Rapidly-metabolized lipid compound

Abstract

Provided is a rapidly-metabolized lipid compound. The present invention relates in particular to a compound represented by formula (I), or a pharmaceutically acceptable salt, an isotopic variant, a tautomer or a stereoisomer thereof. Also provided are a nanoparticle pharmaceutical composition comprising the compound, and a use of the compound and a composition thereof in delivering nucleic acids.

Description

A rapidly metabolized lipid compound

[0001] This application claims priority to Chinese application CN202310720951.5 filed on June 16, 2023, Chinese application CN202310723466.3 filed on June 16, 2023, and Chinese application CN202410115561.X filed on January 26, 2024, which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to a novel class of ionizable cationic lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. The present invention also relates to lipid nanoparticles and pharmaceutical compositions comprising the compounds, as well as the use of the lipid nanoparticles in delivering bioactive substances such as nucleic acids (e.g., mRNA, siRNA, ASO, DNA, etc.). Background Art

[0003] Gene therapy involves the introduction of exogenous genes into target cells to correct or compensate for genetic defects or abnormalities within the cells, thereby achieving therapeutic goals. Over the past few decades, research into the use of gene therapy to treat clinical diseases has gained increasing attention. In particular, the recent FDA approval of siRNA-related drugs and mRNA vaccines for clinical treatment has further advanced research and investment in gene therapy.

[0004] Nucleic acid substances are easily degraded under the action of nucleases in vivo, and the nucleic acid substances themselves are negatively charged and are difficult to enter the cell through the cell membrane. Lipid nanoparticles (LNPs), as a nucleic acid delivery material, have the advantages of simple preparation, good biodegradability, no immunogenicity, good safety, and are currently one of the most important nucleic acid delivery systems. The main components of LNP include cationic lipid molecules (Cationic Lipid), cholesterol, neutral lipids and polyethylene glycol-conjugated lipids. Among them, cationic lipid molecules are the core of the LNP delivery system, and their molecular structure plays a decisive role in aspects such as the delivery efficiency, targeting, and formulation stability of the entire liposome nanoparticle.

[0005] Since the delivery of different types of nucleic acid substances and the specific delivery of different targets have different requirements for the delivery system, in order to meet the different needs of gene therapy, new lipid molecules need to be further developed.

[0006] Summary of the Invention

[0007] The present invention develops a new class of ionizable cationic lipid compounds that can be used to deliver various bioactive substances with high delivery efficiency.

[0008] The inventors' prior patent CN115850104A discloses a class of cationic lipid compounds with both tail chains having a digeminal dialkyl structure, which exhibits high delivery efficiency. Unexpectedly, further research revealed that when the digeminal dialkyl structure is applied to cationic lipids containing a central nitrogen atom, the cationic lipids degrade more slowly in the liver, making them suitable for applications requiring slow degradation. For applications requiring accelerated metabolism in the body, the inventors have developed a new class of ionizable cationic lipid compounds.

[0009] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

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

[0011] In another aspect, the present invention provides a nanoparticle composition comprising a lipid component and, optionally, a cargo; wherein the lipid component comprises a compound of the present invention.

[0012] US11246933B1 discloses that incorporating biodegradable groups into the tail chains of lipid compounds in lipid nanoparticles can accelerate metabolism and eliminate the lipids from the body after the active agent is delivered to the target area, thereby making the lipids containing biodegradable groups less toxic than similar lipids without biodegradable groups. The cationic lipid compounds of the present invention have biodegradable groups in their tail chains, resulting in better toxicity than similar lipids without biodegradable groups, such as DLin-MC3-DMA.

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

[0014] In another aspect, the present invention provides use of a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating, diagnosing, or preventing a disease. In one embodiment, the medicament for treating, diagnosing, or preventing a disease is a therapeutic or prophylactic mRNA vaccine.

[0015] In another aspect, the present invention provides use of a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention in the preparation of a medicament for delivering a cargo.

[0016] 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.

[0017] In another aspect, the present invention provides a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention for use in the treatment, diagnosis, and / or prevention of a disease.

[0018] In another aspect, the present invention provides a method of delivering a cargo 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.

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

[0020] In a specific embodiment, the cargo is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; preferably, the therapeutic agent, prophylactic agent or diagnostic agent is a nucleic acid.

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

[0022] 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 non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polyencoding nucleic acid (MCNA), polyencoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA) or ribozyme, preferably mRNA, more preferably modified mRNA.

[0023] definition

[0024] Chemical definition

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

[0026] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5and C 5-6 alkyl.

[0027] “C 1-20 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms. In some embodiments, C 4-20 Alkyl, C 6-14 Alkyl, C 7-12 Alkyl, C 8-12 Alkyl, C 9-12 Alkyl, C 4-10 Alkyl, C 7-11 Alkyl, C 8-11 Alkyl, C 9-11 Alkyl, C 10-11 Alkyl, C 6-10 Alkyl, C 7-10 Alkyl, C 8-10 Alkyl, C 9-10 Alkyl, C 10 Alkyl, C 8-9 Alkyl, C 6-9 Alkyl, C 7-9 Alkyl, C 4-9 Alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 2-8 Alkyl, C 4-8 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 1-20 Alkyl, C 1-14 Alkyl, C 2-14 Alkyl, C 1-13 Alkyl, C 1-12 Alkyl, C 1-10 Alkyl, C 1-9 Alkyl, C 1-8 Alkyl, C 1-7 Alkyl, C 2-7 Alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 1-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 Alkyl and Me are preferred. 1-6Examples 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 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional 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.

[0028] “C 2-13 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 13 carbon atoms and at least one carbon-carbon double bond. 4-20 "Alkenyl" refers to a straight or branched chain 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 4-10 Alkenyl, C 2-10 Alkenyl, C 2-9 Alkenyl, C 2-6 Alkenyl and C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] “C 2-13 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 13 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 4-20"Alkynyl" refers to a straight or branched chain 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, C 6-14 Alkynyl, C 7-12 Alkynyl, C 4-10 Alkynyl, C 2-10 Alkynyl, C 2-9 Alkynyl, C 2-6 Alkynyl and C 2-4 Alkynyl is preferred. 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), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] “C 1-20 "Alkylene" refers to the removal of C 1-20 In some embodiments, C 4-20 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 8-9 Alkylene, C 4-9 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 1-14 Alkylene, C 2-14 Alkylene, C 1-13 Alkylene, C 1-12 Alkylene, C 1-10 Alkylene, C 1-9 Alkyl, C 1-8 Alkylene, C 1-7 Alkylene, C 2-7Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4 Alkylene, C 2-4 Alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1-2 Alkylene and methylene are preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0031] “C 2-13 "Alkenylene" refers to the removal of C 2-13 A divalent group is formed by adding another hydrogen atom of the alkenyl group and may be substituted or unsubstituted. 4-14 "Alkenylene" refers to the removal of C 4-14 In some embodiments, C 6-14 Alkenylene, C 4-10 Alkenylene, C 2-10 Alkenylene, C 2-9 Alkenylene, C 2-6 Alkenylene and C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-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)-), and the like.

[0032] “C 2-13 "Alkynylidene" refers to the removal of C 2-13 The other hydrogen of the alkynyl group forms a divalent group, which may be substituted or unsubstituted. 4-14 "Alkynylidene" refers to the removal of C 4-14 In some embodiments, C 6-14 Alkynylidene, C 4-10 Alkynylidene, C 2-10 Alkynylidene, C 2-9 Alkynylidene, C 2-6 Alkynylidene and C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0033] “C 0-6 "Alkylene" refers to a chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to a chemical bond and the above-mentioned "C 1-4 "Alkylene".

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

[0035] The term "R 1s There are x carbon atoms between the substitution site on R2 and M2", which means that the variable R2 is replaced by the variable R 1s The sum of the number of carbon atoms between the substituted sites (including the N atoms replaced by -NR'-), and so on for other cases. For example:

[0036] In compound 11b, R 1s There are 3 carbon atoms between the substitution site on R2 and M2.

[0037] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0038] Therefore, “C 1-10 "Haloalkyl" refers to the above-mentioned "C 1-10 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkyl, C 1-4 Halogenated alkyl, C 1-3 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] “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 bonds 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, more preferably cyclopropyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to refer to the number of carbons in the cycloalkyl system. Cycloalkyl also includes cycloalkyl rings as described above in which the substituents on any non-adjacent carbon atoms are linked to form a bridge. Ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes the above-mentioned cycloalkyl ring, wherein the substituents on the same carbon atom are connected to form a ring, together forming a polycycloalkane sharing one carbon atom. Exemplary cycloalkyls 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), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0040] “C 3-14 "Cycloalkylene" refers to the removal of C 3-14 In some embodiments, C 3-10 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene is particularly preferred, and cyclopropylene is especially preferred.

[0041] "3-14 membered heterocyclyl" or "3- to 14-membered heterocyclic group" refers to a saturated or unsaturated radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 3 to 10-membered heterocyclyl is preferably a 3 to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5 to 10-membered heterocyclyl is preferably a 5 to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3 to 8-membered heterocyclyl is preferably a 3 to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 3 to 7-membered heterocyclyl is preferably a 3 to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; 5 to 7-membered heterocyclyl is preferably a A 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 3- to 6-membered heterocyclyl, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 6-membered heterocyclyl, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 5-membered heterocyclyl, which is a 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 6-membered heterocyclyl, which is a 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes a heterocyclyl ring in which any substituents on non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes a heterocyclyl ring in which the substituents on the same carbon atom are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxirane, and thiidine. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups also include those in which the above-mentioned heterocyclyl groups share one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group to form a bridged or spirocyclic ring. The shared atoms may be carbon or nitrogen atoms, as valence permits. Heterocyclyl groups also include those in which the above-mentioned heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0042] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] "5-14 membered heteroaryl" or "5 to 14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment 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 heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl or pyridonyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepinyl, and thieptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups.

[0045] "Alkoxy" refers to the oxygen ether form of a straight or branched chain alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0046] "Optionally substituted..." means that the group may be substituted with a designated substituent or may be unsubstituted.

[0047] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0048] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0049] 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(=NRbb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0050] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =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;

[0051] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0052] R bb Each of the following 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, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0053] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0054] R dd Each of the 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, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0055] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0056] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0057] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, 3-7 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0058] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa)2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0059] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and hybrid molecules thereof. 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 (ASOs). The nucleic acid may be further chemically modified, and the chemical modification is selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. The mRNA molecule contains a protein coding region and may further contain an expression regulatory sequence. Typical expression regulatory sequences include, but are not limited to, a 5' cap (5' cap), a 5' untranslated region (5' UTR), a 3' untranslated region (3' UTR), a polyadenylic acid sequence (PolyA), and a miRNA binding site.

[0060] "Cationic lipid" refers to a lipid molecule that is capable of being positively charged under physiological pH conditions. In some embodiments, the cationic lipid is an amino lipid.

[0061] "Neutral lipids" refer to lipid molecules that are uncharged under specific pH conditions, such as physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0062] "Structured lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentanylphenyl carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol.

[0063] "Polymer lipid" refers to a molecule comprising a polymer portion and a lipid portion. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. Other lipids that can reduce aggregation, such as compounds having uncharged, hydrophilic, steric barrier moieties coupled to lipids, can also be used.

[0064] "Lipid nanoparticles" refer to particles containing lipid components and having nanometer dimensions.

[0065] "Biodegradable groups" refer to functional groups containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can affect the elimination of compounds from the body. The biodegradable groups of the present invention are oriented from the head to the tail of the ionizable lipid molecule.

[0066] Other definitions

[0067] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0068] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0069] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0070] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0071] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0072] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., 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.

[0073] "Disease," "disorder," and "condition" are used interchangeably herein.

[0074] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0075] Generally, an "effective amount" of a pharmaceutical composition refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of the pharmaceutical composition of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount encompasses both a therapeutically effective amount and a prophylactically effective amount.

[0076] As used herein, unless otherwise specified, a "therapeutically effective amount" of a pharmaceutical composition is an amount sufficient to provide a 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. A therapeutically effective amount of a pharmaceutical composition refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0077] Unless otherwise specified, a "prophylactically 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 to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a pharmaceutical composition refers to an amount of a therapeutic agent, when used alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0078] "Combination" and related terms refer to the simultaneous or sequential administration of a pharmaceutical composition of the present invention and other therapeutic agents. For example, a pharmaceutical composition of the present invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. DETAILED DESCRIPTION

[0079] Herein, "compounds of the present invention" refers to the following compounds, pharmaceutically acceptable salts, isotopic variations, tautomers or stereoisomers thereof.

[0080] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0081] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0082] in,

[0083] G1 and G2 are independently selected from chemical bonds, C 1-13 Straight chain alkylene, C 2-13 Straight chain alkenylene and C 2-13 Straight chain alkynylene, which is optionally substituted by one or more R G1 replace;

[0084] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0085] R G1 Independently selected from H, C 1-14 Alkyl, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0086] G3 is selected from C 4-14 Straight chain alkylene, C 4-14 Straight chain alkenylene and C 4-14 Straight chain alkynylene, which is optionally substituted by one or more R G3 replace;

[0087] R G3 Independently selected from H, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0088] L a independently selected from chemical bonds and C 1-14 alkylene;

[0089] R a and R' a Independently selected from H, C 1-14 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0090] G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne group, which is optionally substituted by one or more R G4 replace;

[0091] R G4 Independently selected from H, C 1-6 Alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0092] L b independently selected from chemical bonds and C 1-6 alkylene;

[0093] R b and R' b Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0094] or two R attached to the same carbon atom G4 Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4g replace;

[0095] R 4g are independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8Halogenated alkyl, -L e -OR e 、-L e -SR e and -L e -NR e R' e ;

[0096] L e independently selected from chemical bonds and C 1-8 alkylene;

[0097] R e and R' e Independently selected from H, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0098] M1 and M2 are independently 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 -;

[0099] Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f -、-NR f C(O)NR f -、-OC(O)S-、-OC(O)O-、-NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -、-C(O)NR f -、-NR f C(O)-、-NR f C(O)S-、-SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -、-NR f C(S)O-, -SS-, -S(O) 0-2 -, phenylene and pyridinylene, wherein the phenylene or pyridinylene is optionally substituted with one or more R*;

[0100] R* is independently selected from H, halogen, cyano, C1-10 Alkyl, C 1-10 Halogenated alkyl, -L f -OR f 、-L f -SR f and -L f -NR f R' f ;

[0101] L f independently selected from chemical bonds and C 1-8 alkylene;

[0102] R f and R' f Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0103] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted by one or more R 1s substituted, and wherein one or more methylene units are optionally and independently replaced by -NR'-;

[0104] R 1s Independently selected from H, C 1-20 Alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0105] R and R' are each independently selected from H and C 1-20 alkyl;

[0106] L c independently selected from chemical bonds and C 1-20 alkylene;

[0107] R c and R' c Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0108] 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 heterocyclyl and 5- to 14-membered heteroaryl;

[0109] R g and R' g Independently selected from H, C 1-10 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0110] R" is independently selected from H and C 1-6 alkyl;

[0111] R4 and R5 are independently selected from C 1-8 Alkyl, which is optionally replaced by one or more R 4s replace;

[0112] Or R4, R5 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4s replace;

[0113] R 4s are 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 ;

[0114] L d independently selected from chemical bonds and C 1-8 alkylene;

[0115] R d and R'd Independently selected from H, C 1-8 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0116] In another embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has the structure of formula (II):

[0117] in,

[0118] a = 1, 2, 3, 4, 5, or 6;

[0119] b = 4, 5, 6, 7, 8, 9, or 10;

[0120] c = 1, 2, 3, 4, 5, or 6;

[0121] d = 0, 1, 2, 3, or 4;

[0122] c+d=3, 4, 5, 6, 7, 8, or 9;

[0123] The remaining groups are as defined herein.

[0124] G1 and G2

[0125] In one embodiment, G1 is a chemical bond; in another embodiment, G1 is C 1-13 Straight chain alkylene, preferably C 1-9 Straight chain alkylene, preferably C 1-6 Straight chain alkylene, preferably C 2-6 In another embodiment, G1 is C 2-13 Straight chain alkenylene, preferably C 2-9 Straight chain alkenylene, preferably C 2-6 Straight chain alkenylene; in another embodiment, G1 is C 2-13 Straight chain alkynylene, preferably C 2-9 Straight chain alkynylene, preferably C 2-6 In another embodiment, G1 is optionally replaced by one or more R G1 In another embodiment, G1 is optionally replaced by 1, 2, 3 or 4 R G1 substituted; in another embodiment, G1 is not substituted.

[0126] In a more specific embodiment, G1 is selected from a chemical bond, C 1-9 Straight chain alkylene, C 2-9 Straight chain alkenylene and C 2-9 In another more specific embodiment, G1 is selected from C 1-6Straight chain alkylene, C 2-6 Straight chain alkenylene and C 2-6 In another more specific embodiment, G1 is selected from C 1-6 In another more specific embodiment, G1 is selected from C 2-6 Straight chain alkylene.

[0127] In one embodiment, G2 is a chemical bond; in another embodiment, G2 is C 1-13 Straight chain alkylene, preferably C 1-9 Straight chain alkylene, preferably C 1-6 Straight chain alkylene, preferably C 1-4 In another embodiment, G2 is C 2-13 Straight chain alkenylene, preferably C 2-9 Straight chain alkenylene, preferably C 2-6 Straight chain alkenylene; in another embodiment, G2 is C 2-13 Straight chain alkynylene, preferably C 2-9 Straight chain alkynylene, preferably C 2-6 In another embodiment, G2 is optionally replaced by one or more R G1 In another embodiment, G2 is optionally replaced by 1, 2, 3 or 4 R G1 substituted; in another embodiment, G2 is not substituted.

[0128] In a more specific embodiment, G2 is selected from a chemical bond, C 1-9 Straight chain alkylene, C 2-9 Straight chain alkenylene and C 2-9 In another more specific embodiment, G2 is selected from a chemical bond, C 1-6 Straight chain alkylene, C 2-6 Straight chain alkenylene and C 2-6 In another more specific embodiment, G2 is selected from a chemical bond and C 1-6 In another more specific embodiment, G2 is selected from a chemical bond and C 1-4 Straight chain alkylene.

[0129] 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.

[0130] In a 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 or 6 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 5, 6 or 7 carbon atoms; in another more specific embodiment, the total length of G1 and G2 is 6 or 7 carbon atoms.

[0131] R G1

[0132] In one embodiment, R G1 is H; in another embodiment, R G1 C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R G1 -L a -OR a In another embodiment, R G1 -L a -SR a In another embodiment, R G1 -L a -NR a R' a .

[0133] In a more specific embodiment, R G1 Independently selected from H and C 1-10 Alkyl; in another more specific embodiment, R G1 Independently selected from H and C 1-6 alkyl.

[0134] G3

[0135] In one embodiment, G3 is C 4-14 Straight chain alkylene, preferably C 4-10 Straight chain alkylene, preferably C 4-9 Straight chain alkylene, preferably C 5-8 In another embodiment, G3 is C 4-14 Straight chain alkenylene; in another embodiment, G3 is C 4-14 In another embodiment, G3 is optionally replaced by one or more R G3 In another embodiment, G3 is optionally replaced by 1, 2, 3 or 4 R G3 substituted; in another embodiment, G3 is not substituted.

[0136] In a more specific embodiment, G3 is selected from C 4-10 Straight chain alkylene, C 4-10 Straight chain alkenylene and C 4-10 In another more specific embodiment, G3 is selected from C 4-9 In another more specific embodiment, G3 is selected from C 5-8 Straight chain alkylene.

[0137] R G3

[0138] In one embodiment, R G3 is H; in another embodiment, R G3 -L a -OR a In another embodiment, R G3 -L a -SR a In another embodiment, R G3 -L a -NR a R' a .

[0139] L a 、R a and R' a

[0140] In one embodiment, L a is a chemical bond; in another embodiment, L a C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene.

[0141] In a more specific embodiment, La independently selected from chemical bonds and C 1-10 Alkylene; in another more specific embodiment, L a Selected from chemical bonds and C 1-6 Alkylene.

[0142] In one embodiment, R a is H; in another embodiment, R a C 1-14 Alkyl, preferably C 1-10 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.

[0143] In one embodiment, R' a is H; in another embodiment, R' a C 1-14 Alkyl, preferably C 1-10 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.

[0144] In a more specific embodiment, R a and R' a Independently selected from H, C 1-10 Alkyl, C 3-10 cycloalkyl and 3 to 10 membered heterocyclyl; in another more specific embodiment, R a and R' a Independently selected from H and C 1-6 alkyl.

[0145] G4

[0146] In one embodiment, G4 is a chemical bond; in another embodiment, G4 is C 1-6 Alkylene, preferably C 1-4 Alkylene, preferably C 2-4 Alkylene, preferably C 2-3 Alkylene; in another embodiment, G4 is C 2-6 Alkenylene; in another embodiment, G4 is C 2-6Alkyne; In another embodiment, G4 is optionally replaced by one or more R G4 In another embodiment, G4 is optionally replaced by 1, 2, 3 or 4 R G4 substituted; in another embodiment, G4 is not substituted.

[0147] In a more specific embodiment, G4 is selected from C 1-4 Alkylene, C 2-4 Alkenylene and C 2-4 Alkyne; In another more specific embodiment, G4 is selected from C 2-4 Alkylene; In another more specific embodiment, G4 is selected from C 2-3 Alkylene.

[0148] R G4

[0149] In one embodiment, R G4 is 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 embodiment, R G4 -L b -SR b In another embodiment, R G4 -L b -NR b R' b .

[0150] In a more specific embodiment, R G4 Independently selected from H and C 1-6 alkyl.

[0151] In one embodiment, two R G4 Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C 3-7 In another embodiment, two R G4 Together with the carbon atoms to which they are attached, they form a 3- to 14-membered heterocyclylene, preferably a 3- to 10-membered heterocyclylene, preferably a 3- to 7-membered heterocyclylene; in another embodiment, two R G4 The ring formed together with the carbon atoms to which they are attached is optionally substituted by one or more R 4gIn another embodiment, two R G4 The ring formed together with the carbon atom to which they are attached is optionally substituted by 1, 2 or 3 R 4g In another embodiment, two R G4 The ring formed together with the carbon atom to which they are attached is unsubstituted.

[0152] In a more specific embodiment, two R G4 Together with the carbon atoms to which they are attached, they form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene; in another more specific embodiment, two R G4 Together with the carbon atoms to which they are attached, they form C 3-7 cycloalkylene or 3- to 7-membered heterocyclylene.

[0153] L b 、R b and R' b

[0154] In one embodiment, L b is a chemical bond; in another embodiment, L b C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0155] In a more specific embodiment, L b independently selected from chemical bonds and C 1-4 Alkylene.

[0156] In one embodiment, R b is 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.

[0157] In one embodiment, R' b is 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 3-7Cycloalkyl; in another embodiment, R' b It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0158] In a more specific embodiment, R b and R' b Independently selected from H, C 1-6 Alkyl, C 3-7 cycloalkyl and 3 to 7 membered heterocyclyl; in another more specific embodiment, R b and R' b Independently selected from H and C 1-6 Alkyl; in another more specific embodiment, R b and R' b Independently selected from H and C 1-4 alkyl.

[0159] R 4g

[0160] In one embodiment, R 4g is H; in another embodiment, R 4g is halogen; in another embodiment, R 4g 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, preferably C 1-6 haloalkyl; in another embodiment, R 4g -L e -OR e In another embodiment, R 4g -L e -SR e In another embodiment, R 4g -L e -NR e R' e .

[0161] In a more specific embodiment, R 4g are independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0162] L e 、R e and R' e

[0163] In one embodiment, L eis a chemical bond; in another embodiment, L e C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0164] In a more specific embodiment, 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.

[0165] In one embodiment, R e is 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.

[0166] In one embodiment, R' e is 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.

[0167] In a more specific embodiment, R e and R' e Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3 to 10 membered heterocyclyl; in another more specific embodiment, R e and R' e Independently selected from H and C 1-4 alkyl.

[0168] M1 and M2

[0169] 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)-, such as -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-.

[0170] In one 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 another embodiment, M2 is -NR-; in another embodiment, M2 is -C(O)NR-; in another embodiment, M2 is -NRC(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-.

[0171] In a more specific embodiment, M1 and M2 are independently 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-, -OC(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -OC(O)-.

[0172] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -C(O)S-; in another more specific embodiment, M1 and M2 are -C(O)O-.

[0173] In a more specific embodiment, one of M1 and M2 is -C(O)O- or -C(O)S-, and the other is -OC(O)- or -SC(O)-; in another more specific embodiment, one of M1 and M2 is -C(O)O-, and the other is -OC(O)-.

[0174] In a more specific embodiment, M1 is -OC(O)- or -SC(O)-; in another more specific embodiment, M1 is -OC(O)-; in another more specific embodiment, M2 is -C(O)O- or -C(O)S-; in another more specific embodiment, M2 is -C(O)O-.

[0175] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, and -C(O)NH-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, and -C(O)S-; in another more specific embodiment , one of M1 and M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -OC(O)-; in another more specific embodiment In one embodiment, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably -C(O)O- or -OC(O)-; in another more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably selected from -C(O)O- and -OC(O)-, preferably -C(O)O-, preferably -OC(O)-, and M2 is -OC(O)O-; in another more specific embodiment, In the embodiment, M1 is -OC(O)O-, M2 is -OC(O)- or -OC(O)-, preferably -OC(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-, -OC(O)- and -OC(O)O-; in another more specific embodiment, M1 and M2 are not simultaneously -OC(O)O-.

