Lung-targeting polynitrogen lipid compound

Abstract

Provided in the present invention is a class of lung-targeting polynitrogen lipid compounds. Specifically, the present invention relates to a compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Further provided in the present invention are a nanoparticle pharmaceutical composition containing the compound, and the use of the compound and the composition thereof in the pulmonary targeted delivery of nucleic acids.

Description

Lung-targeting polynitrogen lipid compounds

[0001] This application claims priority to Chinese application 202411734553.X filed on November 28, 2024, and Chinese application 202511726262.0 filed on November 21, 2025, which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to a class of lung-targeting polynitrogenous lipid compounds, or isotopic variants, tautomers, or stereoisomers thereof, or pharmaceutically acceptable salts thereof. The invention also relates to lipid nanoparticles comprising said compounds and pharmaceutical compositions, and the use of said lipid nanoparticles in the lung-targeted delivery of bioactive substances such as nucleic acids (e.g., mRNA, siRNA, ASO, DNA, etc.). Background Technology

[0003] Gene therapy refers to the introduction of exogenous genes into target cells to correct or compensate for gene defects or abnormalities within the cells, thereby achieving therapeutic goals. Over the past few decades, research into using gene therapy to treat clinical diseases has received increasing attention, especially in recent years with the FDA approval of siRNA-related drugs and mRNA vaccines for clinical treatment, further advancing research and investment in the field of gene therapy.

[0004] Nucleic acids are readily degraded in vivo by nucleases, and their negative charge makes them difficult to pass through cell membranes and enter cells. Lipid nanoparticles (LNPs), as a nucleic acid delivery material, offer advantages such as simple preparation, good biodegradability, non-immunogenicity, and good safety, making them one of the most important nucleic acid delivery systems currently available. The main components of LNPs include ionizable lipid molecules, cholesterol, auxiliary lipids, and polyethylene glycol-conjugated lipids. Among these, ionizable lipid molecules are the core of the LNP delivery system, and their molecular structure plays a decisive role in the overall delivery efficiency, targeting, and formulation stability of the liposome nanoparticles.

[0005] Lung-related diseases pose a significant threat to human health, including COVID-19, influenza, cystic fibrosis, primary ciliary dyskinesia, alpha-1 antitrypsin deficiency, asthma, and lung cancer. However, traditional therapies often fail to cure these diseases due to limitations such as the lack of druggable therapeutic targets. With the development of various key technologies, nucleic acid drugs can not only treat diseases directly at the transcriptional level, but also rapidly develop new drugs simply by modifying the sequence of nucleic acid molecules, providing a completely new approach to curing lung diseases. However, current LNP delivery systems tend to accumulate in the liver; therefore, there is an urgent need to design LNPs for targeted delivery of nucleic acid molecules to the lungs. Summary of the Invention

[0006] This invention develops a class of lung-targeting polynitrogenous lipid compounds that can be used to deliver various bioactive substances and have high lung-targeting delivery efficiency.

[0007] This invention provides compounds of formula (I), or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0008] The variables are as defined in this invention.

[0009] In another aspect, the present invention provides a nanoparticle composition comprising a lipid component and optionally a loading; wherein the lipid component contains a compound of the present invention.

[0010] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention or the nanoparticle compositions of the present invention, and optionally pharmaceutically acceptable excipients, such as carriers, adjuvants, or mediators.

[0011] In another aspect, the present invention provides the use of the compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention in the preparation of medicaments for treating, diagnosing, or preventing diseases. In one embodiment, the disease is a lung disease, including obstructive pulmonary disease, restrictive lung disease, pulmonary vascular disease, infectious lung disease, hereditary lung disease, allergic lung disease, and tumors such as pneumonia, influenza, cystic fibrosis, primary ciliary dyskinesia, α-1 antitrypsin deficiency, asthma, pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), lymphangioleiomyomatosis (LAM), or lung cancer. In another embodiment, the medicament for treating, diagnosing, or preventing the disease is a nucleic acid. In another embodiment, the medicament for treating, diagnosing, or preventing the disease is a gene therapy drug. In another embodiment, the medicament for treating, diagnosing, or preventing the disease is a gene editing drug.

[0012] In another aspect, the present invention provides the use of the compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention in the preparation of medicaments for delivery of payloads. In one embodiment, the medicament is a medicament for delivering a payload to the lungs. In another embodiment, the payload is a gene therapy drug. In yet another embodiment, the payload is a gene editing drug.

[0013] In another aspect, the present invention provides methods for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention. In one embodiment, the disease is a lung disease, including obstructive lung disease, restrictive lung disease, pulmonary vascular disease, infectious lung disease, hereditary lung disease, allergic lung disease, and tumors such as pneumonia, influenza, cystic fibrosis, primary ciliary dyskinesia, α-1 antitrypsin deficiency, asthma, pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), lymphangioleiomyomatosis (LAM), or lung cancer. In another embodiment, the method of treating, diagnosing, or preventing the disease is gene therapy. In another embodiment, the method of treating, diagnosing, or preventing the disease is gene editing. In another aspect, the present invention provides compounds of the present invention, nanoparticle compositions of the present invention, or pharmaceutical compositions of the present invention for treating, diagnosing, and / or preventing a disease, preferably for gene therapy, and preferably for gene editing. In one embodiment, the disease is a lung disease, including obstructive lung disease, restrictive lung disease, pulmonary vascular disease, infectious lung disease, hereditary lung disease, allergic lung disease, and tumors such as pneumonia, influenza, cystic fibrosis, primary ciliary dyskinesia, alpha-1 antitrypsin deficiency, asthma, pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), lymphangioleiomyomatosis (LAM), or lung cancer.

[0014] In another aspect, the present invention provides a method for delivering a payload into a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention. In one embodiment, the method is a method for delivering a payload into the lungs of a subject.

[0015] In another aspect, the present invention provides compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for delivering a payload. In one embodiment, it is used for delivering a payload to the lungs.

[0016] In a specific implementation, the application includes any one or a combination of local administration and systemic administration;

[0017] In a more specific embodiment, the administration includes intravenous injection, intraperitoneal injection, arterial injection, or inhalation, more preferably intravenous injection.

[0018] In a specific implementation plan, the drug used for treating, diagnosing, or preventing diseases is a nucleic acid.

[0019] In a specific implementation, the load is selected from one or more of a therapeutic agent, a preventive agent, or a diagnostic agent; preferably, the therapeutic agent, preventive agent, or diagnostic agent is a nucleic acid.

[0020] In a more specific embodiment, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA, or DNA.

[0021] In a more specific embodiment, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA), or ribozymes, preferably one or more of mRNA, siRNA, gRNA, circRNA, SrRNA, miRNA, aRNA, or modified mRNA, more preferably mRNA, siRNA, gRNA, or modified mRNA.

[0022] In a more specific embodiment, the DNA is selected from one or more of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0023] definition

[0024] Chemical definition

[0025] The definitions of specific functional groups and chemical terms are described in more detail below.

[0026] 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 2-3 C 3- 6. C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0027] “C 1-30 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 30 carbon atoms. In some embodiments, C 1-30 Alkyl, C 4-30 Alkyl, C 1-25 Alkyl, C 4-25 Alkyl, C 6-25 Alkyl, C 1-20 Alkyl, C 4-20 Alkyl, C 6-20 Alkyl, C 8-20 Alkyl, C 1-15 Alkyl, C 4-15 Alkyl, C 6-15 Alkyl, C 8-15 Alkyl, C 1-14 Alkyl, C 2-14 Alkyl, C 4-14 Alkyl, C 6-14 Alkyl, C 1-13 Alkyl, C 1-12 Alkyl, C 4-12 Alkyl, C 6-12 Alkyl, C 7-12 Alkyl, C 8-12 Alkyl, C 9-12 Alkyl, C 10-12 Alkyl, C 12 Alkyl, C 7-11 Alkyl, C 8-11 Alkyl, C 9-11 Alkyl, C 10-11 Alkyl, C 11 Alkyl, C 1-10 Alkyl, C 4-10 Alkyl, C 5-10 Alkyl, C 6-10 Alkyl, C 7-10 Alkyl, C 8-10 Alkyl, C 9-10 Alkyl, C 10 Alkyl, C 1-9 Alkyl, C 3-9 Alkyl, C 4-9 Alkyl, C 5-9 Alkyl, C 6-9 Alkyl, C 7-9 Alkyl, C 8-9 Alkyl, C9 alkyl, C 1-8 Alkyl, C 2-8 Alkyl, C 3-8 Alkyl, C 4-8 Alkyl, C 5-8 Alkyl, C 6-8 Alkyl, C 7-8 Alkyl, C8 alkyl, C 1-7 Alkyl, C2-7 Alkyl, C 3-7 Alkyl, C 4-7 Alkyl, C 5-7 Alkyl, C 6-7 Alkyl, C7 alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 4-6 Alkyl, C 5-6 Alkyl, C6 alkyl, C 1-5 Alkyl, C 4-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 Alkyl, C2-alkyl, and Me are preferred. 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 "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). Alkyl groups 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 preferably a straight-chain alkyl group. For example, C 4-12 straight-chain alkyl, C 4-10 straight-chain alkyl, C 4-8 Straight-chain alkyl, C6 straight-chain alkyl.

[0028] “C 2-14 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 14 carbon atoms and at least one carbon-carbon double bond. 4-30 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 4 to 30 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-25 alkenyl, C 4-20 alkenyl, C 6-25 alkenyl, C 6-20 alkenyl, C 4-15 alkenyl, C 6-15 alkenyl, C 8-15 alkenyl, C 15alkenyl, C 4-14 alkenyl, C 6-14 alkenyl, C 7-12 alkenyl, C 8-12 alkenyl, C 9-12 alkenyl, C 10-12 alkenyl, C 2-10 alkenyl, C 4-10 alkenyl, C 8-10 alkenyl, C 10 alkenyl, C 2-9 alkenyl, C9 alkenyl, C 2-8 alkenyl, C 2-6 alkenyl and C 2-4 Alkenyl groups are preferred. C 2-6 Examples 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. In some embodiments, the alkenyl group is preferably a straight-chain alkenyl group.

[0029] “C 2-14 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 14 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 4-30 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 4 to 30 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4-25 alkynyl group, C 6-25 alkynyl group, C 4-20 alkynyl group, C 6-20 alkynyl group, C 4-15 alkynyl group, C 6-15 alkynyl group, C 8-15 alkynyl group, C 4-14 alkynyl group, C 6-14 alkynyl group, C 7-12 alkynyl group, C 8-12 alkynyl group, C 9-12 alkynyl group, C 10-12 alkynyl group, C 2-10 alkynyl group, C 4-10 alkynyl group, C 2-9 alkynyl group, C 2-8 alkynyl group, C 2-6 alkynyl group and C 2-4 Alkyne groups are preferred. C 2-6Examples 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. In some embodiments, the alkynyl is preferably a straight-chain alkynyl.

[0030] “C 1-30 "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 1-25 Alkylene, C 1-20 Alkylene, C 4-20 Alkylene, C 1-15 Alkylene, C 1-14 Alkylene, C 2-14 Alkylene, C 4-14 Alkylene, C 6-14 Alkylene, C 1-13 Alkylene, C 1-12 Alkylene, C 7-12 Alkylene, C 8-12 Alkylene, C 7-11 Alkylene, C 8-11 Alkylene, C 1-10 Alkylene, C 2-10 Alkylene, C 4-10 Alkylene, C 8-10 Alkylene, C 9-10 Alkylene, C 1-9 Alkylene, C 4-9 Alkylene, C 6-9 Alkylene, C 7-9 Alkylene, C 8-9 Alkylene, C9 alkylene, C 1-8 Alkylene, C 2-8 Alkylene, C 5-8 Alkylene, C 7-8 Alkylene, C 1-7 Alkylene, C 2-7 Alkylene, C 4-7 Alkylene, C 5-7 Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C 4-6 Alkylene, C6 alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4Alkylene, C 2-4 Alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1-2 Alkylenes, C2 alkylenes, and methylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. In some embodiments, the alkylene group is preferably a straight-chain alkylene group. For example, C 2-14 straight-chain alkylene, C 2-10 straight-chain alkylene, C 2-8 straight-chain alkylene, C 2-7 straight-chain alkylene, C 4-7 straight-chain alkylene, C 4-7 straight-chain alkylene, C 5-7 Straight-chain alkylene or C6 straight-chain alkylene.

[0031] “C 2-14 "Alkenyl" refers to the group that has been de-carbonied. 2-114 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 4-14 imidene group, C 6-14 imidene group, C 2-10 imidene group, C 4-10 imidene group, C 2-8 imidene group, C 2-9 imidene group, C 2-6 imide and C 2-4Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc. In some embodiments, the alkenyl group is preferably a linear alkenyl group.

[0032] “C 2-14 "Iso-ynyl" refers to the group that has the C group removed. 2-14 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 4-14 Ethyne group, C 6-14 Ethyne group, C 2-10 Ethyne group, C 4-10 Ethyne group, C 2-8 Ethyne group, C 2-9 Ethyne group, C 2-6 etyne and C 2-4 The ynylene group is particularly preferred. Exemplary ynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), etc. In some embodiments, the ynylene group is preferably a straight-chain ynylene group.

[0033] “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". The same logic applies to other similar cases.

[0034] The term "the total length of variables A and B is x carbon atoms" means that the sum of the number of carbon atoms in the main chain of the group represented by variable A and the number of carbon atoms in the main chain of the group represented by variable B is x.

[0035] The term "R" s "x carbon atoms are spaced between the substitution site on R and M2" indicates that the variable R is affected by the variable R. s The sum of the number of carbon atoms (including N atoms replaced by -NR7-) between the substitution site and M2, and so on for other cases. For example:

[0036] In compound 4, R s The substitution site on R is separated from M2 by two carbon atoms.

[0037] The term "linking end" refers to the site where a group connects to other parts of a molecule. In embodiments of the present invention, "N atom as linking end" means that the group is connected to other parts of the compound molecule through an N atom.

[0038] The term "head end" refers to the head orientation of a lipid molecule. In embodiments of the present invention, the head is a head structure formed by a multi-level amine.

[0039] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0040] 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 1-8 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Haloalkyl groups, such as halomethyl groups. Exemplary haloalkyl 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 haloalkyl group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0041] “C 3-14"Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl, and 3- to 6-membered cycloalkyl are particularly preferred, more preferably 5- to 7-membered cycloalkyl, 4- to 6-membered cycloalkyl, 3- to 5-membered cycloalkyl, 3- to 4-membered cycloalkyl, and 5- to 6-membered cycloalkyl, more preferably 5-membered cycloalkyl, more preferably 6-membered cycloalkyl, and more preferably cyclopropyl. Cycloalkyl also includes a cyclic system 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 indicate the number of carbons in the cycloalkyl system. Cycloalkyl also includes a cyclic system in which the aforementioned cycloalkyl ring, Substituents on any non-adjacent carbon atoms are linked together to form a bridged ring, forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups also include the aforementioned cycloalkyl rings, where substituents on the same carbon atom are linked together to form a ring, 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 with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0042] “C 3-14 "Cycloalkylene" refers to the alkylene group after removing C24. 3-14 The cycloalkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 3-10 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene, C 3-4 Cycloalkylene and cyclopropylene are particularly preferred. Examples include cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, with cyclopropylene being especially preferred.

[0043] "3-14 membered heterocyclic group" or "3 to 14 membered heterocyclic group" refers to a saturated or unsaturated group having a 3 to 14 membered non-aromatic ring system with a cyclic carbon atom and 1 to 5 cyclic 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 bonding point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 3- to 10-membered heterocyclic group is preferred, which is a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5- to 10-membered heterocyclic group is preferred, which is a 5- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3- to 8-membered heterocyclic group is preferred, which is a 3- to 8-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, a 3- to 7-membered heterocyclic group is preferred, which is a 3- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 5- to 7-membered heterocyclic group is preferred, which is a 5- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms. Five to seven-membered non-aromatic ring systems with up to three heteroatoms; preferably three to six-membered heterocyclic groups, which are three to six-membered non-aromatic ring systems having a cyclic carbon atom and one to three heteroatoms, more preferably three to seven-membered nitrogen heterocyclic groups; preferably four to six-membered heterocyclic groups, which are four to six-membered non-aromatic ring systems having a cyclic carbon atom and one to three heteroatoms; more preferably five to six-membered heterocyclic groups, which are five to six-membered non-aromatic ring systems having a cyclic carbon atom and one to three heteroatoms; preferably five-membered heterocyclic groups, which are five-membered non-aromatic ring systems having a cyclic carbon atom and one to three heteroatoms; preferably six-membered heterocyclic groups, which are six-membered non-aromatic ring systems having a cyclic carbon atom and one to three 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, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolyl, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-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, disulfuranyl, and dioxalyl. 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, oxasulfuranyl, 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 that the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "3-14 membered heterocyclic group" refers to a divalent group formed by removing another hydrogen atom from a 3-14 membered heterocyclic group, and can be substituted or unsubstituted. In some embodiments, 3-10 membered heterocyclic groups, 3-7 membered heterocyclic groups, 3-6 membered heterocyclic groups (preferably 3 to 7 membered nitride heterocyclic groups), 3-5 membered heterocyclic groups, and 3-4 membered heterocyclic groups are particularly preferred.

[0045] “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.

[0046] “C 6-10 "Asyl" refers to the group that has been depleted of C. 6-10 The aryl group is a divalent group formed by the other hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 10 Aryl groups are preferred; in some embodiments, phenyl groups are particularly preferred.

[0047] "5-14 membered heteroaryl" or "5 to 14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 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 heteroaryls 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. Heteroaryls also include 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 some embodiments, 5-10 membered heteroaryls are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic 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 thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: 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. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadiazinyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0048] "5-14-membered heteroaryl" refers to a divalent group formed by removing another hydrogen atom from a 5-14-membered heteroaryl group, and can be substituted or unsubstituted. In some embodiments, 5-10-membered heteroaryl is preferred; in some embodiments, 5-6-membered heteroaryl is particularly preferred.

[0049] "Hydroxyalkyl" refers to an alkyl group that has been replaced by one or more hydroxyl groups.

[0050] "Alkoxy" refers to the oxyether form of a straight-chain or branched alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0051] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the possibility that the event or condition occurs and the possibility that it does not occur. For example, "optionally replaced by..." means that it can be replaced by a specified substituent or not substituted.

[0052] 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".

[0053] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0054] 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 CO2Raa 、-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)(ORcc )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;

[0055] 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;

[0056] 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;

[0057] 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 -SO2ORcc -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;

[0058] 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;

[0059] 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(Rff )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;

[0060] 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;

[0061] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ffThe 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;

[0062] 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 1-6 Alkyl, -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 1-6Alkyl 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 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 aryl, 3-7 membered heterocyclic, 5-10 membered heteroaryl; or two geminal Rs gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0063] 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.

[0064] "Protecting groups" include "amino protecting groups," "hydroxyl protecting groups," and "carboxyl protecting groups," used to prevent certain functional groups (e.g., amino, hydroxyl, and carboxyl) from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups and the appropriate conditions for protection and deprotection are well known in the art. For example, many protecting groups and their introduction and removal are described in TWGreene and PGMWuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0065] Common amino protecting groups include alkoxycarbonyl protecting groups, acyl protecting groups, or alkyl protecting groups. In some embodiments, alkoxycarbonyl protecting groups are preferred. In some embodiments, acyl protecting groups are preferred.

[0066] Alkoxycarbonyl protecting groups include, but are not limited to: benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), methoxycarbonyl, or ethoxycarbonyl. Preferably, in some embodiments, Fmoc is preferred. In some embodiments, Cbz is preferred. In some embodiments, Boc is preferred.

[0067] Acyl protecting groups include, but are not limited to: phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), formyl, acetyl (Ac), or benzoyl (Bz). In some embodiments, Ac is preferred.

[0068] Alkyl protecting groups include, but are not limited to: triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn), or (trimethylsilyl)ethoxymethyl (Sem).

[0069] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their hybrid molecules. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASO). Nucleic acids can be further chemically modified, with modifications selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. mRNA molecules contain protein-coding regions and may further contain expression regulatory sequences, typical of which include, but are not limited to, a 5' cap, a 5' untranslated region (5'UTR), a 3' untranslated region (3'UTR), a polyadenylated nucleotide sequence (PolyA), and a miRNA binding site.

[0070] "Ionizable lipids" refers to lipids that are ionizable, allowing them to exist in a positively charged or neutral form depending on pH. In some embodiments, ionizable lipids are aminolipids.

[0071] "Assistant lipids" are non-cationic lipids that reduce the toxicity associated with cationic lipids, enhance particle stability, regulate membrane fluidity, and improve drug delivery efficiency. In some embodiments, typical assistant lipids are phospholipids. In some embodiments, they are neutral lipids.

[0072] "Neutral lipids" refer to lipid molecules that are uncharged under specific pH conditions, such as physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearyl-sn-glycerol-3-phosphate choline (DSPC), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline (POPC), 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE), 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate ethanolamine (POPE), and 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE).

[0073] "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.

[0074] "Polymer lipid" refers to a molecule containing both a polymeric moiety and a lipid moiety. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. 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.

[0075] "Lipid nanoparticles" refer to particles containing lipid components and having a nanoscale size.

[0076] "Biodegradable groups" refer to functional groups containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can influence the process of clearing compounds from the body. The orientation of the biodegradable groups in this invention is from the head to the tail of the ionizable lipid molecule. Common biodegradable groups include, but are not limited to: -C(O)O-, -OC(O)-, -O-, -SC(O)O-, and -OC(O)NR. c -、-NRC(O)NR c -、-OC(O)S-、-OC(O)O-、-NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NRc C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, and -S(O) 0-2 -

[0077] Other definitions

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, 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. Salts of amino acids are also included, such as arginine salts, gluconates, and galacturonic acids (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19, incorporated herein by reference).

[0083] 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.

[0084] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0085] 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”).

[0086] Generally, the "effective amount" of a pharmaceutical composition refers to a quantity sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the pharmaceutical compositions of the present invention can be varied depending on factors such as the biological target, the pharmacokinetics of the pharmaceutical composition, 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.

[0087] Unless otherwise stated, the “therapeuticly effective amount” of a pharmaceutical composition 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 pharmaceutical composition 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.

[0088] Unless otherwise stated, the “preventive effective amount” of a pharmaceutical composition 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 preventive effective amount of a pharmaceutical composition refers to the amount of the 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 “preventive effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0089] The term "combination" and related terms refer to the simultaneous or sequential administration of the pharmaceutical composition of the present invention and other therapeutic agents. For example, the pharmaceutical composition 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.

[0090] Those skilled in the art will understand that the numerical values ​​or ranges mentioned herein generally include all values ​​within ±20%, preferably ±10%, of the stated value. For example, 15 mol% refers to all values ​​within the range of 12 mol% to 18 mol%, preferably within the range of 13.5 mol% to 16.5 mol%. Attached Figure Description

[0091] The foregoing summary and the following detailed description of the invention will be better understood when read in conjunction with the accompanying drawings. To illustrate this disclosure, the drawings depict some, but not all, alternative embodiments. However, it should be understood that this disclosure is not limited to the precise arrangements and means shown. These drawings, which are incorporated into and form part of this specification, help to explain the principles of this disclosure.

[0092] Figure 1 shows the IHC results of the lung LNP delivery group compared to the PBS group. From left to right, the groups are: PBS + anti-tdtomato Ab group, LNP + anti-tdtomato Ab group, and LNP without anti-tdtomato Ab group. Brown represents cells that are positive for tdtomato expression.

[0093] Figure 2 shows the IF-CD31 lung endothelial cell transfection signal 8 hours after drug administration.

[0094] Figure 3 shows the IF-EPCAM lung epithelial cell transfection signal 8 hours after drug administration.

[0095] Figure 4 shows the staining results of IF-SFTPC type II alveolar epithelial cells (ATII) 8 hours after drug administration.

[0096] Figure 5 shows the staining results of IF lung basal cells 8 hours after drug administration.

[0097] Figure 6 shows the IHC results of compound 12-LNP in NHP lungs compared with PBS.

[0098] Figure 7 shows the IHC results of compound 12-LNP in NHP liver compared with PBS.

[0099] Figure 8 shows the results of IF-SFTPC type II alveolar epithelial cell (ATII) staining 8 h after administration of compound 12 lung LNP.

[0100] Figure 9 shows the results of 8h-IF staining of lung basal cells 8 hours after administration of compound 12 lung LNP. Detailed Implementation Plan

[0101] In this document, “compounds of the present invention” refers to the following compounds, their isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof.

[0102] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. 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.

[0103] In one embodiment, the present invention relates to a compound of formula (I), or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0104] in,

[0105] y is 2, 3, 4, 5, or 6;

[0106] L1 and L2 are independently selected from C 2-6 Alkylene, C 2-6 imide and C 2-6 The ynyl group, which is optionally substituted with 1, 2 or 3 R*, and wherein 1, 2 or 3 methylene units are optionally and independently substituted with -O-, -S- or -NR7-;

[0107] R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -C 3-10 cycloalkyl, -L a -3 to 10-membered heterocyclic groups, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0108] L a Independently selected from chemical bonds, C 1-6 Alkylene and C 1-6 Heteroalkyl;

[0109] R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0110] R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-10 cycloalkyl, -Lg -M2-3 to 10-membered heterocyclic groups, -L g -M2-C 6-10 Aryl, -L g -M2-5-10 heteroaryl groups and -G1-M2-R; where C 1-14 One, two, or three methylene units in the alkyl group may be optionally and independently replaced by -O-, -S-, or -NR7-;

[0111] L g Independent of chemical bonds or C 1-14 Alkylene, wherein one, two or three methylene units in the alkylene are optionally and independently replaced by -O-, -S- or -NR7-;

[0112] R1, R2, R3, and R4 are independently H or -G1-M2-R; at least one of R1, R2, R3, and R4 is -G1-M2-R;

[0113] G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain sub-olefins, C 2-14 Straight-chain ynyne group, C 3-10 Membered cycloalkylene groups and 3 to 10-membered heterocyclic groups, optionally surrounded by 1, 2, 3 or 4 R groups. G1 Substitution, and one methylene unit therein optionally and independently being replaced by M1, and one methylene unit therein optionally and independently being replaced by C. 3-10 3- to 10-membered heterocyclic alkyl groups, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0114] R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -C 3-10 cycloalkyl, -L b -3 to 10-membered heterocyclic groups, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0115] L b Independently selected from chemical bonds and C 1-14 Alkylene;

[0116] R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0117] M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, -S(O) 0-2 -、

[0118] R c Each is independently selected from H and C. 1-10 alkyl;

[0119] R5 and R6 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0120] Or CR5R6 together form C 3-14 Cycloalkylene or 3 to 14-membered heterocyclic alkylene groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0121] R 5s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0122] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0123] R dand R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0124] Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace;

[0125] n = 1, 2, 3, 4, 5 or 6;

[0126] R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ;

[0127] L f Independently selected from chemical bonds and C 1-10 Alkylene;

[0128] R f and R' f Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0129] M2 is independently selected from chemical bonds, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, and -S(O) 0-2 -;

[0130] R is independently selected from C 4-30 Alkyl, C 4-30 alkenyl and C 4-30 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups s Substitution, and optionally, one, two, three, or four methylene units are replaced independently by -NR7-, and one methylene unit is optionally, and optionally, independently, C-. 3-10 Cycloalkylene, 3 to 10-membered heterocyclic alkylene, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0131] R s Independently selected from H and C 1-30 Alkyl, L e -C 3-10 cycloalkyl, -L e -3 to 10-membered heterocyclic groups, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0132] L e Independently selected from chemical bonds and C 1-30 Alkylene;

[0133] R e and R' e Independently selected from H and C 1-30 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0134] R7 is independently H or C 1-30 alkyl;

[0135] Preferably, at most one of R1, R2, R3 and R4 is H.

[0136] In another embodiment, the present invention relates to a compound of formula (I), or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0137] in,

[0138] y is 2, 3, 4, 5, or 6;

[0139] L1 and L2 are independently selected from C 2-6 Alkylene, C 2-6 imide and C 2-6The ynyl group, which is optionally substituted with 1, 2 or 3 R*, and wherein 1, 2 or 3 methylene units are optionally and independently substituted with -O-, -S- or -NR7-;

[0140] R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -C 3-10 cycloalkyl, -L a -3 to 10-membered heterocyclic groups, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0141] L a Independently selected from chemical bonds, C 1-6 Alkylene and C 1-6 Heteroalkyl;

[0142] R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0143] R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-10 cycloalkyl, -L g -M2-3 to 10-membered heterocyclic groups, -L g -M2-C 6-10 Aryl, -L g -M2-5-10 heteroaryl groups and -G1-M2-R; where C 1-14 One, two, or three methylene units in the alkyl group may be optionally and independently replaced by -O-, -S-, or -NR7-;

[0144] L g Independent of chemical bonds or C 1-14 Alkylene, wherein one, two or three methylene units in the alkylene are optionally and independently replaced by -O-, -S- or -NR7-;

[0145] R1, R2, R3, and R4 are independently -G1-M2-R;

[0146] G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain sub-olefins, C 2-14 Straight-chain ynyne group, C3-10 Membered cycloalkylene groups and 3 to 10-membered heterocyclic groups, optionally surrounded by 1, 2, 3 or 4 R groups. G1 Substitution, and one methylene unit therein optionally and independently being replaced by M1, and one methylene unit therein optionally and independently being replaced by C. 3-10 3- to 10-membered heterocyclic alkyl groups, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0147] R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -C 3-10 cycloalkyl, -L b -3 to 10-membered heterocyclic groups, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0148] L b Independently selected from chemical bonds and C 1-14 Alkylene;

[0149] R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0150] M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, -S(O) 0-2 -、

[0151] R c Each is independently selected from H and C. 1-10 alkyl;

[0152] R5 and R6 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0153] Or CR5R6 together form C 3-14 Cycloalkylene or 3 to 14-membered heterocyclic alkylene groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0154] R 5s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0155] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0156] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0157] Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace;

[0158] n = 1, 2, 3, 4, 5 or 6;

[0159] R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ;

[0160] L f Independently selected from chemical bonds and C1-10 Alkylene;

[0161] R f and R' f Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0162] M2 is independently selected from chemical bonds, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-OC(O)S-、-OC(O)O-、-NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, and -S(O) 0-2 -;

[0163] R is independently selected from C 4-30 Alkyl, C 4-30 alkenyl and C 4-30 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups s Substitution, and optionally, one, two, three, or four methylene units are replaced independently by -NR7-, and one methylene unit is optionally, and optionally, independently, C-. 3-10 Cycloalkylene, 3 to 10-membered heterocyclic alkylene, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0164] R s Independently selected from H and C 1-30 Alkyl, L e -C 3-10 cycloalkyl, -L e -3 to 10-membered heterocyclic groups, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0165] Le Independently selected from chemical bonds and C 1-30 Alkylene;

[0166] R e and R' e Independently selected from H and C 1-30 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0167] R7 is independently H or C 1-30 alkyl.

[0168] In another embodiment, the compound of the present invention further has the structure of formula (II):

[0169] Where x is independently 1, 2 or 3;

[0170] Other variables are as defined in this invention.

[0171] In another embodiment, the compound of the present invention further has the structure of formula (IIB):

[0172] Where x is independently 1, 2 or 3;

[0173] Other variables are as defined in this invention.

[0174] In the compounds of this invention, the variables can be defined as follows.

[0175] y

[0176] In one implementation, y is 2; in another implementation, y is 3; in yet another implementation, y is 4; in yet another implementation, y is 5; in yet another implementation, y is 6.

[0177] In one more specific embodiment, y is 2, 3, 4, or 5; in another more specific embodiment, y is 3, 4, or 5; in another more specific embodiment, y is 3 or 4; in another more specific embodiment, y is 2, 3, or 4; in another more specific embodiment, y is 2 or 3.

[0178] L1 and L2

[0179] In one implementation, L1 is C 2-6 Alkylene, preferably C 2-4 Alkylene, preferably C 2-3 Alkylene, preferably C2 alkylene, for example -CH2CH2-; in another embodiment, L1 is C 2-6 Alkenyl group, preferably C 2-4Ideonyl; in another embodiment, L1 is C 2-6 Alkyne group, preferably C 2-4 The alkynyl group; in another embodiment, L1 is optionally substituted with 1, 2 or 3 R*; in another embodiment, L1 is not substituted; in another embodiment, 1, 2 or 3 methylene units in L1 are optionally and independently substituted with -O-, -S- or -NR7-; in another embodiment, 1, 2 or 3 methylene units in L1 are not substituted.

[0180] In one implementation, L2 is C 2-6 Alkylene, preferably C 2-4 Alkylene, preferably C 2-3 Alkylene, preferably C2 alkylene, for example -CH2CH2-; in another embodiment, L2 is C 2-6 Alkenyl group, preferably C 2-4 alkenyl; in another embodiment, L2 is C 2-6 Alkyne group, preferably C 2-4 In another embodiment, L2 is optionally substituted with 1, 2 or 3 R*; in another embodiment, L2 is not substituted; in another embodiment, 1, 2 or 3 methylene units in L2 are optionally and independently substituted with -O-, -S- or -NR7-; in another embodiment, 1, 2 or 3 methylene units in L2 are not substituted.

[0181] In a more specific implementation, L1 is independently selected from C 2-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group.

[0182] In a more specific implementation, L2 is independently selected from C 2-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group.

[0183] R*

[0184] In one embodiment, R* is H; in another embodiment, R* is a halogen; in yet another embodiment, R* is a cyano group; in still another embodiment, R* is C. 1-6 Alkyl; in another embodiment, R* is C 1-6 Halogenated alkyl; in another embodiment, R* is -L a -C 3-10 cycloalkyl; in another embodiment, R* is -L a -3 to 10-membered heterocyclic groups; in another embodiment, R* is -L a -ORa For example, -OR a In another implementation, R* is -L a -SR a For example, -SR a In another implementation, R* is -L a -NR a R' a For example -NR a R' a .

