Rapidly metabolized lipid compound

Abstract

The invention provides a rapidly metabolized lipid compound, and particularly relates to a compound as shown in formula (I), or pharmaceutically acceptable salt, isotope variant, tautomer or stereoisomer thereof. The invention also provides nanoparticle pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions thereof in delivery of nucleic acids. # imgabs0 #

Description

[0001] This application claims priority to Chinese applications CN202310720951.5 and 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] This invention relates to a new class of ionizable cationic lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. The invention also relates to lipid nanoparticles comprising said compounds and pharmaceutical compositions, and the use of said lipid nanoparticles in the delivery of bioactive substances such as nucleic acids (e.g., mRNA, siRNA, ASO, DNA, etc.). Background Technology

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

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

[0005] Since different types of nucleic acid substances and specific delivery to different targets require different delivery systems, new lipid molecules need to be further developed to meet the different needs of gene therapy. Summary of the Invention

[0006] This invention develops a new class of ionizable cationic lipid compounds that can be used to deliver various bioactive substances with high delivery efficiency.

[0007] The inventors' prior patent CN115850104A discloses a class of cationic lipid compounds with both tail chains having a digethylenedialkyl structure, exhibiting high delivery efficiency. Unexpectedly, further research revealed that when the digethylenedialkyl 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 in vivo metabolism, the inventors have developed a new class of ionizable cationic lipid compounds.

[0008] This invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof:

[0009]

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

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

[0012] US11246933B1 discloses that incorporating biodegradable groups into the tail chain of lipid compounds in lipid nanoparticles can accelerate metabolism and remove lipids from the body after delivering the active agent to the target region, thereby making the lipids containing biodegradable groups less toxic than similar lipids without biodegradable groups. The cationic lipid compounds of this invention have biodegradable groups in their tail chains, thus exhibiting superior toxicity compared to similar lipids without biodegradable groups, such as DLin-MC3-DMA.

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

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

[0015] In another aspect, the present invention provides the use of the compounds of the present invention, the nanoparticle compositions of the present invention, or the pharmaceutical compositions of the present invention in the preparation of a medicament for delivery of a loading.

[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 compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for the treatment, diagnosis, and / or prevention of diseases.

[0018] In another aspect, the present invention provides a method for delivering a payload to 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 compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for delivering payloads.

[0020] In a specific implementation, the load is selected from one or more of a therapeutic agent, a preventive agent, or a diagnostic agent; preferably, the therapeutic agent, preventive agent, or diagnostic agent is a nucleic acid.

[0021] In a more specific embodiment, 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 noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozymes, preferably mRNA, more preferably modified mRNA.

[0023] definition

[0024] Chemical definition

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

[0026] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0027] “C 1-20 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. In some embodiments, C 4-20 Alkyl, C 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 groups and Me are preferred. C1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, the alkyl group is preferably a straight-chain alkyl group.

[0028] “C 2-13 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 13 carbon atoms and at least one carbon-carbon double bond. 4-20 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-14 alkenyl, C 6-14 alkenyl, C 7-12 alkenyl, C 4-10 alkenyl, C 2-10 alkenyl, C 2-9 alkenyl, C 2-6 alkenyl and C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] “C 2-13 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 13 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 4-20"Alkyne" refers to a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4-14 alkynyl group, C 6-14 alkynyl group, C 7-12 alkynyl group, C 4-10 alkynyl group, C 2-10 alkynyl group, C 2-9 alkynyl group, C 2-6 alkynyl group and C 2-4 The alkynyl group is preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0030] “C 1-20 "Alkylene" refers to the removal of C 1-20 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 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 Alkylenes and methylene groups are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0031] “C 2-13 "Alkenyl" refers to the group that has been de-carbonied. 2-13 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. "C 4-14 "Alkenyl" refers to the group that has been de-carbonied. 4-14 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 6-14 imidene group, C 4-10 imidene group, C 2-10 imidene group, C 2-9 imidene group, C 2-6 imide and C 2-4Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0032] “C 2-13 "Iso-ynyl group" refers to the group with the C group removed. 2-13 The alkynyl group is a divalent group formed by the other hydrogen atom, and can be substituted or unsubstituted. "C 4-14 "Iso-ynyl group" refers to the group with the C group removed. 4-14 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 6-14 Ethyne group, C 4-10 Ethyne group, C 2-10 Ethyne group, C 2-9 Ethyne group, C 2-6 etyne and C 2-4 The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0033] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene", "C" 0-4 "alkylene" refers to chemical bonds and the aforementioned "C" 1-4 Alkylene".