[0176] Q

[0177] In one embodiment, Q is a chemical bond; in another embodiment, Q is -C(O)O-; in another embodiment, Q is -O-; in another embodiment, Q is -SC(O)O-; in another embodiment, Q is -OC(O)NR f -; In another embodiment, Q is -NR f C(O)NR f-; in another embodiment, Q is -OC(O)S-; in another embodiment, Q is -OC(O)O-; in another embodiment, Q is -NR f C(O)O-; in another embodiment, Q is -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -; In another embodiment, Q is -C(O)NR f -; In another embodiment, Q is -NR f C(O)-; in another embodiment, Q is -NR f C(O)S-; in another embodiment, Q is -SC(O)NR f -; in another embodiment, Q is -C(O)-; in another embodiment, Q is -OC(S)-; in another embodiment, Q is -C(S)O-; in another embodiment, Q is -OC(S)NR f -; In another embodiment, Q is -NR f C(S)O-; in another embodiment, Q is -SS-; in another embodiment, Q is -S(O) 0-2 -; in another embodiment, Q is phenylene; in another embodiment, Q is pyridinylene; in another embodiment, when Q is phenylene, it is optionally substituted with one or more R*, preferably optionally substituted with 1, 2 or 3 R*; in another embodiment, Q is unsubstituted phenylene; in another embodiment, when Q is pyridinylene, it is optionally substituted with one or more R*, preferably optionally substituted with 1, 2 or 3 R*; in another embodiment, Q is unsubstituted pyridinylene.

[0178] In a more specific embodiment, Q is selected from a chemical bond, -OC(O)- and -SC(O)-; in another more specific embodiment, Q is selected from a chemical bond and -SC(O)-; in another more specific embodiment, when Q is phenylene or pyridinylene, it is optionally substituted with 1, 2 or 3 R*.

[0179] R*

[0180] In one embodiment, R* is H; in another embodiment, Q is halogen; in another embodiment, R* is cyano; in another embodiment, R* is C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R* is C 1-10 Halogenated alkyl, preferably C 1-6haloalkyl; in another embodiment, R* is -L f -OR f In another embodiment, R* is -L f -SR f In another embodiment, R* is -L f -NR f R' f .

[0181] In a more specific embodiment, R* is independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0182] L f 、R f and R' f

[0183] In one embodiment, L f is a chemical bond; in another embodiment, L f C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0184] In a more specific embodiment, L f independently selected from chemical bonds and C 1-6 Alkylene; in another more specific embodiment, L f independently selected from chemical bonds and C 1-4 Alkylene.

[0185] In one embodiment, R f is H; in another embodiment, R f C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R f C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R f It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0186] In one embodiment, R' f is H; in another embodiment, R' f C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' f C 3-14Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R' f It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0187] In a more specific embodiment, R f and R' f Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3 to 10 membered heterocyclyl; in another more specific embodiment, R f and R' f Independently selected from H and C 1-6 Alkyl; in another more specific embodiment, R f and R' f Independently selected from H and C 1-4 alkyl.

[0188] R1 and R2

[0189] In one embodiment, R1 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 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 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 8-10 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 In another embodiment, R1 is C 4-20 Alkynyl, preferably C 6-14 Alkynyl, preferably C 7-12 Alkynyl, preferably C 8-12 Alkynyl; In another embodiment, R1 is optionally replaced by one or more R 1sIn another embodiment, R1 is optionally replaced by 1, 2, 3 or 4 R 1s substituted, preferably optionally with 1 R 1s In another embodiment, R1 is unsubstituted; In another embodiment, one or more methylene units in R1 are optionally and independently replaced by -NR'-, preferably one methylene unit in R1 is optionally replaced by -NR'-; In another embodiment, R1 is optionally replaced by 1 C 1-9 Alkyl (preferably C 6-9 Alkyl, more preferably C 6-7 alkyl) substituted.

[0190] In one embodiment, R1 is -(CH2)5CH3; in another embodiment, R1 is -(CH2)6CH3; in another embodiment, R1 is -(CH2)7CH3; in another embodiment, R1 is -(CH2)8CH3; in another embodiment, R1 is -(CH2)9CH3; in another embodiment, R1 is -(CH2) 10 CH3; in another embodiment, R1 is -(CH2) 11 CH3; in another embodiment, R1 is -CH2-C≡C-(CH2)5CH3; in another embodiment, R1 is -CH2-C≡C-(CH2)6CH3; in another embodiment, R1 is -(CH2)2-C≡C-(CH2)5CH3; in another embodiment, R1 is -(CH2)4-C≡C-(CH2)3CH3; in another embodiment, R1 is -CH2-CH=CH-(CH2)5CH3; in another embodiment, R1 is -CH2-CH=CH-(CH2)6CH3; in another embodiment, R1 is -(CH2)2-CH=CH-(CH2)5CH3; in another embodiment, R1 is -(CH2)4-CH=CH-(CH2)3CH3; in another embodiment, R1 is -(CH2)5-CH=CH-CH2CH3; in another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is

[0191] In one embodiment, R1 is -(CH2)2-C≡C-(CH2)4CH3; in another embodiment, R1 is -(CH2)3-C≡C-(CH2)3CH3; in another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is

[0192] In one embodiment, 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 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 10Alkyl, preferably C9 alkyl, preferably C 8-12 Straight chain alkyl, preferably C 7-11 Straight chain alkyl, preferably C 8-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl, preferably C 11 Straight chain alkyl, preferably C 10 Straight chain alkyl, preferably C 8-10 Straight chain alkyl, preferably C 9-10 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 In another embodiment, R2 is C 4-20 Alkynyl, preferably C 6-14 Alkynyl, preferably C 7-12 Alkynyl, preferably C 8-12 Alkynyl; In another embodiment, R2 is optionally replaced by one or more R 1s In another embodiment, R2 is optionally replaced by 1, 2, 3 or 4 R 1s substituted, preferably optionally with 1 R 1s substituted, preferably optionally with 1 C 1-3 In another embodiment, R2 is unsubstituted; in another embodiment, one or more methylene units in R2 are optionally and independently replaced by -NR'-, preferably one methylene unit in R2 is optionally replaced by -NR'-.

[0193] In one embodiment, only one of R1 and R2 has a substituent; in another embodiment, R1 has R 1s Substituted, and R2 has no R 1s In another embodiment, R2 has R 1s Replaced, and R1 has no R 1s replace.

[0194] In one embodiment, R2 is -(CH2)5CH3; in another embodiment, R2 is -(CH2)6CH3; in another embodiment, R2 is -(CH2)7CH3; in another embodiment, R2 is -(CH2)8CH3; in another embodiment, R2 is -(CH2)9CH3; in another embodiment, R2 is -(CH2) 10 CH3; In another embodiment, R2 is -(CH2) 11CH3; in another embodiment, R2 is -CH2-C≡C-(CH2)5CH3; in another embodiment, R2 is -CH2-C≡C-(CH2)6CH3; in another embodiment, R2 is -(CH2)2-C≡C-(CH2)5CH3; in another embodiment, R2 is -(CH2)4-C≡C-(CH2)3CH3; in another embodiment, R2 is -CH2-CH=CH-(CH2)5CH3; in another embodiment, R2 is -CH2-CH=CH-(CH2)6CH3; in another embodiment, R2 is -(CH2)2-CH=CH-(CH2)5CH3; in another embodiment, R2 is -(CH2)4-CH=CH-(CH2)3CH3; in another embodiment, R2 is -(CH2)5-CH=CH-CH2CH3; in another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is

[0195] In one embodiment, R2 is -(CH2)2-C≡C-(CH2)4CH3; in another embodiment, R2 is -(CH2)3-C≡C-(CH2)3CH3; in another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is

[0196] In a more specific embodiment, R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 In another more specific embodiment, R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 Alkenyl and C 7-12 In another more specific embodiment, R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl; In another more specific embodiment, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0197] In a more specific embodiment, R1 and R2 are independently selected from C7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s substituted; and only one of R1 and R2 has a substituent.

[0198] In a more specific embodiment, R1 and R2 are independently selected from: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, In another more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, In another more specific embodiment, R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3,

[0199] In a more specific embodiment, R1 and R2 are independently selected from: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, In another more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, In another more specific embodiment, R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3,

[0200] In a more specific embodiment, R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, In another more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[0201] In a more specific embodiment, R1 is selected from In another more specific embodiment, R1 is selected from

[0202] In a more specific embodiment, R1 is selected from In another more specific embodiment, R1 is selected from In another more specific embodiment, R1 is selected from -(CH2)8CH3, -(CH2)9CH3, In another more specific embodiment, R1 is selected from In another more specific embodiment, R1 is selected from

[0203] In a more specific embodiment, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from

[0204] In a more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from

[0205] R 1s

[0206] In one embodiment, R 1s is H; in another embodiment, R 1s is H; in another embodiment, R 1s C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-9 Alkyl, preferably C 7-9 Alkyl, preferably C 8-9 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 6-7Alkyl, preferably C9 alkyl, preferably C8 alkyl, preferably C7 alkyl; in another embodiment, R 1s -L c -OR c In another embodiment, R 1s -L c -SR c In another embodiment, R 1s -L c -NR c R' c .

[0207] In one embodiment, R 1s There is 0 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There is one carbon atom between the substitution site on R1 and M1; in another embodiment, R 1s There are 2 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 3 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 4 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 5 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 6 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 7 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 8 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 9 carbon atoms between the substitution site on R1 and M1; in another embodiment, R 1s There are 10 carbon atoms between the substitution site on R1 and M1.

[0208] In one embodiment, R 1s There is 0 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s There is one carbon atom between the substitution site on R2 and M2; in another embodiment, R 1s There are 2 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s There are 3 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1sThere are 4 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s There are 5 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s There are 6 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s There are 7 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s There are 8 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s There are 9 carbon atoms between the substitution site on R2 and M2; in another embodiment, R 1s The substitution site on R2 is separated from M2 by 10 carbon atoms.

[0209] In a more specific embodiment, R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c In another more specific embodiment, R 1s Independently selected from H and C 1-14 Alkyl; in another more specific embodiment, R 1s Independently selected from H and C 1-10 Alkyl; in another more specific embodiment, R 1s Independently selected from H and C 1-9 Alkyl; in another more specific embodiment, R 1s Independently selected from H and C 1-6 Alkyl; in another more specific embodiment, R 1s Independently selected from H and C 1-4 alkyl.

[0210] In a more specific embodiment, R 1s There are 0-10 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 0-6 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 0-4 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 0-2 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1sThere are 0 carbon atoms between the substitution site on R1 or R2 and M1 or M2.

[0211] In a more specific embodiment, R 1s There are 1 to 10 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 1 to 6 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 1 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 1-2 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 2 to 10 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 2-6 carbon atoms between the substitution site on R1 or R2 and M1 or M2; in another more specific embodiment, R 1s There are 2 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2.

[0212] In another more specific embodiment, R1 has no R 1s Replace, and R 1s There are 0-10 carbon atoms between the substitution site on R2 and M2, preferably 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms; in another more specific embodiment, there is no R on R1 1s Replacement, R 1s There are 0-10 carbon atoms between the substitution site on R2 and M2, preferably 0-6 carbon atoms, preferably 0-4 carbon atoms, preferably 0-2 carbon atoms, preferably 0 carbon atoms; in another more specific embodiment, there is no R on R1 1s Replacement, R 1s The substitution site on R2 is separated from M2 by 2 to 10 carbon atoms, preferably by 2 to 6 carbon atoms, and more preferably by 2 to 4 carbon atoms.

[0213] R and R'

[0214] In one embodiment, R is H; in another embodiment, R is C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 alkyl.

[0215] In one embodiment, R' is H; in another embodiment, R' is C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 alkyl.

[0216] In a more specific embodiment, R and R' are each independently selected from H and C 1-20 In another more specific embodiment, R and R' are each independently selected from H and C 1-14 In another more specific embodiment, R and R' are each independently selected from H and C 1-9 In another more specific embodiment, R and R' are each independently selected from H and C 1-6 In another more specific embodiment, R is H.

[0217] L c 、R c and R' c

[0218] In one embodiment, L c is a chemical bond; in another embodiment, L c C 1-20 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene.

[0219] In a more specific embodiment, 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 1-10 Alkylene; in another more specific embodiment, L c independently selected from chemical bonds and C 1-6 Alkylene.

[0220] In one embodiment, R c is H; in another embodiment, R c C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R c C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R cIt is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0221] In one embodiment, R' c is H; in another embodiment, R' c C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 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.

[0222] In a more specific embodiment, R c and R' c Independently selected from H and C 1-14 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 1-6 alkyl.

[0223] R3

[0224] In one embodiment, R3 is CN; in another embodiment, R3 is -OR g , such as -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 embodiment, R3 is -NR g R' g , such as -N(CH3)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 gIn another embodiment, R3 is -N(OR g )C(O)R g In another embodiment, R3 is -N(OR g )S(O)2R g In another embodiment, R3 is -N(OR g )C(O)OR g In another embodiment, R3 is -N(OR g )C(O)R g R' g In another embodiment, R3 is a 3- to 14-membered heterocyclyl; in another embodiment, R3 is a 5- to 14-membered heteroaryl.

[0225] In a more specific embodiment, R3 is selected from CN, -OR g and -NR g R' g In another more specific embodiment, 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; In another more specific embodiment, R3 is -OR g ; In another more specific embodiment, R3 is OH.

[0226] R g and R' g

[0227] In one embodiment, R g is H; in another embodiment, R g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, such as Me; 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.

[0228] In one embodiment, R' g is H; in another embodiment, R' g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' g C 3-10 Cycloalkyl, preferably C3-7 Cycloalkyl; in another embodiment, R' g It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0229] In a more specific embodiment, R g and R' g Independently selected from H, C 1-6 Alkyl, C 3-7 cycloalkyl and 3 to 7 membered heterocyclyl; 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 1-4 Alkyl; in another more specific embodiment, R g and R' g Independently selected from H and Me.

[0230] R”

[0231] In one embodiment, R" is H; in another embodiment, R" is C 1-6 Alkyl, preferably C 1-4 alkyl.

[0232] R4 and R5

[0233] In one embodiment, R4 is C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably methyl; in another embodiment, R4 is optionally replaced by one or more R 4s In another embodiment, R4 is optionally replaced by 1, 2 or 3 R 4s substituted; in another embodiment, R4 is unsubstituted.

[0234] In one embodiment, R5 is C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably methyl; in another embodiment, R5 is optionally replaced by one or more R 4s In another embodiment, R5 is optionally replaced by 1, 2 or 3 R 4s substituted; in another embodiment, R5 is unsubstituted.

[0235] In one embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C3-6 Cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene), preferably forming C 3-5 Cycloalkylene, preferably forming C 3-4 In another embodiment, R4, R5 and the carbon atom to which they are attached form a 3- to 14-membered heterocyclylene, preferably a 3- to 10-membered heterocyclylene, preferably a 3- to 6-membered heterocyclylene; In another embodiment, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted with one or more R 4s In another embodiment, R4, R5 and the carbon atom to which they are attached together form a ring optionally substituted by 1, 2 or 3 R 4s In another embodiment, R4, R5 and the carbon atom to which they are attached together form a ring that is unsubstituted.

[0236] In a more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-10 In another more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-6 In another more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); in another more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-5 In another more specific embodiment, R4, R5 and the carbon atom to which they are attached form a cyclopropylene or cyclopentylene group; in another more specific embodiment, R4, R5 and the carbon atom to which they are attached form a cyclopropylene group; in another more specific embodiment, R4, R5 and the carbon atom to which they are attached do not form a ring.

[0237] R 4s

[0238] In one embodiment, R 4s is H; in another embodiment, R 4s is halogen; in another embodiment, R 4s 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, preferably C 1-6 Halogenated alkyl, preferably C1-3 haloalkyl; in another embodiment, R 4s -L d -OR d In another embodiment, R 4s -L d -SR d In another embodiment, R 4s -L d -NR d R' d .

[0239] In a more specific embodiment, R 4s are 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 embodiment, R 4s are independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R 4s Independently selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0240] L d 、R d and R' d

[0241] In one embodiment, L d is a chemical bond; in another embodiment, L d C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene.

[0242] In a more specific embodiment, 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.

[0243] In one embodiment, R d is H; in another embodiment, R d C 1-8Alkyl, 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.

[0244] In one embodiment, R' d is 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.

[0245] In a more specific embodiment, R d and R' d Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3 to 10 membered heterocyclyl; in another more specific embodiment, R d and R' d Independently selected from H and C 1-6 alkyl.

[0246] a, b, c, and d

[0247] In one embodiment, a is 1; in another embodiment, a is 2; in another embodiment, a is 3; in another embodiment, a is 4; in another embodiment, a is 5; in another embodiment, a is 6.

[0248] In a more specific embodiment, a=2, 3, 4, 5 or 6; in another more specific embodiment, a=2, 3 or 4; in another more specific embodiment, a=2 or 4; in another more specific embodiment, a=2 or 3; in another more specific embodiment, a=3 or 4.

[0249] In one embodiment, b is 4; in another embodiment, b is 5; in another embodiment, b is 6; in another embodiment, b is 7; in another embodiment, b is 8; in another embodiment, b is 9; and in another embodiment, b is 10.

[0250] In a more specific embodiment, b=5, 6, 7 or 8; in another more specific embodiment, b=5, 6 or 7; in another more specific embodiment, b=5 or 7; in another more specific embodiment, b=6 or 7.

[0251] In a more specific embodiment, b=4, 5, 6, 7, 8, 9 or 10; in another more specific embodiment, b=4, 5, 6, 7, 8 or 9; in another more specific embodiment, b=4, 5, 6 or 7; in another more specific embodiment, b=5 or 6; in another more specific embodiment, b=6, 7 or 8; in another more specific embodiment, b=5, 6, 7 or 8;

[0252] In one embodiment, c is 1; in another embodiment, c is 2; in another embodiment, c is 3; in another embodiment, c is 4; in another embodiment, c is 5; in another embodiment, c is 6.

[0253] In a more specific embodiment, c=2, 3, 4, 5 or 6; in another more specific embodiment, c=2, 3 or 4; in another more specific embodiment, c=3 or 4; in another more specific embodiment, c=5 or 6.

[0254] In a more specific embodiment, c=2, 4, 5 or 6; in another more specific embodiment, c=4, 5 or 6; in another more specific embodiment, c=4 or 6; in another more specific embodiment, c=2, 3, 4 or 5; in another more specific embodiment, c=2, 4 or 5; in another more specific embodiment, c=2 or 5;

[0255] In one embodiment, d is 0; in another embodiment, d is 1; in another embodiment, d is 2; in another embodiment, d is 3; in another embodiment, d is 4.

[0256] In a more specific embodiment, d=0, 1, 2 or 4; in another more specific embodiment, d=2, 3 or 4; in another more specific embodiment, d=0 or 1.

[0257] In a more specific embodiment, d=0, 1, 2, 3 or 4; in another more specific embodiment, d=0, 1 or 2; in another more specific embodiment, d=0 or 2; in another more specific embodiment, d is not 0; in another more specific embodiment, d=1, 2, 3 or 4; in another more specific embodiment, d=1 or 2; in another more specific embodiment, d=1, 2 or 4; in another more specific embodiment, d=1 or 4;

[0258] In one embodiment, c+d=3; in another embodiment, c+d=4; in another embodiment, c+d=5; in another embodiment, c+d=6; in another embodiment, c+d=7; in another embodiment, c+d=8; in another embodiment, c+d=9.

[0259] In a more specific embodiment, c+d=4, 5 or 6; in another more specific embodiment, c+d=5 or 6.

[0260] In a more specific embodiment, c+d=3, 4, 5, 6, 7, 8 or 9; in another more specific embodiment, c+d=4, 5, 6 or 7; in another more specific embodiment, c+d=4, 5 or 6; in another more specific embodiment, c+d=5, 6 or 7; in another more specific embodiment, c+d=6, 7 or 8; in another more specific embodiment, c+d=6 or 7.

[0261] 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 G1 can be combined with G2, R G1 , G3, 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 、M1、M2、Q、R*、L f 、R f , R' f , R1, R2, R 1s , R, R', L c 、R c , R' c , R3, Rg , R' g , R", R4, R5, R 4s 、L d 、R d , R' d The present invention is intended to include combinations of all these technical solutions, which are not listed one by one due to space limitations.

[0262] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0263] in,

[0264] G1 and G2 are independently selected from chemical bonds, C 1-13 Straight chain alkylene, C 2-13 Straight chain alkenylene and C 2-13 Straight chain alkynylene, which is optionally substituted by one or more R G1 replace;

[0265] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0266] R G1 Independently selected from H, C 1-14 Alkyl, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0267] G3 is selected from C 4-14 Straight chain alkylene, C 4-14 Straight chain alkenylene and C 4-14 Straight chain alkynylene, which is optionally substituted by one or more R G3 replace;

[0268] R G3 Independently selected from H, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0269] L a independently selected from chemical bonds and C 1-14 alkylene;

[0270] R a and R' a Independently selected from H, C 1-14 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0271] G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne group, which is optionally substituted by one or more R G4 replace;

[0272] R G4 Independently selected from H, C 1-6 Alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0273] L b independently selected from chemical bonds and C 1-6 alkylene;

[0274] R b and R' b Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0275] or two R attached to the same carbon atom G4 Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4g replace;

[0276] R 4g are 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 ;

[0277] L e independently selected from chemical bonds and C 1-8 alkylene;

[0278] R e and R' eIndependently selected from H, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0279] M1 and M2 are independently 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 -;

[0280] Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f -、-NR f C(O)NR f -、-OC(O)S-、-OC(O)O-、-NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -、-C(O)NR f -、-NR f C(O)-、-NR f C(O)S-、-SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -、-NR f C(S)O-, -SS-, -S(O) 0-2 -, phenylene and pyridinylene, wherein the phenylene or pyridinylene is optionally substituted with one or more R*;

[0281] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L f -OR f 、-L f -SR f and -L f -NR f R' f ;

[0282] L f independently selected from chemical bonds and C 1-8 alkylene;

[0283] Rf and R' f Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0284] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted by one or more R 1s substituted, and wherein one or more methylene units are optionally and independently replaced by -NR'-;

[0285] R 1s Independently selected from H, C 1-20 Alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0286] R and R' are each independently selected from H and C 1-20 alkyl;

[0287] L c independently selected from chemical bonds and C 1-20 alkylene;

[0288] R c and R' c Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0289] 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 heterocyclyl and 5- to 14-membered heteroaryl;

[0290] R g and R' g Independently selected from H, C 1-10 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0291] R" is independently selected from H and C 1-6 alkyl;

[0292] R4 and R5 are independently selected from C 1-8 Alkyl, which is optionally replaced by one or more R 4s replace;

[0293] Or R4, R5 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4s replace;

[0294] R 4s are 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 ;

[0295] L d independently selected from chemical bonds and C 1-8 alkylene;

[0296] R d and R' d Independently selected from H, C 1-8 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0297] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein G1 and G2 are independently selected from a chemical bond, C 1-9 Straight chain alkylene, C 2-9 Straight chain alkenylene and C 2-9 Straight chain alkynylene.

[0298] In a more specific embodiment, G1 is selected from C 1-6 Straight chain alkylene, C 2-6 Straight chain alkenylene and C 2-6 Straight chain alkynylene, preferably selected from C 1-6 Straight chain alkylene, preferably selected from C 2-6 Straight chain alkylene.

[0299] In more specific embodiments, G2 is selected from a chemical bond, C 1-6 Straight chain alkylene, C 2-6 Straight chain alkenylene and C 2-6 Straight chain alkynylene, preferably selected from chemical bonds and C 1-6 Straight chain alkylene, preferably selected from chemical bonds and C 1-4 Straight chain alkylene.

[0300] In more specific embodiments, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably the total length is 4, 5 or 6 carbon atoms, preferably the total length is 5 or 6 carbon atoms; preferably the total length is 5, 6 or 7 carbon atoms, preferably the total length is 6 or 7 carbon atoms.

[0301] Preferably, G1 and G2 are optionally replaced by 1, 2, 3 or 4 R G1 replace.

[0302] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R G1 Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 alkyl.

[0303] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein G3 is selected from C 4-10 Straight chain alkylene, C 4-10 Straight chain alkenylene and C 4-10 Straight chain alkynylene; preferably selected from C 4-9 Straight chain alkylene; preferably selected from C 5-8 Straight chain alkylene.

[0304] In more specific embodiments, G3 is optionally replaced by 1, 2, 3 or 4 R G3 replace.

[0305] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L aindependently selected from chemical bonds and C 1-10 Alkylene, preferably selected from chemical bonds and C 1-6 Alkylene.

[0306] In a more specific embodiment, R a and R' a Independently selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 alkyl.

[0307] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein G4 is selected from C 1-4 Alkylene, C 2-4 Alkenylene and C 2-4 Alkyne group; preferably selected from C 2-4 Alkylene; preferably selected from C 2-3 Alkylene.

[0308] In more specific embodiments, G4 is optionally replaced by 1, 2, 3 or 4 R G4 replace.

[0309] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R G4 Independently selected from H and C 1-6 Alkyl; preferably selected from C 1-4 alkyl.

[0310] In a more specific embodiment, two R G4 Together with the carbon atoms to which they are attached, they form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene, preferably forming C 3-7 Cycloalkylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 R 4g replace.

[0311] In a more specific embodiment, R 4g are independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0312] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L b independently selected from chemical bonds and C 1-4 Alkylene.

[0313] In a more specific embodiment, R b and R' b Independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocyclic groups; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

[0314] In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; preferably selected from -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably selected from -C(O)O- and -OC(O)-.

[0315] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-.

[0316] In a more specific embodiment, one of M1 and M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is -OC(O)- or -SC(O)-, preferably -OC(O)-.

[0317] In a more specific embodiment, M1 is -OC(O)- or -SC(O)-, preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-.

[0318] In more specific embodiments, M1 is -C(O)O-, and M2 is -C(O)O- or -C(O)S-.

[0319] In more specific embodiments, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-.

