Ionizable lipid for active targeted delivery, and composition and application thereof

Abstract

The present invention provides an ionizable lipid for active targeted delivery, specifically relating to a compound represented by formula (I), or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The present invention further provides a nanoparticle pharmaceutical composition comprising the compound, and an application of the compound and a composition thereof in delivering a payload to a target organ and / or target tissue (such as an immune organ and / or immune tissue).

Description

Ionizable lipids for active targeted delivery, compositions thereof and their applications

[0001] This application claims priority to Chinese application 202411434340.5 filed on October 14, 2024, Chinese application 202511442211.5 filed on October 10, 2025, and Chinese application 202511442306.7 filed on October 10, 2025, which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to an ionizable lipid compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for active targeted delivery. The invention also relates to lipid nanoparticles comprising said compound and pharmaceutical compositions, and the use of said lipid nanoparticles in delivering bioactive substances, such as payloads (e.g., nucleic acids (e.g., mRNA, siRNA, ASO, DNA, etc.) or gene-edited drugs), to immune tissues or organs (e.g., immune cells or T cells). 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 cross 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, neutral lipids, and polyethylene glycol-conjugated lipids. Among these, the 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] Currently, the ability to control which tissues or cells take up lipid nanoparticles (LNPs) after administration remains very limited. Intravenously administered LNPs are primarily taken up by the liver, lungs, or spleen. With specific formulations combined with intravenous administration, over 90% of LNPs can be targeted to the liver. tLNPs preferentially deliver nucleic acid molecules or other payloads to cells expressing cell surface binding sites (such as antigens) recognized by the tLNP's target portion, enabling LNPs to actively direct to target organs and / or target tissues or cell types. Furthermore, in current delivery systems, only a small fraction of the loaded nucleic acids are successfully delivered to target cells, achieving high levels of cell transfection and protein expression. Existing delivery systems still suffer from off-target delivery, low efficiency in releasing nucleic acids into the cytoplasm, and toxicity associated with the accumulation of component lipids.

[0006] US12311033B2 provides a tLNP that targets immune cells; however, delivery platforms, especially ionizable lipid compounds and their compositions, that can efficiently target target organs and / or tissues for diverse disease treatment scenarios still need to be developed. Summary of the Invention

[0007] This invention provides a class of compounds suitable for use as ionizable lipids in LNPs or tLNPs for delivering payloads to target organs and / or target tissues. The tLNPs containing this compound have high delivery efficiency in cells, and the amount of protein encoded by the nucleic acid expressed after delivery to the cell is greater (stronger MFI intensity).

[0008] In addition to the classic components of LNPs—ionizable lipids, structural lipids, neutral lipids, and polymer lipids (non-functionalized PEG lipids)—tLNPs may optionally include functionalized polymer lipids (functionalized PEG lipids). These functionalized polymer lipids possess highly reactive functionalized groups, such as maleimides, azides, alkynes, dibenzocyclooctylene (DBCO), bromomaleimides, bromomaleimide amides, alkynyl amides, or alkynylimides. They can react with active groups in the targeting moiety, such as covalently binding with SH and N3 groups in Nb-SH, Nb-N3, Ab-SH, and Ab-N3, or with amino groups in the targeting moiety (Nb represents nanobody, Ab represents antibody), forming a targeted LNP (tLNP) with active targeting.

[0009] This invention provides compounds of formula (I), or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0010] Wherein, each group is as defined in this invention.

[0011] In another aspect, the present invention provides a composition comprising the compounds of the present invention.

[0012] 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.

[0013] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention, or compositions of the present invention, or nanoparticle compositions of the present invention, and optionally pharmaceutically acceptable excipients, such as carriers, adjuvants, or mediators.

[0014] In another aspect, the present invention provides the use of the compounds, compositions, nanoparticle compositions, or pharmaceutical compositions of the present invention in the preparation of medicaments for treating, diagnosing, or preventing diseases selected from viral infections, cancer, autoimmune diseases, hereditary diseases (single-gene hereditary diseases, hereditary immunodeficiency diseases), and fibrotic diseases. In one embodiment, the medicament for treating, diagnosing, or preventing the disease is a nucleic acid drug, preferably a therapeutic or preventive nucleic acid drug.

[0015] In one embodiment, the drug used to treat, diagnose, or prevent the disease is a gene therapy drug, such as a gene editing drug, gene interference drug, protein supplementation or protein replacement drug.

[0016] In another aspect, the present invention provides the use of the compounds, compositions, nanoparticle compositions, or pharmaceutical compositions of the present invention in the preparation of medicaments for delivery of loads to target organs and / or target tissues (e.g., immune organs and / or immune tissues).

[0017] In another aspect, the present invention provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention; wherein the disease is selected from viral infections, cancer, autoimmune diseases, hereditary diseases (monogenous genetic diseases, hereditary immunodeficiency diseases), and fibrotic diseases. In one embodiment, the method for treating, diagnosing, or preventing the disease is gene therapy, such as gene editing, gene interference, protein supplementation, or protein replacement.

[0018] In another aspect, the present invention provides compounds, nanoparticle compositions, or pharmaceutical compositions for the treatment, diagnosis, and / or prevention of diseases selected from viral infections, cancer, autoimmune diseases, hereditary diseases (monogenous genetic diseases, hereditary immunodeficiency diseases), and fibrotic diseases. In one embodiment, it is used for gene therapy, such as gene editing, gene interference, protein supplementation, or protein replacement.

[0019] In another aspect, the present invention provides a method for delivering a payload in a subject’s target organ and / or target tissue (e.g., immune organ and / or immune tissue), 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.

[0020] In another aspect, the present invention provides compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for delivering payloads to target organs and / or target tissues (e.g., immune organs and / or immune tissues).

[0021] 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.

[0022] In a more specific embodiment, the nucleic acid is selected from one or more of ASO, RNA, or DNA.

[0023] 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), 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), or ribozymes, preferably mRNA, siRNA, gRNA, circRNA, SrRNA, miRNA, aRNA, or modified mRNA.

[0024] In a more specific embodiment, the mRNA encodes a functional or structural protein; preferably, the protein is selected from T-cell receptors (TCRs), chimeric antigen receptors (CARs), immune cell connectors, or gene-editing nucleases.

[0025] In a more specific embodiment, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), and double-stranded DNA (dsDNA), preferably one or more of microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0026] In some specific implementations, the payload is a gene therapy drug, such as a gene editing, gene interference, protein supplementation, or protein replacement drug.

[0027] In some specific embodiments, the viral infection is a chronic viral infection, preferably a chronic viral infection that is difficult to eliminate, such as HIV, hepatitis B virus, and hepatitis C virus infection. The tLNP in this invention can target and eliminate pathogenic T cells or infected T cells (specifically for chronic viral infections that are difficult to eliminate, such as HIV, hepatitis B, and hepatitis C). By delivering mRNA encoding virus-specific CARs or TCRs to T cells via tLNP, a T cell line capable of accurately recognizing and eliminating infected cells can be rapidly expanded in vivo.

[0028] In some specific embodiments, the cancer is selected from hematologic malignancies and solid tumors. In more specific embodiments, the hematologic malignancies are hematologic systemic malignancies such as B-cell malignancies, preferably selected from leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome. In more specific embodiments, the leukemia is selected from acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. In more specific embodiments, the lymphoma is selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma. In more specific embodiments, the solid tumor is selected from lung cancer, gastric cancer, liver cancer, colorectal cancer, esophageal cancer, pancreatic cancer, breast cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, kidney cancer, bladder cancer, brain tumors, spinal cord tumors, head and neck squamous cell carcinoma, skin squamous cell carcinoma, basal cell carcinoma, melanoma, and various sarcomas.

[0029] In some specific implementations, the autoimmune disease is selected from AL amyloidosis, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, etc. Syndrome, idiopathic thrombocytopenic purpura, antiphospholipid syndrome, Chagas disease, Graves' disease, granulomatous polyangiitis, polyarteritis nodosa, Sjögren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, ANCA-associated vasculitis, Goodpasture's disease, Kawasaki disease, autoimmune hemolytic anemia, and rapidly progressive glomerulonephritis.

[0030] In some specific implementations, the hereditary disease is selected from single-gene hereditary diseases and hereditary immunodeficiency diseases. For immunodeficiency diseases caused by single-gene mutations, tLNP can be used to deliver the correct gene template and gene editing tools to hematopoietic stem cells or T cells for in vivo gene repair.

[0031] In some specific implementations, the fibrotic disease is selected from liver fibrosis, pulmonary fibrosis, cardiac fibrosis, renal fibrosis, skin fibrosis, pancreatic fibrosis, and myelofibrosis.

[0032] definition

[0033] Chemical definition

[0034] The definitions of specific functional groups and chemical terms are described in more detail below.

[0035] 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.

[0036] “C 1-20 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. In some embodiments, C 4-20 Alkyl, C 1-14 Alkyl, C 2-14 Alkyl, C 3-14 Alkyl, C 6-14 Alkyl, C 1-13 Alkyl, C 1-12 Alkyl, C 7- 12 Alkyl, C 8-12 Alkyl, C 9-12 Alkyl, C 10-12 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 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, C4-8 Alkyl, C 5-8 Alkyl, C 6-8 Alkyl, C 7-8 Alkyl, C8 alkyl, C 6-7 Alkyl, C7 alkyl, C 4-6 Alkyl, C 1-7 Alkyl, C 2-7 Alkyl, C 3-7 Alkyl, C 4-7 Alkyl, C 5-7 Alkyl, C 6- 7-alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 5-6 Alkyl, C 1-5 Alkyl, C 4-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 3-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 Alkyl groups and Me are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, the alkyl group is preferably a straight-chain alkyl group. In some embodiments, the alkyl group is preferably a straight-chain alkyl group, such as a C8 straight-chain alkyl group, such as a C9 ... 10 Straight-chain alkyl groups, such as C 11 Straight-chain alkyl groups.

[0037] “C 2-13 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 13 carbon atoms and at least one carbon-carbon double bond. 3-14 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 3 to 14 carbon atoms and at least one carbon-carbon double bond.4-20 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-14 alkenyl, C 6-14 alkenyl, C 7-12 alkenyl, C 8-12 alkenyl, C 4-10 alkenyl, C 2-10 alkenyl, C 2-9 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.

[0038] “C 2-13 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 13 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 3-14 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 3 to 14 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 4-20 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4-14 alkynyl group, C 6-14 alkynyl group, C 7-12 alkynyl group, C 8-12 alkynyl group, C 4-10 alkynyl group, C 2-10 alkynyl group, C 2-9 alkynyl group, C 2-6 alkynyl group and C 2-4 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6"Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkynyl is preferably a straight-chain alkynyl.

[0039] “C 1-20 "Alkylene" refers to the removal of C 1-20 The alkyl group is a divalent group formed by the other hydrogen atom of the alkyl group, and can be substituted or unsubstituted. In some embodiments, C 4-20 Alkylene, C 1-14 Alkylene, C 3-14 Alkylene, C 4-14 Alkylene, C 2-14 Alkylene, C 1-13 Alkylene, C 1-12 Alkylene, C 6-14 Alkylene, C 7-12 Alkylene, C 8-12 Alkylene, C 4-10 Alkylene, C 7-11 Alkylene, C 8-11 Alkylene, C 8-10 Alkylene, C 9-10 Alkylene, C 1-9 Alkylene, C 8-9 Alkylene, C 4-9 Alkylene, C 5-9 Alkylene, C 6-9 Alkylene, C 7-9 Alkylene, C9 alkylene, C 2-8 Alkylene, C 5-8 Alkylene, C 7-8 Alkylene, C 4-6 Alkylene, C 1-20 Alkylene, C 1-10 Alkylene, C 1-8 Alkylene, C 1-7 Alkylene, C 2-7 Alkylene, C 6-7 Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4 Alkylene, C 2-4 Alkylene, C 3-4 Alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1-2Alkylenes and methylene groups are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), 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.

[0040] “C 2-13 "Alkenyl" refers to the group that has been de-carbonied. 2-13 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. "C 3-14 "Alkenyl" refers to the group that has been de-carbonied. 4-14 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 4-10 imidene group, C 2-10 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.

[0041] “C 2-13 "Iso-ynyl" refers to the group that has the C group removed. 2-13 The alkynyl group is a divalent group formed by the other hydrogen atom, and can be substituted or unsubstituted. "C 3-14 "Iso-ynyl" refers to the group that has the C group removed. 4-14 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 4-10 Ethyne group, C 2-10 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.

[0042] “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".

[0043] 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.

[0044] The term "R" s "x carbon atoms are spaced between the substitution site on R1 and M1", indicating that the variable R2 is affected by the variable R. sThe sum of the number of carbon atoms (including N atoms replaced by -NR'-) between the substitution site and M2, and so on for other cases. For example:

[0045] In this compound, R s The substitution site on R1 is separated from M1 by two carbon atoms.

[0046] The term "R" s "x carbon atoms are spaced between the substitution site on R2 and ring A" indicates that the variable R2 is affected by the variable R. s The number of carbon atoms (including N atoms replaced by -NR'-) between the substitution site and ring A is the sum of their numbers, and so on for other cases. For example:

[0047] In compound 1, R s The substitution site on R2 is separated from ring A by two carbon atoms.

[0048] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0049] 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 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] “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.

[0051] “C 3-14 "Cycloalkylene" refers to the alkylene oxide that has had C removed. 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 and C 3-4 Cycloalkylene compounds are particularly preferred. Examples include cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, with cyclopropylene being especially preferred.

[0052] "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; preferably, a 5- to 7-membered heterocyclic group is preferred, which is a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms. A 5- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 3- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 4- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably a 5- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 5-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 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... 2-oxazolidinone. Exemplary 5-membered heterocyclic groups comprising three heteroatoms include, but are not limited to: triazolinyl, Diazolinyl 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, dithianyl, and di... Alkyl groups. 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, oxeheptyl, and thioheptyl. 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, and benzo[…]. Zolpidemone groups, etc. Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referring to 6,6-bicyclic heterocyclic groups herein) 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.

[0053] "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, 3-5 membered heterocyclic groups, and 3-4 membered heterocyclic groups are particularly preferred.

[0054] “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.

[0055] “C 6-10 "Asyl" refers to the absence 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, phenylene is particularly preferred.

[0056] "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, and... azole group, iso Azolyl, thiazolyl, and isothiazolyl groups. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, Diazole groups (e.g., 1,2,4-) Diazolyl 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, oxazirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoyindolyl, indazoleyl, benzotriazolyl, benzothiopheneyl, isobenzothiopheneyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzo[…]. azole group, benzo[a] azole, benzo[ Diazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0057] "5-10-membered heteroaryl" refers to a divalent group formed by removing another hydrogen atom from a 5-10-membered heteroaryl group, and can be substituted or unsubstituted. In some embodiments, 5-6-membered heteroaryl is particularly preferred. In some embodiments, 5-membered heteroaryl is particularly preferred. In some embodiments, 5-10-membered azapyridine is preferred. In some embodiments, 5-6-membered azapyridine is preferred. In some embodiments, 5-membered azapyridine is preferred, for example, diazonidine, triazonidine, or tetrazonidine, for example, diazonidine or triazonidine, for example... For example Preferred Preferred Preferred In some embodiments, the triazole group is preferred, for example Preferred In some embodiments, the diazonium group is preferred, for example Preferred

[0058] "Hydroxyalkyl" refers to an alkyl group that has been replaced by one or more hydroxyl groups.

[0059] "Alkoxy" refers to the oxyether form of a straight-chain or branched alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0060] "Optionally replaced by..." means that it can be replaced by a specified substituent or not replaced.

[0061] 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".

[0062] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0063] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bbC(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa -NR bb SO2R aa -SO2N(R) bb )2、-SO2R aa -SO2OR aa -OSO2R aa -S(=O)R aa -OS(=O)R aa 、-Si(R aa 3. -OSi(R) aa 3. -C(=S)N(R) bb )2、-C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups.dd Group substitution;

[0064] 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;

[0065] 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;

[0066] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bbGroups 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;

[0067] 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;

[0068] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff)2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0069] 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;

[0070] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0071] 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), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6Alkyl, -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.

[0072] 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 cc2. 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.

[0073] "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.

[0074] "Ionizable lipids" refers to lipids that are ionizable, allowing them to exist in a positively charged or neutral form depending on the pH. In some embodiments, ionizable lipids are aminolipids.

[0075] "Neutral lipids" refer to lipid molecules that are uncharged under specific pH conditions, such as physiological pH conditions. Examples of neutral lipids can be phospholipids, including but not limited to distearylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearyl-sn-glycerol-phosphoethanolamine, dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), distearylphosphatidylethanolamine (DSPE), monomethylphosphatidylethanolamine, dimethylphosphatidylethanolamine, 18-1-transPE, 1-stearoyl-2-oleoylphosphatidylethanolamine (SOPE), hydrogenated soybean phosphatidylcholine (HSPC), and egg phosphatidylcholine. Acylcholine (EPC), dioleoylphosphatidylserine or 1,2-dioleoyl-sn-glycero-3-phosphate-L-serine (DOPS), sphingomyelin (SM), dimyristoylphosphatidylglycerol (DMPG), distearate phosphatidylglycerol (DSPG), rutinoylphosphatidylcholine (DEPC), palmitoylphosphatidylglycerol (POPG), dioleoylphosphatidylethanolamine (DEPE), 1,2-dilauroyl- sn-glycerol-3-phosphate ethanolamine (DLPE), 1,2-diphydanoyl-sn-glycerol-3-phosphate ethanolamine (DPHyPE), lecithin, phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, methionine (ESM), cephalin, cardiolipin, phosphatidic acid, cerebroside, hexadecyl phosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine, or mixtures thereof. The acyl groups in these lipids are preferably derived from those having a C 10 -C 24The acyl group of the fatty acid in the carbon chain, such as lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl. Preferably, the phospholipid is selected from 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).

[0076] "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, including but not limited to alfalfa, β-sitosterol, campesterol, ergocalciferol, campesterol, cholesterol, coccidol, dehydrocholesterol, physcosterol, cholesterol, dihydroergocalciferol, dihydrocholesterol, stigmasterol, leucosterol, epicholesterol, ergosterol, fucosterol, hexahydrophotosterol, hydroxycholesterol, photosterol, physcosterol, sitosterol, stigmasterol, stigmasterol, cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, lithocholic acid, ent-cholesterol, epicholesterol, demosterol, cholesterol, cholesterol, cholestyrone, 3p-[N-(N'N'-dimethylaminoethyl)carbamoylcholesterol] DC-Chol), 24(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-dihydroautocalciferol, tomatine, ursolic acid, chenodeoxycholic acid, yeast sterol, diosgenin, etc. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coccosterol, rock saponin, rapeseed sterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol, or campesterol.

[0077] "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, which is a lipid covalently or non-covalently linked to one or more polyethylene glycol (PEG) chains. Other lipids capable of reducing aggregation, such as products of lipid coupling with compounds having uncharged, hydrophilic, or sterically blocking moieties, may also be used. In a preferred embodiment, in some embodiments, the PEG lipid of the present invention is a lipid covalently linked to one or more polyethylene glycol (PEG) chains. 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. Optionally, the PEGylated lipid contains a PEG moiety of about 1000 Da to about 20 kDa, preferably containing a PEG moiety of about 1000 Da to about 5000 Da.In some embodiments, the polyethylene glycol-modified lipids of the present invention include 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'-di(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(tetradecyloxy)propyl)carbamate or 2,3-di( Tetradecyloxypropyl-N-(ω-methoxy(polyethoxy)ethyl)carbamate, PEG-dialkoxypropylcarbamate, N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearyl-sn-glycerol-3-phosphate ethanolamine sodium, PEG-dilauroyloxypropyl, PEG-dimyristoyloxypropyl, PEG-dipalmitoyloxypropyl, PEG-distearyloxypropyl, 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol-PEG (DMG-PEG), distearyl-rac-glycerol-PEG (DSG-PEG), PEG-dilauroylglycerol, PEG-dipalmitoylglycerol, PEG - Distearylglycerol, PEG-dilauroylglyceramide, PEG-dimyristoylglyceramide, PEG-dipalmitoylglyceramide, PEG-distearylglyceramide, (1-[8'-(cholesterol-5-en-3β-oxy)formamido-3',6'-dioxaoctyl]carbamoyl-ω-methyl-poly(ethylene glycol) (PEG-cholesterol), 3,4-bistetradecyloxybenzyl-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-distearyl ... Alkylamine-N-poly(ethylene glycol)-hydroxy (DSPE-PEG-OH). 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.

[0078] "Functionalized polymer lipids" refer to polymer lipids in which one end of the polymer is connected to the lipid moiety, and the other end is connected to a highly reactive functionalized group (for example, one end of polyethylene glycol (PEG) is connected to the lipid moiety, and the methoxy or hydroxyl group at the other end is replaced with a highly reactive functionalized group). The highly reactive functionalized group includes, but is not limited to, maleimide, azide, acetylene, dibenzocyclooctylene (DBCO), bromomaleimide, bromomaleimide amide, alkynylamide, or alkynylimide. This functionalized polymer lipid can be coupled to a targeting moiety, which can bind to surface markers (binding sites) of the target cell type. Preferably, the polymer lipid is connected to the highly reactive functionalized group by a covalent bond. Exemplary functionalized polymer lipids include, but are not limited to: DSPE-PEG-maleimide, DSPE-PEG-bromomaleimide, DSPE-PEG-alkyne, DSPE-PEG-azide, DSPE-PEG-DBCO, DSPE-PEG-alkynylamide, DSPE-PEG-alkynylimide, etc.

[0079] "Lipid nanoparticles" refer to particles containing lipid components and having a nanoscale size.

[0080] "Biodegradable groups" refer to functional groups containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can affect 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-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)S-, -SC(O)NR-, -C(O-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O). 0-2 -

[0081] "Targeting moiety" refers to a protein, polypeptide, oligopeptide or peptide, carbohydrate, nucleic acid, or combination thereof that can specifically bind to one or more targets. Exemplary targeting moieties include full-length antibodies, Fab′, F(ab′)2, Fab, Fv, rlgG, scFv, hcAb (heavy chain antibody), single-domain antibodies, VHH, VNAR, sdAb, receptor extracellular domain or its ligand-binding moiety, or ligands (e.g., cytokines, chemokines). VHH is a functional antibody fragment consisting only of the heavy chain variable region, with a small molecular weight but a typically longer complementarity-determining region (CDR3), capable of forming a convex ring structure and deeply binding into antigen clefts or grooves inaccessible to conventional antibodies. In other embodiments, the targeting moiety comprises a receptor or a ligand-binding domain of a receptor ligand. In some embodiments, the targeting moiety may have multiple specificities, such as bispecific or multispecific conjugates. Various assays are known to be available for identifying the targeting moiety that specifically binds to a particular target in this invention, including Western blotting, ELISA, biomembrane interferometry, and surface plasmon resonance. Targeting portions, such as those comprising variable domains of immunoglobulin light and heavy chains (e.g., scFv), can be integrated into a variety of protein scaffolds or structures described herein, such as antibodies or antigen-binding fragments thereof, scFv-Fc fusion proteins, or fusion proteins comprising two or more such immunoglobulin-binding domains. In some embodiments, the targeting portion comprises an antibody or its antigen-binding portion. In some embodiments, the binding portion is a polypeptide comprising a binding domain and an N- or C-terminal extension, said N- or C-terminal extension comprising an accessible thiol group.

[0082] An antibody is an immunoglobulin molecule that has the ability to specifically bind to a particular antigen. These molecules typically consist of two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain consists of a variable region (or domain) (abbreviated as VH) and a constant region. The constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a variable region (or domain) (abbreviated as VL) and a constant region. The constant region consists of one domain: CL. The variable regions of both the antibody heavy and light chains contain binding domains that interact with the antigen. The constant regions of the antibody mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system such as C1q (the first component in the classical complement activation pathway).

[0083] The term "antigen-binding fragment" in antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to antigens. It has been shown that the antigen-binding function of an antibody can be performed by fragments of the full-length antibody.

[0084] Examples of antigen-binding fragments covered in the term "antigen-binding portion" of an antibody include: (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments containing two Fab fragments linked by disulfide bonds in a hinge region; (iii) Fab' fragments, which are essentially Fab fragments with a partially hinge region; (iv) Fd fragments, consisting of VH and CH1 domains; (v) Fd' fragments, having VH and CH1 domains and one or more cysteine ​​residues at the C-terminus of the CH1 domain; (vi) Fv fragments, consisting of VL and VH domains in a single arm of an antibody; (vii) dAb fragments, consisting of a VH domain; (viii) separated complementarity-determining regions (CDRs); and (ix) nanobodies, heavy chain variable regions containing a single variable domain and two constant domains. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by different genes, they can be linked via synthetic linkers using recombinant methods, enabling them to be made into a single protein chain where the VL and VH regions pair to form a monovalent molecule (called a single-chain Fv (scFv)). Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of antibody. Additionally, the term also includes "straight-chain antibodies" comprising a pair of tandem Fd fragments (VH-CH1-VH-CH1) that together form the antigen-binding region with a complementary light-chain polypeptide, as well as any modified forms of the aforementioned fragments that retain antigen-binding activity.

[0085] These antigen-binding fragments can be obtained using conventional techniques known to those skilled in the art, and their utility can be screened in the same manner as for intact antibodies.

[0086] The target component can be a small molecule ligand, including vitamins, hormones or other small molecules, such as folic acid, galactose / N-acetylgalactosamine, phenylboronic acid, biotin, sugar molecules or small molecule agonists of specific receptors.

[0087] The target component can be a carbohydrate, which is a carbohydrate molecule or its derivative capable of specifically binding to the target molecule (such as a cell surface antigen). This includes various forms of carbohydrates such as monosaccharides, oligosaccharides, and polysaccharides, as long as they can act as binding groups to specifically bind to the target.

[0088] In addition to antibodies and peptide fragments, some complete proteins or ligands can also be used as targeting components, such as transferrin (whose receptor is highly expressed on many rapidly proliferating cells (such as tumor cells), epidermal growth factor (targeting cells with high expression of epidermal growth factor receptor), lectins (capable of specifically binding to sugars and targeting specific glycosylation patterns on the cell surface), etc.

[0089] Other definitions

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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).

[0095] 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.

[0096] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0097] 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”).

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] Those skilled in the art will understand that the numerical values ​​or ranges mentioned herein generally include all values ​​within the range of ±20%, preferably ±10%, of the stated value; for example, 15mol% refers to all values ​​within the range of 12mol% to 18mol%. Attached Figure Description

[0103] Figure 1 shows the comparison results of LNP-1 and LNP-2;

[0104] Figure 2 shows a comparison of L829 and compound 23 at different dosages in the same formulation;

[0105] Figure 3 shows that no significant change in body weight was observed in cynomolgus monkeys before and after injection of the tLNP of the present invention;

[0106] Figure 4 shows the blood routine indicators of cynomolgus monkeys after injection of the tLNP of the present invention;

[0107] Figure 5 shows the blood biochemical parameters of cynomolgus monkeys after injection of the tLNP of the present invention. Detailed Implementation Plan

[0108] In this document, “compounds of the present invention” refers to the following compounds, their pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers.

[0109] 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 single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0110] 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:

[0111] in,

[0112] Ring A is C 6-10 Arenes or 5-10 quinone heteroaryl compounds;

[0113] Z is CH or N;

[0114] G1 and G2 are independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, optionally surrounded by 1, 2, 3, or 4 R groups. G1 replace;

[0115] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0116] R G1 Independently selected from H and C 1-8 Alkyl, -La -OR a -L a -SR a and -L a -NR a R' a ;

[0117] G 3a and G 3b Independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, optionally surrounded by 1, 2, 3, or 4 R groups. G3 replace;

[0118] G 3a and G 3b The total length is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0119] R G3 Independently selected from H and C 1-8 Alkyl, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0120] L a Independently selected from chemical bonds and C 1-14 Alkylene;

[0121] R a and R' a Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0122] G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 The ynyl group, optionally surrounded by 1, 2, 3 or 4 R groups G4 replace;

[0123] R G4 Independently selected from H and C 1-6 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0124] L b Independently selected from chemical bonds and C 1-6 Alkylene;

[0125] R b and R' b Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0126] Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by 1, 2, 3 or 4 R groups. 4g replace;

[0127] R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0128] L e Independently selected from chemical bonds and C 1-8 Alkylene;

[0129] R e and R' e Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0130] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 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 therein are replaced independently by -NR'-;

[0131] M1 is selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S- , -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS- and -S(O) 0-2 -

[0132] M2 is selected from chemical bonds, -(CH2) 1-2 -, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -;

[0133] R and R' are each independently selected from H and C. 1-20 alkyl;

[0134] R s Independently selected from H and C 1-20 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ;

[0135] L c Independently selected from chemical bonds and C 1-20 Alkylene;

[0136] R c and R' c Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0137] R3 is selected from CN, -OR g -C(O)R g -OC(O)R g -NR”C(O)R g -NRg R' g 、-NR”C(O)NR g R' g -NR”C(O)R g -NR”S(O)2R g -OC(O)NR g R' g -NR”C(O)OR g -N(OR) g )C(O)R g -N(OR) g )S(O)2R g -N(OR) g )C(O)OR g -N(OR) g )C(O)R g R' g 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

[0138] R g and R' g Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0139] "R" is independently selected from H and C. 1-6 alkyl;

[0140] R4 and R5 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 4s replace;

[0141] Or R4, R5, together with the carbon atoms they are attached to, form C. 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by 1, 2, 3 or 4 R groups. 4s replace;

[0142] R 4s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0143] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0144] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups.

[0145] In another embodiment, the present invention relates to the above-described compound, or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, having the structure of formula (II):

[0146] in,

[0147] a = 1, 2, 3, 4, 5 or 6;

[0148] b = 1, 2, 3, 4, 5 or 6;

[0149] c = 0, 1, 2, 3, 4 or 5;

[0150] b+c = 3, 4, 5, 6, 7, 8 or 9, with b+c = 4, 5, 6, 7 or 8 being preferred;

[0151] e = 1, 2, 3, 4, 5, 6 or 7;

[0152] f = 1, 2, 3 or 4;

[0153] e+f = 2, 3, 4, 5, 6, 7 or 8;

[0154] The remaining variables are as defined in this article.

[0155] In the compounds of this invention, the variables can be defined as follows.

[0156] Ring A

[0157] In one implementation, ring A is C. 6-10 In another embodiment, ring A is a 5-10-membered heteroaryl group; in another embodiment, ring A is a phenylene group; in another embodiment, ring A is a 5-6-membered heteroaryl group; in another embodiment, ring A is a 5-membered heteroaryl group; in another embodiment, ring A is a 5-membered azapyridine group; in another embodiment, ring A is a diazonyl group, preferably. Preferred Preferred Preferred In another embodiment, ring A is a triazole group, preferably. Preferred Preferred Preferred In another embodiment, ring A is a tetrazolium group, preferably. Preferred Preferred

[0158] In one more specific embodiment, ring A is a phenylene or a 5-6 membered heteroaryl group; in another more specific embodiment, ring A is a diazonyl, triazonyl, or tetrazonyl group; in yet another more specific embodiment, ring A is... In another, more specific implementation, ring A is In another, more specific embodiment, ring A is a diazonium group or a triazonium group; in another, more specific embodiment, ring A is... In another, more specific implementation, ring A is In another, more specific implementation, ring A is In another, more specific implementation, ring A is In another, more specific implementation, ring A is In another, more specific implementation, ring A is In another, more specific implementation, ring A is

[0159] Z

[0160] In one implementation, Z is CH; in another implementation, Z is N.

[0161] In one specific implementation, Z is N or CN.

[0162] G1 and G2

[0163] In one embodiment, G1 is a chemical bond; in another embodiment, G1 is a C bond. 1-13 Straight-chain alkylene, preferably C 1-9 Straight-chain alkylene, preferably C 1-6 Straight-chain alkylene, preferably C 2-6 Straight-chain alkylene; in another embodiment, G1 is C 2-13 Straight-chain alkenyl groups, preferably C 2-9 Straight-chain alkenyl groups, preferably C 2-6 Straight-chain alkenyl groups, preferably C 3-5 Straight-chain alkylene; in another embodiment, G1 is C 2-13 Straight-chain acetylenic groups, preferably C 2-9 Straight-chain acetylenic groups, preferably C 2-6 Straight-chain ynylene group; in another embodiment, G1 is optionally surrounded by 1, 2, 3 or 4 R groups. G1 Replacement; in another implementation, G1 is not replaced.