[0185] In a more specific embodiment, R* is independently selected from H, halogen, cyano, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a In another, more specific embodiment, R* is independently selected from H, halogen, cyano, C. 1-6 Alkyl and C 1-6 Halogenated alkyl group; in another, more specific embodiment, R* is independently selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0186] L a

[0187] In one implementation, L a For chemical bonds; in another embodiment, L a C 1-6 Alkylene, preferably C 1-4 Alkylene; in another embodiment, L a C 1-6 Heteroalkyl groups.

[0188] In a more specific implementation, L a Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L a Independently selected from chemical bonds and C 1-4 Alkylene.

[0189] R a and R' a

[0190] In one implementation, R a H; in another embodiment, R a C 1-6Alkyl; in another embodiment, R a C 3-10 cycloalkyl; in another embodiment, R a C 3-7 cycloalkyl; in another embodiment, R a It is a 3- to 10-membered heterocyclic group; in another embodiment, R a It consists of 3 to 7-membered heterocyclic groups.

[0191] In one implementation, R' a H; in another embodiment, R' a C 1-6 Alkyl; in another embodiment, R' a C 3-10 cycloalkyl; in another embodiment, R' a C 3-7 cycloalkyl; in another embodiment, R' a It is a 3- to 10-membered heterocyclic group; in another embodiment, R' a It consists of 3 to 7-membered heterocyclic groups.

[0192] In a more specific implementation, R a Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R a Independently selected from H and C 1-6 alkyl.

[0193] In a more specific implementation, R' a Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R' a Independently selected from H and C 1-6 alkyl.

[0194] R8

[0195] In one implementation, R8 is H; in another implementation, R8 is C. 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl; in another embodiment, R8 is -L g -M2-C 3-10 cycloalkyl; in another embodiment, R8 is -L g -M2-3 to 10-membered heterocyclic groups; in another embodiment, R8 is -L g -M2-C6-10 Aryl, preferably -L g -M2-phenyl; in another embodiment, R8 is -L g -M2-5-10 heteroaryl group, preferably L g -M2-5-6 heteroaryl; in another embodiment, R8 is -G1-M2-R, for example In another implementation, at most one R8 is -G1-M2-R, for example In another embodiment, when R8 is an alkyl group, one, two, or three methylene units therein are optionally and independently replaced by -O-, -S-, or -NR7-; in another embodiment, when R8 is an alkyl group, one, two, or three methylene units therein are not replaced.

[0196] In a more specific implementation, R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-7 cycloalkyl, -L g -M2-3 to 7-membered heterocyclic groups, -L g -M2-phenyl and -L g -M2-5-6 heteroaryl; in another more specific embodiment, R8 is independently H or C. 1-14 Alkyl; in another, more specific embodiment, R8 is independently H or C. 1- 10 Alkyl; in another, more specific embodiment, R8 is independently H or C. 1-6 Alkyl; in another, more specific embodiment, R8 is independently H or C. 1-3 alkyl.

[0197] In a more specific implementation, R8 is independently selected from H and C. 1-6 Alkyl group and -G1-M2-R; in another more specific embodiment, R8 is independently selected from H, C 1-6 Alkyl and In another, more specific implementation, R8 is independently selected from H and C. 1-3 Alkyl; in another, more specific embodiment, R8 is independently selected from H and

[0198] L g

[0199] In one implementation, L g For chemical bonds; in another embodiment, L g C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6Alkylene, preferably C 1-3 Alkylene; in another embodiment, L g When it is an alkylene group, one, two, or three methylene units are optionally and independently replaced by -O-, -S-, or -NR7-; in another embodiment, L g When it is an alkylene group, one, two, or three methylene units are not replaced.

[0200] In a more specific implementation, L g Independent of chemical bonds or C 1-10 Alkylene; in another, more specific embodiment, L g Independently H or C 1-6 Alkylene; in another, more specific embodiment, L g Independently H or C 1-3 Alkylene.

[0201] R1, R2, R3 and R4

[0202] In one implementation, R1 is -G1-M2-R; in another implementation, R1 is... In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is H.

[0203] In one implementation, R2 is -G1-M2-R; in another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is H.

[0204] In one implementation, R3 is -G1-M2-R; in another implementation, R3 is In another implementation, R3 is In another implementation, R3 is In another implementation, R3 is In another implementation, R3 is H.

[0205] In one implementation, R4 is -G1-M2-R; in another implementation, R4 is In another implementation, R4 is In another implementation, R4 is In another implementation, R4 is In another implementation, R4 is H.

[0206] In a more specific implementation, at least one of R1, R2, R3, and R4 is -G1-M2-R, for example... For example For example For example, In another, more specific implementation, at most one of R1, R2, R3, and R4 is H.

[0207] In one more specific implementation, R2, R3, and R4 are the same; in another more specific implementation, R1, R2, R3, and R4 are the same.

[0208] In a more specific implementation, R1, R2, R3, and R4 are independently...

[0209] In a more specific implementation, R2, R3, and R4 are the same, and R1 is...

[0210] In a more specific implementation, R1 is R2, R3, and R4 are independent

[0211] In a more specific implementation, R1 is R2, R3, and R4 are independent

[0212] In a more specific implementation, R1 is selected from H, R2, R3, and R4 are independent

[0213] G1

[0214] In one implementation, G1 is C 2-14 Straight-chain alkylene, preferably C 2-10 Straight-chain alkylene, preferably C 2-8 Straight-chain alkylene, preferably C 2-7 Straight-chain alkylene, preferably C 4-7 Straight-chain alkylene, preferably C 4-7 Straight-chain alkylene, preferably C 5-7 Straight-chain alkylene, preferably C6 straight-chain alkylene; in another embodiment, G1 is C6. 2-14 Straight-chain alkenyl groups, preferably C 2-10 Straight-chain alkenyl groups, preferably C 2-8 Straight-chain alkenyl group; in another embodiment, G1 is C 2-14Straight-chain acetylenic groups, preferably C 2-10 Straight-chain acetylenic groups, preferably C 2-8 Straight-chain ynyne group; in another embodiment, G1 is C 3-10 In another embodiment, G1 is a 3- to 10-membered heterocyclic group; in yet another embodiment, G1 is optionally surrounded by 1, 2, 3, or 4 (preferably 1 or 2) R groups. G1 In another embodiment, G1 is not substituted; in another embodiment, one methylene unit in G1 is optionally and independently replaced by M1; in another embodiment, the methylene unit in G1 is not replaced by M1; in another embodiment, one methylene unit in G1 is optionally and independently replaced by C 3-10 3- to 10-membered heterocyclic alkyl groups, C 6-10 The methylene unit in G1 is replaced by an arylene or a 5-10-membered heteroarylene; in another embodiment, the methylene unit in G1 is not replaced by a cycloalkyl, heterocyclic, arylene, or heteroarylene; in another embodiment, the methylene unit in G1 is not replaced.

[0215] In a more specific implementation, G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain alkenyl groups and C 2-14 Straight-chain ynylene group; in another, more specific embodiment, G1 is independently selected from C 2-10 straight-chain alkylene, C 2- 10 Straight-chain alkenyl groups and C 2-10 Straight-chain ynylene group; in another, more specific embodiment, G1 is independently selected from C 2-8 straight-chain alkylene, C 2-8 Straight-chain alkenyl groups and C 2-8 Straight-chain acetylenic group.

[0216] In a more specific implementation, when y is 2, G1 is not -CH2CH2-.

[0217] In a more specific implementation, when y is 2, one methylene unit in G1 is replaced by M1.

[0218] R G1

[0219] In one implementation, R G1 H; in another embodiment, R G1 It is a halogen; in another embodiment, R G1 C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3Alkyl, preferably C 1-2 Alkyl; in another embodiment, R G1 -L b -C 3-10 cycloalkyl; in another embodiment, R G1 -L b -3 to 10-membered heterocyclic groups; in another embodiment, R G1 -L b -OR b For example, -OR b For example, -OH; in another embodiment, R G1 -L b -SR b For example, -SR b In another implementation, R G1 -L b -NR b R' b For example -NR b R' b .

[0220] In a more specific implementation, R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b In another, more specific implementation, R G1 Independently selected from H and C 1-10 Alkyl (preferably C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl), -OR b and -NR b R' b H and -OR are preferred. b (e.g., -OH).

[0221] L b

[0222] In one implementation, Lb For chemical bonds; in another embodiment, L b C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0223] In a more specific implementation, L b Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L b Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L b Independently selected from chemical bonds and C 1-4 Alkylene.

[0224] R b and R' b

[0225] In one implementation, R b H; in another embodiment, R b C 1-14 Alkyl; in another embodiment, R b C 1-10 Alkyl; in another embodiment, R b C 1-6 Alkyl; in another embodiment, R b C 3-14 cycloalkyl; in another embodiment, R b C 3-10 cycloalkyl; in another embodiment, R b C 3-7 cycloalkyl; in another embodiment, R b It is a 3- to 14-membered heterocyclic group; in another embodiment, R b It is a 3- to 10-membered heterocyclic group; in another embodiment, R b It consists of 3 to 7-membered heterocyclic groups.

[0226] In one implementation, R' b H; in another embodiment, R' b C 1-14 Alkyl; in another embodiment, R' b C 1-10 Alkyl; in another embodiment, R' b C 1-6 Alkyl; in another embodiment, R' b C 3-14cycloalkyl; in another embodiment, R' b C 3-10 cycloalkyl; in another embodiment, R' b C 3-7 cycloalkyl; in another embodiment, R' b It is a 3- to 14-membered heterocyclic group; in another embodiment, R' b It is a 3- to 10-membered heterocyclic group; in another embodiment, R' b It consists of 3 to 7-membered heterocyclic groups.

[0227] In a more specific implementation, R b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R b Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R b Independently selected from H and C 1-6 alkyl.

[0228] In a more specific implementation, R' b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R' b Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R' b Independently selected from H and C 1-6 alkyl.

[0229] M1

[0230] In one embodiment, M1 is -CR5R6-, for example -CH2-, for example -C(CH3)2-; in another embodiment, M1 is -C(O)O-; in another embodiment, M1 is -OC(O)-; in another embodiment, M1 is -O-; in another embodiment, M1 is -SC(O)O-; in another embodiment, M1 is -OC(O)NR c -, for example -OC(O)NH-; in another embodiment, M1 is -NRC(O)NR c For example, --NHC(O)NH-; in another embodiment, M1 is -C(O)NR c NR cC(O)-, for example -C(O)NHNHC(O)-; in another embodiment, M1 is -OC(O)S-; in another embodiment, M1 is -OC(O)O-; in yet another embodiment, M1 is -NR c C(O)O-, for example -NHC(O)O-; in another embodiment, M1 is -SC(O)-; in another embodiment, M1 is -C(O)S-; in yet another embodiment, M1 is -NR c -; In another embodiment, M1 is -C(O)NR c -, for example -C(O)NH-; in another embodiment, M1 is -NR c C(O)-, for example -NHC(O)-; in another embodiment, M1 is -NR c C(O)S-, for example -NHC(O)S-; in another embodiment, M1 is -SC(O)NR c -, for example -SC(O)NH-, for example; in another embodiment, M1 is -C(O)-; in another embodiment, M1 is -OC(S)-; in another embodiment, M1 is -C(S)O-; in another embodiment, M1 is -OC(S)NR c -; In another implementation, M1 is -NR c C(S)O-; in another embodiment, M1 is -SS-; in yet another embodiment, M1 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-; in another embodiment, M1 is In another implementation, M1 is

[0231] In a more specific embodiment, M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -C(O)NHNHC(O)-, -OC(O)S-, -OC(O)O-, -NHC(O)O-, -SC(O)-, -C(O)S-, -C(O)NH-, -NHC(O)-, -NHC(O)S-, -SC(O)NH-, In another, more specific embodiment, M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -C(O)NHNHC(O)-, -OC(O)O-, -SC(O-), -C(O)S-, -C(O)NH-, -NHC(O-)- and In another, more specific embodiment, M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -C(O)NHNHC(O)-, -C(O)NH- and

[0232] R c

[0233] In one implementation, R c H; in another embodiment, R c C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 alkyl.

[0234] In a more specific implementation, R c Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R c Independently selected from H and C 1-3 alkyl.

[0235] R5 and R6

[0236] In one implementation, R5 is H; in another implementation, R5 is C. 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl, preferably methyl; in another embodiment, R5 is optionally surrounded by 1, 2, 3 or 4 (preferably 1 or 2) R 5s In another implementation, R5 is not replaced.

[0237] In one implementation, R6 is H; in another implementation, R6 is C. 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl, preferably methyl; in another embodiment, R6 is optionally surrounded by 1, 2, 3 or 4 (preferably 1 or 2) R 5s In another embodiment, R6 is not replaced.

[0238] In one implementation, CR5R6 together form C 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C 3-6 Cycloalkylene compounds (e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene), preferably forming C 3-5 Cycloalkylene, preferably forming cyclopentylene, preferably forming C 3-4Cycloalkylene, preferably forming a cyclopropylene group; in another embodiment, CR5R6 together form a 3 to 14-membered heterocyclic group, preferably a 3 to 10-membered heterocyclic group, and more preferably a 3 to 6-membered heterocyclic group; in another embodiment, the ring formed by CR5R6 together is optionally separated by one or more R... 4s Replacement; in another embodiment, the ring formed together by CR5R6 is optionally replaced by 1, 2, 3 or 4 (preferably 1 or 2) R 5s In one embodiment, the ring formed together with CR5R6 is not replaced; in another embodiment, CR5R6 does not form a ring together.

[0239] In a more specific implementation, R5 is independently selected from H and C. 1-6 Alkyl group; in another, more specific embodiment, R5 is independently selected from H and C. 1-3 Alkyl group; in another, more specific embodiment, R5 is independently selected from H and C. 1-2 Alkyl; in another, more specific embodiment, R5 is independently selected from H and methyl.

[0240] In a more specific implementation, R6 is independently selected from H and C. 1-6 Alkyl group; in another, more specific embodiment, R6 is independently selected from H and C. 1-3 Alkyl group; in another, more specific embodiment, R6 is independently selected from H and C. 1-2 Alkyl; in another, more specific embodiment, R6 is independently selected from H and methyl.

[0241] In a more specific embodiment, CR5R6 optionally form C together. 3-10 Cycloalkylene or 3 to 10-membered heterocyclic cycloalkylene; in another more specific embodiment, CR5R6 optionally forms C together. 3-6 Cycloalkylene or 3 to 6-membered heterocyclic cycloalkylene; in another more specific embodiment, CR5R6 optionally forms C together. 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); in another, more specific embodiment, CR5R6 optionally forms C together. 3-5 Cycloalkylene; in another more specific embodiment, CR5R6 optionally forms cyclopropylene or cyclopentylene together; in another more specific embodiment, CR5R6 optionally forms C 3-4 Cycloalkylene; in another, more specific embodiment, CR5R6 optionally forms a cyclopropylene group together.

[0242] R 5s

[0243] In one implementation, R5s H; in another embodiment, R 5s It is a halogen; in another embodiment, R 5s It is cyano; in another embodiment, R 5s C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl; in another embodiment, R 5s C 1-8 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-3 Halogenated alkyl; in another embodiment, R 5s -L d -OR d In another implementation, R 5s -L d -SR d In another implementation, R 5s -L d -NR d R' d .

[0244] In a more specific implementation, R 5s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d In another, more specific implementation, R 5s Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another, more specific embodiment, R 5s Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0245] L d R d and R' d

[0246] In one implementation, L d For chemical bonds; in another embodiment, L d C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene.

[0247] In a more specific implementation, L d Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L d Independently selected from chemical bonds and C 1-3 Alkylene.

[0248] In one implementation, R d H; in another embodiment, R d C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl; in another embodiment, R d C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0249] In one implementation, R' d H; in another embodiment, R' d C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl; in another embodiment, R' d C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0250] In a more specific implementation, R d Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R d Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R d Independently selected from H and C 1-3 alkyl.

[0251] In a more specific implementation, R' d Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R' d Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R'd Independently selected from H and C 1-3 alkyl.

[0252] Ring A

[0253] In one implementation, ring A is C. 3-10 Cycloalkylene; in another embodiment, ring A is a 3- to 10-membered heterocyclic alkylene group; in another embodiment, ring A is a C 3-7 Cycloalkylene; in another embodiment, ring A is a 3- to 7-membered heterocyclic group; in another embodiment, ring A is a 3- to 7-membered nitride heterocyclic group, preferably with a N atom as a linking end, preferably with the N atom attached to -C(O)- or the head end; in another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another implementation, ring A is optionally divided by n R A Replacement; in another embodiment, ring A is not replaced.

[0254] In a more specific implementation, ring A is independently C. 3-7 Cycloalkyl or 3 to 7-membered heterocyclic groups.

[0255] In a more specific implementation, ring A is independently selected from...

[0256] n

[0257] In one implementation, n is 1; in another implementation, n is 2; in another implementation, n is 3; in another implementation, n is 4; in another implementation, n is 5; in another implementation, n is 6.

[0258] In one more specific embodiment, n = 1, 2, 3, 4, 5, or 6; in another more specific embodiment, n = 1, 2, 3, 4, or 5; in another more specific embodiment, n = 1, 2, 3, or 4; in another more specific embodiment, n = 1 or 2; in another more specific embodiment, n = 1.

[0259] R A

[0260] In one implementation, R AH; in another embodiment, R A For oxidation (=O); in another embodiment, R A It is cyano; in another embodiment, R A It is a halogen; in another embodiment, R A C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R A C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl; in another embodiment, R A -L f -OR f For example, -CH2-OR f For example, -OR f In another implementation, R A -L f -SR f For example, -SR f In another implementation, R A -L f -NR f R' f For example, -CH2-NR f R' f For example, -CH2NH2, for example, -NR f R' f .

[0261] In a more specific implementation, R A Independently selected from H, cyano, halogen, oxo, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f In another, more specific implementation, R A Independently selected from H, cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f In another, more specific implementation, R A Independently selected from H, halogen, oxo, C1-6 Alkyl, C 1- 6-Hydroalkyl, -L f -OR f -L f -SR f and -L f -NR f R' f In another, more specific implementation, R A Independently selected from H, halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f and -L f -NR f R' f In another, more specific implementation, R A Independently selected from H, oxo, -L f -OR f and -L f -NR f R' f .

[0262] In one implementation, L f For chemical bonds; in another embodiment, L f C 1-10 Alkylene; in another embodiment, L f C 1-6 Alkylene; in another embodiment, L f C 1-4 Alkylene.

[0263] In a more specific implementation, L f Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L f Independently selected from chemical bonds and C 1-4 Alkylene.

[0264] R f and R' f

[0265] In one implementation, R f H; in another embodiment, R f C 1-10 Alkyl, such as C 1-6 Alkyl; in another embodiment, R f C 1-10 Haloalkyl, such as C 1-6 Halogenated alkyl; in another embodiment, R f C3-10 cycloalkyl, such as C 3-7 cycloalkyl; in another embodiment, R f It is a 3- to 10-membered heterocyclic group, such as a 3- to 7-membered heterocyclic group.

[0266] In one implementation, R' f H; in another embodiment, R' f C 1-10 Alkyl, such as C 1-6 Alkyl; in another embodiment, R' f C 1-10 Haloalkyl, such as C 1-6 Halogenated alkyl; in another embodiment, R' f C 3-10 cycloalkyl, such as C 3-7 cycloalkyl; in another embodiment, R' f It is a 3- to 10-membered heterocyclic group, such as a 3- to 7-membered heterocyclic group.

[0267] In a more specific implementation, R f Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R f Independently selected from H and C 1-6 Alkyl and C 1- 6-Hydroalkyl group.

[0268] In a more specific implementation, R' f Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R' f Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0269] M2

[0270] In one embodiment, M2 is a chemical bond; in another embodiment, M2 is -C(O)O-; in another embodiment, M2 is -OC(O)-; in another embodiment, M2 is -O-; in another embodiment, M2 is -SC(O)O-; in another embodiment, M2 is -OC(O)NR c -, for example -OC(O)NH-; in another embodiment, M2 is -NRC(O)NR c-, for example, --NHC(O)NH-; in another embodiment, M2 is -C(O)NR c NR c C(O)-; in another embodiment, M2 is -OC(O)S-; in another embodiment, M2 is -OC(O)O-; in another embodiment, M2 is -NR c C(O)O-, for example -NHC(O)O-; in another embodiment, M2 is -SC(O)-; in another embodiment, M2 is -C(O)S-; in yet another embodiment, M2 is -NR c -; In another embodiment, M2 is -C(O)NR c -, for example -C(O)NH-; in another embodiment, M2 is -NR c C(O)-, for example -NHC(O)-; in another embodiment, M2 is -NR c C(O)S-, for example -NHC(O)S-; in another embodiment, M2 is -SC(O)NR c -, for example -SC(O)NH-; in another embodiment, M2 is -C(O)-; in another embodiment, M2 is -OC(S)-; in another embodiment, M2 is -C(S)O-; in another embodiment, M2 is -OC(S)NR c -; In another implementation, M2 is -NR c C(S)O-; in another embodiment, M2 is -SS-; in yet another embodiment, M2 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0271] In one more specific embodiment, M2 is independently selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NH-, and -NHC(O)-; in another more specific embodiment, M2 is independently selected from -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O-, and -C(O)S-; in another more specific embodiment, M2 is independently selected from -C(O)O-, -OC(O)-, -SC(O-, and -C(O)S-; in another more specific embodiment, M2 is independently selected from -C(O)O- and -OC(O)-; in another more specific embodiment, M2 is independently selected from -C(O)O-, -OC(O-, and -C(O)NH-.

[0272] R and R'

[0273] In one implementation, R is C 4-30 Alkyl, preferably C 4-25 Alkyl, preferably C 4-20 Alkyl, preferably C 4-15 Alkyl, preferably C 6-15 Alkyl, preferably C 8-15 Alkyl, preferably C 4-14 Alkyl, preferably C 6-14 Alkyl, preferably C 6-12 Alkyl, preferably C 8-12 Alkyl, preferably C 10-12 Alkyl, preferably C 8-11 Alkyl, preferably C 8-10 Alkyl, preferably C 6-9 Alkyl, preferably C 4-8 Alkyl groups, preferably C6 alkyl groups, preferably C8 alkyl groups, preferably C9 alkyl groups, preferably C 10 Alkyl; in another embodiment, R is C 4-30 Alkenyl, preferably C 4-25 Alkenyl, preferably C 4-20 Alkenyl, preferably C 6-15 Alkenyl, preferably C 8-15 Alkenyl, preferably C 4-15 Alkenyl, preferably C 15 Alkenyl, preferably C 4-14 Alkenyl, preferably C 6-14 Alkenyl, preferably C 6-12 Alkenyl, preferably C 8-12 Alkenyl, preferably C 10-12 Alkenyl, preferably C 8-10 Alkenyl, preferably C 10 Alkenyl, preferably C9 alkenyl; in another embodiment, R is C 4-30 Alkyne group, preferably C 4-25 Alkyne group, preferably C 4-20 Alkyne group, preferably C 6-15 Alkyne group, preferably C 8-15 Alkyne group, preferably C 4-15 Alkyne group, preferably C 4-14 Alkyne group, preferably C 6-14 Alkyne group, preferably C 6-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R is optionally surrounded by 1, 2, 3 or 4 (preferably 1 or 2, preferably 1) R groups. sIn another embodiment, the methylene unit in R is not substituted; in another embodiment, 1, 2, 3, or 4 (preferably 1 or 2, preferably 1) methylene units in R are optionally and independently replaced by -NR7-; in another embodiment, the methylene unit in R is not replaced by -NR7-; in another embodiment, 1 methylene unit in R is optionally and independently replaced by C 3-10 Cycloalkylene, 3 to 10-membered heterocyclic alkylene, C 6-10 In another embodiment, the methylene unit in R is not replaced by a cycloalkyl, heterocyclic, aryl, or heteroaryl group; in another embodiment, the methylene unit in R is not replaced.

[0274] In one embodiment, R is -(CH2)5CH3; in another embodiment, R is -(CH2)6CH3; in another embodiment, R is -(CH2)7CH3; in another embodiment, R is -(CH2)8CH3; in another embodiment, R is -(CH2)9CH3; in yet another embodiment, R is -(CH2) 10 CH3; in another embodiment, R is -(CH2). 11 CH3; in another embodiment, R is -(CH2). 12 CH3; in another embodiment, R is -(CH2). 13 CH3; in another embodiment, R is -(CH2). 14 CH3; in another embodiment, R is -(CH2)3-CH=CH-(CH2)4CH3; in another embodiment, R is -(CH2)4-CH=CH-CH2CH3; in another embodiment, R is -CH=CH-(CH2)9CH3; in another embodiment, R is In another implementation, R is In another implementation, R is In another implementation, R is In another implementation, R is In another implementation, R is In another implementation, R is In another implementation, R is In another implementation, R is In another implementation, R is Preferred In another implementation, R is Preferred In another implementation, R is Preferred Preferred In another implementation, R is Preferred In another implementation, R is Preferred

[0275] In a more specific implementation, R is independently selected from C. 4-25 Alkyl, C 4-25 alkenyl and C 4-25 Alkyne group; in another, more specific embodiment, R is independently selected from C. 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group; in another, more specific embodiment, R is independently selected from C. 4-15 Alkyl, C 4-15 alkenyl and C 4-15 Alkyne group; in another, more specific embodiment, R is independently selected from C. 6-15 Alkyl, C 6-15 alkenyl and C 6-15 Alkyne group; in another, more specific embodiment, R is independently selected from C. 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group; in another, more specific embodiment, R is independently selected from C. 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group; in another, more specific embodiment, R is independently selected from C. 8-15 Alkyl and C 8-15 Alkenyl; in another, more specific embodiment, R is independently selected from C. 8-12 Alkyl and C 8-12 Alkenyl; in another, more specific embodiment, R is independently selected from C. 10-12 Alkyl and C 10-12 Alkenyl; in another, more specific embodiment, R is independently selected from C. 10-12 Alkyl (preferably C) 10 alkyl) and C 10 Alkenyl group.

[0276] In a more specific implementation, R is independently selected from C. 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group; in another, more specific embodiment, R is independently selected from C. 4-14 Alkyl, C 4-14 alkenyl and C 4-14Alkyne group; in another, more specific embodiment, R is independently selected from C. 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group.

[0277] In a more specific implementation, R is independently selected from C. 10-12 Alkyl and C 15 Alkenyl, preferably C 10-12 Alkyl; preferably C 8-10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C9 alkenyl.

[0278] In a more specific embodiment, R is independently selected from -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 12 CH3, -(CH2) 13 CH3, -(CH2) 14 CH3, -(CH2)3-CH=CH-(CH2)4CH3, -(CH2)4-CH=CH-CH2CH3, -CH=CH-(CH2)9CH3, In another, more specific embodiment, R is independently selected from -(CH2)5CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, In another, more specific embodiment, R is independently selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3,

[0279] In a more specific embodiment, R is independently selected from -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2) 10 CH3, -(CH2)11 CH3, -(CH2) 12 CH3, -(CH2) 13 CH3, -(CH2) 14 CH3, In another, more specific embodiment, R is independently selected from -(CH2)5CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, In another, more specific embodiment, R is independently selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3,

[0280] In a more specific embodiment, R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3, In another, more specific embodiment, R is independently selected from -(CH2)9CH3, -(CH2) 11 CH3, (Preferred) In another, more specific embodiment, R is independently selected from -(CH2)9CH3, (Preferred) ), In another, more specific embodiment, R is independently selected from; in another, more specific embodiment, R is independently selected from -(CH2)8CH3, -(CH2)9CH3, -(CH2) 11 CH3, -(CH2) 14 CH3,

[0281] In one implementation, R' is defined as R.

[0282] In one embodiment, R' is -(CH2)7CH3; in another embodiment, R' is -(CH2)9CH3.

[0283] In a more specific implementation, R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3.

[0284] R s

[0285] In one implementation, R s H; in another embodiment, R s C 1-30 Alkyl, preferably C 1-25 Alkyl, preferably C 1-20 Alkyl, preferably C 1-15 Alkyl, preferably C 1-14 Alkyl, preferably C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R s For L e -C 3-10 cycloalkyl; in another embodiment, R s -L e -3 to 10-membered heterocyclic groups; in another embodiment, R s -L e -OR e In another implementation, R s -L e -SR e In another implementation, R s -L e -NR e R' e .

[0286] In a more specific implementation, R s Independently selected from H and C 1-25 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e In another, more specific implementation, R s Independently selected from H and C 1-20 Alkyl, -L e -OR e and -L e -NR e R' e In another, more specific implementation, R s Independently selected from H and C1-15 Alkyl, -L e -OR e and -L e -NR e R' e In another, more specific implementation, R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e .

[0287] In one implementation, R s The substitution site on R is separated from M2 by 0 carbon atoms; in another embodiment, R s The substitution site on R is separated from M2 by one carbon atom; in another embodiment, R s The substitution site on R is separated from M2 by two carbon atoms; in another embodiment, R s The substitution site on R is separated from M2 by three carbon atoms; in another embodiment, R s The substitution site on R is spaced 4 carbon atoms apart from M2; in another embodiment, R s The substitution site on R is spaced 5 carbon atoms away from M2; in another embodiment, R s The substitution site on R is separated from M2 by 6 carbon atoms; in another embodiment, R s The substitution site on R is spaced 7 carbon atoms apart from M2; in another embodiment, R s The substitution site on R is spaced 8 carbon atoms away from M2; in another embodiment, R s The substitution site on R is spaced 9 carbon atoms apart from M2; in another embodiment, R s The substitution site on R is spaced 10 carbon atoms away from M2; in another embodiment, R s The substitution site on R is spaced 11 carbon atoms away from M2; in another embodiment, R s The substitution site on R is separated from M2 by 12 carbon atoms.

[0288] In a more specific implementation, R s The substitution site on R is spaced 0-12 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R is spaced 0-10 carbon atoms from M2; in another more specific embodiment, R sThe substitution site on R is spaced 0-6 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R is spaced 0-4 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R is separated from M2 by at least one carbon atom; in another more specific embodiment, R s The substitution site on R is spaced 1-6 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R is spaced 1-4 carbon atoms away from M2; in another more specific embodiment, R s The substitution site on R is separated from M2 by at least two carbon atoms; in another more specific embodiment, R s The substitution site on R is spaced 2-6 carbon atoms away from M2; in another more specific embodiment, R s The substitution site on R is spaced 2-4 carbon atoms away from M2; in another more specific embodiment, R s The substitution site on R is separated from M2 by 2-3 carbon atoms.

[0289] L e

[0290] In one implementation, L e For chemical bonds; in another embodiment, L e C 1-30 Alkylene, preferably C 1-25 Alkylene, preferably C 1-20 Alkylene, preferably C 1-15 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene.

[0291] In a more specific implementation, L e Independently selected from chemical bonds and C 1-30 Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-25 Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-20 Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-15 Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-14Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-6 Alkylene.

[0292] R e and R' e

[0293] In one implementation, R e H; in another embodiment, R e C 1-30 Alkyl, preferably C 1-25 Alkyl, preferably C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R e C 3-14 cycloalkyl; in another embodiment, R e It consists of 3 to 14-membered heterocyclic groups.

[0294] In one implementation, R' e H; in another embodiment, R' e C 1-30 Alkyl, preferably C 1-25 Alkyl, preferably C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' e C 3-14 cycloalkyl; in another embodiment, R' e It consists of 3 to 14-membered heterocyclic groups.

[0295] In a more specific implementation, R e Independently selected from H and C 1-30 Alkyl; in another, more specific embodiment, R e Independently selected from H and C 1-25 Alkyl; in another, more specific embodiment, R e Independently selected from H and C 1-20 Alkyl; in another, more specific embodiment, R e Independently selected from H and C 1-15 Alkyl; in another, more specific embodiment, R e Independently selected from H and C 1-14Alkyl; in another, more specific embodiment, R e Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R e Independently selected from H and C 1-6 alkyl.

[0296] In a more specific implementation, R' e Independently selected from H and C 1-30 Alkyl; in another, more specific embodiment, R' e Independently selected from H and C 1-25 Alkyl; in another, more specific embodiment, R' e Independently selected from H and C 1-20 Alkyl; in another, more specific embodiment, R' e Independently selected from H and C 1-15 Alkyl; in another, more specific embodiment, R' e Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R' e Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R' e Independently selected from H and C 1-6 alkyl.

[0297] R7

[0298] In one implementation, R7 is H; in another implementation, R7 is C. 1-30 Alkyl, preferably C 1-25 Alkyl, C 1-20 Alkyl, preferably C 1-15 Alkyl, preferably C 1-14 Alkyl, preferably C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 alkyl.

[0299] In a more specific implementation, R7 is independently H or C. 1-25 Alkyl; in another, more specific embodiment, R7 is independently H or C. 1-20 Alkyl; in another, more specific embodiment, R7 is independently H or C. 1-15 Alkyl; in another, more specific embodiment, R7 is independently H or C. 1-14 Alkyl; in another, more specific embodiment, R7 is independently H or C. 1-12 Alkyl; in another, more specific embodiment, R7 is independently H or C. 1-10Alkyl; in another, more specific embodiment, R7 is independently H or C. 1-6 alkyl.

[0300] x

[0301] In one implementation, x is 1; in another implementation, x is 2; in yet another implementation, x is 3.

[0302] In one more specific implementation, x is independently 1, 2, or 3; in another more specific implementation, x is independently 1 or 2.

[0303] a and b

[0304] In one implementation, a is 1; in another implementation, a is 2; in another implementation, a is 3; in another implementation, a is 4; in another implementation, a is 5; in another implementation, a is 6.