[0320] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S- and -C(O)NH-, preferably from -C(O)O-, -OC(O)- and -C(O)S-.

[0321] In a more specific embodiment, one of M1 and M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S- and -OC(O)-.

[0322] In a more specific embodiment, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably -C(O)O- or -OC(O)-.

[0323] In a more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably selected from -C(O)O- and -OC(O)-, preferably -C(O)O-, preferably -OC(O)-, and M2 is -OC(O)O-.

[0324] In a more specific embodiment, M1 is -OC(O)O-, and M2 is -OC(O)- or -OC(O)-, preferably -OC(O)-.

[0325] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-, preferably -C(O)O-, -OC(O)- and -OC(O)O-; preferably, M1 and M2 are not both -OC(O)O-.

[0326] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 Alkynyl; preferably selected from C 6-14 Alkyl; preferably selected from C 7-12 Alkyl; preferably selected from C 8-12 alkyl.

[0327] In a more specific embodiment, R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 Alkenyl and C 7-12 Alkynyl, preferably C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12Alkynyl;

[0328] In more specific embodiments, R1 and R2 are optionally replaced by 1, 2, 3 or 4 R 1s substituted, preferably optionally with 1 R 1s replace.

[0329] In more specific embodiments, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0330] In more specific embodiments, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, -(CH2)4-C≡C- (CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0331] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R 1s Independently selected from H, C1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from H and C 1-6 Alkyl, preferably selected from H and C 1-4 alkyl.

[0332] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R and R' are each independently selected from H and C 1-20 Alkyl; preferably selected from H and C 1-14 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from H and C 1-6 Alkyl; preferably R is H.

[0333] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L c independently selected from chemical bonds and C 1-14 Alkylene; preferably selected from chemical bonds and C 1-10 Alkylene; preferably selected from chemical bonds and C 1-6 Alkylene.

[0334] In a more specific embodiment, R c and R' c Independently selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 alkyl.

[0335] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R3 is selected from CN, -OR g and -NR g R' g ; preferably selected from -OR g and -NR g R' g ; preferably -OR g ; preferably OH.

[0336] In a more specific embodiment, R3 is selected from -OH and -N(CH3)2.

[0337] In a more specific embodiment, R g and R' g Independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocyclic groups; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 Alkyl; preferably selected from H and Me.

[0338] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R4 and R5 are independently selected from C 1-6 Alkyl; preferably selected from C 1-3 Alkyl; preferably methyl.

[0339] In more specific embodiments, R4 and R5 are optionally replaced by 1, 2 or 3 R 4s replace.

[0340] In a more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably forms cyclopropylene or cyclopentylene; preferably forms cyclopropylene.

[0341] In more specific embodiments, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted with 1, 2 or 3 R 4s replace.

[0342] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R 4s are 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 ; preferably selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, C 1-3 Alkyl and C 1-3Halogenated alkyl.

[0343] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L d independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-3 Alkylene.

[0344] In a more specific embodiment, R d and R' d Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 alkyl.

[0345] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L e independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-4 Alkylene.

[0346] In a more specific embodiment, R e and R' e Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

[0347] In a more specific embodiment, the present invention provides a compound of the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein Q is selected from a chemical bond, -OC(O)- and -SC(O)-; preferably selected from a chemical bond and -SC(O)-.

[0348] In more specific embodiments, Q is phenylene or pyridinylene, optionally substituted with 1, 2 or 3 R*.

[0349] In more specific embodiments, R* is independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0350] In a more specific embodiment, L f independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-4 Alkylene.

[0351] In a more specific embodiment, R f and R' f Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

[0352] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has a structure of formula (II) or formula (III):

[0353] in,

[0354] a = 1, 2, 3, 4, 5, or 6;

[0355] b = 4, 5, 6, 7, 8, 9, or 10;

[0356] c = 1, 2, 3, 4, 5, or 6;

[0357] d = 0, 1, 2, 3, or 4;

[0358] c+d=3, 4, 5, 6, 7, 8, or 9;

[0359] The remaining groups are as defined herein.

[0360] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0361] Among them, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 0-10 carbon atoms, preferably by 0-6 carbon atoms, preferably by 0-4 carbon atoms, preferably by 0-2 carbon atoms, and preferably by 0 carbon atoms.

[0362] In a more specific embodiment, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 1-10 carbon atoms, preferably by 1-6 carbon atoms, preferably by 1-4 carbon atoms, preferably by 1-2 carbon atoms, preferably by 2-10 carbon atoms, preferably by 2-6 carbon atoms, preferably by 2-4 carbon atoms.

[0363] In a more specific embodiment, R1 has no R 1s Replace, and R 1sThe substitution sites on R2 are separated from M2 by 0-10 carbon atoms, preferably by 1-10 carbon atoms, preferably by 1-6 carbon atoms, preferably by 1-4 carbon atoms, preferably by 1-2 carbon atoms, preferably by 2-10 carbon atoms, preferably by 2-6 carbon atoms, preferably by 2-4 carbon atoms.

[0364] In a more specific embodiment, R1 has R 1s Substituted, and R2 has no R 1s replace.

[0365] In more specific embodiments, R4 and R5 and the carbon atom to which they are attached do not form a ring.

[0366] In a more specific embodiment, d is not zero.

[0367] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0368] in,

[0369] a = 2, 3, 4, 5, or 6;

[0370] b = 4, 5, 6, 7, 8, 9, or 10;

[0371] c = 1, 2, 3, 4, 5, or 6;

[0372] d = 0, 1, 2, 3, or 4;

[0373] c+d=3, 4, 5, 6, 7, 8 or 9; preferably c+d=4, 5 or 6;

[0374] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably, M1 and M2 are independently selected from -C(O)O- and -C(O)S-; or one of M1 and M2 is -C(O)O- or -C(O)S-, and the other is -OC(O)- or -SC(O)-;

[0375] R1 and R2 are independently selected from C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace;

[0376] R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c; preferably selected from H and C 1-14 alkyl;

[0377] L c independently selected from chemical bonds and C 1-14 alkylene;

[0378] R c and R' c Independently selected from H and C 1-14 alkyl;

[0379] R4 and R5 are independently selected from C 1-6 alkyl;

[0380] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

[0381] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0382] a = 2, 3, or 4;

[0383] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7;

[0384] c = 2, 3, 4, 5, or 6;

[0385] d = 0, 1, 2, 3, or 4;

[0386] c + d = 5 or 6;

[0387] M1 and M2 are independently selected from -C(O)O- and -OC(O)-; preferably, M1 and M2 are -C(O)O-; or one of M1 and M2 is -C(O)O- and the other is -OC(O)-;

[0388] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, which is optionally replaced by 1 R 1s replace;

[0389] R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 alkyl;

[0390] R4 and R5 are independently selected from C 1-3 alkyl;

[0391] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene; preferably forming C3-5 Cycloalkylene.

[0392] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0393] a = 2, 3, or 4;

[0394] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7;

[0395] c = 2, 3, 4, 5, or 6;

[0396] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[0397] c+d=5 or 6; preferably c+d=6;

[0398] M1 and M2 are -C(O)O-;

[0399] Or one of M1 and M2 is -C(O)O- and the other is -OC(O)-;

[0400] R1 and R2 are independently selected from: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, Preferably selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, Preferably selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3,

[0401] R4 and R5 are methyl groups;

[0402] Or R4 and R5 and the carbon atom to which they are connected together form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; preferably form cyclopropylene or cyclopentylene; preferably form cyclopropylene.

[0403] In more specific embodiments, only one of R1 and R2 has a substituent.

[0404] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0405] a=2;

[0406] b = 5;

[0407] c=2, 3, 4, 5 or 6; preferably c=6;

[0408] d=0, 1, 2, 3 or 4; preferably d=0;

[0409] c+d=5 or 6; preferably 6;

[0410] M1 and M2 are -C(O)O;

[0411] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0412] R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from C 5-8 Alkyl; preferably selected from C 6-8 Alkyl; preferably selected from C 7-8 alkyl;

[0413] R2 is selected from C 7-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl, preferably C 11 Straight chain alkyl, which is optionally replaced by 1 C 1-3 Alkyl substituted, preferably optionally substituted with 1 methyl group;

[0414] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0415] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene.

[0416] In a more specific embodiment, R1 is selected from Preferably selected from

[0417] In a more specific embodiment, R1 is selected from Preferably selected from

[0418] In more specific embodiments, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and

[0419] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0420] a=2, 3 or 4; preferably a=2;

[0421] b=7;

[0422] c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2;

[0423] d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4;

[0424] c+d=5 or 6; preferably 6;

[0425] M1 and M2 are -C(O)O;

[0426] R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0427] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0428] R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from C 6-9 Alkyl; preferably selected from C 7-8 alkyl;

[0429] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0430] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene.

[0431] In a more specific embodiment, R2 is selected from Preferably selected from Preferably selected from

[0432] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0433] a=2;

[0434] b=7;

[0435] c=3 or 4; preferably c=4;

[0436] d = 2;

[0437] M1 and M2 are -C(O)O;

[0438] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0439] R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 alkyl;

[0440] R2 is selected from C 7-11 Straight chain alkyl, preferably C9 straight chain alkyl;

[0441] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0442] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene.

[0443] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0444] a=2, 3 or 4; preferably a=2 or 4;

[0445] b=6 or 7; preferably b=7;

[0446] c = 2, 3, 4, 5 or 6; preferably c = 5 or 6;

[0447] d = 0, 1, 2, 3 or 4; preferably d = 0 or 1;

[0448] c+d=5 or 6; preferably 6;

[0449] M1 is -OC(O); M2 is -C(O)O;

[0450] R1 is selected from C7-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl;

[0451] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Straight chain alkyl, which is optionally replaced by 1 R 1s replace;

[0452] R 1s Independently selected from C 7-9 alkyl;

[0453] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0454] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene.

[0455] In a more specific embodiment, when a=4, R4 and R5 and the carbon atom to which they are attached do not form a ring; preferably R 1s Independently selected from C 8-9 alkyl.

[0456] In a more specific embodiment, R2 is selected from

[0457] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0458] in,

[0459] a = 2, 3, 4, 5, or 6;

[0460] b = 4, 5, 6, 7, 8, 9, or 10;

[0461] c = 1, 2, 3, 4, 5, or 6;

[0462] d = 0, 1, 2, 3, or 4;

[0463] c+d=3, 4, 5, 6, 7, 8 or 9; preferably c+d=4, 5, 6 or 7;

[0464] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)- and -C(O)NH-, preferably selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably, one of M1 and M2 is -C(O)O- or -C(O)S-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0465] R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 Alkynyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace;

[0466] R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 1-14 alkyl;

[0467] L c independently selected from chemical bonds and C 1-14 alkylene;

[0468] R c and R' c Independently selected from H and C 1-14 alkyl;

[0469] R4 and R5 are independently selected from C 1-6 alkyl;

[0470] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

[0471] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0472] a = 2, 3, or 4;

[0473] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7;

[0474] c = 2, 3, 4, 5, or 6;

[0475] d = 0, 1, 2, 3, or 4;

[0476] c + d = 5, 6, or 7;

[0477] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S- and -C(O)NH-, preferably selected from -C(O)O-, -OC(O)- and -C(O)S-; preferably, one of M1 and M2 is -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably selected from -C(O)O-, -C(O)S- and -OC(O)-;

[0478] R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 Alkenyl and C 7-12 Alkynyl, preferably C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl, which is optionally substituted with 1 R 1s replace;

[0479] R 1s Independently selected from H and C 1-10 alkyl;

[0480] R4 and R5 are independently selected from C 1-3 alkyl;

[0481] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene; preferably forming C 3-5 Cycloalkylene.

[0482] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0483] a = 2, 3, or 4;

[0484] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7;

[0485] c = 2, 3, 4, 5, or 6;

[0486] d = 0, 1, 2, 3, or 4;

[0487] c+d=5, 6 or 7; preferably c+d=6;

[0488] One of M1 and M2 is -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably selected from -C(O)O-, -C(O)S- and -OC(O)-;

[0489] R1 and R2 are independently selected from: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, Preferably selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, Preferably selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3,

[0490] R4 and R5 are methyl groups;

[0491] Or R4 and R5 and the carbon atom to which they are connected together form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; preferably form cyclopropylene or cyclopentylene; preferably form cyclopropylene.

[0492] In more specific embodiments, only one of R1 and R2 has a substituent.

[0493] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0494] a=2;

[0495] b = 5;

[0496] c=5 or 6; preferably c=6;

[0497] d=0 or 1; preferably d=0;

[0498] c+d=5 or 6; preferably 6;

[0499] M1 is -C(O)O-, M2 is -C(O)O- or -C(O)S-; preferably M1 and M2 are -C(O)O-;

[0500] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0501] R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from C 6-8 Alkyl; preferably selected from C 7-8 alkyl;

[0502] R2 is selected from C 7-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl, preferably C 11 Straight chain alkyl, which is optionally replaced by 1 C 1-3 Alkyl substituted, preferably optionally substituted with 1 methyl group;

[0503] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0504] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene.

[0505] In a more specific embodiment, R1 is selected from Preferably selected from

[0506] In more specific embodiments, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and

[0507] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0508] a=2, 3 or 4; preferably a=2;

[0509] b=5, 6 or 7; preferably b=7;

[0510] c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2;

[0511] d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4;

[0512] c+d=5 or 6; preferably 6;

[0513] M1 and M2 are -C(O)O-;

[0514] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s substituted; and only one of R1 and R2 has a substituent;

[0515] R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from C 6-10 Alkyl; preferably selected from C 7-9 alkyl;

[0516] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0517] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming a cyclopropylene; preferably not forming a ring;

[0518] In a more specific embodiment, R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl;

[0519] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s Substitution; when R2 is C 10 When the alkyl group is straight chain, R 1s Selected from C 9-10 Alkyl, preferably C9 alkyl.

[0520] In a more specific embodiment, R2 is selected from Preferably selected from

[0521] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0522] a = 2, 3, or 4;

[0523] b = 6;

[0524] c=4, 5 or 6; preferably c=5 or 6; preferably c=5;

[0525] d=1 or 2; preferably d=1;

[0526] c+d=6, 7 or 8; preferably 6 or 7; preferably 6;

[0527] M1 is -OC(O)-; M2 is -C(O)O-;

[0528] R1 is selected from C 7-12 Straight chain alkyl, preferably C 8-11 Straight chain alkyl, preferably C 9-11 Straight chain alkyl;

[0529] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-12 Alkyl, which is optionally replaced by 1 R 1s replace;

[0530] R 1s Independently selected from C 7-11 Alkyl, preferably C 7-10 alkyl;

[0531] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0532] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene;

[0533] The condition is that when c=4, a=2 or 3.

[0534] In a more specific embodiment, R2 is selected from

[0535] In a more specific embodiment, a=2 or 4; b=6; c=5 or 6, preferably c=5; d=1;

[0536] R1 is selected from C8-9 Straight chain alkyl, preferably C9 straight chain alkyl;

[0537] R2 is selected from C 9-10 Alkyl, preferably C 10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0538] R 1s Independently selected from C 7-8 alkyl;

[0539] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0540] In more specific embodiments, a=2, 3 or 4, preferably a=2 or 4; b=6; c=5; d=2;

[0541] R1 is selected from C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0542] R2 is selected from C 9-11 Alkyl, which is optionally replaced by 1 R 1s replace;

[0543] R 1s Independently selected from C 7-9 alkyl;

[0544] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0545] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0546] a=2, 3 or 4; preferably a=2 or 4;

[0547] b=7;

[0548] c=5 or 6; preferably c=5;

[0549] d=0 or 1; preferably d=1;

[0550] c+d=5 or 6; preferably 6;

[0551] M1 is -OC(O)-; M2 is -C(O)O-;

[0552] R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, which is optionally replaced by 1 C 1-9 Alkyl (preferably C 6-9 Alkyl, more preferably C 6-7alkyl) substituted;

[0553] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0554] R 1s Independently selected from C 7-9 alkyl;

[0555] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0556] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene.

[0557] In more specific embodiments, R1 is selected from -(CH2)8CH3, -(CH2)9CH3,

[0558] R2 is selected from

[0559] In a more specific embodiment, when a=4,

[0560] R1 is selected from C 9-10 Straight chain alkyl;

[0561] R2 is selected from C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0562] R 1s Selected from C 8-9 alkyl;

[0563] R4 and R5 and the carbon atom to which they are connected do not form a ring.

[0564] In a more specific embodiment, when a=2,

[0565] R1 is C 10 Straight chain alkyl.

[0566] In a more specific embodiment, R 1s Selected from C 8-9 Alkyl, preferably C9 alkyl.

[0567] In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein:

[0568] a=2, 3 or 4; preferably a=2 or 4;

[0569] b=7;

[0570] c = 4;

[0571] d = 2;

[0572] M1 is -OC(O)-; M2 is -C(O)O-;

[0573] R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl;

[0574] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0575] R 1s Independently selected from C 7-9 alkyl;

[0576] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0577] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forms cyclopropylene; preferably does not form a ring.

[0578] In a more specific embodiment, R2 is selected from

[0579] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0580] a=2, 3 or 4; preferably a=2;

[0581] b=8;

[0582] c = 5;

[0583] d = 1;

[0584] M1 is -OC(O)-; M2 is -C(O)O-;

[0585] R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl;

[0586] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0587] R 1s Independently selected from C 7-9 Alkyl, preferably C 7-8 alkyl;

[0588] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0589] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forms cyclopropylene; preferably does not form a ring.

[0590] In a more specific embodiment, R2 is selected from

[0591] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0592] a=2;

[0593] b=6, 7 or 8, preferably b=7;

[0594] c = 5;

[0595] d = 1;

[0596] M1 is -OC(O)-; M2 is -C(O)O-;

[0597] R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0598] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0599] R 1s Independently selected from C7 alkyl;

[0600] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0601] In a more specific embodiment, R2 is selected from Preferably

[0602] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0603] a=2 or 3, preferably a=2;

[0604] b=7;

[0605] c = 3;

[0606] d = 3;

[0607] M1 is -OC(O)-; M2 is -C(O)O-;

[0608] R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0609] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0610] R 1s Independently selected from C 6-7 Alkyl, preferably C7 alkyl;

[0611] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0612] In a more specific embodiment, R2 is selected from Preferably

[0613] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0614] in,

[0615] a = 2, 3, 4, 5, or 6;

[0616] b = 4, 5, 6, 7, 8, 9, or 10;

[0617] c = 1, 2, 3, 4, 5, or 6;

[0618] d = 0, 1, 2, 3, or 4;

[0619] c+d=3, 4, 5, 6, 7, 8 or 9; preferably c+d=4, 5 or 6;

[0620] One of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-;

[0621] R1 and R2 are independently selected from C6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace;

[0622] R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 1-14 alkyl;

[0623] L c independently selected from chemical bonds and C 1-14 alkylene;

[0624] R c and R' c Independently selected from H and C 1-14 alkyl;

[0625] R4 and R5 are independently selected from C 1-6 alkyl;

[0626] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

[0627] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0628] a = 2, 3, or 4;

[0629] b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6;

[0630] c = 2, 3, 4, 5 or 6; preferably c = 2, 4, 5 or 6;

[0631] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[0632] c+d=5 or 6; preferably c+d=6;

[0633] One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-;

[0634] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 9-11 Alkyl, which is optionally replaced by 1 R 1s replace;

[0635] R 1sIndependently selected from H and C 1-10 Alkyl; preferably selected from H and C 4-10 alkyl;

[0636] R4 and R5 are independently selected from C 1-3 alkyl;

[0637] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene, preferably forming C 3-4 Cycloalkylene.

[0638] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0639] a = 2, 3, or 4;

[0640] b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6;

[0641] c = 2, 3, 4, 5 or 6; preferably c = 2, 4, 5 or 6;

[0642] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[0643] c+d=5 or 6; preferably c+d=6;

[0644] One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-;

[0645] R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3,

[0646] R4 and R5 are methyl groups;

[0647] Alternatively, R4 and R5 together with the carbon atom to which they are attached form a cyclopropylene group.

[0648] In more specific embodiments, only one of R1 and R2 has a substituent.

[0649] In a more specific embodiment, M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-, and M2 is -OC(O)O-.

[0650] In a more specific embodiment, M1 is -OC(O)O- and M2 is -OC(O)-.

[0651] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0652] a=2;

[0653] b=5 or 6; preferably b=6;

[0654] c=4, 5 or 6; preferably c=4 or 6; preferably c=6;

[0655] d = 0, 1 or 2; preferably d = 0 or 2;

[0656] c+d=6;

[0657] M1 is -C(O)O-, M2 is -OC(O)O-;

[0658] R1 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0659] R 1s Selected from C 7-9 Alkyl, preferably C7 alkyl;

[0660] R2 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0661] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0662] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring.

[0663] In a more specific embodiment, R1 is selected from Preferably

[0664] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0665] a=2;

[0666] b = 6;

[0667] c=4, 5 or 6; preferably c=5 or 6; preferably c=6;

[0668] d = 0, 1 or 2; preferably d = 0 or 1;

[0669] c+d=6;

[0670] M1 is -C(O)O-, M2 is -OC(O)O-;

[0671] R1 is selected from C 8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0672] R2 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0673] R 1s Selected from C 6-7 Alkyl, preferably C7 alkyl;

[0674] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0675] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring.

[0676] In a more specific embodiment, R2 is selected from Preferably

[0677] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0678] a=2;

[0679] b=5 or 6; preferably b=6;

[0680] c = 5;

[0681] d = 1;

[0682] M1 is -OC(O)-, M2 is -OC(O)O-;

[0683] R1 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0684] R 1s Selected from C 6-8 Alkyl, preferably C 6-7 alkyl;

[0685] R2 is selected from C 8-12Straight chain alkyl, preferably C 10-11 Straight chain alkyl;

[0686] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0687] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring.

[0688] In a more specific embodiment, R1 is selected from Preferably

[0689] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0690] a=2, 3 or 4; preferably a=2;

[0691] b = 5, 6, 7 or 8; preferably b = 6 or 7; preferably b = 7;

[0692] c=4, 5 or 6; preferably c=4;

[0693] d=0, 1 or 2; preferably d=1;

[0694] c+d=5 or 6; preferably c+d=5;

[0695] M1 is -OC(O)O-, M2 is -OC(O)-;

[0696] R1 is selected from C 8-12 Alkyl, preferably selected from C 8-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0697] R 1s Selected from C 6-10 Alkyl, preferably selected from C 6-8 alkyl;

[0698] R2 is selected from C 8-12 Straight chain alkyl, preferably C 8-10 Straight chain alkyl;

[0699] R4 and R5 are independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0700] Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring.

[0701] In a more specific embodiment, R1 is

[0702] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0703] in,

[0704] Q is -SC(O)- or -OC(O)-;

[0705] R g and R' g Independently selected from C 1-6 alkyl;

[0706] a=2, 3, 4, 5 or 6, preferably a=2, 3 or 4;

[0707] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6 or 7;

[0708] c = 2, 3, 4, 5, or 6;

[0709] d = 0, 1, 2, 3, or 4;

[0710] c + d = 5 or 6;

[0711] M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-;

[0712] R1 and R2 are independently selected from C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace;

[0713] R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 1-14 alkyl;

[0714] L c independently selected from chemical bonds and C 1-14 alkylene;

[0715] R c and R' c Independently selected from H and C 1-14 alkyl;

[0716] R4 and R5 are independently selected from C 1-6 alkyl;

[0717] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

[0718] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein:

[0719] Q is -SC(O)- or -OC(O)-;

[0720] R g and R' g Independently selected from C 1-3 alkyl;

[0721] a=3 or 4;

[0722] b = 6 or 7;

[0723] c=2, 3, 4 or 5; preferably 2 or 5;

[0724] d = 1, 2, 3 or 4; preferably 1 or 4;

[0725] c + d = 5 or 6;

[0726] M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably, M1 and M2 are not both -OC(O)O-;

[0727] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-10 Alkyl, which is optionally replaced by 1 R 1s replace;

[0728] R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 alkyl;

[0729] R4 and R5 are independently selected from C 1-3 alkyl;

[0730] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene.

[0731] In a more specific embodiment, the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein:

[0732] Q is -SC(O)-;

[0733] R g and R'g is methyl;

[0734] a=3 or 4;

[0735] b = 6 or 7;

[0736] c=2, 4 or 5; preferably 2 or 5;

[0737] d = 1, 2 or 4; preferably 1 or 4;

[0738] c+d=6;

[0739] M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably, M1 and M2 are not both -OC(O)O-;

[0740] R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[0741] R4 and R5 are methyl groups;

[0742] Alternatively, R4 and R5 and the carbon atom to which they are attached together form a cyclopropylene group, preferably not forming a ring.

[0743] In more specific embodiments, only one of R1 and R2 is substituted; preferably, R1 is unsubstituted and R2 is substituted.

[0744] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0745] Wherein, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-;

[0746] The remaining groups are as defined herein.

[0747] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0748] wherein one of M1 and M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is -OC(O)- or -SC(O)-, preferably -OC(O)-;

[0749] The remaining groups are as defined herein.

[0750] In a more specific embodiment, R 1s Independently selected from H and C 1-6 Alkyl, preferably selected from H and C 1-4 alkyl.

[0751] In a more specific embodiment, M1 is -OC(O)- or -SC(O)-, preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-.

[0752] In a more specific embodiment, R 1s Independently selected from C 1-8 Alkyl, preferably selected from C 4-8 Alkyl, preferably selected from C 6-8 Alkyl, preferably selected from C 7-8 Alkyl, preferably C8 alkyl.