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

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

[0036] In compound 11b, R 1s The substitution site on R2 is separated from M2 by 3 carbon atoms.

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

[0038] Therefore, "C" 1-10 "Halogenated alkyl" refers to the above "C 1-10 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-8 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[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 or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl, and 3- to 6-membered cycloalkyl are particularly preferred, more preferably 5- to 7-membered cycloalkyl, 4- to 6-membered cycloalkyl, 3- to 5-membered cycloalkyl, 3- to 4-membered cycloalkyl, and 5- to 6-membered cycloalkyl, more preferably 5-membered cycloalkyl, more preferably 6-membered cycloalkyl, and more preferably cyclopropyl. Cycloalkyl also includes a cyclic system in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system. Cycloalkyl also includes a cyclic system in which the aforementioned cycloalkyl ring, Substituents on any non-adjacent carbon atoms are linked together to form a bridged ring, forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups also include the aforementioned cycloalkyl rings, where substituents on the same carbon atom are linked together to form a ring, forming a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0040] “C 3-14 "Cycloalkylene" refers to the alkylene group after removing C24. 3-14 The cycloalkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 3-10 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene compounds are particularly preferred, especially cyclopropylene compounds.

[0041] "3-14 membered heterocyclic group" or "3 to 14 membered heterocyclic group" refers to a saturated or unsaturated group having a 3 to 14 membered non-aromatic ring system with a cyclic carbon atom and 1 to 5 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 1, 2, or 3 double or triple bonds. In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 3- to 10-membered heterocyclic group is preferred, which is a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5- to 10-membered heterocyclic group is preferred, which is a 5- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3- to 8-membered heterocyclic group is preferred, which is a 3- to 8-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, a 3- to 7-membered heterocyclic group is preferred, which is a 3- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; preferably, a 5- to 7-membered heterocyclic group is preferred, which is a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms. A 5- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 3- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 4- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably a 5- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 5-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolyl, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclic groups also include those that share one or two atoms with a cycloalkyl, heterocyclic, aryl, or heteroaryl group to form a bridged or spirocyclic ring, wherein the shared atom may be a carbon or nitrogen atom, provided that the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

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

[0043] "5-14 membered heteroaryl" or "5 to 14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6, 10, or 14 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryls also include ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryls are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl or pyridoneyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadiazinyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0044] "Hydroxyalkyl" refers to an alkyl group that has been replaced by one or more hydroxyl groups.

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

[0046] "Optionally replaced by..." means that it can be replaced by a specified substituent or not replaced.

[0047] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0048] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional 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, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0050] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0051] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0052] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0053] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0054] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff)2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee 3. -OSi(R) ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0055] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

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

[0057] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(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 groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -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 group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 aryl, 3-7 membered heterocyclic, 5-10 membered heteroaryl; or two geminal Rs gg Substituents can combine to form =O or =S; where X - It is a counterion.

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

[0059] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their hybrid molecules. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASO). Nucleic acids can be further chemically modified, with modifications selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. mRNA molecules contain protein-coding regions and may further contain expression regulatory sequences, typical of which include, but are not limited to, a 5' cap, a 5' untranslated region (5'UTR), a 3' untranslated region (3'UTR), a polyadenylated nucleotide sequence (PolyA), and a miRNA binding site.

[0060] "Cationic lipids" refer to lipid molecules that can carry a positive charge under physiological pH conditions. In some embodiments, cationic lipids are amino lipids.

