a R' b -OC(O)(CH2) 1-3 NR' a R' b -C(O)NH(CH2) 1-3 NR' a R' b -NHC(O)(CH2) 1-3 NR' a R' b -NHC(O)CH(NR' a R' b (CH2) 1-3 NR' a R' b C 3-7 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl or 5-10-membered heteroaryl group, preferably amino, hydroxyl, or cyano, preferably hydroxyl, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more (preferably 1, 2, or 3) groups selected from the following: -(CH2) 1-3 OH, -(CH2) 1-3 NR' a R' b -(CH2) 1-3 C(O)NR' a R' b Or X is: R' a 、R' b Each is independently selected from H and C. 1-3 Alkyl group, -(CH2) 1-3 NH2、-(CH2) 1-3 NH(CH2) 1-3 NH2; or R' a and R' b Together with the nitrogen atom to which it is attached, it forms a 5-10 membered heterocycle (preferably a 5-7 membered heterocycle) comprising 1-3 heteroatoms selected from N, O, or S, wherein the heterocycle is optionally substituted by one or more (preferably 1, 2, or 3) groups selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 Alkylamino; R'2 and R'3 are independently selected from H and C. 2-18 Alkyl, C 4-18 alkenyl or Preferably selected from H, C 2-18 Alkyl or C 4-18 alkenyl; Each M is independently selected from -CH2-, -CH=CH-, -NH-, -C(O)-, -O-, -C(O)O-, -OC(O-, -C(O)NH- or -NHC(O-), preferably selected from -C(O)O-, -OC(O-, -C(O)NH- or -NHC(O-), more preferably -C(O)O- or -C(O)NH-, and most preferably -C(O)O; Each R'6 is independently selected from H, -R'5, -OR'4, or -L'OR'4; Each R'5 is selected from C 1-10 Alkyl or C 3-12 alkenyl; Each R'4 is selected from C 1-10 Alkyl or C 3-12 alkenyl; L' is independently selected from C 1-10 Alkylene or C 3-12 alkenyl; m1 and m2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9; m3 and m4 are each independently selected from 0, 1, 2 or 3, preferably 0 or 1.

28. The lipid composition of any one of claims 25-27, wherein, The ionizable lipid is selected from at least one of the following: DLin-MC3-DMA, ALC-0315, SM-102, 8-(3-hydroxypropyl)(9,12-dienyl-octadecyl-1)-amino-octanoic acid heptadecano-9-ol ester, bis(2,3-bis(hexyloxy)propyl)8,8'-((2-hydroxyethyl)azadiyl)dioctanoate, 2,3-di(hexyloxy)propionyl 12-((8-(2,3-di(hexyloxy))propoxy)-8-oxooctyl)(2-hydroxyethyl)amino)dodecanoate, N,N-dimethyl-2,3-dioleenyloxy)propylamine (DODMA), N,N-dioleenyl-N,N-dimethylammonium chloride (DODAC), N,N-distearate- N,N-Dimethylammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(1-(2,3-diolenoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) and 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA).

29. The lipid composition of any one of claims 24-28, wherein, The polymer lipid further includes polyethylene glycol-modified lipids, wherein the polyethylene glycol-modified lipids are selected from at least one of PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol; Preferably, 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, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000, with DMG-PEG2000 being the most preferred.

30. The lipid composition of claim 29, wherein, The polyethylene glycol-modified lipids: the molar ratio of the compounds in any one of claims 1-23 is (0.5-3):(0.5-3), preferably (0.5-2):(0.5-2), preferably (0.5-1.5):(0.5-1.5), preferably (0.7-1.3):(0.7-1.3), and preferably 1:

1.

31. The lipid composition of any one of claims 25-30, wherein, The structural lipid is selected from steroids; preferably, the steroid is selected from at least one of cholesterol, coprosterol, sitosterol, ergosterol, campesterol, stigmasterol, rapeseed sterol, tomatine, ursolic acid, α-tocopherol, rock saponin, alfalfa sterol and ergocalciferol; cholesterol is preferred.

32. A nanoparticle composition, wherein, The nanoparticle composition comprises a lipid composition according to any one of claims 24-31, and optionally comprises a loading agent; preferably, the loading agent is selected from at least one of DNA, RNA, protein, and pharmaceutically active molecules.

33. The nanoparticle composition according to claim 32, wherein, The RNA is selected from at least one of the following: messenger RNA (mRNA), small interfering RNA (siRNA), aiRNA, microRNA (miRNA), double-stranded RNA (dsRNA), antisense RNA (aRNA), long non-coding RNA (lncRNA), short hairpin RNA (shRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), polymer-coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme.

34. The nanoparticle composition according to claim 33, wherein, The protein is selected from any one of antibodies, enzymes, recombinant proteins, polypeptides, and short peptides.

35. A pharmaceutical composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a lipid composition of any one of claims 24-31, or a nanoparticle composition of any one of claims 32-34, and a pharmaceutically acceptable excipient.

36. Use of any compound of claims 1-23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a lipid composition of any one of claims 24-31, or a nanoparticle composition of any one of claims 32-34, or a pharmaceutical composition of claim 35 in the preparation of a medicament for treating, diagnosing or preventing a disease.

37. Use of any compound of claims 1-23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a lipid composition of any one of claims 24-31, or a nanoparticle composition of any one of claims 32-34, or a pharmaceutical composition of claim 35 in the preparation of a delivery-loaded medicament.

38. A method of treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a nanoparticle composition of any one of claims 32-34, or a pharmaceutical composition of claim 35.

39. The nanoparticle composition of any one of claims 32-34, or the pharmaceutical composition of claim 35, for the treatment, diagnosis, or prevention of disease.

40. A method of delivering a payload into a subject, comprising administering to the subject a nanoparticle composition of any one of claims 32-34, or a pharmaceutical composition of claim 35.

41. The lipid composition of any one of claims 24-31, or the nanoparticle composition of any one of claims 32-34, or the pharmaceutical composition of claim 35, for delivery of a payload.

42. The use of claim 37 or 41, or the method of claim 40, wherein, The payload is selected from at least one of DNA, RNA, protein, and pharmaceutically active molecules; Preferably, the RNA is selected from at least one of the following: messenger RNA (mRNA), small interfering RNA (siRNA), aiRNA, microRNA (miRNA), double-stranded RNA (dsRNA), antisense RNA (aRNA), long non-coding RNA (lncRNA), short hairpin RNA (shRNA), small activating RNA (saRNA), polymer-encoding nucleic acid (MCNA), polymer-encoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozyme; Preferably, the protein is selected from at least one of antibodies, enzymes, recombinant proteins, polypeptides, and short peptides.

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