[0305] In one more specific embodiment, a is independently 1, 2, 3, 4, 5, or 6; in another more specific embodiment, a is independently 1, 2, 3, 4, or 5; in another more specific embodiment, a is independently 1 or 5; in another more specific embodiment, a is independently 4, 5, or 6; in another more specific embodiment, a is independently 1, 2, or 3; in another more specific embodiment, a is independently 1, 2, 3, or 4; in another more specific embodiment, a is independently 2 or 3; in another more specific embodiment, a is independently 2, 3, 4, 5, or 6; in another more specific embodiment, a is independently 3, 4, or 5; in another more specific embodiment, a is independently 3 or 5.

[0306] In one implementation, b is 0; in another implementation, b is 1; in another implementation, b is 2; in one implementation, b is 3; in another implementation, b is 4; in another implementation, b is 5; in another implementation, b is 6.

[0307] In one more specific embodiment, b is independently 0, 1, 2, 3, 4, 5, or 6; in another more specific embodiment, b is independently 0, 1, 2, 3, or 4; in another more specific embodiment, b is independently 0, 1, 2, or 3; in another more specific embodiment, b is independently 0, 1, or 2; in another more specific embodiment, b is independently 0 or 1; in another more specific embodiment, b is independently 1, 2, or 3; in another more specific embodiment, b is independently 1 or 3.

[0308] In one more specific embodiment, b is independently 1, 2, 3, 4, 5, or 6; in another more specific embodiment, b is independently 1, 2, 3, or 4; in another more specific embodiment, b is independently 1 or 4; in another more specific embodiment, b is independently 1, 2, or 3.

[0309] In one implementation, a+b is 1; in another implementation, a+b is 2; in another implementation, a+b is 3; in another implementation, a+b is 4; in another implementation, a+b is 5; in another implementation, a+b is 6; in another implementation, a+b is 5; in another implementation, a+b is 7.

[0310] In one more specific embodiment, a+b is independently 1, 2, 3, 4, 5, 6, or 7; in another more specific embodiment, a+b is independently 5, 6, or 7; in another more specific embodiment, a+b is independently 1 or 6; in another more specific embodiment, a+b is independently 2, 3, 4, 5, 6, or 7; in another more specific embodiment, a+b is independently 3, 4, 5, 6, or 7; in another more specific embodiment, a+b is independently 3, 4, 5, or 6; in another more specific embodiment, a+b is independently 4 or 5; in another more specific embodiment, a+b is independently 4, 5, or 6; in another more specific embodiment, a+b is independently 4 or 6; in another more specific embodiment, a+b is independently 1 or 6.

[0311] In a more specific implementation, when y is 2, a+b is not 1.

[0312] 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 y can be combined with L1, L2, R*, L a R a 、R' a R8, L g R1, R2, R3, R4, G1, R G1 L b R b 、R' b M1, R c R5, R6, R 5s L d R d 、R' d Rings A, n, R A L f R f、R' f M2, R, R s L e R e 、R' e This invention relates to any combination of technical solutions such as R7, x, a, and b. The present invention aims to include combinations of all these technical solutions; however, due to space limitations, they are not listed individually.

[0313] In a more specific embodiment, the present invention provides a compound of formula (I), or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0314] in,

[0315] y is 2, 3, 4, 5, or 6;

[0316] L1 and L2 are independently selected from C 2-6 Alkylene, C 2-6 imide and C 2-6 The ynyl group, which is optionally substituted with 1, 2 or 3 R*, and wherein 1, 2 or 3 methylene units are optionally and independently substituted with -O-, -S- or -NR7-;

[0317] R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -C 3-10 cycloalkyl, -L a -3 to 10-membered heterocyclic groups, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0318] L a Independently selected from chemical bonds, C 1-6 Alkylene and C 1-6 Heteroalkyl;

[0319] R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0320] R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-10 cycloalkyl, -L g-M2-3 to 10-membered heterocyclic groups, -L g -M2-C 6-10 Aryl, -L g -M2-5-10 heteroaryl groups and -G1-M2-R; where C 1-14 One, two, or three methylene units in the alkyl group may be optionally and independently replaced by -O-, -S-, or -NR7-;

[0321] L g Independent of chemical bonds or C 1-14 Alkylene, wherein one, two or three methylene units in the alkylene are optionally and independently replaced by -O-, -S- or -NR7-;

[0322] R1, R2, R3, and R4 are independently H or -G1-M2-R; at least one of R1, R2, R3, and R4 is -G1-M2-R;

[0323] G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain sub-olefins, C 2-14 Straight-chain ynyne group, C 3-10 Membered cycloalkylene groups and 3 to 10-membered heterocyclic groups, optionally surrounded by 1, 2, 3 or 4 R groups. G1 Substitution, and one methylene unit therein optionally and independently being replaced by M1, and one methylene unit therein optionally and independently being replaced by C. 3-10 3- to 10-membered heterocyclic alkyl groups, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0324] R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -C 3-10 cycloalkyl, -L b -3 to 10-membered heterocyclic groups, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0325] L b Independently selected from chemical bonds and C 1-14 Alkylene;

[0326] R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0327] M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, -S(O) 0-2 -、

[0328] R c Each is independently selected from H and C. 1-10 alkyl;

[0329] R5 and R6 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0330] Or CR5R6 together form C 3-14 Cycloalkylene or 3 to 14-membered heterocyclic alkylene groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0331] R 5s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0332] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0333] R d and R' dIndependently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0334] Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace;

[0335] n = 1, 2, 3, 4, 5 or 6;

[0336] R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ;

[0337] L f Independently selected from chemical bonds and C 1-10 Alkylene;

[0338] R f and R' f Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0339] M2 is independently selected from chemical bonds, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, and -S(O) 0-2 -;

[0340] R is independently selected from C 4-30 Alkyl, C 4-30 alkenyl and C 4-30 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups s Substitution, and optionally, one, two, three, or four methylene units are replaced independently by -NR7-, and one methylene unit is optionally, and optionally, independently, C-. 3-10 Cycloalkylene, 3 to 10-membered heterocyclic alkylene, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0341] R s Independently selected from H and C 1-30 Alkyl, L e -C 3-10 cycloalkyl, -L e -3 to 10-membered heterocyclic groups, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0342] L e Independently selected from chemical bonds and C 1-30 Alkylene;

[0343] R e and R' e Independently selected from H and C 1-30 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0344] R7 is independently H or C 1-30 alkyl;

[0345] Preferably, at most one of R1, R2, R3 and R4 is H.

[0346] In a more specific embodiment, the present invention provides a compound of formula (I), or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0347] in,

[0348] y is 2, 3, 4, 5, or 6;

[0349] L1 and L2 are independently selected from C 2-6 Alkylene, C 2-6 imide and C 2-6The ynyl group, which is optionally substituted with 1, 2 or 3 R*, and wherein 1, 2 or 3 methylene units are optionally and independently substituted with -O-, -S- or -NR7-;

[0350] R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -C 3-10 cycloalkyl, -L a -3 to 10-membered heterocyclic groups, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0351] L a Independently selected from chemical bonds, C 1-6 Alkylene and C 1-6 Heteroalkyl;

[0352] R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0353] R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-10 cycloalkyl, -L g -M2-3 to 10-membered heterocyclic groups, -L g -M2-C 6-10 Aryl, -L g -M2-5-10 heteroaryl groups and -G1-M2-R; where C 1-14 One, two, or three methylene units in the alkyl group may be optionally and independently replaced by -O-, -S-, or -NR7-;

[0354] L g Independent of chemical bonds or C 1-14 Alkylene, wherein one, two or three methylene units in the alkylene are optionally and independently replaced by -O-, -S- or -NR7-;

[0355] R1, R2, R3, and R4 are independently -G1-M2-R;

[0356] G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain sub-olefins, C 2-14 Straight-chain ynyne group, C3-10 Membered cycloalkylene groups and 3 to 10-membered heterocyclic groups, optionally surrounded by 1, 2, 3 or 4 R groups. G1 Substitution, and one methylene unit therein optionally and independently being replaced by M1, and one methylene unit therein optionally and independently being replaced by C. 3-10 3- to 10-membered heterocyclic alkyl groups, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0357] R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -C 3-10 cycloalkyl, -L b -3 to 10-membered heterocyclic groups, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0358] L b Independently selected from chemical bonds and C 1-14 Alkylene;

[0359] R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0360] M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, -S(O) 0-2 -、

[0361] R c Each is independently selected from H and C. 1-10 alkyl;

[0362] R5 and R6 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0363] Or CR5R6 together form C 3-14 Cycloalkylene or 3 to 14-membered heterocyclic alkylene groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace;

[0364] R 5s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0365] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0366] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0367] Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace;

[0368] n = 1, 2, 3, 4, 5 or 6;

[0369] R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ;

[0370] L f Independently selected from chemical bonds and C1-10 Alkylene;

[0371] R f and R' f Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0372] M2 is independently selected from chemical bonds, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-OC(O)S-、-OC(O)O-、-NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, and -S(O) 0-2 -;

[0373] R is independently selected from C 4-30 Alkyl, C 4-30 alkenyl and C 4-30 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups s Substitution, and optionally, one, two, three, or four methylene units are replaced independently by -NR7-, and one methylene unit is optionally, and optionally, independently, C-. 3-10 Cycloalkylene, 3 to 10-membered heterocyclic alkylene, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions;

[0374] R s Independently selected from H and C 1-30 Alkyl, L e -C 3-10 cycloalkyl, -L e -3 to 10-membered heterocyclic groups, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0375] Le Independently selected from chemical bonds and C 1-30 Alkylene;

[0376] R e and R' e Independently selected from H and C 1-30 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0377] R7 is independently H or C 1-30 alkyl.

[0378] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein y is 2, 3, 4 or 5, preferably 3, 4 or 5, preferably 3 or 4; preferably 3, preferably 4; preferably 2, 3 or 4, preferably 2 or 3;

[0379] Preferably, R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-7 cycloalkyl, -L g -M2-3 to 7-membered heterocyclic groups, -L g -M2-phenyl and -L g -M2-5-6 heteroaryl; preferably H or C 1-14 Alkyl groups, preferably H or C 1-10 Alkyl groups, preferably H or C 1-6 Alkyl groups, preferably H or C 1-3 alkyl;

[0380] Preferably, R8 is independently selected from H and C. 1-6 Alkyl groups and -G1-M2-R; preferably, at most one R8 is -G1-M2-R;

[0381] Preferably, L g Independent of chemical bonds or C 1-10 Alkylene, preferably H or C 1-6 Alkylene, preferably H or C 1-3 Alkylene.

[0382] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L1 and L2 are independently selected from C 2-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; preferably C 2-3 Alkylene; preferably C2 alkylene, for example -CH2CH2-.

[0383] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a Preferred components include H, halogens, cyano groups, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H or C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0384] Preferably, L a Independently selected from chemical bonds, C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0385] Preferably, R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

[0386] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R2, R3 and R4 are the same or R1, R2, R3 and R4 are the same.

[0387] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain alkenyl groups and C 2-14 Straight-chain acetylenic group; preferably C 2-10 straight-chain alkylene, C 2-10 Straight-chain alkenyl groups and C 2-10 Straight-chain acetylenic group; preferably C 2-8 straight-chain alkylene, C 2-8 Straight-chain alkenyl groups and C 2-8 Straight-chain acetylenic group; preferably C 2-10 Straight-chain alkylene, preferably C 2-8 Straight-chain alkylene, preferably C 2-7 Straight-chain alkylene, preferably C 4-7Straight-chain alkylene, preferably C 4-7 Straight-chain alkylene, preferably C 5-7 Straight-chain alkylene, preferably C6 straight-chain alkylene;

[0388] Preferably, G1 is optionally divided by one or two Rs. G1 replace;

[0389] Preferably, when y is 2, G1 is not -CH2CH2-;

[0390] Preferably, when y is 2, one methylene unit in G1 is replaced by M1.

[0391] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl), -OR b and -NR b R' b H and -OR are preferred. b (e.g., -OH);

[0392] Preferably, L b Independently selected from chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0393] Preferably, R b and R' b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

[0394] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -C(O)NHNHC(O)-, -OC(O)S-, -OC(O)O-, -NHC(O)O-, -SC(O-, -C(O)S-, -C(O)NH-, -NHC(O-, -NHC(O)S-, -SC(O)NH-, Preferred chromatograms include -CR5R6-, -C(O)O-, -OC(O)-, -C(O)NHNHC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NH-, and -NHC(O)-. Preferred chromatograms include -CR5R6-, -C(O)O-, -OC(O)-, -C(O)NHNHC(O)-, and -C(O)NH-.

[0395] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are independently selected from H and C. 1-6 Alkyl groups; preferably H and C 1-3 Alkyl groups; preferably H and C 1-2 Alkyl; preferably H and methyl;

[0396] Preferably, R5 and R6 are optionally separated by one or two R 5s replace;

[0397] Preferably, CR5R6 are optionally formed together to form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene; preferably C 3-6 Cycloalkylene or 3- to 6-membered heterocyclic alkylene; preferably C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably C 3-4 Cycloalkylene; preferably cyclopropylene;

[0398] Preferably, the ring formed by CR5R6 is optionally surrounded by one or two R... 5s replace.

[0399] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 5s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d Preferred components include H, halogens, cyano groups, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H or C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0400] Preferably, L d Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-3 Alkylene;

[0401] Preferably, R d and R' d Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl groups; preferably H and C 1-3 alkyl.

[0402] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic cycloalkylene groups;

[0403] Preferably, ring A is a 3- to 7-membered sub-heterocyclic group, more preferably a 3- to 7-membered nitride-like heterocyclic group, preferably with the N atom as the linking end, and preferably with the N atom connected to -C(O)- or the head end, for example... Preferred More

[0404] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n = 1, 2, 3, 4 or 5; preferably n = 1, 2, 3 or 4; preferably n = 1 or 2; preferably n = 1.

[0405] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R A Independently selected from H, cyano, halogen, oxo, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f Preferred groups include H, cyano, halogen, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f Preferred elements include H, halogens, oxidants, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f Preferred elements include H, halogens, oxidants, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f and -L f -NR f R' f Preferred H, oxidized, -L f -OR f and -L f -NR f R' f .

[0406] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L f Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0407] Preferably, R f and R' f Independently selected from H and C 1-6 Alkyl, C1-6 Haloalkyl, C 3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0408] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein M2 is independently selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NH- and -NHC(O)-, preferably -C(O)O-, -OC(O)O-, -OC(O-, -SC(O- and -C(O)S-, preferably -C(O)O-, -OC(O-, -SC(O- and -C(O)S-, preferably -C(O)O- and -OC(O-), preferably -OC(O-, preferably -C(O)O-;

[0409] Preferably, M2 is independently selected from -C(O)O-, -OC(O)- and -C(O)NH-.

[0410] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from C. 4-25 Alkyl, C 4-25 alkenyl and C 4-25 Alkyne group, preferably C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 4-15 Alkyl, C 4-15 alkenyl and C 4-15 Alkyne group, preferably C 6-15 Alkyl, C 6-15 alkenyl and C 6-15 Alkyne group, preferably C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group; preferably C 8-15 Alkyl and C 8-15 Alkenyl, preferably C 8-12 Alkyl and C 8-12 Alkenyl, preferably C 10-12 Alkyl and C 10-12 Alkenyl, preferably C 10-12 Alkyl (preferably C) 10 alkyl) and C 10 alkenyl;

[0411] Preferably, R is independently selected from C. 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 4-14 Alkyl, C 4-14 alkenyl and C 4-14 Alkyne group, preferably C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; preferably C 4-14 Alkyl, preferably C 6-14 Alkyl, preferably C 6-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 8-10 Alkyl, preferably C8 alkyl, preferably C9 alkyl, preferably C 10 alkyl;

[0412] Preferably, R is independently selected from C. 6-9 Alkyl; preferably C 4-8 Alkyl; preferably C6 alkyl;

[0413] Preferably, R is independently selected from C. 10-12 Alkyl and C 15 Alkenyl, preferably C 10-12 Alkyl; preferably C 8-10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C9 alkenyl;

[0414] Preferably, R is optionally represented by one or two Rs. s Instead, preferably optionally replaced by 1 R s replace;

[0415] Preferably, R is independently selected from -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 12 CH3, -(CH2) 13 CH3, -(CH2) 14 CH3, -(CH2)3-CH=CH-(CH2)4CH3, -(CH2)4-CH=CH-CH2CH3, -CH=CH-(CH2)9CH3, Preferred nucleotides include -(CH2)5CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, Preferred morphologies include -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3,

[0416] Preferably, R is independently selected from -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 12 CH3, -(CH2) 13 CH3, -(CH2) 14 CH3, Preferred nucleotides include -(CH2)5CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, Preferred morphologies include -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3,

[0417] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R s Independently selected from H and C 1-25 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e H and C are preferred.1-20 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e H and C are preferred. 1-15 Alkyl, -L e -OR e and -L e -NR e R' e H and C are preferred 1-14 Alkyl, -L e -OR e and -L e -NR e R' e C is preferred. 1-15 Alkyl, preferably C 1-14 Alkyl, preferably C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 1-6 alkyl;

[0418] Preferably, R s The substitution site on R is spaced 0-12 carbon atoms from M2, preferably 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-4 carbon atoms; preferably at least 1 carbon atom, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms; preferably at least 2 carbon atoms, preferably 2-6 carbon atoms, preferably 2-4 carbon atoms, for example, 2-3 carbon atoms.

[0419] Preferably, L e Independently selected from chemical bonds and C 1-25 Alkylene; preferably chemical bonds and C 1-20 Alkylene; preferably chemical bonds and C 1-15 Alkylene; preferably chemical bonds and C 1-14 Alkylene; preferably selected from chemical bonds and C 1-10 Alkylene; preferably selected from chemical bonds and C 1-6 Alkylene;

[0420] Preferably, R e and R' e Independently selected from H and C 1-25 Alkyl groups; preferably H and C 1-20 Alkyl groups; preferably H and C 1-15 Alkyl groups; preferably H and C 1-14 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C1-6 alkyl.

[0421] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R7 is independently H or C. 1-25 Alkyl groups, preferably H or C 1-20 Alkyl groups, preferably H or C 1-15 Alkyl groups, preferably H or C 1-14 Alkyl groups, preferably H or C 1-12 Alkyl groups, preferably H or C 1-10 Alkyl groups, preferably H or C 1-6 alkyl.

[0422] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, having a structure of formula (II) or formula (IIB):

[0423] Where x is independently 1, 2 or 3;

[0424] The remaining variables are as defined in this invention.

[0425] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

[0426] in,

[0427] x can be 1, 2 or 3 independently, preferably 1 or 2;

[0428] y is 2, 3, 4 or 5, preferably 3, 4 or 5;

[0429] R1, R2, R3, and R4 are independent

[0430] a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3, 4 or 5;

[0431] b can be 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0, 1 or 2, preferably 0 or 1;

[0432] a+b can be 1, 2, 3, 4, 5, 6 or 7 independently, preferably 5, 6 or 7;

[0433] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-;

[0434] R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 6-15 Alkyl, C 6-15 alkenyl and C 6-15 Alkyne group, preferably C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace;

[0435] R s Independently for H and C 1-15 Alkyl, -L e -OR e and -L e -NR e R' e ;

[0436] L e Independently selected from chemical bonds and C 1-15 Alkylene;

[0437] R e and R' e Independently selected from H and C 1-15 Alkyl group; R5 and R6 are independently selected from H and C. 1-3 alkyl;

[0438] Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene, preferably C 3-6 Cycloalkylene;

[0439] Preferably, when y is 2, a+b is not 1.

[0440] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0441] x can be 1 or 2 independently, preferably 1;

[0442] y is selected from 2, 3 or 4, preferably 3 or 4;

[0443] R1, R2, R3, and R4 are independent

[0444] a can be 1 or 5 independently, preferably 5;

[0445] b can be 0 or 1 independently, preferably 1;

[0446] a+b independently equals 1 or 6;

[0447] M2 is independently selected from -C(O)O-, -OC(O-) and -C(O)NH-, preferably -C(O)O- and -OC(O-); preferably -C(O)O-;

[0448] R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl groups, which are optionally surrounded by one or two R groups s replace;

[0449] R s Independently for C 1-15 Alkyl, preferably C 1-6 alkyl;

[0450] R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl;

[0451] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0452] Preferably,

[0453] R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3, -(CH2)3-CH=CH-(CH2)4CH3, -(CH2)4-CH=CH-CH2CH3, -CH=CH-(CH2)9CH3, Preferred types are -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3,

[0454] Preferably, R1, R2, R3 and R4 are the same.

[0455] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0456] x can be 1 or 2 independently, preferably 1;

[0457] y is 3, 4, or 5, preferably 3 or 4;

[0458] R1, R2, R3, and R4 are independent

[0459] a can be 4, 5, or 6 independently, with 5 being preferred;

[0460] b can be 0, 1, or 2 independently, preferably 1;

[0461] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -C(O)NH-, -NHC(O)- and -SC(O-), preferably -C(O)O-, -OC(O)- and -C(O)NH-;

[0462] R is independently selected from C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace;

[0463] R s Independently for C 1-15 alkyl;

[0464] R5 and R6 are independently selected from H and C. 1-3 alkyl;

[0465] Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene.

[0466] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0467] x is 1;

[0468] y is 3 or 4, preferably 3;

[0469] R1, R2, R3, and R4 are independent

[0470] a is 5;

[0471] b is 1;

[0472] M2 is independently selected from -C(O)O- and -OC(O-); preferably -C(O)O-;

[0473] R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl, preferably C 10-12 Alkyl and C 10-12 Alkenyl, preferably C 10-12 Alkyl (preferably C) 10 alkyl) and C 10 Alkenyl groups, which are optionally surrounded by one or two R groups s replace;

[0474] R sIndependently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 alkyl;

[0475] R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl;

[0476] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0477] Preferably,

[0478] R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3、、 Preferred options are -(CH2)9CH3 and -(CH2). 11 CH3 and Preferred -(CH2)9CH3 and

[0479] Preferably, R1, R2, R3 and R4 are the same.

[0480] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

[0481] in,

[0482] x can be 1, 2 or 3 independently, preferably 1 or 2;

[0483] y is 2, 3, 4 or 5, preferably 3, 4 or 5;

[0484] R1 is

[0485] R2, R3, and R4 are independent

[0486] a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2 or 3;

[0487] b can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3 or 4;

[0488] a+b can be 2, 3, 4, 5, 6 or 7 independently, preferably 3, 4, 5, 6 or 7;

[0489] M1 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH-, -NHC(O)- and -C(O)NHNHC(O)-, preferably -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)- and -C(O)NHNHC(O)-;

[0490] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-;

[0491] R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace;

[0492] R' is independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace;

[0493] R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e ;

[0494] L e Independently selected from chemical bonds and C 1-14 Alkylene;

[0495] R e and R' e Independently selected from H and C 1-14 alkyl.

[0496] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0497] x is 1;

[0498] y is 3 or 4;

[0499] R1 is

[0500] R2, R3, and R4 are independent

[0501] a is 2;

[0502] b is either 1 or 4;

[0503] M1 is independently selected from -C(O)O-, -C(O)NH- and -C(O)NHNHC(O)-, preferably -C(O)NH- and -C(O)NHNHC(O)-, especially -C(O)NH-;

[0504] M2 is independently selected from -C(O)O-, -OC(O)- and -C(O)NH-, preferably -C(O)O- and -OC(O-), especially -OC(O-;

[0505] R is independently selected from C 8-12 Alkyl, preferably C 8-11 Alkyl groups, optionally marked with one or two R groups s replace;

[0506] R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl groups, optionally marked with one or two R groups s replace;

[0507] R s Independently for C 1-12 Alkyl, preferably C 1-10 alkyl;

[0508] Preferably, R1, R2, R3, and R4 are the same;

[0509] Preferably, R2, R3, and R4 are the same, and R1 is...

[0510] Preferably,

[0511] R is independently selected from -(CH2)7CH3, -(CH2)8CH3, and -(CH2). 10 CH3;

[0512] R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3.

[0513] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0514] x is independently 1 or 2, preferably 1;

[0515] y is 3, 4, or 5, preferably 3 or 4; preferably 4;

[0516] R1 is Preferred

[0517] R2, R3, and R4 are independent

[0518] a can be 1, 2, or 3 independently, with 2 being preferred;

[0519] b can be 1, 2, 3 or 4 independently, preferably 1 or 4;

[0520] a+b can be 2, 3, 4, 5, 6 or 7 independently, preferably 3, 4, 5 or 6;

[0521] M1 is independently selected from -C(O)NH-, -NHC(O)- and -C(O)NHNHC(O)-, preferably -C(O)NH- and -C(O)NHNHC(O)-; preferably -C(O)NH- and -NHC(O)-, especially -C(O)NH-;

[0522] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O-), preferably -C(O)O- and -OC(O-); preferably -OC(O- and -SC(O-), especially -OC(O)-;

[0523] R is independently selected from C 8-12 Alkyl, preferably C 8-11 Alkyl groups, preferably C8 alkyl groups, optionally marked with one or two R groups. s replace;

[0524] R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 10 Alkyl groups, optionally marked with one or two R groups s replace;

[0525] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl;

[0526] Preferably, R1, R2, R3, and R4 are the same;

[0527] Preferably, R2, R3, and R4 are the same, and R1 is...

[0528] Preferably,

[0529] R is independently selected from -(CH2)7CH3, -(CH2)8CH3, and -(CH2). 10 CH3, preferably -(CH2)7CH3;

[0530] R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3, preferably -(CH2)9CH3.

[0531] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

[0532] in,

[0533] x can be 1, 2 or 3 independently, preferably 1 or 2;

[0534] y is 2, 3, 4 or 5, preferably 3, 4 or 5;

[0535] R1 is

[0536] R2, R3, and R4 are independent

[0537] a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3 or 4;

[0538] b can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3 or 4;

[0539] a+b independently represents 2, 3, 4, 5, 6, or 7;

[0540] n = 0, 1, 2, 3, 4 or 5;

[0541] R A Independently selected from H and C 1-6 Alkyl, -L f -OR f -L f -SR f and -L f NR f R' f ;

[0542] L f Independently selected from chemical bonds and C 1-6 Alkylene;

[0543] R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups;

[0544] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-, preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0545] R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 4-14 Alkyl, C 4-14 alkenyl and C 4-14 Alkyne group, preferably C 4-14 Alkyl groups, optionally marked with one or two R groups s replace;

[0546] R' is independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace;

[0547] R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e ;

[0548] L e Independently selected from chemical bonds and C 1-14 Alkylene;

[0549] R e and R' e Independently selected from H and C 1-14 alkyl.

[0550] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0551] x is independently 1 or 2, preferably 1;

[0552] y is 3, 4 or 5, preferably 3 or 4, preferably 4;

[0553] R1 is

[0554] R2, R3, and R4 are independent

[0555] a can be 1, 2, 3 or 4 independently, preferably 2 or 3, preferably 3;

[0556] b can be 1, 2, or 3 independently, with 2 being preferred;

[0557] a+b can be independently 3, 4, 5, 6 or 7, preferably 4 or 5; preferably 4, 5 or 6, preferably 5;

[0558] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O-), preferably -C(O)O- and -OC(O-); preferably -OC(O- and -SC(O-), especially -OC(O)-;

[0559] R is independently selected from C 6-12 Alkyl, preferably C 6-9 Alkyl groups, preferably C6 alkyl groups, preferably C9 alkyl groups, optionally marked with one or two R groups. s replace;

[0560] R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C8 alkyl, preferably C 10 Alkyl groups, optionally marked with one or two R groups s replace;

[0561] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl;

[0562] Preferably, R1, R2, R3, and R4 are the same;

[0563] Preferably, R2, R3, and R4 are the same, and R1 is...

[0564] Preferably,

[0565] R is independently selected from -(CH2)5CH3 and -(CH2)8CH3, preferably -(CH2)8CH3;

[0566] R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3, preferably -(CH2)7CH3.

[0567] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants or tautomers.

[0568] The construct or stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure of formula (IIB):

[0569] in,

[0570] x can be 1, 2 or 3 independently, preferably 1 or 2;

[0571] y is 2, 3, 4 or 5, preferably 2, 3 or 4;

[0572] R1 is selected from H, Preferred

[0573] R2, R3, and R4 are independent

[0574] R8 is independently selected from H and C. 1-6 Alkyl and

[0575] a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3, 4 or 5;

[0576] b can be 0, 1, 2, 3, 4, 5 or 6 independently, preferably 0, 1, 2, 3 or 4;

[0577] a+b can be 1, 2, 3, 4, 5, 6 or 7 independently, preferably 3, 4, 5, 6 or 7;

[0578] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-;

[0579] R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 6-15 Alkyl, C 6-15 alkenyl and C 6-15 Alkyne group, preferably C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace;

[0580] R' is independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace;

[0581] R s Independently for H and C 1-15 Alkyl, -L e -OR e and -L e -NR e R'e ;

[0582] L e Independently selected from chemical bonds and C 1-15 Alkylene;

[0583] R e and R' e Independently selected from H and C 1-15 alkyl;

[0584] R5 and R6 are independently selected from H and C. 1-3 alkyl;

[0585] Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene, preferably C 3-6 Cycloalkylene;

[0586] Preferably, when y is 2, a+b is not 1.

[0587] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0588] x can be 1 or 2 independently, preferably 1;

[0589] y is 2, 3, 4 or 5, preferably 2, 3 or 4;

[0590] R1 is selected from H, Preferred

[0591] R2, R3, and R4 are independent

[0592] R8 is independently selected from H and C. 1-6 Alkyl and H and C are preferred 1-3 Alkyl; preferably H and H is preferred; at most one R8 is preferred.

[0593] a can be 2, 3, 4, 5 or 6 independently, preferably 3, 4 or 5, preferably 3, preferably 5;

[0594] b can be 0, 1, 2, 3 or 4 independently, preferably 1, 2 or 3, preferably 1, preferably 3;

[0595] a+b can be independently 3, 4, 5, 6 or 7, preferably 4, 5 or 6, preferably 4 or 6, preferably 6;

[0596] M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -C(O)NH-, -NHC(O)- and -SC(O)-, preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, especially -C(O)O- and -OC(O)-;

[0597] R is independently selected from C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace;

[0598] R' is independently selected from C 8-12 Alkyl groups, optionally marked with one or two R groups s replace;

[0599] R s Independently for C 1-15 alkyl;

[0600] R5 and R6 are independently selected from H and C. 1-3 alkyl;

[0601] Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene, preferably C 3-6 Cycloalkylene.

[0602] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0603] x is 1;

[0604] y is 2, 3 or 4, preferably 3 or 4, preferably 3;

[0605] R1 is selected from H, Preferred

[0606] R2, R3, and R4 are independent

[0607] R8 is independently selected from H and C. 1-6 Alkyl and H and C are preferred 1-3 Alkyl; preferably H and H is preferred; at most one R8 is preferred.

[0608] a can be 3, 4 or 5 independently, preferably 3 or 5, preferably 5;

[0609] b can be 1, 2 or 3 independently, preferably 1 or 3, preferably 1;

[0610] a+b can be 4, 5 or 6 independently, preferably 4 or 6, preferably 6;

[0611] M2 is independently selected from -C(O)O- and -OC(O-); preferably -OC(O-);

[0612] R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl groups, which are optionally surrounded by one or two R groups s replace;

[0613] R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl groups, optionally marked with one or two R groups s replace;

[0614] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 alkyl;

[0615] R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl;

[0616] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0617] Preferably,

[0618] R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3,

[0619] R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3;

[0620] Preferably, R2, R3, and R4 are the same; more preferably, R1, R2, R3, and R4 are the same.

[0621] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IIB):

[0622] in,

[0623] x is 1;

[0624] y is 2;

[0625] R1, R2, R3, and R4 are independent

[0626] R8 is independently selected from H and C. 1-3 Alkyl; preferably H;

[0627] a can be 3, 4, or 5 independently, preferably 5;

[0628] b can be 1, 2, or 3 independently, with 1 being preferred;

[0629] a+b can be 4, 5, or 6 independently, with 6 being the preferred value;

[0630] M2 is selected from -OC(O)- and -C(O)O-;

[0631] R is independently selected from C 10-12 Alkyl, preferably C 10 Alkyl groups, optionally marked with one or two R groups s replace;

[0632] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-3 alkyl;

[0633] R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl;

[0634] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0635] Preferably,

[0636] R is independently selected from -(CH2)9CH3;

[0637] Preferably, R1, R2, R3 and R4 are the same.

[0638] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IIB):

[0639] in,

[0640] x is 1;

[0641] y is 3;

[0642] R1, R2, R3, and R4 are independent

[0643] R8 is independently selected from H and And only one R8 is H is preferred;

[0644] a can be 3, 4 or 5 independently, preferably 3 or 5, preferably 5;

[0645] b can be 1, 2 or 3 independently, preferably 1 or 3, preferably 1;

[0646] a+b can be 4, 5 or 6 independently, preferably 4 or 6, preferably 6;

[0647] M2 is -OC(O)-;

[0648] R is independently selected from C 10-12 Alkyl and C 15 Alkenyl groups, which are optionally surrounded by one or two R groups s replace;

[0649] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-3 alkyl;

[0650] R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl;

[0651] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0652] Preferably,

[0653] R is independently selected from -(CH2)9CH3, -(CH2) 11 CH3, (Preferred)

[0654] Preferably, R1, R2, R3 and R4 are the same.

[0655] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

[0656] in,

[0657] x is 1;

[0658] y is 3;

[0659] R1, R2, R3, and R4 are independent

[0660] a can be 3, 4 or 5 independently, preferably 3 or 5, preferably 5;

[0661] b can be 1, 2 or 3 independently, preferably 1 or 3, preferably 1;

[0662] a+b can be 4, 5 or 6 independently, preferably 4 or 6, preferably 6;

[0663] M2 is -C(O)O-;

[0664] R is independently selected from C 8-10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C 8-10 Alkenyl groups, which are optionally surrounded by one or two R groups s replace;

[0665] R s Independently for C 1-3 alkyl;

[0666] R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; preferably H;

[0667] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0668] Preferably,

[0669] R is independently selected from -(CH2)9CH3, (Preferred) ),

[0670] Preferably, R1, R2, R3 and R4 are the same.