[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-distearyl-sn-glycerol-3-phosphate choline (DSPC), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline (POPC), 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE), 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate ethanolamine (POPE), and 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE).

[0062] "Structural lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentane-polyhydrophenanthrene carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coccosterol, rock saponin, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol, or campesterol.

[0063] "Polymer lipid" refers to a molecule containing both a polymeric moiety and a lipid moiety. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. Other lipids capable of reducing aggregation, such as products of lipid coupling with compounds having uncharged, hydrophilic, or sterically barrier moieties, may also be used.

[0064] "Lipid nanoparticles" refer to particles containing lipid components and having a nanoscale size.

[0065] "Biodegradable groups" refer to functional groups containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can affect the process of clearing compounds from the body. In this invention, the orientation of the biodegradable groups is from the head to the tail of the ionizable lipid molecule.

[0066] Other definitions

[0067] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0068] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

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

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

[0071] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0072] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0073] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0074] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0075] Generally, the "effective amount" of a pharmaceutical composition refers to a quantity sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the pharmaceutical compositions of the present invention can be varied depending on factors such as the biological target, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0076] Unless otherwise stated, the “therapeuticly effective amount” of a pharmaceutical composition as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a pharmaceutical composition refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeuticly effective amount” can include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0077] Unless otherwise stated, the “preventive effective amount” of a pharmaceutical composition as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventive effective amount of a pharmaceutical composition refers to the amount of the therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventive effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0078] The term "combination" and related terms refer to the simultaneous or sequential administration of the pharmaceutical composition of the present invention and other therapeutic agents. For example, the pharmaceutical composition of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation Plan

[0079] In this document, “compounds of the present invention” refers to the following compounds, their pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers.

[0080] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[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]

[0083] in,

[0084] G1 and G2 are independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, which are optionally surrounded by one or more R groups G1 replace;

[0085] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0086] R G1 Independently selected from H and C 1-14 Alkyl, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0087] G3 is selected from C 4-14 straight-chain alkylene, C 4-14 Straight-chain alkenyl groups and C 4-14Straight-chain ynylene groups, which are optionally surrounded by one or more R groups G3 replace;

[0088] R G3 Independently selected from H, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0089] L a Independently selected from chemical bonds and C 1-14 Alkylene;

[0090] R a and R' a Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0091] G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group, which is optionally surrounded by one or more R G4 replace;

[0092] R G4 Independently selected from H and C 1-6 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0093] L b Independently selected from chemical bonds and C 1-6 Alkylene;

[0094] R b and R' b Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0095] Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4g replace;

[0096] R 4gIndependently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0097] L e Independently selected from chemical bonds and C 1-8 Alkylene;

[0098] R e and R' e Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0099] 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 -;

[0100] Q is selected from chemical bonds, -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 - Phenylidene and pyridylene, wherein the phenylene or pyridylene is optionally substituted with one or more R*;

[0101] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ;

[0102] L f Independently selected from chemical bonds and C 1-8 Alkylene;

[0103] R f and R' f Independently selected from H and C 1-10 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0104] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, which is optionally surrounded by one or more R groups 1s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-;

[0105] R 1s Independently selected from H and C 1-20 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ;

[0106] R and R' are each independently selected from H and C. 1-20 alkyl;

[0107] L c Independently selected from chemical bonds and C 1-20 Alkylene;

[0108] R c and R' c Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0109] R3 is selected from CN, -OR g -C(O)R g -OC(O)R g-NR”C(O)R g -NR g R' g 、-NR”C(O)NR g R' g -NR”C(O)R g -NR”S(O)2R g -OC(O)NR g R' g -NR”C(O)OR g -N(OR) g )C(O)R g -N(OR) g )S(O)2R g -N(OR) g )C(O)OR g -N(OR) g )C(O)R g R' g 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

[0110] R g and R' g Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0111] "R" is independently selected from H and C. 1-6 alkyl;

[0112] R4 and R5 are independently selected from C 1-8 Alkyl groups, which are optionally composed of one or more R groups 4s replace;

[0113] Or R4, R5, together with the carbon atoms they are attached to, form C. 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4s replace;

[0114] R 4s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0115] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0116] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups.