[0753] In a more specific embodiment, the present invention provides a compound of formula (II) or formula (III) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0754] in,

[0755] Q is selected from a chemical bond, -SC(O)-, and -OC(O)-;

[0756] R g and R' g Independently selected from C 1-6 alkyl;

[0757] a = 2, 3, 4, 5, or 6;

[0758] b = 6 or 7;

[0759] c = 5 or 6;

[0760] d = 0 or 1;

[0761] c + d = 5 or 6;

[0762] M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-;

[0763] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, which is optionally replaced by 1 R 1s replace;

[0764] R 1s Independently selected from H and C 1-10 alkyl;

[0765] R4 and R5 are independently selected from C1-6 alkyl;

[0766] Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene.

[0767] In more specific embodiments, only one of R1 and R2 is substituted; preferably, R1 is unsubstituted and R2 is substituted.

[0768] In a more specific embodiment, the present invention provides the above-mentioned formula (II) or compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0769] Q is -SC(O)- or -OC(O)-, preferably -SC(O)-;

[0770] R g and R' g Independently selected from C 1-3 an alkyl group, preferably a methyl group;

[0771] a=2, 3 or 4; preferably a=2 or 4; more preferably a=4;

[0772] b=6 or 7; preferably b=7;

[0773] c=5 or 6; preferably c=5;

[0774] d=0 or 1; preferably d=1;

[0775] c+d=5 or 6; preferably 6;

[0776] M1 is -OC(O)-; M2 is -C(O)O-;

[0777] R1 is selected from C 7-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0778] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace;

[0779] R 1s Independently selected from C 1-9 Alkyl, preferably selected from C 1-8 Alkyl, preferably selected from C 4-9 Alkyl, preferably selected from C 4-8 alkyl;

[0780] R4 and R5 are independently selected from C1-3 an alkyl group, preferably a methyl group;

[0781] Or R4 and R5 and their connected carbon atoms together form C 3-4 The cycloalkylene group preferably forms a cyclopropylene group.

[0782] In a more specific embodiment, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 0-10 carbon atoms, preferably by 0-6 carbon atoms, preferably by 0-4 carbon atoms, preferably by 0-2 carbon atoms, and preferably by 0 carbon atoms.

[0783] In a more specific embodiment, R1 has no R 1s Replace, and R 1s The substitution sites on R2 are separated from M2 by 0-10 carbon atoms, preferably by 1-10 carbon atoms, preferably by 1-6 carbon atoms, preferably by 1-4 carbon atoms, preferably by 1-2 carbon atoms, preferably by 2-10 carbon atoms, preferably by 2-6 carbon atoms, preferably by 2-4 carbon atoms.

[0784] In a more specific embodiment, R2 is selected from Preferably selected from Preferably selected from Preferred

[0785] In more specific embodiments, R4 and R5 and the carbon atom to which they are attached do not form a ring.

[0786] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein the compound is selected from Table (I).

[0787] Table (I)

[0788] The present invention also provides a method for preparing the compound of formula (II), which comprises:

[0789] reacting a compound of formula (IIA) with a compound of formula (IIB) to obtain a compound of formula (II);

[0790] wherein X is a halogen, and the remaining variables are as defined herein.

[0791] The present invention also provides a method for preparing the compound of formula (II), which comprises:

[0792] reacting a compound of formula (IIC) with a compound of formula (IID) to obtain a compound of formula (II);

[0793] wherein X is a halogen, and the remaining variables are as defined herein.

[0794] In a specific embodiment, the compound is selected from the following:

[0795] In a more specific embodiment, the present invention provides a nanoparticle composition comprising a lipid component, and optionally a cargo; wherein the lipid component comprises a compound of the present invention.

[0796] Optionally, the lipid component comprises the following components in molar percentages:

[0797] Ionizable cationic lipids 20 mol%-85 mol%:

[0798] Structural lipids 10 mol%-75 mol%;

[0799] Neutral lipids 1.0 mol%-30 mol%;

[0800] Polymer lipid 0.25mol%-10mol%;

[0801] Optionally, the lipid component comprises the following components in molar percentages:

[0802] 50 mol% of any of the above compounds of the present invention;

[0803] Neutral lipids 10 mol%;

[0804] structural lipids 38.5 mol%;

[0805] Polymer lipid 1.5 mol%.

[0806] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE, preferably DSPC and / or DOPE.

[0807] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the structured lipid is selected from one or more of cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol.

[0808] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the polymer lipid is a pegylated lipid.

[0809] Optionally, the PEGylated lipid is selected from one or more of: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol.

[0810] Optionally, the PEGylated lipid comprises a PEG moiety of about 1000 Da to about 20 kDa, preferably a PEG moiety of about 1000 Da to about 5000 Da.

[0811] Optionally, the PEGylated lipid is selected from one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000, preferably DMG-PEG2000.

[0812] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent;

[0813] Preferably, the therapeutic, prophylactic or diagnostic agent is a nucleic acid;

[0814] Preferably, the nucleic acid is selected from one or more of ASO, RNA or DNA;

[0815] Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polyencoding nucleic acid (MCNA), polyencoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA) or ribozyme, preferably mRNA, more preferably modified mRNA.

[0816] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present 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 enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0817] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0818] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (IV) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually 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, 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. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (IV) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0819] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (IV) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0820] Pharmaceutical compositions and kits

[0821] In another aspect, the present invention provides a pharmaceutical composition comprising a nanoparticle composition of the present invention and a pharmaceutically acceptable excipient, wherein the nanoparticle composition comprises a compound of the present invention.

[0822] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0823] The present invention also includes kits (e.g., pharmaceutical packaging). The provided kits can include the nanoparticle composition of the present invention and other therapeutic, diagnostic, or prophylactic agents, as well as 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 the other therapeutic, diagnostic, or prophylactic agent. In some embodiments, the provided kits can also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the nanoparticle composition of the present invention and / or other therapeutic, diagnostic, or prophylactic agent. In some embodiments, the nanoparticle composition of the present invention and the other therapeutic, diagnostic, or prophylactic agent provided in the first and second containers are combined to form a unit dosage form.

[0824] Drug administration

[0825] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0826] Typically, an effective amount of the pharmaceutical composition of the present invention is administered. The amount of the pharmaceutical composition actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated or prevented, the route of administration selected, the pharmaceutical composition actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0827] When used to prevent the conditions described herein, the pharmaceutical compositions provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0828] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0829] 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 injection, for example, in order 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 ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0830] To provide blood levels similar to, or lower than, those obtained with an injectable 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, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0831] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0832] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0833] Example

[0834] In order to make the technical solution of the present invention clearer and more specific, the present invention is further described in detail by the following examples. The following examples are only used to illustrate the specific embodiments 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 not specifically described are conventional technical means or methods in the art. The materials, reagents, etc. used in the examples, unless otherwise specified, can be obtained from commercial sources.

[0835] Table 1

[0836] Example 1: Synthesis of Compound 1a

[0837] To a 500 mL three-necked round-bottom flask at room temperature were added 1-nonanol (15 g, 104.0 mmol, 1.0 eq.), 8-bromooctanoic acid (25.5 g, 114.0 mmol, 1.1 eq.), DMAP (2.54 g, 20.8 mmol, 0.2 eq.), DIEA (40.3 g, 312.0 mmol, 3.0 eq.), and EDCI (25.9 g, 135 mmol, 1.3 eq.), followed by 250 mL of DCM. The reaction mixture was stirred at room temperature for 4 hours, and the reaction was monitored for completion by TLC. The reaction mixture was poured into 200 mL of saturated aqueous ammonium chloride and extracted with 3 x 100 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 21 g of compound 1a-2 as a yellow oil.

[0838] To a 250 mL three-necked round-bottom flask, compound 1a-2 (21 g, 60.1 mmol, 1.0 eq.) and 2-aminoethanol (110 g, 1.80 mol, 30.0 eq.) were added at room temperature and dissolved in 100 mL of methanol. The mixture was heated to 60°C and stirred for 18 hours. The solvent was removed by concentration, and saturated aqueous ammonium chloride and ethyl acetate were added. The organic phases were separated and extracted. The combined organic phases were dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 14 g of compound 1a-3 as a yellow oil.

[0839] To a 250 mL three-necked round-bottom flask at room temperature, 9-heptadecanol (9.8 g, 38.2 mmol, 1.0 eq.) and triethylamine (15.5 g, 152.8 mmol, 4.0 eq.) were added and dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and then 2-methylpropanoyl chloride (9.8 g, 91.7 mmol, 2.4 eq.) was slowly added. The reaction was allowed to warm to room temperature overnight. TLC monitored the reaction for completion, and the reaction was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 8.7 g of compound 1a-5 as a yellow oil.

[0840] To a 250 mL three-necked round-bottom flask at room temperature, compound 1a-5 (8.7 g, 26.6 mmol, 1.0 eq.) was added and dissolved in 60 mL of THF. The reaction system was cooled to -40°C, and LDA (13.1 mL, 26.2 mmol, 0.98 eq.) was slowly added dropwise. The reaction was stirred for 1 hour. 1,6-Dibromohexane (9.03 g, 37.0 mmol, 1.39 eq.) and DMPU (0.48 g, 3.73 mmol, 0.14 eq.) were then added to the reaction system. The reaction was allowed to warm to room temperature overnight. TLC monitored the reaction completion, and the reaction was quenched by adding saturated ammonium chloride in an ice-cold solution. The organic phases were extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 10.1 g of compound 1a-6 as a yellow oil.

[0841] To a 20 mL round-bottom flask, compound 1a-6 (1.48 g, 3.04 mmol, 2.0 eq.), compound 1a-3 (500 mg, 1.52 mmol, 1.0 eq.), K2CO3 (628.2 mg, 4.55 mmol, 3.0 eq.), KI (302.3 mg, 1.82 mmol, 1.2 eq.), cyclopentyl methyl ether (7.5 mL), and acetonitrile (2.5 mL) were added. The reaction mixture was heated to 80°C. After TLC monitoring, the reaction was quenched by adding saturated aqueous ammonium chloride solution and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 96.98 mg of compound 1a as an oil.

[0842] 1 H NMR(400MHz, CDCl3)δ:4.86-4.80(m,1H),4.04(t,J=7.2Hz,2H),3.57(m,2H),2.62(t,J=7.2Hz ,2H),2.49(t,J=7.2Hz,4H),2.29(t,J=7.2Hz,2H),1.62(m,4H),1.51-1.45(m,10H),1.38-1.23 (m,49H),1.15(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:738.60[M+H] + .

[0843] Example 2: Synthesis of Compound 2a

[0844] To a 250 mL three-necked round-bottom flask at room temperature, 1-nonanol (8.8 g, 61.0 mmol, 1.0 eq.) and triethylamine (24.7 g, 244.0 mmol, 4.0 eq.) were added and dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and then 2-methylpropanoyl chloride (15.6 g, 146.4 mmol, 2.4 eq.) was slowly added. The reaction was allowed to warm to room temperature. TLC monitored the reaction for completion, and the reaction was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 10.8 g of compound 2a-2 as a yellow oil.

[0845] To a 250 mL three-necked round-bottom flask at room temperature, compound 2a-2 (4.8 g, 22.4 mmol, 1.0 eq.) was added and dissolved in 50 mL of THF. The reaction system was cooled to -40°C, and LDA (11.0 mL, 21.9 mmol, 0.98 eq.) was slowly added dropwise. The reaction was stirred for 1 hour, followed by the addition of 1,6-dibromohexane (7.59 g, 31.1 mmol, 1.39 eq.) and DMPU (0.57 g, 4.48 mmol, 0.2 eq.). The reaction was allowed to warm to room temperature overnight. TLC monitored the reaction completion, and the reaction was quenched by the addition of saturated ammonium chloride in ice water. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 4.6 g of compound 2a-3 as a yellow oil.

[0846] To a 250 mL three-necked round-bottom flask, compound 2a-3 (4.6 g, 12.2 mmol, 1.0 eq.) and 2-aminoethanol (14.9 g, 244.0 mmol, 20.0 eq.) were added at room temperature and dissolved in 50 mL of ethanol. The mixture was stirred and heated to 60°C for 18 hours. The solvent was then concentrated to remove the solvent. Saturated aqueous ammonium chloride and ethyl acetate were then added, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to afford 2.2 g of compound 2a-4 as a yellow oil.

[0847] To a 20 mL round-bottom flask were added compound 2a-4 (500 mg, 1.4 mmol, 1.0 eq.), compound 1a-6 (1.37 g, 2.8 mmol, 2.0 eq.), K2CO3 (579 mg, 4.2 mmol, 3.0 eq.), KI (279 mg, 1.68 mmol, 1.2 eq.), cyclopentyl methyl ether (7.5 mL), and acetonitrile (2.5 mL). The temperature was raised to 80°C. Following completion of the reaction, the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to afford 137.9 mg of compound 2a as an oil.

[0848] 1 H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.04 (t, J = 7.2Hz, 2H), 3.55 (t, J = 5.6Hz, 2H), 2.60 (t, J = 5.6Hz, 2H), 2.47 (t, J=7.2Hz,4H),1.62(m,2H),1.52-1.40(m,12H),1.36-1.20(m,48H),1.15(m,12H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:766.50[M+H] + .

[0849] Example 3: Synthesis of Compound 3a

[0850] Compound 3a was prepared by referring to the method of Example 1 to obtain 114.7 mg of an oily product.

[0851] 1 H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.06 (t, J=7.2Hz, 2H), 3.59 (m, 2H), 2.66 (m, 2H), 2.54 (m, 4H), 2.30 (t, J= 7.2Hz,2H),1.70-1.56(m,4H),1.50(m,10H),1.32-1.26(m,49H),1.15(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:738.55[M+H] + .

[0852] Example 4: Synthesis of Compound 4a

[0853] Compound 4a was prepared by referring to the method of Example 1 to obtain 112.1 mg of an oily product.

[0854] 1 H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.05 (t, J = 7.2Hz, 2H), 3.80 (t, J = 5.4Hz, 2H), 2.51-2.73 (m, 6H ),2.29(t,J=7.2Hz,2H),1.65-1.44(m,16H),1.26(m,49H),1.15(s,6H),0.93-0.82(m,9H); ESI-MS m / z:752.70[M+H] + .

[0855] Example 5: Synthesis of Compound 5a

[0856] Compound 5a was prepared by referring to the method of Example 1 to obtain 150.8 mg of an oily product.

[0857] 1 H NMR (300MHz, CDCl3) δ: 4.84 (m, 1H), 4.05 (t, J = 7.2Hz, 2H), 3.60 (m, 2H), 2.41-2.63 (m, 4H), 2.29 ( t,J=7.2Hz,2H),1.65-1.44(m,18H),1.26-1.34(m,51H),1.14(s,6H),0.93-0.82(m,9H); ESI-MS m / z:766.70[M+H] + .

[0858] Example 6: Synthesis of Compound 6a

[0859] Dissolve tert-butyl cyclopropanecarboxylate (15.0 g, 150.0 mmol, 1.0 eq.) in 150 mL of anhydrous tetrahydrofuran and cool to -60°C. Add LDA (150.0 mL, 300.0 mmol, 2.0 eq.) to the reaction mixture under nitrogen. Stir the reaction at the same temperature for 1 hour, then add 1-bromo-6-chlorohexane (44.9 g, 225.0 mmol, 1.5 eq.). Continue stirring at room temperature for 3 hours. Monitor the reaction by TLC until completion. Quench the reaction with saturated aqueous ammonium chloride, extract with DCM, and combine the organic phases, drying over anhydrous sodium sulfate. Filter and concentrate the filtrate to dryness to obtain the crude product, which is then purified on a silica gel column to afford 19 g of compound 6a-1 as a colorless oil.

[0860] 10.0 mL of trifluoroacetic acid was added to a solution of compound 6a-1 (10.0 g, 38.3 mmol) in DCM (30.0 mL). The mixture was stirred at room temperature for 3 hours. The reaction solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column to obtain 6.9 g of colorless oily compound 6a-2.

[0861] Compound 6a-2 (500.0 mg, 2.45 mmol, 2.0 eq.) was dissolved in DCM (5.0 mL). 2-3 drops of DMF and oxalyl chloride (311.1 mg, 2.45 mmol, 2.0 eq.) were added to the reaction system under ice-bath conditions. After stirring for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain the acid chloride intermediate. The obtained acid chloride was dissolved in DCM (5.0 mL), and then 9-heptadecanol (312.3 mg, 1.22 mmol, 1.0 eq.) and triethylamine (247.5 mg, 2.45 mmol, 2.0 eq.) were added. The reaction was allowed to react at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 240 mg of oily compound 6a-3.

[0862] To a solution of compound 6a-3 (200.0 mg, 0.45 mmol, 1.5 eq.) in DMF (3.0 mL) were added potassium carbonate (124.2 mg, 0.90 mmol, 3.0 eq.), sodium iodide (112.5 mg, 0.75 mmol, 2.5 eq.), and compound 1a-3 (99.0 mg, 0.30 mmol, 1.0 eq.). The reaction mixture was heated to 80°C and stirred for 5 hours. After completion, the reaction system was cooled to room temperature and quenched with saturated sodium chloride solution. The mixture was extracted with dichloromethane (DCM), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified by preparative liquid chromatography to afford 75.2 mg of compound 6a. (Column model: XSelect C18 (19×150 mm, 5 μm); mobile phase A: water: acetonitrile = 90:10 (10 mmol / L ammonium bicarbonate + 0.5% ammonia water), mobile phase B: isopropanol: acetonitrile = 90:10; flow rate: 25 mL / min; gradient: the proportion of B in 0-12 minutes is 75%-80%, and the proportion of B after 12 minutes is 90%).

[0863] 1 H NMR(400MHz, CDCl3)δ:4.82(m,1H),4.05(t,J=7.2Hz,2H),2.57(m,6H),2.29(t,J=7.2Hz,2H),1.61(m,7H),1 .52(m,13H);1.21-1.37(m,45H),1.16(q,J=4.4Hz,2H),0.88(t,J=7.2Hz,9H),0.64(q,J=4.4Hz,2H); ESI-MS m / z:736.55[M+H] + .

[0864] Example 7: Synthesis of Compound 7a

[0865] Compound 7a was prepared by referring to the method of Example 1 to obtain 102.4 mg of an oily product.

[0866] 1 H NMR (300MHz, CDCl3) δ: 4.08 (td, J = 7.2Hz, 4H), 3.58 (m, 2H), 2.57 (d, J = 40.6Hz, 6H), 2.31 (t, J =7.2Hz,2H),1.73-1.40(m,14H),1.20-1.39(m,45H),1.17(s,6H),0.96-0.85(m,9H); ESI-MS m / z:710.55[M+H] + .

[0867] Example 8: Synthesis of Compound 8a

[0868] Compound 8a was prepared by referring to the method of Example 1 to obtain 44.9 mg of an oily product.

[0869] 1 H NMR(300MHz, CDCl3)δ:4.07-3.91(m,4H),3.56(m,2H),2.31-2.62(m,6H),2.29(t,J=7.2 Hz,2H),1.73-1.40(m,12H),1.39-1.20(m,44H),1.16(s,6H),0.93-0.82(m,9H); ESI-MS m / z:696.50[M+H] + .

[0870] Example 9: Synthesis of Compound 9a

[0871] In a 250 mL round-bottom flask, 5-bromo-1-pentanol (30 g, 180.0 mmol, 1.0 eq.) and imidazole (30.6 g, 449.0 mmol, 2.5 eq.) were dissolved in 120 mL of DMF. The reaction system was placed in an ice bath, and then TBSCl (29.8 g, 198 mmol, 1.1 eq.) was added. The reaction was allowed to warm to room temperature overnight. After TLC monitoring, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The organic phases were extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 26 g of compound 9a-1 as a pale yellow oil.

[0872] To a 250 mL three-necked round-bottom flask, add Mg (1.70 g, 70.1 mmol, 1.6 eq.), I (0.01 g, 0.039 mmol), and 50 mL of anhydrous THF. The reaction system was heated to 37°C, and compound 9a-1 (18.5 g, 65.7 mmol, 1.5 eq.) was slowly added over 30 minutes. The reaction was allowed to proceed until the magnesium powder almost completely disappeared, thereby preparing the Grignard reagent. Under nitrogen, a 250 mL three-necked round-bottom flask was charged with CuBr (0.63 g, 4.38 mmol, 0.1 eq.), LiCl (0.37 g, 8.76 mmol, 0.2 eq.), and 50 mL of anhydrous THF. The mixture was stirred at 0°C for 30 minutes. Methyl 3,3-dimethacrylate (5 g, 43.8 mmol, 1.0 eq.) and TMSCl (7.14 g, 65.7 mmol, 1.5 eq.) were then added dropwise to the resulting copper lithium reagent solution. Stirring was continued at 0°C for 30 minutes. The prepared Grignard reagent was slowly added dropwise to the reaction solution. The reaction was continued for 2 hours after the addition was complete. TLC was used to monitor the reaction until completion. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 13 g of compound 9a-2 as a pale yellow oil.

[0873] TBAF (21.5 g, 82.1 mmol, 2.0 eq.) was added portionwise to a THF solution of compound 9a-2 (13 g, 41.1 mmol, 1.0 eq.) under ice-cooling conditions and stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain crude product 9a-3, which was used directly in the next step without purification.

[0874] Compound 9a-3 (14 g, 69.2 mmol, 1 eq.) and PPh3 (21.8 g, 83.0 mmol, 1.2 eq.) were dissolved in 140 mL of dichloromethane. The reaction system was cooled to 0°C, and CBr4 (25.3 g, 76.1 mmol, 1.1 eq.) was then added portionwise. The reaction was stirred at room temperature until completion as monitored by TLC. The reaction was quenched with ice-saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 7.6 g of compound 9a-4 as a pale yellow oil.

[0875] TMSOK (4.35 g, 33.9 mmol, 1.5 eq.) was added to a 60 mL THF solution of compound 9a-4 (6 g, 22.6 mmol, 1 eq.). The reaction was stirred at room temperature until completion as monitored by TLC. The pH of the reaction system was adjusted to 4.0 with 2.0 M hydrochloric acid and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 2.5 g of compound 9a-5 as a pale yellow oil.

[0876] Referring again to the method of Example 1, compound 9a was prepared to obtain 81.7 mg of an oily product.

[0877] 1 H NMR (300MHz, CDCl3) δ: 4.85 (m, 1H), 4.05 (t, J = 7.2Hz, 2H), 3.66 (s, 2H), 2.59 (m, 4H), 2.31 (t, J = 7.2H z,2H),2.19(s,2H),1.64-1.43(m,12H),1.22-1.38(m,51H),1.12(s,6H),0.95-0.85(m,9H); ESI-MS m / z:738.65[M+H] + .

[0878] Example 10: Synthesis of Compound 10a

[0879] In a 100 mL round-bottom flask, methyl 4-bromobutyrate (4 g, 22.1 mmol, 1.0 eq.) was dissolved in 40 mL of MTBE. The reaction system was placed in an ice bath, and then methylmagnesium bromide (22.1 mL, 66.3 mmol, 3.0 eq.) was added. The reaction was allowed to warm to room temperature until complete as monitored by TLC. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 3.5 g of compound 10a-2.

[0880] Under nitrogen, a 100 mL round-bottom flask was charged with compound 10a-2 (3 g, 16.6 mmol, 1.0 eq.), triethylsilyl chloride (7.49 g, 49.7 mmol, 3.0 eq.), zinc powder (3.25 g, 49.7 mmol, 3.0 eq.), Cp*TiCl3 (519 mg, 1.80 mmol, 0.1 eq.), and 5A molecular sieves (2.4 g). 24 mL of anhydrous THF was then added. The reaction system was heated to 50°C, and ethyl acrylate (2.49 g, 24.9 mmol, 1.5 eq.) was added. The temperature was raised to 60°C and the reaction was continued for 12 hours. The reaction solution was cooled to room temperature and quenched with saturated sodium chloride solution. The reaction was extracted with EtOAc, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to yield 2.4 g of compound 10a-3.

[0881] In a 40 mL reaction flask, compound 10a-3 (1 g, 3.77 mmol, 1.0 eq.) was dissolved in a mixture of 10 mL of ethanol and 2 mL of water. Lithium hydroxide (0.27 g, 11.3 mmol, 3.0 eq.) was then added to the reaction system. The reaction was allowed to react at room temperature until completion, as monitored by TLC. The organic solvent was removed by rotary evaporation, and the pH of the solution was adjusted to approximately 4 with 2.0 M dilute hydrochloric acid. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with EtOAc. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to afford 800 mg of compound 10a-4.

[0882] Referring again to the method of Example 1, compound 10a was prepared to obtain 93.4 mg of an oily product.

[0883] 1 H NMR (300MHz, CDCl3) δ: 4.92-4.72 (m, 1H), 4.05 (t, J = 7.2Hz, 2H), 3.59 (m, 2H), 2.64-2. 51(m,6H),2.33-2.18(m,4H),1.55(m,14H),1.34-1.24(m,45H),0.83(m,15H); ESI-MS m / z:724.55[M+H] + .

[0884] Example 11: Synthesis of Compound 11a

[0885] Compound 11a was prepared by referring to the method of Example 1 to obtain 69.5 mg of an oily product.

[0886] 1H NMR (400MHz, CDCl3) δ: 4.90-4.80 (m, 1H), 4.08 (t, J = 7.2Hz, 2H), 3.81 (t, J = 5.2Hz, 2H), 2.55 (m, 6H), 2. 33(t,J=7.2Hz,2H),1.71-1.46(m,16H),1.40-1.26(m,49H),1.17(s,6H),0.90(t,J=7.2Hz,9H); ESI-MS m / z:752.60[M+H] + .

[0887] Example 12: Synthesis of Compound 12a

[0888] Compound 12a was prepared by referring to the method of Example 1 to obtain 178.6 mg of an oily product.