[0164] In one embodiment, G2 is a chemical bond; in another embodiment, G2 is a C bond. 1-13 Straight-chain alkylene, preferably C 1-9 Straight-chain alkylene, preferably C 1-6 Straight-chain alkylene, preferably C 1-4 Straight-chain alkylene, preferably C 1-3 Straight-chain alkylene; in another embodiment, G2 is C 2-13 Straight-chain alkenyl groups, preferably C 2-9 Straight-chain alkenyl groups, preferably C 2-6 Straight-chain alkenyl; in another embodiment, G2 is C 2-13 Straight-chain acetylenic groups, preferably C 2-9 Straight-chain acetylenic groups, preferably C 2-6 Straight-chain ynylene group; in another embodiment, G2 is optionally surrounded by one or more R groups. G1 In another embodiment, G2 is optionally replaced by 1, 2, 3 or 4 Rs. G1 In another implementation, G2 is not replaced.

[0165] In one embodiment, the total length of G1 and G2 is 3 carbon atoms; in another embodiment, the total length of G1 and G2 is 4 carbon atoms; in another embodiment, the total length of G1 and G2 is 5 carbon atoms; in another embodiment, the total length of G1 and G2 is 6 carbon atoms; in another embodiment, the total length of G1 and G2 is 7 carbon atoms; in another embodiment, the total length of G1 and G2 is 8 carbon atoms; in another embodiment, the total length of G1 and G2 is 9 carbon atoms; in another embodiment, the total length of G1 and G2 is 10 carbon atoms; in another embodiment, the total length of G1 and G2 is 11 carbon atoms; in another embodiment, the total length of G1 and G2 is 12 carbon atoms; in another embodiment, the total length of G1 and G2 is 13 carbon atoms.

[0166] In a more specific implementation, G1 is selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2- 9. Straight-chain ynyne group; in another, more specific embodiment, G1 is selected from C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynyne group; in another, more specific embodiment, G1 is selected from C 1-6 Straight-chain alkylene; in another, more specific embodiment, G1 is selected from C 2-6 Straight-chain alkylene groups.

[0167] In a more specific implementation, G2 is selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2- 9. Straight-chain ynyne group; in another, more specific embodiment, G2 is selected from chemical bonds, C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynyne group; in another, more specific embodiment, G2 is selected from chemical bonds and C 1-6 Straight-chain alkylene groups; in another, more specific embodiment, G2 is selected from chemical bonds and C 1-4 Straight-chain alkylene groups.

[0168] In one more specific embodiment, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8, or 9 carbon atoms; in another more specific embodiment, the total length of G1 and G2 is 4, 5, 6, or 7 carbon atoms; in another more specific embodiment, the total length of G1 and G2 is 5, 6, or 7 carbon atoms; in another more specific embodiment, the total length of G1 and G2 is 5 or 6 carbon atoms; in another more specific embodiment, the total length of G1 and G2 is 6 or 7 carbon atoms.

[0169] R G1

[0170] In one implementation, R G1 H; in another embodiment, R G1 C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R G1 -L a -OR a In another implementation, R G1 -L a -SR a In another implementation, R G1 -L a -NR a R' a .

[0171] In a more specific implementation, R G1 Independently selected from H and C 1-8 Alkyl; in another, more specific embodiment, R G1 Independently selected from H and C 1-6 alkyl.

[0172] G 3a and G 3b

[0173] In one implementation, G 3a For chemical bonds; in another embodiment, G 3a C 1-13 Straight-chain alkylene, preferably C 1-9 Straight-chain alkylene, preferably C 2-6 Straight-chain alkylene, preferably C 3-5 Linear alkylene; in another embodiment, G 3a C 2-13 Straight-chain alkenyl groups, preferably C 2-9 Straight-chain alkenyl groups, preferably C 2-6 Straight-chain alkenyl groups; in another embodiment, G 3a C 2-13 Straight-chain acetylenic groups, preferably C 2-9 Straight-chain acetylenic groups, preferably C 2-6 Straight-chain acetylenic group; in another embodiment, G 3a Can be arbitrarily divided by 1, 2, 3 or 4 Rs G3 Replace; in another implementation, G 3a It has not been replaced.

[0174] In one implementation, G 3b For chemical bonds; in another embodiment, G 3a C 1-13 Straight-chain alkylene, preferably C 1-9 Straight-chain alkylene, preferably C 1-4 Straight-chain alkylene, preferably C 1-2 Linear alkylene; in another embodiment, G 3b C 2-13 Straight-chain alkenyl groups, preferably C 2-9 Straight-chain alkenyl groups, preferably C 2-4 Straight-chain alkenyl groups; in another embodiment, G 3b C 2-13 Straight-chain acetylenic groups, preferably C 2-9 Straight-chain acetylenic groups, preferably C 2-4 Straight-chain acetylenic group; in another embodiment, G 3b Can be arbitrarily divided by 1, 2, 3 or 4 Rs G3 Replace; in another implementation, G 3b It has not been replaced.

[0175] In one implementation, G 3a and G 3b The total length is 3 carbon atoms; in another embodiment, G 3a and G 3b The total length is 4 carbon atoms; in another embodiment, G 3a and G 3bThe total length is 5 carbon atoms; in another embodiment, G 3a and G 3b The total length is 6 carbon atoms; in another embodiment, G 3a and G 3b The total length is 7 carbon atoms; in another embodiment, G 3a and G 3b The total length is 8 carbon atoms; in another embodiment, G 3a and G 3b The total length is 9 carbon atoms; in another embodiment, G 3a and G 3b The total length is 10 carbon atoms; in another embodiment, G 3a and G 3b The total length is 11 carbon atoms; in another embodiment, G 3a and G 3b The total length is 12 carbon atoms; in another embodiment, G 3a and G 3b Its total length is 13 carbon atoms.

[0176] In a more specific implementation, G 3a Selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain acetylenic group; in another, more specific embodiment, G 3a Selected from C 2-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain acetylenic group.

[0177] In a more specific implementation, G 3b Selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain acetylenic group; in another, more specific embodiment, G 3b Selected from C 1-4 straight-chain alkylene, C 2-4 Straight-chain alkenyl groups and C 2-4 Straight-chain acetylenic group.

[0178] In a more specific implementation, G 3a and G 3b The total length is 3, 4, 5, 6, 7, 8, or 9 carbon atoms; in another more specific embodiment, G 3a and G 3b The total length is 4, 5, 6, or 7 carbon atoms; in another, more specific embodiment, G3a and G 3b The total length is 4, 5 or 6 carbon atoms.

[0179] R G3

[0180] In one implementation, R G3 H; in another embodiment, R G3 C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl, preferably methyl; in another embodiment, R G3 -L a -OR a In another implementation, R G3 -L a -SR a In another implementation, R G3 -L a -NR a R' a .

[0181] In a more specific implementation, R G3 Independently selected from H and C 1-6 Alkyl, -L a -OR a and -L a -NR a R' a In another, more specific implementation, R G3 Independently selected from H and C 1-6 alkyl.

[0182] L a R a and R' a

[0183] In one implementation, L a For chemical bonds; in another embodiment, L a C 1-14 Alkylene, preferably C 1- 8-alkylene group, preferably C 1-6 Alkylene.

[0184] In one implementation, R a H; in another embodiment, R a C 1-14 Alkyl, preferably C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R a C3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R a It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0185] In one implementation, R' a H; in another embodiment, R' a C 1-14 Alkyl, preferably C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' a C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' a It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0186] In a more specific implementation, L a Independently selected from chemical bonds and C 1-8 Alkylene; in another, more specific embodiment, L a Independently selected from chemical bonds and C 1-6 Alkylene;

[0187] In a more specific implementation, R a and R' a Independently selected from H and C 1-8 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R a and R' a Independently selected from H and C 1-6 alkyl.

[0188] G4

[0189] In one embodiment, G4 is a chemical bond; in another embodiment, G4 is a C bond. 1-6 Alkylene, preferably C 1- 4-alkylene group, preferably C 2-4 Alkylene, preferably C 2-3 Alkylene, preferably C 3-4 Alkylene; in another embodiment, G4 is C 2-6 alkenyl groups, preferably C 2-4 alkenyl; in another embodiment, G4 is C 2-6 Alynyl group, preferably C 2-4 Ethyne group; in another embodiment, G4 is optionally surrounded by 1, 2, 3 or 4 R groups. G4 Replacement; in another implementation, G4 is not replaced.

[0190] In a more specific implementation, G4 is selected from C. 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group.

[0191] R G4

[0192] In one implementation, R G4 H; in another embodiment, R G4 C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R G4 -L b -OR b In another implementation, R G4 -L b -SR b In another implementation, R G4 -L b -NR b R' b .

[0193] In one implementation, two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C 3-7 Cycloalkylene, preferably forming C 3-4 Cycloalkylene, preferably cyclopropyl; in another embodiment, two R atoms attached to the same carbon atom G4 Together with the carbon atoms attached to them, they form 3 to 14-membered heterocyclic groups, preferably 3 to 10-membered heterocyclic groups, and more preferably 3 to 7-membered heterocyclic groups; in another embodiment, two R atoms attached to the same carbon atom G4 The rings formed together with the carbon atoms attached to them are optionally bounded by 1, 2, or 3 R atoms. 4g Substitution; in another embodiment, two R atoms attached to the same carbon atom G4 The rings formed by the carbon atoms connected to them were not replaced.

[0194] In a more specific implementation, R G4 Independently selected from H and C 1-6 alkyl.

[0195] In a more specific embodiment, two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups; in another more specific embodiment, two R groups attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3 to 7-membered heterocyclic groups.

[0196] L b R b and R' b

[0197] In one implementation, L b For chemical bonds; in another embodiment, L b C 1-6 Alkylene, preferably C 1- 4-alkylene compounds.

[0198] In one implementation, R b H; in another embodiment, R b C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R b C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R b It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0199] In one implementation, R' b H; in another embodiment, R' b C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' b C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' b It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0200] In a more specific implementation, L b Independently selected from chemical bonds and C 1-4 Alkylene.

[0201] In a more specific implementation, R b and 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 and R' b Independently selected from H and C 1-6Alkyl; in another, more specific embodiment, R b and R' b Independently selected from H and C 1-4 alkyl.

[0202] R 4g

[0203] In one implementation, R 4g H; in another embodiment, R 4g It is a halogen; in another embodiment, R 4g It is cyano; in another embodiment, R 4g C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R 4g C 1-8 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl; in another embodiment, R 4g -L e -OR e In another implementation, R 4g -L e -SR e In another implementation, R 4g -L e -NR e R' e .

[0204] In a more specific implementation, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0205] L e R e and R' e

[0206] In one implementation, L e For chemical bonds; in another embodiment, L e C 1-8 Alkylene, preferably C 1- 6-alkylene group, preferably C 1-4 Alkylene.

[0207] In one implementation, R e H; in another embodiment, R e C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R e C3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R e It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0208] In one implementation, R' e H; in another embodiment, R' e C 1-8 Alkyl, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene; in another embodiment, R' e C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' e It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0209] In a more specific implementation, L e Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L a Selected from chemical bonds and C 1-4 Alkylene.

[0210] In a more specific implementation, R e and R' e 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 e and R' e Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R e and R' e Independently selected from H and C 1-4 alkyl.

[0211] R1 and R2

[0212] In one implementation, R1 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 10-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 10 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, preferably C8-12 Straight-chain alkyl, preferably C 7-11 Straight-chain alkyl, preferably C 8-11 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C 8-9 Straight-chain alkyl, preferably C 11 Straight-chain alkyl, preferably C 10 Straight-chain alkyl, preferably C9 straight-chain alkyl; in another embodiment, R1 is C 4-20 Alkenyl, preferably C 6-14 Alkenyl, preferably C 7-12 Alkenyl, preferably C 8-12 Alkenyl; in another embodiment, R1 is C 4-20 Alkyne group, preferably C 6-14 Alkyne group, preferably C 7-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R1 is optionally surrounded by 1, 2, 3 or 4 R groups. s Instead, preferably optionally replaced by 1, 2 or 3 R s Instead, preferably optionally replaced by 1 or 2 R s Instead, preferably optionally replaced by 1 R s Substitution; in another embodiment, R1 is not substituted; in another embodiment, 1, 2, 3 or 4 methylene units in R1 are optionally and independently substituted with -NR'-, preferably one methylene unit in R1 is optionally substituted with -NR'-.

[0213] In one implementation, R2 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-12 Alkyl, preferably C 10-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, preferably C 10 Alkyl, preferably C 8-12 Straight-chain alkyl, preferably C 7-11 Straight-chain alkyl, preferably C 8-11 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 8- 10Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C 8-9 Straight-chain alkyl, preferably C 11 Straight-chain alkyl, preferably C 10 Straight-chain alkyl, preferably C9 straight-chain alkyl; in another embodiment, R2 is C 4-20 Alkenyl, preferably C 6-14 Alkenyl, preferably C 7-12 Alkenyl, preferably C 8-12 Alkenyl; in another embodiment, R2 is C 4-20 Alkyne group, preferably C 6-14 Alkyne group, preferably C 7-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R2 is optionally surrounded by 1, 2, 3 or 4 R groups. s Instead, preferably optionally replaced by 1, 2 or 3 R s Instead, preferably optionally replaced by 1 or 2 R s Instead, preferably optionally replaced by 1 R s Substitution; in another embodiment, R2 is not substituted; in another embodiment, one, two, three or four methylene units in R2 are optionally and independently substituted with -NR'-, preferably one methylene unit in R2 is optionally substituted with -NR'-.

[0214] In one embodiment, R1 and R2 are not substituted simultaneously; in another embodiment, one of R1 and R2 is substituted while the other is not; in another embodiment, R1 is not substituted and R2 is substituted; in another embodiment, R1 is substituted while R2 is not substituted; in yet another embodiment, one of R1 and R2 is replaced by 1, 2, 3, or 4 (preferably 1 or 2, preferably 1) R s One is replaced, and the other is not replaced; in another embodiment, R1 is replaced by 1, 2, 3 or 4 (preferably 1 or 2, preferably 1) R s In one embodiment, R1 is not replaced, and R2 is replaced by 1, 2, 3, or 4 (preferably 1 or 2, preferably 1) R s replace.

[0215] In one embodiment, R1 is -(CH2)8CH3; in another embodiment, R1 is -(CH2)9CH3; in yet another embodiment, R1 is -(CH2). 10 CH3; in another embodiment, R1 is 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 In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is

[0216] In one embodiment, R2 is -(CH2)8CH3; in another embodiment, R2 is -(CH2)9CH3; in yet another embodiment, R2 is -(CH2). 10 CH3; in another embodiment, R2 is 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 In another implementation, R2 is

[0217] In a more specific implementation, R1 and R2 are independently selected from C. 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; in another, more specific embodiment, R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group; in another, more specific embodiment, R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group.

[0218] In a more specific embodiment, R1 and R2 are independently selected from the following groups: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3,

[0219] In a more specific embodiment, R1 and R2 are independently selected from the following groups: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, In another, more specific embodiment, R1 and R2 are independently selected from -(CH2)8CH3, -(CH2)9CH3,

[0220] In a more specific implementation, R1 is selected from -(CH2)8CH3, -(CH2) 10 CH3, Preferred are -(CH2)8CH3 and -(CH2). 10 CH3, In another, more specific embodiment, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3.

[0221] In a more specific implementation, R1 is selected from -(CH2)8CH3, -(CH2) 10 CH3 and

[0222] In a more specific implementation, R2 is selected from -(CH2)9CH3, Preferred

[0223] In a more specific implementation, R2 is selected from -(CH2)9CH3, In another, more specific implementation, R2 is selected from...

[0224] In a more specific implementation, R2 is selected from -(CH2)9CH3, In another, more specific embodiment, R2 is selected from -(CH2)9CH3, In another, more specific embodiment, R2 is selected from -(CH2)9CH3, In another, more specific embodiment, R2 is selected from -(CH2)9CH3, In another, more specific implementation, R2 is selected from...

[0225] In a more specific implementation, R2 is selected from -(CH2)9CH3, In another, more specific embodiment, R2 is selected from -(CH2)9CH3 and

[0226] In a more specific implementation, R2 is selected from -(CH2)9CH3 and

[0227] In a more specific implementation, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3.

[0228] In a more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from...

[0229] M1 and M2

[0230] In one 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-; in another embodiment, M1 is -NRC(O)NR-; in another embodiment, M1 is -OC(O)S-; in another embodiment, M1 is -OC(O)O-; in another embodiment, M1 is -NRC(O)O-; in another embodiment, M1 is -SC(O)-; in another embodiment, M1 is -C(O)S-; in another embodiment, M1 is -NR-; In another embodiment, M1 is -C(O)NR-, for example -C(O)NH-; in another embodiment, M1 is -NRC(O)-, for example -NHC(O)-; in another embodiment, M1 is -NRC(O)S-; in another embodiment, M1 is -SC(O)NR-; 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-; in another embodiment, M1 is -NRC(S)O-; in another embodiment, M1 is -SS-; in another embodiment, M1 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0231] In one embodiment, M2 is a chemical bond; in another embodiment, M2 is -(CH2). 1-2-, for example -CH2-, for example -CH2CH2-; 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-; in another embodiment, M2 is -NRC(O)NR-; in another embodiment, M2 is -OC(O)S-; in another embodiment, M2 is -OC(O)O-; in another embodiment, M2 is -NRC(O)O-; in another embodiment, M2 is -SC(O)-; in another embodiment, M2 is -C(O)S-; in another embodiment In one embodiment, M2 is -NR-; in another embodiment, M2 is -C(O)NR-, for example -C(O)NH-; in another embodiment, M2 is -NRC(O)-, for example -NHC(O)-; in another embodiment, M2 is -NRC(O)S-; in another embodiment, M2 is -SC(O)NR-; 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-; in another embodiment, M2 is -NRC(S)O-; in another embodiment, M2 is -SS-; in another embodiment, M2 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0232] In one more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-; in yet another more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -OC(O)-.

[0233] In a more specific embodiment, M2 is selected from chemical bonds, -(CH2). 1-2-, -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; in another more specific embodiment, M2 is selected from chemical bonds, -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; in another more specific embodiment, M2 is selected from -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; in another more specific embodiment, M2 is selected from -CH2CH2-, -C(O)O- or -OC(O)-; in another more specific embodiment, M2 is selected from -CH2CH2- or -C(O)O-.

[0234] R and R'

[0235] In one implementation, R is H; in another implementation, R is C. 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 alkyl.

[0236] In one implementation, R' is H; in another implementation, R' is C. 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 alkyl.

[0237] In a more specific implementation, R and R' are each independently selected from H and C. 1-20 Alkyl; in another, more specific embodiment, R and R' are each independently selected from H and C. 1-14 Alkyl; in another, more specific embodiment, R and R' are each independently selected from H and C. 1-9 Alkyl; in another, more specific embodiment, R and R' are each independently selected from H and C. 1-6 Alkyl; in another, more specific embodiment, R is H.

[0238] R s

[0239] In one implementation, R s H; in another embodiment, R s C 1-20 Alkyl; in another embodiment, R s C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-12 Alkyl, preferably C 1-10Alkyl, preferably C 1-9 Alkyl, preferably C 7-9 Alkyl, preferably C 8-9 Alkyl, preferably C 4-8 Alkyl, preferably C 5-8 Alkyl, preferably C 1-7 Alkyl, preferably C 5-7 Alkyl, preferably C 6-7 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, preferably C 7-11 Alkyl, preferably C 4-10 Alkyl, preferably C 6-10 Alkyl, preferably C 7-10 Alkyl, preferably C 9-10 Alkyl, preferably C 4-9 Alkyl, preferably C 6-9 Alkyl, preferably C 1-8 Alkyl, preferably C 4-8 Alkyl, preferably C 6-8 Alkyl, preferably C 7-8 Alkyl, preferably C 6-7 Alkyl, preferably C9 alkyl, preferably C8 alkyl, preferably C7 alkyl; in another embodiment, R s -L c -OR c In another implementation, R s -L c -SR c In another implementation, R s -L c -NR c R' c .

[0240] In one implementation, R s The substitution site on R1 is separated from M1 by 0 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by one carbon atom; in another embodiment, R s The substitution site on R1 is separated from M1 by two carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by three carbon atoms; in another embodiment, R s The substitution site on R1 is spaced 4 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 5 carbon atoms away from M1; in another embodiment, R s The substitution site on R1 is separated from M1 by 6 carbon atoms; in another embodiment, R sThe substitution site on R1 is spaced 7 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 8 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 9 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 10 carbon atoms away from M1; in another embodiment, R s The substitution site on R1 is spaced 11 carbon atoms from M1; in another embodiment, R s The substitution site on R1 is separated from M1 by 12 carbon atoms.

[0241] In one implementation, R s The substitution site on R2 is separated from ring A by 0 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by one carbon atom; in another embodiment, R s The substitution site on R2 is separated from ring A by two carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by three carbon atoms; in another embodiment, R s The substitution site on R2 is spaced 4 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is spaced 5 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is spaced 6 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is spaced 7 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is spaced 8 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is spaced 9 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is spaced 10 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is spaced 11 carbon atoms from ring A; in another embodiment, R s The substitution site on R2 is separated from ring A by 12 carbon atoms.

[0242] In a more specific implementation, R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -Lc -NR c R' c In another, more specific implementation, R s Independently selected from H and C 1-14 alkyl.

[0243] In a more specific implementation, R s The substitution site on R1 is spaced 0-10 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-6 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-5 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-4 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-3 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-2 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is separated from M1 by 0 carbon atoms.

[0244] In a more specific implementation, R s The substitution site on R2 is spaced 0-10 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 0-6 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 0-5 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 0-4 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 0-3 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 0-2 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is separated from ring A by 0 carbon atoms.

[0245] In a more specific implementation, R s The substitution site on R1 is separated from M1 by at least one carbon atom; in another more specific embodiment, R sThe substitution site on R1 is spaced 1-4 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 1-2 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is separated from M1 by at least two carbon atoms; in another more specific embodiment, R s The substitution site on R1 is spaced 2-4 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 2-3 carbon atoms away from M1; in another more specific embodiment, R s The substitution site on R1 is separated from M1 by 3-4 carbon atoms.

[0246] In a more specific implementation, R s The substitution site on R2 is separated from ring A by at least one carbon atom; in another more specific embodiment, R s The substitution site on R2 is spaced 1-4 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 1-2 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced at least two carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 2-4 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is spaced 2-3 carbon atoms from ring A; in another more specific embodiment, R s The substitution site on R2 is separated from ring A by 3-4 carbon atoms.

[0247] L c R c and R' c

[0248] In one implementation, L c For chemical bonds; in another embodiment, L c C 1-20 Alkylene, preferably C 1- 14 Alkylene, preferably C 1-12 Alkylene, preferably C 1-10 Alkylene, preferably C 1-8 Alkylene, preferably C 1-6 Alkylene.

[0249] In one implementation, Rc H; in another embodiment, R c C 1-20 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 c C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R c It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0250] In one implementation, R' c H; in another embodiment, R' c C 1-20 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' c C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' c It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0251] In a more specific implementation, L c Independently selected from chemical bonds and C 1-14 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-12 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-8 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-6 Alkylene.

[0252] In a more specific implementation, R c and R' c Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R c and R' cIndependently selected from H and C 1-12 Alkyl; in another, more specific embodiment, R c and R' c Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R c and R' c Independently selected from H and C 1-8 Alkyl; in another, more specific embodiment, R c and R' c Independently selected from H and C 1-6 alkyl.

[0253] R3

[0254] In one implementation, R3 is CN; in another implementation, R3 is -OR. g For example, -OH; in another embodiment, R3 is -C(O)R g In another embodiment, R3 is -OC(O)R g In another embodiment, R3 is -NR”C(O)R g In another implementation, R3 is -NR g R' g For example, -N(CH3)2, for example -N(CH2CH3)2; in another embodiment, R3 is -NR”C(O)NR g R' g In another embodiment, R3 is -NR”C(O)R g In another embodiment, R3 is -NR”S(O)2R g In another embodiment, R3 is -OC(O)NR g R' g In another embodiment, R3 is -NR”C(O)OR g In another implementation, R3 is -N(OR) g )C(O)R g In another implementation, R3 is -N(OR) g )S(O)2R g In another implementation, R3 is -N(OR) g )C(O)OR g In another implementation, R3 is -N (OR g )C(O)R g R' g In another embodiment, R3 is a 3- to 14-membered heterocyclic group; in another embodiment, R3 is a 5- to 14-membered heteroaryl group.

[0255] In a more specific implementation, R3 is selected from CN, -OR g and -NR g R' g In another, more specific implementation, R3 is selected from -OR g and -NR g R' g In another more specific embodiment, R3 is selected from -OH and -N(CH3)2; preferably -N(CH3)2 or -N(CH2CH3)2.

[0256] In one more specific embodiment, R3 is selected from -OH, -N(CH3)2 and -N(CH2CH3)2; in another more specific embodiment, R3 is selected from -OH and -N(CH3)2.

[0257] R g and R' g

[0258] In one implementation, R g H; in another embodiment, R g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, preferably C 1-3 Alkyl, such as methyl, such as ethyl; in another embodiment, R g C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R g It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0259] In one implementation, R' g H; in another embodiment, R' g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, preferably C 1-3 Alkyl, such as methyl, such as ethyl; in another embodiment, R' g C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' g It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0260] In a more specific implementation, R g and R' g Independently selected from H and C 1-6 Alkyl, C 3-7cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R g and R' g Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R g and R' g Independently selected from H and C 1-3 Alkyl; in another, more specific embodiment, R g and R' g Independently selected from H, methyl, and ethyl; in another, more specific embodiment, R g and R' g It is independently selected from H and methyl.

[0261] R”

[0262] In one implementation, R” is H; in another implementation, R” is C. 1-6 Alkyl, preferably C 1-4 alkyl.

[0263] R4 and R5

[0264] In one implementation, R4 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, R4 is optionally surrounded by 1, 2, 3 or 4 Rs. 4s Replace; in another embodiment, R4 is optionally replaced by one R 4s In another embodiment, R4 is not replaced.

[0265] In one 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 Rs. 4s Replace; in another embodiment, R5 is optionally replaced by one R 4s In another implementation, R5 is not replaced.

[0266] In one implementation, R4, R5, together with the carbon atoms they are attached to, 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 3-5Cycloalkylene, preferably forming C 3-4 The cycloalkyl group, preferably forming a cyclopropyl group; in another embodiment, R4, R5 together with the carbon atoms to which they are attached 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 R4, R5 together with the carbon atoms to which they are attached is optionally surrounded by 1, 2, 3 or 4 R groups. 4s Replacement; in another embodiment, the ring formed by R4, R5 and the carbon atoms they are attached to is optionally replaced by one R 4s Substitution; in another embodiment, the rings formed by R4, R5 and the carbon atoms they are attached to are not substituted; in another embodiment, R4, R5 and the carbon atoms they are attached to do not form rings.

[0267] In a more specific embodiment, R4, R5, together with the carbon atoms they are bonded to, form C. 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups; in another more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene groups; in another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); in another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C14. 3-5 Cycloalkylene (e.g., cyclopropylene or cyclopentylene); in another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C 3-4 Cycloalkylene; in another more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form cyclopropylene.

[0268] R 4s

[0269] In one implementation, R 4s H; in another embodiment, R 4s It is a halogen; in another embodiment, R 4s It is cyano; in another embodiment, R 4s C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl; in another embodiment, R 4s C 1-8 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-3 Halogenated alkyl; in another embodiment, R 4s -Ld -OR d In another implementation, R 4s -L d -SR d In another implementation, R 4s -L d -NR d R' d .

[0270] In a more specific implementation, R 4s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -OR d -L d -SR d and -L d -NR d R' d In another, more specific implementation, R 4s Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another, more specific embodiment, R 4s Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0271] L d R d and R' d

[0272] In one implementation, L d For chemical bonds; in another embodiment, L d C 1-8 Alkylene, preferably C 1- 6-alkylene group, preferably C 1-3 Alkylene.

[0273] In one implementation, R d H; in another embodiment, R d C 1-8 Alkyl, preferably C 1-6 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.

[0274] In one implementation, R' dH; in another embodiment, R' d C 1-8 Alkyl, preferably C 1-6 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.

[0275] 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.

[0276] In a more specific implementation, 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; in another more specific embodiment, R d and R' d Independently selected from H and C 1-6 alkyl.

[0277] a, b, c, e, and f

[0278] 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.

[0279] In one implementation, b is 1; in another implementation, b is 2; in another implementation, b is 3; in another implementation, b is 4; in another implementation, b is 5; in another implementation, b is 6.

[0280] In one implementation, c is 0; in another implementation, c is 1; in another implementation, c is 2; in another implementation, c is 3; in another implementation, c is 4; in another implementation, c is 5.

[0281] In one embodiment, b+c = 3; in another embodiment, b+c = 4; in another embodiment, b+c = 5; in another embodiment, b+c = 6; in another embodiment, b+c = 7; in another embodiment, b+c = 8; in another embodiment, b+c = 9.

[0282] In one implementation, e is 1; in another implementation, e is 2; in another implementation, e is 3; in another implementation, e is 4; in another implementation, e is 5; in another implementation, e is 6; in another implementation, e is 7.

[0283] In one implementation, f is 1; in another implementation, f is 2; in yet another implementation, f is 3; and in still another implementation, f is 4.

[0284] In one implementation, e+f = 2; in another implementation, e+f = 3; in another implementation, e+f = 4; in another implementation, e+f = 5; in another implementation, e+f = 6; in another implementation, e+f = 7; in another implementation, e+f = 8.

[0285] In one more specific embodiment, a = 2, 3, 4, 5 or 6; in another more specific embodiment, a = 2, 3, 4 or 5; in another more specific embodiment, a = 2, 3 or 4; in another more specific embodiment, a = 2 or 3; in another more specific embodiment, a = 3 or 4.

[0286] In one more specific embodiment, b = 2, 3, 4, 5, or 6; in another more specific embodiment, b = 3, 4, or 5; in another more specific embodiment, b = 3, 4, or 5; in another more specific embodiment, b = 3 or 5.

[0287] In one more specific embodiment, c = 0, 1, 2, 3, 4 or 5; in another more specific embodiment, c = 0, 1, 2, 3 or 4; in another more specific embodiment, c = 1, 2 or 3; in another more specific embodiment, c = 3 or 1.

[0288] In one more specific embodiment, b+c = 4, 5, 6, 7 or 8; in another more specific embodiment, b+c = 5, 6 or 7; in yet another more specific embodiment, b+c = 5 or 6.

[0289] In one more specific embodiment, d = 4, 5, 6, 7 or 8 is preferred; in another more specific embodiment, d = 5, 6 or 7.

[0290] In one more specific embodiment, e = 2, 3, 4, 5, 6, or 7; in another more specific embodiment, e = 2, 3, 5, or 7; in another more specific embodiment, e = 2, 3, 4, 5, or 6; in another more specific embodiment, e = 2, 3, 4, or 5; in another more specific embodiment, e = 2, 3, or 4; in another more specific embodiment, e = 2 or 3; in another more specific embodiment, e = 3, 4, or 5; in another more specific embodiment, e = 3 or 5.

[0291] In one more specific implementation, f = 1, 2, or 3; in another more specific implementation, f = 1 or 2.

[0292] In one more specific embodiment, e+f = 3, 4, 5, 6, 7, or 8; in another more specific embodiment, e+f = 3, 4, 5, 6, or 7; in another more specific embodiment, e+f = 4, 5, 6, 7, or 8; in another more specific embodiment, e+f = 4, 5, 6, or 8; in another more specific embodiment, e+f = 4, 5, or 6; in another more specific embodiment, e+f = 4 or 6.

[0293] 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 ring A can be combined with Z, G1, G2, R G1 G 3a G 3b R G3 L a R a 、R' a G4, R G4 L b R b 、R' b R 4g L e R e 、R' e ,R1,R2,M1,M2,R,R',R s L c R c 、R' c R3, R g 、R' g R, R4, R5, R 4s L d R d 、R' dThis invention relates to any combination of technical solutions, such as a, b, c, d, e, and f, etc. The present invention aims to include combinations of all these technical solutions; however, due to space limitations, they are not listed individually.