[0117] In another embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, having the structure of formula (II):

[0118]

[0119] in,

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

[0121] b = 4, 5, 6, 7, 8, 9 or 10;

[0122] c = 1, 2, 3, 4, 5 or 6;

[0123] d = 0, 1, 2, 3 or 4;

[0124] c+d = 3, 4, 5, 6, 7, 8 or 9;

[0125] The remaining groups are as defined in this document.

[0126] G1 and G2

[0127] In one embodiment, G1 is a chemical bond; in another embodiment, G1 is a C bond. 1-13 Straight-chain alkylene, preferably C 1-9 Straight-chain alkylene, preferably C 1-6 Straight-chain alkylene, preferably C 2-6 Straight-chain alkylene; in another embodiment, G1 is C 2-13 Straight-chain alkenyl groups, preferably C 2-9 Straight-chain alkenyl groups, preferably C 2-6 Straight-chain alkenyl group; in another embodiment, G1 is C 2-13 Straight-chain acetylenic groups, preferably C 2-9 Straight-chain acetylenic groups, preferably C 2-6 Straight-chain ynyne group; in another embodiment, G1 is optionally surrounded by one or more R groups. G1 In another embodiment, G1 is optionally replaced by 1, 2, 3 or 4 Rs. G1 Replacement; in another implementation, G1 is not replaced.

[0128] In a more specific implementation, G1 is selected from chemical bonds, C 1-9 straight-chain alkylene, C2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain ynyne group; in another, more specific embodiment, G1 is selected from C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynyne group; in another, more specific embodiment, G1 is selected from C 1-6 Straight-chain alkylene; in another, more specific embodiment, G1 is selected from C 2-6 Straight-chain alkylene groups.

[0129] In one embodiment, G2 is a chemical bond; in another embodiment, G2 is a C bond. 1-13 Straight-chain alkylene, preferably C 1-9 Straight-chain alkylene, preferably C 1-6 Straight-chain alkylene, preferably C 1-4 Straight-chain alkylene; in another embodiment, G2 is C 2-13 Straight-chain alkenyl groups, preferably C 2-9 Straight-chain alkenyl groups, preferably C 2-6 Straight-chain alkenyl; in another embodiment, G2 is C 2-13 Straight-chain acetylenic groups, preferably C 2-9 Straight-chain acetylenic groups, preferably C 2-6 Straight-chain ynylene group; in another embodiment, G2 is optionally surrounded by one or more R groups. G1 In another embodiment, G2 is optionally replaced by 1, 2, 3 or 4 Rs. G1 In another implementation, G2 is not replaced.

[0130] In a more specific implementation, G2 is selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain ynyne group; in another, more specific embodiment, G2 is selected from chemical bonds, C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynyne group; in another, more specific embodiment, G2 is selected from chemical bonds and C 1-6 Straight-chain alkylene groups; in another, more specific embodiment, G2 is selected from chemical bonds and C 1-4 Straight-chain alkylene groups.

[0131] 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.

[0132] In one more specific embodiment, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8, or 9 carbon atoms; in another more specific embodiment, the total length of G1 and G2 is 4, 5, 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 yet another more specific embodiment, the total length of G1 and G2 is 6 or 7 carbon atoms.

[0133] R G1

[0134] In one implementation, R G1 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 implementation, R G1 -L a -SR a In another implementation, R G1 -L a -NR a R' a .

[0135] In a more specific implementation, 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.

[0136] G3

[0137] In one implementation, 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 Straight-chain alkylene; in another embodiment, G3 is C 4-14 Straight-chain alkenyl; in another embodiment, G3 is C 4-14 Straight-chain ynyne group; in another embodiment, G3 is optionally surrounded by one or more R groups. G3 In another embodiment, G3 is optionally replaced by 1, 2, 3 or 4 Rs. G3 In another implementation, G3 is not replaced.