[0671] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

[0672] in,

[0673] x is 1;

[0674] y is 4;

[0675] R1, R2, R3, and R4 are independent

[0676] a can be 1, 2, 3, 4 or 5 independently, preferably 1 or 5, preferably 5;

[0677] b can be 0, 1, 2 or 3 independently, preferably 0 or 1, preferably 1;

[0678] a+b can be 1, 2, 3, 4, 5 or 6 independently, preferably 1 or 6, preferably 6;

[0679] M2 is -OC(O)-, -OC(O)- or -C(O)NH-, preferably -OC(O)- or -OC(O)-, preferably -OC(O)-;

[0680] R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl, preferably C 10 Alkyl and C9 alkenyl groups, optionally separated by one or two R groups. s replace;

[0681] R s Independently for H and C 1-15 Alkyl group, preferably H;

[0682] R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl;

[0683] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0684] Preferably,

[0685] R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3,

[0686] Preferably, R1, R2, R3 and R4 are the same.

[0687] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II):

[0688] in,

[0689] x is 1;

[0690] y is 2 or 3;

[0691] R1, R2, R3, and R4 are independent

[0692] a is 5;

[0693] b is 1;

[0694] M2 is -OC(O)-;

[0695] R is independently selected from C 10-12 Alkyl and C 10-12 Alkenyl, preferably C 10-12 Alkyl, preferably C 10 alkyl;

[0696] R5 and R6 are independently selected from C 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably methyl;

[0697] Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene;

[0698] Preferably, R1, R2, R3 and R4 are the same.

[0699] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table (I).

[0700] Table I

[0701] In a more specific embodiment, the present invention also provides a nanoparticle composition comprising a lipid component and optionally a loading; wherein the lipid component contains a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the loading is selected from one or more therapeutic agents, preventive agents or diagnostic agents.

[0702] Preferably, the lipid component contains the following components in molar percentage:

[0703] Ionizable lipids 20 mol% - 98 mol%

[0704] Structural lipids: 0 mol% - 75 mol%;

[0705] Assisted lipids 0 mol% - 30 mol%;

[0706] Polymer lipids: 0.25 mol% - 10 mol%;

[0707] Preferably, the lipid component contains the following components in molar percentage:

[0708] Ionizable lipids 20 mol% - 85 mol%

[0709] Structural lipids: 10 mol% - 75 mol%;

[0710] Supporting lipids: 1.0 mol% - 30 mol%;

[0711] Polymer lipids: 0.25 mol% - 10 mol%;

[0712] Preferably, the lipid component contains the following components in molar percentage:

[0713] 50 mol% of the compound of the present invention;

[0714] 10 mol% of auxiliary lipids;

[0715] Structural lipids 38.5 mol%;

[0716] Polymer lipid 1.5 mol%;

[0717] The ionizable lipids are selected from the compounds of this invention.

[0718] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the lipid component comprises a component selected from any one of the following (1)-(3) in molar percentage:

[0719] (1) The lipid component contains the following components in molar percentage:

[0720] Ionizable lipids: 90 mol% - 99.5 mol%;

[0721] Polymer lipids: 0.5 mol% - 10 mol%;

[0722] Preferably, the lipid component contains the following components in molar percentage:

[0723] Ionizable lipids: 94 mol% - 99.5 mol%;

[0724] Polymer lipids: 0.5 mol% - 6 mol%;

[0725] Preferably, the lipid component contains the following components in molar percentage:

[0726] Ionizable lipids 95 mol% - 98 mol%

[0727] Polymer lipids 2 mol% - 5 mol%;

[0728] (2) The lipid component contains the following components in molar percentage:

[0729] Ionizable lipids: 25 mol% - 80 mol%;

[0730] Structural lipids: 10 mol% - 60 mol%;

[0731] Assisted lipids 0 mol% - 30 mol%;

[0732] Polymer lipids: 0.5 mol% - 5 mol%;

[0733] Preferably, the lipid component contains the following components in molar percentage:

[0734] Ionizable lipids: 25 mol% - 75 mol%;

[0735] Structural lipids: 15 mol% - 60 mol%;

[0736] Assisted lipids 2 mol% - 30 mol%;

[0737] Polymer lipids 1 mol% - 5 mol%;

[0738] Preferably, the lipid component contains the following components in molar percentage:

[0739] Ionizable lipids: 30 mol% - 70 mol%;

[0740] Structural lipids: 23 mol% - 52 mol%;

[0741] Assisted lipids 4 mol% - 20 mol%;

[0742] Polymer lipids: 1 mol% - 3.5 mol%;

[0743] Preferably, the lipid component contains the following components in molar percentage:

[0744] Ionizable lipids: 30 mol% - 70 mol%;

[0745] Structural lipids: 23 mol% - 52 mol%;

[0746] Assisted lipids 4 mol% - 20 mol%;

[0747] Polymer lipids: 1.5 mol% - 3 mol%;

[0748] (3) The lipid component contains the following components in molar percentage:

[0749] Ionizable lipids: 20 mol% - 50 mol%;

[0750] Structural lipids: 10 mol% - 50 mol%;

[0751] Assisted lipids 10 mol% - 30 mol%;

[0752] Polymer lipids: 0.5 mol% - 5 mol%;

[0753] Permanent cationic compounds, 10 mol% - 50 mol%;

[0754] Preferably, the lipid component contains the following components in molar percentage:

[0755] Ionizable lipids: 20 mol% - 50 mol%;

[0756] Structural lipids: 15 mol% - 40 mol%;

[0757] 10 mol% - 20 mol% of auxiliary lipids;

[0758] Polymer lipids: 0.5 mol% - 5 mol%;

[0759] Permanent cationic compounds, 10 mol% - 40 mol%;

[0760] Preferably, the lipid component contains the following components in molar percentage:

[0761] Ionizable lipids: 25 mol% - 45 mol%;

[0762] Structural lipids: 20 mol% - 35 mol%;

[0763] 12 mol% - 18 mol% of auxiliary lipids;

[0764] Polymer lipids: 0.5 mol% - 3.5 mol%;

[0765] Permanent cationic compounds, 15 mol% - 35 mol%;

[0766] Preferably, the lipid component contains the following components in molar percentage:

[0767] Ionizable lipids: 30 mol% - 40 mol%;

[0768] Structural lipids: 24.5 mol% - 29.5 mol%;

[0769] The auxiliary lipids are 12 mol%-18 mol%, preferably 15 mol%.

[0770] Polymer lipids: 0.5 mol% - 3 mol%;

[0771] Permanent cationic compounds 20 mol% - 30 mol%;

[0772] Preferably, the lipid component contains the following components in molar percentage:

[0773] Ionizable lipids: 30 mol% - 40 mol%;

[0774] Structural lipids: 24.5 mol% - 29.5 mol%;

[0775] The auxiliary lipids are 12 mol%-18 mol%, preferably 15 mol%.

[0776] Polymer lipids: 0.5 mol% - 1.8 mol%;

[0777] Permanent cationic compounds 20 mol% - 30 mol%;

[0778] Preferably, the lipid component does not contain accessory lipids;

[0779] The ionizable lipids are selected from the compounds of this invention.

[0780] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the lipid component comprises a component selected from any one of the following (2-1), (2-2), and (3-1) in a molar percentage:

[0781] (2-1) The lipid component contains the following components in molar percentage:

[0782] Ionizable lipids: 45 mol% - 75 mol%;

[0783] Structural lipids 20 mol% - 30 mol%;

[0784] Assisted lipids 2 mol% - 25 mol%;

[0785] Polymer lipids: 1.5 mol% - 4 mol%;

[0786] Preferably, the lipid component contains the following components in molar percentage:

[0787] Ionizable lipids: 50 mol% - 70 mol%;

[0788] Structural lipids: 23.9 mol% - 27 mol%;

[0789] Assisted lipids 4 mol% - 20 mol%;

[0790] Polymer lipids 2.1 mol% - 3 mol%;

[0791] (2-2) The lipid component contains the following components in molar percentage:

[0792] Ionizable lipids: 45 mol%-55 mol%, preferably 50 mol%;

[0793] Structural lipids 30 mol%-40 mol%, preferably 37 mol%;

[0794] The auxiliary lipids are 5 mol%-15 mol%, preferably 10 mol%.

[0795] Polymer lipids 2 mol%-4 mol%, preferably 3 mol%;

[0796] Preferably, the lipid component contains the following components in molar percentage:

[0797] Ionizable lipids: 47 mol%-53 mol%, preferably 50 mol%;

[0798] Structural lipids 35 mol%-40 mol%, preferably 37 mol%;

[0799] The auxiliary lipids are 8 mol%-12 mol%, preferably 10 mol%.

[0800] The polymer lipid content is 2.5 mol% to 3.5 mol%, preferably 3 mol%.

[0801] (3-1) The lipid component contains the following components in molar percentage:

[0802] Ionizable lipids: 25 mol% - 35 mol%;

[0803] Structural lipids: 26 mol% - 32 mol%;

[0804] 12 mol% - 18 mol% of auxiliary lipids;

[0805] Polymer lipids: 0.5 mol% - 2.5 mol%;

[0806] Permanent cationic compounds, 25 mol% - 35 mol%;

[0807] Preferably, the lipid component contains the following components in molar percentage:

[0808] Ionizable lipids: 27 mol% - 33 mol%, preferably 30 mol%;

[0809] Structural lipids: 28.2 mol% - 29.5 mol%;

[0810] The auxiliary lipids are 12 mol%-18 mol%, preferably 15 mol%.

[0811] Polymer lipids: 0.5 mol% - 1.8 mol%;

[0812] 27 mol%-33 mol%, preferably 30 mol% of a permanent cationic compound;

[0813] The ionizable lipids are selected from the compounds of this invention.

[0814] In some specific embodiments, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of ionizable lipids in the lipid component is 20 mol%-98 mol%, preferably 20 mol%-70 mol%, preferably 20 mol%-50 mol%, preferably 20 mol%-45 mol%, preferably 25 mol%-45 mol%, preferably 25 mol%-80 mol%, preferably 25 mol%-75 mol%, preferably 45 mol%-75 mol%, preferably 25 mol%-70 mol%, preferably 50 mol%-70 mol%, preferably 25 mol%-60 mol%, preferably 25 mol%-50 mol%. 0 mol%, preferably 25 mol%-40 mol%, preferably 25 mol%-35 mol%, preferably 27 mol%-33 mol%, preferably 30 mol%-70 mol%, preferably 30 mol%-60 mol%, preferably 30 mol%-50 mol%, preferably 30 mol%-40 mol%, preferably 35 mol%-75 mol%, preferably 35 mol%-60 mol%, preferably 35 mol%-50 mol%, preferably 35 mol%-40 mol%, preferably 40 mol%-75 mol%, preferably 40 mol%-60 mol%, preferably 40 mol%-50 mol%, preferably 45 mol%. mol%-70mol%, preferably 45mol%-60mol%, preferably 45mol%-55mol%, preferably 47mol%-53mol%, preferably 50mol%-75mol%, preferably 50mol%-60mol%, preferably 55mol%-75mol%, preferably 55mol%-65mol%, preferably 60mol%-90mol%, preferably 60mol%-75mol%, preferably 80mol%-98mol%, preferably 90mol%-99.5mol%, preferably 94mol%-99.5mol%, preferably 95mol%-98mol%, for example 25mol%, 3 0mol%, 35mol%, 40mol%, 45mol%, 46mol%, 47mol%, 48mol%, 49mol%, 50mol%, 51mol%, 52mol%, 53mol%, 54mol%, 55mol%, 56mol%, 57mol%, 58mol% , 59mol%, 60mol%, 61mol%, 62mol%, 63mol%, 64mol%, 65mol%, 70mol%, 75mol%, 80mol%, 85mol%, 90mol%, 95mol%, 96mol%, 97mol%, 98mol% or 99%.

[0815] In some specific embodiments, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of structural lipids in the lipid component is 0 mol%-75 mol%, preferably 5 mol%-75 mol%, preferably 10 mol%-75 mol%, preferably 10 mol%-60 mol%, preferably 10 mol%-50 mol%, preferably 15 mol%-60 mol%, preferably 15 mol%-40 mol%, preferably 12 mol%-50 mol%, preferably 12 mol%-45 mol%, preferably 15 mol%-50 mol%, preferably 15 mol%-45 mol%, preferably 20 mol%-50 mol%, preferably 20 mol%. %-45mol%, preferably 20mol%-35mol%, preferably 20mol%-30mol%, preferably 23mol%-52mol%, preferably 23.9mol%-27mol%, preferably 24.5mol%-29.5mol%, preferably 25mol%-50mol%, preferably 25mol%-45mol%, preferably 25mol%-32mol%, preferably 26mol%-32mol%, preferably 28mol%-50mol%, preferably 28mol%-30.5mol%, preferably 28.2mol%-29.5mol%, preferably 30mol%-50mol%, preferably 30mol%-45mol%. Preferably 30 mol%-42.5 mol%, preferably 30 mol%-41.5 mol%, preferably 30 mol%-40 mol%, preferably 32 mol%-45 mol%, preferably 32 mol%-38 mol%, preferably 33.5 mol%-41.5 mol%, preferably 33.5 mol%-38.5 mol%, preferably 35 mol%-40 mol%, preferably 38.5 mol%-50 mol%, preferably 38.5 mol%-43.5 mol%, for example 5 mol%, 10 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, 16 mol%, 17 mol%, 18 mol%, 1 8.5mol%, 19mol%, 20mol%, 21mol%, 22mol%, 23mol%, 23.5mol%, 24mol%, 25mol%, 25.5mol%, 26mol%, 27mol%, 28mol%, 28.5mol%, 29mol%, 30mol%, 30. 5mol%, 31mol%, 31.5mol%, 32mol%, 33mol%, 33.5mol%, 34mol%, 35mol%, 35.5mol%, 36mol%, 37mol%, 38mol%, 38.5mol%, 39mol%, 40mol%, 41mol%, 41.5 mol%, 42 mol%, 43 mol%, 44 mol%, 45 mol%, 46 mol%, 47 mol%, 48 mol%, 48.5 mol%, 49 mol%, 50 mol%, 55 mol%, 60 mol%, 65 mol%, or 70 mol%. In another, more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the lipid component does not contain structural lipids.

[0816] In some specific embodiments, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of the auxiliary lipids in the lipid component is 0 mol%-30 mol%, preferably 2 mol%-30 mol%, preferably 2 mol%-25 mol%, preferably 4 mol%-30 mol%, preferably 4 mol%-25 mol%, preferably 4 mol%-20 mol%, preferably 4 mol%-15 mol%, preferably 4 mol%-10 mol%, preferably 5 mol%-30 mol%, preferably 5 mol%-25 mol%, preferably 5 mol%-20 mol%, preferably 5 mol%-15 mol%, preferably 6 mol%-30 mol%, preferably 6 mol%-25 mol%, preferably 6 mol%-20 mol%, preferably 6 mol%-15 mol%, preferably 6 mol%-13 mol%, preferably 7 mol%-25 mol%, preferably 7 mol%-20 mol%, preferably 8 mol%-25 mol%, preferably 8 mol%-20 mol%, preferably 8 mol%-18 mol%, preferably 8 mol%-15 mol%. mol%, preferably 8mol%-12mol%, preferably 8mol%-10mol%, preferably 10mol%-30mol%, preferably 10mol%-25mol%, preferably 10mol%-20mol%, preferably 11mol%-22mol%, preferably 12mol%-25mol%, preferably 12mol%-20mol%, 12mol%-18mol%; 12mol%-15mol%, preferably 15mol%-30mol%, preferably 20mol%-30mol%, preferably... The concentration is selected as 15 mol%-23 mol%, preferably 15 mol%-20 mol%, for example 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 11 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, 16 mol%, 17 mol%, 18 mol%, 19 mol%, 20 mol%, 21 mol%, 22 mol%, 23 mol%, 24 mol% or 25 mol%. In another more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the lipid component does not contain auxiliary lipids.

[0817] In some specific embodiments, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of polymeric lipids in the lipid component is 0.25 mol%-10 mol%, preferably 0.25 mol%-6 mol%, preferably 0.25 mol%-5 mol%, preferably 0.25 mol%-4 mol%, preferably 0.25 mol%-3.5 mol%, preferably 0.25 mol%-3 mol%, preferably 0.25 mol%-2 mol%, preferably 0.25 mol%-1.8 mol%, preferably 0.5 mol%-10 mol%, preferably 0.5 mol%-6 mol%, preferably 0.5 mol%. 1 mol%-5 mol%, preferably 0.5 mol%-3.5 mol%, preferably 0.5 mol%-3 mol%, preferably 0.5 mol%-2.8 mol%, preferably 0.5 mol%-2.5 mol%, preferably 0.5 mol%-2 mol%, preferably 0.5 mol%-1.8 mol%, preferably 1 mol%-5 mol%, preferably 1 mol%-3.5 mol%, preferably 1 mol%-3 mol%, preferably 1 mol%-2.8 mol%, preferably 1 mol%-2.5 mol%, preferably 1.5 mol%-5 mol%, preferably 1.5 mol%-4.5 mol%, preferably 1. 5 mol%-4 mol%, preferably 1.5 mol%-3.5 mol%, preferably 1.5 mol%-3 mol%, preferably 1.5 mol%-2.5 mol%, preferably 1.5 mol%-2 mol%, preferably 1.5 mol%-1.8 mol%, preferably 2 mol%-5 mol%, preferably 2 mol%-4 mol%, preferably 2 mol%-3 mol%, preferably 2.1 mol%-5 mol%, preferably 2.1 mol%-3 mol%, preferably 2.5 mol%-5 mol%, preferably 2.5 mol%-3.5 mol%, for example, 0.5 mol%, 0.6 mol%, 0. 7mol%, 0.8mol%, 0.9mol%, 1mol%, 1.1mol%, 1.2mol%, 1.3mol%, 1.4mol%, 1.5mol%, 1.6mol%, 1.7mol%, 1.8mol%, 1.9mol%, 2.0mol%, 2.1mol %, 2.2 mol%, 2.3 mol%, 2.4 mol%, 2.5 mol%, 2.6 mol%, 2.7 mol%, 2.8 mol%, 2.9 mol%, 3.0 mol%, 3.1 mol%, 3.2 mol%, 3.3 mol%, 3.4 mol% or 3.5 mol%.

[0818] In some specific embodiments, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of the permanent cationic compound in the lipid component is 10 mol%-50 mol%, preferably 10 mol%-40 mol%, preferably 15 mol%-40 mol%, preferably 15 mol%-35 mol%, preferably 20 mol%-50 mol%, preferably 20 mol%-40 mol%, preferably 20 mol%-30 mol%, preferably 25 mol%-35 mol%, preferably 27 mol%-33 mol%, for example 10 mol%, 12 mol%, 13 mol%, 14 mol%, 15 mol%, 16 mol%, 17 mol%. 1%, 18 mol%, 18.5 mol%, 19 mol%, 20 mol%, 21 mol%, 22 mol%, 23 mol%, 24 mol%, 25 mol%, 26 mol%, 27 mol%, 28 mol%, 29 mol%, 30 mol%, 31 mol%, 32 mol%, 33 mol%, 34 mol%, 35 mol%, 36 mol%, 37 mol%, 38 mol%, 39 mol%, 40 mol%, 41 mol%, 42 mol%, 43 mol%, 44 mol%, 45 mol%, 46 mol%, 47 mol%, 48 mol%, 49 mol%, or 50 mol%. In another more specific embodiment, the present invention provides the above-described nanoparticle composition wherein the lipid component is free of permanent cationic compounds.

[0819] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein one or more of the following (i)-(v) are met:

[0820] (i) The auxiliary lipid is a phospholipid;

[0821] Preferably, the phospholipid is selected from phosphatidylcholine and / or phosphatidylethanolamine;

[0822] Preferably, the phospholipid is selected from distearylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), palmitoylphosphatidylcholine (POPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoylphosphatidylethanolamine (POPE), distearyl-sn-glycerol-phosphoethanolamine, and di- Palmitoyl phosphatidyl ethanolamine (DPPE), dimyristoyl phosphatidyl ethanolamine (DMPE), distearate phosphatidyl ethanolamine (DSPE), monomethylphosphatidyl ethanolamine, dimethylphosphatidyl ethanolamine, 18-1-transPE, 1-stearoyl-2-oleoyl phosphatidyl ethanolamine (SOPE), hydrogenated soybean phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), dioleoyl phosphatidyl serine or 1,2-dioleoyl-sn-glycero-3-phosphate-L-serine (DOPS) Sphingomyelin (SM), Dimyristic phosphatidylglycerol (DMPG), Distearate phosphatidylglycerol (DSPG), Rutinyl phosphatidylcholine (DEPC), Palmitoyl phosphatidylglycerol (POPG), Dioleoyl-phosphatidylethanolamine (DEPE), 1,2-Dilauroyl-sn-glycerol-3-phosphate ethanolamine (DLPE), 1,2-Diphydanyl-sn-glycerol-3-phosphate ethanolamine (DPHyPE), Lecithin, Phosphatidylethanolamine, Lysophosphatidyl Ethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, methionine (ESM), cephalin, cardiolipin, phosphatidic acid, cerebroside, hexadecyl phosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine or mixtures thereof, preferably one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, DOPG, DPPG, DSPE, DOPS, DMPG, POPE or DPPE, more preferably DSPC and / or DOPE;

[0823] (ii) The structural lipid is a steroid or an analogue thereof;

[0824] Preferably, the steroid or its analogue is selected from alfalfa sterol, β-sitosterol, campesterol, ergocalciferol, campesterol, cholesterol, coccidosterol, dehydrocholesterol, sterol, dihydroergocalciferol, cholesterol, dihydrocholesterol, dihydroergosterol, stigmasterol, epicholesterol, ergosterol, fucosterol, hexahydrophotosterol, hydroxycholesterol, photosterol, phycosterol, sitosterol, stigmasterol, stigmasterol, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, lithocholic acid, ent-cholesterol, epicholesterol, demosterol, cholesterol, cholesterol, cholestenone, 3p-[N-(N'N'-dimethylaminoethyl)carbamoylcholesterol (DC-Chol), 2 4(S)-hydroxycholesterol, 25-hydroxycholesterol, 25(R)-27-hydroxycholesterol, 22-oxacholesterol, 23-oxacholesterol, 24-oxacholesterol, cycloluterol, 22-ketosterol, 20-hydroxysterol, 7-hydroxycholesterol, 19-hydroxycholesterol, 22-hydroxycholesterol, 25-hydroxycholesterol, 7-dehydrocholesterol, dehydroergosterol, dehydroepiandrosterone, lanosterol, dihydrolanosterol, luminesterol, citopalcitol, calcipotriol, fecal prostaglandin, cholecalciferol, lupeol, ergocalciferol, 22,23-dihydrocalciferidol, tomatine, ursolic acid, chenodeoxycholic acid, yeast sterol, diosgenin, or one or more of these compounds;

[0825] Preferably, the steroid or its analogue is selected from one or more of cholesterol, sitosterol, coccosterol, lycopene, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol;

[0826] (iii) The polymer lipid is a polyethylene glycol-modified lipid;

[0827] Preferably, the PEGylated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol;

[0828] Preferably, the PEGylated lipid contains a PEG portion of about 1000 Da to about 20 kDa, and more preferably contains a PEG portion of about 1000 Da to about 5000 Da;

[0829] Preferably, the polyethylene glycol-modified lipid is selected from polyethylene glycol-modified diacylglycerol (PEG-DAG), polyethylene glycol-modified phosphatidylethanolamine (PEG-PE), polyethylene glycol-modified succinate diacylglycerol (PEG-S-DAG), such as 4-O-(2',3'-bis(tetradecyloxy)propyl-1-O-(ω-methoxy(polyethoxy)ethyl)succinate (salt) (PEG-S-DMG), polyethylene glycol-modified ceramide (PEG-cer), or polyethylene glycol-modified dialkoxypropyl carbamate (e.g. ω- -Methoxy(polyethoxy)ethyl-N-(2,3-di(tetradecoxy)propyl)carbamate or 2,3-di(tetradecoxy)propyl-N-(ω-methoxy(polyethoxy)ethyl)carbamate), PEG-dialkoxypropylcarbamate, N-(carbonyl-methoxy polyethylene glycol 2000)-1,2-distearyl-sn-glycerol-3-phosphate ethanolamine sodium sodium, PEG-dilauroyloxypropyl, PEG-dimyristoyloxypropyl, PEG-dipalmitoyloxypropyl, PEG-distearyl 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol-PEG (DMG-PEG), distearyl-rac-glycerol-PEG (DSG-PEG), PEG-dilauroylglycerol, PEG-dipalmitoylglycerol, PEG-distearylglycerol, PEG-dilauroylglycerol amide, PEG-dimyristoylglycerol amide, PEG-dipalmitoylglycerol amide, PEG-distearylglycerol amide, (1-[8'-(cholest-5-en-3β-oxy)methyl... One or more of the following: [acylamino-3',6'-dioxaoctyl]carbamoyl-ω-methyl-poly(ethylene glycol) (PEG-cholesterol), 3,4-bistetradecoxybenzyl-ω-methyl-poly(ethylene glycol) ether (PEG-DMB), 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine-N-[methoxy(polyethylene glycol) (DSPE-PEG)] and 1,2-distearate-sn-glycerol-3-phosphate ethanolamine-N-poly(ethylene glycol)-hydroxy (DSPE-PEG-OH);

[0830] 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, preferably one or more of DSPE-PEG2000 and DMG-PEG2000, more preferably DSPE-PEG2000, and even more preferably DMG-PEG2000;

[0831] (iv) The permanent cationic compound contains quaternary ammonium ions;

[0832] Preferably, the permanent cationic compound is a permanent cationic compound of WO2024213102A1, for example, the permanent cationic compound has the structure of formula (P-1):

[0833] Or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, wherein:

[0834] It can be a single bond or a double bond;

[0835] Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -、-NR 2a C(O)NR 2a -、-OC(O)S-、-OC(O)O-、-NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -、-C(O)NR 2a -、-NR 2a C(O)-、-NR 2a C(O)S-、-SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -、-NR 2a C(S)O-、-OP(O)(OR 205 )O- or -S(O) 0-2 - and the left-hand connection is a connection in the direction of V1;

[0836] Y1 either does not exist or is -C(O)O-, -O-, -NH-, -SC(O)O-, or -OC(O)NR. 2a -、-NR 2a C(O)NR 2a -、-OC(O)S-、-OC(O)O-、-NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -、-C(O)NR 2a -、-NR 2a C(O)-、-NR 2a C(O)S-、-SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -、-NR 2a C(S)O- or -S(O) 0-2 - and the left-hand connection is a connection in the direction of V1;

[0837] R 2a Each instance is independently H, C 1-10 Alkyl, C 3-14 Cycloalkyl or 3- to 14-membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally and independently C 1-10 Alkyl, L 2b -OR 2b L b -SR 2b L 2b -NR 2b R' 2b L 2b N + R 2b R' 2b R” 2b L 2b -OC(O)R 2b or L 2b -C(O)OR 2b replace;

[0838] R 201 R 202 R 203 R 204 Each instance is independently H, OH, C 1-6 Alkyl, C 1-6 Alkoxy, -L 2b -NR 21 R 22 -L 2b -N + R 21 R 22 R23 -L 2b -OC(O)R 21 or -L 2b -C(O)OR 21 ;

[0839] R 205 Absent or cations, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Alkynyl, wherein the alkyl, haloalkyl, alkenyl, and alkynyl groups are optionally surrounded by 1, 2, 3, or 4 R groups. 20s replace;

[0840] m is an integer from 1 to 12;

[0841] m1 is an integer from 0 to 12;

[0842] V1 is NR 21 R 22 N + R 21 R 22 R 23 Imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazine, oxazoline, dithioureaazole, triazole, isothiazole, tetrazolium, pentaazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinoline, isoquinoline, amidine, guanidine, or urea;

[0843] M is absent or is an anion independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelic acid, methanesulfonate, gluconate, aspartate, or glutamate.

[0844] R 21 R 22 R 23 Each instance is independently H, optionally by 1, 2, 3 or 4 Rs. 20s Replacement C 1-8 Alkyl, -L 2b -OR 2b -L 2b -SR 2b-L 2b -NR 2b R' 2b R” 2b L 2b -OC(O)R 2b or L 2b -C(O)OR 2b ;

[0845] L 2b It does not exist or is optionally represented by 1, 2, 3 or 4 Rs 20s Replacement C 1-10 Alkylene;

[0846] R 2b 、R' 2b and R” 2b Each instance is independently H or C 1-10 alkyl;

[0847] R z1 C 1-14 Alkyl or C 1-14 Alkenyl, wherein the alkyl and alkenyl groups are optionally surrounded by 1, 2, 3 or 4 R groups. 20s replace;

[0848] R 20s Independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0849] Preferably, the permanent cationic compound is a SORT lipid in WO2020051223A1, for example, a compound selected from the structure of formula (P-2), formula (P-3) or formula (P-4).

[0850] Preferably, the permanent cationic compound has the structure of formula (P-2):

[0851] in,

[0852] R 301 and R 302 Each is C independently 8-24 Alkyl or C 8-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 301s replace;

[0853] R 301s Independently selected from H, halogen, C 1-24 Alkyl, C 1-24 Halogenated alkyl and C 2-24 Alkenyl groups, preferably H, halogens, or C. 1-24 Alkyl and C 1-24 Halogenated alkyl groups;

[0854] R 303 R 303 ′ and R 303 "Each is independent of the other." 1-6 Alkyl groups or those with 1, 2, 3 or 4 R groups 303s Replacement C 1-6 alkyl;

[0855] X - It is a monovalent anion;

[0856] R 303s Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 Alkenyl groups, preferably H, halogens, or C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0857] Preferably, the permanent cationic compound has the structure of formula (P-3):

[0858] in:

[0859] R 304 and R 304 Each is C independently 6-24 Alkyl or C 6-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 304s replace;

[0860] R 304 "It is C" 1-24 Alkyl or C 2-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 304s replace;

[0861] R 304s Independently selected from H, halogen, C 1-24 Alkyl, C 1-24 Halogenated alkyl and C 2-24 Alkenyl groups, preferably H, halogens, or C. 1-24 Alkyl and C 1-24 Halogenated alkyl groups;

[0862] R 304 "′ is C 1-8 Alkyl or C 2-8 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 304s 'replace;

[0863] R 304s 'Independently selected from H, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 2-8Alkenyl groups, preferably H, halogens, or C. 1-8 Alkyl and C 1-8 Halogenated alkyl groups; and

[0864] X2 - It is a monovalent anion;

[0865] Preferably, the permanent cationic compound has the structure of formula (P-4):

[0866] in:

[0867] R 301 and R 302 Each is C independently 8-24 Alkyl, C 8-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 301s replace;

[0868] R 301s Independently selected from H, halogen, C 1-24 Alkyl, C 1-24 Halogenated alkyl and C 2-24 Alkenyl groups, preferably H, halogens, or C. 1-24 Alkyl and C 1-24 Halogenated alkyl groups;

[0869] R 303 R 303 ′ and R 303 "Each is independent of the other." 1-6 Alkyl groups or those with 1, 2, 3 or 4 R groups 303s Replacement C 1-6 alkyl;

[0870] R 304 It is C 1-6 Alkyl groups or those with 1, 2, 3 or 4 R groups 304s Replacement C 1-6 alkyl;

[0871] R 303s and R 304s Independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and

[0872] X - It is a monovalent anion;

[0873] Preferably, the permanent cationic compound is a permanent cationic compound of US10196637B2, for example, having the structure of formula (P-5):

[0874] in:

[0875] R501 and R 502 Selected independently from C 10-18 Alkyl and C 12-18 alkenyl;

[0876] R 503 and R 504 Selected independently from C 1-6 Alkyl and -C 2-6 alkylene-OH;

[0877] X is selected from -CH2-, -S-, -O-, or does not exist;

[0878] Y is selected from -(CH2) n -、-S(CH2) n -、-O(CH2) n - Thiophene group, -SO2(CH2) n -and-C(O)O-;

[0879] n = 1, 2, 3 or 4;

[0880] a = 1, 2, 3 or 4;

[0881] b = 1, 2, 3, or 4;

[0882] c = 1, 2, 3 or 4;

[0883] Z - It is a counterion;

[0884] Preferably, the permanent cationic compound is selected from one or more of the following: N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP), ethylphosphatidylcholine (EPC) and its derivatives, 1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]butylcarbamoyl)ethyl]-3,4-di[oleoyloxy]-benzamide (MVL5), bis(octadecylamido)glycine tetramine (DOGS), N-bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteroloxycarbonylaminoethyl)ammonium bromide (BHEM-Chol), bis(octadecyl dimethylammonium bromide) (DDAB), and BHEM-Chol, DOTAP or preferred One or more of the following; preferably

[0885] (v) The ionizable lipid is selected from the following structures:

[0886] In some embodiments, the permanent cationic compound of the present invention, including its preparation method, can be found in US2017081663A1, WO2020051223A1, WO2024213102 A1, etc., the entire contents of which are incorporated herein by reference.

[0887] In some embodiments, the present invention provides lipid nanoparticles as described above, wherein the N:P molar ratio of N atoms in the ionizable lipid to P atoms in the loaded molecule is (1-15):1, preferably (2-12):1, and more preferably (2-9):1;

[0888] Preferably, the N:P molar ratio of the N atoms in the ionizable lipid to the P atoms in the loaded molecule is (2-15):1, more preferably (2-12):1, more preferably (2-10):1, more preferably (2-8):1, and even more preferably (2-6):1;

[0889] Preferably, the N:P molar ratio of the N atom in the ionizable lipid to the P atom in the loaded molecule is (1-12):1, more preferably (3-11):1, more preferably (3-10):1, and even more preferably (3-9):1.