[0889] 1 H NMR (400MHz, CDCl3) δ: 4.88-4.77 (m, 1H), 4.05 (t, J = 7.2Hz, 2H), 3.60 (t, J = 5.6Hz, 2H), 2.57 (m, 6H), 2. 30(t,J=7.2Hz,2H),1.71-1.46(m,12H),1.43-1.15(m,55H),1.11(s,6H),0.89(t,J=7.2Hz,9H); ESI-MS m / z:766.70[M+H] + .

[0890] Example 13: Synthesis of Compound 13a

[0891] Compound 13a was prepared by referring to the method of Example 1 to obtain 43.5 mg of an oily product.

[0892] 1 H NMR (400MHz, CDCl3) δ: 4.81 (p, J = 6.4Hz, 1H), 4.06 (t, J = 6.8Hz, 2H), 3.58 (m, 2H), 2.58-2.36 (m, 6H), 2.30 (t, J = 7.6Hz, 2 ESI-MS m / z:736.60[M+H] + .

[0893] Example 14: Synthesis of Compound 14a

[0894] Compound 14a was prepared by referring to the method of Example 1 to obtain 56.3 mg of an oily product.

[0895] 1 H NMR (400MHz, CDCl3) δ: 4.08 (t, J = 6.8 Hz, 2H), 4.01 (d, J = 4.8 Hz, 2H), 3.97 (d, J = 5.6 Hz, 2H), 3.17-3.06 (m, 5H ),2.36(t,J=7.2Hz,2H),1.87-1.63(m,16),1.57-1.29(m,45H),1.19(s,6H),0.91(t,J=7.2Hz,9H); ESI-MS m / z:724.55[M+H] + .

[0896] Example 15: Synthesis of Compound 15a

[0897] Compound 15a was prepared by referring to the method of Example 1 to obtain 120.3 mg of an oily product.

[0898] 1 H NMR(400MHz, CDCl3)δ:4.09-4.03(m,4H),3.56(m,2H),2.62-2.49(m,5H),2.30(t,J=6.0H z,2H),1.66-1.55(m,14H),1.52-1.26(m,45H),1.15(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:710.55[M+H] + .

[0899] Example 16: Synthesis of Compound 16a

[0900] Compound 16a was prepared by referring to the method of Example 1 to obtain 80.8 mg of an oily product.

[0901] 1 H NMR(400MHz, CDCl3)δ:4.07-3.92(m,4H),3.60(m,2H),2.66-2.46(m,6H),2.30(t,J=7.6H z,2H),1.68-1.44(m,12H),1.38-1.07(m,44H),1.05(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:696.55[M+H] + .

[0902] Example 17: Synthesis of Compound 17a

[0903] Compound 17a was prepared by referring to the method of Example 1 to obtain 125.7 mg of an oily product.

[0904] 1 H NMR (400MHz, CDCl3) δ: 4.86-4.80 (m, 1H), 4.05 (t, J = 6.8Hz, 2H), 3.55 (m, 2H), 2.60-2.47 (m, 6H), 2.29 (t,J=7.6Hz,2H),1.66-1.48(m,14H),1.43-1.26(m,49H),1.15(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:738.65[M+H] + .

[0905] Example 18: Synthesis of Compound 18a

[0906] Compound 18a was prepared by referring to the method of Example 1 to obtain 127.4 mg of an oily product.

[0907] 1 H NMR(400MHz, CDCl3)δ:4.86-4.80(m,1H),4.06(t,J=6.8Hz,2H),3.53(t,J=4.8Hz,2H),2.58(t,J=4.8Hz,2H),2.43(t,J =4.8Hz,4H),2.29(t,J=7.6Hz,2H),1.65-1.43(m,14H),1.38-1.18(m,49H),1.15(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:738.66[M+H] + .

[0908] Example 19: Synthesis of Compound 19a

[0909] Compound 19a was prepared by referring to the method of Example 9 to obtain 79.7 mg of an oily product.

[0910] 1H NMR(300MHz, CDCl3)δ:4.89-4.82(m,1H),4.06(t,J=6.9Hz,2H),3.67(m,2H),2.70-2.34(m,4H),2.31(t,J= 7.5Hz,2H),2.17(s,2H),1.70-1.49(m,12H),1.38-1.18(m,49H),0.99(s,6H),0.88(t,J=6.9Hz,9H); ESI-MS m / z:738.65[M+H] + .

[0911] Example 20: Synthesis of Compound 20a

[0912] Compound 20a was prepared by referring to the method of Example 10 to obtain 74.5 mg of an oily product.

[0913] 1 H NMR (400MHz, CDCl3) δ: 4.89-4.85 (m, 1H), 4.06 (t, J = 7.2Hz, 2H), 3.63 (m, 2H), 2.69-2.57 (m, 6H),2.35-2.20(m,4H),1.71-1.53(m,15H),1.39-1.19(m,46H),0.94-0.85(m,15H); ESI-MS m / z:738.45[M+H] + .

[0914] The compounds in Table 2 were synthesized using the methods of the above examples, or similar methods using the corresponding intermediates.

[0915] Table 2

[0916] Example 30: Synthesis of Compound 1b

[0917] 9-Heptadecanol 1b-1 (200.0 mg, 0.78 mmol, 1.0 eq.) was dissolved in DCM (2.0 mL). 8-Bromooctanoic acid (226.2 mg, 1.01 mmol, 1.3 eq.), EDCI (179.4 mg, 0.94 mmol, 1.2 eq.), and DMAP (42.9 mg, 1.17 mmol, 1.5 eq.) were added to the solution. The reaction solution was stirred at room temperature for 3 hours. The mixture was poured into 10 mL of saturated sodium chloride solution and extracted with 3 x 20 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 300 mg of compound 1b-2 as a yellow oil.

[0918] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0°C. LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction mixture under nitrogen. The reaction temperature was raised to room temperature and stirred for 30 minutes before the addition of 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.). The reaction was monitored by TLC until completion. The reaction was quenched with saturated aqueous ammonium chloride and extracted with 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to afford 30 g of compound 1b-4 as a yellow oil.

[0919] Compound 1b-4 (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, 100.0 mL) was added dropwise to the reaction system under nitrogen. The temperature was raised to 75°C and stirred for 3 hours. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with 3 x 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain crude product 1b-5 (13.6 g), which was used directly in the next step without purification.

[0920] Decanoyl chloride (11.0 g, 58.0 mmol, 1.3 eq.) was added to a solution of compound 1b-5 (10.0 g, 44.0 mmol, 1.0 eq.) in DCM (100 mL). Triethylamine (13.5 g, 134.0 mmol, 3.0 eq.) was then added to the reaction system and allowed to react at room temperature for 3 hours. The reaction solution was poured into 100 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 10 g of compound 1b-6.

[0921] Potassium carbonate (1.5 g, 11.1 mmol, 3.0 eq.) and compound 1b-6 (1.4 g, 3.7 mmol, 1.0 eq.) were added to a solution of ethanolamine (2.3 g, 37.2 mmol, 10.0 eq.) in acetonitrile (15.0 mL). The mixture was heated to 70°C and stirred for 3 hours. The reaction solution was poured into 30 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 1.4 g of compound 1b-7. 1H NMR(300MHz,CD3Cl)δ:0.85-0.89(m,9H),1.20-1.26(m,21H),1.59-1.62(m,4H), 2.29-2.34(m,2H),2.73-2.76(m,2H),2.87-2.91(m,2H),3.72-3.77(m,3H).

[0922] Compound 1b-2 (300.0 mg, 0.84 mmol, 1.0 eq.) and compound 1b-7 (503.4 mg, 1.09 mmol, 1.3 eq.) were dissolved in DMF (3.0 mL). Potassium carbonate (289.9 mg, 2.1 mmol, 2.5 eq.) and sodium iodide (314.4 mg, 2.1 mmol, 2.5 eq.) were added. The mixture was heated to 70°C and stirred for 2 hours. The reaction solution was poured into 20 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain compound 1b (158.9 mg).

[0923] 1 H NMR(400MHz, Methanol-d4)δ:0.85-0.95(m,15H),1.17-1.34(m,48H),1.52-1.59(m,8H),1.62-1.64(m,4H),2.27-2 .35(m,4H),2.48-2.53(m,4H),2.63(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),3.80(s,2H),4.84-4.89(m,1H); ESI-MS m / z:738.65[M+H] + .

[0924] Example 31: Synthesis of Compound 2b

[0925] Potassium carbonate (549.3 mg, 4.0 mmol, 3.0 eq.) and compound 1b-6 (500.0 mg, 1.33 mmol, 1.0 eq.) were added to a solution of 3-amino-1-propanol (1.0 g, 13.3 mmol, 10.0 eq.) in acetonitrile (10.0 mL). The mixture was heated to 70°C and stirred for 3 hours. The reaction solution was poured into 30 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 350 mg of compound 2b-1 as a colorless oil.

[0926] Compound 1b-2 (565 mg, 1.22 mmol, 1.3 eq.) and compound 2b-1 (350 mg, 0.94 mmol, 1.0 eq.) were dissolved in DMF (5.0 mL). Potassium carbonate (389 mg, 2.82 mmol, 3.0 eq.) and sodium iodide (353 mg, 2.35 mmol, 2.5 eq.) were added. The mixture was heated to 70°C and stirred for 5 hours. The reaction solution was poured into 20 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to obtain compound 2b (160 mg).

[0927] 1 H NMR(400MHz, Methanol-d4)δ:0.85-0.95(m,15H),1.20-1.40(m,48H),1.62-1.70(m,12H),1.72-1.78(m,2H),2.28 -2.35(m,4H),2.60-2.66(m,4H),2.74-2.79(m,2H),3.64(t,J=6.0Hz,2H),3.80(s,2H),4.82-4.89(m,1H); ESI-MS m / z:752.65[M+H] + .

[0928] Example 32: Synthesis of Compound 3b

[0929] Potassium carbonate (549 mg, 4.0 mmol, 3.0 eq.) and compound 1b-6 (500 mg, 1.33 mmol, 1.0 eq.) were added to a solution of 4-amino-1-butanol (1.2 g, 13.3 mmol, 10.0 eq.) in DMF (10.0 mL). The mixture was heated to 70°C and stirred for 3 hours. The reaction solution was poured into 30 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 300 mg of compound 3b-1 as a colorless oil.

[0930] Compound 1b-2 (462 mg, 1.0 mmol, 1.3 eq.) and compound 3b-1 (297 mg, 0.77 mmol, 1.0 eq.) were dissolved in DMF (5.0 mL). Potassium carbonate (269 mg, 1.9 mmol, 2.5 eq.) and sodium iodide (285 mg, 1.9 mmol, 2.5 eq.) were then added. The mixture was heated to 70°C and stirred for 5 hours. The reaction solution was poured into 20 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to obtain compound 3b (228 mg).

[0931] 1 H NMR(400MHz, CDCl3)δ:0.80-0.90(m,15H),1.25-1.40(m,48H),1.49-1.66(m,8H),1.74-1.81(m ,8H),2.24-2.37(m,4H),2.47-2.58(m,6H),3.56(s,2H),3.77(s,2H),4.81-4.88(m,1H); ESI-MS m / z:766.85[M+H] + .

[0932] Example 33: Synthesis of Compound 4b

[0933] Methyl isobutyrate (21 g, 205 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0°C. LDA (205 mL, 410 mmol, 2.0 eq.) was added to the reaction mixture under nitrogen. The reaction temperature was raised to room temperature and stirred for 30 minutes. 1,6-dibromohexane (50 g, 205 mmol, 1.0 eq.) was then added. The reaction was monitored by TLC until completion. The reaction was quenched with saturated aqueous ammonium chloride and extracted with 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 34 g of compound 4b-2 as a yellow oil. 1 H NMR (400MHz, CD3Cl) δ: 1.05-1.52(m,14H), 1.78-1.91(m,2H), 3.36-3.42(m,2H), 3.71(s,3H).

[0934] Compound 4b-2 (10.0 g, 37.6 mmol, 1.0 eq.) was added to aqueous hydrobromic acid (50.0 mL). The reaction mixture was heated to 100°C and stirred for 24 hours. After completion, the reaction system was cooled to room temperature and quenched with saturated sodium chloride solution. The mixture was extracted with dichloromethane (DCM), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 7.4 g of compound 4b-3 as a yellow oil. 1 H NMR (400MHz, CD3Cl) δ: 1.19 (s, 6H), 1.25-1.28 (m, 4H), 1.30-1.56 (m, 4H), 1.80-1.89 (m, 2H), 3.37-3.42 (m, 2H).

[0935] Compound 4b-3 (5.0 g, 19.9 mmol, 1.0 eq.) was dissolved in DCM (50.0 mL). DMF (291.0 mg, 3.98 mmol, 0.2 eq.) and oxalyl chloride (5.1 g, 39.8 mmol, 2.0 eq.) were added to the reaction system under ice-cooling conditions. After stirring for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain the acid chloride intermediate. The resulting acid chloride was dissolved in DCM (50.0 mL), followed by the addition of 9-heptadecanol (4.08 g, 15.9 mmol, 0.8 eq.) and triethylamine (6.03 g, 59.7 mmol, 3.0 eq.), and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction solution was poured into 300 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to obtain 4.3 g of compound 4b-4 as an oil.

[0936] To a solution of compound 4b-4 (492.9 mg, 1.0 mmol, 1.2 eq.) in DMF (3.0 mL) were added potassium carbonate (347.8 mg, 2.5 mmol, 3.0 eq.), sodium iodide (314.4 mg, 2.1 mmol, 2.5 eq.), and compound 1b-7 (300.0 mg, 0.8 mmol, 1.0 eq.). The reaction mixture was heated to 70°C and stirred for 2 hours. After completion, the reaction system was cooled to room temperature and quenched with saturated sodium chloride solution. The mixture was extracted with dichloromethane (DCM), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified by preparative liquid chromatography to afford 106 mg of compound 4b. (Column model: XBridge Shield RP18 OBD Column 19x150 mm, 5μm; mobile phase A: acetonitrile: water (10mmol / L ammonium bicarbonate + 0.05% ammonia water), mobile phase B: isopropanol: acetonitrile; flow rate: 20mL / min; gradient: the proportion of mobile phase B is gradually increased from 75% B to 95% B within 9 minutes).

[0937] 1 H NMR(400MHz, Methanol-d4)δ:0.85-0.95(m,15H),1.15(s,6H),1.20-1.40(m,48H),1.47-1.54(m,10H),1.60-1.64(m,2H), 2.31-2.34(m,2H),2.47-2.51(m,4H),2.61(t,J=6.4Hz,2H),3.61(t,J=6.4Hz,2H),3.80(s,2H),4.81-4.88(m,1H); ESI-MS m / z:766.70[M+H] + .

[0938] Example 34: Synthesis of Compound 5b

[0939] Compound 5b was prepared by the method of Example 30 to obtain 174 mg of an oily product.

[0940] 1 H NMR(400MHz,Methanol-d4)δ:0.85-0.95(m,15H),1.20-1.40(m,43H),1.50-1.60(m,4H),1.61-1.70(m ,7H),2.28-2.33(m,4H),2.48-2.64(m,5H),3.51-3.63(m,2H),3.80(s,2H),4.04-4.08(m,2H); ESI-MS m / z:696.60[M+H] + .

[0941] Example 35: Synthesis of Compound 6b

[0942] Compound 6b was prepared by the method of Example 30 to obtain 113 mg of an oily product.

[0943] 1 H NMR(400MHz, Methanol-d4)δ:0.85-0.95(m,9H),1.25(s,6H),1.35-1.55(m,48H),1.58-1.65(m,14H),2.27-2.3 2(m,2H),2.46-2.51(m,4H),2.58-2.62(m,2H),3.58-3.64(m,2H),4.04-4.08(m,2H),4.83-4.87(m,1H); ESI-MS m / z:738.65[M+H] + .

[0944] Example 36: Synthesis of Compound 7b

[0945] Compound 7b was prepared by referring to the method of Example 30 to obtain 91 mg of an oily product.

[0946] 1H NMR(400MHz, CDCl3)δ:0.85-0.90(m,12H),1.14(s,6H),1.23-1.49(m,56H),1.56-1.64(m,14H), 2.24-2.29(m,2H),2.51-2.65(m,5H),3.60(s,2H),4.03-4.07(m,2H),4.80-4.84(m,1H); ESI-MS m / z:809.05[M+H] + .

[0947] Example 37: Synthesis of Compound 8b

[0948] Compound 8b was prepared by referring to the method of Example 30 to obtain 124 mg of an oily product.

[0949] 1 H NMR(400MHz, CDCl3)δ:0.85-0.95(m,6H),1.27-1.49(m,42H),1.52-1.63(m,12H),2.26-2.3 1(m,2H),2.52-2.57(m,4H),2.65-2.68(m,2H),3.47-3.64(m,2H),4.01-4.07(m,4H); ESI-MS m / z:626.65[M+H] + .

[0950] Example 38: Synthesis of Compound 9b

[0951] Tert-butyl cyclopropanecarboxylate (15.0 g, 150.0 mmol, 1.0 eq.) was dissolved in 150 mL of anhydrous tetrahydrofuran and cooled to -60°C. LDA (150.0 mL, 300.0 mmol, 2.0 eq.) was added to the reaction mixture under nitrogen. The reaction was stirred at the same temperature for 1 hour, followed by the addition of 1-bromo-6-chlorohexane (44.9 g, 225.0 mmol, 1.5 eq.). The reaction was stirred at room temperature for 3 hours. TLC was used to monitor the reaction until completion. The reaction was quenched with saturated aqueous ammonium chloride and extracted with 3 x 300 mL of dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 19 g of compound 9b-1 as a colorless oil.

[0952] 10.0 mL of trifluoroacetic acid was added to a solution of compound 9b-1 (10.0 g, 38.3 mmol) in DCM (30.0 mL). The mixture was stirred at room temperature for 3 hours. The reaction solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column to obtain 6.9 g of colorless oily compound 9b-2.

[0953] Compound 9b-2 (500.0 mg, 2.45 mmol, 2.0 eq.) was dissolved in DCM (5.0 mL). 2-3 drops of DMF and oxalyl chloride (311.1 mg, 2.45 mmol, 2.0 eq.) were added to the reaction system under ice-bath conditions. After stirring for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain the acid chloride intermediate. The resulting acid chloride was dissolved in DCM (5.0 mL), followed by the addition of 9-heptadecanol (312.3 mg, 1.22 mmol, 1.0 eq.) and triethylamine (247.5 mg, 2.45 mmol, 2.0 eq.), and the reaction was allowed to proceed at room temperature for 5 hours. After completion of the reaction, the reaction solution was poured into 50 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 240 mg of compound 9b-3 as an oil.

[0954] To a solution of compound 9b-3 (200.0 mg, 0.45 mmol, 1.5 eq.) in DMF (3.0 mL) were added potassium carbonate (124.2 mg, 0.90 mmol, 3.0 eq.), sodium iodide (112.5 mg, 0.75 mmol, 2.5 eq.), and compound 6b-1 (99.0 mg, 0.30 mmol, 1.0 eq.). The reaction mixture was heated to 70°C and stirred for 5 hours. After completion, the reaction system was cooled to room temperature and quenched with saturated sodium chloride solution. The mixture was extracted with dichloromethane (DCM), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified by preparative liquid chromatography to afford 85.4 mg of compound 9b. (Column model: XBridge Shield RP18 OBD Column 19x150 mm, 5μm; mobile phase A: acetonitrile: water (10mmol / L ammonium bicarbonate + 0.05% ammonia water), mobile phase B: isopropanol: acetonitrile; flow rate: 20mL / min; gradient: 75% B to 95% B in 9min).

[0955] 1 H NMR(400MHz, CDCl3)δ:0.60-0.70(m,2H),0.85-0.95(m,9H),1.13-1.31(m,48H),1.46-1.48(m,12H),1.57-1.63(m,4H), 2.26-2.31(m,2H),2.42-2.47(m,4H),2.56-2.59(m,2H),3.50-3.54(m,2H),4.03-4.07(m,2H),4.80-4.84(m,1H); ESI-MS m / z:736.65[M+H] + .

[0956] Example 39: Synthesis of Compound 10b

[0957] Compound 10b was prepared by referring to the method of Example 30 to obtain 128 mg of an oily product.

[0958] 1 H NMR(300MHz, CDCl3)δ:0.85-0.95(m,15H),1.12-1.36(m,43H),1.40-1.63(m,12H),2.26-2. 31(m,4H),2.42-2.65(m,6H),3.50-3.54(m,2H),3.78(s,2H),4.08(t,J=7.2Hz,2H); ESI-MS m / z:710.80[M+H] + .

[0959] Example 40: Synthesis of Compound 11b

[0960] Compound 11b was prepared by the method of Example 30 to obtain 92 mg of an oily product.

[0961] 1 H NMR(300MHz, CDCl3)δ:0.83-0.94(m,15H),1.18-1.42(m,43H),1.48-1.67(m,10H),2.28-2.35(m,4H),2. 46-2.52(m,4H),2.61(t,J=6.6Hz,2H),3.61(t,J=6.6Hz,2H),3.80(s,2H),4.05(t,J=6.6Hz,2H); ESI-MS m / z:696.60[M+H] + .

[0962] Example 41: Synthesis of Compound 12b

[0963] Compound 12b was prepared by referring to the method of Example 30 to obtain 105 mg of an oily product.

[0964] 1H NMR(400MHz, CDCl3)δ:0.85-0.95(m,15H),1.19-1.34(m,41H),1.42-1.58(m,4H),1.59-1.63(m,6H),2.23(q,J=7.6H z,4H),2.53(q,J=7.6Hz,4H),2.62(q,J=7.6Hz,2H),3.62(t,J=6.4Hz,2H),3.80(s,2H),4.07(t,J=6.4Hz,2H); ESI-MS m / z:682.60[M+H] + .

[0965] The compounds in Table 3 were synthesized using the methods of the above examples, or similar methods using the corresponding intermediates.

[0966] Table 3

[0967] Example 54: Synthesis of Compound 30a

[0968] In a 250 mL round-bottom flask, 9-heptadecanol (10.0 g, 39.0 mmol, 1.0 eq.) and pyridine (6.17 g, 78.0 mmol, 2 eq.) were dissolved in 100 mL of dichloromethane. The reaction system was then cooled to 0°C and isobutyryl chloride (10.39 g, 97.5 mmol, 2.5 eq.) was slowly added to the reaction solution. The mixture was then stirred at room temperature for 2 hours. The reaction was quenched by adding water at 0°C and extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na2SO4. The desiccant was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified on a silica gel column to afford Compound 1a-5 (10.4 g) as a yellow oil.

[0969] Compound 1a-5 (10.0 g, 30.62 mmol, 1.0 eq.) was dissolved in anhydrous THF (100 mL). The reaction was cooled to -40°C and, under a nitrogen atmosphere, LDA (15.3 mL, 30.6 mmol, 1 eq.) was added. The mixture was stirred at -40°C for 1 hour, followed by the addition of 1,6-dibromohexane (14.9 g, 61.2 mmol, 2.0 eq.) and DMPU (471 mg, 3.7 mmol, 0.12 eq.) at the same temperature. The reaction was slowly warmed to room temperature and allowed to react overnight. After completion of the reaction, the reaction mixture was added to a saturated NH₄Cl solution and extracted with DCM. The organic phases were combined and dried over anhydrous Na₂SO₄. The desiccant was filtered and the solvent was removed by rotary evaporation to yield crude compound 1a-6, which was used directly in the next step without purification.

[0970] Compound 1a-6 (15 g, 30.6 mmol, 1.0 eq.) and ethanolamine (37.4 g, 612.0 mmol, 20.0 eq.) were dissolved in 80 ml of ethanol and the reaction system was heated to 60°C for 2 hours. After the reaction, the reaction system was cooled to room temperature and the ethanol solvent was removed by rotary evaporation. The crude product was dissolved in ethyl acetate and then added with saturated sodium chloride solution. After extraction, the organic phases were combined and dried over anhydrous Na2SO4. The desiccant was filtered and the solvent was removed by rotary evaporation. The crude product was purified on a silica gel column to obtain compound 30a-1 (12.4 g) as a yellow oil.

[0971] In a 50 mL reaction flask, 6-bromo-1-hexanol (1.5 g, 8.3 mmol, 1.0 eq.) and pyridine (1.31 g, 16.6 mmol, 2.0 eq.) were dissolved in 15 mL of DCM. Nonyl chloroformate (1.88 g, 9.1 mmol, 1.1 eq.) was added dropwise over 15 minutes under an ice bath and allowed to stand overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM. The combined organic phases were dried over anhydrous NaSO, the desiccant was removed by filtration, and the solvent was removed by rotary evaporation. The crude product was purified on a silica gel column to afford Compound 30a-4 (2.5 g) as a yellow oil.

[0972] To an 8 mL sealed tube, compound 30a-4 (200 mg, 0.57 mmol, 1.0 eq.), compound 30a-1 (294.2 mg, 0.63 mmol, 1.1 eq.), KI (113.4 mg, 0.68 mmol, 1.2 eq.), KCO (236.0 mg, 1.71 mmol, 3.0 eq.), and 5.0 mL of anhydrous acetonitrile were added. The mixture was heated to 80°C and stirred overnight. The mixture was cooled to room temperature and filtered. The filter cake was washed with acetonitrile, and the organic phases were combined and the solvent was removed by rotary evaporation to obtain the crude product. Purification by preparative liquid chromatography afforded compound 30a (87.9 mg).

[0973] 1 H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.12 (t, J = 6.6Hz, 4H), 3.61 (m, 2H), 2.62 (m, 6H), 1. 70–1.63(m,4H),1.50(m,8H),1.26(m,49H),1.15(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:740.55[M+H] + .

[0974] Example 55: Synthesis of Compound 31a

[0975] Compound 31a was prepared by the method of Example 54 to obtain 80.7 mg of an oily product.