[0138] In a more specific implementation, G3 is selected from C. 4-10 straight-chain alkylene, C 4-10 Straight-chain alkenyl groups and C 4-10 Straight-chain ynyne group; in another, more specific embodiment, G3 is selected from C 4-9 Straight-chain alkylene; in another, more specific embodiment, G3 is selected from C 5-8 Straight-chain alkylene groups.

[0139] R G3

[0140] In one implementation, R G3 H; in another embodiment, R G3 -L a -OR a In another implementation, R G3 -L a -SR a In another implementation, R G3 -L a -NR a R' a .

[0141] L a R a and R' a

[0142] In one implementation, L a For chemical bonds; in another embodiment, L a C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene.

[0143] In a more specific implementation, 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.

[0144] In one implementation, R a 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.

[0145] In one implementation, R' a 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.

[0146] In a more specific implementation, R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R a and R' a Independently selected from H and C 1-6 alkyl.

[0147] G4

[0148] In one embodiment, G4 is a chemical bond; in another embodiment, G4 is a C bond. 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 alkenyl; in another embodiment, G4 is C 2-6Ethyne group; in another embodiment, G4 is optionally surrounded by one or more R groups. G4 In another embodiment, G4 is optionally replaced by 1, 2, 3 or 4 Rs. G4 Replacement; in another implementation, G4 is not replaced.

[0149] In a more specific implementation, G4 is selected from C. 1-4 Alkylene, C 2-4 imide and C 2-4 Ethyne group; 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.

[0150] R G4

[0151] In one implementation, R G4 H; in another embodiment, R G4 C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R G4 -L b -OR b In another implementation, R G4 -L b -SR b In another implementation, R G4 -L b -NR b R' b .

[0152] In a more specific implementation, R G4 Independently selected from H and C 1-6 alkyl.

[0153] In one implementation, two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C 3-7 Cycloalkylene; in another embodiment, two R atoms attached to the same carbon atom G4 Together with the carbon atoms attached to them, they form 3 to 14-membered heterocyclic groups, preferably 3 to 10-membered heterocyclic groups, and more preferably 3 to 7-membered heterocyclic groups; in another embodiment, two R atoms attached to the same carbon atom G4 The rings formed together with the carbon atoms attached to them are optionally bounded by one or more R 4gSubstitution; in another embodiment, two R atoms attached to the same carbon atom G4 The rings formed together with the carbon atoms attached to them are optionally bounded by 1, 2, or 3 R atoms. 4g Substitution; in another embodiment, two R atoms attached to the same carbon atom G4 The rings formed by the carbon atoms connected to them were not replaced.

[0154] In a more specific embodiment, two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups; in another more specific embodiment, two R groups attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3 to 7-membered heterocyclic groups.

[0155] L b R b and R' b

[0156] In one implementation, L b For chemical bonds; in another embodiment, L b C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0157] In a more specific implementation, L b Independently selected from chemical bonds and C 1-4 Alkylene.

[0158] In one implementation, R b H; in another embodiment, R b C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R b C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R b It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0159] In one implementation, R' b H; in another embodiment, R' b C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' b C 3-10 Cycloalkyl, preferably C 3-7cycloalkyl; in another embodiment, R' b It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0160] In a more specific implementation, R b and R' b Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R b and R' b Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R b and R' b Independently selected from H and C 1-4 alkyl.

[0161] R 4g

[0162] In one implementation, R 4g H; in another embodiment, R 4g It is a halogen; in another embodiment, R 4g It is cyano; in another embodiment, R 4g C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R 4g C 1-8 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl; in another embodiment, R 4g -L e -OR e In another implementation, R 4g -L e -SR e In another implementation, R 4g -L e -NR e R' e .

[0163] In a more specific implementation, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0164] L e R e and R' e

[0165] In one implementation, L eFor chemical bonds; in another embodiment, L e C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0166] In a more specific implementation, L e Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L a Selected from chemical bonds and C 1-4 Alkylene.

[0167] In one implementation, R e H; in another embodiment, R e C 1-8 Alkyl, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene; in another embodiment, R e C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R e It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0168] In one implementation, R' e H; in another embodiment, R' e C 1-8 Alkyl, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene; in another embodiment, R' e C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' e It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0169] In a more specific implementation, R e and R' e Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R e and R' e Independently selected from H and C 1-4 alkyl.