[0890] In some embodiments, this application provides lipid nanoparticles as described above, wherein the lipid nanoparticles have a particle size of 30-500 nm, such as 30-300 nm, 30-275 nm, 30-250 nm, 30-225 nm, 30-200 nm, 30-175 nm, 30-150 nm, 30-120 nm, 30-100 nm, 40-300 nm, 40-275 nm, 40-250 nm, 40-225 nm, 40-200 nm, 40-175 nm, 40-150 nm, 40- The size of the lipid nanoparticles is 120 nm or 40-100 nm, preferably 40-80 nm, 50-80 nm, and more preferably 50-70 nm. In some embodiments, this application provides lipid nanoparticles as described above, wherein the size of the lipid nanoparticles is 40-180 nm, such as 40-170 nm, 40-160 nm, 40-150 nm, 40-140 nm, 40-130 nm, 40-120 nm, 40-110 nm, 40-100 nm, 40-90 nm, preferably 40-80 nm, and more preferably 40-70 nm.

[0891] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the auxiliary lipid is a phospholipid; preferably, the phospholipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE, and more preferably DSPC and / or DOPE.

[0892] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the structural lipid is a steroid; preferably, the steroid is selected from one or more of cholesterol, sitosterol, coccosterol, lycopene, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol.

[0893] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the polymer lipid is a polyethylene glycol-modified lipid.

[0894] Optionally, the PEGylated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol.

[0895] Optionally, the PEGylated lipid contains a PEG portion of about 1000 Da to about 20 kDa, preferably a PEG portion of about 1000 Da to about 5000 Da.

[0896] Optionally, 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.

[0897] In a more specific embodiment, the present invention also provides a pharmaceutical composition comprising the compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0898] In a more specific embodiment, the present invention also provides a method for preparing a compound of formula (I), the method comprising:

[0899] The compound of formula (IA) is reacted with the compound of formula (IB-I) or formula (IB-II) to give the compound of formula (IC);

[0900] Alternatively, reacting compound (IA) with compound (ID) yields compound (IA'), and then reacting the resulting compound (IA') with compound (IB-I) or compound (IB-II) yields compound (IC').

[0901] Wherein, PG is an independent amino protecting group, preferably Boc;

[0902] X is independently a halogen, such as Cl, Br or I, preferably Br;

[0903] All other variables are as defined in this invention;

[0904] Preferably, the compound of formula (IC) or formula (IC') is deprotected to obtain the compound of formula (I).

[0905] R8 stands for H.

[0906] 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.

[0907] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. A tautomer is a special type of functional group isomer; a pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most prominent examples are enol and keto tautomers.

[0908] Unless otherwise stated, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom in the double bond is attached to two different substituents (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered as one of the substituents it is attached to), if the atoms in the double bond and their substituents in the compound are separated by a wavy line... The connection indicates that the compound is a (Z) type isomer, an (E) type isomer, or a mixture of the two isomers.

[0909] The present invention also includes isotopically labeled compounds (isotope variants) equivalent to those described in formulas (I) and (II), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (IV) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes and / or the methods disclosed in the examples and preparation examples below.

[0910] This invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or formula (II) or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such formulations are included in this invention.

[0911] Pharmaceutical Compositions and Kits

[0912] In another aspect, the present invention provides a pharmaceutical composition comprising the nanoparticle composition of the present invention and a pharmaceutically acceptable excipient, said nanoparticle composition comprising the compounds of the present invention.

[0913] 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 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.

[0914] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the nanoparticle composition of the present invention and / or other therapeutic, diagnostic, or preventative agents. In some embodiments, the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents provided in the first and second containers form a unit dosage form.

[0915] Dosage

[0916] 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.

[0917] Typically, an effective amount of the pharmaceutical composition of the present invention is administered. The amount of pharmaceutical composition actually administered may be determined by a physician, depending on relevant circumstances, including the condition being treated or prevented, the chosen route of administration, the actual amount of pharmaceutical composition administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0918] When used to prevent the conditions described in this invention, the pharmaceutical composition provided herein is 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.

[0919] 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.

[0920] 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 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 component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component 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 intravenous infusion, thereby providing a steady-state concentration of the active component 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.

[0921] 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.

[0922] 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.

[0923] 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.

[0924] Example

[0925] To make the technical solution of the present invention clearer and more explicit, the present invention will be further described in detail through the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art. Unless otherwise specified, the materials, reagents, etc., used in the embodiments can be obtained commercially.

[0926] Table 1

[0927] Example 1: Synthesis of Compound 1

[0928] In a 2L three-necked flask, methyl isobutyrate (33.10 g, 324.04 mmol, 1.0 eq.) and tetrahydrofuran (1 L) were added. The system was cooled to -40°C, and LDA (162.02 mL, 324.04 mmol, 1.0 eq.) was added dropwise. After this, the mixture was kept at -40°C for 1 hour. At this temperature, compound 1-1 (100 g, 388.85 mmol, 1.2 eq.) was added dropwise, followed by a catalytic amount of DBU (4.98 g, 38.89 mmol, 0.12 eq.). The mixture was allowed to warm to room temperature overnight. The system was cooled to 0°C, and saturated ammonium chloride aqueous solution (1 L) was added dropwise. The mixture was extracted with ethyl acetate (3 x 500 mL). The organic phase was collected and washed with saturated brine (1 x 500 mL). The mixture was dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a yellow oily compound 1-2 (125 g, crude product), which was directly added to the next step.

[0929] Compounds 1-2 (125 g, crude) were dissolved in 800 mL of tetrahydrofuran in a 2 L three-necked flask. BH3-tetrahydrofuran (1 M, 0.45 L) was slowly added dropwise at room temperature, and the reaction was exothermic. The mixture was then heated to reflux for 5 hours, and the reaction was monitored by TLC until completion. The reaction mixture was cooled to room temperature and slowly poured into 1 L of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (3 x 500 mL), and the organic phase was collected and washed with saturated brine (1 x 1000 mL). The solution was dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give a yellow oily compound 1-3 (57.4 g).

[0930] In a 500 mL three-necked flask, compounds 1-3 (26 g, 103.84 mmol, 1.0 eq.), undecanoic acid (19.35 g, 103.84 mmol, 1.0 eq.), EDCI (24.18 g, 155.76 mmol, 1.5 eq.), and DMAP (2.54 g, 20.77 mmol, 0.2 eq.) were dissolved in dichloromethane (260 mL) at room temperature and reacted overnight at room temperature. The reaction was quenched with 200 mL of water, extracted with dichloromethane (2 x 200 mL), washed with brine (1 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to give a yellow oily compound 1-4 (35 g).

[0931] In a 500 mL single-necked flask, 1-4 (35 g, 83.60 mmol, 1.0 eq.), Pd / C (3.5 g), isopropanol (300 mL), and tetrahydrofuran (50 mL) were added. After replacing the air in the reaction system with hydrogen three times, a hydrogen gas supply was connected, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LC-MS until the reactants were almost completely reacted. The mixture was then filtered, the filter cake was washed with ethanol, and the filtrates were combined and concentrated to give a yellow oily compound 1-5 (33 g, crude product). This compound was used directly in the next reaction without further purification.

[0932] Oxaloyl chloride (27.10 g, 273.94 mmol, 3.0 eq.) and dichloromethane (300 mL) were added to a 1 L three-necked flask. The system was cooled to -60 °C, and DMSO (42.81 g, 547.88 mmol, 6.0 eq.) was slowly added dropwise. After this was completed, the mixture was kept at -25 °C for 10 minutes. Then, compounds 1-5 (30 g, crude product) were dissolved in dichloromethane (300 mL) and added dropwise to the system at the same temperature, and the mixture was kept at this temperature for 1 hour. Triethylamine (55.44 g, 547.88 mmol, 6.0 eq.) was then slowly added to the system. The mixture was allowed to warm naturally to room temperature and the reaction was continued for 1 hour. The system was cooled to 0°C, quenched with 150 mL of water, extracted with dichloromethane (2 x 250 mL), washed with organic phase brine (1 x 150 mL), dried over anhydrous Na2SO4, filtered, and purified by silica gel column chromatography to obtain yellow oily compound 1-6 (16.8 g).

[0933] In a 250 mL three-necked flask, tetraethylenepentamine 1-7 (3.0 g, 15.85 mmol, 1.0 eq.) and dichloromethane (150 mL) were added at room temperature. Ethyl trifluoroacetate (4.73 g, 33.28 mmol, 2.1 eq.) dissolved in dichloromethane (65 mL) was added dropwise to the system at 0 °C over 1 hour. The reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was not treated and was directly added to the next step.

[0934] Boc anhydride (13.83 g, 63.36 mmol, 4.0 eq.) was dissolved in dichloromethane (24 mL) and added dropwise to the synthesis reaction system 1-8 over 0.5 hours. Then, triethylamine (6.41 g, 63.36 mmol, 4.0 eq.) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was concentrated to 50 mL under reduced pressure, and extracted with water (50 mL). The aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined organic phases were washed with saturated NaHCO3 (3 x 100 mL), 5% citric acid (100 mL), and water (100 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was redissolved in hexane:dichloromethane (60 mL:16 mL), stirred at 0 °C for 3 hours, filtered, and the filter cake was washed with hexane:dichloromethane (3.75:1 mL) (3 x 5 mL). The filter cake was collected to obtain a white crude product (5.38 g). 3 g of the crude product was purified by silica gel column chromatography to obtain 1.96 g of yellow oily compound 1-9.

[0935] Compound 1-9 (1.96 g, 2.88 mmol, 1.0 eq.) and ethanol (25 mL) were added to a 250 mL three-necked flask at room temperature, followed by slow dropwise addition of NaOH (25 mL, 3 M) over 30 minutes. The mixture was stirred at room temperature for 6 hours. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give 877 mg of a yellow oily compound 1-10.

[0936] Compound 1-10 (182.6 mg, 0.37 mmol, 1.0 eq.), aldehyde 1-6 (547.9 mg, 1.68 mmol, 4.5 eq.), and tetrahydrofuran (18.2 mL) were added to a 40 mL sealed tube at room temperature. The mixture was stirred at room temperature for 4 h, then cooled to 0 °C. Sodium triacetoxyborohydride (1.11 g, 5.22 mmol, 14.0 eq.) was added in portions, and the mixture was slowly heated to room temperature for another 18 h. The reaction was monitored by LC-MS, and the starting material was completely converted. The mixture was cooled to 0 °C, and the reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated NaCl (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give 880 mg of crude yellow oily compound 1-11.

[0937] Crude product 1-11 (880 mg) and 6 mL of dichloromethane were added to a 50 mL round-bottom flask at room temperature. The system was cooled to 0 °C, and 2 mL of trifluoroacetic acid was added dropwise. The reaction was carried out at room temperature for 2 h, and the reaction was monitored by LC-MS. The starting material was basically completely converted. The system was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography. Column: XBridge Prep Phenyl OBD, 30 x 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 1% NH3·H2O) / CH3CN = 6:4, Mobile Phase B: CH3CN / IPA = 1:9; Flow rate: 60 mL / min; Gradient (B%): 68% B to 94% B in 12 min; Wave Length: 254 nm / 220 nm; RT1 (min): 9.5, yielding a yellow oily compound 1 (147.2 mg).

[0938] 1 H NMR (300MHz, CDCl3): δ3.78(s,8H),2.78(s,8H),2.73-2.58(m,8H),2.56-2.2 9(m,16H),1.68-1.57(m,8H),1.53-1.24(m,89H),0.93-0.85(m,36H); ESI-MS m / z:716.55

[0939] [M / 2+H] + .

[0940] Example 2: Synthesis of Compound 2

[0941] In a 250 mL three-necked flask at room temperature, N,N'-di(2-aminoethyl)-1,3-propanediamine 2-1 (2.00 g, 12.48 mmol, 1.0 eq.) and triethylamine (3.79 g, 37.44 mmol, 3.0 eq.) were dissolved in 100 mL of methanol, and ethyl trifluoroacetate (4.43 g, 31.20 mmol, 2.5 eq.) was slowly added dropwise. The mixture was stirred at room temperature for 8 hours. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give 1.92 g of a white solid 2-2.

[0942] Compound 2-2 (1.92 g, 5.45 mmol, 1.0 eq.), Boc-anhydride (3.57 g, 16.35 mmol, 3.0 eq.), triethylamine (3.31 g, 32.70 mmol, 6.0 eq.), and tetrahydrofuran (23 mL) were added to a 100 mL single-necked flask at room temperature. The system was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was cooled to 0 °C, and the reaction was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated NaCl (1 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was redissolved in MTBE (20 mL), slurried, filtered, and the filter cake was washed with MTBE (3 x 5 mL). The filter cake was collected, dried, and yielded white crude product 2-3 (2.25 g).

[0943] Compound 2-3 (2.25 g, 4.07 mmol, 1.0 eq.) and ethanol (27 mL) were added to a 250 mL three-necked flask at room temperature. NaOH (27 mL, 3 M) was then slowly added dropwise over 30 minutes, and the mixture was stirred at room temperature and allowed to react overnight. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was concentrated under reduced pressure to obtain a crude product (2.5 g), which was then purified to give compound 2-4 (800 mg).

[0944] Compound 2-4 (80 mg, 0.22 mmol, 1.0 eq.), aldehyde 1-6 (326.1 mg, 1.0 mmol, 4.5 eq.), and tetrahydrofuran (5 mL) were added to a 40 mL sealed tube at room temperature. The reaction was allowed to proceed at room temperature for 4 h. The system was then cooled to 0 °C, and STAB (658.46 mg, 3.11 mmol, 14.0 eq.) was added in portions. The mixture was then brought back to room temperature and stirred for another 18 h. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was cooled to 0 °C, and the reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated NaCl (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude yellow oily compound 2-5 (430 mg).

[0945] Compound 2-5 (430 mg) was dissolved in 3 mL of dichloromethane in a 10 mL single-necked flask. The system was cooled to 0 °C, and 1 mL of trifluoroacetic acid was added dropwise. The reaction was carried out at room temperature for 2 h, and the reaction was monitored by LC-MS. The starting material was basically completely converted. The system was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain a yellow oily compound 2 (136.3 mg).

[0946] 1H NMR (300MHz, CDCl3): δ3.78 (s, 8H), 2.79-2.59 (m, 15H), 2.41 (m, 8H), 2.31 (t, J = 7.5Hz, 8H), 1 .82(bs,2H),1.68-1.58(m,8H),1.43(m,8H),1.35-1.24(m,79H),0.89-0.86(m,36H); ESI-MS m / z:702.05[M / 2+H] + .

[0947] Example 3: Synthesis of Compound 3

[0948] Compound 3 was prepared according to the method in Example 1, yielding 86.3 mg of an oily product.

[0949] 1 H NMR (300MHz, CDCl3): δ3.78(s,8H),2.77-2.56(m,16H),2.42-2.27(m,16H),2. 10(bs,3H),1.65-1.58(m,8H),1.42-1.24(m,124H),0.90-0.88(m,48H); ESI-MS m / z:884.65[M / 2+H] + .

[0950] Example 4: Synthesis of Compound 4

[0951] Compound 4 was prepared according to the method of Example 1, yielding 112 mg of an oily product.

[0952] 1 H NMR (300MHz, CDCl3): δ5.76 (s, 3H), 3.26-3.19 (dd, J=14.7Hz, 6.0Hz, 8H), 2.76 (m, 8H), 2.64 (d, J=6.0Hz, 4H), 2.55 (d, J=5 .4Hz,4H),2.38(t,J=6.6Hz,8H),2.17-2.02(m,14H),1.68-1.58(m,9H),1.47-1.18(m,127H),0.92-0.89(m,24H); ESI-MS m / z:798.65[M / 2+H] + .

[0953] Example 5: Synthesis of Compound 5

[0954] Compound 5 was prepared according to the method of Example 1, yielding 95.7 mg of an oily product.

[0955] 1 H NMR (300MHz, CDCl3): δ3.78(s,8H),2.76(s,12H),2.66(t,J=6.0Hz,4H),2.55(t,J=5.4Hz,4H),2. 42-2.31(m,16H),2.13(bs,4H),1.65-1.58(m,8H),1.48-1.23(m,89H),0.92-0.89(m,36H); ESI-MS m / z:738.00[M / 2+H] + .

[0956] Example 6: Synthesis of Compound 6

[0957] Under nitrogen protection, 8-hydroxyoctanoic acid (15 g, 93.63 mmol, 1.0 eq.), imidazole (9.56 g, 140.44 mmol, 1.5 eq.), and TBDPSCl (28.31 g, 102.99 mmol, 1.1 eq.) were dissolved in DMF (150 mL) and reacted overnight at room temperature. The solution was diluted with ethyl acetate (200 mL) and washed with saturated brine (3 x 500 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give a pale yellow oily compound 6-1 (30 g).

[0958] Compound 6-1 (11 g, 27.59 mmol, 1.05 eq.), n-decyl alcohol (4.16 g, 26.28 mmol, 1.0 eq.), EDCI (7.93 g, 41.37 mmol, 1.5 eq.), and DMAP (0.67 g, 5.48 mmol, 0.2 eq.) were dissolved in 100 mL of dichloromethane and reacted overnight at room temperature. The reaction was quenched with 100 mL of water, the organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give compound 6-2 (12.5 g) as a colorless oil.

[0959] A tetrahydrofuran solution of TABF (1 M, 46.38 mL) was added to a tetrahydrofuran solution of compound 6-2 (12.5 g, 23.19 mmol, 1.0 eq.) at room temperature, and the reaction was allowed to proceed overnight at room temperature. The solution was diluted with ethyl acetate (150 mL), washed with saturated brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and purified by silica gel column chromatography to give a pale yellow oily compound 6-3 (6.4 g).

[0960] Dichloromethane (200 mL) was added to a 500 mL three-necked flask, and the mixture was cooled to -60 °C under nitrogen protection. Oxaloyl chloride (14.95 g, 117.81 mmol, 3.0 eq.) was added. DMSO (18.4 g, 235.62 mmol, 6.0 eq.) was slowly added dropwise, followed by a slow increase in temperature to -25 °C and stirring for 10 minutes. Compound 6-3 (11.8 g, 39.27 mmol, 1.0 eq.) was dissolved in 50 mL of tetrahydrofuran and added dropwise to the above reaction system. The mixture was stirred at -25 °C for 1 hour, followed by the addition of triethylamine (23.84 g, 235.62 mmol, 6.0 eq.), and then the mixture was brought to room temperature and stirred for 1 hour. After the reaction was completed, the reaction system was cooled to 0℃, ice water (300mL) was added dropwise, and the organic phases were extracted with dichloromethane and combined. The mixture was dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by gel column chromatography to obtain a light yellow oily compound 6-4 (9.3g).

[0961] Compound 6 was prepared according to the method of Example 1, yielding 129.2 mg of an oily product.

[0962] 1 H NMR (300MHz, CD3OD): δ4.06 (t, J=6.6Hz, 8H), 2.75 (s, 4H), 2.70-2.40 (m, 16H), 2.31 ( t,J=7.2Hz,8H),1.68-1.61(m,24H),1.47-1.25(m,87H),0.95-0.85(m,12H); ESI-MS m / z:660.35[M / 2+H] + .

[0963] Example 7: Synthesis of Compound 7

[0964] Compound 7 was prepared according to the method of Example 6, yielding 156.7 mg of an oily product.

[0965] 1 H NMR (300MHz, CD3OD): δ4.07(t,J=6.6Hz,8H),2.75-2.58(m,12H),2.47(t,J=6.9Hz,6H),2 .30(t,J=7.2Hz,8H),1.63-1.58(m,16H),1.48-1.24(m,89H),0.92-0.88(m,12H); ESI-MS m / z:660.30[M / 2+H] + .

[0966] Example 8: Synthesis of Compound 8

[0967] Compound 8 was prepared according to the method of Example 6, yielding 99.9 mg of an oily product.

[0968] 1 H NMR (300MHz, CDCl3): δ4.05 (t, J = 6.6Hz, 8H), 2.91-2.56 (m, 24H), 2.47-2.26 (m, 16H) ),2.02(m,4H),1.72-1.59(m,13H),1.50-1.26(m,84H),0.92-0.88(m,12H); ESI-MS m / z:680.90[M / 2+H] + .

[0969] Example 9: Synthesis of Compound 9

[0970] Compound 9 was prepared according to the method of Example 6, yielding 200.4 mg of an oily product.

[0971] 1 H NMR (300MHz, CDCl3): δ4.05 (t, J=6.6Hz, 8H), 2.79-2.26 (m, 36H), 1.64-1.59 (m, 16H), 1.43-1.27 (m, 88H), 0.94-0.88 (m, 12H); ESI-MS m / z:681.90[M / 2+H] + .

[0972] Example 10: Synthesis of Compound 10

[0973] Compound 10 was prepared according to the method of Example 6, yielding 210.6 mg of an oily product.

[0974] 1 H NMR (300MHz, CD3OD): δ5.45-5.39(m,8H),4.05(t,J=6.6Hz,8H),2.73-2.31(m,32H),2 .10-1.96(m,16H),1.72-1.61(m,18H),1.52-1.24(m,72H),0.94-0.88(m,12H); ESI-MS m / z:656.25[M / 2+H] + .

[0975] Example 11: Synthesis of Compound 11

[0976] Compound 11 was prepared according to the method of Example 6, yielding 226.9 mg of an oily product.

[0977] 1 H NMR (300MHz, CDCl3): δ5.43-5.26(m,8H),4.06(t,J=6.6Hz,8H),3.06-2.60(m,16H),2.53-2.26(m,16H),2 .10-1.99(m,16H),1.68-1.59(m,16H),1.45-1.26(m,48H),0.98-0.93(m,12H),0.88-0.83(m,6H); ESI-MS m / z:621.45[M / 2+H] + .

[0978] Example 12: Synthesis of Compound 12

[0979] Compound 12 was prepared according to the method of Example 1, yielding an oily product of 460.6 mg.

[0980] 1 H NMR (400MHz, CD3OD): δ3.80(s,8H),2.75-2.59(m,12H),2.46(t,J=7.2Hz,8H),2.33(t,J=7.2Hz ,8H),1.62(t,J=7.2Hz,8H),1.52-1.48(m,8H),1.42-1.28(m,80H),0.94-0.90(m,36H); ESI-MS m / z:695.00[M / 2+H] + .

[0981] Example 13: Synthesis of Compound 13

[0982] Compound 13 was prepared according to the method of Example 1, yielding an oily product of 495.0 mg.

[0983] 1 H NMR (300MHz, CDCl3): δ3.78(s,8H),2.76(m,8H),2.66-2.54(m,8H),2.39(t,J=6.9Hz,8H),2.31(t, J=7.5Hz,8H),1.65-1.58(m,8H),1.48-1.42(m,8H),1.40-1.24(m,97H),0.94-0.89(m,36H); ESI-MS m / z:772.55[M / 2+H] + .

[0984] Example 14: Synthesis of Compound 14

[0985] Compound 14 was prepared according to the method of Example 1, yielding an oily product of 367.5 mg.

[0986] 1 H NMR (300MHz, CDCl3): δ3.78(s,8H),2.80-2.75(m,12H),2.66-2.54(m,8H),2.39(t,J=7.2Hz,8H),2.31( t,J=7.5Hz,8H),1.65-1.60(m,8H),1.48-1.42(m,8H),1.41-1.18(m,100H),0.98-0.86(m,36H); ESI-MS m / z:709.95[M / 2+H] + .

[0987] Example 15: Synthesis of Compound 15

[0988] Compound 15 was prepared according to the method of Example 1, yielding 248.8 mg of an oily product.

[0989] 1 H NMR (300MHz, CDCl3): δ3.78(s,8H),2.95-2.57(m,26H),2.40(m,8H),2.31(t,J=7.5Hz,8H ),1.65-1.60(m,8H),1.48-1.42(m,8H),1.40-1.18(m,118H),0.89-0.86(m,36H); ESI-MS m / z:878.10[M / 2+H] + .

[0990] Example 16: Synthesis of Compound 16

[0991] Compound 16 was prepared according to the method of Example 1, yielding 260.3 mg of an oily product.

[0992] 1 H NMR (300MHz, CDCl3): δ5.62-5.48(m,8H),3.79(s,8H),3.10(m,4H),3.02(m,4H),2.77-2.56( m,16H),2.48-2.40(m,8H),2.08-1.99(m,8H),1.56-1.21(m,91H),0.91-0.86(m,36H); ESI-MS m / z:768.45[M / 2+H] + .

[0993] Example 17: Synthesis of Compound 17

[0994] Compound 17 was prepared according to the method of Example 1, yielding 261.4 mg of an oily product.

[0995] 1 H NMR (300MHz, CDCl3): δ3.78(s,8H),2.75(s,8H),2.69-2.61(m,4H),2.57-2.51(m,4H),2.41-2.37(m,8H),2 .31(t,J=7.5Hz,8H),1.65-1.58(m,8H),1.49-1.42(m,8H),1.41-1.24(m,75H),0.95-0.89(m,36H); ESI-MS m / z:688.40[M / 2+H] + .

[0996] Example 18: Synthesis of Compound 18

[0997] Under nitrogen protection, dodecaneamine (5 g, 26.98 mmol, 1.0 eq.) and triethylamine (8.19 g, 80.93 mmol, 3.0 eq.) were dissolved in dichloromethane (50 mL), and acryloyl chloride (2.69 g, 29.67 mmol, 1.10 eq.) was added dropwise at 0 °C. After the addition was complete, the mixture was slowly brought to room temperature and stirred overnight. After the reaction was complete, water (100 mL) was added to quench the reaction. The organic phases were extracted with dichloromethane and combined, washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give a white solid compound 18-1 (5.4 g).

[0998] Compound 18-1 (1.47 g, 6.10 mmol, 10.0 eq.), compound 1-10 (300 mg, 0.61 mmol, 1.0 eq.), and H3BO3 (9 mL) were dissolved in ethanol (9 mL) in a 40 mL sealed tube and stirred at 80 °C for 7 days. The reaction system was cooled to room temperature, and the organic solvent was removed by rotary evaporation. The crude product was extracted with brine and ethyl acetate to separate the layers. The organic phase was collected, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give a yellow oily compound 18-2.

[0999] Compound 18-2 (600 mg) and dichloromethane (6 mL) were added to a 100 mL single-necked flask at room temperature. The system was cooled to 0 °C, and TFA (2 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was monitored by LC-MS. The starting material was essentially completely converted. The system was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain a white solid compound 18 (165.3 mg).

[1000] 1 H NMR (300MHz, CD3OD): δ3.15 (t, J=7.2Hz, 8H), 2.76-2.69 (m, 16H), 2.59-2.57 (m, 4H), 2.3 2(t,J=6.6Hz,8H),1.51-1.48(m,8H),1.34-1.23(m,69H),0.90(t,J=6.6Hz,12H); ESI-MS m / z:574.25[M / 2+H] + .

[1001] Example 19: Synthesis of Compound 19

[1002] Compound 19 was prepared according to the method of Example 18, yielding 227.2 mg of an oily product.

[1003] 1 H NMR (300MHz, CD3OD): δ3.15 (t, J=7.2Hz, 8H), 2.75-2.66 (m, 23H), 2.59-2.57 (m, 4H), 2.3 2(t,J=6.6Hz,8H),1.52-1.48(m,8H),1.34-1.24(m,73H),0.90(t,J=6.6Hz,12H); ESI-MS m / z:595.85[M / 2+H] + .

[1004] Example 20: Synthesis of Compound 20

[1005] In a 250 mL three-necked round-bottom flask, n-undecyl alcohol (4.66 g, 27.04 mmol, 1.0 eq.), Boc-glycine (5.21 g, 29.75 mmol, 1.1 eq.), EDCI (6.30 g, 40.57 mmol, 1.5 eq.), DMAP (0.66 g, 5.41 mmol, 0.2 eq.), and dichloromethane (47 mL) were added at room temperature. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was monitored by TLC until the reactants were almost completely reacted. The mixture was concentrated under reduced pressure, redissolved in ethyl acetate (50 mL), and extracted with saturated NH4Cl (50 mL). The organic phase was washed with saturated NaCl (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give a colorless oily compound 20-1 (8.38 g).

[1006] 20-1 (8.38 g, 25.43 mmol, 1.0 eq.) and dichloromethane (42 mL) were added to a 250 mL three-necked flask at room temperature. The system was cooled to 0 °C, and dioxane hydrochloride solution (42 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by LC-MS, and the starting material was completely converted. The system was concentrated to give crude yellow oily compound 20-2 (6.4 g).

[1007] Compound 20-2 (6.4 g, 24.08 mmol, 1.0 eq.) and DIEA (9.34 g, 72.24 mmol, 3.0 eq.) were dissolved in dichloromethane (300 mL) at room temperature in a 1 L three-necked flask. The system was cooled to 0 °C, and acryloyl chloride (2.18 g, 24.08 mmol, 1.0 eq.) was added dropwise. The system was stirred at 0 °C for 1 h. The reaction was monitored by TLC until the reactants were almost completely reacted. The mixture was concentrated under reduced pressure, extracted with ethyl acetate (20 mL), and the combined organic phases were washed with saturated NaCl (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give a colorless oily compound 20-3 (4.47 g).

[1008] Compound 20 was prepared according to the method of Example 18, yielding 216.6 mg of an oily product.

[1009] 1 H NMR (300MHz, CD3OD): δ4.12(t,J=6.6Hz,8H),3.93(s,8H),2.83-2.64(m,24H),2.43(t ,J=6.0Hz,8H),1.67-1.60(m,8H),1.39-1.25(m,67H),0.90(t,J=6.6Hz,12H); ESI-MS m / z:662.25[M / 2+H] + .

[1010] Example 21: Synthesis of Compound 21

[1011] Compound 21 was prepared according to the method of Example 20, yielding 88.9 mg of an oily product.

[1012] 1 H NMR (300MHz, CD3OD): δ4.13 (t, J=6.6Hz, 8H), 3.93 (s, 8H), 2.99-2.67 (m, 28H), 2.43 (t,J=6.0Hz,8H),1.68-1.61(m,8H),1.39-1.23(m,72H),0.92-0.89(m,12H); ESI-MS m / z:683.95[M / 2+H] + .

[1013] Example 22: Synthesis of Compound 22

[1014] Compound 1-10 (7.0 g, 14.30 mmol, 1.0 eq.) and epoxide 22-1 (527.16 mg, 2.86 mmol, 0.2 eq.) were dissolved in ethanol (150 mL) in a round-bottom flask. The reaction mixture was heated to 70 °C and reacted until the reactants were completely consumed. After cooling the reaction system to room temperature, the organic solvent was removed by rotary evaporation. The crude product was redissolved in ethyl acetate and saturated brine, extracted and separated into layers. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the crude product obtained after solvent removal was purified by silica gel column chromatography to give compound 22-2 (5.5 g).

[1015] Under nitrogen protection, 1-octanol (10 g, 76.79 mmol, 1.0 eq.), Boc-5-aminovaleric acid (18.35 g, 84.47 mmol, 1.1 eq.), DCC (23.77 g, 115.18 mmol, 1.5 eq.), and DMAP (1.88 g, 15.34 mmol, 0.2 eq.) were dissolved in dichloromethane (100 mL) in a 500 mL single-necked flask and stirred overnight at room temperature. The mixture was extracted with water (100 mL), washed with organic phase brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. Purification by silica gel column chromatography yielded a pale yellow oily compound 22-4 (13.6 g).

[1016] Compound 22 was prepared according to the method of Example 18, yielding 104.1 mg of an oily product.

[1017] 1H NMR (300MHz, CD3OD): δ4.06 (t, J=6.6Hz, 6H), 3.18 (t, J=6.9Hz, 6H), 2.80-2.4 1(m,20H),2.37-2.32(m,14H),1.64-1.26(m,72H),0.94-0.90(m,12H); ESI-MS m / z:612.70[M / 2+H] + .

[1018] Example 23: Synthesis of Compound 23

[1019] Compound 23 was prepared according to the method of Example 22, yielding 123.0 mg of an oily product.

[1020] 1 H NMR (300MHz, CD3OD): δ4.08 (t, J=6.6Hz, 6H), 3.63-3.56 (m, 2H), 3.20 (t, J=6.6Hz, 6H), 2.77-2.41 (m,20H),2.33-2.28(m,14H),1.69-1.58(m,18H),1.40-1.24(m,50H),0.92-0.89(m,12H); ESI-MS m / z:612.50[M / 2+H] + .

[1021] Example 24: Synthesis of Compound 24

[1022] Compound 24 was prepared according to the method of Example 18, yielding 60.0 mg of an oily product.

[1023] 1 H NMR (300MHz, CD3OD): δ4.06 (t, J=6.6Hz, 8H), 3.18 (t, J=6.6Hz, 8H), 2.83-2.60 (m, 20H), 2.37-2.33(m,16H),1.66-1.51(m,24H),1.42-1.28(m,40H),0.96-0.90(m,12H); ESI-MS m / z:662.25[M / 2+H] + .

[1024] Example 25: Synthesis of Compound 25

[1025] Compound 25 was prepared according to the method of Example 18, yielding 45.1 mg of an oily product.

[1026] 1H NMR (300MHz, CD3OD): δ4.06 (t, J=6.6Hz, 8H), 3.18 (t, J=6.9Hz, 8H), 2.83-2.62 (m, 22H), 2.37-2.32(m,14H),1.68-1.47(m,24H),1.43-1.25(m,44H),0.92-0.88(m,12H); ESI-MS m / z:683.75[M / 2+H] + .