[0294] 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:

[0295] in,

[0296] Ring A is C 6-10 Arenes or 5-10 quinone heteroaryl compounds;

[0297] Z is CH or N;

[0298] G1 and G2 are independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, optionally surrounded by 1, 2, 3, or 4 R groups. G1 replace;

[0299] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0300] R G1 Independently selected from H and C 1-8 Alkyl, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0301] G 3a and G 3b Independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, optionally surrounded by 1, 2, 3, or 4 R groups. G3 replace;

[0302] G 3a and G 3b The total length is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0303] R G3 Independently selected from H and C 1-8 Alkyl, -L a -OR a -La -SR a and -L a -NR a R' a ;

[0304] L a Independently selected from chemical bonds and C 1-14 Alkylene;

[0305] R a and R' a Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0306] G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 The ynyl group, optionally surrounded by 1, 2, 3 or 4 R groups G4 replace;

[0307] R G4 Independently selected from H and C 1-6 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0308] L b Independently selected from chemical bonds and C 1-6 Alkylene;

[0309] R b and R' b Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0310] Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by 1, 2, 3 or 4 R groups. 4g replace;

[0311] R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L e -OR e -L e -SR e and -Le -NR e R' e ;

[0312] L e Independently selected from chemical bonds and C 1-8 Alkylene;

[0313] R e and R' e Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0314] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 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 therein are replaced independently by -NR'-;

[0315] M1 is selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S- , -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS- and -S(O) 0-2 -

[0316] M2 is selected from chemical bonds, -(CH2) 1-2 -, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -;

[0317] R and R' are each independently selected from H and C. 1-20 alkyl;

[0318] R s Independently selected from H and C 1-20 Alkyl, -L c -ORc -L c -SR c and -L c -NR c R' c ;

[0319] L c Independently selected from chemical bonds and C 1-20 Alkylene;

[0320] R c and R' c Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0321] R3 is selected from CN, -OR g -C(O)R g -OC(O)R g -NR”C(O)R g -NR g R' g 、-NR”C(O)NR g R' g -NR”C(O)R g -NR”S(O)2R g -OC(O)NR g R' g -NR”C(O)OR g -N(OR) g )C(O)R g -N(OR) g )S(O)2R g -N(OR) g )C(O)OR g -N(OR) g )C(O)R g R' g 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

[0322] R g and R' g Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0323] "R" is independently selected from H and C. 1-6 alkyl;

[0324] R4 and R5 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 4s replace;

[0325] Or R4, R5, together with the carbon atoms they are attached to, form C. 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by 1, 2, 3 or 4 R groups. 4s replace;

[0326] R 4s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0327] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0328] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups.

[0329] 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 ring A is phenylene or a 5-6-membered heteroaryl group; preferably 5-6-membered heteroaryl; preferably 5-membered heteroaryl; preferably 5-membered azapyridine; preferably diazolinone, triazolene, or tetrazolium; preferably diazolinone or triazolene; preferably triazolene; preferably... Preferred Preferred Preferred Preferred Preferred Preferred

[0330] 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 Z is N; preferably, Z is CH.

[0331] 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 G1 and G2 are independently selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C2-9 Straight-chain acetylenic group;

[0332] Preferably, G1 is selected from C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain acetylenic groups, preferably C 1-6 Straight-chain alkylene, preferably C 2-6 Straight-chain alkylene, preferably C 3-5 Straight-chain alkylene;

[0333] Preferably, G2 is selected from chemical bonds, C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynylene groups, preferably selected from chemical bonds and C 1-6 Straight-chain alkylene groups, preferably selected from chemical bonds and C 1-4 Straight-chain alkylene, preferably C 1-3 Straight-chain alkylene;

[0334] Preferably, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, more preferably 4, 5, 6 or 7 carbon atoms; more preferably 5, 6 or 7 carbon atoms, more preferably 5 or 6 carbon atoms, more preferably 6 or 7 carbon atoms.

[0335] 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 and C 1-8 Alkyl groups; preferably H and C 1-6 alkyl.

[0336] 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 G 3a and G 3b Independently selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain acetylenic group;

[0337] Preferably, G 3a Selected from C 2-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain acetylenic groups, preferably C 2-6 Straight-chain alkylene, preferably C 3-5 Straight-chain alkylene;

[0338] Preferably, G 3b Selected from C1-4 straight-chain alkylene, C 2-4 Straight-chain alkenyl groups and C 2-4 Straight-chain acetylenic groups, preferably C 1-4 Straight-chain alkylene, preferably C 1-2 Straight-chain alkylene;

[0339] Preferably, G 3a and G 3b The total length is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably 3, 4, 5, 6 or 7 carbon atoms, and more preferably 4, 5 or 6 carbon atoms.

[0340] 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 G3 Independently selected from H and C 1-6 Alkyl, -L a -OR a and -L a -NR a R' a H and C are preferred. 1-6 Alkyl; preferably C 1-3 Alkyl; preferably C 1-2 Alkyl; preferably methyl;

[0341] Preferably, L a Independently selected from chemical bonds and C 1-8 Alkylenes, preferably selected from chemical bonds and C 1-6 Alkylene;

[0342] Preferably, R a and R' a Independently selected from H and C 1-8 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 alkyl.

[0343] 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 G4 is selected from C 1-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; preferably C 2-4 Alkylene; preferably C 2-3 Alkylene; preferably C 3-4 Alkylene.

[0344] 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 RG4 Independently selected from H and C 1-6 Alkyl; preferably C 1- 4-alkyl;

[0345] Preferably, L b Independently selected from chemical bonds and C 1-4 Alkylene;

[0346] Preferably, R b and R' b 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 groups; preferably H and C 1-4 alkyl;

[0347] Preferably, the two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups, preferably forming C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic cycloalkylene groups;

[0348] Preferably, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0349] Preferably, L e Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0350] Preferably, R e and R' e 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 1-4 alkyl.

[0351] 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 R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; preferably C 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group; preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 alkynyl group;

[0352] Preferably, R1 and R2 are independently selected from C 6-14 Alkyl; preferably C 7-12 Alkyl; preferably C 8-12 Alkyl; preferably C 9-11 Alkyl; preferably C 9-10 alkyl;

[0353] Preferably, R1 and R2 are optionally divided by one or two R... s Instead, preferably optionally replaced by 1 R s replace;

[0354] Preferably, R1 and R2 are not substituted at the same time; preferably, one of R1 and R2 is substituted and the other is not substituted; preferably, R1 is not substituted and R2 is substituted; preferably, R1 is substituted and R2 is not substituted.

[0355] Preferably, R1 and R2 are independently selected from the following groups: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, Preferably selected from -(CH2)8CH3, -(CH2)9CH3,

[0356] Preferably, one methylene unit in R1 and R2 is optionally and independently replaced by -NR'-.

[0357] 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 selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; preferably -C(O)O-, -C(O)S-, -OC(O-, -SC(O-), and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O-), and -SC(O-); preferably -C(O)O- and -OC(O-); preferably -OC(O)-;

[0358] Preferably, M2 is selected from chemical bonds, -(CH2). 1-2-, -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; preferably chemical bonds, -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O)-, -SC(O- and -OC(O)O-; preferably -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O- and -SC(O-); preferably -CH2CH2-, -C(O)O- or -OC(O-); preferably -CH2CH2- or -C(O)O-.

[0359] 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 and R' are each independently selected from H and C. 1-14 Alkyl groups; preferably H and C 1-9 Alkyl groups; preferably H and C 1-6 Alkyl group; preferably R is H.

[0360] 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 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl; preferably C 1-14 Alkyl; preferably C 1-12 Alkyl; preferably C 1-10 Alkyl; preferably C 1-9 Alkyl; preferably C 4-8 Alkyl; preferably C 5-8 Alkyl; preferably C 1-7 Alkyl; preferably C 5-7 Alkyl; preferably C 6- 7-alkyl; preferably C 1-6 alkyl;

[0361] Preferably, L c Independently selected from chemical bonds and C 1-14 Alkylene; preferably chemical bonds and C 1-12 Alkylene; preferably chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-8 Alkylene; preferably chemical bonds and C 1-6 Alkylene;

[0362] Preferably, R c and R'c Independently selected from H and C 1-14 Alkyl groups; preferably H and C 1-12 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C 1-8 Alkyl groups; preferably H and C 1-6 alkyl.

[0363] 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 R3 is selected from CN, -OR g and -NR g R' g Preferred - OR g and -NR g R' g Preferred - OR g Preferred -OH; Preferred -NR g R' g Preferred -N(CH3)2 or -N(CH2CH3)2;

[0364] Preferably, R3 is selected from -OH, -N(CH3)2 and -N(CH2CH3)2; more preferably -OH and -N(CH3)2; more preferably -OH;

[0365] Preferably, R g and R' g 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 groups; preferably H and C 1-3 Alkyl; preferably H, methyl and ethyl; preferably H and methyl.

[0366] 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 R4 and R5 are independently selected from C 1-6 Alkyl; preferably C 1-3 Alkyl; preferably C 1-2 Alkyl; preferably methyl;

[0367] Preferably, R4 and R5 are optionally separated by one R 4s replace;

[0368] Preferably, R4, R5, together with the carbon atoms they are bonded to, form C. 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene; preferably forming C 3-6Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably C 3-4 Cycloalkylene; preferably cyclopropylene;

[0369] Preferably, the rings formed by R4, R5 and the carbon atoms they are attached to are optionally separated by one R 4s replace;

[0370] Preferably, R4, R5 and the carbon atoms they are connected to do not form rings.

[0371] 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 4s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -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-Hydroalkyl group; preferably H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0372] Preferably, L d Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-3 Alkylene;

[0373] 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.

[0374] 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 sThe substitution site on R1 is spaced from M1 by 0-12 carbon atoms, preferably 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-5 carbon atoms, preferably 0-4 carbon atoms, preferably 0-3 carbon atoms, preferably 0-2 carbon atoms; preferably at least 1 carbon atom, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms; preferably at least 2 carbon atoms, preferably 2-4 carbon atoms, preferably 2-3 carbon atoms, preferably 3-4 carbon atoms;

[0375] Preferably, R s The substitution site on R2 is spaced from ring A by 0-12 carbon atoms, preferably 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-5 carbon atoms, preferably 0-4 carbon atoms, preferably 0-3 carbon atoms, preferably 0-2 carbon atoms; preferably at least 1 carbon atom, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms; preferably at least 2 carbon atoms, preferably 2-4 carbon atoms, preferably 2-3 carbon atoms, preferably 3-4 carbon atoms.

[0376] 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):

[0377] in,

[0378] a = 1, 2, 3, 4, 5 or 6;

[0379] b = 1, 2, 3, 4, 5 or 6;

[0380] c = 0, 1, 2, 3, 4 or 5;

[0381] b+c = 3, 4, 5, 6, 7, 8 or 9, with b+c = 4, 5, 6, 7 or 8 being preferred;

[0382] e = 1, 2, 3, 4, 5, 6 or 7;

[0383] f = 1, 2, 3 or 4;

[0384] e+f = 2, 3, 4, 5, 6, 7 or 8;

[0385] The remaining variables are as defined in this article.

[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, having the structure of formula (II):

[0387] in,

[0388] Ring A is phenylene or a 5-6 membered heteroaryl group; preferably a 5-6 membered heteroaryl group.

[0389] a = 2, 3, 4 or 5; preferably a = 2, 3 or 4; preferably a = 2 or 3;

[0390] b = 3, 4, or 5; b = 3 or 5 is preferred.

[0391] c = 1, 2, or 3; c = 1 or 3 is preferred.

[0392] b+c = 4, 5, 6, 7 or 8; b+c = 5, 6 or 7 is preferred.

[0393] e = 1, 2, 3, 4, 5, 6 or 7; preferably e = 3, 4 or 5;

[0394] f = 1, 2, 3, or 4; f = 1 is preferred.

[0395] e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6;

[0396] M1 is -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- or -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0397] M2 is -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O-)- or -SC(O-); preferably -CH2CH2-, -C(O)O- or -C(O)S-;

[0398] R1 is C 6-14 Straight-chain alkyl groups, optionally bounded by 1, 2, 3 or 4 R groups. s Replacement; preferably R1 is not replaced;

[0399] R2 is C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. s replace;

[0400] R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR b R' c H and C are preferred. 1-14 alkyl;

[0401] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0402] R c and R'c Independently selected from H and C 1-14 alkyl;

[0403] R3 is selected from -OR g and -NR g R' g Preferred - OR g ;

[0404] R g and R' g Independently selected from H and C 1-6 alkyl;

[0405] R4 and R5 are independently selected from H and C. 1-6 Alkyl groups, preferably H and C 1-3 alkyl;

[0406] Or CR4R5 together form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0407] 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...

[0408] Ring A is a 5-membered heteroaryl group; preferably a 5-membered zazoaryl group.

[0409] a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2.

[0410] b = 3, 4, or 5; b = 3 or 5 is preferred.

[0411] c = 1, 2, or 3; c = 1 or 3 is preferred.

[0412] b+c = 5, 6, or 7; b+c = 6 is preferred.

[0413] e = 2, 3, 4, 5 or 6; preferably e = 3, 4 or 5;

[0414] f = 1 or 2; f = 1 is preferred.

[0415] e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6;

[0416] M1 is -C(O)O- or -OC(O-); preferably -OC(O-);

[0417] M2 is -CH2CH2-, -C(O)O-, or -OC(O-); preferably -CH2CH2- or -C(O)O-.

[0418] R1 is C 8-12 Straight-chain alkyl, preferably C 9-11Straight-chain alkyl group, optionally marked with one R s Replacement; preferably R1 is not replaced;

[0419] R2 is C 8-12 Alkyl, preferably C 9-12 Alkyl group, which is optionally marked with one R s replace;

[0420] R s Independently for C 1-12 Alkyl, preferably C 1-10 alkyl;

[0421] R3 is -OR g and -NR g R' g Preferred - OR g ;

[0422] R g and R' g Independently selected from H and C 1-3 alkyl;

[0423] R4 and R5 are independently selected from H and C. 1-3 alkyl;

[0424] Or CR4R5 together form C 3-6 Cycloalkylene;

[0425] Preferably,

[0426] R s The substitution site on R1 is separated from M1 by at least one carbon atom, preferably at least two carbon atoms;

[0427] R s The substitution site on R2 is separated from ring A by at least one carbon atom, preferably at least two carbon atoms.

[0428] 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...

[0429] Ring A is diazolidine or triazolidine; preferably diazolidine; preferably Preferred

[0430] a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2.

[0431] b = 3 or 5;

[0432] c = 1 or 3;

[0433] b + c = 6;

[0434] e = 3, 4, or 5; preferably e = 3 or 5.

[0435] f = 1;

[0436] M1 is -OC(O)-;

[0437] M2 is -CH2CH2- or -C(O)O-;

[0438] R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups, optionally marked with one R s Replacement; preferably R1 is not replaced;

[0439] R2 is C 8-12 Alkyl, preferably C 9-12 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R s replace;

[0440] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-9 Alkyl, preferably C 1-7 Alkyl, preferably C 6-7 alkyl;

[0441] R3 is -OH or -N(CH3)2; preferably -OH.

[0442] R4 and R5 are independently selected from H and methyl;

[0443] Or CR4R5 together form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds;

[0444] Preferably,

[0445] R s The substitution site on R2 is spaced 1-4 carbon atoms from ring A, preferably 2-4 carbon atoms, and more preferably 2-3 carbon atoms;

[0446] Preferably, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3;

[0447] R2 is selected from Preferred

[0448] 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):

[0449] in,

[0450] Ring A is phenylene or a 5-6 membered heteroarylene; preferably a 5-6 membered heteroarylene; preferably a diazonyl group; preferably...

[0451] a = 2, 3, 4 or 5; preferably a = 2, 3 or 4; preferably a = 2 or 3;

[0452] b = 5;

[0453] c = 1;

[0454] e = 1, 2, 3, 4, 5, 6 or 7; preferably e = 3, 4 or 5; preferably e = 5;

[0455] f = 1, 2, 3, or 4; f = 1 is preferred.

[0456] e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6;

[0457] M1 is -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- or -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0458] M2 is -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O-)- or -SC(O-); preferably -C(O)O- or -C(O)S-;

[0459] R1 is C 6-14 Straight-chain alkyl groups, optionally bounded by 1, 2, 3 or 4 R groups. s Replacement; preferably R1 is not replaced;

[0460] R2 is C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. s replace;

[0461] R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR b R' c H and C are preferred. 1-14 alkyl;

[0462] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0463] Rc and R' c Independently selected from H and C 1-14 alkyl;

[0464] R3 is selected from -OR g and -NR g R' g Preferred - OR g ;

[0465] R g and R' g Independently selected from H and C 1-6 alkyl;

[0466] R4 and R5 are independently selected from H and C. 1-6 Alkyl groups, preferably H and C 1-3 Alkyl, preferably C 1-3 alkyl;

[0467] Or CR4R5 together form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0468] 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...

[0469] Ring A is a 5-membered heteroaryl group; preferably a 5-membered azapyridine group; preferably a diazonyl group; preferably...

[0470] a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2.

[0471] b = 5;

[0472] c = 1;

[0473] e = 2, 3, 4, 5 or 6; preferably e = 3, 4 or 5; preferably e = 5;

[0474] f = 1 or 2; f = 1 is preferred.

[0475] e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6;

[0476] M1 is -C(O)O- or -OC(O-); preferably -OC(O-);

[0477] M2 is -CH2CH2-, -C(O)O-, or -OC(O-); preferably -C(O)O- or -OC(O-); preferably -C(O)O-.

[0478] R1 is C 8-12 Straight-chain alkyl, preferably C 9-11Straight-chain alkyl group, optionally marked with one R s Replacement; preferably R1 is not replaced;

[0479] R2 is C 8-12 Alkyl, preferably C 9-11 Alkyl group, which is optionally marked with one R s replace;

[0480] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl;

[0481] R3 is -OR g and -NR g R' g Preferred - OR g ;

[0482] R g and R' g Independently selected from H and C 1-3 alkyl;

[0483] R4 and R5 are independently selected from H and C. 1-3 Alkyl, preferably C 1-3 alkyl;

[0484] Or CR4R5 together form C 3-6 Cycloalkylene compounds; preferably CR4R5, which does not form rings;

[0485] Preferably,

[0486] R s The substitution site on R1 is separated from M1 by at least one carbon atom, preferably at least two carbon atoms;

[0487] R s The substitution site on R2 is separated from ring A by at least one carbon atom, preferably at least two carbon atoms.

[0488] 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...

[0489] Ring A is diazolidine or triazolidine; preferably diazolidine; preferably Preferred Preferred

[0490] a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2.

[0491] b = 5;

[0492] c = 1;

[0493] e = 3, 4, or 5; preferably e = 3 or 5; preferably e = 5;

[0494] f = 1;

[0495] M1 is -OC(O)-;

[0496] M2 is -CH2CH2- or -C(O)O-; preferably -C(O)O-;

[0497] R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups, optionally marked with one R s Replacement; preferably R1 is not replaced;

[0498] R2 is C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R s replace;

[0499] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 Alkyl, preferably C 6-7 Alkyl groups, preferably C7 alkyl groups;

[0500] R3 is -OH or -N(CH3)2; preferably -OH.

[0501] R4 and R5 are independently selected from H and methyl; methyl is preferred;

[0502] Or CR4R5 together form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds; preferably CR4R5 does not form a ring;

[0503] Preferably,

[0504] R s The substitution site on R2 is spaced 1-4 carbon atoms from ring A, preferably 2-4 carbon atoms, and more preferably 2-3 carbon atoms;

[0505] Preferably, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3;

[0506] R2 is selected from

[0507] 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):

[0508] in,

[0509] Ring A is phenylene or a 5-6 membered heteroarylene; preferably a 5-6 membered heteroarylene; preferably a triazolyl; preferably...

[0510] a = 2, 3, 4 or 5; preferably a = 2, 3 or 4; preferably a = 2 or 3;

[0511] b = 3;

[0512] c = 3;

[0513] e = 1, 2, 3, 4, 5, 6 or 7; preferably e = 3, 4 or 5; preferably e = 3;

[0514] f = 1, 2, 3, or 4; f = 1 is preferred.

[0515] e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6;

[0516] M1 is -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- or -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0517] M2 is -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O-)- or -SC(O-); preferably -CH2CH2-;

[0518] R1 is C 6-14 Straight-chain alkyl groups, optionally bounded by 1, 2, 3 or 4 R groups. s Replacement; preferably R1 is not replaced;

[0519] R2 is C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. s replace;

[0520] R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR b R' c H and C are preferred. 1-14 alkyl;

[0521] L cIndependently selected from chemical bonds and C 1-14 Alkylene;

[0522] R c and R' c Independently selected from H and C 1-14 alkyl;

[0523] R3 is selected from -OR g and -NR g R' g Preferred - OR g ;

[0524] R g and R' g Independently selected from H and C 1-6 alkyl;

[0525] R4 and R5 are independently selected from H and C. 1-6 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 alkyl;

[0526] Or CR4R5 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene groups;

[0527] Preferably, CR4R5 are used together to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0528] 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...

[0529] Ring A is a 5-membered heteroaryl group; preferably a 5-membered azapyridine group; preferably a triazole group; preferably...

[0530] a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2.

[0531] b = 3;

[0532] c = 3;

[0533] e = 2, 3, 4, 5 or 6; preferably e = 3, 4 or 5; preferably e = 3;

[0534] f = 1 or 2; f = 1 is preferred.

[0535] e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6;

[0536] M1 is -C(O)O- or -OC(O-); preferably -OC(O-);

[0537] M2 is -CH2CH2-, -C(O)O-, or -OC(O-); preferably -CH2CH2-.

[0538] R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl group, optionally marked with one R s Replacement; preferably R1 is not replaced;

[0539] R2 is C 8-12 Alkyl, preferably C 10-12 Alkyl, preferably C 9-11 Alkyl group, which is optionally marked with one R s replace;

[0540] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl;

[0541] R3 is -OR g and -NR g R' g Preferred - OR g ;

[0542] R g and R' g Independently selected from H and C 1-3 alkyl;

[0543] R4 and R5 are independently selected from H and C. 1-3 Alkyl, preferably C 1-3 Alkyl groups; or CR4R5 together to form C 3-6 Cycloalkylene;

[0544] Preferably, CR4R5 are used together to form C 3-6 Cycloalkylene;

[0545] Preferably,

[0546] R s The substitution site on R1 is separated from M1 by at least one carbon atom, preferably at least two carbon atoms;

[0547] R s The substitution site on R2 is separated from ring A by at least one carbon atom, preferably at least two carbon atoms.

[0548] 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...

[0549] Ring A is diazolidine or triazole; preferably triazole; preferably Preferred Preferred

[0550] a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2.

[0551] b = 3;

[0552] c = 3;

[0553] e = 3, 4, or 5; e = 3 is preferred.

[0554] f = 1;

[0555] M1 is -OC(O)-;

[0556] M2 is -CH2CH2- or -C(O)O-; preferably -CH2CH2-;

[0557] R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups, optionally marked with one R s Replacement; preferably R1 is not replaced;

[0558] R2 is C 8-12 Alkyl, preferably C 10-12 Alkyl, preferably C 9-11 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R s replace;

[0559] R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-9 Alkyl, preferably C 6-9 Alkyl, preferably C 7-9 Alkyl, preferably C 1-7 Alkyl groups, preferably C7 alkyl groups;

[0560] R3 is -OH or -N(CH3)2; preferably -OH.

[0561] R4 and R5 are independently selected from H and methyl; preferably methyl; or CR4R5 together form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds;

[0562] Preferably, CR4R5 are used together to form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds;

[0563] Preferably,

[0564] R sThe substitution site on R2 is spaced 1-4 carbon atoms from ring A, preferably 2-4 carbon atoms, and more preferably 2-3 carbon atoms;

[0565] Preferably, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3;

[0566] R2 is selected from Preferred

[0567] In a more specific embodiment, the present invention provides the above-described compounds, or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein the compounds are selected from the compounds in Table I, preferably the compounds in Table II.

[0568] Table I

[0569] Table II

[0570] In a more specific embodiment, the present invention provides a composition comprising any of the compounds of the present invention described above, or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0571] In a more specific embodiment, the present invention provides a nanoparticle composition comprising a lipid component and optionally a loading agent; wherein the lipid component contains any of the compounds of the present invention described above, or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, and the loading agent is selected from one or more therapeutic agents, preventive agents or diagnostic agents.

[0572] Preferably, the lipid component contains the following components in molar percentage:

[0573] Ionizable lipids 20 mol% - 85 mol%

[0574] Neutral lipids: 1.0 mol% - 30 mol%;

[0575] Structural lipids: 10 mol% - 75 mol%;

[0576] Polymer lipids: 0.25 mol% - 10 mol%;

[0577] Optionally, it further includes 0.01 mol% to 1 mol% of functionalized polymeric lipids; or

[0578] Optionally, it further includes 0.01 mol% to 1 mol% of the targeting conjugate;

[0579] Preferably, the lipid component contains the following components in molar percentage:

[0580] Ionizable lipids: 30 mol% - 65 mol%;

[0581] Neutral lipids 2 mol% - 25 mol%;

[0582] Structural lipids: 12 mol% - 50 mol%;

[0583] Polymer lipids: 0.5 mol% - 5 mol%;

[0584] Optionally, the functionalized polymer lipid or targeting conjugate is 0.05 mol% to 0.5 mol%.

[0585] Preferably, the lipid component contains the following components in molar percentage:

[0586] Ionizable lipids: 40 mol% - 65 mol%;

[0587] Neutral lipids 5 mol%-20 mol%, preferably 5 mol%-15 mol%;

[0588] Structural lipids: 20 mol%-50 mol%, preferably 25 mol%-45 mol%;

[0589] Polymer lipids: 0.5 mol% - 3 mol%, preferably 1 mol% - 2.5 mol%;

[0590] Optionally, the functionalized polymer lipid or targeting conjugate is present at 0.05 mol%-0.3 mol%, preferably 0.05 mol%-0.2 mol%.

[0591] Preferably, the lipid component contains the following components in molar percentage:

[0592] Ionizable lipids: 50 mol% - 58 mol%;

[0593] Neutral lipids 10 mol%;

[0594] Structural lipids: 30.5 mol% - 38.5 mol%;

[0595] Polymer lipids 1.4 mol%;

[0596] Optionally, 0.1 mol% of the functionalized polymer lipid or targeting conjugate;

[0597] The ionizable lipids are selected from the compounds of this invention;

[0598] The targeted conjugate is a conjugate of a targeted portion and a functionalized polymer lipid.

[0599] The targeting portion is selectively targeted and can target target organs and / or target tissues, such as the liver, spleen, kidney, heart, brain, lymph nodes, thymus, bone marrow, muscle, blood, skin, and mucosa-associated lymphoid tissue.

[0600] Preferably, the targeting portion targets immune organs and / or immune tissues;

[0601] Preferably, the targeting portion targets hematopoietic cells;

[0602] More preferably, the targeting portion targets immune cells, stem cells, or progenitor cells, such as T cells, natural killer (NK) cells, dendritic cells, macrophages, hematopoietic stem cells (HSCs), pluripotent stem cells, mesenchymal stem cells (MSCs), multipotent progenitor cells, hematopoietic progenitor cells, and / or oligopotent progenitor cells.

[0603] The functionalized polymer lipid is composed of polymer lipid and functionalized groups;

[0604] Preferably, the functionalized group is selected from maleimide, azide, alkynyl (alkynylene), dibenzocyclooctylene (DBCO), bromomaleimide, bromomaleimide amide, alkynyl amide or alkynyl imide; preferably, the functionalized group is maleimide;

[0605] Preferably, the targeting portion is selected from peptides, small molecule ligands, proteins / ligands, carbohydrates, or nucleic acids;

[0606] Preferably, the targeting portion is selected from the antibody or its antigen-binding portion;

[0607] Preferably, the targeting portion specifically binds to CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b (Mac-1), CD13, CD14, CD16a, CD25, CD28, CD29, CD31, CD32, CD32A, CD34, CD40, CD44, CD45, CD56, CD64, CD68, CD70, CD73, CD90, CD98, CD105, CD271, 4-1BB, CD166, CD117, CD133, CD137, CD146, CD205, CD2 71. Cell surface proteins of CD326, CTLA-4, GITR, LAG-3, OX40, PD-1, TIM-3, low-affinity IL-2 receptor, IL-7 receptor, IL-12 receptor, IL-15 receptor, IL-18 receptor, IL-21 receptor, BMPR2, CTLA-4, GD2, GITR, DEC205, LAG-3, TREM2, Sca-1, SSEA-4, Stro-1, Stro-4, MSCA-1, SUSD2, TIM-3, PODXL, ASGPR, EPCAM, TfR, OX40, and PD-1.

[0608] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of ionizable lipids in the lipid component is 20 mol%-85 mol%, preferably 30 mol%-65 mol%, preferably 40 mol%-65 mol%, preferably 50 mol%-58 mol%; for example, 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%, 30 mol%, 51 mol%, 52 mol%, 53 mol%, 54 mol%, 55 mol%, 56 mol%, 57 mol%, 58 mol%, 59 mol%, 60 mol%, 61 mol%, 62 mol%, 63 mol%, 64 mol%, or 65 mol%.

[0609] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of neutral lipids in the lipid component is 1.0 mol%-30 mol%, preferably 2 mol%-25 mol%, preferably 5 mol%-25 mol%, preferably 5 mol%-20 mol%, preferably 5 mol%-15 mol%, preferably 10 mol%-25 mol%, preferably 10 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%.

[0610] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the molar percentage of structural lipids in the lipid component is 10 mol%-75 mol%, preferably 12 mol%-50 mol%, preferably 20 mol%-50 mol%, preferably 25 mol%-45 mol%, preferably 30.5 mol%-38.5 mol%; for example, 12 mol%, 13 mol%, 14 mol%, 15 mol%, 16 mol%, 17 mol%, 18 mol%, 18.5 mol%, 19 mol%, 20 mol%, 21 mol%, 22 mol%, 23 mol%, 23.5 mol%, 24 mol%, 25 mol%, 25.5 mol%. mol%, 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%, 41.5mol%, 42mol%, 43mol%, 44mol%, 45mol%, 46mol%, 47mol%, 48mol%, 48.5mol%, 49mol% or 50mol%.

[0611] In a more specific embodiment, 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 0.5 mol%-5 mol%, preferably 0.5 mol%-3.5 mol%, preferably 0.5 mol%-3 mol%, preferably 1 mol%-2.5 mol%, for example, 1 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, 1.6 mol%, 1.7 mol%, 1.8 mol%, 1.9 mol%, 2.0 mol%, 2.1 mol%, 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%.

[0612] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, optionally further comprising functionalized polymer lipids or targeting conjugates, wherein the molar percentage of the functionalized polymer lipids or targeting conjugates in the lipid component is 0.01 mol%-1 mol%, preferably 0.05 mol%-0.5 mol%, preferably 0.05 mol%-0.3 mol%, preferably 0.05 mol%-0.25 mol%, preferably 0.05 mol%-0.2 mol%, for example, 0.01 mol%, 0.02 mol%, 0.03 mol%, 0.04 mol%, 0.05 mol%, 0.06 mol%, etc. mol%, 0.07mol%, 0.08mol%, 0.09mol%, 0.1mol%, 0.11mol%, 0.12mol%, 0.13mol%, 0.14mol%, 0.15mol%, 0.16mol%, 0.17mol%, 0.18mol%, 0 .19mol%, 0.2mol%, 0.25mol%, 0.3mol%, 0.35mol%, 0.4mol%, 0.45mol%, 0.5mol%, 0.55mol%, 0.6mol%, 0.7mol%, 0.8mol%, 0.9mol% or 1mol%.

[0613] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein it further includes a load, said load being nucleic acid;

[0614] The N:P molar ratio of the N atom in the ionizable lipid to the P atom in the loaded molecule is 1-15:1, preferably 3-12:1, preferably 3-10:1, preferably 4.5-8.5:1, for example 4.5:1, 6:1, 7:1, 7.5:1, 7.75:1 or 8.5:1;

[0615] In a more specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a composition of the present invention, or a nanoparticle composition of the present invention, and a pharmaceutically acceptable excipient.

[0616] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the neutral lipid is a phospholipid, for example, but not limited to, distearylphosphatidylcholine (DSPC), dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearyl-sn-glycerol-phosphoethanolamine, dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), distearylphosphatidylethanolamine (DSPE), monomethylphosphatidylethanolamine, dimethylphosphatidylethanolamine, 18-1-transPE, 1-stearoyl-2-oleoylphosphatidylethanolamine (SOPE), hydrogenated soybean phosphate. Acylcholine (HSPC), egg phosphatidylcholine (EPC), dioleoylphosphatidylserine or 1,2-dioleoyl-sn-glycero-3-phosphate-L-serine (DOPS), sphingomyelin (SM), dimyristoylphosphatidylglycerol (DMPG), distearate phosphatidylglycerol (DSPG), rutinoylphosphatidylcholine (DEPC), palmitoylphosphatidylglycerol (POPG), dioleoylphosphatidylethanolamine (DEPE), 1, 2-Dilauroyl-sn-glycerol-3-phosphate ethanolamine (DLPE), 1,2-diphydanoyl-sn-glycerol-3-phosphate ethanolamine (DPHyPE), lecithin, phosphatidylethanolamine, lysophosphatidyl lecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, methionine (ESM), cephalin, cardiolipin, phosphatidic acid, cerebroside, hexadecyl phosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine, or mixtures thereof. The acyl group in these lipids is preferably derived from a group having a C- group. 10 -C 24The acyl group of the fatty acid in the carbon chain is one or more of lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl. 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.