[0976] 1 H NMR (400MHz, CDCl3) δ: 4.83 (p, J = 6.6 Hz, 1H), 4.12 (td, J = 7.2, 2.4 Hz, 4H), 3.61 (m, 2H), 2.61 (m,6H),1.68(m,4H),1.50(m,8H),1.26(m,49H),1.15(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:740.65[M+H] + .

[0977] Example 56: Synthesis of Compound 32a

[0978] Compound 32a was prepared by the method of Example 54 to obtain 93.9 mg of an oily product.

[0979] 1 H NMR (300MHz, CDCl3) δ: 4.85 (p, J = 6.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 4H), 3.79 (t, J = 5.1 Hz, 2H), 2.65 (m, 2H), 2.42 (m, 4 H),1.77-1.64(m,6H),1.51(t,J=6.0Hz,10H),1.28(d,J=4.5Hz,47H),1.17(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:754.60[M+H] + .

[0980] Example 57: Synthesis of Compound 33a

[0981] Compound 33a was prepared by the method of Example 54 to obtain 164.2 mg of an oily product.

[0982] 1 H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.8 Hz, 4H), 3.95 (d, J = 5.6 Hz, 2H), 3.54 (t, J = 5.2 Hz, 2H), 2.59 (t, J = 5.2 Hz, 2H), 2.50-2.41 (m, 4H), 1.67 (m, 5H), 1.53 -1.19(m,53H),1.16(s,6H),0.88(t,J=6.8Hz,9H); ESI-MS m / z:726.50[M+H] + .

[0983] Example 58: Synthesis of Compound 34a

[0984] Compound 34a was prepared by the method of Example 54 to obtain 150.1 mg of an oily product.

[0985] 1 H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.8 Hz, 4H), 4.08 (t, J = 6.8 Hz, 2H), 3.56 (m, 2H), 2.61-2 .48(m,6H),1.66(m,5H),1.61-1.26(m,51H),1.15(s,6H),0.88(t,J=6.8Hz,9H); ESI-MS m / z:712.60[M+H] + .

[0986] Example 59: Synthesis of Compound 35a

[0987] Compound 35a was prepared by the method of Example 54 to obtain 217.9 mg of an oily product.

[0988] 1 H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.8 Hz, 4H), 4.03 (t, J = 6.8 Hz, 2H), 3.53 (t, J = 5.2 Hz, 2H), 2.58 (t, J = 5.2 Hz ,2H),2.47-2.40(m,4H),1.73-1.62(m,6H),1.60-1.19(m,48H),1.16(s,6H),0.88(t,J=6.8Hz,9H); ESI-MS m / z:698.55[M+H] + .

[0989] Example 60: Synthesis of Compound 36a

[0990] Compound 36a was prepared by the method of Example 54 to obtain 169.7 mg of an oily product.

[0991] 1H NMR(300MHz, CDCl3)δ:4.83(p,J=6.6Hz,1H),4.16-4.10(m,4H),3.53(t,J=5.1Hz,2H),2.58(t,J=5.1H z,2H),2.52-2.42(m,4H),1.67(m,4H),1.59-1.18(m,57H),1.15(s,6H),0.89(t,J=6.6Hz,9H); ESI-MS m / z:740.60[M+H] + .

[0992] Example 61: Synthesis of Compound 37a

[0993] Compound 37a was prepared by the method of Example 54 to obtain 59.4 mg of an oily product.

[0994] 1 H NMR (400MHz, CDCl3) δ: 4.12 (q, J = 6.8Hz, 4H), 3.95 (d, J = 5.2Hz, 2H), 3.58 (m, 2H), 2.64-2.51 (m,6H),1.74-1.43(m,12H),1.39-1.19(m,46H),1.16(s,6H),0.88(t,J=6.8Hz,9H); ESI-MS m / z:726.50[M+H] + .

[0995] Example 62: Synthesis of Compound 38a

[0996] Compound 38a was prepared by the method of Example 54 to obtain 44.8 mg of an oily product.

[0997] 1 H NMR(300MHz, CDCl3)δ:4.16-4.04(m,6H),3.62(m,2H),2.69-2.58(m,6H),1. 74-1.41(m,12H),1.39-1.18(m,44H),1.15(s,6H),0.92-0.87(m,9H); ESI-MS m / z:712.55[M+H] + .

[0998] Example 63: Synthesis of Compound 39a

[0999] Compound 39a was prepared by the method of Example 54 to obtain 105.4 mg of an oily product.

[1000] 1 H NMR (400MHz, CDCl3) δ: 4.13-4.10 (m, 4H), 4.03 (t, J = 6.8Hz, 2H), 3.56 (m, 2H), 2.4 6(m,6H),1.73-1.67(m,8H),1.64-1.19(m,50H),1.15(s,6H),0.88(m,9H); ESI-MS m / z:726.50[M+H] + .

[1001] Example 64: Synthesis of Compound 40a

[1002] To a 500 mL round-bottom flask, nonanoic acid (15.0 g, 94.8 mmol, 1.0 eq.) and THF (150 mL) were added at room temperature under nitrogen. The reaction mixture was cooled to 0°C, and NaH (3.64 g, 151.7 mmol, 1.6 eq.) and LDA (85.3 mL, 170.6 mmol, 1.8 eq., 2 M in THF) were added portionwise. The mixture was stirred at room temperature for 1 hour. 1-Iodoheptane (23.6 g, 104.3 mmol, 1.1 eq.) was then added at 0°C. The mixture was stirred at 80°C overnight. TLC monitoring revealed a new product. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted three times with DCM. The combined organic phases were washed once with saturated NaCl solution, dried over Na2SO4, filtered, and concentrated. The crude product was purified on a silica gel column to afford 2-heptylnonanoic acid (16.36 g) as a yellow oil.

[1003] In a 250 mL round-bottom flask, 2-heptylnonanoic acid (7.0 g, 27.3 mmol, 1.0 eq.) was dissolved in 70 mL of anhydrous THF at room temperature. The system was cooled to 0°C and LiAlH₄ (16.38 mL, 2.5 M in THF) was added dropwise over 30 minutes. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. TLC confirmed complete conversion of the starting material. The reaction mixture was poured into saturated sodium chloride solution to quench the reaction. The organic phases were extracted with ethyl acetate and combined, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified on a silica gel column to afford 2-heptylnonanol (6.97 g) as a pale yellow oil.

[1004] To a 50 mL three-necked round-bottom flask, 2-heptylnonanol (400 mg, 1.65 mmol, 1.0 eq.), pyridine (261.0 mg, 3.30 mmol, 2.0 eq.), DMAP (40.3 mg, 0.33 mmol, 0.2 eq.), p-nitrophenyl chloroformate (399.0 mg, 1.98 mmol, 1.2 eq.), and DCM (4 mL) were added at room temperature. The reaction system was stirred at room temperature for 1 hour. Subsequently, 6-bromo-1-hexanol (896.2 mg, 4.95 mmol, 3.0 eq.) and DIEA (639.7 mg, 4.95 mmol, 3.0 eq.) were added to the reaction system. The system was stirred at room temperature overnight. The reaction was diluted with DCM (4 mL) and washed once with saturated sodium bicarbonate solution (6 mL). The organic phase was washed once with saturated NaCl (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column to obtain the carbonate intermediate compound 40a-4 (325 mg) as a light yellow oil.

[1005] To an 8 mL sealed tube, compound 40a-4 (250 mg, 0.56 mmol, 1.0 eq.), compound 2a-4 (179.0 mg, 0.50 mmol, 0.9 eq.), potassium iodide (110.8 mg, 0.67 mmol, 1.2 eq.), potassium carbonate (230.6 mg, 1.68 mmol, 3.0 eq.), and acetonitrile (2.5 mL) were added at room temperature. The mixture was heated to 80°C and stirred overnight. The reaction was monitored by LC-MS. The reaction system was cooled to room temperature. The product was filtered, concentrated, and purified by Prep-HPLC to afford compound 40a (84.3 mg) as a pale yellow oil.

[1006] 1 H NMR (400MHz, CDCl3) δ: 4.14 (t, J = 6.8 Hz, 2H), 4.06 (dd, J = 8.0, 6.0 Hz, 4H), 3.60 (m, 2H), 2.65-2 .53(m,6H),1.73-1.60(m,12H),1.42-1.22(m,46H),1.18(s,6H),0.90(t,J=6.8Hz,9H); ESI-MS m / z:726.50[M+H] + .

[1007] Example 65: Synthesis of Compound 41a

[1008] Compound 41a was prepared by the method of Example 64 to obtain 113.3 mg of an oily product.

[1009] 1H NMR (400MHz, CDCl3) δ: 4.14 (td, J=9.2, 6.8Hz, 4H), 4.06 (t, J=6.8Hz, 2H), 3.57 (m, 2H), 2.62-2 .49(m,6H),1.71-1.63(m,6H),1.57-1.22(m,50H),1.17(s,6H),0.90(t,J=6.8Hz,9H); ESI-MS m / z:712.55[M+H] + .

[1010] Example 66: Synthesis of Compound 42a

[1011] Compound 42a was prepared by the method of Example 64 to obtain 124.2 mg of an oily product.

[1012] 1 H NMR (300MHz, CDCl3) δ: 4.12 (td, J = 6.6, 4.8Hz, 4H), 4.04 (t, J = 6.6Hz, 2H), 3.55 (t, J = 5.7Hz, 2H), 2.60-2.47(m,6H),1.72-1.62(m,6H),1.59-1.19(m,48H),1.15(s,6H),0.93-0.83(m,9H); ESI-MS m / z:698.55[M+H] + .

[1013] Example 67: Synthesis of Compound 43a

[1014] Compound 43a was prepared by the method of Example 64 to obtain 97.7 mg of an oily product.

[1015] 1 H NMR (400MHz, CDCl3) δ: 4.15 (td, J=6.8, 1.6Hz, 4H), 4.06 (t, J=6.8Hz, 2H), 3.64 (m, 2H), 2.68 -2.56(m,6H),1.76-1.60(m,8H),1.54-1.22(m,44H),1.18(s,6H),0.96-0.86(m,9H); ESI-MS m / z:684.45[M+H] + .

[1016] Example 68: Synthesis of Compound 44a

[1017] In a 20 mL round-bottom flask, compound 44a-1 (587.58 mg, 2.34 mmol, 1.2 eq.), 2-heptylnonanol (500 mg, 1.95 mmol, 1.0 eq.), EDCI (560.58 mg, 2.93 mmol, 1.5 eq.), and DMAP (47.63 mg, 0.39 mmol, 0.2 eq.) were dissolved in 5 mL of dichloromethane and allowed to react overnight at room temperature. After completion, the reaction was quenched with saturated sodium chloride solution, extracted with dichloromethane, and the combined organic phases were dried over NaSO, filtered, and concentrated to yield 1 g of crude product 44a-2, which was used directly in subsequent reactions.

[1018] Compound 44a was prepared by the method of Example 54 to obtain 165.3 mg of an oily product.

[1019] 1 H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.8 Hz, 4H), 3.96 (d, J = 5.6 Hz, 2H), 3.59 (m, 2H), 2.53-2.42 ( m,6H),2.26-2.20(m,2H),1.70-1.63(m,7H),1.56-1.19(m,49H),0.92-0.83(m,15H); ESI-MS m / z:726.50[M+H] + .

[1020] Example 69: Synthesis of Compound 45a

[1021] Compound 45a was prepared by the method of Example 68 to obtain 107.2 mg of an oily product.

[1022] 1 H NMR(300MHz, CDCl3)δ:4.12(t,J=6.6Hz,2H),4.04(t,J=6.6Hz,4H),3.57(m,2H),2.63-2.51(m, 6H),2.18(s,2H),1.73-1.61(m,5H),1.59-1.21(m,51H),0.98(s,6H),0.93-0.83(m,9H); ESI-MS m / z:726.55[M+H] + .

[1023] Example 70: Synthesis of Compound 46a

[1024] Compound 46a was prepared by the method of Example 68 to obtain 116.7 mg of an oily product.

[1025] 1 H NMR(300MHz, CDCl3)δ:4.12(t,J=6.6Hz,2H),4.07-4.02(m,4H),3.58(m,2H),2.64-2.49(m ,6H),2.27-2.21(m,2H),1.73-1.60(m,5H),1.56-1.21(m,51H),0.93-0.82(m,15H); ESI-MS m / z:726.45[M+H] + .

[1026] Example 71: Synthesis of Compound 47a

[1027] Compound 47a was prepared by the method of Example 68 to obtain 24.2 mg of an oily product.

[1028] 1 H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.8 Hz, 2H), 4.07-4.02 (m, 4H), 3.73 (m, 2H), 2.81-2.63 (m, 6 H),2.31(t,J=6.8Hz,2H),1.76-1.59(m,10H),1.58-1.22(m,46H),0.92-0.87(m,15H); ESI-MS m / z:726.55[M+H] + .

[1029] Example 72: Synthesis of Compound 48a

[1030] Compound 48a was prepared by the method of Example 54 to obtain 258.1 mg of an oily product.

[1031] 1 H NMR (300MHz, CDCl3) δ: 4.85 (p, J = 6.0Hz, 1H), 4.12 (t, J = 6.6Hz, 4H), 3.59 (m, 2H), 2.65-2.5 2(m,6H),1.67-1.62(m,5H),1.49-1.20(m,60H),1.15(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:782.72[M+H] + .

[1032] Example 73: Synthesis of Compound 49a

[1033] Compound 49a was prepared by the method of Example 54 to obtain 27.9 mg of an oily product.

[1034] 1 H NMR (300MHz, CDCl3) δ: 4.82 (p, J = 6.0 Hz, 1H), 4.12 (t, J = 6.6 Hz, 4H), 3.65 (m, 2H), 2.73-2.6 1(m,6H),1.83-1.62(m,9H),1.51-1.19(m,64H),1.15(s,6H),0.89(t,J=6.6Hz,9H); ESI-MS m / z:824.70[M+H] + .

[1035] Example 74: Synthesis of Compound 50a

[1036] Compound 50a was prepared by the method of Example 68 to obtain 75.9 mg of an oily product.

[1037] 1 H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.6 Hz, 2H), 4.03 (d, J = 6.0 Hz, 2H), 3.96 (d, J = 6.0 Hz, 2H), 3.61 (m, 2H), 2.67-2.55(m,6H),2.32(t,J=7.2Hz,2H),1.72-1.54(m,10H),1.52-1.20(m,57H),0.89(m,18H); ESI-MS m / z:824.65[M+H] + .

[1038] Example 75: Synthesis of Compound 51a

[1039] Under nitrogen, a 250 mL reaction flask was charged with methyl isobutyrate (3.5 g, 34.3 mmol, 1.0 eq.) and THF (40 mL). The temperature was lowered to -40°C, and LDA (17.2 mL, 34.3 mmol, 1.0 eq., 2 M in THF) was added dropwise over 10 minutes. The reaction was continued for 1.5 hours. 1,4-Dibromobutane (14.80 g, 68.5 mmol, 2.0 eq.) and DMPU (0.88 g, 6.85 mmol, 0.2 eq.) were then added dropwise over 5 minutes at the same temperature. The temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, and concentrated to remove the organic solvent by rotary evaporation to yield 7.5 g of crude methyl 2,2-dimethyl-6-bromohexanoate.

[1040] In a 250 mL round-bottom flask, methyl 2,2-dimethyl-6-bromohexanoate (7.5 g, crude) was dissolved in 75 mL of anhydrous THF. After cooling to 0°C, LiAlH₄ (10.12 mL, 25.3 mmol, 2.5 M in THF) was added dropwise. The reaction was continued for 30 min. After completion, saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over Na₂SO₄, filtered, and concentrated to remove the organic solvent by rotary evaporation to afford 7.5 g of the crude product. This was then purified on a silica gel column to afford 2.5 g of 2,2-dimethyl-6-bromohexanol.

[1041] Compound 51a was prepared by the method of Example 64 to obtain 205.5 mg of an oily product.

[1042] 1 H NMR (300MHz, CDCl3) δ: 4.08-4.02 (m, 4H), 3.85 (s, 2H), 3.54 (t, J = 5.1Hz, 2H), 2.59 (t, J = 5.1Hz, 2H), 2.4 9-2.43(m,4H),2.29(t,J=7.5Hz,2H),1.66-1.57(m,6H),1.55-1.22(m,50H),0.92-0.83(m,15H); ESI-MS m / z:726.80[M+H] + .

[1043] Example 76: Synthesis of Compound 25b

[1044] Compound 25b was prepared by the method of Example 75 to obtain 152.1 mg of an oily product.

[1045] 1 H NMR(300MHz, CDCl3)δ:4.08-4.02(m,4H),3.85(s,2H),3.58(m,2H),2.64-2.51(m,6H),2 .29(t,J=7.5Hz,2H),1.79-1.59(m,6H),1.47-1.24(m,50H),0.95-0.85(m,15H); ESI-MS m / z:726.50[M+H] + .

[1046] Example 77: Synthesis of Compound 26b

[1047] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0°C. LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction mixture under nitrogen. The reaction temperature was raised to room temperature and stirred for 30 minutes. 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.) was then added. TLC was used to monitor the reaction until completion. The reaction was quenched with saturated aqueous ammonium chloride and extracted with 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to obtain 30 g of methyl 2,2-dimethyl-7-bromoheptanoate as a yellow oil.

[1048] Methyl 2-dimethyl-7-bromoheptanoate (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0°C. Lithium aluminum hydride solution (2 M, 50.0 mL) was added dropwise to the reaction system under nitrogen. The reaction was stirred for 3 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with 3 x 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain crude 2,2-dimethyl-7-bromoheptanol (13.6 g), which was used directly in the next step without purification.

[1049] 2,2-Dimethyl-7-bromoheptanol (500.0 mg, 2.24 mmol, 1.0 eq.) was dissolved in DCM (10.0 mL). 4-Hexyldecanoic acid (746.2 mg, 2.91 mmol, 1.3 eq.), EDCI (515.7 mg, 2.69 mmol, 1.2 eq.), and DMAP (410.5 mg, 3.36 mmol, 1.5 eq.) were added to the solution. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was poured into 10 mL of saturated sodium chloride aqueous solution and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 858 mg of compound 26b-4 as a yellow oil.

[1050] Compound 26b was prepared by the method of Example 64 to obtain 99.0 mg of an oily product.

[1051] 1H NMR(300MHz,MeOH-d4)δ:0.86-0.91(m,15H),1.21-1.40(m,50H),1.58-1.71(m,6H),2.32(t, J=7.5Hz,2H),2.48-2.53(m,4H),2.62(t,J=6.6Hz,2H),3.61(t,J=6.3Hz,2H),3.80(s,2H),4.10(td,J=2.7,6.3Hz,4H); ESI-MS m / z:726.70[M+H] + .

[1052] Example 78: Synthesis of Compound 27b

[1053] Compound 27b was prepared by referring to the method of Example 77 to obtain 70.0 mg of an oily product.

[1054] 1 H NMR(300MHz,MeOH-d4)δ:0.85-0.95(m,15H),1.25-1.55(m,48H),1.59-1.83(m,10H),2.25(d,J=6.6Hz,2H),2. 48-2.53(m,4H),2.62(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),3.79(s,2H),4.11(td,J=3.0,6.6Hz,4H); ESI-MS m / z:740.65[M+H] + .

[1055] Example 79: Synthesis of Compound 28b

[1056] Compound 28b was prepared by referring to the method of Example 77 to obtain 97.8 mg of an oily product.

[1057] 1 H NMR(300MHz,MeOH-d4)δ:0.85-0.95(m,15H),1.21-1.55(m,48H),1.60-1.84(m,10H),2.25(d,J=6.6Hz,2H),2. 47-2.53(m,4H),2.61(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),3.79(s,2H),4.11(td,J=4.5,6.3Hz,4H); ESI-MS m / z:740.80[M+H] + .

[1058] Example 80: Synthesis of Compound 29b

[1059] Compound 29b was prepared by the method of Example 77 to obtain 107.7 mg of an oily product.

[1060] 1 H NMR(300MHz,MeOH-d4)δ:0.85-0.95(m,15H),1.21-1.55(m,53H),1.60-1.84(m,5H),2.25(d,J=6.6Hz,2H),2. 50-2.55(m,4H),2.64(t,J=6.3Hz,2H),3.60(t,J=6.3Hz,2H),3.79(s,2H),4.11(td,J=1.8,6.6Hz,4H); ESI-MS m / z:740.60[M+H] + .

[1061] Example 81: Synthesis of Compound 30b

[1062] Compound 30b was prepared by the method of Example 77 to obtain 82.4 mg of an oily product.

[1063] 1 H NMR(300MHz,MeOH-d4)δ:0.87-0.92(m,15H),1.21-1.53(m,49H),1.55-1.83(m,13H),2.25(d,J=6. 9Hz, 2H), 2.46-2.52 (m, 6H), 3.55 (t, J=5.7Hz, 2H), 3.79 (s, 2H), 4.11 (td, J=3.0, 6.6Hz, 4H); ESI-MS m / z:768.70[M+H] + .

[1064] Example 82: Synthesis of Compound 31b

[1065] Compound 31b was prepared by the method of Example 77 to obtain 107.7 mg of an oily product.

[1066] 1H NMR(300MHz,MeOH-d4)δ:0.86-0.92(m,15H),1.21-1.53(m,49H),1.55-1.83(m,13H),2.25(d,J=6.6 Hz,2H),2.47-2.54(m,6H),3.55(t,J=5.7Hz,2H),3.79(s,2H),4.10(td,J=6.6,12.3Hz,4H); ESI-MS m / z:768.70[M+H] + .

[1067] Example 83: Synthesis of Compound 32b

[1068] Compound 32b was prepared by the method of Example 77 to obtain 84.3 mg of an oily product.

[1069] 1 H NMR(300MHz,MeOH-d4)δ:0.88-0.93(m,15H),1.22-1.53(m,49H),1.56-1.83(m,13H),2.25(d,J=6. 6Hz,2H),2.49-2.54(m,6H),3.55(t,J=5.4Hz,2H),3.79(s,2H),4.10(td,J=2.1,6.6Hz,4H); ESI-MS m / z:768.65[M+H] + .

[1070] Example 84: Synthesis of Compound 33b

[1071] Compound 33b was prepared by the method of Example 77 to obtain 74.9 mg of an oily product.

[1072] 1 H NMR(300MHz,MeOH-d4)δ:0.88-0.92(m,15H),1.22-1.53(m,51H),1.48-1.69(m,9H),2.33(t,J=7.5Hz,2H),2.50-2.55 (m,4H),2.63(t,J=6.3Hz,2H),3.62(t,J=6.6Hz,2H),3.80(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.6Hz,2H); ESI-MS m / z:754.60[M+H] + .

[1073] Example 85: Synthesis of Compound 34b

[1074] Compound 34b was prepared by the method of Example 77 to obtain 76.6 mg of an oily product.

[1075] 1 H NMR(300MHz,MeOH-d4)δ:0.36-0.46(m,4H),0.88-0.92(m,9H),1.20-1.51(m,55H),1.56-1.69(m,5H),2.32(t,J=7.5Hz,2H),2. 51-2.55(m,4H),2.64(t,J=6.3Hz,2H),3.62(t,J=6.3Hz,2H),3.92(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.6Hz,2H); ESI-MS m / z:752.60[M+H] + .

[1076] Example 86: Synthesis of Compound 35b

[1077] Compound 35b was prepared by referring to the method of Example 77 to obtain 100.0 mg of an oily product.

[1078] 1 H NMR(300MHz,MeOH-d4)δ:0.88-0.92(m,15H),1.24-1.72(m,64H),2.33(t,J=7.5Hz,2H),2.45-2.5 1(m,6H),3.55(t,J=6.0Hz,2H),3.80(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.3Hz,2H); ESI-MS m / z:782.65[M+H] + .

[1079] Example 87: Synthesis of Compound 36b

[1080] Compound 36b was prepared by referring to the method of Example 77 to obtain 107.0 mg of an oily product.

[1081] 1H NMR(300MHz,MeOH-d4)δ:0.34-0.46(m,4H),0.87-0.92(m,9H),1.22-1.72(m,64H),2.32(t,J=7.2Hz,2H), 2.45-2.51(m,6H),3.55(t,J=5.7Hz,2H),3.92(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.3Hz,2H); ESI-MS m / z:780.80[M+H] + .

[1082] Example 88: Synthesis of Compound 37b

[1083] Compound 37b was prepared by the method of Example 77 to obtain 71.6 mg of an oily product.

[1084] 1 H NMR(300MHz,MeOH-d4)δ:0.89-0.94(m,18H),1.24-1.69(m,67H),2.32(t,J=7.5Hz,2H),2.50-2.55(m ,4H),2.64(t,J=6.3Hz,2H),3.62(t,J=6.3Hz,2H),3.80(s,2H),4.11(td,J=6.3,14.7Hz,4H); ESI-MS m / z:824.70[M+H] + .

[1085] Example 89: Synthesis of Compound 52a

[1086] Compound 52a was prepared by referring to the method of Example 1 to obtain 243.8 mg of an oily product.

[1087] 1 H NMR (300MHz, CDCl3) δ: 4.87-4.81 (m, 1H), 3.59 (m, 2H), 2.86 (t, J = 7.2Hz, 2H), 2.65-2.51 (m, 8H), 1. 64-1.58(m,4H),1.57-1.43(m,11H),1.39-1.19(m,48H),1.15(s,6H),0.90(t,J=7.2Hz,9H); ESI-MS m / z:754.60[M+H] + .

[1088] Example 90: Synthesis of Compound 53a

[1089] Compound 53a was prepared by referring to the method of Example 1 to obtain 262.7 mg of an oily product.