[0170] M1 and M2

[0171] In one embodiment, M1 is -C(O)O-; in another embodiment, M1 is -OC(O)-; in another embodiment, M1 is -O-; in another embodiment, M1 is -SC(O)O-; in another embodiment, M1 is -OC(O)NR-; in another embodiment, M1 is -NRC(O)NR-; in another embodiment, M1 is -OC(O)S-; in another embodiment, M1 is -OC(O)O-; in another embodiment, M1 is -NRC(O)O-; in another embodiment, M1 is -SC(O)-; in another embodiment, M1 is -C(O)S-; in another embodiment, M1 is -NR-; In another embodiment, M1 is -C(O)NR-, for example -C(O)NH-; in another embodiment, M1 is -NRC(O)-, for example -NHC(O)-; in another embodiment, M1 is -NRC(O)S-; in another embodiment, M1 is -SC(O)NR-; in another embodiment, M1 is -C(O)-; in another embodiment, M1 is -OC(S)-; in another embodiment, M1 is -C(S)O-; in another embodiment, M1 is -OC(S)NR-; in another embodiment, M1 is -NRC(S)O-; in another embodiment, M1 is -SS-; in another embodiment, M1 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0172] 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 one 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-.

[0173] In one 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 yet another more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -OC(O)-.

[0174] In one 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-.

[0175] In one 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)-.

[0176] In one 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-.

[0177] In one 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 yet another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, and -C(O)S-; in yet 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- and -OC(O-); in another more specific instance 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-, and M2 is -OC(O)O-; in another more specific embodiment In one embodiment, M1 is -OC(O)O-, and 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 both -OC(O)O-.

[0178] Q

[0179] In one embodiment, Q is a chemical bond; in another embodiment, Q is -C(O)O-; in yet another embodiment, Q is -O-; in yet another embodiment, Q is -SC(O)O-; in yet another embodiment, Q is -OC(O)NR f -; In another implementation, 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 implementation, Q is -C(O)NR f -; In another implementation, Q is -NR f C(O)-; in another implementation, 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 implementation, Q is -NR f C(S)O-; in another embodiment, Q is -SS-; in yet another embodiment, Q is -S(O) 0-2 -; In another embodiment, Q is phenylene; in another embodiment, Q is pyridylene; 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 pyridylene, it is optionally substituted with one or more R*, preferably optionally substituted with 1, 2 or 3 R*; in another embodiment, Q is unsubstituted pyridylene.

[0180] In one more specific embodiment, Q is selected from chemical bonds, -OC(O)-, and -SC(O)-; in another more specific embodiment, Q is selected from chemical bonds and -SC(O)-; in yet another more specific embodiment, when Q is phenylene or pyridylene, it is optionally substituted with 1, 2, or 3 R*.

[0181] R*

[0182] In one embodiment, R* is H; in another embodiment, Q is a halogen; in yet another embodiment, R* is a cyano group; in still another embodiment, R* is C. 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R* is C 1-10 Halogenated alkyl groups, preferably C 1-6Halogenated alkyl; in another embodiment, R* is -L f -OR f In another implementation, R* is -L f -SR f In another implementation, R* is -L f -NR f R' f .

[0183] In a more specific embodiment, R* is independently selected from H, halogen, cyano, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0184] L f R f and R' f

[0185] In one implementation, L f For chemical bonds; in another embodiment, L f C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0186] In a more specific implementation, L f Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L f Independently selected from chemical bonds and C 1-4 Alkylene.

[0187] In one implementation, R f 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.

[0188] In one implementation, R' f 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.

[0189] In a more specific implementation, R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R 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.