[1027] Example 26: Synthesis of Compound 26

[1028] Compound 26 was prepared according to the method of Example 22, yielding 269.0 mg of an oily product.

[1029] 1 H NMR (300MHz, CD3OD): δ4.08(t,J=6.6Hz,6H),3.15(t,J=6.9Hz,6H),2.88-2.41(m,30H) ,2.21-2.19(m,6H),1.75-1.66(m,12H),1.54-1.25(m,60H),0.95-0.90(m,12H); ESI-MS m / z:612.60[M / 2+H] + .

[1030] Example 27: Synthesis of Compound 27

[1031] Compound 27 was prepared according to the method of Example 18, yielding 111.2 mg of an oily product.

[1032] 1 H NMR (400MHz, CD3OD): δ4.10(t,J=6.8Hz,8H),3.18(t,J=7.2Hz,8H),2.79-2.59(m,22H),2.50-2.47(m,8H) ,2.25-2.22(m,8H),1.70-1.65(m,16H),1.53-1.51(m,8H),1.41-1.29(m,42H),0.96-0.92(m,12H); ESI-MS m / z:662.25[M / 2+H] + .

[1033] Example 28: Synthesis of Compound 28

[1034] Compound 28-1 (9.0 g, 70.24 mmol, 1.0 eq.) and N-Boc-hydrazine (10.2 g, 77.26 mmol, 1.1 eq.) were added to water in a round-bottom flask. The reaction system was reacted at room temperature. The reaction was confirmed to be complete by LC-MS. After removing the solvent, crude product 28-2 (20.08 g) was obtained. No purification was required, and it was used directly in the next reaction.

[1035] The crude product of compound 28-2 (20.08 g, 79.9 mmol, 1.0 eq.), EDCI (22.98 g, 119.9 mmol, 1.5 eq.), and DMAP (1.95 g, 16.0 mmol, 0.2 eq.) were dissolved in 500 mL of dichloromethane and reacted at room temperature for 2 h. After the reaction was completed, saturated brine was added to quench the reaction. The organic phases were extracted and combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain compound 28-3 (7.6 g).

[1036] A solution of dioxane hydrochloride was added to a dichloromethane solution of compound 28-3 (7.6 g), and the reaction was carried out at room temperature for 2 h. After removing the solvent by rotary evaporation, crude compound 28-4 (6.04 g) was obtained, which could be used directly in the next reaction without purification.

[1037] Compound 28-4 (6.04 g, 18.71 mmol, 1.0 eq.) and sodium bicarbonate (3.14 g, 37.42 mmol, 2.0 eq.) were dissolved in a mixed solvent of tetrahydrofuran and water (10:1). After stirring at room temperature for 10 min, acryloyl chloride (2.03 g, 22.45 mmol, 1.2 eq.) was added to the reaction system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, saturated brine was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain compound 28-5 (3.6 g).

[1038] Compound 28 was prepared according to the method of Example 18, yielding 29.3 mg of an oily product.

[1039] 1 H NMR (300MHz, CD3OD): δ4.06 (t, J=6.6Hz, 8H), 3.80-3.48 (m, 26H), 2.90-2.78 (m, 10H), 2 .38-2.30(m,18H),1.78-1.61(m,26H),1.40-1.27(m,54H),0.94-0.91(m,12H); ESI-MS m / z:797.85[M / 2+H] + .

[1040] Example 29: Synthesis of Compound 29

[1041] Compound 29 was prepared according to the method of Example 28, yielding an oily product of 449.4 mg.

[1042] 1 H NMR (300MHz, CD3OD): δ4.05 (t, J=6.6Hz, 8H), 2.87-2.58 (m, 24H), 2.41-2.20 (m,26H),1.67-1.58(m,26H),1.43-1.24(m,56H),0.92-0.88(m,12H); ESI-MS m / z:776.35[M / 2+H] + .

[1043] Example 30: Synthesis of Compound 30

[1044] Compound 30 was prepared according to the method described in the above embodiments, yielding 152.5 mg of an oily product.

[1045] 1 H NMR (300MHz, CD3OD): δ4.53-4.48(m,3H),4.14(t,J=6.3Hz,6H),4.01-3.96(m,3H),3.63-3.62(m,2H),3.12-3.03(m ,4H),2.96-2.55(m,30H),2.31(t,J=7.5Hz,8H),1.87-1.58(m,24H),1.46-1.09(m,52H),0.97-0.89(m,12H); ESI-MS m / z:630.80[M / 2+H] + .

[1046] Example 31: Synthesis of Compound 31

[1047] Compound 31 was prepared according to the method of Example 18, yielding 175.0 mg of an oily product.

[1048] 1H NMR (300MHz, CD3OD): δ4.53-4.49(m,4H),4.14(t,J=6.6Hz,8H),4.01-3.97(m,4H),3.54(m,2H),3.12-3.08(m,6H ),3.04-2.56(m,36H),2.31(t,J=7.2Hz,8H),1.85-1.56(m,24H),1.40-1.07(m,38H),0.93-0.88(m,12H); ESI-MS m / z:686.20[M / 2+H] + .

[1049] Example 32: Synthesis of Compound 32

[1050] Compound 32 was prepared according to the method of Example 18, yielding 178.9 mg of an oily product.

[1051] 1 H NMR (300MHz, CD3OD): δ4.53-4.48(m,4H),4.14(t,J=6.3Hz,8H),3.98-3.94(m,4H),3.12-3.03(m,4H),2.9 3-2.55(m,38H),2.31(t,J=7.5Hz,8H),1.84-1.52(m,32H),1.40-1.03(m,36H),0.93-0.88(m,12H); ESI-MS m / z:707.70[M / 2+H] + .

[1052] Example 33: Synthesis of Compound 33

[1053] Compound 33 was prepared according to the method of Example 6, yielding 96.8 mg of an oily product.

[1054] 1 H NMR (300MHz, CD3OD): δ4.53-4.49(m,4H),4.14(t,J=6.6Hz,8H),4.02-3.98(m,4H),3.63-3.54(m,2H),3.10-3.02(m ,4H),2.78-2.38(m,32H),2.31(t,J=7.2Hz,8H),1.83-1.59(m,34H),1.40-1.03(m,34H),0.93-0.88(m,12H); ESI-MS m / z:714.20[M / 2+H] + .

[1055] Example 34: Synthesis of Compound 34

[1056] Compound 34 was prepared according to the method of Example 6, yielding 60.4 mg of an oily product.

[1057] 1 H NMR (300MHz, CD3OD): δ4.53-4.49(m,4H),4.14(t,J=6.3Hz,8H),3.98-3.94(m,4H),3.54(m,2H),3.10-3.02(m,4H ),2.83-2.38(m,32H),2.31(t,J=7.2Hz,8H),1.84-1.50(m,36H),1.40-1.03(m,56H),0.92-0.88(m,12H); ESI-MS m / z:798.40[M / 2+H] + .

[1058] Example 35: Synthesis of Compound 35

[1059] Compound 35 was prepared according to the method of Example 6, yielding an oily product of 464.3 mg.

[1060] 1 H NMR (300MHz, CD3OD): δ4.53-4.49(m,3H),4.14(t,J=6.3Hz,6H),3.98-3.94(m,3H),3.54(m,2H),3.11-3.03(m,4H),2.98-2 .89(m,14H),2.69-2.41(m,20H),2.31(t,J=7.2Hz,8H),1.84-1.59(m,30H),1.40-1.07(m,52H),0.91-0.88(m,12H); ESI-MS m / z:673.35[M / 2+H] + .

[1061] Example 36: Synthesis of Compound 36

[1062] Compound 36 was prepared according to the method of Example 6, yielding 214.7 mg of an oily product.

[1063] 1H NMR (400MHz, CD3OD): δ4.53-4.49(m,3H),4.14(t,J=6.4Hz,6H),4.01-3.95(m,3H),3.63-3.62(m,2H),3.12-3.06(m ,4H),2.89-2.39(m,30H),2.31(t,J=7.2Hz,6H),1.83-1.57(m,26H),1.49-1.10(m,46H),0.92-0.88(m,12H); ESI-MS m / z:651.85[M / 2+H] + .

[1064] Example 37: Synthesis of Compound 37

[1065] Compound 37 was prepared according to the method of Example 6, yielding 239.1 mg of an oily product.

[1066] 1 H NMR (300MHz, CD3OD): δ4.53-4.49(m,3H),4.14(t,J=6.3Hz,6H),3.98-3.94(m,3H),3.62-3.53(m,2H),3.11-3.02(m ,4H),2.89-2.41(m,36H),2.31(t,J=7.2Hz,8H),1.89-1.52(m,28H),1.47-1.08(m,60H),0.93-0.89(m,12H); ESI-MS m / z:722.35[M / 2+H] + .

[1067] Example 38: Synthesis of Compound 38

[1068] Compound 38 was prepared according to the method of Example 6, yielding an oily product of 335.8 mg.

[1069] 1 H NMR (300MHz, CD3OD): δ4.53-4.49(m,3H),4.14(t,J=6.3Hz,6H),3.98-3.94(m,3H),3.62-3.53(m,2H),3.11-3.02(m ,4H),2.89-2.41(m,36H),2.31(t,J=7.2Hz,8H),1.89-1.52(m,28H),1.47-1.08(m,64H),0.93-0.89(m,12H); ESI-MS m / z:736.40[M / 2+H] + .

[1070] Example 39: Synthesis of Compound 39

[1071] Compound 39 was prepared according to the method of Example 28, yielding 106.6 mg of an oily product.

[1072] 1 H NMR (300MHz, CD3OD): δ4.06 (t, J=6.6Hz, 6H), 3.63 (m, 1H), 2.78-2.48 (m, 22H), 2.40 -2.12(m,22H),1.79-1.62(m,22H),1.47-1.08(m,58H),0.93-0.89(m,12H); ESI-MS m / z:705.85[M / 2+H] + .

[1073] Example 40: Synthesis of Compound 40

[1074] Compound 40 was prepared according to the method of Example 1, yielding 193.5 mg of an oily product.

[1075] 1 H NMR (300MHz, CD3OD): δ3.78(s,8H),2.75(m,8H),2.66-2.64(m,4H),2.56-2.54(m,4H),2.41-2.37 (m,8H),2.31(t,J=7.5Hz,8H),1.65-1.58(m,8H),1.42-1.18(m,88H),0.95-0.82(m,36H); ESI-MS m / z:709.95[M / 2+H] + .

[1076] Example 41: Synthesis of Compound 41

[1077] In a 250 mL three-necked flask, Boc-8-aminooctanoic acid 41-1 (10 g, 38.56 mmol, 1.0 eq.), 4-n-hexyl-1-decyl alcohol (10.28 g, 42.42 mmol, 1.1 eq.), DMAP (4.71 g, 38.56 mmol, 1.0 eq.), and DCC (11.93 g, 57.84 mmol, 1.5 eq.) were dissolved in 100 mL of dichloromethane and stirred at room temperature for 18 h. The reaction was monitored by TLC. After complete conversion of the starting material, the reaction was quenched with water (100 mL), extracted with dichloromethane, and the combined organic phases were collected and dried over anhydrous sodium sulfate. After filtration and rotary evaporation, the crude product was purified by silica gel column chromatography to give 14.3 g of a yellow oily compound 41-2.

[1078] A 4M, 37mL solution of hydrochloric acid in 1,4-dioxane was added to a 50mL solution of dichloromethane containing 12.3g (25.42mmol, 1.0eq.) of compound 41-2. The mixture was stirred at room temperature for 1h and then concentrated under reduced pressure to remove the solvent, yielding a crude yellow oily compound 41-3 (12.8g). This crude product was used directly in the next reaction without further purification.

[1079] In a 250 mL reaction flask, compounds 41-3 (12.8 g, crude), 41-4 (11.93 g, 30.47 mmol), potassium carbonate (21.05 g, 152.34 mmol), and KI (6.07 g, 36.56 mmol) were dissolved in 120 mL of acetonitrile. The reaction system was heated to 80 °C and reacted overnight. After the reactants were completely consumed, the mixture was cooled to room temperature by LC-MS monitoring. The mixture was filtered, and the filter cake was washed with acetonitrile (2 x 100 mL). The filtrates were combined and evaporated to dryness to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 10.3 g of yellow oily compound 41-5.

[1080] In a 250 mL reaction flask, compound 41-5 (5.3 g, 7.64 mmol, 1.0 eq.), 3-bromo-1-propanol (1.06 g, 7.64 mmol, 1.0 eq.), potassium carbonate (3.17 g, 22.91 mmol, 3.0 eq.), and KI (1.52 g, 9.16 mmol, 1.1 eq.) were dissolved in a mixed solvent of acetonitrile (25 mL) and CPME (75 mL). The reaction system was heated to 80 °C and reacted overnight. After the reactants were completely consumed as monitored by LC-MS, the mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (2 x 20 mL). The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 3.86 g of brown oily compound 41-6.

[1081] Add 41-6 (2.0 g, 2.66 mmol, 1.0 eq.) and triphenylphosphine (1.67 g, 6.38 mmol, 2.4 eq.) dissolved in tetrahydrofuran (20 mL) to a 100 mL reaction flask. After cooling to 0 °C under nitrogen protection, add carbon tetrabromide (1.94 g, 5.85 mmol, 2.2 eq.) in portions. Stir at room temperature for 1 h. Monitor the reaction by TLC; the starting material was completely converted. Add 50 mL of petroleum ether to the reaction mixture and stir. Filter, wash the filter cake with petroleum ether (2 x 5 mL), collect and combine the filtrates, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography to obtain 1.34 g of a yellow oily compound 41-7.

[1082] Compound 41-7 (300 mg, 0.37 mmol, 1.0 eq.) and 2 mL of methylamine ethanol solution were added to a 40 mL sealed tube. The system was heated to 70 °C and stirred for 1 h. The reaction was monitored by TLC and LC-MS. After the starting material was completely converted, the reaction system was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (2 x 20 mL), and the organic phase was washed once with saturated NaCl (20 mL) and dried over anhydrous Na₂SO₄. The filtrate was collected after filtration, and the crude product was obtained by rotary evaporation under reduced pressure. After purification by silica gel column chromatography, compound 41-8 (183 mg) was obtained as a pale yellow oil.

[1083] Compounds 41-8 (183.0 mg, 0.24 mmol, 1.0 eq.), 41-7 (331.37 mg, 0.41 mmol, 1.7 eq.), potassium carbonate (99.14 mg, 0.72 mmol, 3.0 eq.), potassium iodide (47.63 mg, 0.29 mmol, 1.2 eq.), CPME (3 mL), and acetonitrile (1 mL) were added to an 8 mL sealed tube. The system was heated to 80 °C and reacted for 18 h. The reaction was monitored by LC-MS, and the starting materials were found to be substantially completely reacted. After the reaction system cooled to room temperature, it was filtered. The filter cake was washed with ethyl acetate (2 x 3 mL), and the filtrates were combined and concentrated to obtain the crude product. The crude product was sent to preparative liquid chromatography for purification to obtain a yellow oily compound 41 (103.5 mg). Preparation conditions (Column: UniHybrid 8-200C8 OBD, 30x 150mm, 8μm; Eluent A: H2O / CH3CN 60 / 40, 10mM NH4HCO3 + 1% NH3·H2O; Eluent B: IPA / CH3CN 90 / 10; Flow rate: 60mL / min; Gradient program: 65%-85% B in 12min).

[1084] 1 H NMR (300MHz, CDCl3): δ4.04 (t, J=6.6Hz, 4H), 3.78 (s, 4H), 2.40-2.23 (m, 27H), 1.67-1.61 (m, 16H), 1.44-1.24 (m, 106H), 0.89-0.86 (m, 30H); ESI-MS m / z:750.55[M / 2+H] + .

[1085] Example 42: Synthesis of compound 42)

[1086] Compound 42 was prepared according to the method of Example 1, yielding 119.1 mg of an oily product.

[1087] 1 H NMR (300MHz, CDCl3): δ3.78 (s, 8H), 2.80-2.54 (m, 16H), 2.41 (t, J = 7.5Hz, 8H), 2.31 ( t,J=7.5Hz,8H),1.65-1.58(m,8H),1.43-1.24(m,131H),0.89-0.86(m,36H); ESI-MS m / z:856.60[M / 2+H] + .

[1088] Example 43: Synthesis of Compound 43

[1089] Compound 43 was prepared according to the method of Example 1, yielding an oily product of 320.6 mg.

[1090] 1 H NMR (300MHz, CDCl3): δ5.26-5.32(m,8H),3.79(s,8H),2.80-2.59(m,16H),2.41(t,J=7.5Hz,8H),2.31( t,J=7.2Hz,8H),2.02-1.98(m,16H),1.71-1.60(m,12H),1.52-1.24(m,95H),0.96-0.89(m,36H); ESI-MS m / z:852.70[M / 2+H] + .

[1091] Example 44: Synthesis of Compound 44

[1092] Compound 44 was prepared according to the method of Example 1, yielding an oily product of 331.3 mg.

[1093] 1 H NMR (300MHz, CDCl3): δ5.50-5.36(m,8H),3.78(s,8H),2.78-2.57(m,16H),2.43- 2.27(m,24H),2.03-1.93(m,8H),1.43-1.24(m,52H),0.94-0.88(m,36H); ESI-MS m / z:1367.40[M+H] + .

[1094] Example 45: Synthesis of Compound 45

[1095] Compound 45 was prepared according to the method of Example 1, yielding an oily product of 389.7 mg.

[1096] 1 H NMR (300MHz, CDCl3): δ4.03(t,J=6.9Hz,8H),2.77-2.57(m,16H),2.38(t,J=7.2Hz,8H),2 .29(t,J=7.5Hz,8H),1.64-1.51(m,14H),1.36-1.19(m,80H),0.96-0.87(m,36H); ESI-MS m / z:716.55[M / 2+H] + .

[1097] Example 46: Synthesis of Compound 46

[1098] Compound 46 was prepared according to the method of Example 1, yielding 79.2 mg of an oily product.

[1099] 1 H NMR (300MHz, CD3OD): δ3.93(s,8H),2.76-2.60(m,16H),2.47(t,J=7.2Hz,8H),2.32(t,J=7.2Hz ,8H),1.65-1.60(m,10H),1.48-1.28(m,102H),0.92-0.88(m,12H),0.51-0.38(m,16H); ESI-MS m / z:768.60[M / 2+H] + .

[1100] Example 47: Synthesis of Compound 47

[1101] Compound 47 was prepared according to the method of Example 1, yielding an oily product of 699.0 mg.

[1102] 1 H NMR (300MHz, CDCl3): δ4.05(t,J=6.9Hz,8H),2.77-2.55(m,12H),2.40(t,J=7.5Hz,8H),2 .31(t,J=7.5Hz,8H),1.64-1.59(m,16H),1.42-1.26(m,90H),0.90-0.86(m,12H); ESI-MS m / z:1276.50[M+H] + .

[1103] Example 48: Synthesis of Compound 48

[1104] Compound 48 was prepared according to the method of Example 1, yielding an oily product of 556.9 mg.

[1105] 1 H NMR (300MHz, CD3OD): δ4.06 (t, J=6.6Hz, 8H), 2.76-2.56 (m, 16H), 2.46 (t, J=7.5Hz, 8H), 2.32 (t, J= 7.5Hz,8H),1.89-1.61(m,16H),1.59-1.49(m,8H),1.46-1.29(m,81H),0.96-0.88(m,12H); ESI-MS m / z:1319.30[M+H] + .

[1106] Example 49: Synthesis of Compound 49

[1107] Compound 49 was prepared according to the method of Example 1, yielding 229.5 mg of an oily product.

[1108] 1 H NMR (300MHz, CDCl3): δ4.05(t,J=6.9Hz,8H),2.83-2.62(m,16H),2.43(m,8H),2.29( t,J=7.5Hz,8H),1.66-1.59(m,16H),1.46-1.24(m,91H),0.90-0.86(m,12H); ESI-MS m / z:660.45[M / 2+H] + .

[1109] Example 50: Synthesis of Compound 50

[1110] Compound 50 was prepared according to the method of Example 1, yielding 119.1 mg of an oily product.

[1111] 1 H NMR (300MHz, CD3OD): δ5.46-5.31(m,8H),4.06(t,J=6.3Hz,8H),2.75-2.57(m,16H),2.46(t,J=7.2Hz,8H),2 .32(t,J=7.2Hz,8H),2.07-2.00(m,16H),1.72-1.55(m,18H),1.47-1.26(m,54H),0.93-0.88(m,12H); ESI-MS m / z:656.40[M / 2+H] + .

[1112] Example 51: Synthesis of Compound 51

[1113] Compound 51 was prepared according to the method of Example 1, yielding 134.7 mg of an oily product.

[1114] 1 H NMR (300MHz, CD3OD): δ5.41-5.29(m,8H),4.07(t,J=6.6Hz,8H),2.75-2.67(m,16H),2.46(t,J=7.2Hz,8H),2 .31(t,J=7.2Hz,8H),2.11-2.00(m,16H),1.68-1.61(m,18H),1.58-1.28(m,38H),0.93-0.88(m,12H); ESI-MS m / z:600.45[M / 2+H] + .

[1115] Example 52: Synthesis of Compound 52

[1116] Compound 52 was prepared according to the method of Example 1, yielding an oily product of 311.3 mg.

[1117] 1 H NMR (400MHz, CDCl3): δ4.05(t,J=6.8Hz,8H),2.78-2.57(m,16H),2.40(t,J=7.2Hz,8H),2.29(t,J=7 .6Hz,8H),1.65-1.60(m,16H),1.58-1.48(m,4H),1.43-1.14(m,83H),0.88(d,J=7.6Hz,24H); ESI-MS m / z:688.55[M / 2+H] + .

[1118] Example 53: Synthesis of Compound 53

[1119] Compound 53 was prepared according to the method of Example 1, yielding 217.2 mg of an oily product.

[1120] 1 H NMR (300MHz, CDCl3): δ4.08(t,J=6.9Hz,8H),2.78-2.56(m,16H),2.40(t,J=7.5Hz,8H),2 .28(t,J=7.5Hz,8H),1.63-1.53(m,16H),1.41-1.25(m,134H),0.90-0.86(m,24H); ESI-MS m / z:1712.90[M+H] + .

[1121] Example 54: Synthesis of Compound 54

[1122] Compound 54 was prepared according to the method of Example 22, yielding 204.6 mg of an oily product.

[1123] 1 H NMR (400MHz, CDCl3): δ4.05 (t, J=6.8Hz, 6H), 3.04-2.41 (m, 23H), 2.31-2.27 (m,8H),1.63-1.60(m,12H),1.43-1.26(m,86H),0.90-0.86(m,12H); ESI-MS m / z:1221.30[M+H] + .

[1124] Example 55: Synthesis of Compound 55

[1125] Compound 55 was prepared according to the method of Example 22, yielding 237.1 mg of an oily product.

[1126] 1 H NMR (300MHz, CDCl3): δ4.05 (t, J=6.6Hz, 6H), 2.94-2.38 (m, 25H), 2.31-2.26 (m,8H),1.64-1.59(m,12H),1.41-1.27(m,86H),0.90-0.86(m,12H); ESI-MS m / z:1221.25[M+H] + .

[1127] Example 56: Synthesis of Compound 56

[1128] Compound 56 was prepared according to the method of Example 1, yielding 275.9 mg of an oily product.

[1129] 1 H NMR (300MHz, CDCl3): δ5.62-5.48(m,8H),3.84(s,8H),3.11-3.02(m,8H),2.89-2.65(m,20H ),2.40(t,J=7.5Hz,8H),2.08-1.99(m,8H),1.48-1.21(m,92H),0.92-0.86(m,36H); ESI-MS m / z:790.00[M / 2+H] + .

[1130] Example 57: Synthesis of Compound 57

[1131] Compound 57 was prepared according to the method of Example 1, yielding 265.8 mg of an oily product.

[1132] 1 H NMR (300MHz, CDCl3): δ5.52-5.35(m,8H),3.78(s,8H),2.76-2.55(m,18H),2.42- 2.27(m,24H),2.03-1.93(m,10H),1.42-1.25(m,60H),0.92-0.86(m,36H); ESI-MS m / z:705.95[M / 2+H] + .

[1133] Example 58: Synthesis of Compound 58

[1134] Compound 58 was prepared according to the method of Example 1, yielding 139.0 mg of an oily product.

[1135] 1 H NMR (300MHz, CDCl3): δ3.90(s,8H),2.78-2.68(m,24H),2.44(t,J=7.2Hz,8H),2.31(t,J=7.2H z,8H),1.65-1.60(m,8H),1.43-1.24(m,104H),0.97-0.89(m,12H),0.47-0.38(m,16H); ESI-MS m / z:789.90[M / 2+H] + .

[1136] Example 59: Synthesis of Compound 59

[1137] Compound 59 was prepared according to the method of Example 1, yielding 89.8 mg of an oily product.

[1138] 1 H NMR (300MHz, CDCl3): δ5.43-5.31(m,8H),4.06(t,J=6.6Hz,8H),2.76-2.55(m,18H),2.39(t,J=6.6Hz,8H),2 .29(t,J=7.5Hz,8H),2.14-1.98(m,16H),1.72-1.63(m,16H),1.53-1.22(m,62H),0.96-0.89(m,12H); ESI-MS m / z:677.90[M / 2+H] + .

[1139] Example 60: Synthesis of Compound 60

[1140] Compound 60 was prepared according to the method of Example 1, yielding 221.6 mg of an oily product.

[1141] 1 H NMR (300MHz, CDCl3): δ5.49-5.32(m,8H),4.06(t,J=6.6Hz,8H),2.76-2.54(m,18H),2.39(t,J=7.5Hz,8H),2 .29(t,J=7.5Hz,8H),2.08-1.94(m,16H),1.73-1.59(m,16H),1.53-1.22(m,62H),0.91-0.86(m,12H); ESI-MS m / z:677.85[M / 2+H] + .

[1142] Example 61: Synthesis of Compound 61

[1143] Compound 7 (336.1 mg) and formaldehyde aqueous solution (0.15 mL, 37%) were dissolved in tetrahydrofuran solution in a 50 mL round-bottom flask. The reaction was stirred overnight at room temperature, and the reaction was monitored by LC-MS, indicating that the starting material was essentially completely reacted. The system was cooled to 0 °C, and sodium triacetoxyborohydride (566.98 mg, 2.68 mmol) was added in portions. After the addition was complete, the temperature was allowed to rise to room temperature, and the reaction was continued for 18 h. The reaction was monitored by LC-MS, indicating that the starting material was essentially completely converted. The reaction was quenched with water, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (80 mL x 1). The organic phase was collected and dried over anhydrous sodium sulfate. The filtrate was collected and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 177.0 mg of a pale yellow oily compound 61.

[1144] 1 H NMR (300MHz, CDCl3): δ4.05 (t, J=6.6Hz, 8H), 2.66-2.42 (m, 22H), 2.31-2.26 (m,17H),1.64-1.57(m,16H),1.43-1.26(m,90H),0.90-0.86(m,12H); ESI-MS m / z:681.55[M / 2+H] + .

[1145] Example 62: Synthesis of Compound 62

[1146] Compound 62 was prepared according to the method of Example 61, yielding 164.4 mg of an oily product.

[1147] 1 H NMR (300MHz, CD3OD): δ4.07 (t, J=6.6Hz, 8H), 2.70-2.54 (m, 20H), 2.33-2.28 (m,14H),1.64-1.52(m,24H),1.37-1.20(m,80H),0.92-0.86(m,12H); ESI-MS m / z:1304.10[M+H] + .

[1148] Example 63: Synthesis of Compound 63

[1149] Compound 63 was prepared according to the method of Example 61, yielding 198.0 mg of an oily product.

[1150] 1 H NMR (300MHz, CDCl3): δ4.05 (t, J=6.6Hz, 8H), 2.68-2.41 (m, 22H), 2.31-2.26 (m,17H),1.64-1.57(m,16H),1.43-1.27(m,90H),0.90-0.86(m,12H); ESI-MS m / z:681.45[M / 2+H] + .

[1151] Example 64: Synthesis of Compound 64

[1152] Compound 64 was prepared according to the method of Example 61, yielding 94.9 mg of an oily product.

[1153] 1 H NMR (300MHz, CDCl3): δ3.78 (s, 8H), 2.71-2.53 (m, 25H), 2.31 (t, J = 7.5Hz, 16H), 1.65-1.60 (m, 8H), 1.46-1.26 (m, 88H), 0.96-0.88 (m, 36H); ESI-MS m / z:737.60[M / 2+H] + .

[1154] Example 65: Synthesis of Compound 65

[1155] Following the method of Example 1, the amount of aldehyde compound was controlled to be 2.8 times that of reactants 1-10 to prepare compound 65, yielding an oily product of 198.0 mg.

[1156] 1 H NMR (300MHz, CDCl3): δ4.05 (t, J=6.9Hz, 6H), 2.80-2.47 (m, 20H), 2.40 (t, J=7.5Hz, 4H), 2.29(t,J=7.5Hz,6H),1.64-1.57(m,12H),1.45-1.23(m,68H),0.90-0.86(m,9H); ESI-MS m / z:519.25[M / 2+H] + .

[1157] Example 66: Synthesis of Compound 66

[1158] Compound 66 was prepared according to the method of Example 22, yielding 196.0 mg of an oily product.

[1159] 1 H NMR (300MHz, CDCl3): δ3.78(s,6H),2.80-2.05(m,32H),1.65-1.58(m,6H),1.42-1.24(m,84H),0.89-0.83(m,30H); ESI-MS m / z:1305.35[M+H] + .

[1160] Example 67: Synthesis of Compound 67

[1161] Compound 67 was prepared according to the method of Example 1, yielding an oily product of 399.9 mg.

[1162] 1 H NMR (300MHz, CDCl3): δ5.36-5.32(m,8H),3.78(s,8H),2.77-2.28(m,40H),2.02- 1.95(m,16H),1.73-1.60(m,8H),1.42-1.24(m,96H),0.92-0.85(m,36H); ESI-MS m / z:1746.65[M+H] + .

[1163] Example 68: Synthesis of Compound 68

[1164] Compound 1 (370 mg, 0.26 mmol, 1.0 eq.) dissolved in tetrahydrofuran solution was added to a 40 mL sealed tube at room temperature, followed by compounds 1-6 (67.52 mg, 0.21 mmol, 0.8 eq.). The mixture was stirred at room temperature for 18 h. The system was cooled to 0 °C, and sodium triacetoxyborohydride (164.35 mg, 0.78 mmol, 3.0 eq.) was added. The mixture was stirred at room temperature for another 1 h. The reaction was monitored by LC-MS until the starting material was almost completely reacted. The reaction was quenched with water at 0 °C and extracted with ethyl acetate (3 x 15 mL). The organic phase was washed with saturated sodium chloride aqueous solution (2 x 50 mL), collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the organic solvent, yielding the crude product. The crude product was purified by preparative liquid chromatography under the following conditions (Column: XBridge Shield RP18 OBD Column 30*150mm, 5μm; Eluent A: H2O / CH3CN 60 / 40, 10mM NH4HCO3+1% NH3H2O; Eluent B: IPA / CH3CN 90 / 10; Flow rate: 60mL / min; Gradient program: 50%-70% B in 0-12min), yielding a yellow oily compound 68 (134.3mg).

[1165] 1 H NMR (300MHz, CDCl3): δ3.78(s,10H),2.81-2.28(m,36H),1.65-1.60(m,10H),1.47-1.41(m,10H),1.37-1.24(m,102H),0.86-0.89(m,45H); ESI-MS m / z:871.70[M / 2+H] + .

[1166] Pharmacological experiments

[1167] Experimental Example 1: Preparation of Nanoparticles

[1168] Materials used for assembling lipid nanoparticles include: (1) ionizable lipid compounds, such as the lung-targeting lipid compound (ionizable lipid compound) designed and synthesized in this application, Lipid5 (purchased from AVT); (2) structural lipids, such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids, such as DSPC: 1,2-distearyl-SN-glycerol-3-phosphocholine (purchased from AVT), DOPE, DOPC (purchased from AVT); (4) polyethylene glycol-modified lipid compounds, such as DMG-PEG2000: dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (purchased from AVT); (5) permanently cationic compounds, such as permanently positively charged steroid compounds; (6) effective components of nucleic acid fragments, such as Luciferase mRNA, siRNA, CRISPR Cas 9mRNA, etc. (self-made or commercially available); the names and structural formulas of lipid nanoparticle assembly materials are detailed in Table 2.

[1169] Table 2. Structures and names of compounds in the control group and excipients.

[1170] Preparation method of lipid nanoparticles: (1) Dissolve and mix the ionizable lipid compound to be tested, cholesterol, phospholipid and polyethylene glycol-modified lipid in ethanol at (molar percentage) 50%, 38.5%, 10% and 1.5% respectively; (2) Dissolve the mRNA active ingredient in 25mM sodium acetate solution (pH=4-4.5); (3) Use an automated high-throughput microfluidic system to mix the organic phase containing the lipid mixture and the aqueous phase containing the mRNA at a flow rate ratio of 1:1 to 1:4, with a mixing speed of 10mL / min to 18mL / min; (4) Dilute the prepared lipid nanoparticles with phosphate buffer solution and ultrafilter the nanoparticle solution to the original preparation volume using an ultrafiltration tube with a molecular weight cutoff of 100kDa (purchased from Millipore); (5) After sterilization by filtration through a 0.2μm sterile filter membrane, store the obtained nanoparticles in a sealed glass bottle at low temperature.

[1171] Lipid nanoparticles can be prepared using microfluidic mixing systems, but are not limited to this method; other methods include T-type mixers and ethanol injection.