[1090] 1 H NMR(300MHz, CDCl3)δ:4.90-4.78(m,1H),3.56(t,J=5.1Hz,2H),2.86(t,J=7.2Hz,2H ),2.63-2.48(m,8H),1.81-1.19(m,63H),1.16(s,6H),0.89(t,J=7.2Hz,9H); ESI-MS m / z:754.60[M+H] + .

[1091] Example 91: Synthesis of Compound 54a

[1092] Compound 54a was prepared by referring to the method of Example 1 to obtain 287.7 mg of an oily product.

[1093] 1 H NMR (300MHz, CDCl3) δ: 4.89-4.79 (m, 1H), 4.66 (t, J = 2.1Hz, 2H), 3.53 (t, J = 5.4Hz, 2H), 2.58 (t, J = 5.4Hz, 2H), 2.45 (t, J=7.2Hz,4H),2.34(t,J=7.2Hz,2H),2.24-2.20(m,2H),1.79-1.17(m,57H),1.15(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:734.60[M+H] + .

[1094] Example 92: Synthesis of Compound 55a

[1095] Compound 55a was prepared by referring to the method of Example 1 to obtain 173.5 mg of an oily product.

[1096] 1 H NMR(300MHz, CDCl3)δ:4.89-4.78(m,1H),4.13(t,J=7.2Hz,2H),3.56(m,2H),2.63(m,2H),2.51-2.45( m,6H),2.31(t,J=7.2Hz,2H),2.16-2.10(m,2H),1.78-1.17(m,55H),1.15(s,6H),0.90(m,9H); ESI-MS m / z:734.50[M+H] + .

[1097] Example 93: Synthesis of Compound 56a

[1098] Compound 56a was prepared by referring to the method of Example 1 to obtain 112.2 mg of an oily product.

[1099] 1 H NMR(300MHz, CDCl3)δ:4.87-4.79(m,1H),4.16(t,J=6.6Hz,2H),3.60(m,2H),2.67-2.53(m,6H),2.32-2 .11(m,6H),2.32-2.11(m,6H),1.85-1.76(m,2H),1.66-1.18(m,53H),1.14(s,6H),0.88(m,9H); ESI-MS m / z:734.55[M+H] + .

[1100] Example 94: Synthesis of Compound 57a

[1101] Compound 57a was prepared by referring to the method of Example 1 to obtain 45.0 mg of an oily product.

[1102] 1 H NMR (400MHz, CDCl3) δ: 5.68-5.49 (m, 2H), 4.85-4.79 (m, 1H), 4.63 (d, J = 6.8Hz, 2H), 3.84 (m, 2H), 2.95-2. 76(m,6H),2.31(t,J=7.2Hz,2H),2.12-2.07(m,2H),1.66-1.18(m,57H),1.16(s,6H),0.88(m,9H); ESI-MS m / z:736.60[M+H] + .

[1103] Example 95: Synthesis of Compound 58a

[1104] In a 50 mL round-bottom flask, the reactants 1-nonylamine (286.5 mg, 2.0 mmol), 8-bromooctanoic acid (535.5 mg, 2.4 mmol), NMM (202.3 mg, 2.0 mmol), and HATU (1.14 g, 3.0 mmol) were dissolved in a mixture of DMF (2.0 mL) and DCM (10.0 mL). The mixture was stirred at room temperature until the 1-nonylamine reaction was complete as monitored by TLC. The reaction solution was poured into 100 mL of saturated sodium chloride solution and extracted with DCM (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 610 mg of compound 58a-2.

[1105] Compound 58a was prepared by referring to the method of Example 1 to obtain 104.0 mg of an oily product.

[1106] 1 H NMR (300MHz, CDCl3) δ: 5.53 (s, 1H), 4.87-4.79 (m, 1H), 3.22 (dd, J1 = 6.9Hz, J2 = 13.2Hz, 2H), 2.67- 2.52(m,6H),2.15(t,J=7.2Hz,2H),1.65-1.19(m,63H),1.15(s,6H),0.88(t,J=6.9Hz,9H); ESI-MS m / z:737.60[M+H] + .

[1107] Example 96: Synthesis of Compound 59a

[1108] In a 100 mL sealed tube, add 4-dimethylamino-1-butanol (3.0 g, 25.5 mmol, 1.0 eq.) and thiourea (8.4 g, 110.0 mmol, 4.3 eq.) and then add an aqueous solution of HBr (48%, 60 mL). Heat to 120°C and stir overnight to react. The product was directly used in the next step without purification.

[1109] The system was cooled to 0°C, and NaOH (10.2 g, 255.0 mmol, 10.0 eq.) was added portionwise. The mixture was heated to 120°C and reacted for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed to yield 2.45 g of compound 59a-3 as a colorless oil.

[1110] In a 100 mL three-necked flask, compound 59a-6 (1.5 g, 5.8 mmol, 1.0 eq.), 2-heptyl-1-nonanol (1.40 g, 5.8 mmol, 1.0 eq.), EDCI (1.66 g, 8.7 mmol, 1.5 eq.), and DMAP (0.35 g, 2.9 mmol, 0.5 eq.) were dissolved in 20 mL of dichloromethane and stirred at room temperature overnight. The mixture was washed with water (3 x 15 mL). The organic phase was then rotary evaporated under reduced pressure and directly mixed. Purification by silica gel column chromatography afforded 3.3 g of compound 59a-7.

[1111] In a 100 mL three-necked flask, compound 59a-7 (2.8 g, 5.8 mmol, 1.0 eq.) was dissolved in 20 mL of dichloromethane. HCl / dioxane (4 M, 14 mL) was added and stirred at room temperature overnight. The organic solvent was removed by rotary evaporation, and the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was then extracted with 3 x 20 mL of DCM. The organic phase was collected and dried over anhydrous NaSO. Purification on a silica gel column afforded 1.95 g of compound 8.

[1112] In a 40 mL sealed tube, compound 59a-8 (680 mg, 1.8 mmol, 1.0 eq.), KI (365 mg, 2.2 mmol, 1.2 eq.), KCO (745 mg, 5.4 mmol, 3.0 eq.), and 59a-5 (668.9 mg, 1.8 mmol, 1.0 eq.) were dissolved in 10 mL of acetonitrile. The mixture was heated to 80°C and stirred overnight. After the reaction, the mixture was cooled to room temperature, filtered, and the filter cake was washed with 5 mL of ACN. The filtrate was collected and dried. Purification by column chromatography afforded 580 mg of compound 59a-9 as a yellow oil.

[1113] In a 20 mL sealed tube, compound 59a-9 (200 mg, 0.29 mmol, 1.0 eq.) was dissolved in 5 mL of DCM. The reaction system was cooled to 5°C, and TEA (59.5 mg, 0.59 mmol, 2.0 eq.) and BTC (87.3 mg, 0.29 mmol, 1.0 eq.) were added dropwise. The reaction was stirred at 5°C for 1 hour. The DCM was concentrated and 5 mL of tetrahydrofuran was added. In another 20 mL sealed tube, compound 59a-3 (101.9 mg, 0.76 mmol, 2.6 eq.) was dissolved in 5 mL of tetrahydrofuran. The reaction was cooled to 0°C, and NaH (60%, 58.0 mg, 1.45 mmol, 5.0 eq.) was added. After stirring at 0°C for 1 hour, the THF mixture prepared above was added dropwise, and the reaction was continued for 1 hour. The reaction mixture was poured into 10 mL of ice water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed to obtain the crude product. Purification by Prep-HPLC (Column: XSelect C18 (30×150 mm, 5 μm); Eluent A: H2O / ACN 60 / 40, 10 mM NH4HCO3 + 1% NH3·H2O; Eluent B: IPA / ACN 90 / 10; Flow rate: 60 mL / min; Gradient program: 65%-85% B in 0-12 min) afforded 126.9 mg of compound 59a as a pale yellow oil.

[1114] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J = 6.6 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.36-3.15 (m, 4H), 2.90 (t, J=6.9Hz,2H),2.41(s,2H),2.31-2.24(m,10H),1.64-1.16(m,61H),0.93-0.77(m,15H); ESI-MS m / z:839.65[M+H] + .

[1115] Example 97: Synthesis of Compound 60a

[1116] Compound 60a was prepared by the method of Example 96 to obtain 157.3 mg of an oily product.

[1117] 1H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 4.06 (t, J = 6.9Hz, 2H), 3.37-3.17 (m, 4H), 2 .90(t,J=6.9Hz,2H),2.39-2.25(m,12H),1.79-1.18(m,70H),0.93-0.83(m,15H); ESI-MS m / z:895.80[M+H] + .

[1118] Example 98: Synthesis of Compound 61a

[1119] Compound 61a was prepared by the method of Example 96 to obtain 184.0 mg of an oily product.

[1120] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J=6.9Hz, 2H), 3.96 (d, J=5.7Hz, 2H), 3.35-3.18 (m, 4H), 2.91 (t, J= 7.2Hz,2H),2.43-2.27(m,12H),1.87-1.77(m,2H),1.61-1.18(m,57H),0.93-0.84(m,15H); ESI-MS m / z:825.55[M+H] + .

[1121] Example 99: Synthesis of Compound 38b

[1122] Compound 38b was prepared by the method of Example 96 to obtain 228 mg of an oily product.

[1123] 1 H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 3.78 (s, 2H), 3.33-3.18 (m, 4H), 2.90 (t, J = 6.6Hz ,2H),2.38-2.25(m,12H),1.69-1.44(m,16H),1.34-1.17(m,48H),0.90-0.85(m,15H); ESI-MS m / z:853.65[M+H] + .

[1124] Example 100: Synthesis of Compound 39b

[1125] Compound 39b was prepared by the method of Example 96 to obtain 117.9 mg of an oily product.

[1126] 1 H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 3.78 (s, 2H), 3.36-3.17 (m, 4H), 2.92 (t, J = 7.2Hz, 2H), 2.46 (t, J = 7.2 Hz,2H),2.34-2.22(m,10H),1.90-1.80(m,3H),1.62-1.49(m,14H),1.34-1.17(m,51H),0.93-0.86(m,15H); ESI-MS m / z:881.65[M+H] + .

[1127] Example 101: Synthesis of Compound 40b

[1128] Compound 40b was prepared by the method of Example 96 to obtain 75.3 mg of an oily product.

[1129] 1 H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 3.78 (s, 2H), 3.36-3.17 (m, 4H), 2.91 (t, J = 6.6Hz ,2H),2.48-2.28(m,12H),1.89-1.60(m,10H),1.51-1.16(m,60H),0.93-0.87(m,15H); ESI-MS m / z:895.70[M+H] + .

[1130] Example 102: Synthesis of Compound 41b

[1131] Compound 41b was prepared by the method of Example 96 to obtain 95.1 mg of an oily product.

[1132] 1 H NMR (400MHz, CDCl3) δ: 4.86 (p, J = 6.4Hz, 1H), 4.09 (t, J = 7.6Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 7 .6Hz,2H),2.40-2.26(m,12H),1.63-1.50(m,21H),1.32-1.16(m,49H),0.90-0.86(m,15H); ESI-MS m / z:895.80[M+H] + .

[1133] Example 103: Synthesis of Compound 42b

[1134] Compound 42b was prepared by the method of Example 96 to obtain 63.6 mg of an oily product.

[1135] 1 H NMR (400MHz, CDCl3) δ: 4.09 (p, J = 7.6Hz, 2H), 3.96 (d, J = 6.0Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 7 .2Hz,2H),2.57-2.26(m,12H),1.67-1.43(m,20H),1.32-1.16(m,41H),0.90-0.86(m,15H); ESI-MS m / z:839.70[M+H] + .

[1136] Example 104: Synthesis of Compound 43b

[1137] Compound 43b was prepared by the method of Example 96 to obtain 130.5 mg of an oily product.

[1138] 1 H NMR (300MHz, CDCl3) δ: 3.96 (d, J = 6.0Hz, 2H), 3.89 (s, 2H), 3.35-3.18 (m, 4H), 2.91 (t, J = 7.2Hz, 2H), 2.44-2.28 ( m,12H),1.87-1.79(m,2H),1.77-1.60(m,10H),1.34-1.17(m,47H),0.90-0.85(m,9H),0.52-0.32(m,4H); ESI-MS m / z:823.60[M+H] + .

[1139] Example 105: Synthesis of Compound 44b

[1140] Compound 44b was prepared by the method of Example 96 to obtain 79.4 mg of an oily product.

[1141] 1H NMR (300MHz, CDCl3) δ: 3.95 (d, J = 5.7Hz, 2H), 3.90 (s, 2H), 3.35-3.19 (m, 4H), 2.90 (t, J = 7.2Hz, 2H), 2.67 (s, 4H),2.34-2.27(m,4H),1.72-1.51(m,16H),1.29-1.21(m,49H),0.90-0.83(m,9H),0.46-0.36(m,4H); ESI-MS m / z:837.75[M+H] + .

[1142] Example 106: Synthesis of Compound 45b

[1143] Compound 45b was prepared by the method of Example 96 to obtain 41 mg of an oily product.

[1144] 1 H NMR (400MHz, CDCl3) δ: 4.13 (s, 2H), 3.96 (d, J = 6.0Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 6.8Hz, 2H), 2. 54-2.26(m,10H),1.67-1.45(m,18H),1.29-1.21(m,45H),0.90-0.82(m,9H),0.32-0.29(m,4H); ESI-MS m / z:837.70[M+H] + .

[1145] Example 107: Synthesis of Compound 46b

[1146] Under nitrogen, compound 46b-1 (1.0 g, 4.60 mmol, 1.0 eq.), pyridine (0.74 mL, 9.2 mmol, 2.0 eq.), DMAP (112.4 mg, 0.92 mmol, 0.2 eq.), and p-nitrophenyl chloroformate (1.11 g, 5.52 mmol, 1.2 eq.) were dissolved in 20 mL of dichloromethane in a 100 mL three-necked round-bottom flask at room temperature. The reaction system was stirred at room temperature for 1 hour. 2-Nonyl-1-decanol (3.93 g, 13.8 mmol, 3.0 eq.) and DIEA (2.40 mL, 13.8 mmol, 3.0 eq.) were then added to the reaction system. The reaction system was stirred at room temperature overnight. TLC monitoring revealed a new product. The product was diluted with DCM (20 mL) and washed once with saturated sodium bicarbonate solution (10 mL). The organic phase was washed twice with saturated NaCl solution (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column to give compound 46b-2 (1.68 g) as a light yellow oil.

[1147] Compound 46b was prepared by referring to the method of Example 96 to obtain 78.5 mg of an oily product.

[1148] 1 H NMR (300MHz, CDCl3) δ: 4.68 (p, J = 6.0Hz, 1H), 4.11 (t, J = 6.6Hz, 2H), 3.78 (s, 2H), 3.36-3.22 (m, 4H), 2.90 (t,J=6.9Hz,2H),2.47-2.29(m,10H),1.70-1.56(m,18H),1.29-1.21(m,50H),0.90-0.86(m,15H); ESI-MS m / z:897.70[M+H] + .

[1149] Example 108: Synthesis of Compound 47b

[1150] Compound 47b was prepared by referring to the method of Example 107 to obtain 189.8 mg of an oily product.

[1151] 1H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.4Hz, 2H), 4.02 (d, J = 5.6Hz, 2H), 3.78 (s, 2H), 3.32-3.24 (m, 4H), 2.92 (t, J = 7.2 Hz,2H),2.47-2.30(m,10H),1.85-1.84(m,2H),1.66-1.40(m,7H),1.26-1.18(m,48H),0.93-0.88(m,15H); ESI-MS m / z:827.55[M+H] + .

[1152] Example 109: Synthesis of Compound 48b

[1153] Compound 48b was prepared by referring to the method of Example 107 to obtain 129.4 mg of an oily product.

[1154] 1 H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.6 Hz, 2H), 4.02 (d, J = 5.7 Hz, 2H), 3.78 (s, 2H), 3.36-3.21 (m, 4H), 2.90 (t,J=6.9Hz,2H),2.36-2.26(m,10H),1.63-1.41(m,13H),1.26-1.18(m,46H),0.89-0.86(m,15H); ESI-MS m / z:841.65[M+H] + .

[1155] Example 110: Synthesis of Compound 49b

[1156] Compound 49b was prepared by referring to the method of Example 107 to obtain 135.6 mg of an oily product.

[1157] 1 H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.3Hz, 2H), 4.02 (d, J = 5.7Hz, 2H), 3.89 (s, 2H), 3.31-3.22 (m, 4H), 2.90 (t, J = 6.9 Hz,2H),2.34-2.26(m,10H),1.65-1.48(m,13H),1.27-1.19(m,46H),0.90-0.86(m,9H),0.45-0.35(m,4H); ESI-MS m / z:839.50[M+H] + .

[1158] Example 111: Synthesis of Compound 50b

[1159] Compound 50b was prepared by referring to the method of Example 107 to obtain 123.1 mg of an oily product.

[1160] 1 H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.6 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 3.84 (s, 2H), 3.34-3.19 (m, 4H), 2.90 (t, J = 6 .6Hz,2H),2.46-2.20(m,10H),1.84(m,2H),1.65-1.44(m,13H),1.27-1.19(m,46H),0.92-0.86(m,15H); ESI-MS m / z:855.60[M+H] + .

[1161] The compounds in the following table were synthesized by the methods of the above examples, or by similar methods using the corresponding intermediates.

[1162] Compound 1c-283c was synthesized using the methods of the above examples or similar methods using corresponding intermediates.

[1163] Pharmacological experiments

[1164] Experimental Example 1: Nanoparticle Preparation

[1165] The materials used for lipid nanoparticle assembly include: (1) ionizable lipid compounds, such as the ionizable lipids designed and synthesized in the present invention or DLin-MC3-DMA (purchased from AVT) as a control group; (2) structural lipids, such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids, such as DSPC (distearoylphosphatidylcholine, purchased from AVT); (4) PEGylated lipid compounds, such as DMG-PEG2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, purchased from AVT); and (5) nucleic acid fragment active ingredients, such as Luciferase mRNA, siRNA, CRISPR Cas 9 mRNA, etc. (self-made). The names and structural formulas of the lipid nanoparticle assembly materials are detailed in Table 4.

[1166] Table 4

[1167] Preparation method of lipid nanoparticles: (1) ionizable lipid compound, cholesterol, phospholipid and PEGylated lipid are dissolved and mixed in ethanol in molar percentages of 50%, 38.5%, 10% and 1.5%, respectively; (2) mRNA active ingredient is dissolved in 25mM sodium acetate solution (pH=4.5); (3) an automated high-throughput microfluidic system is used to mix the organic phase containing the lipid mixture and the aqueous phase containing the mRNA component at a flow rate ratio ranging from 1:1 to 1:4, and the mixing speed is between 10mL / min and 18mL / min; (4) the prepared lipid nanoparticles (N / P ratio of 6) are diluted with phosphate buffered saline solution, and the nanoparticle solution is ultrafiltered to the original preparation volume using an ultrafiltration tube with a molecular weight cutoff of 30kDa (purchased from Millipore); (5) the obtained nanoparticles are sterilized by filtration through a 0.2μm sterile filter membrane and stored at low temperature in a sealed glass bottle.

[1168] Methods for preparing lipid nanoparticles include, but are not limited to, microfluidic mixing systems and also include T-type mixers and ethanol injection methods.

[1169] Experimental Example 2: Characterization of physical properties of lipid nanoparticles

[1170] The particle size and particle size dispersion index (PDI) of the prepared lipid nanoparticles were measured using Zetasizer Pro (purchased from Malvern Instruments Ltd) and DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instruments. The degree of RNA encapsulation of lipid nanoparticles is characterized by the encapsulation efficiency (Encapsulation Efficiency%), which reflects the degree of binding between lipid nanoparticles and RNA fragments. This coefficient is measured by Quant-it TM The lipid nanoparticle sample was diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH = 7.5), and a portion of the sample solution was added with 0.5% Triton X-100 and allowed to stand at 37°C for 30 minutes. Immediately after the reaction, the fluorescence value was read on a Varioskan LUX multifunctional microplate reader (purchased from Thermofisher) at an absorption wavelength of 485 nm and an emission wavelength of 528 nm to obtain the encapsulation efficiency value.

[1171] Experimental Example 3: Animal Experiment

[1172] The efficacy and safety of nanoparticles loaded with luciferase mRNA (Trilink, L-7202) were evaluated in mice. The experimental mice were SPF-grade C57BL / 6 female mice, 6-8 weeks old, weighing 18-22 g, purchased from Beijing Sibeifu Biotechnology Co., Ltd. All animals were acclimated for at least 7 days prior to the experiment. During the experiment, they had free access to food and water. The experimental period was a 12 / 12 hour light / dark cycle, the room temperature was 20-26°C, and the humidity was 40-70%. The mice were randomly divided into groups. The lipid nanoparticles loaded with luciferase mRNA prepared above were intravenously injected into the mice at a single dose of 0.5 mg / kg mRNA. Six hours after administration, the mice were monitored for bioluminescence using an in vivo small animal imaging system (IVIS LUMINA III, purchased from PerkinElmer). The specific detection steps are as follows: A 15 mg / mL D-luciferin solution was prepared in normal saline and administered intraperitoneally to each mouse. Ten minutes after the administration of the substrate, the mouse was placed in an anesthesia box and anesthetized with 2.5% isoflurane. The anesthetized mouse was placed in an IVIS for fluorescence imaging and data collection and analysis of the site of concentrated fluorescence distribution.

[1173] The in vivo delivery efficiency of the lipid nanoparticle carriers is expressed as the average fluorescence intensity and total photon count of different animals within the same test group, as shown in Tables 5-11. Higher values ​​for fluorescence intensity and total photon count indicate higher in vivo delivery efficiency of the lipid nanoparticles for the mRNA fragment. Lipid nanoparticles containing the cationic lipids of the present invention exhibit excellent in vivo delivery efficiency.

[1174] Table 5

[1175] Table 6

[1176] Table 7

[1177] Table 8

[1178] Table 9

[1179] Table 10

[1180] Table 11

[1181] Experimental Example 4: In vitro delivery efficiency and safety evaluation

[1182] The in vitro cellular delivery and safety of nanoparticles loaded with luciferase mRNA were evaluated. Human embryonic kidney 293 (HEK293T) cells were cultured in Dulbecco's modified Eagle's medium (DMEM) (Thermo Fisher Scientific) supplemented with 10% fetal bovine serum and 5% penicillin-streptomycin at 37°C and 5% CO2. The cells were evenly dissected and plated in a 48-well plate. After 24 hours of incubation, a solution of lipid nanoparticles loaded with luciferase mRNA was added. After 24 hours, the cells were disrupted, and the intracellular luciferase expression intensity and relative light units (RLU) of each lipid nanoparticle were measured using a luciferase assay reagent (Promega). Higher expression levels indicate higher cellular delivery efficiency. Additionally, 24 hours later, parallel lipid nanoparticle-treated cells were tested for cytotoxicity using CCK-8 reagent (DOJINDO). The experiment used a negative control group containing only PBS. The specific steps were as follows: After adding CCK-8 solution to the cells, the cells were incubated at 37°C for 4 hours. The absorbance was then read using a multifunctional microplate reader at 450nm. The ratio of the absorbance of the nanoparticle-treated cells to that of the negative control was used as a parameter to characterize cell viability.

[1183] The delivery effect and toxicity data of nanoparticles at the in vitro cellular level are shown in Table 12.

[1184] Table 12

[1185] Experimental Example 5: Ionizable Liposome Intracellular Clearance Rate Experiment

[1186] 6-8 week old C57 WT female mice (n=3) were injected via the tail vein with 100 μL of unloaded LNPs (0.1 mg / mL) composed of ionizable lipids, cholesterol, DSPC, and DMG-PEG 2000 at a ratio of 50:38.5:10:1.5. The animals were sacrificed by cervical dislocation and their livers were removed 24 and 72 hours after administration. Livers from untreated animals from the same batch served as a blank control group. The liver samples were homogenized with water, protein precipitated, and compared to calibration standards prepared from matched blank liver tissue. The ionizable lipid content in the samples was quantified by LC-MS / MS.

[1187] The clearance rate data of ionizable liposomes are shown in Table 13.

[1188] Table 13

[1189] The control group compound has the following structure:

[1190] From the data in Table 13, it can be seen that the bis-dimethyl compound in the control group degrades slowly in the liver, with about 90% still remaining in the liver 72 hours after administration; while the compound of the present invention has a faster degradation rate and can be completely degraded in about 72 hours.