[0617] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the structural lipid is a steroid or an analogue thereof;

[0618] In some embodiments, the steroids or analogues described herein have the following tetracyclic skeleton structure.

[0619] This includes naturally occurring or synthetic steroids and their analogues, including but not limited to alfalfa sterol, β-sitosterol, campesterol, ergocalciferol, campesterol, cholesterol, coccidosterol, dehydrocholesterol, sterol, dihydroergocalciferol, cholesterol, dihydrocholesterol, dihydroergosterol, serotonol, 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 (D C-Chol), 24(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-dihydroautocalciferol, tomatine, ursolic acid, chenodeoxycholic acid, yeast sterol, diosgenin, etc. In some embodiments, the structural lipids described herein are selected from one or more of cholesterol, β-sitosterol, coccosterol, rock saponin, rapeseed sterol, ergosterol, tomatine, ursolic acid, stigmasterol, alfalfa sterol, ergocalciferol, or campesterol.

[0620] 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.

[0621] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the polymeric lipid is a polyethylene glycol-modified lipid. In some embodiments, the polyethylene glycol-modified lipid (PEG lipid) of the present invention is a lipid covalently or non-covalently linked to one or more polyethylene glycol (PEG) chains. In some embodiments, the PEG lipid of the present invention is a lipid covalently linked to one or more polyethylene glycol (PEG) chains.

[0622] 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.

[0623] 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.

[0624] In some embodiments, the polyethylene glycol-modified lipids of the present invention include 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 diekoxypropyl Carbamates (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-distearate-sn-glycerol-3-phosphate ethanolamine sodium sodium, PEG-dilauroyloxypropyl, PEG-dimyristoyloxypropyl, PEG-dipalmitoyloxypropyl, PEG-disteayloxypropyl, 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol-PEG (DMG-PEG), disteayl-rac-glycerol-PEG (DSG-PEG), PEG-dilauroylglycerol, PEG-dipalmitoylglycerol, PEG-disteaylglycerol, PEG-dilauroylglycerol amide, PEG-dimyristoylglycerol amide, PEG-dipalmitoylglycerol amide, PEG-disteaylglycerol amide, (1-[8'-(cholesterol-5-ene) [-3β-oxy)formamido-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).

[0625] 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 DSPE-PEG2000 and / or DMG-PEG2000, with DSPE-PEG2000 being the most preferred.

[0626] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the loading is selected from one or more therapeutic agents, preventive agents, or diagnostic agents;

[0627] Preferably, the therapeutic agent, preventive agent, or diagnostic agent is a nucleic acid;

[0628] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA, or DNA;

[0629] 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, and is preferably mRNA, siRNA, gRNA, circRNA, SrRNA, miRNA, aRNA, or modified mRNA;

[0630] Preferably, the mRNA encodes a functional protein or a structural protein; preferably, the protein is selected from T cell receptors (TCRs), chimeric antigen receptors (CARs), immune cell connectors, or gene-editing nucleases.

[0631] Preferably, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), and double-stranded DNA (dsDNA), and more preferably from one or more of microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0632] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the loading is a gene therapy drug, such as a gene editing, gene interference, protein supplementation, or protein replacement drug.

[0633] 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.

[0634] 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.

[0635] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), 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 36Cl. 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 (I) 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 described below and / or the techniques disclosed in the examples and preparation examples.

[0636] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are subject to the present invention.

[0637] Pharmaceutical Compositions and Kits

[0638] 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.

[0639] 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.

[0640] 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.

[0641] Dosage

[0642] 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.

[0643] 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.

[0644] 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.

[0645] 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.

[0646] 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.

[0647] 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.

[0648] 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.

[0649] 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.

[0650] Example

[0651] 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.

[0652] Table 1

[0653] Example 1: Synthesis of Compound 1

[0654] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0 °C. Under nitrogen protection, LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction solution. The reaction temperature was raised to room temperature, stirred for 30 minutes, and then 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.) was added. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with dichloromethane (3 x 300 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography to give 30 g of a yellow oily compound 1-1.

[0655] Compound 1-1 (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0 °C. Borane-tetrahydrofuran solution (1 M, 100 mL) was added dropwise to the reaction system under nitrogen protection. The temperature was raised to 75 °C, and the reaction was stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with dichloromethane (3 x 100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to give crude product 1-2 (13.6 g), which was used directly in the next reaction without further purification.

[0656] Decanoyl chloride (11.0 g, 58.0 mmol, 1.3 eq.) was added to compounds 1-2 (10.0 g, 44.0 mmol, 1.0 eq.) in 100 mL of dichloromethane. Triethylamine (13.5 g, 134.0 mmol, 3.0 eq.) was then added to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. The reaction solution was poured into 100 mL of water, extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product. Purification by silica gel column chromatography yielded 10 g of compounds 1-3.

[0657] Potassium carbonate (3.0 g, 22.0 mmol, 3.0 eq.) and compounds 1-3 (2.8 g, 7.4 mmol, 1.0 eq.) were added to a 20 mL ethanol solution of 4-hydroxybutylamine (6.6 g, 74.0 mmol, 10.0 eq.). The mixture was heated to 60 °C and stirred for 3 hours. The reaction solution was poured into 80 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product. This crude product was purified by silica gel column chromatography to give 2.4 g of compounds 1-4.

[0658] Compound 1-5 (1.5 g, 4.70 mmol, 1.0 eq.), THF (45 mL), and PPh3 (1.36 g, 5.17 mmol, 1.1 eq.) were added to a 250 mL single-necked flask. The system was cooled to 0 °C, and DIAD (1.04 g, 5.17 mmol, 1.1 eq.) was added dropwise. After stirring in an ice bath for 30 min, DPPA (1.40 g, 5.07 mmol, 1.08 eq.) was added dropwise. The system was then warmed to room temperature and the reaction was continued for 18 h. The reaction was monitored by TLC until the starting material was almost completely reacted. The mixture was concentrated under reduced pressure, redissolved in petroleum ether (100 mL), slurried, filtered, and the filter cake was washed with petroleum ether (3 x 5 mL). The filtrate was collected and concentrated. The crude product was purified by silica gel column chromatography to give 1.3 g of a yellow oily compound 1-6.

[0659] Compounds 1-6 (1 g, 3.55 mmol, 1.0 eq.), 8-bromo-1-octyne 1-7 (0.67 g, 3.55 mmol, 1.0 eq.), anhydrous copper sulfate (0.28 g, 1.77 mmol, 0.5 eq.), sodium ascorbate (0.35 g, 1.77 mmol, 0.5 eq.), methanol (5 mL), tert-butanol (5 mL), and water (5 mL) were added to a 40 mL sealed tube. The reaction was stirred at room temperature for 18 h, and the reaction was monitored by LC-MS until the starting material was almost completely converted. The system was diluted with ethyl acetate (20 mL), filtered, and the filter cake was washed with ethyl acetate (2 x 5 mL). The filtrate was collected and concentrated under reduced pressure. Extraction was performed with ethyl acetate (30 mL) and water (30 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.34 g of yellow oily compound 1-8.

[0660] Compounds 1-4 (150 mg, 0.39 mmol, 1.0 eq.), compounds 1-8 (274.57 mg, 0.58 mmol, 1.5 eq.), potassium iodide (77.48 mg, 0.47 mmol, 1.2 eq.), and potassium carbonate (162.45 mg, 1.17 mmol, 3.0 eq.) were dissolved in a mixed solvent of acetonitrile (1 mL) and cyclopentyl methyl ether (3 mL) in a 40 mL sealed tube. The reaction was heated to 80 °C for 18 h, and then cooled to room temperature. The mixture was filtered, and the filter cake was washed with ethyl acetate (2 x 5 mL). The filtrate was concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography under the following conditions (Column: X Bridge Shield RP18 OBD Column 30*150mm, 5μm; Eluent A: H2O / CH3CN 60 / 40, 10mM NH4HCO3+1% NH3˙H2O; Eluent B: IPA / CH3CN 90 / 10; Flow rate: 60mL / min; Gradient program: 50%-70% B in 0-12min), yielding a pale yellow oily compound 1 (165.6mg).

[0661] 1 H NMR(300MHz, CDCl3)δ:7.25(s,1H),4.31(t,J=7.8Hz,2H),3.78(s,2H),3.56(s,2H),2.70(t,J=7.8Hz,2H),2.46(s,6H ),2.31(t,J=7.5Hz,2H),1.83(m,2H),1.72-1.60(m,8H),1.58(m,4H),1.34-1.22(m,50H),0.93-0.89(m,15H); ESI-MS m / z:775.75[M+H] + .

[0662] Example 2: Synthesis of Compound 2

[0663] Compound 2 was prepared according to the method of Example 1, yielding 125.3 mg of an oily product.

[0664] 1H NMR(400MHz, CDCl3)δ:7.26(s,1H),4.31(t,J=7.6Hz,2H),3.81-3.78(m,4H),2.70(t,J=7.6Hz,4H),2.45(bs,4H ),2.32(t,J=7.6Hz,2H),1.86-1.80(m,2H),1.71-1.50(m,10H),1.41-1.24(m,48H),0.90-0.88(m,15H); ESI-MS m / z:761.70[M+H] + .

[0665] Example 3: Synthesis of Compound 3

[0666] Compound 3 was prepared according to the method in Example 1, yielding 167.2 mg of an oily product.

[0667] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.31 (t, J = 7.8Hz, 2H), 3.78 (s, 2H), 3.67 (s, 2H), 2.76-2.63 (m, 8H), 2. 32(t,J=7.5Hz,2H),1.87-1.80(m,2H),1.73-1.58(m,8H),1.44-1.22(m,48H),0.93-0.88(m,15H); ESI-MS m / z:747.60[M+H] + .

[0668] Example 4: Synthesis of Compound 4

[0669] Compound 4 was prepared according to the method of Example 1, yielding 135.6 mg of an oily product.

[0670] 1 H NMR (300MHz, CDCl3) δ: 7.22 (s, 1H), 4.19 (d, J = 6.9Hz, 2H), 3.78 (s, 2H), 3.58 (s, 2H), 2.70 (t, J = 7.5Hz, 2H), 2.51 (bs,4H),2.32(t,J=7.5Hz,2H),1.90(m,1H),1.68-1.54(m,13H),1.44-1.25(m,52H),0.90-0.86(m,15H); ESI-MS m / z:789.70[M+H] + .

[0671] Example 5: Synthesis of Compound 5

[0672] Compound 5 was prepared according to the method of Example 1, yielding 171.4 mg of an oily product.

[0673] 1 H NMR(400MHz, CDCl3)δ:7.26(s,1H),4.28(t,J=7.2Hz,2H),3.78(s,2H),3.57(bs,2H),2.71(t,J=7.6Hz,2H),2.69(s,2H),2.63( s,4H),2.32(t,J=7.6Hz,2H),1.87-1.83(m,2H),1.70-1.61(m,4H),1.48(m,4H),1.45-1.22(m,46H),0.90-0.88(m,15H); ESI-MS m / z:733.65[M+H] + .

[0674] Example 6: Synthesis of Compound 6

[0675] Compound 6 was prepared according to the method of Example 1, yielding 180.0 mg of an oily product.

[0676] 1 H NMR(400MHz, CDCl3)δ:7.27(s,1H),4.28(t,J=7.2Hz,2H),3.81-3.78(m,4H),2.71(t,J=7.6Hz,4H),2.45(bs,4H ),2.32(t,J=7.6Hz,2H),1.87-1.83(m,2H),1.70-1.51(m,10H),1.41-1.19(m,46H),0.90-0.88(m,15H); ESI-MS m / z:747.65[M+H] + .

[0677] Example 7: Synthesis of Compound 7

[0678] Compound 7 was prepared according to the method of Example 1, yielding 151.7 mg of an oily product.

[0679] 1H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.28 (t, J = 7.2Hz, 2H), 3.78 (s, 2H), 3.56 (s, 2H), 2.70 (t, J = 7.5Hz, 2H), 2.47 (bs ,5H),2.31(t,J=7.2Hz,2H),1.91-1.80(m,2H),1.67-1.51(m,12H),1.44-1.21(m,47H),0.92-0.88(m,15H); ESI-MS m / z:761.85[M+H] + .

[0680] Example 8: Synthesis of Compound 8

[0681] Compound 8 was prepared according to the method of Example 1, yielding 103.7 mg of an oily product.

[0682] 1 H NMR(400MHz, CDCl3)δ:7.25(s,1H),4.31(t,J=7.2Hz,2H),3.78(s,2H),3.56(s,2H),2.71(t,J=7.6Hz,2H),2.61(s,2H),2.48(b s,4H),2.32(t,J=7.6Hz,2H),1.88-1.85(m,2H),1.70-1.61(m,4H),1.47(m,4H),1.40-1.18(m,44H),0.93-0.89(m,15H); ESI-MS m / z:719.60[M+H] + .

[0683] Example 9: Synthesis of Compound 9

[0684] Compound 9 was prepared according to the method of Example 1, yielding 139.0 mg of an oily product.

[0685] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.31 (t, J = 7.2Hz, 2H), 3.81-3.78 (m, 4H), 2.71 (t, J = 7.5Hz, 4H), 2.47 (bs, 4 H),2.32(t,J=7.5Hz,2H),1.89-1.82(m,2H),1.73-1.51(m,9H),1.44-1.26(m,45H),0.93-0.89(m,15H); ESI-MS m / z:733.65[M+H] + .

[0686] Example 10: Synthesis of Compound 10

[0687] Compound 10 was prepared according to the method of Example 1, yielding 149.0 mg of an oily product.

[0688] 1 H NMR(300MHz, CDCl3)δ:7.26(s,1H),4.31(t,J=7.2Hz,2H),3.78(s,2H),3.58(s,2H),2.70(t,J=7.5Hz,2H),2.49(bs ,6H),2.31(t,J=7.5Hz,2H),1.89-1.82(m,2H),1.67-1.52(m,12H),1.44-1.26(m,44H),0.93-0.89(m,15H); ESI-MS m / z:747.55[M+H] + .

[0689] Example 11: Synthesis of Compound 11

[0690] Compound 11 was prepared according to the method of Example 1, yielding 80.0 mg of an oily product.

[0691] 1 H NMR (300MHz, CDCl3) δ: 7.25 (s, 1H), 4.30 (m, 2H), 3.78 (s, 2H), 3.55 (t, J = 5.1Hz, 2H), 2.70 (t, J = 7.5Hz, 2H), 2.73-2.44(m,8H),2.32(t,J=7.5Hz,2H),1.86-1.80(m,2H),1.72-1.26(m,50H),0.91-0.88(m,15H); ESI-MS m / z:719.60[M+H] + .

[0692] Example 12: Synthesis of Compound 12

[0693] Compound 12 was prepared according to the method of Example 1, yielding 234.6 mg of an oily product.

[0694] 1H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.31 (t, J = 7.5Hz, 2H), 3.81-3.78 (m, 4H), 2.73-2.63 (m ,4H),2.44-2.29(m,6H),1.87-1.80(m,2H),1.72-1.26(m,54H),0.93-0.89(m,15H); ESI-MS m / z:733.55[M+H] + .

[0695] Example 13: Synthesis of Compound 13

[0696] Compound 13 was prepared according to the method of Example 1, yielding 180.2 mg of an oily product.

[0697] 1 H NMR(300MHz, CDCl3)δ:7.25(s,1H),4.31(t,J=7.8Hz,2H),3.78(s,2H),3.55(s,2H),2.70(t,J=7.5Hz,2H),2.44(t,J=7.5Hz,6H) ,2.31(t,J=7.5Hz,2H),1.87-1.80(m,2H),1.72-1.60(m,8H),1.54-1.49(m,4H),1.46-1.26(m,44H),0.93-0.89(m,15H); ESI-MS m / z:747.55[M+H] + .

[0698] Example 14: Synthesis of Compound 14

[0699] Compound 14 was prepared according to the method of Example 1, yielding 173.1 mg of an oily product.

[0700] 1 H NMR (300MHz, CDCl3) δ: 7.25 (s, 1H), 4.31 (t, J = 7.8Hz, 2H), 3.78 (s, 2H), 3.54 (t, J = 5.4Hz, 2H), 2.70 (t, J = 7.5Hz, 2H), 2.59 (t, J = 5.4Hz, 2H),2.46(t,J=7.2Hz,4H),2.32(t,J=7.5Hz,2H),1.86-1.80(m,2H),1.72-1.60(m,4H),1.46-1.25(m,56H),0.93-0.88(m,15H); ESI-MS m / z:775.65[M+H] + .

[0701] Example 15: Synthesis of Compound 15

[0702] Compound 15 was prepared according to the method of Example 1, yielding 195.0 mg of an oily product.

[0703] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.31 (t, J = 7.5Hz, 2H), 3.81-3.78 (m, 4H), 2.73-2.66 (m, 4H), 2.43 (t, J = 7.2Hz ,4H),2.32(t,J=7.5Hz,2H),1.86-1.80(m,2H),1.69-1.60(m,6H),1.46-1.25(m,56H),0.93-0.88(m,15H); ESI-MS m / z:789.60[M+H] + .

[0704] Example 16: Synthesis of Compound 16

[0705] Compound 16 was prepared according to the method of Example 1, yielding 223.7 mg of an oily product.

[0706] 1 H NMR(300MHz, CDCl3)δ:7.25(s,1H),4.31(t,J=7.8Hz,2H),3.78(s,2H),3.56(s,2H),2.70(t,J=7.5Hz,2H),2.45(bs ,6H),2.32(t,J=7.5Hz,2H),1.86-1.80(m,2H),1.72-1.60(m,10H),1.46-1.25(m,54H),0.93-0.88(m,15H); ESI-MS m / z:803.60[M+H] + .

[0707] Example 17: Synthesis of Compound 17

[0708] Compound 17 was prepared according to the method of Example 1, yielding 219.6 mg of an oily product.

[0709] 1H NMR (300MHz, CDCl3) δ: 7.25 (s, 1H), 4.31 (t, J = 7.8Hz, 2H), 4.03 (t, J = 6.9Hz, 2H), 3.55 (t, J = 5.1Hz, 2H), 2.70 (t, J = 7.5Hz, 2H), 2.62-2.59 (m,2H),2.50-2.42(m,4H),2.29(t,J=7.5Hz,2H),1.86-1.79(m,2H),1.72-1.51(m,10H),1.49-1.18(m,46H),0.91-0.86(m,15H); ESI-MS m / z:747.65[M+H] + .

[0710] Example 18: Synthesis of Compound 18

[0711] Compound 18 was prepared according to the method of Example 1, yielding 166.5 mg of an oily product.

[0712] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.31 (t, J = 7.8Hz, 2H), 4.03 (t, J = 6.9Hz, 2H), 3.79 (t, J = 5.1Hz, 2H), 2.73-2.66 ( m,4H),2.43-2.41(m,4H),2.29(t,J=7.5Hz,2H),1.87-1.80(m,2H),1.70-1.19(m,58H),0.91-0.88(m,15H); ESI-MS m / z:761.55[M+H] + .

[0713] Example 19: Synthesis of Compound 19

[0714] Compound 19 was prepared according to the method of Example 1, yielding 221.9 mg of an oily product.

[0715] 1 H NMR(300MHz, CDCl3)δ:7.25(s,1H),4.31(t,J=7.8Hz,2H),4.03(t,J=6.9Hz,2H),3.57(m,2H),2.70(t,J=7.5H z,2H),2.48(bs,6H),2.29(t,J=7.5Hz,2H),1.87-1.80(m,2H),1.72-1.19(m,60H),0.91-0.88(m,15H); ESI-MS m / z:775.60[M+H]+ .

[0716] Example 20: Synthesis of Compound 20

[0717] Compound 20 was prepared according to the method of Example 1, yielding 121.1 mg of an oily product.

[0718] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.28 (t, J = 7.5Hz, 2H), 4.03 (t, J = 6.9Hz, 2H), 3.55 (t, J = 5.1Hz, 2H), 2.71 (t, J = 7.2Hz, 2H) ),2.61(s,2H),2.47-2.45(m,4H),2.29(t,J=7.5Hz,2H),1.88-1.80(m,2H),1.72-1.19(m,54H),0.91-0.88(m,15H); ESI-MS m / z:733.60[M+H] + .

[0719] Example 21: Synthesis of Compound 21

[0720] Compound 21 was prepared according to the method of Example 1, yielding 115.9 mg of an oily product.

[0721] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.28 (t, J = 7.5Hz, 2H), 4.03 (t, J = 6.9Hz, 2H), 3.79 (t, J = 5.1Hz, 2H), 2.73-2.65 ( m,4H),2.42-2.40(m,4H),2.29(t,J=7.5Hz,2H),1.90-1.80(m,2H),1.73-1.18(m,56H),0.92-0.88(m,15H); ESI-MS m / z:747.60[M+H] + .

[0722] Example 22: Synthesis of Compound 22

[0723] Compound 22 was prepared according to the method of Example 1, yielding 139.0 mg of an oily product.

[0724] 1H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.28 (t, J = 7.5Hz, 2H), 4.03 (t, J = 6.9Hz, 2H), 3.58 (s, 2H), 2.70 (t, J = 7.5H z,2H),2.52(bs,6H),2.29(t,J=7.5Hz,2H),1.90-1.80(m,2H),1.68-1.19(m,58H),0.92-0.88(m,15H); ESI-MS m / z:761.60[M+H] + .

[0725] Example 23: Synthesis of Compound 23

[0726] Compound 23 was prepared according to the method of Example 1, yielding an oily product of 298.7 mg.

[0727] 1 H NMR (300MHz, CDCl3) δ: 7.25 (s, 1H), 4.31 (t, J = 7.8Hz, 2H), 4.06 (t, J = 6.6Hz, 2H), 3.56 (s, 2H), 2.70 (t, J = 7.5Hz, 2H), 2.62 (s,2H),2.49(s,4H),2.28(t,J=7.5Hz,2H),1.86-1.80(m,2H),1.72-1.22(m,56H),0.92-0.88(m,9H),0.27(s,4H); ESI-MS m / z:745.50[M+H] + .

[0728] Example 24: Synthesis of Compound 24

[0729] Compound 24 was prepared according to the method of Example 1, yielding 262.2 mg of an oily product.

[0730] 1 H NMR (300MHz, CDCl3) δ: 7.25 (s, 1H), 4.31 (t, J = 7.8Hz, 2H), 4.06 (t, J = 6.9Hz, 2H), 3.79 (t, J = 5.1Hz, 2H), 2.73-2.66 (m, 4H), 2.42 ( s,4H),2.28(t,J=7.5Hz,2H),1.86-1.80(m,2H),1.70-1.47(m,12H),1.44-1.24(m,46H),0.92-0.88(m,9H),0.26(s,4H); ESI-MS m / z:759.65[M+H] +.

[0731] Example 25: Synthesis of Compound 25

[0732] Compound 25 was prepared according to the method of Example 1, yielding an oily product of 207.7 mg.

[0733] 1 H NMR (300MHz, CDCl3) δ: 7.27 (s, 1H), 4.31 (t, J = 7.8Hz, 2H), 4.06 (t, J = 6.9Hz, 2H), 3.56 (s, 2H), 2.71 (t, J = 7.5Hz, 2H) ,2.45(s,6H),2.29(t,J=7.5Hz,2H),1.87-1.81(m,2H),1.73-1.25(m,60H),0.92-0.88(m,9H),0.28(s,4H); ESI-MS m / z:773.70[M+H] + .

[0734] Example 26: Synthesis of Compound 26

[0735] Compound 26 was prepared according to the method of Example 1, yielding an oily product of 234.8 mg.

[0736] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.28 (t, J = 7.5Hz, 2H), 4.06 (t, J = 6.9Hz, 2H), 3.64 (s, 2H), 2.73-2.59 (m ,8H),2.28(t,J=7.5Hz,2H),1.88-1.80(m,2H),1.67-1.19(m,54H),0.92-0.88(m,9H),0.28(s,4H); ESI-MS m / z:731.65[M+H] + .

[0737] Example 27: Synthesis of Compound 27

[0738] Compound 27 was prepared according to the method of Example 1, yielding 158.7 mg of an oily product.

[0739] 1H NMR (300MHz, CD3OD) δ: 7.73 (s, 1H), 4.36 (t, J = 7.5Hz, 2H), 4.08 (t, J = 6.6Hz, 2H), 3.62 (t, J = 6.0Hz, 2H), 2.69 (t, J = 7.5Hz, 2H), 2.59 (t, J = 7.2Hz, 2H),2.48-2.42(m,4H),2.29(t,J=7.5Hz,2H),1.91-1.81(m,2H),1.74-1 .44(m,12H),1.43-1.19(m,44H),0.92-0.87(m,9H),0.25(s,4H); ESI-MS m / z:745.60[M+H] + .

[0740] Example 28: Synthesis of Compound 28

[0741] Compound 28 was prepared according to the method of Example 1, yielding 196.0 mg of an oily product.

[0742] 1 H NMR (300MHz, CD3OD) δ: 7.73 (s, 1H), 4.34 (t, J = 6.9Hz, 2H), 4.06 (t, J = 6.6Hz, 2H), 3.55 (t, J = 6.0Hz, 2H), 2.69 (t, J = 7.5Hz, 2H), 2.49-2. 43(m,6H),2.30(t,J=7.5Hz,2H),1.94-1.86(m,2H),1.72-1.48(m,14H),1.44-1.19(m,44H),0.90(t,J=6.9Hz,9H),0.25(s,4H); ESI-MS m / z:759.65[M+H] + .

[0743] Example 29: Synthesis of Compound 29

[0744] Compound 29 was prepared according to the method of Example 1, yielding 141.4 mg of an oily product.

[0745] 1H NMR (300MHz, CD3OD) δ: 7.72 (s, 1H), 4.35 (t, J = 7.2Hz, 2H), 4.06 (t, J = 6.6Hz, 2H), 3.55 (t, J = 5.7Hz, 2H), 2.69 (t, J = 7.5Hz, 2H), 2.48-2 .42(m,6H),2.30(t,J=7.5Hz,2H),1.93-1.86(m,2H),1.74-1.48(m,14H),1.42-1.22(m,35H),0.90-0.87(m,6H),0.26(s,4H); ESI-MS m / z:675.55[M+H] + .

[0746] Example 30: Synthesis of Compound 30

[0747] In a 250 mL round-bottom flask, 3-heptadecyl alcohol (2.9 g, 11.31 mmol, 1.0 eq.) and PPh3 (3.26 g, 12.44 mmol, 1.1 eq.) were dissolved in THF (87 mL). The system was cooled to 0 °C, and DIAD (2.52 g, 12.44 mmol, 1.1 eq.) was added dropwise. After stirring at 0 °C for 30 min, DPPA (3.36 g, 12.21 mmol, 1.08 eq.) was added dropwise. The reaction was continued at room temperature for 18 h, and the reaction was monitored by TLC until the reactants were almost completely reacted. The mixture was concentrated under reduced pressure, redissolved in petroleum ether (100 mL), slurried, filtered, and the filter cake was washed with petroleum ether (2 x 5 mL). The filtrate was collected and concentrated. The crude product was purified by silica gel column chromatography to give 2.43 g of a colorless oily compound 30-1.

[0748] Compound 30-1 (2.43 g, 8.63 mmol, 1.0 eq.), an alkyne compound (1.21 g, 8.63 mmol, 1.0 eq.), anhydrous copper sulfate (0.69 g, 4.32 mmol, 0.5 eq.), sodium ascorbate (0.86 g, 4.32 mmol, 0.5 eq.), methanol (12.5 mL), tert-butanol (12.5 mL), and water (12.5 mL) were added to a 100 mL round-bottom flask. The reaction was carried out at room temperature for 18 h, and the reaction was monitored by LC-MS. The starting material was basically completely converted. The system was diluted with ethyl acetate (30 mL), filtered, and the filter cake was washed with ethyl acetate (2 x 5 mL). The filtrate was collected and concentrated under reduced pressure. Extraction was carried out with ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with saturated NaCl (50 mL), dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3.59 g of pale yellow oily compound 30-2.

[0749] Compound 30-2 (3.49 g, 8.28 mmol, 1.0 eq.), p-toluenesulfonic acid (0.43 g, 2.48 mmol, 0.3 eq.), and methanol (35 mL) were added to a 100 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was monitored by LC-MS until the reactants were almost completely reacted. The system was then cooled to 0 °C, the reaction was quenched with water (30 mL), concentrated under reduced pressure, and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated NaCl (50 mL), collected, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2.60 g of colorless oily compound 30-3.

[0750] Compound 30-3 (2.60 g, 7.70 mmol, 1.0 eq.), 4-bromobutyric acid (1.54 g, 9.24 mmol, 1.2 eq.), EDCI (1.79 g, 11.56 mmol, 1.5 eq.), DMAP (0.19 g, 1.54 mmol, 0.2 eq.), and DCM (30 mL) were added to a 250 mL round-bottom flask. The reaction was carried out at room temperature for 2 h, and the reaction was monitored by TLC until the reactants were almost completely reacted. DCM (50 mL) and water (100 mL) were added for extraction and separation. The organic phase was washed with saturated NaCl (100 mL), collected, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2.50 g of colorless oily compound 30-4.

[0751] Compound 30 was prepared according to the method of Example 1, yielding 135.4 mg of an oily product.

[0752] 1 H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 2.6 4-2.29(m,10H),1.89-1.82(m,4H),1.65-1.60(m,2H),1.67-1.19(m,46H),0.92-0.88(m,15H); ESI-MS m / z:763.65[M+H] + .

[0753] Example 31: Synthesis of Compound 31

[0754] Compound 31 was prepared according to the method of Example 30, yielding 215.3 mg of an oily product.

[0755] 1H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 3.80-3.76 (m, 4H), 2.67 (s, 2H), 2.48-2.29(m,8H),1.89-1.82(m,4H),1.78-1.58(m,6H),1.49-1.23(m,44H),0.94-0.88(m,15H); ESI-MS m / z:777.60[M+H] + .

[0756] Example 32: Synthesis of Compound 32

[0757] Compound 32 was prepared according to the method of Example 30, yielding 137.1 mg of an oily product.

[0758] 1 H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 3.78 (s, 2H), 3.57 (s, 2H),2.50-2.29(m,10H),1.89-1.50(m,12H),1.48-1.26(m,44H),0.94-0.89(m,15H); ESI-MS m / z:791.65[M+H] + .

[0759] Example 33: Synthesis of Compound 33

[0760] Compound 33 was prepared according to the method of Example 30, yielding 195.4 mg of an oily product.

[0761] 1 H NMR (300MHz, CDCl3) δ: 7.61 (s, 1H), 5.22 (s, 2H), 4.32 (t, J = 7.5Hz, 2H), 3.78 (s, 2H), 3.56 (s, 2H), 2.6 2-2.29(m,10H),1.90-1.80(m,4H),1.65-1.46(m,4H),1.44-1.24(m,42H),0.96-0.90(m,15H); ESI-MS m / z:749.60[M+H] + .

[0762] Example 34: Synthesis of Compound 34

[0763] Compound 34 was prepared according to the method of Example 30, yielding 172.9 mg of an oily product.

[0764] 1 H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.32 (t, J = 7.5Hz, 2H), 3.80-3.76 (m, 4H), 2.65 (t, J = 5.1Hz, 2H), 2.49 -2.29(m,8H),1.93-1.82(m,4H),1.79-1.66(m,4H),1.52-1.44(m,2H),1.42-1.21(m,42H),0.93-0.88(m,15H); ESI-MS m / z:763.60[M+H] + .

[0765] Example 35: Synthesis of Compound 35

[0766] Compound 35 was prepared according to the method of Example 30, yielding 152.8 mg of an oily product.

[0767] 1 H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.32 (t, J = 7.5Hz, 2H), 3.77 (s, 2H), 3.56 (s, 2H), 2.46-2.29 (m ,10H),1.93-1.82(m,4H),1.79-1.60(m,6H),1.58-1.48(m,2H),1.43-1.23(m,42H),0.91-0.88(m,15H); ESI-MS m / z:777.60[M+H] + .

[0768] Example 36: Synthesis of Compound 36

[0769] In a 250 mL round-bottom flask, 3-heptyldecyl alcohol (2.5 g, 9.75 mmol, 1.0 eq.) and PPh3 (2.81 g, 10.72 mmol, 1.1 eq.) were dissolved in 80 mL of tetrahydrofuran. After cooling the system to 0 °C, DIAD (2.17 g, 10.72 mmol, 1.1 eq.) was added dropwise, followed by stirring for 30 min. Then, DPPA (2.90 g, 10.53 mmol, 1.08 eq.) was added dropwise, and the ice bath was removed after the addition was complete. The reaction was allowed to proceed overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction solution was concentrated under reduced pressure, slurried with petroleum ether (150 mL), filtered, and the filter cake was washed with petroleum ether (2 x 20 mL). The filtrate was collected and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 2.0 g of a colorless, transparent oily compound 36-1.