[0190] R1 and R2

[0191] In one implementation, R1 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 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 Alkenyl; in another embodiment, R1 is C 4-20 Alkyne group, preferably C 6-14 Alkyne group, preferably C 7-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R1 is optionally surrounded by one or more R groups. 1sIn another embodiment, R1 is optionally replaced by 1, 2, 3 or 4 Rs. 1s Replace, preferably optionally by 1 R 1s Substitution; in another embodiment, R1 is not substituted; in another embodiment, one or more methylene units in R1 are optionally and independently substituted with -NR'-, preferably one methylene unit in R1 is optionally substituted with -NR'-; in another embodiment, R1 is optionally substituted with one C 1-9 Alkyl (preferably C) 6-9 Alkyl, more preferably C 6-7 Alkyl) substitution.

[0192] 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 yet 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 implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is

[0193] In one embodiment, R1 is -(CH2)2-C≡C-(CH2)4CH3; in another embodiment, R1 is -(CH2)3-C≡C-(CH2)3CH3; in yet another embodiment, R1 is... In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is

[0194] In one implementation, R2 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 10 Alkyl, preferably C9 alkyl, preferably C 8-12 Straight-chain alkyl, preferably C 7-11Straight-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 Alkenyl; in another embodiment, R2 is C 4-20 Alkyne group, preferably C 6-14 Alkyne group, preferably C 7-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R2 is optionally surrounded by one or more R groups. 1s In another embodiment, R2 is optionally replaced by 1, 2, 3 or 4 Rs. 1s Replace, preferably optionally by 1 R 1s Replace, preferably, optionally, by 1 C 1-3 Alkyl substitution, preferably optionally substituted with one methyl group; in another embodiment, R2 is not substituted; in another embodiment, one or more methylene units in R2 are optionally and independently substituted with -NR'-, preferably one methylene unit in R2 is optionally substituted with -NR'-.

[0195] In one embodiment, only one of R1 and R2 has a substituent; in another embodiment, R1 has R. 1s Replacement, and there is no R on R2. 1s Replacement; in another embodiment, R2 has R 1s Replacement, and there is no R on R1 1s replace.

[0196] 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 yet 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 implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is

[0197] In one embodiment, R2 is -(CH2)2-C≡C-(CH2)4CH3; in another embodiment, R2 is -(CH2)3-C≡C-(CH2)3CH3; in yet another embodiment, R2 is... In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is

[0198] In a more specific implementation, R1 and R2 are independently selected from C. 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; in another, more specific embodiment, R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group; in another, more specific embodiment, R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group; 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,

[0199] In a more specific implementation, R1 and R2 are independently selected from C. 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C9-10 Alkyl group, which is optionally marked with one R 1s Substitution; and only one of R1 and R2 has a substituent.

[0200] 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

[0201] 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,

[0202] In a more specific implementation, 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,

[0203] In a more specific implementation, R1 is selected from... In another, more specific implementation, R1 is selected from...

[0204] In a more specific implementation, R1 is selected from... In another, more specific implementation, R1 is selected from... In another, more specific embodiment, R1 is selected from -(CH2)8CH3, -(CH2)9CH3, In another, more specific implementation, R1 is selected from... In another, more specific implementation, R1 is selected from...

[0205] In a more specific implementation, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from...

[0206] In a more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from... In another, more specific implementation, R2 is selected from...

[0207] R 1s

[0208] In one implementation, R 1s H; in another embodiment, R 1s 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 6-7 Alkyl, preferably C9 alkyl, preferably C8 alkyl, preferably C7 alkyl; in another embodiment, R 1s -L c -OR cIn another implementation, R 1s -L c -SR c In another implementation, R 1s -L c -NR c R' c .

[0209] In one implementation, R 1s The substitution site on R1 is separated from M1 by 0 carbon atoms; in another embodiment, R 1s The substitution site on R1 is separated from M1 by one carbon atom; in another embodiment, R 1s The substitution site on R1 is separated from M1 by two carbon atoms; in another embodiment, R 1s The substitution site on R1 is separated from M1 by three carbon atoms; in another embodiment, R 1s The substitution site on R1 is spaced 4 carbon atoms apart from M1; in another embodiment, R 1s The substitution site on R1 is spaced 5 carbon atoms away from M1; in another embodiment, R 1s The substitution site on R1 is separated from M1 by 6 carbon atoms; in another embodiment, R 1s The substitution site on R1 is spaced 7 carbon atoms apart from M1; in another embodiment, R 1s The substitution site on R1 is spaced 8 carbon atoms apart from M1; in another embodiment, R 1s The substitution site on R1 is spaced 9 carbon atoms apart from M1; in another embodiment, R 1s The substitution site on R1 is separated from M1 by 10 carbon atoms.