[1191] Although the present invention has been fully described through its embodiments, it is noteworthy that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, G1 and G2 are independently selected from a chemical bond, C 1-13 Straight chain alkylene, C 2-13 Straight chain alkenylene and C 2-13 A straight chain alkynylene group, which is optionally substituted by one or more R 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, C 1-14 Alkyl, -L a -OR a , -L a -SR a and -L a -NR a R' a ; G3 is selected from C 4-14 Straight chain alkylene, C 4-14 Straight chain alkenylene and C 4-14 A straight chain alkynylene group, which is optionally substituted by one or more R G3 replace; R G3 Independently selected from H, -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, C 1-14 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne, which is optionally substituted by one or more R G4 replace; R G4 Independently selected from H, 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, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3- to 10-membered heterocyclyl; or two R attached to the same carbon atom G4 Together with the carbon atom to which they are attached, they form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4g replace; R 4g are independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl, -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, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; M1 and M2 are independently 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 -; Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f -、-NR f C(O)NR f -、-OC(O)S-、-OC(O)O-、-NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -、-C(O)NR f -、-NR f C(O)-、-NR f C(O)S-、-SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -、-NR f C(S)O-, -SS-, -S(O) 0-2 -, phenylene and pyridinylene, wherein the phenylene or pyridinylene is optionally substituted with one or more R*; R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Haloalkyl, -L f -OR f , -L f -SR f and -L f -NR f R' f ; L f Independently selected from chemical bonds and C 1-8 Alkylene; R f and R' f Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted with one or more R 1s substituted, and one or more methylene units therein are optionally and independently replaced by -NR'-; R 1s Independently selected from H, C 1-20 Alkyl, -L c -OR c , -L c -SR c and -L c -NR c R' c ; R and R' are each independently selected from H and C 1-20 alkyl; L c Independently selected from chemical bonds and C 1-20 Alkylene; R c and R' c Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; 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 heterocyclyl and 5- to 14-membered heteroaryl; R g and R' g Independently selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and 3- to 10-membered heterocyclyl; R" is independently selected from H and C 1-6 alkyl; R4 and R5 are independently selected from C 1-8 Alkyl, which is optionally substituted by one or more R 4s replace; Or R4, R5 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4s replace; R 4s are independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl, -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, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: G1 and G2 are independently selected from a chemical bond, C 1-9 Straight chain alkylene, C 2-9 Straight chain alkenylene and C 2-9 straight chain alkynylene; Preferably, G1 is selected from C 1-6 Straight chain alkylene, C 2-6 Straight chain alkenylene and C 2-6 Straight chain alkynylene, preferably selected from C 1-6 Straight chain alkylene, preferably selected from C 2-6 Straight chain alkylene; Preferably, G2 is selected from a chemical bond, C 1-6 Straight chain alkylene, C 2-6 Straight chain alkenylene and C 2-6 Straight chain alkynylene, preferably selected from chemical bonds and C 1-6 Straight chain alkylene, preferably selected from chemical bonds and C 1-4 Straight chain alkylene; Preferably, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably the total length is 4, 5 or 6 carbon atoms, preferably the total length is 5 or 6 carbon atoms; preferably the total length is 5, 6 or 7 carbon atoms, preferably the total length is 6 or 7 carbon atoms; Preferably, G1 and G2 are optionally replaced by 1, 2, 3 or 4 R G1 replace.

3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R G1 Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 alkyl.

4. A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: G3 is selected from C 4-10 Straight chain alkylene, C 4-10 Straight chain alkenylene and C 4-10 Straight chain alkynylene; preferably selected from C 4-9 Straight chain alkylene; preferably selected from C 5-8 Straight chain alkylene; Preferably, G3 is optionally replaced by 1, 2, 3 or 4 R G3 replace.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: L a Independently selected from chemical bonds and C 1-10 Alkylene, preferably selected from chemical bonds and C 1-6 Alkylene; Preferably, R a and R' a Independently selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 alkyl.

6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: G4 is selected from C 1-4 Alkylene, C 2-4 Alkenylene and C 2-4 Alkyne; preferably selected from C 2-4 Alkylene; preferably selected from C 2-3 Alkylene; Preferably, G4 is optionally replaced by 1, 2, 3 or 4 R G4 replace.

7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R G4 Independently selected from H and C 1-6 Alkyl; preferably selected from C 1-4 alkyl; Preferably, the two R attached to the same carbon atom G4 Together with the carbon atom to which they are attached, they form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene, preferably forming C 3-7 Cycloalkylene or 3 to 7 membered heterocyclylene, which is optionally substituted by 1, 2 or 3 R 4g replace; Preferably, R 4g are independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: L b Independently selected from chemical bonds and C 1-4 Alkylene; Preferably, R b and R' b Independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

9. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; preferably selected from -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably selected from -C(O)O- and -OC(O)-; Preferably, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-; Preferably, one of M1 and M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is -OC(O)- or -SC(O)-, preferably -OC(O)-; Preferably, M1 is -OC(O)- or -SC(O)-, preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-; Preferably, M1 is -C(O)O-, and M2 is -C(O)O- or -C(O)S-; Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)- and -C(O)NH-; Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S- and -C(O)NH-, preferably selected from -C(O)O-, -OC(O)- and -C(O)S-; Preferably, one of M1 and M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; Preferably, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably -C(O)O- or -OC(O)-; Preferably, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably selected from -C(O)O- and -OC(O)-, preferably -C(O)O-, preferably -OC(O)-, and M2 is -OC(O)O-; Preferably, M1 is -OC(O)O-, M2 is -OC(O)- or -OC(O)-, preferably -OC(O)-; Preferably, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-, preferably -C(O)O-, -OC(O)- and -OC(O)O-; preferably, M1 and M2 are not -OC(O)O- at the same time.

10. A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 Alkynyl; preferably selected from C 6-14 Alkyl; preferably selected from C 7-12 Alkyl; preferably selected from C 8-12 alkyl; Preferably, R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 Alkenyl and C 7-12 Alkynyl, preferably C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl; Preferably, R1 and R2 are optionally replaced by 1, 2, 3 or 4 R 1s substituted, preferably optionally with 1 R 1s replace; Preferably, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, -(CH2)4-C≡C- (CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3, Preferably, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3, 11. A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from H and C 1-6 Alkyl, preferably selected from H and C 1-4 alkyl.

12. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R and R' are each independently selected from H and C 1-20 Alkyl; preferably selected from H and C 1-14 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from H and C 1-6 Alkyl; preferably R is H.

13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: L c Independently selected from chemical bonds and C 1-14 Alkylene; preferably selected from chemical bonds and C 1-10 Alkylene; preferably selected from chemical bonds and C 1-6 Alkylene; Preferably, R c and R' c Independently selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 alkyl.

14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R3 is selected from CN, -OR g and-NR g R' g ; preferably selected from -OR g and-NR g R' g ; preferably -OR g ; preferably OH; Preferably, R3 is selected from OH and -N(CH3)2; Preferably, R g and R' g Independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 Alkyl; preferably selected from H and Me.

15. A compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R4 and R5 are independently selected from C 1-6 Alkyl; preferably selected from C 1-3 Alkyl; preferably methyl; Preferably, R4 and R5 are optionally replaced by 1, 2 or 3 R 4s replace; Preferably, R4, R5 together with the carbon atom to which they are attached form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably forms cyclopropylene or cyclopentylene; preferably forms cyclopropylene; Preferably, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted by 1, 2 or 3 R 4s replace.

16. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: R 4s are independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -OR d , -L d -SR d and -L d -NR d R' d ; preferably selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 preferably selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

17. A compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: L d Independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-3 Alkylene; Preferably, R d and R' d Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 alkyl.

18. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: L e Independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-4 Alkylene; Preferably, R e and R' e Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

19. A compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: Q is selected from a chemical bond, -OC(O)- and -SC(O)-; preferably selected from a chemical bond and -SC(O)-; Preferably, when Q is phenylene or pyridinylene, it is optionally substituted with 1, 2 or 3 R*; Preferably, R* is independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Haloalkyl; Preferably, L f Independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-4 Alkylene; Preferably, R f and R' f Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

20. A compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has a structure of formula (II) or formula (III): in, a=1, 2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=3, 4, 5, 6, 7, 8 or 9; The remaining groups are as defined in any one of claims 1 to 19.

21. A compound of formula (II) or (III) according to claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 0-10 carbon atoms, preferably by 0-6 carbon atoms, preferably by 0-4 carbon atoms, preferably by 0-2 carbon atoms, preferably by 0 carbon atoms; Preferably, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 1 to 10 carbon atoms, preferably by 1 to 6 carbon atoms. Atoms, preferably 1-4 carbon atoms apart, preferably 1-2 carbon atoms apart, preferably 2-10 carbon atoms apart, preferably 2-6 carbon atoms apart, preferably 2-4 carbon atoms apart; Preferably, there is no R on R1 1s Replace, and R 1s The substitution sites on R2 are separated from M2 by 0-10 carbon atoms, preferably by 1-10 carbon atoms, preferably by 1-6 carbon atoms, preferably by 1-4 carbon atoms, preferably by 1-2 carbon atoms, preferably by 2-10 carbon atoms, preferably by 2-6 carbon atoms, preferably by 2-4 carbon atoms; Preferably, R1 has R 1s Replaced, and R2 has no R 1s replace; Preferably, R4 and R5 and the carbon atoms to which they are attached do not form a ring; Preferably, d is not zero.

22. A compound of formula (II) according to claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, a=2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=3, 4, 5, 6, 7, 8 or 9; preferably c+d=4, 5 or 6; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably, M1 and M2 are independently selected from -C(O)O- and -C(O)S-; or one of M1 and M2 is -C(O)O- or -C(O)S-, and the other is -OC(O)- or -SC(O)-; R1 and R2 are independently selected from C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace; R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 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; R4 and R5 are independently selected from C 1-6 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

23. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7; c = 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=5 or 6; M1 and M2 are independently selected from -C(O)O- and -OC(O)-; preferably, M1 and M2 are -C(O)O-; or one of M1 and M2 is -C(O)O-, the other is -OC(O)-; R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 alkyl; R4 and R5 are independently selected from C 1-3 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene; preferably forming C 3-5 Cycloalkylene.

24. The compound of formula (II) according to claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7; c = 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4; c+d=5 or 6; preferably c+d=6; M1 and M2 are -C(O)O-; Or one of M1 and M2 is -C(O)O-, and the other is -OC(O)-; R1 and R2 are independently selected from: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, Preferably selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, Preferably selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, R4 and R5 are methyl groups; Or R4 and R5 and the carbon atom to which they are connected together form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; preferably form cyclopropylene or cyclopentylene; preferably form cyclopropylene; Preferably, only one of R1 and R2 has a substituent.

25. The compound of formula (II) according to claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a＝2； b＝5； c=2, 3, 4, 5 or 6; preferably c=6; d = 0, 1, 2, 3 or 4; preferably d = 0; c+d=5 or 6; preferably 6; M1 and M2 are -C(O)O-; R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from C 6-8 Alkyl; preferably selected from C 7-8 alkyl; R2 is selected from C 7-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl, preferably C 11 Straight chain alkyl, which is optionally substituted with 1 C 1-3 Alkyl substituted, preferably optionally substituted with 1 methyl group; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; Preferably, R1 is selected from Preferably selected from Preferably, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and 26. The compound of formula (II) according to claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; preferably a=2; b＝7； c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2; d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4; c+d=5 or 6; preferably 6; M1 and M2 are -C(O)O-; R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from C 6-9 Alkyl; preferably selected from C 7-8 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; Preferably, R2 is selected from Preferably selected from 27. The compound of formula (II) according to claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a＝2； b＝7； c=3 or 4; preferably c=4; d＝2； M1 and M2 are -C(O)O-; R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 alkyl; R2 is selected from C 7-11 Straight chain alkyl, preferably C9 straight chain alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably cyclopropylene.

28. The compound of formula (II) according to claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; preferably a=2 or 4; b=6 or 7; preferably b=7; c=2, 3, 4, 5 or 6; preferably c=5 or 6; d = 0, 1, 2, 3 or 4; preferably d = 0 or 1; c+d=5 or 6; preferably 6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 7-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl; R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 A straight chain alkyl group, which is optionally substituted by 1 R 1s replace; R 1s Independently selected from C 7-9 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; Preferably, when a=4, R4 and R5 and the carbon atoms to which they are connected do not form a ring; preferably R 1s Independently selected from C 8-9 alkyl; Preferably, R2 is selected from 29. A compound of formula (II) according to claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, a=2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=3, 4, 5, 6, 7, 8 or 9; preferably c+d=4, 5, 6 or 7; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)- and -C(O)NH-, preferably selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably, one of M1 and M2 is -C(O)O- or -C(O)S-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- and -SC(O)-, preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 Alkynyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace; R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 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; R4 and R5 are independently selected from C 1-6 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

30. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7; c = 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=5, 6 or 7; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S- and -C(O)NH-, preferably selected from -C(O)O-, -OC(O)- and -C(O)S-; preferably, one of M1 and M2 is -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably selected from -C(O)O-, -C(O)S- and -OC(O)-; R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 Alkenyl and C 7-12 Alkynyl, preferably C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl, which is optionally substituted with 1 R 1s replace; R 1s Independently selected from H and C 1-10 alkyl; R4 and R5 are independently selected from C 1-3 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene; preferably forming C 3-5 Cycloalkylene.

31. The compound of formula (II) of claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7; c = 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=5, 6 or 7; preferably c+d=6; One of M1 and M2 is -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably selected from -C(O)O-, -C(O)S- and -OC(O)-; R1 and R2 are independently selected from: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3、-CH2-CH=CH-(CH2)5CH3、-CH2-C≡C-(CH2)5CH3、-(CH2)2-C≡C-(CH2)4CH3、-(CH2)3-C≡C-(CH2)3CH3、 Preferably selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, Preferably selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, R4 and R5 are methyl groups; Or R4 and R5 and the carbon atom to which they are connected together form cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; preferably form cyclopropylene or cyclopentylene; preferably form cyclopropylene; Preferably, only one of R1 and R2 has a substituent.

32. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a＝2； b＝5； c=5 or 6; preferably c=6; d=0 or 1; preferably d=0; c+d=5 or 6; preferably 6; M1 is -C(O)O-, M2 is -C(O)O- or -C(O)S-; preferably M1 and M2 are -C(O)O-; R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 Alkyl; preferably selected from C 6-8 Alkyl; preferably selected from C 7-8 alkyl base; R2 is selected from C 7-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl, preferably C 11 Straight chain alkyl, which is optionally substituted with 1 C 1-3 Alkyl substituted, preferably optionally substituted with 1 methyl group; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; Preferably, R1 is selected from Preferably selected from Preferably, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and 33. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; preferably a=2; b=5, 6 or 7; preferably b=7; c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2; d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4; c+d=5 or 6; preferably 6; M1 and M2 are -C(O)O-; R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s Substitution; and only one of R1 and R2 has a substituent; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from C 6-10 Alkyl; preferably selected from C 7-9 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; preferably not forming a ring; Preferably, R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl; R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s Substitution; when R2 is C 10 When the alkyl group is a straight chain, R 1s Selected from C 9-10 Alkyl, preferably C9 alkyl; Preferably, R2 is selected from Preferably selected from 34. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; b＝6； c=4, 5 or 6; preferably c=5 or 6; preferably c=5; d=1 or 2; preferably d=1; c+d=6, 7 or 8; preferably 6 or 7; preferably 6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 7-12 Straight chain alkyl, preferably C 8-11 Straight chain alkyl, preferably C 9-11 Straight chain alkyl; R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-12 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 7-11 Alkyl, preferably C 7-10 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; The condition is that when c = 4, a = 2 or 3; Preferably, R2 is selected from Preferably, a=2 or 4; b=6; c=5 or 6, preferably c=5; d=1; R1 is selected from C 8-9 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 9-10 Alkyl, preferably C 10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 7-8 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Preferably, a=2, 3 or 4, preferably a=2 or 4; b=6; c=5; d=2; R1 is selected from C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 9-11 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 7-9 alkyl; R4 and R5 are independently selected from C 1-3 The alkyl group is preferably a methyl group.

35. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; preferably a=2 or 4; b＝7； c=5 or 6; preferably c=5; d=0 or 1; preferably d=1; c+d=5 or 6; preferably 6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, which is optionally substituted with 1 C 1-9 Alkyl (preferably C 6-9 Alkyl, more preferably C 6-7 Alkyl) substituted; R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 7-9 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; Preferably, R1 is selected from -(CH2)8CH3, -(CH2)9CH3, R2 is selected from Preferably, when a=4, R1 is selected from C 9-10 Straight chain alkyl; R2 is selected from C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Selected from C 8-9 alkyl; R4 and R5 and the carbon atoms to which they are connected do not form a ring; Preferably, when a=2, R1 is C 10 Straight chain alkyl; Preferred R 1s Selected from C 8-9 Alkyl group, preferably C9 alkyl group.

36. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; preferably a=2 or 4; b＝7； c＝4； d＝2； M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl; R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 7-9 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; preferably not forming a ring; Preferably, R2 is selected from 37. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; preferably a=2; b＝8； c＝5； d＝1； M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl; R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 7-9 Alkyl, preferably C 7-8 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably forming cyclopropylene; preferably not forming a ring; Preferably, R2 is selected from 38. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a＝2； b = 6, 7 or 8, preferably b = 7; c＝5； d＝1； M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C7 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Preferably, R2 is selected from Preferably 39. The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2 or 3, preferably a=2; b＝7； c＝3； d＝3； M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 6-7 Alkyl, preferably C7 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Preferably, R2 is selected from Preferably 40. A compound of formula (II) according to claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, a=2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=3, 4, 5, 6, 7, 8 or 9; preferably c+d=4, 5 or 6; One of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; R1 and R2 are independently selected from C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace; R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 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; R4 and R5 are independently selected from C 1-6 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

41. The compound of formula (II) of claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6; c=2, 3, 4, 5 or 6; preferably c=2, 4, 5 or 6; d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4; c+d=5 or 6; preferably c+d=6; One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-; R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 9-11 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 4-10 alkyl; R4 and R5 are independently selected from C 1-3 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene, preferably forming C 3-4 Cycloalkylene.

42. The compound of formula (II) of claim 40 or 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6; c=2, 3, 4, 5 or 6; preferably c=2, 4, 5 or 6; d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4; c+d=5 or 6; preferably c+d=6; One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-; R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, R4 and R5 are methyl groups; Or R4 and R5 together with the carbon atom to which they are attached form a cyclopropylene group; Preferably, only one of R1 and R2 has a substituent; Preferably, M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-, and M2 is -OC(O)O-; Preferably, M1 is -OC(O)O-, and M2 is -OC(O)-.

43. The compound of formula (II) of claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a＝2； b=5 or 6; preferably b=6; c=4, 5 or 6; preferably c=4 or 6; preferably c=6; d = 0, 1 or 2; preferably d = 0 or 2; c+d=6; M1 is -C(O)O-, M2 is -OC(O)O-; R1 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Selected from C 7-9 Alkyl, preferably C7 alkyl; R2 is selected from C 8-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring; Preferably, R1 is selected from Preferably 44. The compound of formula (II) of claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a＝2； b＝6； c=4, 5 or 6; preferably c=5 or 6; preferably c=6; d = 0, 1 or 2; preferably d = 0 or 1; c+d=6; M1 is -C(O)O-, M2 is -OC(O)O-; R1 is selected from C 8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Selected from C 6-7 Alkyl, preferably C7 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring; Preferably, R2 is selected from Preferably 45. The compound of formula (II) of claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a＝2； b=5 or 6; preferably b=6; c＝5； d＝1； M1 is -OC(O)-, M2 is -OC(O)O-; R1 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Selected from C 6-8 Alkyl, preferably C 6-7 alkyl; R2 is selected from C 8-12 Straight chain alkyl, preferably C 10-11 Straight chain alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring; Preferably, R1 is selected from Preferably 46. ​​The compound of formula (II) of claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: a=2, 3 or 4; preferably a=2; b=5, 6, 7 or 8; preferably b=6 or 7; preferably b=7; c=4, 5 or 6; preferably c=4; d = 0, 1 or 2; preferably d = 1; c+d=5 or 6; preferably c+d=5; M1 is -OC(O)O-, M2 is -OC(O)-; R1 is selected from C 8-12 Alkyl, preferably selected from C 8-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Selected from C 6-10 Alkyl, preferably selected from C 6-8 alkyl; R2 is selected from C 8-12 Straight chain alkyl, preferably C 8-10 Straight chain alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene; preferably not forming a ring; Preferably, R1 is 47. A compound of formula (III) according to claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, Q is -SC(O)- or -OC(O)-; R g and R' g Independently selected from C 1-6 alkyl; a=2, 3, 4, 5 or 6, preferably a=2, 3 or 4; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6 or 7; c = 2, 3, 4, 5 or 6; d = 0, 1, 2, 3 or 4; c+d=5 or 6; M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; R1 and R2 are independently selected from C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R 1s replace; R 1s Independently selected from H, C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; preferably selected from H and C 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; R4 and R5 are independently selected from C 1-6 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

48. The compound of formula (III) of claim 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: Q is -SC(O)- or -OC(O)-; R g and R' g Independently selected from C 1-3 alkyl; a=3 or 4; b = 6 or 7; c=2, 3, 4 or 5; preferably 2 or 5; d = 1, 2, 3 or 4; preferably 1 or 4; c+d=5 or 6; M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably, M1 and M2 are not simultaneously -OC(O)O-; R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-10 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 Alkyl; preferably selected from H and C 1-9 alkyl; R4 and R5 are independently selected from C 1-3 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene.

49. A compound of formula (III) according to claim 47 or 48, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: Q is -SC(O)-; R g and R' g is methyl; a=3 or 4; b = 6 or 7; c=2, 4 or 5; preferably 2 or 5; d = 1, 2 or 4; preferably 1 or 4; c+d=6; M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably, M1 and M2 are not simultaneously -OC(O)O-; R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, R4 and R5 are methyl groups; Or R4 and R5 and the carbon atom to which they are attached together form a cyclopropylene group, preferably without forming a ring; Preferably, only one of R1 and R2 has a substituent; preferably, R1 has no substituent and R2 has a substituent.

50. A compound of formula (II) according to claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-; The remaining groups are as defined in any one of claims 21-27 and 29-33.

51. A compound of formula (II) according to claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, One of M1 and M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is -OC(O)- or -SC(O)-, preferably -OC(O)-; The remaining groups are as defined in any one of claims 21-24, 29-31 and 34-39; Preferably, R 1s Independently selected from H and C 1-6 Alkyl, preferably selected from H and C 1-4 alkyl; Preferably, R 1s Independently selected from C 1-8 Alkyl, preferably selected from C 4-8 Alkyl, preferably selected from C 6-8 Alkyl, preferably selected from C 7-8 Alkyl, preferably C8 alkyl; Preferably, M1 is -OC(O)- or -SC(O)-, preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-.

52. A compound of formula (II) or (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, Q is selected from a chemical bond, -SC(O)- and -OC(O)-; R g and R' g Independently selected from C 1-6 alkyl; a=2, 3, 4, 5 or 6; b = 6 or 7; c = 5 or 6; d = 0 or 1; c+d=5 or 6; M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-; R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from H and C 1-10 alkyl; R4 and R5 are independently selected from C 1-6 alkyl; Or R4 and R5 and their connected carbon atoms together form C 3-6 Cycloalkylene; Preferably, only one of R1 and R2 has a substituent; preferably, R1 has no substituent and R2 has a substituent.

53. The compound of formula (II) or (III) of claim 52, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: Q is -SC(O)- or -OC(O)-, preferably -SC(O)-; R g and R' g Independently selected from C 1-3 Alkyl, preferably methyl; a=2, 3 or 4; preferably a=2 or 4; more preferably a=4; b=6 or 7; preferably b=7; c=5 or 6; preferably c=5; d=0 or 1; preferably d=1; c+d=5 or 6; preferably 6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 7-11 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is optionally replaced by 1 R 1s replace; R 1s Independently selected from C 1-9 Alkyl, preferably selected from C 1-8 Alkyl, preferably selected from C 4-9 Alkyl, preferably selected from C 4-8 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl, preferably methyl; Or R4 and R5 and their connected carbon atoms together form C 3-4 Cycloalkylene, preferably forming cyclopropylene; Preferably, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 0-10 carbon atoms, preferably by 0-6 carbon atoms, preferably by 0-4 carbon atoms, preferably by 0-2 carbon atoms, preferably by 0 carbon atoms; Preferably, there is no R on R1 1s Replace, and R 1s The substitution sites on R2 are separated from M2 by 0-10 carbon atoms, preferably by 1-10 carbon atoms, preferably by 1-6 carbon atoms, preferably by 1-4 carbon atoms, preferably by 1-2 carbon atoms, preferably by 2-10 carbon atoms, preferably by 2-6 carbon atoms, preferably by 2-4 carbon atoms; Preferably, R2 is selected from Preferably selected from Preferably selected from Best Preferably, R4 and R5 and the carbon atom to which they are attached do not form a ring.

54. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein: The compound is selected from the compounds of Table (I).

55. A pharmaceutical composition comprising a compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient.

56. A nanoparticle composition comprising a lipid component and, optionally, a load; wherein, The lipid component contains the compound of any one of claims 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and the cargo is selected from one or more of a therapeutic agent, a preventive agent or a diagnostic agent.

57. Use of a compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition of claim 55, or a nanoparticle composition of claim 56 in the preparation of a medicament for treating, diagnosing or preventing a disease; preferably, the medicament for treating, diagnosing or preventing a disease is a therapeutic or preventive mRNA vaccine.

58. Use of a compound of any one of claims 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition of claim 55, or a nanoparticle composition of claim 56 in the preparation of a medicament for delivering a load selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

59. A method of treating, diagnosing or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 55, or the nanoparticle composition of claim 56.

60. A compound of any one of claims 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition of claim 55, or a nanoparticle composition of claim 56, for use in treating, diagnosing or preventing a disease.

61. A method of delivering a payload into a subject, comprising administering to the subject the pharmaceutical composition of claim 55 or the nanoparticle composition of claim 56; in, The cargo is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

62. A compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 55, or a nanoparticle composition according to claim 56, for use in delivering a cargo; in, The cargo is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

63. The nanoparticle composition of claim 56, or the use of claim 58 or 62, or the method of claim 61, wherein the therapeutic, prophylactic, or diagnostic agent is a nucleic acid; Preferably, the nucleic acid is selected from one or more of 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), long non-coding RNA (lncRNA), micro RNA (miRNA), small activating RNA (saRNA), polycoding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA) or ribozyme, preferably mRNA, more preferably modified mRNA.

64. A method for preparing a compound of formula (II), the method comprising: reacting a compound of formula (IIA) with a compound of formula (IIB) to obtain a compound of formula (II); wherein X is halogen, and the remaining variables are as defined in any one of claims 20-46.

65. A method for preparing a compound of formula (II), the method comprising: reacting a compound of formula (IIC) with a compound of formula (IID) to obtain a compound of formula (II); wherein X is halogen, and the remaining variables are as defined in any one of claims 20-46.

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