[0770] In a 250 mL round-bottom flask, compound 36-1 (2.0 g, 7.11 mmol, 1.0 eq.), 1-yntynebutanol (0.50 g, 7.115 mmol, 1.0 eq.), anhydrous copper sulfate (0.57 g, 3.55 mmol, 0.5 eq.), and sodium ascorbate (0.70 g, 3.55 mmol, 0.5 eq.) were dissolved in a mixed solvent of methanol (10 mL), water (10 mL), and tert-butanol (10 mL). The reaction was carried out overnight at room temperature under nitrogen protection, and the reaction was monitored by LC-MS. After the reaction was complete, ethyl acetate (30 mL) was added to the reaction solution to make the reaction homogeneous. The mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The crude product was extracted with ethyl acetate (2 x 50 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.25 g of a light yellow oily product 36-2.

[0771] In a 100 mL round-bottom flask, 36-2 (2.0 g, 5.69 mmol, 1.0 eq.) and TEA (0.86 g, 8.53 mmol, 1.5 eq.) were dissolved in 20 mL of dichloromethane. After cooling to 0 °C, acryloyl chloride (0.72 g, 7.97 mmol, 1.4 eq.) was added over 10 min. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored by TLC. After the reaction was complete, the mixture was extracted with dichloromethane (3 x 10 mL), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain 2 g of a pale yellow oily product, 36-3.

[0772] Add 36-3 (357.33 mg, 0.88 mmol, 1.05 eq.), a hydroxyethyl-substituted amine compound (300 mg, 0.84 mmol, 1.0 eq.), TEA (424.49 mg, 4.20 mmol, 5.0 eq.), and 5 mL of isopropanol to a 20 mL sealed tube. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LC-MS. After the reaction was complete, the reaction solution was redissolved in isopropanol (2 mL) and purified by Prep-HPLC to obtain 289.7 mg of a pale yellow oily compound 36.

[0773] 1 H NMR (300MHz, CDCl3) δ: 7.37 (s, 1H), 4.39-4.30 (m, 4H), 3.78 (s, 2H), 3.55 (t, J = 5.1Hz, 2H), 3.07 (t, J = 6.9Hz, 2H), 2.81 (t, J = 6.9Hz, 2H), 2.59 (t ,J=5.1Hz,2H),2.49-2.43(m,4H),2.32(t,J=7.2Hz,2H),1.87-1.82(m, 2H),1.72-1.59(m,2H),1.46-1.24(m,46H),0.95-0.89(m,15H); ESI-MS m / z:763.60[M+H] + .

[0774] Example 37: Synthesis of Compound 37

[0775] Compound 37 was prepared according to the method of Example 36, yielding 174.7 mg of an oily product.

[0776] 1 H NMR (300MHz, CDCl3) δ: 7.39 (s, 1H), 4.40-4.30 (m, 4H), 3.79-3.75 (m, 4H), 3.08 (t, J = 6.9Hz, 2H), 3.10- 2.50(m,8H),2.32(t,J=7.2Hz,2H),1.88-1.81(m,2H),1.73-1.26(m,50H),0.93-0.86(m,15H); ESI-MS m / z:777.60[M+H] + .

[0777] Example 38: Synthesis of Compound 38

[0778] Compound 38 was prepared according to the method of Example 36, yielding an oily product of 373.4 mg.

[0779] 1 H NMR (300MHz, CDCl3) δ: 7.39 (s, 1H), 4.39-4.30 (m, 4H), 3.77 (s, 2H), 3.58 (s, 2H), 3.07 (t, J = 6.9Hz, 2H), 2.87 (s, 2H), 2.56 -2.51(m,6H),2.32(t,J=7.5Hz,2H),1.88-1.81(m,2H),1.65-1.52(m,6H),1.46-1.23(m,46H),0.92-0.88(m,15H); ESI-MS m / z:791.55[M+H] + .

[0780] Example 39: Synthesis of Compound 39

[0781] Compound 39 was prepared according to the method of Example 30, yielding 248.9 mg of an oily product.

[0782] 1 H NMR (300MHz, CDCl3) δ: 7.56 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 4.03 (t, J = 6.9Hz, 2H), 3.54 (t, J = 5.1Hz ,2H),2.61-2.27(m,10H),1.89-1.80(m,4H),1.77-1.51(m,4H),1.43-1.10(m,44H),0.91-0.85(m,15H); ESI-MS m / z:763.45[M+H] + .

[0783] Example 40: Synthesis of Compound 40

[0784] Compound 40 was prepared according to the method of Example 30, yielding 250.0 mg of an oily product.

[0785] 1 H NMR (300MHz, CD3OD) δ: 8.01 (s, 1H), 5.18 (s, 2H), 4.42 (t, J = 7.5Hz, 2H), 4.04 (t, J = 6.6Hz, 2H), 3.61 (t, J = 6.0Hz, 2H), 2.57 (t ,J=7.2Hz,2H),2.50-2.36(m,6H),2.30(t,J=7.5Hz,2H),1.85-1.55(m,10H),1.43-1.15(m,44H),0.92-0.88(m,15H); ESI-MS m / z:777.55[M+H]+ .

[0786] Example 41: Synthesis of Compound 41

[0787] Compound 41 was prepared according to the method of Example 30, yielding 291.0 mg of an oily product.

[0788] 1 H NMR (300MHz, CDCl3) δ: 7.59 (s, 1H), 5.21 (s, 2H), 4.34 (t, J = 7.5Hz, 2H), 4.03 (t, J = 6.9Hz, 2H), 3.56 (t ,J=5.1Hz,2H),2.50-2.26(m,10H),1.89-1.81(m,4H),1.78-1.15(m,52H),0.94-0.88(m,15H); ESI-MS m / z:791.60[M+H] + .

[0789] Example 42: Synthesis of Compound 42

[0790] Compound 42 was prepared according to the method of Example 30, yielding an oily product of 313.9 mg.

[0791] 1 H NMR (300MHz, CDCl3) δ: 7.59 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 4.03 (t, J=6.9Hz,2H),3.54(t,J=5.1Hz,2H),2.59(t,J=5.1Hz,2H),2.52-2.42(m,4H),2 .35(t,J=7.5Hz,2H),2.28(t,J=7.5Hz,2H),1.89-1.79(m,4H),1.77-1.68(m,4H ),1.59-1.46(m,2H),1.44-1.15(m,42H),0.93-0.88(m,9H),0.27(s,4H); ESI-MS m / z: 761.55 [M+H] + .

[0792] Example 43: Synthesis of Compound 43

[0793] Compound 43 was prepared according to the method of Example 30, yielding an oily product of 333.3 mg.

[0794] 1H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.5Hz, 2H), 4.06 (t, J = 6.9Hz, 2H), 3.77 (t, J = 5.1Hz, 2H), 2.66 ( m,2H),2.48-2.26(m,8H),1.89-1.77(m,4H),1.72-1.48(m,8H),1.44-1.19(m,42H),0.93-0.87(m,9H),0.26(s,4H); ESI-MS m / z:775.55[M+H] + .

[0795] Example 44: Synthesis of Compound 44

[0796] Compound 44 was prepared according to the method of Example 30, yielding 234.5 mg of an oily product.

[0797] 1 H NMR (300MHz, CDCl3) δ: 7.59 (s, 1H), 5.21 (s, 2H), 4.34 (t, J = 7.5Hz, 2H), 4.05 (t, J = 6.9Hz, 2H), 3.56 (t, J = 5. 1Hz,2H),2.49-2.25(m,10H),1.89-1.77(m,4H),1.75-1.19(m,52H),0.93-0.87(m,9H),0.25(s,4H); ESI-MS m / z:789.65[M+H] + .

[0798] Example 45: Synthesis of Compound 45

[0799] In a 100 mL round-bottom flask, 2-butylhexanol (1.12 g, 7.10 mmol, 1.0 eq.), 3-azidopropionic acid (0.90 g, 7.81 mmol, 1.1 eq.), EDCI (1.65 g, 10.65 mmol, 1.5 eq.), DMAP (0.87 g, 7.10 mmol, 1.0 eq.), and dichloromethane (12 mL) were added. The reaction was carried out at room temperature for 1 h, and the reaction was monitored by TLC until the starting material was completely converted. The reaction mixture was poured into 50 mL of water, extracted with dichloromethane (3 x 30 mL), and the organic phase was collected and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to give 415 mg of a pale yellow oily compound 45-1.

[0800] Compound 45-1 (415 mg, 1.63 mmol, 1.0 eq.), 8-bromo-1-octyne (307.31 mg, 1.63 mmol, 1.0 eq.), anhydrous copper sulfate (129.69 mg, 0.82 mmol, 0.5 eq.), and sodium ascorbate (160.98 mg, 0.82 mmol, 0.5 eq.) were dissolved in a mixture of methanol (2 mL), tert-butanol (2 mL), and water (2 mL) in a 40 mL sealed tube. The reaction was carried out at room temperature for 18 h, and the reaction was monitored by LC-MS until the starting materials were basically completely converted. The system was diluted with ethyl acetate (10 mL), filtered, and the filter cake was washed with ethyl acetate (2 x 5 mL). The filtrate was collected and concentrated under reduced pressure. Extraction was carried out with ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with saturated NaCl (50 mL), collected, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 611.1 mg of a yellow oily compound 45-2.

[0801] Compound 45-2 (203.6 mg, 0.46 mmol, 1.0 eq.), a hydroxyethyl-substituted amine compound (196.56 mg, 0.55 mmol, 1.2 eq.), potassium carbonate (189.93 mg, 1.38 mmol, 3.0 eq.), and potassium iodide (91.25 mg, 0.55 mmol, 1.2 eq.) were added to a 40 mL sealed tube and dissolved in a mixed solvent of CPME (3 mL) and acetonitrile (1 mL). The system was heated to 80 °C and reacted for 18 h. The reaction was monitored by LC-MS until the starting material was almost completely reacted. After cooling to room temperature, the system was filtered. The filter cake was washed with ethyl acetate (2 x 5 mL), and the filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain 148.8 mg of a pale yellow oily compound 45-2.

[0802] 1 H NMR(300MHz, CDCl3)δ:7.36(s,1H),4.61(t,J=6.6Hz,2H),4.00(t,J=6.0Hz,2H),3.78(s,2H),3.56(m,2H),2.96(t,J=6.6Hz,2H ),2.69(t,J=7.5Hz,2H),2.62(s,2H),2.57-2.49(m,4H),2.32(t,J=7.5Hz,2H),1.72-1.24(m,44H),0.95-0.89(m,15H); ESI-MS m / z:721.55[M+H] + .

[0803] Example 46: Synthesis of Compound 46

[0804] Compound 46 was prepared according to the method of Example 45, yielding 176.2 mg of an oily product.

[0805] 1 H NMR (400MHz, CDCl3) δ: 7.37 (s, 1H), 4.61 (t, J = 7.2Hz, 2H), 4.00 (t, J = 6.0Hz, 2H), 3.81-3.78 (m, 4H), 2.96 (t, J = 6.6H) z,2H),2.71-2.63(m,4H),2.52-2.45(m,4H),2.32(t,J=7.5Hz,2H),1.72-1.24(m,46H),0.95-0.89(m,15H); ESI-MS m / z:735.60[M+H] + .

[0806] Example 47: Synthesis of Compound 47

[0807] Compound 47 was prepared according to the method of Example 45, yielding 185.9 mg of an oily product.

[0808] 1 H NMR (400MHz, CDCl3) δ: 7.36 (s, 1H), 4.61 (t, J = 7.2Hz, 2H), 4.00 (t, J = 5.7Hz, 2H), 3.77 (s, 2H), 3.56 (s, 2H), 2.96 (t, J = 6.6Hz,2H),2.69(t,J=7.5Hz,2H),2.49(s,6H),2.32(t,J=7.5Hz,2H),1.72-1.25(m,48H),0.93-0.88(m,15H); ESI-MS m / z:749.55[M+H] + .

[0809] Example 48: Synthesis of Compound 48

[0810] Compound 48 was prepared according to the method of Example 30, yielding 58.6 mg of an oily product.

[0811] 1H NMR (400MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 4.09 (t, J = 7.8Hz, 2H), 3.78 (t, J = 5.1Hz, 2H), 2.71 (s, 2H ),2.52(s,4H),2.37(t,J=7.2Hz,2H),2.28(t,J=7.5Hz,2H),1.89-1.82(m,6H),1.72-1.23(m,48H),0.94-0.88(m,15H); ESI-MS m / z:777.60[M+H] + .

[0812] Example 49: Synthesis of Compound 49

[0813] Compound 49 was prepared according to the method of Example 1, yielding 154.2 mg of an oily product.

[0814] 1 H NMR (400MHz, CDCl3) δ: 7.26 (s, 1H), 4.28 (t, J = 7.6Hz, 2H), 4.05 (t, J = 6.8Hz, 2H), 3.55 (s, 2H), 2.70 (t, J = 7.6Hz, 2H), 2. 44(s,6H),2.29(t,J=7.6Hz,2H),1.89-1.82(m,2H),1.71-1.61(m,10H),1.59-1.21(m,50H),0.94-0.88(m,9H); ESI-MS m / z:733.55[M+H] + .

[0815] Example 50: Synthesis of Compound 50

[0816] Compound 50 was prepared according to the method of Example 1, yielding 124.4 mg of an oily product.

[0817] 1 H NMR (300MHz, CDCl3) δ: 7.26 (s, 1H), 4.28 (t, J = 7.5Hz, 2H), 4.05 (t, J = 6.9Hz, 2H), 3.55 (s, 2H), 2.70 (t, J = 7.5Hz, 2H), 2. 44(s,6H),2.29(t,J=7.5Hz,2H),1.90-1.81(m,2H),1.72-1.61(m,10H),1.59-1.21(m,50H),0.94-0.88(m,9H); ESI-MS m / z:733.60[M+H]+ .

[0818] Example 51: Synthesis of Compound 51

[0819] Compound 51 was prepared according to the method of Example 30, yielding 215.2 mg of an oily product.

[0820] 1 H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 4.05 (t, J = 6.9Hz, 2H), 3.58 (s, 2H), 2.66-2.53 (m, 6H), 2 .37(t,J=7.2Hz,2H),2.29(t,J=7.5Hz,2H),1.89-1.82(m,4H),1.64-1.59(m,4H),1.48-1.26(m,46H),0.94-0.88(m,9H); ESI-MS m / z:735.60[M+H] + .

[0821] Example 52: Synthesis of Compound 52

[0822] Compound 52 was prepared according to the method of Example 30, yielding 199.8 mg of an oily product.

[0823] 1 H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 4.05 (t, J = 6.6Hz, 2H), 3.77 (t, J = 5.1Hz, 2H), 2.65 (t,J=5.7Hz,2H),2.49-2.26(m,8H),1.89-1.82(m,4H),1.79-1.61(m,6H),1.55-1.21(m,46H),0.94-0.88(m,9H); ESI-MS m / z:749.60[M+H] + .

[0824] Example 53: Synthesis of Compound 53

[0825] Compound 53 was prepared according to the method of Example 30, yielding 243.8 mg of an oily product.

[0826] 1H NMR (300MHz, CDCl3) δ: 7.60 (s, 1H), 5.22 (s, 2H), 4.34 (t, J = 7.8Hz, 2H), 4.05 (t, J = 6.6Hz, 2H), 3.57 (s, 2H), 2.51 (s, 6H), 2.36 (t,J=7.2Hz,2H),2.29(t,J=7.2Hz,2H),1.89-1.82(m,4H),1.65-1.50(m,10H),1.46-1.23(m,44H),0.94-0.88(m,9H); ESI-MS m / z:763.60[M+H] + .

[0827] Example 54: Synthesis of Compound 54

[0828] Compound 54-1 (1.2 g, 3.20 mmol, 1.0 eq.), 4-methoxybenzylamine (8.77 g, 64.00 mmol, 20.0 eq.), and ethanol (12 mL) were added to a 40 mL sealed tube. The reaction was heated to 70 °C and allowed to proceed overnight. The reaction was monitored by LC-MS. After concentration, 20 mL of water was added, and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 54-2 (1.36 g), which could be used directly in the next step without further purification.

[0829] Compounds 54-2 (500 mg, 1.16 mmol, 1.0 eq.), 54-3 (555.28 mg, 1.22 mmol, 1.05 eq.), KI (230.74 mg, 1.39 mmol, 1.2 eq.), and K₂CO₃ (800.43 mg, 5.79 mmol, 5.0 eq.) were added to a 50 mL round-bottom flask and dissolved in a mixed solvent of acetonitrile (2 mL) and CPME (2 mL). The mixture was heated to 80 °C and reacted overnight, with the reaction monitored by LC-MS. After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3 x 5 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 444 mg of the pale yellow oily product 54-4.

[0830] Compound 54-4 (444 mg, 0.55 mmol, 1.0 eq.), isopropanol (5 mL), and Pd / C (450 mg, 4.23 mmol, 7.69 eq.) were added to a 100 mL round-bottom flask. The mixture was purged three times with hydrogen gas and reacted overnight under a hydrogen atmosphere, monitored by LC-MS until complete. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (6 x 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain crude 54-5 (355 mg), which was directly added to the next step.

[0831] In a 50 mL round-bottom flask, compound 54-5 (355 mg, 0.52 mmol, 1.0 eq.) and BTC (153.30 mg, 0.52 mmol, 1.0 eq.) were dissolved in dichloromethane (5 mL). After cooling the system to 0 °C, pyridine (204.33 mg, 2.60 mmol, 5.0 eq.) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then 5 mL of pyridine was added to redissolve the solvent. The mixture was then cooled to 0 °C, and 4-mercapto-N,N-dimethylbutylamine (438.38 mg, 2.60 mmol, 5.0 eq.) was added rapidly. The reaction was allowed to proceed at room temperature for 48 hours. The reaction was monitored by LC-MS, and the starting material was almost completely converted. The mixture was extracted with ethyl acetate (3 x 10 mL), and the combined organic phases were washed with saturated sodium chloride aqueous solution (3 x 10 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography to obtain 181.4 mg of a light yellow oily compound 54.

[0832] 1 H NMR (400MHz, CD3OD) δ: 7.73 (s, 1H), 4.34 (t, J = 6.8Hz, 2H), 4.06 (t, J = 6.8Hz, 2H), 3.31 (m, 2H), 2.90 (t, J = 6.8Hz, 2H), 2.70 (t, J = 7.6Hz, 2H),2.36-2.28(m,4H),2.23(s,6H),1.90-1.82(m,2H),1.76-1.53(m,14H),1.42-1.19(m,45H),0.94-0.88(m,9H),0.27(s,4H); ESI-MS m / z:846.60[M+H] + .

[0833] Example 55: Synthesis of Compound 55

[0834] Compound 55 was prepared according to the method of Example 54, yielding 220.0 mg of an oily product.

[0835] 1H NMR (300MHz, CD3OD) δ: 7.73 (s, 1H), 4.34 (t, J = 6.9Hz, 2H), 4.06 (t, J = 6.6Hz, 2H), 3.31 (m, 2H), 2.89 (t, J = 6.6Hz, 2H), 2.70 (t, J = 7 .5Hz,2H),2.36-2.28(m,4H),2.23(s,6H),1.89-1.83(m,2H),1.71-1.61(m,14H),1.52-1.23(m,47H),0.94-0.89(m,9H); ESI-MS m / z:820.60[M+H] + .

[0836] Example 56: Synthesis of Compound 56

[0837] Compound 56 was prepared according to the method of Example 54, yielding 173.5 mg of an oily product.

[0838] 1 H NMR(300MHz, CD3OD)δ:7.73(s,1H),4.34(t,J=6.6Hz,2H),4.06(t,J=6.6Hz,2H),3.31(m,2H),2.89(t,J=6.6Hz,2H),2.70(t,J=7 .5Hz,2H),2.36-2.28(m,4H),2.23(s,6H),1.89-1.81(m,2H),1.71-1.61(m,14H),1.48-1.24(m,47H),0.94-0.89(m,9H); ESI-MS m / z:820.60[M+H] + .

[0839] Example 57: Synthesis of Compound 57

[0840] Compound 57 was prepared according to the method of Example 54, yielding 289.5 mg of an oily product.

[0841] 1H NMR (300MHz, CD3OD) δ: 7.72 (s, 1H), 4.35 (t, J = 6.9Hz, 2H), 4.06 (t, J = 6.6Hz, 2H), 3.32 (m, 2H), 2.90 (t, J = 6.6Hz, 2H), 2.69 (t, J = 7.5Hz, 2H),2.35-2.27(m,4H),2.23(s,6H),1.88-1.80(m,2H),1.68-1.61(m,14H),1.50-1.23(m,36H),0.94-0.89(m,6H),0.28(s,4H); ESI-MS m / z:762.45[M+H] + .

[0842] Example 58: Synthesis of Compound 58

[0843] In a 100 mL round-bottom flask, 3.0 g of 4-hexyldecyl alcohol (12.37 mmol, 1.0 eq.) and 12.98 g of triphenylphosphine (49.48 mmol, 4.0 eq.) were dissolved in 30 mL of tetrahydrofuran. The reaction mixture was cooled to 0 °C, and then carbon tetrabromide (8.21 g, 24.74 mmol, 2.0 eq.) was added in portions. The mixture was then brought to room temperature and stirred overnight. The solution was evaporated to dryness, slurried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2.8 g of a yellow oily compound 58-1.

[0844] Compound 58-1 (2.8 g, 19.98 mmol, 1.0 eq.), ethyl 4-pyrazolate (7.32 g, 23.97 mmol, 1.2 eq.), and potassium carbonate (8.28 g, 59.94 mmol, 3.0 eq.) were dissolved in 28 mL of acetonitrile in a 40 mL sealed tube. The reaction mixture was heated to 60 °C and stirred overnight. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 x 10 mL), washed with saturated NaCl (10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was collected and concentrated. The crude product was purified by silica gel column chromatography to give 2.2 g of a yellow oily compound 58-2.

[0845] Lithium aluminum hydride solution (2.5 M, 1.93 mL) was slowly added dropwise to a THF solution of 58-2 (2.2 g, 6.03 mmol, 1.0 eq.) in 22 mL of ice bath. After the addition was complete, the reaction system was stirred at room temperature for 2 hours. The reaction was quenched by adding crystalline sodium sulfate (985 mg) at 0 °C, followed by extraction with 3N hydrochloric acid (20 mL) and dichloromethane (3 x 20 mL). The organic phase was washed with saturated NaCl (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain crude yellow oily compound 58-3 (1.64 g). No purification was required, and it was used directly in the next reaction.

[0846] In a 50 mL round-bottom flask, 58-3 (1.64 g crude), triethylamine (1.54 g, 15.26 mmol, 3.0 eq.), and dichloromethane (20 mL) were added. After cooling the reaction mixture to 0 °C, 4-bromobutyryl chloride (1.41 g, 7.63 mmol, 1.5 eq.) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL), extracted with dichloromethane (3 x 20 mL), washed with saturated NaCl (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.45 g of a yellow oily compound, 58-4.

[0847] Add 58-4 (395.60 mg, 0.84 mmol, 1.0 eq.), hydroxyethyl substituted amine (300 mg, 0.84 mmol, 1.0 eq.), potassium iodide (167.13 mg, 1.01 mmol, 1.2 eq.), potassium carbonate (347.85 mg, 2.52 mmol, 3.0 eq.), and acetonitrile (3 mL) to an 8 mL sealed tube. Heat the system to 80 °C and react overnight. Monitor the reaction by LC-MS. Cool the reaction system to room temperature. Filter, wash the filter cake with acetonitrile, collect the organic phase, concentrate to obtain the crude product, and purify the crude product by HPLC to obtain a pale yellow oily compound 58 (193.5 mg).

[0848] 1 H NMR (400MHz, CDCl3) δ: 7.51 (s, 1H), 7.44 (s, 1H), 5.01 (s, 2H), 4.05 (t, J = 7.6Hz, 2H), 3.78 (s, 2H), 2.3 8-2.30(m,4H),1.84-1.80(m,2H),1.64-1.57(m,8H),1.29-1.21(m,48H),0.89-0.86(m,15H); ESI-MS m / z:748.55[M+H] + .

[0849] Example 59: Synthesis of Compound 59

[0850] Compound 59 was prepared according to the method of Example 58, yielding 230.0 mg of an oily product.

[0851] 1 H NMR (400MHz, CDCl3) δ: 7.50 (s, 1H), 7.44 (s, 1H), 5.01 (s, 2H), 4.05 (t, J = 7.6Hz, 2H), 3.81-3.78 (m, 4H), 2 .35-2.30(m,4H),1.84-1.80(m,2H),1.64-1.57(m,10H),1.29-1.21(m,46H),0.89-0.88(m,15H); ESI-MS m / z:762.60[M+H] + .

[0852] Example 60: Synthesis of Compound 60

[0853] Compound 60 was prepared according to the method of Example 58, yielding 258.2 mg of an oily product.

[0854] 1 H NMR (400MHz, CDCl3) δ: 7.50 (s, 1H), 7.44 (s, 1H), 5.00 (s, 2H), 4.05 (t, J = 7.2Hz, 2H), 3.78-3.60 (m, 4H), 2 .34-2.30(m,4H),1.86-1.78(m,2H),1.66-1.59(m,12H),1.33-1.21(m,46H),0.91-0.89(m,15H); ESI-MS m / z:776.60[M+H] + .

[0855] Example 61: Synthesis of Compound 61

[0856] In a 250 mL round-bottom flask, 61-1 (8.6 g, 33.53 mmol, 1.0 eq.) and PPh3 (10.55 g, 40.24 mmol, 1.2 eq.) were dissolved in 80 mL of tetrahydrofuran. After cooling the system to 0 °C, CBr4 (12.23 g, 36.89 mmol, 1.1 eq.) was added in portions. The system was allowed to warm to room temperature naturally and stirred for 1 h. The reaction was monitored by TLC, and the starting material was completely converted. The mixture was concentrated under reduced pressure, slurried with petroleum ether, filtered, and the filter cake was washed with petroleum ether (3 x 5 mL). The filtrate was collected and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 10.6 g of a pale yellow oily compound 61-2.

[0857] In a 500 mL round-bottom flask, trimethylsilylacetylene (3.88 g, 39.45 mmol, 4.5 eq.) was dissolved in 80 mL of tetrahydrofuran. The system was cooled to -78 °C, and n-butyllithium (2.25 g, 35.07 mmol, 4.0 eq.) was added dropwise. After stirring for 5 min, the system was slowly heated to room temperature and stirred for another 15 min. The system was then cooled to -50 °C, and a THF solution of compound 61-2 (2.8 g, 8.77 mmol, 1.0 eq.) and DMPU (6.18 g, 48.22 mmol, 5.5 eq.) was added dropwise. The system was stirred at -78 °C for 30 min, then heated to room temperature and stirred for another 18 h. The reaction was monitored by TLC, and the starting material was completely converted. The system was cooled to 0°C, and the reaction was quenched by adding ice water (100 mL). The organic solvent was removed by concentration under reduced pressure. The mixture was extracted and separated by adding ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated NaCl solution (3 x 100 mL). The organic phases were collected, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 2.5 g of colorless oily compound 61-3.

[0858] Under ice bath conditions, TBAF (7.5 mL, 1 M, 1.0 eq.) was added dropwise to a tetrahydrofuran solution of compound 61-3 (2.5 g, 7.43 mmol, 1.0 eq.) in a 100 mL round-bottom flask. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC, and the starting material was completely converted. The reaction was quenched with water (20 mL), concentrated under reduced pressure to remove the organic solvent, extracted with ethyl acetate (2 x 40 mL), and the organic phases were combined and washed with saturated NaCl (2 x 40 mL). The organic phases were collected, dried, filtered, and concentrated to give 2.02 g of crude product 61-4, which was used directly in the next step without further purification.

[0859] Compound 61-4 (1 g, 3.78 mmol, 1.0 eq.), 6-bromohexyl azide (0.78 g, 3.78 mmol, 1.0 eq.), anhydrous copper sulfate (0.30 g, 1.89 mmol, 0.5 eq.), sodium ascorbate (0.37 g, 1.89 mmol, 0.5 eq.), methanol (5 mL), tert-butanol (5 mL), and water (5 mL) were added to a 40 mL sealed tube at room temperature. The reaction was allowed to proceed at room temperature for 18 h, and the reaction was monitored by LC-MS until the starting material was almost completely converted. The system was diluted with ethyl acetate (20 mL), filtered, and the filter cake was washed with ethyl acetate (2 x 5 mL). The mixture was concentrated under reduced pressure, and extracted with ethyl acetate (2 x 30 mL) and water (30 mL). The organic phase was washed with saturated NaCl, collected, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.3 g of yellow oily compound 61-5.

[0860] Compound 61 was prepared according to the method of Example 1, yielding 153.8 mg of an oily product.

[0861] 1 H NMR (300MHz, CDCl3) δ: 7.25 (s, 1H), 4.31 (d, J = 7.2Hz, 2H), 3.78 (s, 2H), 3.63 (s, 2H), 2.71-2.56 ( m,7H),2.32(t,J=7.2Hz,2H),1.92-1.90(m,2H),1.65-1.25(m,57H),0.89-0.86(m,15H); ESI-MS m / z:747.65[M+H] + .

[0862] Example 62: Synthesis of Compound 62

[0863] Compound 62 was prepared according to the method of Example 61, yielding 121.6 mg of an oily product.

[0864] 1 H NMR (300MHz, CDCl3) δ: 7.25 (s, 1H), 4.30 (t, J = 7.2Hz, 2H), 3.78 (s, 2H), 3.60 (s, 2H), 2.71-2.53 (m, 6H), 2. 32(t,J=7.2Hz,2H),1.92-1.88(m,2H),1.67-1.58(m,12H),1.46-1.26(m,50H),0.90-0.88(m,15H); ESI-MS m / z:775.65[M+H] + .

[0865] Example 63: Synthesis of Compound 1b

[0866] In a round-bottom flask, 3-heptyldecyl alcohol (2.9 g, 11.31 mmol, 1.0 eq.) and PPh3 (3.26 g, 12.44 mmol, 1.1 eq.) were dissolved in tetrahydrofuran (87 mL). The system was cooled to 0 °C, and DIAD (2.52 g, 12.44 mmol, 1.1 eq.) was added dropwise. After stirring at 0 °C for 30 min, DPPA (3.36 g, 12.21 mmol, 1.08 eq.) was added dropwise. The reaction was continued at room temperature for 18 h, and the reaction was monitored by TLC until the reactants were almost completely reacted. The mixture was concentrated under reduced pressure, redissolved in petroleum ether (100 mL), slurried, filtered, and the filter cake was washed with petroleum ether (15 mL x 2). The filtrate was collected and concentrated. The crude product was purified by silica gel column chromatography to give 2.43 g of a colorless oily compound 1b-1.

[0867] Compound 1b-1 (2.43 g, 8.63 mmol, 1.0 eq.), 2-(2-propoxy)tetrahydropyran (1.21 g, 8.63 mmol, 1.0 eq.), anhydrous copper sulfate (0.69 g, 4.32 mmol, 0.5 eq.), sodium L-ascorbate (0.86 g, 4.32 mmol, 0.5 eq.), methanol (12.5 mL), tert-butanol (12.5 mL), and water (12.5 mL) were added to a round-bottom flask. The reaction was allowed to proceed at room temperature for 18 h, and the reaction was monitored by LC-MS until the starting material was almost completely converted. The system was diluted with ethyl acetate (30 mL), filtered, and the filter cake was washed with ethyl acetate (15 mL x 2). The filtrate was collected and concentrated under reduced pressure. Extraction was performed with ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 3.59 g of a pale yellow oily compound 1b-2.

[0868] Compound 1b-2 (3.49 g, 8.28 mmol, 1.0 eq.), p-toluenesulfonic acid (0.43 g, 2.48 mmol, 0.3 eq.), and methanol (35 mL) were added to a 100 mL round-bottom flask. The reaction was allowed to proceed at room temperature for 2 h, and the reaction was monitored by LC-MS until the reactants were almost completely reacted. The system was then cooled to 0 °C, and the reaction was quenched with water (30 mL). The mixture was concentrated under reduced pressure, and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated sodium chloride aqueous solution (80 mL), collected, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2.60 g of colorless oily compound 1b-3.