[1172] Experimental Example 2: Characterization of the physical properties of lipid nanoparticles

[1173] The particle size and particle size distribution index (PDI) of the prepared lipid nanoparticles were measured using a Zetasizer Pro (purchased from Malvern Instruments Ltd) and a DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instrument. The degree of RNA encapsulation by the lipid nanoparticles was characterized by the encapsulation efficiency (%), which reflects the degree of binding between the lipid nanoparticles and nucleic acid fragments. This coefficient was determined by Quant-it... TM The RiboGreen RNA Assay (purchased from Invitrogen) method was used for measurement. Lipid nanoparticle samples were diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.5). A portion of the sample solution was taken and added to 0.5% Triton X-100 and incubated at 37°C for 30 minutes. Immediately after the reaction, the fluorescence values ​​were read using a Varioskan LUX multi-functional microplate reader (purchased from Thermofisher) at an absorption wavelength of 485 nm and an emission wavelength of 528 nm to obtain the encapsulation loading rate.

[1174] Experiment Example 3: Animal Experiment

[1175] The delivery efficiency and safety of nanoparticles loaded with luciferase mRNA (Trilink, L-7202) in mice were evaluated. SPF-grade female C57BL / 6 mice, 6-8 weeks old and weighing 18-22g, were purchased from Beijing Spefol Biotechnology Co., Ltd. All animals underwent acclimatization for at least 7 days prior to the experiment, with free access to food and water, 12 / 12-hour light / dark cycles, and an indoor temperature of 20-26℃ and humidity of 40-70%. Mice were randomly assigned to groups (n=3). The prepared lipid nanoparticles loaded with luciferase mRNA were administered intravenously to mice at a single dose of 0.1 mg / kg mRNA. Five to six hours after administration, the mice were dissected and organs were removed. Bioluminescence detection of the mouse organs was performed using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer). The specific steps of the detection are as follows: Prepare a 30 mg / mL D-fluorescein solution with physiological saline. Administer the substrate to each mouse via intraperitoneal injection. Seven minutes after administration, drag the mouse by the neck and dissect the organs. Place the removed mouse organs into IVIS for fluorescence imaging, and collect and analyze data from areas of concentrated fluorescence distribution.

[1176] The organ distribution of lipid nanoparticle carriers delivered in vivo is expressed as the average fluorescence intensity and total photon count of different animal organs within the same test group. Targeting of the lung can be represented by the ratio of bioluminescence intensity in the lung and liver after injection of the lipid nanoparticles. Specific data are shown in Table 3. Higher values ​​for fluorescence intensity and total photon count indicate higher delivery efficiency of the lipid nanoparticles for the nucleic acid (e.g., mRNA) fragment in that organ (liver or lung). A larger ratio indicates better targeting of the lipid nanoparticles for the nucleic acid (e.g., mRNA) fragment in that organ (liver or lung).

[1177] Table 3

[1178] Experimental Example 4: Preparation of different LNP formulations and lipid nanoparticles

[1179] The materials used for assembling lipid nanoparticles are as described in Experimental Example 1. The LNP formulations are shown in Tables 4, 5, and 6, where the mass ratio refers to the ratio of the sum of the masses of all lipid components in the LNP to the mass of the mRNA.

[1180] Table 4 Two-component LNP formulation

[1181] Table 5 Four-component LNP formulation

[1182] Table 6 Five-component LNP formulation

[1183] Experiment Example 5: Mouse Organ IVIS Imaging Experiment

[1184] The delivery efficiency and safety of nanoparticles carrying luciferase mRNA (Trilink, L-7202) in mice were evaluated. The LNP formulation is shown in Tables 4, 5, and 6. Animal experiments were conducted as described in Example 3, with a single intravenous dose of 0.1 mg / kg mRNA. Retrieved mouse organs were placed in an IVIS for fluorescence imaging, and data were collected and analyzed from areas of concentrated fluorescence distribution. Organ distribution and delivery efficiency of the lipid nanoparticle carriers are expressed as the average fluorescence intensity and total photon count within the same test group, as shown in Tables 7, 8, and 9. Higher fluorescence intensity and total photon count values ​​indicate higher delivery efficiency of the lipid nanoparticles for the mRNA fragment in that organ. The lipid nanoparticles containing the cationic lipids of this invention exhibit good lung delivery efficiency and efficacy at the organ level.

[1185] Table 7 Results of two-component LNP imaging

[1186] Table 8 Results of four-component LNP imaging

[1187] Table 9. Five-component LNP imaging results

[1188] Experimental Example 6: Delivery Effect of the LNP of the Present Invention in NHP

[1189] Evaluation of the delivery efficiency and organ distribution of nanoparticles loaded with luciferase mRNA (Trilink, L-7202) in NHP within the animal population. Cynomolgus monkeys (provided by Medicilon Pharmaceuticals (Shanghai) Co., Ltd.) were selected, with animals under 7 years of age and weighing between 2 kg and 8 kg. The prepared lipid nanoparticles loaded with luciferase mRNA (formulation and characterization information are shown in Table 10) were administered intravenously to the cynomolgus monkeys at a single dose of 0.1 mg / kg mRNA. Six hours after administration, the monkeys were dissected, and organs such as the heart, liver, spleen, lungs, and kidneys were harvested. Bioluminescence detection of the isolated organs was performed using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer). The specific operational steps were as follows: A 30 mg / mL D-luciferin solution was prepared with physiological saline, and the substrate was administered to each monkey via intraperitoneal injection. Ten minutes after substrate administration, the animals were sacrificed, and organs such as the liver, lungs, and spleen were dissected and removed. The extracted animal organs were immersed in D-fluorescein solution, then removed and placed in IVIS for fluorescence imaging. Data were collected and analyzed from areas of concentrated fluorescence distribution. As shown in Table 11, the NHP imaging results revealed that all lung-targeting LNPs exhibited strong expression signals in the lungs.

[1190] Table 10 NHP-Lung LNP Characterization Information

[1191] Table 11. Organ Imaging Results of NHP-IVIS

[1192] Experimental Example 7: NHP Lung Cell Type Delivery Analysis

[1193] The delivery efficacy of tdtomato mRNA-encapsulated nanoparticles in different cell types of cynomolgus monkey lungs was evaluated. Cynomolgus monkeys were administered tdtomato mRNA-encapsulated lipid nanoparticles (compound 1, the ionizable lipid used to prepare LNPs, formulation name 5C) via intravenous injection at a single dose of 1 mg / kg mRNA (provided by Medicilon Pharmaceuticals (Shanghai) Co., Ltd.). Eight hours after administration, lung tissue was collected for IHC and IF analysis. The lung tissue was removed whole, fixed in 4% PFA fixative, dehydrated with sucrose solution, and then embedded in OCT and frozen.

[1194] For IHC detection of tdtomato protein expression, frozen tissue sections were blocked at room temperature with blocking buffer containing 10% normal goat serum. RFP primary antibody (Rockland) was added and incubated at 4°C. Sections were thoroughly washed with PBST and PBS, and then incubated with biotinylated secondary antibody (goat anti-rabbit IgG, Vector Laboratories) at room temperature. After washing with PBS, the sections were reacted with the ABC-HRP complex (Vector) at room temperature. DAB staining (Vector) was performed, followed by hematoxylin counterstaining, ethanol dehydration and clearing, and mounting with neutral resin. Full-section images were acquired using a 3DHISTECH Pannoramic MIDI scanner.

[1195] For immunofluorescence co-staining of CD31, CD271, and KRT5 with tdtomato, the corresponding primary antibody mixture was added according to Table 12 and incubated at 4°C. After washing three times with PBST, the corresponding secondary antibody mixture was added and incubated at room temperature in the dark. After washing with PBST, DAPI (Sigma) staining was performed, and finally, the staining was performed using a fluorescence scanner.

[1196] Multiplex immunohistochemical analysis of CD326 and SFTPC with tdtomato was performed using a sequential staining method (Table 13). First, RFP antibody staining and staining with goat anti-rabbit secondary antibody (Shanghai Yuanxi Biotechnology Co., Ltd.) and fluorescent dyes (Shanghai Yuanxi Biotechnology Co., Ltd.) were performed. The mixture was then incubated at 38°C with antibody elution buffer (Shanghai Yuanxi Biotechnology Co., Ltd.), followed by staining with CD326 or SFTPC. Finally, after DAPI staining, the results were scanned using a fluorescence imaging scanner (Pannoramic MIDI).

[1197] Five to six fields of view were randomly selected from each lung tissue section for quantitative analysis using Halo analysis software. The positive rate of each cell type was calculated as double positive cells / single positive cells for cell-specific markers × 100%. For example, the positive rate of endothelial cells was calculated as (tdTomato+CD31+ cells / CD31+ cells) × 100%. Positive signals were detected in 43.6% of lung endothelial cells and 35.7% of lung epithelial cells.

[1198] The positivity rates of different cell types in lung epithelial cells were statistically analyzed. The positivity rate for type II lung epithelial cells (ATII) was 33.8%, the positivity rate for KRT5-labeled lung basal cells (KRT5+Basal cells) was 50%, and the positivity rate for CD271-labeled lung basal cells (CD271+Basal cells) was 15.6%. The IHC results are shown in Figure 1. tdTomato mRNA delivered via lung-targeting LNPs can achieve broad expression in various lung cell types. The IF results are shown in Figures 2-5.

[1199] Figure 2 shows the IF-CD31 transfection signal in lung endothelial cells 8 hours after drug administration. We used cell-specific markers and tdtomato for immunofluorescence co-staining; the co-localization of the two represents cell-specific protein expression. The endothelial cell-specific marker is CD31, marked in red in Figure 2. The blue signal represents dapi (nucleus), and the green signal represents tdtomato expression. The leftmost part of Figure 2 shows the result of combining the three signals, the middle part shows the result of combining tdtomato and CD31, and the rightmost part shows the result of combining dapi and CD31. The area circled in red in the middle shows the co-localization of CD31 and tdtomato, indicating tdtomato expression in endothelial cells. According to the semi-quantitative results obtained from Halo analysis software, the positive rate is approximately 46.3%. The pink circle shows tdtomato expression in CD31-negative cells, indicating that it is also expressed in other non-endothelial cells of the lung.

[1200] Figure 3 shows the transfection signal of IF-EPCAM in lung epithelial cells 8 hours after drug administration. The marker used for epithelial cells is Epcam, which is marked in pink. The orange arrows in Figure 3 indicate cells co-localized with tdtomato and Epcam, representing lung epithelial cells expressing Tdtomato, accounting for approximately 35.7%.

[1201] Figure 4 shows IF-SFTPCII type ATII alveolar epithelial cells (ATII) staining 8 hours after drug administration. The specific marker for ATII in type II alveolar epithelial cells is pink-labeled SFTPC, or lung surfactant protein C. The orange arrows in Figure 4 indicate cells co-localized with SFTPC, which is also distributed in the cytoplasm. According to the semi-quantitative analysis results, approximately 34% of AT2 cells express tdtomato, indicating that the lung-targeting LNP of the present invention can achieve ATII delivery.

[1202] Figure 5 shows the immunofluorescence colocalization results of KRT5 and CD271 with tdtomato in serial sections of the airway. On the left, multiple arrows indicate the colocalization of KRT5 and tdtomato, with a software semi-quantitative positive rate of approximately 50%. On the right, colocalization of CD271 and tdtomato is also detected at a similar location. This demonstrates that the lung-targeting LNP of the present invention can achieve a certain degree of delivery to basal cells, with a software semi-quantitative positive rate of approximately 15.6%.

[1203] Table 12 Antibodies co-stained with immunofluorescence

[1204] Table 13 Antibodies for Multiplex Immunohistochemical Analysis

[1205] Experimental Example 8: NHP Lung Cell Type Delivery Analysis

[1206] The delivery efficacy of tdtomato mRNA-loaded nanoparticles in different cell types of cynomolgus monkey lungs was evaluated. Lipid nanoparticles loaded with tdtomato mRNA (compound 12, the ionizable lipid used to prepare LNP, formulation name 5C) were administered intravenously to cynomolgus monkeys at a single dose of 1 mg / kg mRNA (provided by Medicilon Pharmaceuticals (Shanghai) Co., Ltd.). Eight hours after administration, liver and lung tissues were collected for IHC and IF analysis, following the same analytical methods as in Experiment 7. The results are shown in Figures 6-9.

[1207] Figure 6 shows the IHC results of LNP versus PBS in NHP lungs, demonstrating that LNP exhibits extensive protein expression in different cell populations of NHP lungs.

[1208] Figure 7 shows the IHC results of LNP versus PBS in NHP liver, showing that TdTomato+ labeled cells in the liver are hepatocytes (majority, red circles) and Kupffer cells (minority, pink arrows).

[1209] Figure 8 shows the staining results of 8h-IF-SFTPC I type alveolar epithelial cells (ATII) after LNP administration. Co-localization of tdTomato with SFTPC+ cells (ATII) was detected, indicating that tdTomato is expressed in SFTPC type II alveolar epithelial cells. According to the semi-quantitative results obtained by Halo analysis software, the positive rate is approximately 63.1%.

[1210] Figure 9 shows the staining results of lung basal cells 8 h after LNP administration. Figure 9 illustrates the co-localization of tdTomato with CD271+ cells and KRT5+ cells, respectively. According to the semi-quantitative results obtained from Halo analysis software, the positive rates were approximately 8.5% and 28.3%, respectively. This demonstrates that the LNP of the present invention can achieve a certain degree of basal cell delivery.

[1211] IHC and IF analyses of liver and lung tissues showed that LNP containing the ionizable lipid compounds of this invention has high delivery efficiency in both the liver and lungs, enabling simultaneous targeting of both organs.

[1212] While the invention has been fully described through its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims.