[0869] Compound 1b-3 (2.60 g, 7.70 mmol, 1.0 eq.), 6-bromohexanoic acid (1.80 g, 9.24 mmol, 1.2 eq.), EDCI (1.79 g, 11.56 mmol, 1.5 eq.), DMAP (0.19 g, 1.54 mmol, 0.2 eq.), and dichloromethane (30 mL) were added to a round-bottom flask. The reaction was carried out at room temperature for 2 h, and the reaction was monitored by TLC until the reactants were almost completely reacted. Dichloromethane (50 mL) and water (100 mL) were added for extraction and separation. The organic phase was washed with saturated sodium chloride aqueous solution (100 mL), collected, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2.58 g of colorless oily compound 1b-4.

[0870] Compound 1b-5 (8.65 g, 34.44 mmol, 1.0 eq.) was dissolved in tetrahydrofuran in a reaction flask. The system was cooled to 0 °C and a borane-tetrahydrofuran solution (1.0 M, 90 mL, 89.54 mmol, 2.6 eq.) was added dropwise. After the addition was complete, the system was heated to 75 °C and reacted for 18 h. After the reaction was complete, the system was cooled to 0 °C, and the reaction was quenched by adding saturated NaHCO3 (50 mL). The mixture was then concentrated. The mixture was extracted with ethyl acetate (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), and the organic phase was collected and dried over anhydrous Na2SO4. The mixture was filtered and concentrated to give 8.07 g of yellow oily crude product 1b-6, which was used directly in subsequent reactions without further purification.

[0871] Compound 1b-6 (4.04 g, crude) was dissolved in dichloromethane in a round-bottom flask at room temperature. Decanoic acid (3.43 g, 19.89 mmol), EDCI (4.21 g, 27.12 mmol), and DMAP (0.44 g, 3.62 mmol) were then added. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by TLC until the reactants were almost completely reacted. The mixture was extracted with saturated NH4Cl aqueous solution (50 mL), followed by extraction with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (100 mL), collected, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give 6.21 g of a colorless oily compound 1b-7.

[0872] Compound 1b-7 (1.0 g, 2.66 mmol, 1.0 eq.) and ethanolamine (3.24 g, 53.20 mmol, 20.0 eq.) were dissolved in ethanol in a 40 mL sealed tube. The system was heated to 70 °C and reacted for 3 h. The reaction was monitored by LC-MS until the reactants were almost completely reacted. The system was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (30 mL x 3) and water (30 mL). The organic phase was washed with water (50 mL x 2), collected, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give 870.2 mg of yellow oily compound 1b-8.

[0873] Compound 1b-4 (395.75 mg, 0.77 mmol, 1.1 eq.) and compound 1b-8 (250 mg, 0.70 mmol, 1.0 eq.) dissolved in a mixed solution of CPME (3 mL) and acetonitrile (1 mL) were added to a 40 mL sealed tube at room temperature. Then, potassium carbonate (289.88 mg, 2.10 mmol, 3.0 eq.) and potassium iodide (139.27 mg, 0.84 mmol, 1.2 eq.) were added. The system was heated to 80 °C and stirred for 18 h. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (5 mL x 2), concentrated under reduced pressure, and extracted with ethyl acetate (30 mL x 3) and water (30 mL). The organic phase was washed with saturated sodium chloride solution (30 mL), collected, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC to obtain 181.2 mg of a pale yellow oily compound 1b.

[0874] 1 H NMR(300MHz, CDCl3)δ:0.86-0.92(m,15H),1.25-1.48(m,50H),1.59-1.69(m,4H),1.81-1.88(m,2H),2.29-2.36(m,4H),2.46( t,J=7.2Hz,4H),2.59(t,J=5.4Hz,2H),3.54(t,J=5.4Hz,2H),3.78(s,2H),4.32-4.37(m,2H),5.21(s,2H),7.59(s,1H); ESI-MS m / z:791.75[M+H] + .

[0875] Example 64: Synthesis of compound 2b

[0876] Compound 2b was prepared according to the method of Example 63, yielding 241.7 mg of an oily compound.

[0877] 1 H NMR(300MHz, CDCl3)δ:0.88-0.95(m,15H),1.26-1.40(m,46H),1.46-1.50(m,4H),1.60-1.69(m,6H),1.84-1.87(m,2H),2.29-2 .36(m,4H),2.42(t,J=7.5Hz,4H),2.65(t,J=5.4Hz,2H),3.78-3.80(m,4H),4.32-4.37(m,2H),5.21(s,2H),7.59(s,1H); ESI-MS m / z:805.85[M+H]+ .

[0878] Example 65: Synthesis of compound 3b

[0879] Compound 3b was prepared according to the method of Example 63, yielding 229.3 mg of an oily compound.

[0880] 1 H NMR(300MHz, CDCl3)δ:0.88-0.96(m,15H),1.26-1.40(m,46H),1.43-1.50(m,4H),1.60-1.69(m,8H),1.82-1.89(m,2H),2.29 -2.36(m,4H),2.42-2.47(m,6H),3.55(t,J=5.1Hz,2H),3.78(s,2H),4.34(t,J=7.8Hz,2H),5.21(s,2H),7.59(s,1H); ESI-MS m / z:819.80[M+H] + .

[0881] Example 66: Synthesis of compound 4b

[0882] Compound 4b was prepared according to the method of Example 63, yielding 144.6 mg of an oily compound.

[0883] 1 H NMR(300MHz, CDCl3)δ:0.88-0.95(m,15H),1.26-1.45(m,58H),1.60-1.66(m,4H),1.81-1.88(m,2H),2.32(t,J=7.5Hz,4H),2.47 (t,J=6.9Hz,4H),2.60(t,J=5.4Hz,2H),3.55(t,J=5.1Hz,2H),3.78(s,2H),4.32-4.37(m,2H),5.21(s,2H),7.58(s,1H); ESI-MS m / z:848.15[M+H] + .

[0884] Example 67: Synthesis of compound 5b

[0885] Compound 5b was prepared according to the method of Example 63, yielding 272.3 mg of an oily compound.

[0886] 1H NMR(300MHz, CDCl3)δ:0.88-0.96(m,15H),1.26-1.41(m,54H),1.43-1.47(m,4H),1.61-1.71(m,6H),1.81-1.88(m,2H),2.32(t ,J=7.8Hz,4H),2.40-2.44(m,4H),2.64(t,J=5.1Hz,2H),3.78-3.81(m,4H),4.32-4.37(m,2H),5.21(s,2H),7.58(s,1H); ESI-MS m / z:861.75[M+H] + .

[0887] Example 68: Synthesis of compound 6b

[0888] Compound 6b was prepared according to the method of Example 63, yielding 247.4 mg of an oily compound.

[0889] 1 H NMR(300MHz, CDCl3)δ:0.86-0.92(m,15H),1.26-1.40(m,56H),1.42-1.48(m,4H),1.61-1.66(m,6H),1.81-1.88(m,2H),2.31( ESI-MS m / z:875.85[M+H] + .

[0890] Example 69: Synthesis of compound 7b

[0891] Compound 7b was prepared according to the method of Example 63, yielding 77.9 mg of an oily compound.

[0892] 1H NMR(300MHz, CDCl3)δ:0.87-0.92(m,9H),1.25-1.42(m,44H),1.44-1.93(m,12H),2.30(t,J=7.5Hz,2H),2.34(t,J=7.5Hz,2H),2.43-2.48(m,4H ),2.64-2.68(m,2H),3.56(t,J=5.1Hz,2H),3.78(t,J=5.1Hz,2H),3.96(d,J=5.7Hz,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.59(s,1H); ESI-MS m / z:749.65[M+H] + .

[0893] Example 70: Synthesis of Compound 8b

[0894] Compound 8b was prepared according to the method of Example 63, yielding 189.4 mg of an oily compound.

[0895] 1 H NMR(300MHz, CDCl3)δ:0.86-0.92(m,9H),1.26-1.54(m,44H),1.55-1.79(m,6H),1.82-1.93(m,4H),2.28(t,J=7.5Hz,2H),2.36(t,J=7.5Hz,2 ESI-MS m / z:735.65[M+H] + .

[0896] Example 71: Synthesis of compound 9b

[0897] Following the method of Example 63, compound 9b was prepared, yielding 125.9 mg of an oily compound.

[0898] 1H NMR(300MHz, CDCl3)δ:0.88-0.96(m,12H),1.26-1.48(m,55H),1.56-1.80(m,6H),1.82-1.89(m,4H),2.28(t,J=7.5Hz,2H),2.35(t,J=7.5Hz ,2H),2.45-2.49(m,4H),2.63-2.67(m,2H),3.78(t,J=5.1Hz,2H),4.08(t,J=7.2Hz,2H),4.32-4.37(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:833.75[M+H] + .

[0899] Example 72: Synthesis of Compound 10b

[0900] Following the method of Example 63, compound 10b was prepared, yielding 236.5 mg of an oily compound.

[0901] 1 H NMR (300MHz, CDCl3) δ: 0.86-0.94 (m, 18H), 1.26-1.58 (m, 53H), 1.60-1.69 (m, 2H), 1.82-1.89 (m, 4H), 2.30 (t, J = 7.5Hz, 2H), 2. 36(t,J=7.2Hz,2H),2.45-2.61(m,6H),3.56(t,J=5.1Hz,2H),3.78(s,2H),4.32-4.37(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:833.75[M+H] + .

[0902] Example 73: Synthesis of compound 11b

[0903] Compound 11b was prepared according to the method of Example 63, yielding 214.3 mg of an oily compound.

[0904] 1H NMR(300MHz, CDCl3)δ:0.86-0.92(m,18H),1.26-1.42(m,51H),1.49-1.70(m,6H),1.82-1.89(m,4H),2.30(t,J=7.5Hz,2H),2 .36(t,J=7.2Hz,2H),2.43-2.50(m,4H),2.69(m,2H),3.77-3.80(m,4H),4.32-4.37(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:847.75[M+H] + .

[0905] Example 74: Synthesis of Compound 12b

[0906] Compound 12b was prepared according to the method of Example 63, yielding 155.4 mg of an oily compound.

[0907] 1 H NMR(300MHz, CDCl3)δ:0.88-0.96(m,18H),1.23-1.41(m,51H),1.49-1.64(m,8H),1.80-1.89(m,4H),2.27-2 .38(m,4H),2.42-2.52(m,6H),3.57(m,2H),3.78(s,2H),4.32-4.37(m,2H),5.22(s,2H),7.59(s,1H); ESI-MS m / z:861.75[M+H] + .

[0908] Example 75: Synthesis of Compound 13b

[0909] Compound 13b was prepared according to the method of Example 63, yielding 267.5 mg of an oily compound.

[0910] 1H NMR(400MHz, CDCl3)δ:0.88-0.94(m,12H),1.29-1.41(m,51H),1.43-1.47(m,2H),1.57-1.62(m,4H),1.83-1.88(m,4H),2.29(t,J=7.6Hz, 2H),2.37(t,J=7.2Hz,2H),2.51-2.65(m,6H),3.58(m,2H),4.04(t,J=6.8Hz,2H),4.35(t,J=8.0Hz,2H),5.22(s,2H),7.61(s,1H); ESI-MS m / z:805.80[M+H] + .

[0911] Example 76: Synthesis of Compound 14b

[0912] Compound 14b was prepared according to the method of Example 63, yielding 272.7 mg of an oily compound.

[0913] 1 H NMR(400MHz, CDCl3)δ:0.86-0.92(m,12H),1.26-1.40(m,51H),1.42-1.70(m,8H),1.83-1.88(m,4H),2.29(t,J=7.6Hz,2H),2.36(t,J=7.2Hz ,2H),2.48-2.54(m,4H),2.64-2.74(m,2H),3.78(t,J=5.2Hz,2H),4.04(t,J=6.8Hz,2H),4.33-4.37(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:819.75[M+H] + .

[0914] Example 77: Synthesis of Compound 15b

[0915] Compound 15b was prepared according to the method of Example 63, yielding 312.6 mg of an oily compound.

[0916] 1H NMR (400MHz, CDCl3) δ: 0.88-0.94 (m, 12H), 1.29-1.40 (m, 51H), 1.43-1.65 (m, 10H), 1.83-1.88 (m, 4H), 2.29 (t, J = 7.6Hz, 2H), 2. 36(t,J=7.2Hz,2H),2.50-2.61(m,6H),3.57(m,2H),4.04(t,J=6.8Hz,2H),4.33-4.36(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:833.80[M+H] + .

[0917] Example 78: Synthesis of Compound 16b

[0918] Compound 16b was prepared according to the method of Example 63, yielding 164.0 mg of an oily compound.

[0919] 1 H NMR (300MHz, CDCl3) δ: 0.88-0.94 (m, 12H), 1.23-1.49 (m, 49H), 1.54-1.64 (m, 8H), 1.82-1.89 (m, 4H), 2.27 (t, J = 7.5Hz, 2H), 2. 38(t,J=6.9Hz,2H),2.54-2.65(m,6H),3.59(m,2H),4.05(t,J=6.6Hz,2H),4.32-4.37(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:805.70[M+H] + .

[0920] Example 79: Synthesis of Compound 17b

[0921] Compound 17b was prepared according to the method of Example 63, yielding 258.3 mg of an oily compound.

[0922] 1H NMR(400MHz, CDCl3)δ:0.88-0.94(m,12H),1.25-1.42(m,51H),1.50-1.71(m,8H),1.83-1.88(m,4H),2.27(t,J=7.6Hz,2H),2.37(t ,J=7.2Hz,2H),2.51-2.70(m,6H),3.78(t,J=5.2Hz,2H),4.05(t,J=6.8Hz,2H),4.33-4.36(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:819.80[M+H] + .

[0923] Example 80: Synthesis of compound 18b

[0924] Compound 18b was prepared according to the method of Example 63, yielding 269.9 mg of an oily compound.

[0925] 1 H NMR (300MHz, CDCl3) δ: 0.88-0.94 (m, 12H), 1.24-1.42 (m, 51H), 1.47-1.79 (m, 10H), 1.82-1.89 (m, 4H), 2.27 (t, J = 7.5Hz, 2H), 2. 35(t,J=7.2Hz,2H),2.43-2.51(m,6H),3.56(m,2H),4.05(t,J=6.9Hz,2H),4.32-4.37(m,2H),5.21(s,2H),7.59(s,1H); ESI-MS m / z:833.75[M+H] + .

[0926] Example 81: Synthesis of compound 19b

[0927] Compound 19b was prepared according to the method of Example 63, yielding 211.3 mg of an oily compound.

[0928] 1H NMR(300MHz, CDCl3)δ:0.86-0.92(m,9H),1.25-1.50(m,40H),1.59-1.64(m,6H),1.76-1.93(m,4H),2.27(t,J=7.5Hz,2H),2.36(t,J=7.2Hz, 2H),2.45-2.55(m,4H),2.60-2.63(m,2H),3.51-3.57(m,2H),4.05(t,J=6.9Hz,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:708.00[M+H] + .

[0929] Example 82: Synthesis of compound 20b

[0930] Compound 20b was prepared according to the method of Example 63, yielding 240.6 mg of an oily compound.

[0931] 1 H NMR(300MHz, CDCl3)δ:0.86-0.92(m,9H),1.24-1.40(m,40H),1.44-1.80(m,8H),1.88-1.93(m,4H),2.27(t,J=7.5Hz,2H),2.38(t,J =7.2Hz,2H),2.45-2.72(m,6H),3.77(t,J=5.4Hz,2H),4.05(t,J=6.9Hz,2H),4.34(t,J=7.2Hz,2H),5.22(s,2H),7.61(s,1H); ESI-MS m / z:722.00[M+H] + .

[0932] Example 83: Synthesis of compound 21b

[0933] Compound 21b was prepared according to the method of Example 63, yielding 288.0 mg of an oily compound.

[0934] 1H NMR(400MHz, CDCl3)δ:0.88-0.92(m,9H),1.25-1.42(m,40H),1.48-1.63(m,10H),1.82-1.92(m,4H),2.27(t,J=7.6Hz,2H),2.36 (t,J=7.2Hz,2H),2.44-2.53(m,6H),3.56(m,2H),4.05(t,J=6.8Hz,2H),4.34(t,J=7.2Hz,2H),5.22(s,2H),7.59(s,1H); ESI-MS m / z:736.00[M+H] + .

[0935] Example 84: Synthesis of compound 22b

[0936] Compound 22b was prepared according to the method of Example 63, yielding 80.0 mg of an oily compound.

[0937] 1 H NMR(400MHz, CDCl3)δ:0.88-0.92(m,9H),1.23-1.40(m,40H),1.42-1.53(m,2H),1.57-1.63(m,4H),1.82-1.92(m,4H),2.29(t,J=7.6Hz,2H) ,2.37(t,J=7.2Hz,2H),2.44-2.62(m,6H),3.52-3.56(m,2H),4.04(t,J=6.8Hz,2H),4.34(t,J=7.2Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:707.60[M+H] + .

[0938] Example 85: Synthesis of compound 23b

[0939] Compound 23b was prepared according to the method of Example 63, yielding 79.7 mg of an oily compound.

[0940] 1H NMR(300MHz, CDCl3)δ:0.88-0.94(m,9H),1.24-1.40(m,40H),1.50-1.74(m,8H),1.88-1.93(m,4H),2.29(t,J=7.5Hz,2H),2.38(t,J=7.2Hz,2 ESI-MS m / z:721.60[M+H] + .

[0941] Example 86: Synthesis of compound 24b

[0942] Compound 24b was prepared according to the method of Example 63, yielding 108.0 mg of an oily compound.

[0943] 1 H NMR(300MHz, CDCl3)δ:0.88-0.92(m,9H),1.24-1.41(m,40H),1.43-1.64(m,10H),1.81-1.93(m,4H),2.29(t,J=7.5Hz,2H),2.36 (t,J=7.2Hz,2H),2.45-2.59(m,6H),3.57(m,2H),4.04(t,J=6.9Hz,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.59(s,1H); ESI-MS m / z:735.80[M+H] + .

[0944] Example 87: Synthesis of compound 25b

[0945] Compound 25b was prepared according to the method of Example 63, yielding 117.8 mg of an oily compound.

[0946] 1H NMR(300MHz, CDCl3)δ:0.86-0.92(m,15H),1.23-1.39(m,40H),1.52-1.65(m,4H),1.80-1.93(m,4H),2.30(t,J=7.5Hz,2H), 2.38(t,J=7.2Hz,2H),2.51-2.67(m,6H),3.59(m,2H),3.78(s,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:735.75[M+H] + .

[0947] Example 88: Synthesis of compound 26b

[0948] Compound 26b was prepared according to the method of Example 63, yielding 149.5 mg of an oily compound.

[0949] 1 H NMR (300MHz, CDCl3) δ: 0.86-0.94 (m, 15H), 1.24-1.40 (m, 40H), 1.47-1.78 (m, 6H), 1.81-1.93 (m, 4H), 2.30 (t, J = 7.5Hz, 2H), 2. 36(t,J=7.2Hz,2H),2.44-2.49(m,4H),2.68(m,2H),3.76-3.80(m,4H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.59(s,1H); ESI-MS m / z:749.70[M+H] + .

[0950] Example 89: Synthesis of Compound 27b

[0951] Compound 27b was prepared according to the method of Example 63, yielding 168.9 mg of an oily compound.

[0952] 1H NMR(300MHz, CDCl3)δ:0.86-0.90(m,15H),1.23-1.39(m,40H),1.52-1.66(m,8H),1.82-1.93(m,4H),2.30(t,J=7.5Hz,2H), 2.38(t,J=7.2Hz,2H),2.51-2.64(m,6H),3.59(m,2H),3.78(s,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.59(s,1H); ESI-MS m / z:763.75[M+H] + .

[0953] Example 90: Synthesis of compound 28b

[0954] Compound 28b was prepared according to the method of Example 63, yielding 244.0 mg of an oily compound.

[0955] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,9H),1.22-1.38(m,40H),1.54-1.72(m,6H),1.81-1.90(m,4H),2.28(t,J=7.5Hz,2H) ,2.37(t,J=7.2Hz,2H),2.51-2.66(m,6H),3.59(m,2H),4.06(t,J=6.9Hz,2H),4.32(t,J=7.5Hz,2H),5.22(s,2H),7.61(s,1H); ESI-MS m / z:747.80[M+H] + .

[0956] Example 91: Synthesis of compound 29b

[0957] Compound 29b was prepared according to the method of Example 63, yielding 207.2 mg of an oily compound.

[0958] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,9H),1.22-1.38(m,40H),1.54-1.72(m,8H),1.86-1.93(m,4H),2.28(t,J=7.5Hz,2H),2.38(t ,J=7.2Hz,2H),2.54(m,4H),2.73(m,2H),3.78(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.32(t,J=7.5Hz,2H),5.23(s,2H),7.61(s,1H); ESI-MS m / z:761.75[M+H] + .

[0959] Example 92: Synthesis of compound 30b

[0960] Following the method of Example 63, compound 30b was prepared, yielding 444.8 mg of an oily compound.

[0961] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.88-0.94(m,9H),1.22-1.39(m,40H),1.54-1.76(m,10H),1.83-1.93(m,4H),2.28(t,J=7.5Hz, 2H),2.37(t,J=7.2Hz,2H),2.54(m,6H),3.58(m,2H),4.05(t,J=6.9Hz,2H),4.32(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:775.80[M+H] + .

[0962] Example 93: Synthesis of compound 31b

[0963] Compound 31b was prepared according to the method of Example 63, yielding 220.4 mg of an oily compound.

[0964] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,9H),1.26-1.39(m,54H),1.51-1.69(m,6H),1.82-1.89(m,4H),2.28(t,J=7.5Hz,2H) ,2.36(t,J=7.2Hz,2H),2.52-2.63(m,6H),3.58(m,2H),4.05(t,J=6.9Hz,2H),4.32(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:845.65[M+H] + .

[0965] Example 94: Synthesis of compound 32b

[0966] Compound 32b was prepared according to the method of Example 63, yielding 222.4 mg of an oily compound.

[0967] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,9H),1.22-1.39(m,54H),1.51-1.70(m,8H),1.82-1.89(m,4H),2.28(t,J=7.5Hz,2H),2.3 6(t,J=7.2Hz,2H),2.43-2.66(m,6H),3.77(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:859.65[M+H] + .

[0968] Example 95: Synthesis of compound 33b

[0969] Compound 33b was prepared according to the method of Example 63, yielding 150.2 mg of an oily compound.

[0970] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,9H),1.26-1.39(m,54H),1.53-1.69(m,10H),1.82-1.87(m,4H),2.28(t,J=7.5Hz, 2H),2.36(t,J=7.2Hz,2H),2.48(m,6H),3.57(m,2H),4.05(t,J=6.9Hz,2H),4.34(t,J=7.5Hz,2H),5.21(s,2H),7.59(s,1H); ESI-MS m / z:873.90[M+H] + .

[0971] Example 96: Synthesis of compound 34b

[0972] Compound 34b was prepared according to the method of Example 63, yielding 262.2 mg of an oily compound.

[0973] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,9H),1.24-1.41(m,38H),1.53-1.67(m,6H),1.83-1.90(m,4H),2.28(t,J=7.5Hz,2H) ,2.37(t,J=7.2Hz,2H),2.52-2.74(m,6H),3.57(m,2H),4.05(t,J=6.9Hz,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:733.70[M+H] + .

[0974] Example 97: Synthesis of Compound 35b

[0975] Compound 35b was prepared according to the method of Example 63, yielding 323.3 mg of an oily compound.

[0976] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.91(m,9H),1.23-1.45(m,38H),1.50-1.70(m,8H),1.72-1.93(m,4H),2.27(t,J=7.5Hz,2H),2.36(t,J =7.2Hz,2H),2.40-2.49(m,4H),2.65(m,2H),3.77(t,J=5.4Hz,2H),4.06 (t,J=6.9Hz,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:747.60[M+H] + .

[0977] Example 98: Synthesis of compound 36b

[0978] Compound 36b was prepared according to the method of Example 63, yielding 302.4 mg of an oily compound.

[0979] 1 H NMR (300MHz, CDCl3) δ: 0.24 (m, 4H), 0.86-0.92 (m, 9H), 1.24-1.40 (m, 38H), 1.53-1.64 (m, 10H), 1.83-1.89 (m, 4H), 2.28 (t, J = 7.5Hz, 2H), 2. 37(t,J=7.2Hz,2H),2.52-2.68(m,6H),3.57(t,J=5.4Hz,2H),4.05(t,J=6.9Hz,2H),4.34(t,J=7.5Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:761.90[M+H] + .

[0980] Example 99: Synthesis of Compound 37b

[0981] Compound 37b was prepared according to the method of Example 63, yielding 241.8 mg of an oily compound.

[0982] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,12H),1.24-1.40(m,49H),1.53-1.72(m,6H),1.82-1.89(m,4H),2.27(t,J=7.5Hz,2H),2 .37(t,J=7.2Hz,2H),2.51-2.62(m,6H),3.57(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.32-4.37(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:831.65[M+H] + .

[0983] Example 100: Synthesis of compound 38b

[0984] Compound 38b was prepared according to the method of Example 63, yielding 256.6 mg of an oily compound.

[0985] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,12H),1.24-1.40(m,49H),1.53-1.72(m,8H),1.82-1.89(m,4H),2.27(t,J=7.5Hz,2H),2 .37(t,J=7.2Hz,2H),2.48-2.70(m,6H),3.78(t,J=5.1Hz,2H),4.06(t,J=6.9Hz,2H),4.32-4.37(m,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:846.15[M+H] + .

[0986] Example 101: Synthesis of compound 39b

[0987] Compound 39b was prepared according to the method of Example 63, yielding 265.1 mg of an oily compound.

[0988] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.90(m,12H),1.23-1.40(m,49H),1.53-1.74(m,10H),1.82-1.89(m,4H),2.27(t,J=7.5Hz,2H ),2.36(t,J=7.2Hz,2H),2.48(m,6H),3.57(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.32-4.37(m,2H),5.21(s,2H),7.60(s,1H); ESI-MS m / z:859.70[M+H] + .

[0989] Example 102: Synthesis of compound 40b

[0990] Following the method of Example 63, compound 40b was prepared to obtain 315.0 mg of an oily compound.

[0991] 1 H NMR (300MHz, CDCl3) δ: 0.24 (m, 4H), 0.86-0.91 (m, 12H), 1.24-1.40 (m, 47H), 1.43-1.72 (m, 6H), 1.83-1.93 (m, 4H), 2.27 (t, J = 7.5Hz, 2H), 2. 37(t,J=7.2Hz,2H),2.51-2.75(m,6H),3.58(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.32(t,J=7.5Hz,2H),5.22(s,2H),7.61(s,1H); ESI-MS m / z:817.70[M+H] + .

[0992] Example 103: Synthesis of compound 41b

[0993] Compound 41b was prepared according to the method of Example 63, yielding 290.9 mg of an oily compound.

[0994] 1H NMR (300MHz, CDCl3) δ: 0.26 (m, 4H), 0.86-0.90 (m, 12H), 1.23-1.40 (m, 47H), 1.46-1.72 (m, 8H), 1.83-1.93 (m, 4H), 2.27 (t, J = 7.5Hz, 2H), 2. 37(t,J=7.2Hz,2H),2.51-2.71(m,6H),3.79(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.32(t,J=7.5Hz,2H),5.23(s,2H),7.61(s,1H); ESI-MS m / z:831.70[M+H] + .

[0995] Example 104: Synthesis of compound 42b

[0996] Compound 42b was prepared according to the method of Example 63, yielding 336.5 mg of an oily compound.

[0997] 1 H NMR (300MHz, CDCl3) δ: 0.26 (m, 4H), 0.86-0.91 (m, 12H), 1.24-1.40 (m, 47H), 1.43-1.76 (m, 10H), 1.83-1.96 (m, 4H), 2.27 (t, J = 7.5Hz, 2H), 2. 38(t,J=7.2Hz,2H),2.52-2.70(m,6H),3.60(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.32(t,J=7.5Hz,2H),5.22(s,2H),7.61(s,1H); ESI-MS m / z:845.70[M+H] + .

[0998] Example 105: Synthesis of compound 43b

[0999] Compound 43b was prepared according to the method of Example 63, yielding 346.3 mg of an oily compound.

[1000] 1H NMR(300MHz, CDCl3)δ:0.26(m,4H),0.86-0.91(m,9H),1.23-1.42(m,42H),1.51-1.71(m,6H),1.80-1.87(m,2H),2.28(t,J=7.5Hz,2H),2 .49-2.64(m,6H),2.86(m,2H),3.07(t,J=6.9Hz,2H),3.59(t,J=5.4Hz,2H),4.05(t,J=6.9Hz,2H),4.30-4.39(m,4H),7.38(s,1H); ESI-MS m / z:761.80[M+H] + .

[1001] Example 106: Synthesis of compound 44b

[1002] Compound 44b was prepared according to the method of Example 63, yielding 284.1 mg of an oily compound.

[1003] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.91(m,9H),1.23-1.42(m,42H),1.51-1.72(m,8H),1.81-1.88(m,2H),2.28(t,J=7.5Hz, 2H),2.48-2.85(m,8H),3.07(t,J=6.9Hz,2H),3.77(t,J=5.4Hz,2H),4.05(t,J=6.9Hz,2H),4.30-4.40(m,4H),7.39(s,1H); ESI-MS m / z:775.65[M+H] + .

[1004] Example 107: Synthesis of compound 45b

[1005] Compound 45b was prepared according to the method of Example 63, yielding 410.1 mg of an oily compound.

[1006] 1H NMR(300MHz, CDCl3)δ:0.26(m,4H),0.86-0.91(m,9H),1.23-1.40(m,42H),1.51-1.71(m,10H),1.81-1.88(m,2H),2.28(t,J=7.5Hz,2H),2 .42-2.62(m,6H),2.86(m,2H),3.07(t,J=6.9Hz,2H),3.58(t,J=5.4Hz,2H),4.05(t,J=6.9Hz,2H),4.30-4.39(m,4H),7.39(s,1H); ESI-MS m / z:789.65[M+H] + .

[1007] Example 108: Synthesis of compound 46b

[1008] Compound 46b was prepared according to the method of Example 63, yielding 233.9 mg of an oily compound.

[1009] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.90(m,9H),1.26-1.40(m,42H),1.52-1.72(m,6H),1.82-1.87(m,4H),2.28(t,J=7.5Hz,2H),2.34( t,J=7.2Hz,2H),2.40-2.66(m,6H),3.07(t,J=6.9Hz,2H),3.58(t,J=5.4Hz,2H),4.05(t,J=6.9Hz,2H),4.30-4.38(m,4H),7.39(s,1H); ESI-MS m / z:775.70[M+H] + .

[1010] Example 109: Synthesis of compound 47b

[1011] Compound 47b was prepared according to the method of Example 63, yielding 176.8 mg of an oily compound.

[1012] 1H NMR(300MHz, CDCl3)δ:0.25(m,4H),0.86-0.90(m,9H),1.26-1.43(m,42H),1.55-1.72(m,8H),1.83-1.95(m,4H),2.28(t,J=7.5Hz,2H),2.35(t,J =7.2Hz,2H),2.50(m,4H),2.70(m,2H),3.07(t,J=6.9Hz,2H),3.79(t,J= 5.1Hz, 2H), 4.05 (t, J = 6.9Hz, 2H), 4.30-4.38 (m, 4H), 7.39 (s, 1H); ESI-MS m / z:789.80[M+H] + .

[1013] Example 110: Synthesis of compound 48b

[1014] Compound 48b was prepared according to the method of Example 63, yielding 266.3 mg of an oily compound.

[1015] 1 H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.90(m,9H),1.26-1.43(m,42H),1.54-1.72(m,10H),1.82-1.96(m,4H),2.28(t,J=7.5Hz,2H),2.34( ESI-MS m / z:803.75[M+H] + .

[1016] Example 111: Synthesis of compound 49b

[1017] Compound 49b was prepared according to the method of Example 63, yielding 262.1 mg of an oily compound.

[1018] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,12H),1.23-1.41(m,49H),1.56-1.72(m,6H),1.82-1.87(m,2H),2.27(t,J=7.5Hz,2H),2.5 1-2.64(m,6H),2.78-2.86(m,2H),3.07(t,J=6.9Hz,2H),3.59(t,J=5.1Hz,2H),4.06(t,J=6.6Hz,2H),4.30-4.39(m,4H),7.38(s,1H); ESI-MS m / z:831.65[M+H] + .

[1019] Example 112: Synthesis of Compound 50b

[1020] Compound 50b was prepared according to the method of Example 63, yielding 315.0 mg of an oily compound.

[1021] 1 H NMR(300MHz, CDCl3)δ:0.25(m,4H),0.86-0.90(m,12H),1.23-1.42(m,49H),1.56-1.72(m,8H),1.81-1.88(m,2H),2.27(t,J=7.5Hz ,2H),2.49-2.83(m,8H),3.07(t,J=6.9Hz,2H),3.77(t,J=5.4Hz,2H),4.06(t,J=6.9Hz,2H),4.30-4.40(m,4H),7.39(s,1H); ESI-MS m / z:845.65[M+H] + .

[1022] Example 113: Synthesis of compound 51b

[1023] Compound 51b was prepared according to the method of Example 63, yielding 301.7 mg of an oily compound.

[1024] 1H NMR(300MHz, CDCl3)δ:0.24(m,4H),0.86-0.92(m,12H),1.23-1.41(m,49H),1.56-1.72(m,10H),1.81-1.88(m,2H),2.27(t,J=7.5Hz,2H), 2.51-2.69(m,6H),2.88(m,2H),3.07(t,J=6.9Hz,2H),3.59(t,J=5.1Hz,2H),4.05(t,J=6.6Hz,2H),4.30-4.39(m,4H),7.39(s,1H); ESI-MS m / z:859.70[M+H] + .

[1025] Example 114: Synthesis of compound 52b

[1026] Compound 52b was prepared according to the method of Example 63, yielding 235.7 mg of an oily compound.

[1027] 1 H NMR(300MHz, CDCl3)δ:0.88-0.92(m,12H),1.23-1.47(m,60H),1.56-1.71(m,8H),1.78-1.89(m,4H),2.36(t,J=7.2Hz,2H),2.4 5-2.61(m,6H),3.36-3.44(m,2H),3.51-3.59(m,4H),4.32-4.37(m,2H),4.45(t,J=5.7Hz,1H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:877.85[M+H] + .

[1028] Example 115: Synthesis of compound 53b

[1029] Compound 53b was prepared according to the method of Example 63, yielding 196.9 mg of an oily compound.

[1030] 1H NMR(300MHz, CDCl3)δ:0.86-0.90(m,12H),1.23-1.40(m,64H),1.51-1.65(m,8H),1.82-1.89(m,4H),2.35-2.64(m,8 H),3.36-3.43(m,2H),3.51-3.59(m,4H),4.32-4.37(m,2H),4.44(t,J=5.7Hz,1H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:905.75[M+H] + .

[1031] Example 116: Synthesis of compound 54b

[1032] Add 6-bromo-1-hexene (6.0 g, 36.80 mmol, 1.0 eq.), trichlorosilane (49.84 g, 368.0 mmol, 10.0 eq.), platinum(O)-1,3-diethylene-1,1,3,3-tetramethyldisiloxane (1.82 g, 4.78 mmol, 0.13 eq.), and toluene (60 mL) to a round-bottom flask. Stir the reaction mixture overnight at room temperature. After the reaction is complete, quench with water (80 mL), extract with ethyl acetate (60 mL x 2), combine the organic phases, wash with saturated sodium chloride solution (150 mL), dry the organic phase with anhydrous Na₂SO₄, filter, collect the filtrate, and concentrate to remove the organic solvent, yielding 9.7 g of crude yellow oily compound 54b-2. This crude compound can be used directly in subsequent reactions without further purification.

[1033] Compound 54b-2 (9.7 g, crude), 1-decyl alcohol (15.43 g, 97.49 mmol), and TEA (13.15 g, 129.98 mmol) were dissolved in dichloromethane in a reaction flask at room temperature. The reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water (100 mL), separated, and extracted with dichloromethane (100 mL x 2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was collected, concentrated to remove the solvent, and the crude product was purified by silica gel column chromatography to give 9.1 g of a yellow oily compound 54b-3.

[1034] Compound 54b-3 (1.5 g, 2.26 mmol, 1.0 eq.), ethanolamine (2.76 g, 45.20 mmol, 20.0 eq.), and ethanol (15 mL) were added to a 40 mL sealed tube at room temperature. The reaction mixture was heated to 70 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Ethyl acetate (30 mL) was added to redissolve the compound, and the mixture was washed with water (30 mL x 2). The organic phase was dried over anhydrous Na₂SO₄, filtered, and the filtrate was collected and concentrated to remove the solvent, yielding a crude product. After purification by silica gel column chromatography, 1.35 g of a pale yellow oily compound 54b-4 was obtained.

[1035] Compound 54b-4 (300 mg, 0.47 mmol, 1.0 eq.), triazole reactant (228.67 mg, 0.47 mmol, 1.0 eq.), potassium iodide (92.77 mg, 0.56 mmol, 1.2 eq.), potassium carbonate (194.58 mg, 1.41 mmol, 3.0 eq.), and acetonitrile (5 mL) were added to an 8 mL sealed tube at room temperature. The reaction system was heated to 80 °C and reacted overnight. After the reaction was completed, the reaction system was cooled to room temperature. The mixture was filtered, and the filter cake was washed with acetonitrile (5 mL x 2). The filtrates were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain 234.8 mg of a pale yellow oily compound 54b.

[1036] 1 H NMR(400MHz, CDCl3)δ:0.58-0.65(m,2H),0.86-0.90(m,15H),1.26-1.38(m,80H),1.52-1.57(m,8H),1.82-1 .88(m,2H),2.45-2.57(m,6H),3.71(t,J=6.8Hz,6H),4.35(t,J=8.0Hz,2H),5.22(s,2H),7.61(s,1H); ESI-MS m / z:1050.00[M+H] + .

[1037] Example 117: Synthesis of compound 55b

[1038] Compound 55b was prepared according to the method of Example 116, yielding 161.0 mg of an oily compound.

[1039] 1H NMR(300MHz, CDCl3)δ:0.59-0.66(m,2H),0.86-0.90(m,15H),1.25-1.58(m,84H),1.81-1.92(m,4H),2.36(t,J=7.2H z,2H),2.42-2.60(m,6H),3.55(m,2H),3.71(t,J=6.6Hz,6H),4.23(d,J=6.9Hz,2H),5.22(s,2H),7.56(s,1H); ESI-MS m / z:1064.05[M+H] + .

[1040] Example 118: Synthesis of Compound 56b

[1041] Following the method of Example 116, compound 56b was prepared, yielding 126.8 mg of an oily compound.

[1042] 1 H NMR(300MHz, CDCl3)δ:0.59-0.66(m,2H),0.86-0.90(m,15H),1.25-1.58(m,86H),1.83-1.92(m,6H),2.37(t,J=7.2Hz,2H ),2.44-2.69(m,6H),3.71(t,J=6.6Hz,6H),3.78(t,J=5.1Hz,2H),4.23(d,J=6.9Hz,2H),5.23(s,2H),7.56(s,1H); ESI-MS m / z:1078.00[M+H] + .

[1043] Example 119: Synthesis of Compound 57b

[1044] Compound 57b was prepared according to the method of Example 116, yielding 54.8 mg of an oily compound.

[1045] 1 H NMR(300MHz, CDCl3)δ:0.59-0.66(m,2H),0.86-0.90(m,15H),1.25-1.64(m,88H),1.81-1.91(m,4H),2.36 -2.64(m,8H),3.57(m,2H),3.71(t,J=6.9Hz,6H),4.23(d,J=6.9Hz,2H),5.22(s,2H),7.55(s,1H); ESI-MS m / z:1092.05[M+H] + .

[1046] Example 120: Synthesis of compound 58b

[1047] Following the method described in the above embodiments, compound 58b was prepared, yielding 285.7 mg of an oily compound.

[1048] 1 H NMR(300MHz, CDCl3)δ:0.86-0.90(m,12H),1.26-1.39(m,51H),1.73-1.89(m,8H),2.34(t,J=7.2Hz,4H),2.49(t ,J=7.2Hz,4H),2.59(t,J=5.1Hz,2H),3.53(t,J=5.1Hz,2H),4.32-4.37(m,4H),5.21(s,4H),7.61(s,2H); ESI-MS m / z:872.65[M+H] + .

[1049] Example 121: Synthesis of compound 59b

[1050] Following the method described in the above embodiments, compound 59b was prepared, yielding 323.8 mg of an oily compound.

[1051] 1 H NMR(300MHz, CDCl3)δ:0.86-0.90(m,12H),1.26-1.39(m,51H),1.65-1.70(m,2H),1.75-1.89(m,8H),2.35(t,J=7.2Hz,4H ),2.47(t,J=7.2Hz,4H),2.64(t,J=5.4Hz,2H),3.75(t,J=5.4Hz,2H),4.32-4.37(m,4H),5.21(s,4H),7.61(s,2H); ESI-MS m / z:886.65[M+H] + .

[1052] Example 122: Synthesis of compound 60b

[1053] Following the method described in the above embodiments, compound 60b was prepared, yielding 276.3 mg of an oily compound.

[1054] 1H NMR(300MHz, CDCl3)δ:0.86-0.91(m,12H),1.26-1.40(m,53H),1.60-1.65(m,2H),1.74-1.89(m,8H),2.35(t ,J=7.2Hz,4H),2.45-2.50(m,6H),3.57(t,J=5.1Hz,2H),4.32-4.37(m,4H),5.21(s,4H),7.61(s,2H); ESI-MS m / z:900.70[M+H] + .

[1055] Example 123: Synthesis of compound 61b

[1056] Following the method described in the above embodiments, compound 61b was prepared to obtain 123.3 mg of an oily compound.

[1057] 1 H NMR(300MHz, CDCl3)δ:0.88-0.94(m,15H),1.23-1.47(m,45H),1.58-1.88(m,8H),2.23(s, 6H),2.25-2.43(m,12H),3.78(s,2H),4.31-4.37(m,2H),5.21(s,2H),7.58(s,1H); ESI-MS m / z:804.65[M+H] + .

[1058] Example 124: Synthesis of compound 62b

[1059] Following the method described in the above embodiments, compound 62b was prepared, yielding 175.5 mg of an oily compound.

[1060] 1 H NMR(300MHz, CDCl3)δ:0.86-0.91(m,9H),1.26-1.40(m,45H),1.59-1.69(m,6H),1.71-1.79(m,2H),1.81-1.89(m ,2H),2.20(s,6H),2.22-2.42(m,12H),4.05(t,J=6.9Hz,2H),4.31-4.37(m,2H),5.21(s,2H),7.58(s,1H); ESI-MS m / z:776.60[M+H] + .

[1061] Example 125: Synthesis of Compound 63b

[1062] Following the method described in the above embodiments, compound 63b was prepared, yielding 114.8 mg of an oily compound.

[1063] 1 H NMR(300MHz, CDCl3)δ:0.86-0.91(m,9H),1.26-1.40(m,45H),1.61-1.70(m,6H),1.72-1.79(m,2H),1.81-1.89(m ,2H),2.23(s,6H),2.26-2.48(m,12H),4.05(t,J=6.9Hz,2H),4.31-4.37(m,2H),5.21(s,2H),7.59(s,1H); ESI-MS m / z:776.50[M+H] + .

[1064] Example 126: Synthesis of compound 64b

[1065] Compound 64b-1 (5.0 g, 13.25 mmol, 1.0 eq.) and 4-methoxybenzylamine (36.35 g, 265.00 mmol, 20.0 eq.) were dissolved in ethanol. The reaction system was heated to 70 °C and stirred for 2 h. The reaction was monitored by LC-MS. After the reactants had reacted almost completely, the mixture was concentrated under reduced pressure to remove the ethanol. The solution was diluted with saturated sodium chloride solution and then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous Na₂SO₄, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give 3.51 g of a pale yellow oily compound 64b-2.

[1066] Compounds 64b-2 (594.23 mg, 1.37 mmol, 1.0 eq.) and 64b-3 (700 mg, 1.44 mmol, 1.05 eq.) were dissolved in a mixed solvent of CPME (6 mL) and acetonitrile (2 mL) in a 40 mL sealed tube at room temperature. Potassium carbonate (227.7 mg, 1.65 mmol, 1.2 eq.) and potassium iodide (273.9 mg, 1.65 mmol, 1.2 eq.) were then added. The reaction mixture was heated to 80 °C and reacted for 18 h. The reaction was monitored by LC-MS until the reactants were almost completely reacted. After cooling to room temperature, the mixture was filtered. The filter cake was washed with ethyl acetate (5 mL x 3), and the combined filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 752.2 mg of a pale yellow oily compound 64b-4.

[1067] Compound 64b-4 (752.2 mg, 0.89 mmol, 1.0 eq.) was dissolved in tetrahydrofuran in a reaction flask, followed by the addition of aqueous palladium / carbon (10%, 2.25 g). The reaction system was cooled to 0 °C, and HCl / dioxane (4.0 M, 0.25 mL) was added dropwise. The mixture was purged with hydrogen three times, and the system was heated to room temperature and the reaction continued for 2 h. The reaction was monitored by LC-MS until the reactants were almost completely reacted. The mixture was filtered, and the filter cake was washed with tetrahydrofuran (5 mL x 3). The combined filtrates were concentrated under reduced pressure to obtain 635.1 mg of crude yellow oily compound 64b-5, which was used directly in subsequent reactions without further purification.

[1068] Compound 64b-5 (635 mg crude) was dissolved in dichloromethane in a 50 mL three-necked flask. The system was cooled to 0 °C, and BTC (262.01 mg, 0.88 mmol) was added. Then, pyridine (0.36 mL, 4.42 mmol) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 4 h. The system was concentrated under reduced pressure to remove the solvent, yielding the crude product. The crude product was dissolved in pyridine and cooled to 0 °C. 4-Dimethylamino-1-butanethiol (588.29 mg, 4.42 mmol) was quickly added. The system was heated to room temperature and reacted for another 48 h. The reaction was monitored by LC-MS, and the starting material was almost completely converted. The system was concentrated under reduced pressure, and water (30 mL) and ethyl acetate (30 mL x 3) were added for extraction. The combined organic phases were washed with saturated sodium chloride solution, collected, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by Prep-HPLC to obtain 378.1 mg of yellow oily compound 64b.

[1069] 1 H NMR(400MHz, CDCl3)δ:0.87-0.91(m,15H),1.26-1.43(m,45H),1.52-1.63(m,6H),1.82-1.88(m,4H),2.30-2.35(m, 12H),2.89(t,J=6.8Hz,2H),3.27-3.31(m,4H),3.78(s,2H),4.34(t,J=7.6Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:878.65[M+H] + .

[1070] Example 127: Synthesis of Compound 65b

[1071] Compound 65b was prepared according to the method of Example 126, yielding 209.6 mg of an oily compound.

[1072] 1H NMR(300MHz, CDCl3)δ:0.86-0.90(m,9H),1.26-1.43(m,43H),1.51-1.61(m,10H),1.82-1.89(m,4H),2.25(s,6H),2.29-2.35( m,6H),2.89(t,J=6.9Hz,2H),3.23-3.38(m,4H),4.05(t,J=6.6Hz,2H),4.34(t,J=8.4Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:850.60[M+H] + .

[1073] Example 128: Synthesis of Compound 66b

[1074] Compound 66b was prepared according to the method of Example 126, yielding 417.9 mg of an oily compound.

[1075] 1 H NMR(300MHz, CDCl3)δ:0.88-0.93(m,9H),1.26-1.43(m,43H),1.51-1.63(m,10H),1.82-1.89(m,4H),2.27-2.34(m,12H) ,2.89(t,J=6.6Hz,2H),3.23-3.38(m,4H),4.05(t,J=6.9Hz,2H),4.34(t,J=8.4Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:850.60[M+H] + .

[1076] Example 129: Synthesis of Compound 67b

[1077] Compound 67b was prepared according to the method of Example 126, yielding 310.5 mg of an oily compound.

[1078] 1H NMR(300MHz, CDCl3)δ:0.86-0.92(m,15H),1.26-1.43(m,43H),1.51-1.70(m,8H),1.82-1.89(m,4H),2.27-2.34(m, 12H),3.17-3.35(m,4H),3.77(s,2H),4.06(t,J=6.3Hz,2H),4.34(t,J=8.4Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:862.60[M+H] + .

[1079] Example 130: Synthesis of Compound 68b

[1080] Compound 68b was prepared according to the method of Example 126, yielding 168.5 mg of an oily compound.

[1081] 1 H NMR(300MHz, CDCl3)δ:0.86-0.91(m,9H),1.26-1.43(m,43H),1.50-1.64(m,10H),1.82-1.89(m,4H),2.26- 2.36(m,12H),3.17-3.32(m,4H),4.03-4.08(m,4H),4.34(t,J=8.4Hz,2H),5.21(s,2H),7.60(s,1H); ESI-MS m / z:834.70[M+H] + .

[1082] Example 131: Synthesis of compound 69b

[1083] Following the method of Example 126, compound 69b was prepared, yielding 292.9 mg of an oily compound.

[1084] 1 H NMR(300MHz, CDCl3)δ:0.86-0.91(m,9H),1.26-1.42(m,43H),1.49-1.70(m,10H),1.82-1.89(m,4H),2.26- 2.36(m,12H),3.16-3.32(m,4H),4.03-4.07(m,4H),4.34(t,J=8.4Hz,2H),5.22(s,2H),7.60(s,1H); ESI-MS m / z:834.80[M+H] + .

[1085] Example 132: Synthesis of compound 70b

[1086] Under a nitrogen atmosphere, pyrazole-4-carboxylic acid ethyl ester (3.6 g, 25.69 mmol, 1.0 eq.), 3-hepty-1-decyl alcohol (6.46 g, 25.17 mmol, 0.98 eq.), and PPh3 (7.41 g, 28.26 mmol, 1.1 eq.) were dissolved in tetrahydrofuran. The reaction mixture was cooled to 0 °C, and DIAD (5.71 g, 28.26 mmol, 1.1 eq.) was added dropwise. After the addition was complete, the mixture was heated to room temperature and allowed to react overnight. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was collected and the solvent was removed by vacuum distillation to obtain the crude product. Column chromatography purification yielded 8.4 g of a yellow oily compound 70b-1.

[1087] Under nitrogen protection, compound 70b-1 (8.4 g, 22.19 mmol, 1.0 eq.) was dissolved in tetrahydrofuran in a reaction flask. The reaction solution was cooled to 0 °C and LAH (2.5 M, 9.76 mL, 24.41 mmol, 1.1 eq.) was added dropwise. The reaction system was then heated to room temperature and the reaction was continued for 3 h. After the reaction was completed, the reaction solution was cooled to 0 °C and the reaction was quenched by adding Na₂SO₄·10H₂O in portions. The insoluble matter in the reaction solution was dissolved by adding 1N HCl (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated sodium chloride aqueous solution (100 mL x 2). The organic phase was collected, dried over anhydrous Na₂SO₄, filtered, and the filtrate was distilled under reduced pressure to remove the solvent, yielding a crude product. After purification by silica gel column chromatography, 7.3 g of yellow oily compound 70b-2 was obtained.

[1088] Compound 70b-2 (4.0 g, 11.89 mmol, 1.0 eq.), 6-bromohexanoic acid (2.55 g, 13.07 mmol, 1.1 eq.), EDCI (2.77 g, 17.83 mmol, 1.5 eq.), and DMAP (0.29 g, 2.38 mmol, 0.2 eq.) were dissolved in dichloromethane and reacted overnight at room temperature. The reaction was monitored by LC-MS. After the starting material was completely consumed, the reaction solution was poured into 50 mL of ice water and extracted with dichloromethane. The organic phase was collected, dried over anhydrous Na₂SO₄, filtered, and the filtrate was distilled under reduced pressure to remove the solvent, yielding a crude product. After purification by silica gel column chromatography, 5.3 g of a yellow oily compound 70b-3 was obtained.

[1089] Compound 1b-8 (300 mg, 0.84 mmol, 1.0 eq.), compound 70-3 (473.99 mg, 0.92 mmol, 1.1 eq.), KI (167.13 mg, 1.01 mmol, 1.2 eq.), and potassium carbonate (231.90 mg, 1.68 mmol, 2.0 eq.) were dissolved in acetonitrile in a reaction flask. The reaction system was heated to 80 °C and reacted overnight. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (5 mL x 2). The filtrates were collected and combined, and the solvent was removed by rotary distillation under reduced pressure to obtain the crude product. The crude product was purified by Prep-HPLC (Column: XBridge Prep Phenyl OBD, 30x 150mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3 + 1% NH3·H2O) / CH3CN = 6:4, Mobile Phase B: CH3CN / IPA = 1:9; Flow rate: 60mL / min; Gradient (B%): 65% B to 95% B in 12min; Wave Length: 220nm; RT1 (min): 9.5) to obtain 323.7mg of pale yellow oily compound 70b.

[1090] 1 H NMR(400MHz, CDCl3)δ:0.86-0.91(m,15H),1.25-1.39(m,46H),1.42-1.52(m,4H),1.61-1.67(m,4H),1.78-1.83(m,2H),2.30(t, J=7.6Hz,4H),2.46-2.60(m,6H),3.54(m,2H),3.78(s,2H),4.08(t,J=8.0Hz,2H),4.99(s,2H),7.43(s,1H),7.49(s,1H); ESI-MS m / z:790.75[M+H] + .

[1091] Example 133: Synthesis of compound 71b

[1092] Compound 71b was prepared according to the method of Example 132, yielding 320.7 mg of an oily compound.

[1093] 1H NMR(300MHz,CD3OD)δ:0.88-0.92(m,15H),1.25-1.39(m,46H),1.42-1.79(m,12H),2.31(t,J=7.2Hz,4H),2.33-2.47(m,4H),2 .59(t,J=6.9Hz,2H),3.62(t,J=6.0Hz,2H),3.80(s,2H),4.13(t,J=7.5Hz,2H),5.00(s,2H),7.49(s,1H),7.67(s,1H); ESI-MS m / z:804.60[M+H] + .

[1094] Example 134: Synthesis of compound 72b

[1095] Compound 72b was prepared according to the method of Example 132, yielding 456.8 mg of an oily compound.

[1096] 1 H NMR(300MHz,CD3OD)δ:0.88-0.92(m,15H),1.25-1.38(m,46H),1.46-1.68(m,12H),1.71-1.77(m,2H),2.28-2.35(m,4H),2 .42-2.48(m,6H),3.55(t,J=6.0Hz,2H),3.80(s,2H),4.13(t,J=7.2Hz,2H),5.00(s,2H),7.48(s,1H),7.67(s,1H); ESI-MS m / z:818.65[M+H] + .

[1097] Example 135: Synthesis of Compound 73b

[1098] Compound 73b was prepared according to the method of Example 132, yielding 300.4 mg of an oily compound.

[1099] 1H NMR(300MHz,CD3OD)δ:0.88-0.94(m,15H),1.26-1.39(m,50H),1.42-1.53(m,4H),1.57-1.77(m,4H),1.79-1.86(m,2H),2.28-2.35(m,4H),2.4 4-2.50(m,4H),2.60(t,J=6.3Hz,2H),3.60(t,J=6.3Hz,2H),3.80(s,2H),4.13(t,J=7.2Hz,2H),5.00(s,2H),7.48(s,1H),7.66(s,1H); ESI-MS m / z:818.65[M+H] + .

[1100] Example 136: Synthesis of compound 74b

[1101] Compound 74b was prepared according to the method of Example 132, yielding 203.2 mg of an oily compound.

[1102] 1 H NMR(300MHz,CD3OD)δ:0.88-0.92(m,15H),1.25-1.38(m,52H),1.43-1.52(m,4H),1.61-1.78(m,6H),2.29-2.35(m,4H),2.43-2.49(m ,4H),2.60(t,J=6.9Hz,2H),3.62(t,J=6.3Hz,2H),3.80(s,2H),4.13(t,J=7.2Hz,2H),5.00(s,2H),7.48(s,1H),7.67(s,1H); ESI-MS m / z:832.65[M+H] + .

[1103] Example 137: Synthesis of compound 75b

[1104] Compound 75b was prepared according to the method of Example 132, yielding 300.3 mg of an oily compound.

[1105] 1H NMR(300MHz,CD3OD)δ:0.88-0.92(m,15H),1.25-1.42(m,54H),1.47-1.77(m,10H),2.28-2.35(m,4H),2.41-2.47 (m,6H),3.54(t,J=6.0Hz,2H),3.80(s,2H),4.13(t,J=7.2Hz,2H),5.00(s,2H),7.48(s,1H),7.66(s,1H); ESI-MS m / z:846.70[M+H] + .

[1106] Example 138: Synthesis of compound 76b

[1107] In a reaction flask, 1.45 g of ethyl 5-carboxylate tetrazolium (10.20 mmol, 1.1 eq) and 2.96 g of 3-heptyl-1-bromodecane (2.96 g, 9.27 mmol, 1.0 eq.) were dissolved in DMF, followed by the addition of Cs₂CO₃ (4.53 g, 13.90 mmol, 1.5 eq.). The reaction system was heated to 80 °C and reacted for 3 hours under TLC monitoring until the reactants were completely reacted. The reaction solution was cooled to room temperature and filtered to obtain a filtrate. The filter cake was washed with ethyl acetate (30 mL x 3). The organic phases were combined and water (100 mL) was added, resulting in layer separation. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were backwashed with water (200 mL x 4), collected, and dried over anhydrous Na₂SO₄. The filtrate was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 1.78 g of a pale yellow oily compound 76b-2.

[1108] Compound 76b-2 (1.68 g, 4.41 mmol, 1.0 eq.) was dissolved in 30 mL of ethanol, and then NaBH4 (0.50 g, 13.23 mmol, 3.0 eq.) was added under ice bath conditions. The reaction was brought to room temperature and stirred for 2 hours. The reaction was monitored by LC-MS and TLC, and the starting material was essentially completely converted. The reaction was quenched with water, followed by extraction with dichloromethane (40 mL x 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding 1.73 g of a grayish-white oily compound 76b-3, which was used directly in the next reaction without further purification.

[1109] Compound 76b was prepared according to the method of Example 63, yielding 210.2 mg of an oily compound.

[1110] 1H NMR(300MHz, CDCl3)δ:0.25(m,4H),0.86-0.90(m,9H),1.26-1.38(m,40H),1.62-1.81(m,10H),1.93-2.00(m,4H),2.28(t ,J=7.5Hz,2H),2.43-2.74(m,8H),3.79(t,J=5.4Hz,2H),4.06(t,J=6.6Hz,2H),4.61(t,J=7.8Hz,2H),5.36(s,2H); ESI-MS m / z:776.70[M+H] + .

[1111] Example 139: Synthesis of Compound 77b

[1112] Compound 77b was prepared according to the method of Example 138, yielding 150.8 mg of an oily compound.

[1113] 1 H NMR(300MHz, CDCl3)δ:0.86-0.91(m,15H),1.26-1.39(m,44H),1.58-1.83(m,6H),1.93-2.00(m,4H),2 .32(t,J=7.5Hz,2H),2.46-2.76(m,8H),3.78-3.82(m,4H),4.61(t,J=7.8Hz,2H),5.37(s,2H); ESI-MS m / z:778.70[M+H] + .

[1114] Example 140: Synthesis of compound 78b

[1115] Compound 78b was prepared according to the method of Example 138, yielding 294.0 mg of an oily compound.

[1116] 1 H NMR(300MHz, CDCl3)δ:0.86-0.90(m,9H),1.25-1.41(m,44H),1.52-1.71(m,8H),1.88-2.00(m,4H),2.29(t,J=7.5Hz,2H) ,2.41-2.50(m,6H),2.70(m,2H),3.79(t,J=5.1Hz,2H),4.05(t,J=6.9Hz,2H),4.61(t,J=7.5Hz,2H),5.36(s,2H); ESI-MS m / z:751.05[M+H] + .

[1117] Example 141: Synthesis of compound 79b

[1118] Compound 79b was prepared according to the method of Example 138, yielding 98.4 mg of an oily compound.

[1119] 1 H NMR(400MHz, CDCl3)δ:0.24(m,4H),0.86-0.91(m,9H),1.24-1.43(m,42H),1.53-1.69(m,8H),1.84-1.87(m,4H),2.28(t,J=7.6 Hz,2H),2.41-2.52(m,6H),2.68(m,2H),3.77(t,J=4.8Hz,2H),4.05(t,J=6.8Hz,2H),4.39(t,J=7.6Hz,2H),5.37(s,2H); ESI-MS m / z:776.65[M+H] + .

[1120] Example 142: Synthesis of compound 80b

[1121] Following the method of Example 138, compound 80b was prepared, yielding 63.5 mg of an oily compound.

[1122] 1 H NMR(300MHz, CDCl3)δ:0.89-0.92(m,9H),1.27-1.41(m,44H),1.43-1.71(m,8H),1.84-1.89(m,4H),2.29(t,J=7.5Hz,2H) ,2.41-2.50(m,6H),2.69(m,2H),3.77(t,J=5.4Hz,2H),4.05(t,J=6.6Hz,2H),4.39(t,J=7.8Hz,2H),5.37(s,2H); ESI-MS m / z:750.70[M+H] + .

[1123] Pharmacological experiments

[1124] Experimental Example 1: Preparation of Nanoparticles

[1125] Materials used for assembling lipid nanoparticles include: (1) ionizable lipid compounds: such as the ionizable lipids designed and synthesized in this invention or SM102 (purchased from AVT / MCE) as a control group; (2) structural lipids: such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids: such as DSPC, which is 1,2-distearyl-SN-glycerol-3-phosphocholine (purchased from AVT); (4) polyethylene glycol-modified lipid compounds: such as DSPE-PEG 2000, which is distearyl phosphoethanolamine-PEG 2000 (purchased from AVT / SINOPEG); (5) effective components of nucleic acid fragments: such as luciferase mRNA (Trilink, L-7202). The names and structural formulas of the lipid nanoparticle assembly materials are detailed in Table 2.

[1126] Table 2

[1127] Preparation method of lipid nanoparticles: (1) Dissolve ionizable lipid compounds, cholesterol, DSPC, DSPE-PEG 2000 and DSPE-PEG2000-maleimide in ethanol in sequence; (2) Dissolve mRNA active ingredient in citrate buffer (25mM, 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 total mixing flow rate of 10-18 mL / 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 0.22μm sterile filter membrane, the obtained nanoparticle solution is sealed in an EP tube and stored at low temperature.

[1128] 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.

[1129] A certain amount of the above-mentioned lipid nanoparticles with reactive groups was mixed with CD8 nanobody (purchased from NBbio) at a molar ratio of DSPE-PEG-Mal to CD8 nanobody of 1:1 and incubated overnight at 4°C. Sucrose solution was added to the overnight incubated lipid nanoparticle mixture for dilution, and purification was performed using a 100kD ultrafiltration tube. After aseptic filtration in a clean bench using a PES filter with a pore size of 0.22μm, the final nanobody-modified lipid nanoparticles (tLNP) were obtained.

[1130] Experimental Example 2: Characterization of the physical properties of lipid nanoparticles

[1131] 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 the RNA fragments. This coefficient was obtained from 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), and a portion of the sample solution was 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 rate.

[1132] Experiment Example 3: In vitro cell transfection experiment

[1133] Human primary T cells were diluted to 1 million / mL using 1640 complete medium (10% Gibco FBS, 1% PS antibiotics) supplemented with IL-2 (working concentration 400 U / mL). 0.2 million cells were added to each well of a 96-well plate. After cell seeding, the plates were stabilized at 37°C and 5% CO2 for 4 h before adding CD8-targeting lipid nanoparticles (CD8-tLNP). CD8-tLNP encapsulated with tdTomato-mRNA was added to achieve a working concentration of 0.6 μg / mL of LNP in the wells. PBS was used as a negative control. After 24 h, the expression rate of tdTomato-mRNA in the CD8+ cell subset of human primary T cells was detected by flow cytometry. The LNP (tLNP) formulation and expression rate data are shown in Tables 3 and 4.

[1134] Example 4: In vivo transfection experiment in immune-reconstituted mice

[1135] Six- to eight-week-old female NOG mice that had passed quarantine and met the SPF (specific pathogen-free) standard were selected. Each NOG mouse was injected intravenously with 20M hPBMC cells (100 μL). Approximately two weeks later, blood samples were collected to assess the immune reconstitution rate. Mice were then divided into groups of three based on their immune reconstitution rate. Each NOG mouse received 10 μg of tdTomato mRNA-tLNP (approximately 0.5 mpk mRNA) intravenously in a 100 μL volume. Twenty-four hours after administration, peripheral blood and splenic erythrocytes were collected, and the expression rate of tdTomato mRNA in each cell subset was analyzed by flow cytometry. The LNP (tLNP) formulation and expression rate data are shown in Tables 3 and 4.

[1136] Table 3

[1137] Table 4

[1138] The data in Table 4 and Figure 1 show that the in vivo transfection efficiency is close to saturation. However, as can be seen from Figure 1, after the tLNP of compound 23 delivers nucleic acid to the cells, the average fluorescence intensity of the reporter protein expressed by the reporter gene is much higher than that of L829 (Table 5), indicating that the compound of the present invention is more advantageous for tLNP.