[1213] sequence list

Claims

Compound of formula (I), or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof: in, y is 2, 3, 4, 5, or 6; L1 and L2 are independently selected from C 2-6 Alkylene, C 2-6 imide and C 2-6 The ynyl group, which is optionally substituted with 1, 2 or 3 R*, and wherein 1, 2 or 3 methylene units are optionally and independently substituted with -O-, -S- or -NR7-; R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -C 3-10 cycloalkyl, -L a -3 to 10-membered heterocyclic groups, -L a -OR a -L a -SR a and -L a -NR a R' a ; L a Independently selected from chemical bonds, C 1-6 Alkylene and C 1-6 Heteroalkyl; R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-10 cycloalkyl, -L g -M2-3 to 10-membered heterocyclic groups, -L g -M2-C 6-10 Aryl, -L g -M2-5-10 heteroaryl groups and -G1-M2-R; where C 1-14 One, two, or three methylene units in the alkyl group may be optionally and independently replaced by -O-, -S-, or -NR7-; L g Independent of chemical bonds or C 1-14 Alkylene, wherein one, two or three methylene units in the alkylene are optionally and independently replaced by -O-, -S- or -NR7-; R1, R2, R3, and R4 are independently H or -G1-M2-R; at least one of R1, R2, R3, and R4 is -G1-M2-R; G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain sub-olefins, C 2-14 Straight-chain ynyne group, C 3-10 Membered cycloalkylene groups and 3 to 10-membered heterocyclic groups, optionally surrounded by 1, 2, 3 or 4 R groups. G1 Substitution, and one methylene unit therein optionally and independently being replaced by M1, and one methylene unit therein optionally and independently being replaced by C. 3-10 3- to 10-membered heterocyclic alkyl groups, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions; R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -C 3-10 cycloalkyl, -L b -3 to 10-membered heterocyclic groups, -L b -OR b -L b -SR b and -L b -NR b R' b ; L b Independently selected from chemical bonds and C 1-14 Alkylene; R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -, -NRC(O)NR c -, -C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -, -C(O)NR c -, -NR c C(O)-, -NR c C(O)S-, -SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -, -NR c C(S)O-, -S-S-, -S(O) 0-2 -, R c Each is independently selected from H and C. 1-10 alkyl; R5 and R6 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace; Or CR5R6 together form C 3-14 Cycloalkylene or 3 to 14-membered heterocyclic alkylene groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace; R 5s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ; L d Independently selected from chemical bonds and C 1-8 Alkylene; R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace; n = 1, 2, 3, 4, 5 or 6; R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ; L f Independently selected from chemical bonds and C 1-10 Alkylene; R f and R' f Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; M2 is independently selected from chemical bonds, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, and -S(O) 0-2 -; R is independently selected from C 4-30 Alkyl, C 4-30 alkenyl and C 4-30 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups s Substitution, and optionally, one, two, three, or four methylene units are replaced independently by -NR7-, and one methylene unit is optionally, and optionally, independently, C-. 3-10 Cycloalkylene, 3 to 10-membered heterocyclic alkylene, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions; R s Independently selected from H and C 1-30 Alkyl, L e -C 3-10 cycloalkyl, -L e -3 to 10-membered heterocyclic groups, -L e -OR e -L e -SR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-30 Alkylene; R e and R' e Independently selected from H and C 1-30 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; R7 is independently H or C 1-30 alkyl; Preferably, at most one of R1, R2, R3 and R4 is H. Compound of formula (I), or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof: in, y is 2, 3, 4, 5, or 6; L1 and L2 are independently selected from C 2-6 Alkylene, C 2-6 imide and C 2-6 The ynyl group, which is optionally substituted with 1, 2 or 3 R*, and wherein 1, 2 or 3 methylene units are optionally and independently substituted with -O-, -S- or -NR7-; R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -C 3-10 cycloalkyl, -L a -3 to 10-membered heterocyclic groups, -L a -OR a -L a -SR a and -L a -NR a R' a ; L a Independently selected from chemical bonds, C 1-6 Alkylene and C 1-6 Heteroalkyl; R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-10 cycloalkyl, -L g -M2-3 to 10-membered heterocyclic groups, -L g -M2-C 6-10 Aryl, -L g -M2-5-10 heteroaryl groups and -G1-M2-R; where C 1-14 One, two, or three methylene units in the alkyl group may be optionally and independently replaced by -O-, -S-, or -NR7-; L g Independent of chemical bonds or C 1-14 Alkylene, wherein one, two or three methylene units in the alkylene are optionally and independently replaced by -O-, -S- or -NR7-; R1, R2, R3, and R4 are independently -G1-M2-R; G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain sub-olefins, C 2-14 Straight-chain ynyne group, C 3-10 Membered cycloalkylene groups and 3 to 10-membered heterocyclic groups, optionally surrounded by 1, 2, 3 or 4 R groups. G1 Substitution, and one methylene unit therein optionally and independently being replaced by M1, and one methylene unit therein optionally and independently being replaced by C. 3-10 3- to 10-membered heterocyclic alkyl groups, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions; R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -C 3-10 cycloalkyl, -L b -3 to 10-membered heterocyclic groups, -L b -OR b -L b -SR b and -L b -NR b R' b ; L b Independently selected from chemical bonds and C 1-14 Alkylene; R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -, -NRC(O)NR c -, -C(O)NR c NR c C(O)-, -OC(O)S-, -OC(O)O-, -NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -, -C(O)NR c -, -NR c C(O)-, -NR c C(O)S-, -SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -, -NR c C(S)O-, -S-S-, -S(O) 0-2 - R c Each is independently selected from H and C. 1-10 alkyl; R5 and R6 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace; Or CR5R6 together form C 3-14 Cycloalkylene or 3 to 14-membered heterocyclic alkylene groups, optionally surrounded by 1, 2, 3 or 4 R groups. 5s replace; R 5s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ; L d Independently selected from chemical bonds and C 1-8 Alkylene; R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace; n = 1, 2, 3, 4, 5 or 6; R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ; L f Independently selected from chemical bonds and C 1-10 Alkylene; R f and R' f Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; M2 is independently selected from chemical bonds, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR c -、-NRC(O)NR c -、-OC(O)S-、-OC(O)O-、-NR c C(O)O-, -SC(O)-, -C(O)S-, -NR c -、-C(O)NR c -、-NR c C(O)-、-NR c C(O)S-、-SC(O)NR c -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR c -、-NR c C(S)O-, -SS-, and -S(O) 0-2 -; R is independently selected from C 4-30 Alkyl, C 4-30 alkenyl and C 4-30 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups s Substitution, and optionally, one, two, three, or four methylene units are replaced independently by -NR7-, and one methylene unit is optionally, and optionally, independently, C-. 3-10 Cycloalkylene, 3 to 10-membered heterocyclic alkylene, C 6-10 Arene-containing or 5-10 quinone heteroaryl substitutions; R s Independently selected from H and C 1-30 Alkyl, L e -C 3-10 cycloalkyl, -L e -3 to 10-membered heterocyclic groups, -L e -OR e -L e -SR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-30 Alkylene; R e and R' e Independently selected from H and C 1-30 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; R7 is independently H or C 1-30 alkyl. The compound of claim 1 or 2, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, y is 2, 3, 4 or 5, preferably 3, 4 or 5, preferably 3 or 4; preferably 3, preferably 4; preferably 2, 3 or 4, preferably 2 or 3; Preferably, R8 is independently selected from H and C. 1-14 Alkyl, -L g -M2-C 3-7 cycloalkyl, -L g -M2-3 to 7-membered heterocyclic groups, -L g -M2-phenyl and -L g -M2-5-6 heteroaryl; preferably H or C 1-14 Alkyl groups, preferably H or C 1-10 Alkyl groups, preferably H or C 1-6 Alkyl groups, preferably H or C 1-3 alkyl; Preferably, R8 is independently selected from H and C. 1-6 Alkyl groups and -G1-M2-R; preferably, at most one R8 is -G1-M2-R; Preferably, L g Independent of chemical bonds or C 1-10 Alkylene, preferably H or C 1-6 Alkylene, preferably H or C 1-3 Alkylene. The compound of any one of claims 1-3, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L1 and L2 are independently selected from C 2-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; preferably C 2-3 Alkylene; preferably C2 alkylene, for example -CH2CH2-. The compound of any one of claims 1-4, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a Preferred components include H, halogens, cyano groups, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H or C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, L a Independently selected from chemical bonds, C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R a and R' a Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl. The compound of any one of claims 1-5, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R2, R3, and R4 are the same, or R1, R2, R3, and R4 are the same. The compound of any one of claims 1-6, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G1 is independently selected from C 2-14 straight-chain alkylene, C 2-14 Straight-chain alkenyl groups and C 2- 14 Straight-chain acetylenic group; preferably C 2-10 straight-chain alkylene, C 2-10 Straight-chain alkenyl groups and C 2-10 Straight-chain acetylenic group; preferably C 2-8 straight-chain alkylene, C 2-8 Straight-chain alkenyl groups and C 2-8 Straight-chain acetylenic group; preferably C 2-10 Straight-chain alkylene, preferably C 2-8 Straight-chain alkylene, preferably C 2-7 Straight-chain alkylene, preferably C 4-7 Straight-chain alkylene, preferably C 4-7 Straight-chain alkylene, preferably C 5-7 Straight-chain alkylene, preferably C6 straight-chain alkylene; Preferably, G1 is optionally divided by one or two Rs. G1 replace; Preferably, when y is 2, G1 is not -CH2CH2-; Preferably, when y is 2, one methylene unit in G1 is replaced by M1. The compound of any one of claims 1-7, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R G1 Independently selected from H, halogen, C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl), -OR b and -NR b R' b H and -OR are preferred. b (e.g., -OH); Preferably, L b Independently selected from chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R b and R' b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl. The compound of any one of claims 1-8, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, M1 is independently selected from -CR5R6-, -C(O)O-, -OC(O)-, -SC(O)O-, -OC(O)NH-, -NHC(O)NH-, -C(O)NHNHC(O)-, -OC(O)S-, -OC(O)O-, -NHC(O)O-, -SC(O-, -C(O)S-, -C(O)NH-, -NHC(O-, -NHC(O)S-, -SC(O)NH-, Preferred chromatograms include -CR5R6-, -C(O)O-, -OC(O)-, -C(O)NHNHC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NH-, and -NHC(O)-. Preferred chromatograms include -CR5R6-, -C(O)O-, -OC(O)-, -C(O)NHNHC(O)-, and -C(O)NH-. The compound of any one of claims 1-9, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R5 and R6 are independently selected from H and C. 1-6 Alkyl groups; preferably H and C 1-3 Alkyl groups; preferably H and C 1-2 Alkyl; preferably H and methyl; Preferably, R5 and R6 are optionally separated by one or two R 5s replace; Preferably, CR5R6 are optionally formed together to form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene; preferably C 3-6 Cycloalkylene or 3- to 6-membered heterocyclic alkylene; preferably C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably C 3-4 Cycloalkylene; preferably cyclopropylene; Preferably, the ring formed by CR5R6 is optionally surrounded by one or two R... 5s replace. The compound of any one of claims 1-10, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 5s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d Preferred components include H, halogens, cyano groups, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably H or C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Preferably, L d Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-3 Alkylene; Preferably, R d and R' d Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl groups; preferably H and C 1-3 alkyl. The compound of any one of claims 1-11, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic cycloalkylene groups; Preferably, ring A is a 3- to 7-membered sub-heterocyclic group, more preferably a 3- to 7-membered nitride-like heterocyclic group, preferably with the N atom as the linking end, and preferably with the N atom connected to -C(O)- or the head end, for example... Preferred More The compound of any one of claims 1-12, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, n = 1, 2, 3, 4 or 5; preferably n = 1, 2, 3 or 4; preferably n = 1 or 2; preferably n = 1. The compound of any one of claims 1-13, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R A Independently selected from H, cyano, halogen, oxo, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f Preferred groups include H, cyano, halogen, oxo, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f Preferred elements include H, halogens, oxidants, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f Preferred elements include H, halogens, oxidants, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L f -OR f and -L f -NR f R' f Preferred H, oxidized, -L f -OR f and -L f -NR f R' f . The compound of any one of claims 1-14, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L f Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R f and R' f Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. The compound of any one of claims 1-15, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, M2 is independently selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NH- and -NHC(O)-, preferably -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O- and -C(O)S-, preferably -C(O)O-, -OC(O-, -SC(O- and -C(O)S-, preferably -C(O)O- and -OC(O-), preferably -OC(O-, preferably -C(O)O-; Preferably, M2 is independently selected from -C(O)O-, -OC(O)- and -C(O)NH-. The compound of any one of claims 1-16, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R is independently selected from C 4-25 Alkyl, C 4-25 alkenyl and C 4-25 Alkyne group, preferably C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 4-15 Alkyl, C 4-15 alkenyl and C 4-15 Alkyne group, preferably C 6-15 Alkyl, C 6-15 alkenyl and C 6-15 Alkyne group, preferably C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group; preferably C 8-15 Alkyl and C 8-15 Alkenyl, preferably C 8-12 Alkyl and C 8-12 Alkenyl, preferably C 10-12 Alkyl and C 10-12 Alkenyl, preferably C 10-12 Alkyl (preferably C) 10 alkyl) and C 10 alkenyl; Preferably, R is independently selected from C. 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 4-14 Alkyl, C 4-14 alkenyl and C 4-14 Alkyne group, preferably C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; preferably C 4-14 Alkyl, preferably C 6-14 Alkyl, preferably C 6-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 8-10 Alkyl, preferably C8 alkyl, preferably C9 alkyl, preferably C 10 alkyl; Preferably, R is independently selected from C. 6-9 Alkyl; preferably C 4-8 Alkyl; preferably C6 alkyl; Preferably, R is independently selected from C. 10-12 Alkyl and C 15 Alkenyl, preferably C 10-12 Alkyl; preferably C 8-10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C9 alkenyl; Preferably, R is optionally represented by one or two Rs. s Instead, preferably optionally replaced by 1 R s replace; Preferably, R is independently selected from -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 12 CH3, -(CH2) 13 CH3, -(CH2) 14 CH3, -(CH2)3-CH=CH-(CH2)4CH3, -(CH2)4-CH=CH-CH2CH3, -CH=CH-(CH2)9CH3, Preferred nucleotides include -(CH2)5CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, Preferred morphologies include -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, Preferably, R is independently selected from -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 12 CH3, -(CH2) 13 CH3, -(CH2) 14 CH3, Preferred nucleotides include -(CH2)5CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, Preferred morphologies include -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 10 CH3, -(CH2) 11 CH3, -(CH2) 14 CH3, The compound of any one of claims 1-17, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R s Independently selected from H and C 1-25 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e H and C are preferred. 1-20 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e H and C are preferred. 1-15 Alkyl, -L e -OR e and -L e -NR e R' e H and C are preferred 1-14 Alkyl, -L e -OR e and -L e -NR e R' e C is preferred. 1-15 Alkyl, preferably C 1-14 Alkyl, preferably C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 1-6 alkyl; Preferably, R s The substitution site on R is spaced 0-12 carbon atoms from M2, preferably 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-4 carbon atoms; preferably at least 1 carbon atom, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms; preferably at least 2 carbon atoms, preferably 2-6 carbon atoms, preferably 2-4 carbon atoms, for example, 2-3 carbon atoms. Preferably, L e Independently selected from chemical bonds and C 1-25 Alkylene; preferably chemical bonds and C 1-20 Alkylene; preferably chemical bonds and C 1-15 Alkylene; preferably chemical bonds and C 1-14 Alkylene; preferably selected from chemical bonds and C 1-10 Alkylene; preferably selected from chemical bonds and C 1-6 Alkylene; Preferably, R e and R' e Independently selected from H and C 1-25 Alkyl groups; preferably H and C 1-20 Alkyl groups; preferably H and C 1-15 Alkyl groups; preferably H and C 1-14 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C 1-6 alkyl. The compound of any one of claims 1-18, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R7 is independently H or C 1-25 Alkyl groups, preferably H or C 1-20 Alkyl groups, preferably H or C 1-15 Alkyl groups, preferably H or C 1-14 Alkyl groups, preferably H or C 1-12 Alkyl groups, preferably H or C 1-10 Alkyl groups, preferably H or C 1-6 alkyl. The compound of any one of claims 1-19, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II) or formula (IIB): in, x can be 1, 2, or 3 independently; The remaining variables are defined as described in any one of claims 1-18. The compound of claim 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II): in, x can be 1, 2 or 3 independently, preferably 1 or 2; y is 2, 3, 4 or 5, preferably 3, 4 or 5; R1, R2, R3, and R4 are independent a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3, 4 or 5; b can be 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4, preferably 0, 1 or 2, preferably 0 or 1; a+b can be 1, 2, 3, 4, 5, 6 or 7 independently, preferably 5, 6 or 7; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-; R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 6-15 Alkyl, C 6-15 alkenyl and C 6-15 Alkyne group, preferably C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace; R s Independently for H and C 1-15 Alkyl, -L e -OR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-15 Alkylene; R e and R' e Independently selected from H and C 1-15 alkyl; R5 and R6 are independently selected from H and C. 1-3 alkyl; Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene, preferably C 3-6 Cycloalkylene; Preferably, when y is 2, a+b is not 1. The compound of claim 21, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x can be 1 or 2 independently, preferably 1; y is selected from 2, 3 or 4, preferably 3 or 4; R1, R2, R3, and R4 are independent a can be 1 or 5 independently, preferably 5; b can be 0 or 1 independently, preferably 1; a+b independently equals 1 or 6; M2 is independently selected from -C(O)O-, -OC(O-) and -C(O)NH-, preferably -C(O)O- and -OC(O-); preferably -C(O)O-; R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl groups, which are optionally surrounded by one or two R groups s replace; R s Independently for C 1-15 Alkyl, preferably C 1-6 alkyl; R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3, -(CH2)3-CH=CH-(CH2)4CH3, -(CH2)4-CH=CH-CH2CH3, -CH=CH-(CH2)9CH3, Preferred types are -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3, Preferably, R1, R2, R3 and R4 are the same. The compound of claim 21, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x can be 1 or 2 independently, preferably 1; y is 3, 4, or 5, preferably 3 or 4; R1, R2, R3, and R4 are independent a can be 4, 5, or 6 independently, with 5 being preferred; b can be 0, 1, or 2 independently, preferably 1; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -C(O)NH-, -NHC(O)- and -SC(O-), preferably -C(O)O-, -OC(O)- and -C(O)NH-; R is independently selected from C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace; R s Independently for C 1-15 alkyl; R5 and R6 are independently selected from H and C. 1-3 alkyl; Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene. The compound of claim 23, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x is 1; y is 3 or 4, preferably 3; R1, R2, R3, and R4 are independent a is 5; b is 1; M2 is independently selected from -C(O)O- and -OC(O-); preferably -C(O)O-; R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl, preferably C 10-12 Alkyl and C 10-12 Alkenyl, preferably C 10-12 Alkyl (preferably C) 10 alkyl) and C 10 Alkenyl groups, which are optionally surrounded by one or two R groups s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 alkyl; R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3, Preferred options are -(CH2)9CH3 and -(CH2). 11 CH3 and Preferred -(CH2)9CH3 and Preferably, R1, R2, R3 and R4 are the same. The compound of claim 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II): in, x can be 1, 2 or 3 independently, preferably 1 or 2; y is 2, 3, 4 or 5, preferably 3, 4 or 5; R1 is R2, R3, and R4 are independent a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2 or 3; b can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3 or 4; a+b can be 2, 3, 4, 5, 6 or 7 independently, preferably 3, 4, 5, 6 or 7; M1 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH-, -NHC(O)- and -C(O)NHNHC(O)-, preferably -C(O)O-, -OC(O)-, -C(O)NH-, -NHC(O)- and -C(O)NHNHC(O)-; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-; R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace; R' is independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-14 Alkylene; R e and R' e Independently selected from H and C 1-14 alkyl. The compound of claim 25, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x is 1; y is 3 or 4; R1 is R2, R3, and R4 are independent a is 2; b is either 1 or 4; M1 is independently selected from -C(O)O-, -C(O)NH- and -C(O)NHNHC(O)-, preferably -C(O)NH- and -C(O)NHNHC(O)-, especially -C(O)NH-; M2 is independently selected from -C(O)O-, -OC(O)- and -C(O)NH-, preferably -C(O)O- and -OC(O-), especially -OC(O-; R is independently selected from C 8-12 Alkyl, preferably C 8-11 Alkyl groups, optionally marked with one or two R groups s replace; R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 alkyl; Preferably, R1, R2, R3, and R4 are the same; Preferably, R2, R3, and R4 are the same, and R1 is... Preferably, R is independently selected from -(CH2)7CH3, -(CH2)8CH3, and -(CH2). 10 CH3; R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3. The compound of claim 25, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x is independently 1 or 2, preferably 1; y is 3, 4, or 5, preferably 3 or 4; preferably 4; R1 is Preferred R2, R3, and R4 are independent a can be 1, 2, or 3 independently, with 2 being preferred; b can be 1, 2, 3 or 4 independently, preferably 1 or 4; a+b can be 2, 3, 4, 5, 6 or 7 independently, preferably 3, 4, 5 or 6; M1 is independently selected from -C(O)NH-, -NHC(O)- and -C(O)NHNHC(O)-, preferably -C(O)NH- and -C(O)NHNHC(O)-; preferably -C(O)NH- and -NHC(O)-, especially -C(O)NH-; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O-), preferably -C(O)O- and -OC(O-); preferably -OC(O- and -SC(O-), especially -OC(O)-; R is independently selected from C 8-12 Alkyl, preferably C 8-11 Alkyl groups, preferably C8 alkyl groups, optionally marked with one or two R groups. s replace; R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 10 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl; Preferably, R1, R2, R3, and R4 are the same; Preferably, R2, R3, and R4 are the same, and R1 is... Preferably, R is independently selected from -(CH2)7CH3, -(CH2)8CH3, and -(CH2). 10 CH3, preferably -(CH2)7CH3; R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3, preferably -(CH2)9CH3. The compound of claim 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II): in, x can be 1, 2 or 3 independently, preferably 1 or 2; y is 2, 3, 4 or 5, preferably 3, 4 or 5; R1 is R2, R3, and R4 are independent a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3 or 4; b can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3 or 4; a+b independently represents 2, 3, 4, 5, 6, or 7; n = 0, 1, 2, 3, 4 or 5; R A Independently selected from H and C 1-6 Alkyl, -L f -OR f -L f -SR f and -L f NR f R' f ; L f Independently selected from chemical bonds and C 1-6 Alkylene; R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-, preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 4-14 Alkyl, C 4-14 alkenyl and C 4-14 Alkyne group, preferably C 4-14 Alkyl groups, optionally marked with one or two R groups s replace; R' is independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-14 Alkylene; R e and R' e Independently selected from H and C 1-14 alkyl. The compound of claim 28, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x is independently 1 or 2, preferably 1; y is 3, 4 or 5, preferably 3 or 4, preferably 4; R1 is R2, R3, and R4 are independent a can be 1, 2, 3 or 4 independently, preferably 2 or 3, preferably 3; b can be 1, 2, or 3 independently, with 2 being preferred; a+b can be independently 3, 4, 5, 6 or 7, preferably 4 or 5; preferably 4, 5 or 6, preferably 4 or 5, more preferably 5; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O-), preferably -C(O)O- and -OC(O-); preferably -OC(O- and -SC(O-), especially -OC(O)-; R is independently selected from C 6-12 Alkyl, preferably C 6-9 Alkyl groups, preferably C6 alkyl groups, preferably C9 alkyl groups, optionally marked with one or two R groups. s replace; R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C8 alkyl, preferably C 10 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl; Preferably, R1, R2, R3, and R4 are the same; Preferably, R2, R3, and R4 are the same, and R1 is... Preferably, R is independently selected from -(CH2)5CH3 and -(CH2)8CH3, preferably -(CH2)8CH3; R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3, preferably -(CH2)7CH3. The compound of claim 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (IIB): in, x can be 1, 2 or 3 independently, preferably 1 or 2; y is 2, 3, 4 or 5, preferably 2, 3 or 4; R1 is selected from H, Preferred R2, R3, and R4 are independent R8 is independently selected from H and C. 1-6 Alkyl and a can be 1, 2, 3, 4, 5 or 6 independently, preferably 1, 2, 3, 4 or 5; b can be 0, 1, 2, 3, 4, 5 or 6 independently, preferably 0, 1, 2, 3 or 4; a+b can be 1, 2, 3, 4, 5, 6 or 7 independently, preferably 3, 4, 5, 6 or 7; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -C(O)NH- and -NHC(O)-; R is independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, preferably C 6-15 Alkyl, C 6-15 alkenyl and C 6-15 Alkyne group, preferably C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace; R' is independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, preferably C 6-14 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently for H and C 1-15 Alkyl, -L e -OR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-15 Alkylene; R e and R' e Independently selected from H and C 1-15 alkyl; R5 and R6 are independently selected from H and C. 1-3 alkyl; Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene, preferably C 3-6 Cycloalkylene; Preferably, when y is 2, a+b is not 1. The compound of claim 30, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x can be 1 or 2 independently, preferably 1; y is 2, 3, 4 or 5, preferably 2, 3 or 4; R1 is selected from H, Preferred R2, R3, and R4 are independent R8 is independently selected from H and C. 1-6 Alkyl and H and C are preferred 1-3 Alkyl; preferably H and H is preferred; at most one R8 is preferred. a can be 2, 3, 4, 5 or 6 independently, preferably 3, 4 or 5, preferably 3, preferably 5; b can be 0, 1, 2, 3 or 4 independently, preferably 1, 2 or 3, preferably 1, preferably 3; a+b can be independently 3, 4, 5, 6 or 7, preferably 4, 5 or 6, preferably 4 or 6, preferably 6; M2 is independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -C(O)NH-, -NHC(O)- and -SC(O)-, preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, especially -C(O)O- and -OC(O)-; R is independently selected from C 8-15 Alkyl, C 8-15 alkenyl and C 8-15 Alkyne group, which is optionally surrounded by 1 or 2 R groups s replace; R' is independently selected from C 8-12 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently for C 1-15 alkyl; R5 and R6 are independently selected from H and C. 1-3 alkyl; Or CR5 and R6 can be chosen together to form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene, preferably C 3-6 Cycloalkylene. The compound of claim 31, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, x is 1; y is 2, 3 or 4, preferably 3 or 4, preferably 3; R1 is selected from H, Preferred R2, R3, and R4 are independent R8 is independently selected from H and C. 1-6 Alkyl and H and C are preferred 1-3 Alkyl; preferably H and H is preferred; at most one R8 is preferred. a can be 3, 4 or 5 independently, preferably 3 or 5, preferably 5; b can be 1, 2 or 3 independently, preferably 1 or 3, preferably 1; a+b can be 4, 5 or 6 independently, preferably 4 or 6, preferably 6; M2 is independently selected from -C(O)O- and -OC(O-); preferably -OC(O-); R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl groups, which are optionally surrounded by one or two R groups s replace; R' is independently selected from C 8-12 Alkyl, preferably C 8-10 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 alkyl; R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3, R' is independently selected from -(CH2)7CH3 and -(CH2)9CH3; Preferably, R2, R3, and R4 are the same; more preferably, R1, R2, R3, and R4 are the same. The compound of claim 30, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (IIB): in, x is 1; y is 2; R1, R2, R3, and R4 are independent R8 is independently selected from H and C. 1-3 Alkyl; preferably H; a can be 3, 4, or 5 independently, preferably 5; b can be 1, 2, or 3 independently, with 1 being preferred; a+b can be 4, 5, or 6 independently, with 6 being the preferred value; M2 is selected from -OC(O)- and -C(O)O-; R is independently selected from C 10-12 Alkyl, preferably C 10 Alkyl groups, optionally marked with one or two R groups s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-3 alkyl; R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R is independently selected from -(CH2)9CH3; Preferably, R1, R2, R3 and R4 are the same. The compound of claim 30, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (IIB): in, x is 1; y is 3; R1, R2, R3, and R4 are independent R8 is independently selected from H and And only one R8 is H is preferred; a can be 3, 4 or 5 independently, preferably 3 or 5, preferably 5; b can be 1, 2 or 3 independently, preferably 1 or 3, preferably 1; a+b can be 4, 5 or 6 independently, preferably 4 or 6, preferably 6; M2 is -OC(O)-; R is independently selected from C 10-12 Alkyl and C 15 Alkenyl groups, which are optionally surrounded by one or two R groups s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-3 alkyl; R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R is independently selected from -(CH2)9CH3, -(CH2) 11 CH3, (Preferred) )and Preferably, R1, R2, R3 and R4 are the same. The compound of claim 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II): in, x is 1; y is 3; R1, R2, R3, and R4 are independent a can be 3, 4 or 5 independently, preferably 3 or 5, preferably 5; b can be 1, 2 or 3 independently, preferably 1 or 3, preferably 1; a+b can be 4, 5 or 6 independently, preferably 4 or 6, preferably 6; M2 is -C(O)O-; R is independently selected from C 8-10 Alkyl and C 8-10 Alkenyl, preferably C 10 Alkyl and C 8-10 Alkenyl groups, which are optionally surrounded by one or two R groups s replace; R s Independently for C 1-3 alkyl; R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; preferably H; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R is independently selected from -(CH2)9CH3, (Preferred) )、 Preferably, R1, R2, R3 and R4 are the same. The compound of claim 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II): in, x is 1; y is 4; R1, R2, R3, and R4 are independent a can be 1, 2, 3, 4 or 5 independently, preferably 1 or 5, preferably 5; b can be 0, 1, 2 or 3 independently, preferably 0 or 1, preferably 1; a+b can be 1, 2, 3, 4, 5 or 6 independently, preferably 1 or 6, preferably 6; M2 is -OC(O)-, -OC(O)- or -C(O)NH-, preferably -OC(O)- or -OC(O)-, preferably -OC(O)-; R is independently selected from C 8-15 Alkyl and C 8-15 Alkenyl, preferably C 10 Alkyl and C9 alkenyl groups, optionally separated by one or two R groups. s replace; R s Independently for H and C 1-15 Alkyl group, preferably H; R5 and R6 are independently selected from H and C. 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably H and methyl; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R is independently selected from -(CH2)8CH3, -(CH2)9CH3, and -(CH2). 11 CH3, -(CH2) 14 CH3, Preferably, R1, R2, R3 and R4 are the same. The compound of claim 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II): in, x is 1; y is 2 or 3; R1, R2, R3, and R4 are independent a is 5; b is 1; M2 is -OC(O)-; R is independently selected from C 10-12 Alkyl and C 10-12 Alkenyl, preferably C 10-12 Alkyl, preferably C 10 alkyl; R5 and R6 are independently selected from C 1-3 Alkyl (preferably C) 1-2 Alkyl); preferably methyl; Or CR5 and R6 can be chosen together to form C 3-4 Cycloalkylene, preferably cyclopropylene; Preferably, R1, R2, R3 and R4 are the same. The compound of claim 1, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from the compounds in Table (I). A nanoparticle composition comprising a lipid component and optionally a loading agent; wherein, The lipid component contains a compound of any one of claims 1-38, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the loading is selected from one or more therapeutic agents, preventive agents, or diagnostic agents. Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids 20 mol% - 98 mol% Structural lipids: 0 mol% - 75 mol%; Assisted lipids 0 mol% - 30 mol%; Polymer lipids: 0.25 mol% - 10 mol%; Preferably, the lipid component contains the following components in molar percentage: 50 mol% of ionizable lipids; 10 mol% of auxiliary lipids; Structural lipids 38.5 mol%; Polymer lipid 1.5 mol%; The ionizable lipid is selected from the compounds of any one of claims 1-38. The nanoparticle composition of claim 39, wherein, The lipid component contains a component selected from any of the following (1)-(3) in molar percentage: (1) The lipid component contains the following components in molar percentage: Ionizable lipids: 90 mol% - 99.5 mol%; Polymer lipids: 0.5 mol% - 10 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 94 mol% - 99.5 mol%; Polymer lipids: 0.5 mol% - 6 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids 95 mol% - 98 mol% Polymer lipids 2 mol% - 5 mol%; (2) The lipid component contains the following components in molar percentage: Ionizable lipids: 25 mol% - 80 mol%; Structural lipids: 10 mol% - 60 mol%; Assisted lipids 0 mol% - 30 mol%; Polymer lipids: 0.5 mol% - 5 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 25 mol% - 75 mol%; Structural lipids: 15 mol% - 60 mol%; Assisted lipids 2 mol% - 30 mol%; Polymer lipids 1 mol% - 5 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 30 mol% - 70 mol%; Structural lipids: 23 mol% - 52 mol%; Assisted lipids 4 mol% - 20 mol%; Polymer lipids: 1 mol% - 3.5 mol%; Preferably, the lipid component contains the following molar percentages of ionizable lipids: 30 mol% - 70 mol%; Structural lipids: 23 mol% - 52 mol%; Assisted lipids 4 mol% - 20 mol%; Polymer lipids: 1.5 mol% - 3 mol%; (3) The lipid component contains the following components in molar percentage: Ionizable lipids: 20 mol% - 50 mol%; Structural lipids: 10 mol% - 50 mol%; Assisted lipids 10 mol% - 30 mol%; Polymer lipids: 0.5 mol% - 5 mol%; Permanent cationic compounds, 10 mol% - 50 mol%; Preferably, the lipid component contains the following molar percentage of components: 20 mol%-50 mol% of ionizable lipids; Structural lipids: 15 mol% - 40 mol%; 10 mol% - 20 mol% of auxiliary lipids; Polymer lipids: 0.5 mol% - 5 mol%; Permanent cationic compounds, 10 mol% - 40 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 25 mol% - 45 mol%; Structural lipids: 20 mol% - 35 mol%; 12 mol% - 18 mol% of auxiliary lipids; Polymer lipids: 0.5 mol% - 3.5 mol%; Permanent cationic compounds, 15 mol% - 35 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 30 mol% - 40 mol%; Structural lipids: 24.5 mol% - 29.5 mol%; The auxiliary lipids are 12 mol%-18 mol%, preferably 15 mol%. Polymer lipids: 0.5 mol% - 3 mol%; Permanent cationic compounds 20 mol% - 30 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 30 mol% - 40 mol%; Structural lipids: 24.5 mol% - 29.5 mol%; The auxiliary lipids are 12 mol%-18 mol%, preferably 15 mol%. Polymer lipids: 0.5 mol% - 1.8 mol%; Permanent cationic compounds 20 mol% - 30 mol%; The ionizable lipid is selected from the compounds of any one of claims 1-38. The nanoparticle composition of claim 40, wherein, The lipid component comprises a component selected from any one of the following (2-1), (2-2), and (3-1) in molar percentage: (2-1) The lipid component contains the following components in molar percentage: Ionizable lipids: 45 mol% - 75 mol%; Structural lipids 20 mol% - 30 mol%; Assisted lipids 2 mol% - 25 mol%; Polymer lipids: 1.5 mol% - 4 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 50 mol% - 70 mol%; Structural lipids: 23.9 mol% - 27 mol%; Assisted lipids 4 mol% - 20 mol%; Polymer lipids 2.1 mol% - 3 mol%; (2-2) The lipid component contains the following components in molar percentage: Ionizable lipids: 45 mol%-55 mol%, preferably 50 mol%; Structural lipids 30 mol%-40 mol%, preferably 37 mol%; The auxiliary lipids are 5 mol%-15 mol%, preferably 10 mol%. Polymer lipids 2 mol%-4 mol%, preferably 3 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 47 mol%-53 mol%, preferably 50 mol%; Structural lipids 35 mol%-40 mol%, preferably 37 mol%; The auxiliary lipids are 8 mol%-12 mol%, preferably 10 mol%. The polymer lipid content is 2.5 mol% to 3.5 mol%, preferably 3 mol%. (3-1) The lipid component contains the following components in molar percentage: Ionizable lipids: 25 mol% - 35 mol%; Structural lipids: 26 mol% - 32 mol%; 12 mol% - 18 mol% of auxiliary lipids; Polymer lipids: 0.5 mol% - 2.5 mol%; Permanent cationic compounds, 25 mol% - 35 mol%; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 27 mol% - 33 mol%, preferably 30 mol%; Structural lipids: 28.2 mol% - 29.5 mol%; The auxiliary lipids are 12 mol%-18 mol%, preferably 15 mol%. Polymer lipids: 0.5 mol% - 1.8 mol%; 27 mol%-33 mol%, preferably 30 mol% of a permanent cationic compound; The ionizable lipid is selected from the compounds of any one of claims 1-38. The nanoparticle composition according to any one of claims 39-41, wherein, It meets one or more of the following (i)-(v): (i) The auxiliary lipid is a phospholipid; Preferably, the phospholipid is selected from phosphatidylcholine and / or phosphatidylethanolamine; Preferably, the phospholipid is selected from distearylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), palmitoylphosphatidylcholine (POPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoylphosphatidylethanolamine (POPE), distearyl-sn-glycerol-phosphoethanolamine, and di- Palmitoyl phosphatidyl ethanolamine (DPPE), dimyristoyl phosphatidyl ethanolamine (DMPE), distearate phosphatidyl ethanolamine (DSPE), monomethylphosphatidyl ethanolamine, dimethylphosphatidyl ethanolamine, 18-1-transPE, 1-stearoyl-2-oleoyl phosphatidyl ethanolamine (SOPE), hydrogenated soybean phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), dioleoyl phosphatidyl serine or 1,2-dioleoyl-sn-glycero-3-phosphate-L-serine (DOPS) Sphingomyelin (SM), Dimyristic phosphatidylglycerol (DMPG), Distearate phosphatidylglycerol (DSPG), Rutinyl phosphatidylcholine (DEPC), Palmitoyl phosphatidylglycerol (POPG), Dioleoyl-phosphatidylethanolamine (DEPE), 1,2-Dilauroyl-sn-glycerol-3-phosphate ethanolamine (DLPE), 1,2-Diphydanyl-sn-glycerol-3-phosphate ethanolamine (DPHyPE), Lecithin, Phosphatidylethanolamine, Lysophosphatidyl Ethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, methionine (ESM), cephalin, cardiolipin, phosphatidic acid, cerebroside, hexadecyl phosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine or mixtures thereof, preferably one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, DOPG, DPPG, DSPE, DOPS, DMPG, POPE or DPPE, more preferably DSPC and / or DOPE; (ii) The structural lipid is a steroid or an analogue thereof; Preferably, the steroid or its analogue is selected from alfalfa sterol, β-sitosterol, campesterol, ergocalciferol, campesterol, cholesterol, coccidosterol, dehydrocholesterol, sterol, dihydroergocalciferol, cholesterol, dihydrocholesterol, dihydroergosterol, stigmasterol, epicholesterol, ergosterol, fucosterol, hexahydrophotosterol, hydroxycholesterol, photosterol, phycosterol, sitosterol, stigmasterol, stigmasterol, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, lithocholic acid, ent-cholesterol, epicholesterol, demosterol, cholesterol, cholesterol, cholestenone, 3p-[N-(N'N'-dimethylaminoethyl)carbamoylcholesterol (DC-Chol), 2 4(S)-hydroxycholesterol, 25-hydroxycholesterol, 25(R)-27-hydroxycholesterol, 22-oxacholesterol, 23-oxacholesterol, 24-oxacholesterol, cycloluterol, 22-ketosterol, 20-hydroxysterol, 7-hydroxycholesterol, 19-hydroxycholesterol, 22-hydroxycholesterol, 25-hydroxycholesterol, 7-dehydrocholesterol, dehydroergosterol, dehydroepiandrosterone, lanosterol, dihydrolanosterol, luminesterol, citopalcitol, calcipotriol, fecal prostaglandin, cholecalciferol, lupeol, ergocalciferol, 22,23-dihydrocalciferidol, tomatine, ursolic acid, chenodeoxycholic acid, yeast sterol, diosgenin, or one or more of these compounds; Preferably, the steroid or its analogue is selected from one or more of cholesterol, sitosterol, coccosterol, lycopene, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol; (iii) The polymer lipid is a polyethylene glycol-modified lipid; Preferably, the PEGylated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol; Preferably, the PEGylated lipid contains a PEG portion of about 1000 Da to about 20 kDa, and more preferably contains a PEG portion of about 1000 Da to about 5000 Da; Preferably, the polyethylene glycol-modified lipid is selected from polyethylene glycol-modified diacylglycerol (PEG-DAG), polyethylene glycol-modified phosphatidylethanolamine (PEG-PE), polyethylene glycol-modified succinate diacylglycerol (PEG-S-DAG), such as 4-O-(2',3'-bis(tetradecyloxy)propyl-1-O-(ω-methoxy(polyethoxy)ethyl)succinate (salt) (PEG-S-DMG), polyethylene glycol-modified ceramide (PEG-cer), or polyethylene glycol-modified dialkoxypropyl carbamate (e.g. ω- -Methoxy(polyethoxy)ethyl-N-(2,3-di(tetradecoxy)propyl)carbamate or 2,3-di(tetradecoxy)propyl-N-(ω-methoxy(polyethoxy)ethyl)carbamate), PEG-dialkoxypropylcarbamate, N-(carbonyl-methoxy polyethylene glycol 2000)-1,2-distearyl-sn-glycerol-3-phosphate ethanolamine sodium sodium, PEG-dilauroyloxypropyl, PEG-dimyristoyloxypropyl, PEG-dipalmitoyloxypropyl, PEG-distearyl 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol-PEG (DMG-PEG), distearyl-rac-glycerol-PEG (DSG-PEG), PEG-dilauroylglycerol, PEG-dipalmitoylglycerol, PEG-distearylglycerol, PEG-dilauroylglycerol amide, PEG-dimyristoylglycerol amide, PEG-dipalmitoylglycerol amide, PEG-distearylglycerol amide, (1-[8'-(cholest-5-en-3β-oxy)methyl... One or more of the following: [acylamino-3',6'-dioxaoctyl]carbamoyl-ω-methyl-poly(ethylene glycol) (PEG-cholesterol), 3,4-bistetradecoxybenzyl-ω-methyl-poly(ethylene glycol) ether (PEG-DMB), 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine-N-[methoxy(polyethylene glycol) (DSPE-PEG)] and 1,2-distearate-sn-glycerol-3-phosphate ethanolamine-N-poly(ethylene glycol)-hydroxy (DSPE-PEG-OH); 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, preferably one or more of DSPE-PEG2000 and DMG-PEG2000, more preferably DSPE-PEG2000, and even more preferably DMG-PEG2000; (iv) The permanent cationic compound contains quaternary ammonium ions; Preferably, the permanent cationic compound has the structure of formula (P-1): Or its stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts, wherein: It can be a single bond or a double bond; Y is -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR 2a -、-NR 2a C(O)NR 2a -、-OC(O)S-、-OC(O)O-、-NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -、-C(O)NR 2a -、-NR 2a C(O)-、-NR 2a C(O)S-、-SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -、-NR 2a C(S)O-、-OP(O)(OR 205 )O- or -S(O) 0-2 - and the left-hand connection is a connection in the direction of V1; Y1 either does not exist or is -C(O)O-, -O-, -NH-, -SC(O)O-, or -OC(O)NR. 2a -、-NR 2a C(O)NR 2a -、-OC(O)S-、-OC(O)O-、-NR 2a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR 2a -、-C(O)NR 2a -、-NR 2a C(O)-、-NR 2a C(O)S-、-SC(O)NR 2a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR 2a -、-NR 2a C(S)O- or -S(O) 0-2 - and the left-hand connection is a connection in the direction of V1; R 2a Each instance is independently H, C 1-10 Alkyl, C 3-14 Cycloalkyl or 3- to 14-membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally and independently C 1-10 Alkyl, L 2b -OR 2b L b -SR 2b L 2b -NR 2b R' 2b L 2b N + R 2b R' 2b R” 2b L 2b -OC(O)R 2b or L 2b -C(O)OR 2b replace; R 201 R 202 R 203 R 204 Each instance is independently H, OH, C 1-6 Alkyl, C 1-6 Alkoxy, -L 2b -NR 21 R 22 -L 2b -N + R 21 R 22 R 23 -L 2b -OC(O)R 21 or -L 2b -C(O)OR 21 ; R 205 Absent or cations, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Alkynyl, wherein the alkyl, haloalkyl, alkenyl, and alkynyl groups are optionally surrounded by 1, 2, 3, or 4 R groups. 20s replace; m is an integer from 1 to 12; m1 is an integer from 0 to 12; V1 is NR 21 R 22 N + R 21 R 22 R 23 Imidazole, pyridine, pyrrole, pyrrolidine, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazine, oxazoline, dithioureaazole, triazole, isothiazole, tetrazolium, pentaazole, indole, dihydroindole, pyrimidine, pyrazine, quinazoline, piperazine, piperidine, morpholine, pyran, quinoxaline, quinoline, quinoline, isoquinoline, amidine, guanidine, or urea; M is absent or is an anion independently selected from chloride, bromide, iodide, sulfate, nitrate, perchlorate, formate, citrate, sulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, pyrosulfate, bisulfite, sulfite, phosphate, pyrophosphate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, decanoate, octanoate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, fumarate, maleate, benzoate, phthalate, phenylacetate, lactate, glycolate, tartrate, mandelic acid, methanesulfonate, gluconate, aspartate, or glutamate. R 21 R 22 R 23 Each instance is independently H, optionally by 1, 2, 3 or 4 Rs. 20s Replacement C 1-8 Alkyl, -L 2b -OR 2b -L 2b -SR 2b -L 2b -NR 2b R' 2b R” 2b L 2b -OC(O)R 2b or L 2b -C(O)OR 2b ; L 2b It does not exist or is optionally represented by 1, 2, 3 or 4 Rs 20s Replacement C 1-10 Alkylene; R 2b 、R' 2b and R” 2b Each instance is independently H or C 1-10 alkyl; R z1 C 1-14 Alkyl or C 1-14 Alkenyl, wherein the alkyl and alkenyl groups are optionally surrounded by 1, 2, 3 or 4 R groups. 20s replace; R 20s Independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, the permanent cationic compound has the structure of formula (P-2): in, R 301 and R 302 Each is C independently 8-24 Alkyl or C 8-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 301s replace; R 301s Independently selected from H, halogen, C 1-24 Alkyl, C 1-24 Halogenated alkyl and C 2-24 Alkenyl groups, preferably H, halogens, or C. 1-24 Alkyl and C 1-24 Halogenated alkyl groups; R 303 R 303 ′ and R 303 "Each is independent of the other." 1-6 Alkyl groups or those with 1, 2, 3 or 4 R groups 303s Replacement C 1-6 alkyl; X - It is a monovalent anion; R 303s Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 2-6 Alkenyl groups, preferably H, halogens, or C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, the permanent cationic compound has the structure of formula (P-3): in: R 304 and R 304 Each is C independently 6-24 Alkyl or C 6-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 304s replace; R 304 "It is C" 1-24 Alkyl or C 2-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 304s replace; R 304s Independently selected from H, halogen, C 1-24 Alkyl, C 1-24 Halogenated alkyl and C 2-24 Alkenyl groups, preferably H, halogens, or C. 1-24 Alkyl and C 1-24 Halogenated alkyl groups; R 304 "′ is C 1-8 Alkyl or C 2-8 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 304s 'replace; R 304s 'Independently selected from H, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl and C 2-8 Alkenyl groups, preferably H, halogens, or C. 1-8 Alkyl and C 1-8 Halogenated alkyl groups; and X2 - It is a monovalent anion; Preferably, the permanent cationic compound has the structure of formula (P-4): in: R 301 and R 302 Each is C independently 8-24 Alkyl, C 8-24 Alkenyl groups, optionally surrounded by 1, 2, 3 or 4 R groups 301s replace; R 301s Independently selected from H, halogen, C 1-24 Alkyl, C 1-24 Halogenated alkyl and C 2-24 Alkenyl groups, preferably H, halogens, or C. 1-24 Alkyl and C 1-24 Halogenated alkyl groups; R 303 R 303 ′ and R 303 "Each is independent of the other." 1-6 Alkyl groups or those with 1, 2, 3 or 4 R groups 303s Replacement C 1-6 alkyl; R 304 It is C 1-6 Alkyl groups or those with 1, 2, 3 or 4 R groups 304s Replacement C 1-6 alkyl; R 303s and R 304s Independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; and X - It is a monovalent anion; Preferably, the permanent cationic compound has the structure of formula (P-5): in: R 501 and R 502 Selected independently from C 10-18 Alkyl and C 12-18 alkenyl; R 503 and R 504 Selected independently from C 1-6 Alkyl and -C 2-6 alkylene-OH; X is selected from -CH2-, -S-, -O-, or does not exist; Y is selected from -(CH2) n -、-S(CH2) n -、-O(CH2) n - Thiophene group, -SO2(CH2) n -and-C(O)O-; n = 1, 2, 3 or 4; a = 1, 2, 3 or 4; b = 1, 2, 3, or 4; c = 1, 2, 3 or 4; Z - It is a counterion; Preferably, the permanent cationic compound is selected from one or more of the following: N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP), ethylphosphatidylcholine (EPC) and its derivatives, 1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]butylcarbamoyl)ethyl]-3,4-di[oleoyloxy]-benzamide (MVL5), bis(octadecylamido)glycine tetramine (DOGS), N-bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteroloxycarbonylaminoethyl)ammonium bromide (BHEM-Chol), bis(octadecyl dimethylammonium bromide) (DDAB), and BHEM-Chol, DOTAP or preferred One or more of the following; preferably (v) The ionizable lipid is selected from the following structures: A pharmaceutical composition comprising a compound of any one of claims 1-38, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a nanoparticle composition of any one of claims 39-42, and a pharmaceutically acceptable excipient. Use of any compound of claims 1-38, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a nanoparticle composition of any one of claims 39-42, or a pharmaceutical composition of claim 43 in the preparation of a medicament for treating, diagnosing or preventing a disease. Preferably, the disease is a lung disease, including obstructive lung disease, restrictive lung disease, pulmonary vascular disease, infectious lung disease, hereditary lung disease, allergic lung disease, and tumors, such as pneumonia, influenza, cystic fibrosis, primary ciliary dyskinesia, α-1 antitrypsin deficiency, asthma, pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), lymphangioleiomyomatosis (LAM), or lung cancer; Preferably, the drug used for treating, diagnosing, or preventing the disease is a nucleic acid; Preferably, the drug used for treating, diagnosing, or preventing the disease is a gene therapy drug; Preferably, the drug used for treating, diagnosing, or preventing the disease is a gene-editing drug; Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA, or DNA; Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA), or ribozymes, preferably one or more of mRNA, siRNA, gRNA, circRNA, SrRNA, miRNA, aRNA, or modified mRNA, preferably mRNA, siRNA, gRNA, or modified mRNA; Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), and more preferably from one or more of plasmid DNA (pDNA), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA). The use of any compound of claims 1-38, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a nanoparticle composition of any one of claims 39-42, or a pharmaceutical composition of claim 43, in the preparation of a medicament for delivery of a payload, wherein the payload is selected from one or more therapeutic agents, preventive agents or diagnostic agents. Preferably, the drug is a drug that delivers a load to the lungs; Preferably, the payload is a gene therapy drug; Preferably, the payload is a gene-editing drug. 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 39-42, or a pharmaceutical composition of claim 43; Preferably, the disease is a lung disease, including obstructive lung disease, restrictive lung disease, pulmonary vascular disease, infectious lung disease, hereditary lung disease, allergic lung disease, and tumors, such as pneumonia, influenza, cystic fibrosis, primary ciliary dyskinesia, α-1 antitrypsin deficiency, asthma, pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), lymphangioleiomyomatosis (LAM), or lung cancer; Preferably, the method for treating, diagnosing, or preventing the disease is gene therapy; Preferably, the method for treating, diagnosing, or preventing the disease is gene editing. The compound of any one of claims 1-38, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of any one of claims 39-42, or the pharmaceutical composition of claim 43, is used for treating, diagnosing or preventing a disease; preferably for gene therapy; preferably for gene editing. Preferably, the disease is a lung disease, including obstructive lung disease, restrictive lung disease, pulmonary vascular disease, infectious lung disease, hereditary lung disease, allergic lung disease, and tumors such as pneumonia, influenza, cystic fibrosis, primary ciliary dyskinesia, α-1 antitrypsin deficiency, asthma, pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), lymphangioleiomyomatosis (LAM), or lung cancer. A method of delivering a payload into a subject, comprising administering to the subject the nanoparticle composition of any one of claims 39-42, or the pharmaceutical composition of claim 43; in, The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents; Preferably, the method is a method of delivering a load to the lungs of a subject. The method of claim 46 or 48, wherein the administration comprises any one or a combination of local administration and systemic administration; Preferably, the administration includes intravenous injection, intraperitoneal injection, arterial injection, or inhalation, more preferably intravenous injection. The compound of any one of claims 1-38, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of any one of claims 39-42, or the pharmaceutical composition of claim 43, for delivery of a payload; in, The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents; Preferably, it is used to deliver a load to the lungs. The nanoparticle composition of any one of claims 39-42, or the method of claim 48 or 49, or the compound or pharmaceutical composition or nanoparticle composition of claim 50, wherein, The therapeutic, preventative, or diagnostic agent is a nucleic acid; Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA, or DNA; Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA), or ribozymes, preferably one or more of mRNA, siRNA, gRNA, circRNA, SrRNA, miRNA, aRNA, or modified mRNA, more preferably mRNA, siRNA, gRNA, or modified mRNA; Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), and more preferably from one or more of plasmid DNA (pDNA), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA). A method for preparing a compound of formula (I), the method comprising: The compound of formula (IA) is reacted with the compound of formula (IB-I) or formula (IB-II) to give the compound of formula (IC); Alternatively, reacting compound (IA) with compound (ID) yields compound (IA'), and then reacting the resulting compound (IA') with compound (IB-I) or compound (IB-II) yields compound (IC'). Wherein, PG is an independent amino protecting group, preferably Boc; X is independently a halogen, such as Cl, Br or I, preferably Br; The remaining variables are defined as described in any one of claims 1-38; Preferably, the compound of formula (IC) or formula (IC') is deprotected to obtain the compound of formula (I). R8 stands for H.

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