[1139] Table 5

[1140] This application provides further evaluation of the delivery effect of the ionizable lipids of the present invention (see Table 7 and Figure 2). In the tLNP, the PEG lipid used is DSPE-PEG 2000 (1.4 mol%), the functionalized polymer lipid is DSPE-PEG-Mal (0.1 mol%), the molar ratio of CD8 nanobody to DSPE-PEG-Ma is 1:1, and the other components used and their specific proportions are shown in Table 5. The N / P ratio is 6.

[1141] Table 6

[1142] Table 7

[1143] In the formulation of LNP-2, compounds 23 and L829 were used as ionizable lipids to prepare tLNPs, which were then loaded with tdTomato mRNA. The delivery efficiency at different doses (0.5 mpk and 0.2 mpk) was tested. The results in Figure 2 and Table 8 (where "L829-0.2" indicates that the ionizable lipid used to prepare tLNPs was L829 and the mRNA dose was 0.2 mpk, and the meanings of other groups are similar; "CTL" refers to cytotoxic T lymphocytes) show that, at different doses, compound 23 had better transfection efficiency and better mean fluorescence intensity (MFI) of reporter proteins expressed by reporter genes after nucleic acid delivery to cells compared to L829.

[1144] Table 8

[1145] Experimental Example 5: NHP Test

[1146] One cynomolgus monkey (NHP, a non-human primate) that passed quarantine and met the required weight was selected. The tLNP formulation was compound 23:CHO:DSPC:DSPE-PEG2000:DSPE-PEG-Mal with a molar percentage of 58:30.5:10:1.4:0.1, encapsulated with tdTomato mRNA, N / P=6. After preparing LNP, it was mixed with CD8 nanobody (NBbio) at a 1:1 molar ratio to obtain tLNP. The specific method is the same as in Experiment 1. The prepared tdTomato mRNA-tLNP was administered intravenously at a dose of 1.5mpk. Weight was measured before administration and at 24h and 168h after administration; blood routine and blood biochemistry tests were performed before administration and at 6h, 24h, 48h, 72h and 168h after administration. The results showed that NHP did not exhibit significant weight changes before and after injection (Figure 3). Neutrophils showed a transient increase after injection, while monocytes showed a decreasing trend; both gradually recovered after one day (Figure 4). Other blood routine indicators showed little change. Blood biochemical indicators AST and CK showed a transient increase, which then returned to pre-drug levels within one week (Figure 5). These data indicate that the tLNP has high safety at a dose of 1.5 mpk, and preliminary results show good transfection efficacy.

[1147] 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 inclu...

Claims

1. A compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Ring A is C 6-10 Arenes or 5-10 quinone heteroaryl compounds; Z is CH or N; G1 and G2 are independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, optionally surrounded by 1, 2, 3, or 4 R groups. G1 replace; The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R G1 Independently selected from H and C 1-8 Alkyl, -L a -OR a -L a -SR a and -L a -NR a R' a ; G 3a and G 3b Independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, optionally surrounded by 1, 2, 3, or 4 R groups. G3 replace; G 3a and G 3b The total length is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R G3 Independently selected from H and C 1-8 Alkyl, -L a -OR a -L a -SR a and -L a -NR a R' a ; L a Independently selected from chemical bonds and C 1-14 Alkylene; R a and R' a Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 The ynyl group, optionally surrounded by 1, 2, 3 or 4 R groups G4 replace; R G4 Independently selected from H and C 1-6 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ; L b Independently selected from chemical bonds and C 1-6 Alkylene; R b and R' b Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by 1, 2, 3 or 4 R groups. 4g replace; R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-8 Alkylene; R e and R' e Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 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 therein are replaced independently by -NR'-; M1 is selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -S-S- and -S(O) 0-2 - M2 is selected from a chemical bond, -(CH2) 1-2 -, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -S-S- and -S(O) 0-2 -; R and R' are each independently selected from H and C. 1-20 alkyl; R s Independently selected from H and C 1-20 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ; L c Independently selected from chemical bonds and C 1-20 Alkylene; R c and R' c Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; R3 is selected from CN, -OR g -C(O)R g -OC(O)R g -NR”C(O)R g -NR g R' g 、-NR”C(O)NR g R' g -NR”C(O)R g -NR”S(O)2R g -OC(O)NR g R' g -NR”C(O)OR g -N(OR) g )C(O)R g -N(OR) g )S(O)2R g -N(OR) g )C(O)OR g -N(OR) g )C(O)R g R' g 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups; R g and R' g Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; "R" is independently selected from H and C. 1-6 alkyl; R4 and R5 are independently selected from H and C. 1-8 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 4s replace; Or R4, R5, together with the carbon atoms they are attached to, form C. 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by 1, 2, 3 or 4 R groups. 4s replace; R 4s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -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 and 3 to 14-membered heterocyclic groups.

2. The compound of claim 1, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is phenylene or a 5-6 membered heteroarylene; preferably 5-6 membered heteroarylene; preferably 5 membered heteroarylene; preferably 5 membered azapyridine; preferably diazonidine, triazonidine, or tetrazonidine; preferably diazonidine or triazonidine; preferably triazonidine; preferably... Preferred Preferred Preferred Preferred Preferred Preferred 3. The compound of claim 1 or 2, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Z is N; preferably, Z is CH.

4. The compound of any one of claims 1-3, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G1 and G2 are independently selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain acetylenic group; Preferably, G1 is selected from C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain acetylenic groups, preferably C 1-6 Straight-chain alkylene, preferably C 2-6 Straight-chain alkylene, preferably C 3-5 Straight-chain alkylene; Preferably, G2 is selected from chemical bonds, C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynylene groups, preferably selected from chemical bonds and C 1-6 Straight-chain alkylene groups, preferably selected from chemical bonds and C 1-4 Straight-chain alkylene, preferably C 1-3 Straight-chain alkylene; Preferably, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, more preferably 4, 5, 6 or 7 carbon atoms; more preferably 5, 6 or 7 carbon atoms, more preferably 5 or 6 carbon atoms, more preferably 6 or 7 carbon atoms.

5. 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 G1 Independently selected from H and C 1-8 Alkyl groups; preferably H and C 1-6 alkyl.

6. The compound of any one of claims 1-5, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G 3a and G 3b Independently selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain acetylenic group; Preferably, G 3a Selected from C 2-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain acetylenic groups, preferably C 2-6 Straight-chain alkylene, preferably C 3-5 Straight-chain alkylene; Preferably, G 3b Selected from C 1-4 straight-chain alkylene, C 2-4 Straight-chain alkenyl groups and C 2-4 Straight-chain acetylenic groups, preferably C 1-4 Straight-chain alkylene, preferably C 1-2 Straight-chain alkylene; Preferably, G 3a and G 3b The total length is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably 3, 4, 5, 6 or 7 carbon atoms, and more preferably 4, 5 or 6 carbon atoms.

7. The compound of any one of claims 1-6, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R G3 Independently selected from H and C 1-6 Alkyl, -L a -OR a and -L a -NR a R' a H and C are preferred. 1-6 Alkyl; preferably C 1-3 Alkyl; preferably C 1-2 Alkyl; preferably methyl; Preferably, L a Independently selected from chemical bonds and C 1-8 Alkylenes, preferably selected from chemical bonds and C 1-6 Alkylene; Preferably, R a and R' a Independently selected from H and C 1-8 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 alkyl.

8. The compound of any one of claims 1-7, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G4 is selected from C 1-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; preferably C 2-4 Alkylene; preferably C 2-3 Alkylene; preferably C 3-4 Alkylene.

9. The compound of any one of claims 1-8, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R G4 Independently selected from H and C 1-6 Alkyl; preferably C 1-4 alkyl; Preferably, L b Independently selected from chemical bonds and C 1-4 Alkylene; Preferably, R b and R' b 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 groups; preferably H and C 1-4 alkyl; Preferably, the two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups, preferably forming C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic cycloalkylene groups; Preferably, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, L e Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R e and R' e 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 1-4 alkyl.

10. The compound of any one of claims 1-9, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; preferably C 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group; preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 alkynyl group; Preferably, R1 and R2 are independently selected from C 6-14 Alkyl; preferably C 7-12 Alkyl; preferably C 8-12 Alkyl; preferably C 9-11 Alkyl; preferably C 9-10 alkyl; Preferably, R1 and R2 are optionally divided by one or two R... s Instead, preferably optionally replaced by 1 R s replace; Preferably, R1 and R2 are not substituted at the same time; preferably, one of R1 and R2 is substituted and the other is not substituted; preferably, R1 is not substituted and R2 is substituted; preferably, R1 is substituted and R2 is not substituted. Preferably, R1 and R2 are independently selected from the following groups: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, Preferably selected from -(CH2)8CH3, -(CH2)9CH3, Preferably, one methylene unit in R1 and R2 is optionally and independently replaced by -NR'-.

11. The compound of any one of claims 1-10, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, M1 is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; preferably -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -OC(O)-; preferably -OC(O)-; Preferably, M2 is selected from chemical bonds, -(CH2). 1-2 -, -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; preferably chemical bonds, -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O)-, -SC(O- and -OC(O)O-; preferably -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O- and -SC(O-); preferably -CH2CH2-, -C(O)O- or -OC(O-); preferably -CH2CH2- or -C(O)O-.

12. The compound of any one of claims 1-11, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R and R' are each independently selected from H and C. 1-14 Alkyl groups; preferably H and C 1-9 Alkyl groups; preferably H and C 1-6 Alkyl group; preferably R is H.

13. The compound of any one of claims 1-12, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl; preferably C 1-14 Alkyl; preferably C 1-12 Alkyl; preferably C 1-10 Alkyl; preferably C 1-9 Alkyl; preferably C 4-8 Alkyl; preferably C 5-8 Alkyl; preferably C 1-7 Alkyl; preferably C 5-7 Alkyl; preferably C 6-7 Alkyl; preferably C 1- 6-alkyl; Preferably, L c Independently selected from chemical bonds and C 1-14 Alkylene; preferably chemical bonds and C 1-12 Alkylene; preferably chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-8 Alkylene; preferably chemical bonds and C 1-6 Alkylene; Preferably, R c and R' c Independently selected from H and C 1-14 Alkyl groups; preferably H and C 1-12 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C 1-8 Alkyl groups; preferably H and C 1-6 alkyl.

14. The compound of any one of claims 1-13, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from CN, -OR g and -NR g R' g Preferred - OR g and -NR g R' g Preferred - OR g Preferred -OH; Preferred -NR g R' g Preferred -N(CH3)2 or -N(CH2CH3)2; Preferably, R3 is selected from -OH, -N(CH3)2 and -N(CH2CH3)2; more preferably -OH and -N(CH3)2; more preferably -OH; Preferably, R g and R' g 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 groups; preferably H and C 1-3 Alkyl; preferably H, methyl and ethyl; preferably H and methyl.

15. The compound of any one of claims 1-14, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R4 and R5 are independently selected from C 1-6 Alkyl; preferably C 1-3 Alkyl; preferably C 1-2 Alkyl; preferably methyl; Preferably, R4 and R5 are optionally separated by one R 4s replace; Preferably, R4, R5, together with the carbon atoms they are bonded to, form C. 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably C 3-4 Cycloalkylene; preferably cyclopropylene; Preferably, the rings formed by R4, R5 and the carbon atoms they are attached to are optionally separated by one R 4s replace; Preferably, R4, R5 and the carbon atoms they are connected to do not form rings.

16. The compound of any one of claims 1-15, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -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.

17. 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 s The substitution site on R1 is spaced from M1 by 0-12 carbon atoms, preferably 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-5 carbon atoms, preferably 0-4 carbon atoms, preferably 0-3 carbon atoms, preferably 0-2 carbon atoms; preferably at least 1 carbon atom, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms; preferably at least 2 carbon atoms, preferably 2-4 carbon atoms, preferably 2-3 carbon atoms, preferably 3-4 carbon atoms; Preferably, R s The substitution site on R2 is spaced from ring A by 0-12 carbon atoms, preferably 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-5 carbon atoms, preferably 0-4 carbon atoms, preferably 0-3 carbon atoms, preferably 0-2 carbon atoms; preferably at least 1 carbon atom, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms; preferably at least 2 carbon atoms, preferably 2-4 carbon atoms, preferably 2-3 carbon atoms, preferably 3-4 carbon atoms.

18. The compound of any one of claims 1-17, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II): in, a = 1, 2, 3, 4, 5 or 6; b = 1, 2, 3, 4, 5 or 6; c = 0, 1, 2, 3, 4 or 5; b+c = 3, 4, 5, 6, 7, 8 or 9, with b+c = 4, 5, 6, 7 or 8 being preferred; e = 1, 2, 3, 4, 5, 6 or 7; f = 1, 2, 3 or 4; e+f = 2, 3, 4, 5, 6, 7 or 8; The remaining variables are defined as described in any one of claims 1-17.

19. The compound of claim 18, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II): in, Ring A is phenylene or a 5-6 membered heteroaryl group; preferably a 5-6 membered heteroaryl group. a = 2, 3, 4 or 5; preferably a = 2, 3 or 4; preferably a = 2 or 3; b = 3, 4, or 5; b = 3 or 5 is preferred. c = 1, 2, or 3; c = 1 or 3 is preferred. b+c = 4, 5, 6, 7 or 8; b+c = 5, 6 or 7 is preferred. e = 1, 2, 3, 4, 5, 6 or 7; preferably e = 3, 4 or 5; f = 1, 2, 3, or 4; f = 1 is preferred. e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6; M1 is -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- or -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; M2 is -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O-)- or -SC(O-); preferably -CH2CH2-, -C(O)O- or -C(O)S-; R1 is C 6-14 Straight-chain alkyl groups, optionally bounded by 1, 2, 3 or 4 R groups. s Replacement; preferably R1 is not replaced; R2 is C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. s replace; R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR b R' c H and C are preferred. 1-14 alkyl; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R3 is selected from -OR g and -NR g R' g Preferred - OR g ; R g and R' g Independently selected from H and C 1-6 alkyl; R4 and R5 are independently selected from H and C. 1-6 Alkyl groups, preferably H and C 1-3 alkyl; Or CR4R5 together form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

20. The compound of claim 19, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is a 5-membered heteroaryl group; preferably a 5-membered zazoaryl group. a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2. b = 3, 4, or 5; b = 3 or 5 is preferred. c = 1, 2, or 3; c = 1 or 3 is preferred. b+c = 5, 6, or 7; b+c = 6 is preferred. e = 2, 3, 4, 5 or 6; preferably e = 3, 4 or 5; f = 1 or 2; f = 1 is preferred. e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6; M1 is -C(O)O- or -OC(O-); preferably -OC(O-); M2 is -CH2CH2-, -C(O)O-, or -OC(O-); preferably -CH2CH2- or -C(O)O-. R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl group, optionally marked with one R s Replacement; preferably R1 is not replaced; R2 is C 8-12 Alkyl, preferably C 9-12 Alkyl group, which is optionally marked with one R s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 alkyl; R3 is -OR g and -NR g R' g Preferred - OR g ; R g and R' g Independently selected from H and C 1-3 alkyl; R4 and R5 are independently selected from H and C. 1-3 alkyl; Or CR4R5 together form C 3-6 Cycloalkylene; Preferably, R s The substitution site on R1 is separated from M1 by at least one carbon atom, preferably at least two carbon atoms; R s The substitution site on R2 is separated from ring A by at least one carbon atom, preferably at least two carbon atoms.

21. The compound of claim 19 or 20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is diazolidine or triazolidine; preferably diazolidine; preferably Preferred a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2. b = 3 or 5; c = 1 or 3; b + c = 6; e = 3, 4, or 5; preferably e = 3 or 5. f＝1； M1 is -OC(O)-; M2 is -CH2CH2- or -C(O)O-; R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups, optionally marked with one R s Replacement; preferably R1 is not replaced; R2 is C 8-12 Alkyl, preferably C 9-12 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-9 Alkyl, preferably C 1-7 Alkyl, preferably C 6-7 alkyl; R3 is -OH or -N(CH3)2; preferably -OH. R4 and R5 are independently selected from H and methyl; Or CR4R5 together form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds; Preferably, R s The substitution site on R2 is spaced 1-4 carbon atoms from ring A, preferably 2-4 carbon atoms, and more preferably 2-3 carbon atoms; Preferably, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3; R2 is selected from Preferred 22. The compound of claim 18, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II): in, Ring A is phenylene or a 5-6 membered heteroarylene; preferably a 5-6 membered heteroarylene; preferably a diazonyl group; preferably... a = 2, 3, 4 or 5; preferably a = 2, 3 or 4; preferably a = 2 or 3; b＝5； c＝1； e = 1, 2, 3, 4, 5, 6 or 7; preferably e = 3, 4 or 5; preferably e = 5; f = 1, 2, 3, or 4; f = 1 is preferred. e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6; M1 is -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- or -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; M2 is -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O-)- or -SC(O-); preferably -C(O)O- or -C(O)S-; R1 is C 6-14 Straight-chain alkyl groups, optionally bounded by 1, 2, 3 or 4 R groups. s Replacement; preferably R1 is not replaced; R2 is C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. s replace; R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR b R' c H and C are preferred. 1-14 alkyl; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R3 is selected from -OR g and -NR g R' g Preferred - OR g ; R g and R' g Independently selected from H and C 1-6 alkyl; R4 and R5 are independently selected from H and C. 1-6 Alkyl groups, preferably H and C 1-3 Alkyl, preferably C 1-3 alkyl; Or CR4R5 together form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

23. The compound of claim 22, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is a 5-membered heteroaryl group; preferably a 5-membered azapyridine group; preferably a diazonyl group; preferably... a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2. b＝5； c＝1； e = 2, 3, 4, 5 or 6; preferably e = 3, 4 or 5; preferably e = 5; f = 1 or 2; f = 1 is preferred. e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6; M1 is -C(O)O- or -OC(O-); preferably -OC(O-); M2 is -CH2CH2-, -C(O)O-, or -OC(O-); preferably -C(O)O- or -OC(O-); preferably -C(O)O-. R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl group, optionally marked with one R s Replacement; preferably R1 is not replaced; R2 is C 8-12 Alkyl, preferably C 9-11 Alkyl group, which is optionally marked with one R s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl; R3 is -OR g and -NR g R' g Preferred - OR g ; R g and R' g Independently selected from H and C 1-3 alkyl; R4 and R5 are independently selected from H and C. 1-3 Alkyl, preferably C 1-3 alkyl; Or CR4R5 together form C 3-6 Cycloalkylene compounds; preferably CR4R5, which does not form rings; Preferably, R s The substitution site on R1 is separated from M1 by at least one carbon atom, preferably at least two carbon atoms; R s The substitution site on R2 is separated from ring A by at least one carbon atom, preferably at least two carbon atoms.

24. The compound of claim 22 or 23, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is diazolidine or triazolidine; preferably diazolidine; preferably Preferred Preferred a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2. b＝5； c＝1； e = 3, 4, or 5; preferably e = 3 or 5; preferably e = 5; f＝1； M1 is -OC(O)-; M2 is -CH2CH2- or -C(O)O-; preferably -C(O)O-; R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups, optionally marked with one R s Replacement; preferably R1 is not replaced; R2 is C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 Alkyl, preferably C 6-7 Alkyl groups, preferably C7 alkyl groups; R3 is -OH or -N(CH3)2; preferably -OH. R4 and R5 are independently selected from H and methyl; methyl is preferred; Or CR4R5 together form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds; preferably CR4R5 does not form a ring; Preferably, R s The substitution site on R2 is spaced 1-4 carbon atoms from ring A, preferably 2-4 carbon atoms, and more preferably 2-3 carbon atoms; Preferably, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3; R2 is selected from 25. The compound of claim 18, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II): in, Ring A is phenylene or a 5-6 membered heteroarylene; preferably a 5-6 membered heteroarylene; preferably a triazolyl; preferably... a = 2, 3, 4 or 5; preferably a = 2, 3 or 4; preferably a = 2 or 3; b＝3； c＝3； e = 1, 2, 3, 4, 5, 6 or 7; preferably e = 3, 4 or 5; preferably e = 3; f = 1, 2, 3, or 4; f = 1 is preferred. e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6; M1 is -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- or -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; M2 is -CH2CH2-, -C(O)O-, -C(O)S-, -OC(O-)- or -SC(O-); preferably -CH2CH2-; R1 is C 6-14 Straight-chain alkyl groups, optionally bounded by 1, 2, 3 or 4 R groups. s Replacement; preferably R1 is not replaced; R2 is C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. s replace; R s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR b R' c H and C are preferred. 1-14 alkyl; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R3 is selected from -OR g and -NR g R' g Preferred - OR g ; R g and R' g Independently selected from H and C 1-6 alkyl; R4 and R5 are independently selected from H and C. 1-6 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 alkyl; Or CR4R5 together form C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene groups; Preferably, CR4R5 are used together to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

26. The compound of claim 25, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is a 5-membered heteroaryl group; preferably a 5-membered azapyridine group; preferably a triazole group; preferably... a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2. b＝3； c＝3； e = 2, 3, 4, 5 or 6; preferably e = 3, 4 or 5; preferably e = 3; f = 1 or 2; f = 1 is preferred. e+f = 3, 4, 5, 6 or 7; preferably e+f = 4, 5 or 6; M1 is -C(O)O- or -OC(O-); preferably -OC(O-); M2 is -CH2CH2-, -C(O)O-, or -OC(O-); preferably -CH2CH2-. R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl group, optionally marked with one R s Replacement; preferably R1 is not replaced; R2 is C 8-12 Alkyl, preferably C 10-12 Alkyl, preferably C 9-11 Alkyl group, which is optionally marked with one R s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 alkyl; R3 is -OR g and -NR g R' g Preferred - OR g ; R g and R' g Independently selected from H and C 1-3 alkyl; R4 and R5 are independently selected from H and C. 1-3 Alkyl, preferably C 1-3 Alkyl groups; or CR4R5 together to form C 3-6 Cycloalkylene; Preferably, CR4R5 are used together to form C 3-6 Cycloalkylene; Preferably, R s The substitution site on R1 is separated from M1 by at least one carbon atom, preferably at least two carbon atoms; R s The substitution site on R2 is separated from ring A by at least one carbon atom, preferably at least two carbon atoms.

27. The compound of claim 25 or 26, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is diazolidine or triazole; preferably triazole; preferably Preferred Preferred a = 2, 3, or 4; preferably a = 2 or 3; preferably a = 2. b＝3； c＝3； e = 3, 4, or 5; e = 3 is preferred. f＝1； M1 is -OC(O)-; M2 is -CH2CH2- or -C(O)O-; preferably -CH2CH2-; R1 is C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups, optionally marked with one R s Replacement; preferably R1 is not replaced; R2 is C 8-12 Alkyl, preferably C 10-12 Alkyl, preferably C 9-11 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R s replace; R s Independently for C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-9 Alkyl, preferably C 6-9 Alkyl, preferably C 7-9 Alkyl, preferably C 1-7 Alkyl groups, preferably C7 alkyl groups; R3 is -OH or -N(CH3)2; preferably -OH. R4 and R5 are independently selected from H and methyl; preferably methyl; or CR4R5 together form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds; Preferably, CR4R5 are used together to form C 3-4 Cycloalkylene compounds, such as cyclopropylene compounds; Preferably, R s The substitution site on R2 is spaced 1-4 carbon atoms from ring A, preferably 2-4 carbon atoms, and more preferably 2-3 carbon atoms; Preferably, R1 is selected from -(CH2)8CH3 and -(CH2). 10 CH3; R2 is selected from Preferred 28. 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 those in Table I, with a preference for those in Table II.

29. A composition comprising a compound of any one of claims 1-28, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

30. A nanoparticle composition comprising a lipid component and optionally a loading component; wherein, The lipid component contains a compound of any one of claims 1-28, 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% - 85 mol% Neutral lipids: 1.0 mol% - 30 mol%; Structural lipids: 10 mol% - 75 mol%; Polymer lipids: 0.25 mol% - 10 mol%; Optionally, it further includes 0.01 mol% to 1 mol% of functionalized polymeric lipids; or Optionally, it further includes 0.01 mol% to 1 mol% of the targeting conjugate; Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 30 mol% - 65 mol%; Neutral lipids 2 mol% - 25 mol%; Structural lipids: 12 mol% - 50 mol%; Polymer lipids: 0.5 mol% - 5 mol%; Optionally, the functionalized polymer lipid or targeting conjugate is 0.05 mol% to 0.5 mol%. Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 40 mol% - 65 mol%; Neutral lipids: 5 mol%-25 mol%, preferably 10 mol%-20 mol%; Structural lipids: 20 mol%-50 mol%, preferably 25 mol%-45 mol%; The polymer lipid content is 0.5 mol% to 3.5 mol%, preferably 1 mol% to 2.5 mol%. Optionally, the functionalized polymer lipid or targeting conjugate is present at 0.05 mol%-0.3 mol%, preferably 0.05 mol%-0.25 mol%. Preferably, the lipid component contains the following components in molar percentage: Ionizable lipids: 50 mol% - 58 mol%; Neutral lipids 10 mol%; Structural lipids: 30.5 mol% - 38.5 mol%; Polymer lipids 1.4 mol%; Optionally, the functionalized polymer lipid or targeting conjugate is 0.1 mol%; wherein, The ionizable lipid is selected from the compounds of any one of claims 1-28; The targeting conjugate is a conjugate of a targeting portion and a functionalized polymer lipid, wherein the targeting portion has selective targeting properties and can target target organs and / or target tissues, such as liver, spleen, kidney, heart, brain, lymph nodes, thymus, bone marrow, muscle, blood, skin, and mucosa-associated lymphoid tissue. Preferably, the targeting portion targets immune organs and / or immune tissues; Preferably, the targeting portion targets hematopoietic cells; More preferably, the targeting portion targets immune cells, stem cells, or progenitor cells, such as T cells, natural killer (NK) cells, dendritic cells, macrophages, hematopoietic stem cells (HSCs), pluripotent stem cells, mesenchymal stem cells (MSCs), multipotent progenitor cells, hematopoietic progenitor cells, and / or oligopotent progenitor cells. The functionalized polymer lipid is composed of polymer lipid and functionalized groups; Preferably, the functionalized group is selected from maleimide, azide, alkynyl (alkynylene), dibenzocyclooctylene (DBCO), bromomaleimide, bromomaleimide amide, alkynyl amide or alkynyl imide; preferably, the functionalized group is maleimide; Preferably, the targeting portion is selected from peptides, small molecule ligands, proteins / ligands, carbohydrates, or nucleic acids; Preferably, the polypeptide is selected from antibodies or their antigen-binding portions; Preferably, the targeting portion specifically binds to CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b (Mac-1), CD13, CD14, CD16a, CD25, CD28, CD29, CD31, CD32, CD32A, CD34, CD40, CD44, CD45, CD56, CD64, CD68, CD70, CD73, CD90, CD98, CD105, CD271, 4-1BB, CD166, CD117, CD133, CD137, CD146, CD205, CD2 71. Cell surface proteins of CD326, CTLA-4, GITR, LAG-3, OX40, PD-1, TIM-3, low-affinity IL-2 receptor, IL-7 receptor, IL-12 receptor, IL-15 receptor, IL-18 receptor, IL-21 receptor, BMPR2, CTLA-4, GD2, GITR, DEC205, LAG-3, TREM2, Sca-1, SSEA-4, Stro-1, Stro-4, MSCA-1, SUSD2, TIM-3, PODXL, ASGPR, EPCAM, TfR, OX40, and PD-1.

31. A pharmaceutical composition comprising a compound of any one of claims 1-28, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the composition of claim 29, or the nanoparticle composition of claim 30, and a pharmaceutically acceptable excipient.

32. Use of any compound of claims 1-28, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the composition of claim 29, or the nanoparticle composition of claim 30, or the pharmaceutical composition of claim 31, in the preparation of a medicament for treating, diagnosing, or preventing a disease; wherein the disease is selected from viral infections, cancer, autoimmune diseases, hereditary diseases (single-gene hereditary diseases, hereditary immunodeficiency diseases), and fibrotic diseases; Preferably, the drug used for treating, diagnosing, or preventing the disease is a nucleic acid drug, and more preferably a therapeutic or preventive nucleic acid drug; preferably, the drug used for treating, diagnosing, or preventing the disease is a gene therapy drug, such as a gene editing, gene interference, protein supplementation, or protein replacement drug.

33. Use of any compound of claims 1-28, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the composition of claim 29, or the nanoparticle composition of claim 30, or the pharmaceutical composition of claim 31, in the preparation of a medicament for delivering a payload to a target organ and / or target tissue (e.g., an immune organ and / or immune tissue), said payload being selected from one or more therapeutic agents, preventative agents, or diagnostic agents; preferably, said payload is a gene therapy drug, such as gene editing, gene interference, protein supplementation, or protein replacement.

34. A method of treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject the composition of claim 29, or the nanoparticle composition of claim 30, or the pharmaceutical composition of claim 31; wherein the disease is selected from viral infections, cancer, autoimmune diseases, hereditary diseases (single-gene hereditary diseases, hereditary immunodeficiency diseases), and fibrotic diseases; Preferably, the method for treating, diagnosing, or preventing the disease is gene therapy, such as gene editing, gene interference, protein supplementation, or protein replacement.

35. A compound of any one of claims 1-28, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a composition of claim 29, or a nanoparticle composition of claim 30, or a pharmaceutical composition of claim 31, for the treatment, diagnosis, or prevention of a disease; said disease being selected from viral infections, cancer, autoimmune diseases, hereditary diseases (single-gene hereditary diseases, hereditary immunodeficiency diseases), and fibrotic diseases; It is preferred for use in gene therapy, such as gene editing, gene interference, protein supplementation or protein replacement.

36. A method of delivering a payload to a target organ and / or target tissue (e.g., an immune organ and / or immune tissue) of a subject, comprising administering to the subject the composition of claim 29, or the nanoparticle composition of claim 30, or the pharmaceutical composition of claim 31; in, The payload is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents; preferably, the payload is a gene therapy drug, such as a gene editing, gene interference, protein supplementation, or protein replacement drug.

37. The compound of any one of claims 1-28, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the composition of claim 29, or the nanoparticle composition of claim 30, or the pharmaceutical composition of claim 31, for delivering a payload to a target organ and / or target tissue (e.g., an immune organ or immune tissue). in, The payload is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents; preferably, the payload is a gene therapy drug, such as a gene editing, gene interference, protein supplementation, or protein replacement drug.

38. The nanoparticle composition of claim 30, or the use of claim 33, or the method of claim 36, or the compound, pharmaceutical composition, or nanoparticle composition of claim 37, 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), polymerase-coding nucleic acid (MCNA), polymerase-coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA), or ribozymes, preferably mRNA, siRNA, gRNA, circRNA, SrRNA, miRNA, aRNA, or modified mRNA; Preferably, the mRNA encodes a functional or structural protein; preferably, the protein is selected from T-cell receptors (TCR), chimeric antigen receptors (CAR), immune cell connectors, or gene-editing nucleases; preferably, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), and double-stranded DNA (dsDNA), and more preferably from one or more of microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

39. The use of claim 32, or the method of claim 34, or the compound, pharmaceutical composition, or nanoparticle composition of claim 35, wherein, The disease meets one or more of the following criteria: 1) The viral infection is a chronic viral infection, preferably a chronic viral infection that is difficult to clear, such as HIV, hepatitis B virus, and hepatitis C virus infection; 2) The cancers mentioned are selected from hematologic malignancies and solid tumors; Preferably, the hematologic malignancy is a hematologic malignancy such as a B-cell malignancy, and is more preferably selected from leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome; preferably, the leukemia is selected from acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.; preferably, the lymphoma is selected from Hodgkin's lymphoma and non-Hodgkin's lymphoma. Preferably, the solid tumor is selected from lung cancer, gastric cancer, liver cancer, colorectal cancer, esophageal cancer, pancreatic cancer, breast cancer, cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, kidney cancer, bladder cancer, brain tumor, spinal cord tumor, head and neck squamous cell carcinoma, skin squamous cell carcinoma, basal cell carcinoma, melanoma, and various sarcomas; 3) The autoimmune diseases mentioned are selected from AL amyloidosis, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, etc. Syndrome, idiopathic thrombocytopenic purpura, antiphospholipid syndrome, Chagas disease, Graves' disease, granulomatous polyangiitis, polyarteritis nodosa, Sjögren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, ANCA-associated vasculitis, Goodpasture's disease, Kawasaki disease, autoimmune hemolytic anemia, and rapidly progressive glomerulonephritis; 4) The hereditary diseases mentioned are selected from single-gene hereditary diseases and hereditary immunodeficiency diseases; 5) The fibrotic diseases mentioned are selected from liver fibrosis, pulmonary fibrosis, cardiac fibrosis, renal fibrosis, skin fibrosis, pancreatic fibrosis and myelofibrosis.

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