[0210] In one implementation, R 1s The substitution site on R2 is separated from M2 by 0 carbon atoms; in another embodiment, R 1s The substitution site on R2 is separated from M2 by one carbon atom; in another embodiment, R 1s The substitution site on R2 is separated from M2 by two carbon atoms; in another embodiment, R 1s The substitution site on R2 is separated from M2 by three carbon atoms; in another embodiment, R 1s The substitution site on R2 is spaced 4 carbon atoms away from M2; in another embodiment, R 1s The substitution site on R2 is spaced 5 carbon atoms away from M2; in another embodiment, R 1sThe substitution site on R2 is separated from M2 by 6 carbon atoms; in another embodiment, R 1s The substitution site on R2 is spaced 7 carbon atoms apart from M2; in another embodiment, R 1s The substitution site on R2 is spaced 8 carbon atoms apart from M2; in another embodiment, R 1s The substitution site on R2 is spaced 9 carbon atoms apart from M2; in another embodiment, R 1s The substitution site on R2 is separated from M2 by 10 carbon atoms.

[0211] In a more specific implementation, R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c In another, more specific implementation, 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.

[0212] In a more specific implementation, R 1s The substitution site on R1 or R2 is spaced 0-10 carbon atoms from M1 or M2; in another more specific embodiment, R 1s The substitution site on R1 or R2 is spaced 0-6 carbon atoms from M1 or M2; in another more specific embodiment, R 1s The substitution site on R1 or R2 is spaced 0-4 carbon atoms from M1 or M2; in another more specific embodiment, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 0-2 carbon atoms; in another more specific embodiment, R 1s The substitution sites on R1 or R2 are separated from M1 or M2 by 0 carbon atoms.

[0213] In a more specific implementation, R 1sThe substitution site on R1 or R2 is spaced 1-10 carbon atoms from M1 or M2; in another more specific embodiment, R 1s The substitution sites on R1 or R2 are spaced 1-6 carbon atoms apart from M1 or M2; in another more specific embodiment, R 1s The substitution site on R1 or R2 is spaced 1-4 carbon atoms from M1 or M2; in another more specific embodiment, R 1s The substitution site on R1 or R2 is spaced 1-2 carbon atoms from M1 or M2; in another more specific embodiment, R 1s The substitution sites on R1 or R2 are spaced 2-10 carbon atoms apart from M1 or M2; in another more specific embodiment, R 1s The substitution sites on R1 or R2 are spaced 2-6 carbon atoms apart from M1 or M2; in another more specific embodiment, R 1s The substitution sites on R1 or R2 are spaced 2-4 carbon atoms apart from M1 or M2.

[0214] In another, more specific implementation, R1 has no R 1s Replace, and R 1s The substitution site on R2 is spaced 0-10 carbon atoms from M2, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms, more preferably 1-4 carbon atoms, and more preferably 1-2 carbon atoms; in another more specific embodiment, R1 has no R. 1s Replace, R 1s The substitution site on R2 is spaced 0-10 carbon atoms from M2, preferably 0-6 carbon atoms, more preferably 0-4 carbon atoms, more preferably 0-2 carbon atoms, and more preferably 0 carbon atoms; in another more specific embodiment, R1 has no R. 1s Replace, R 1s The substitution site on R2 is spaced 2-10 carbon atoms from M2, preferably 2-6 carbon atoms, and more preferably 2-4 carbon atoms.

[0215] R and R'

[0216] In one implementation, R is H; in another implementation, R is C. 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 alkyl.

[0217] In one implementation, R' is H; in another implementation, R' is C. 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9Alkyl, preferably C 1-6 alkyl.

[0218] In a more specific implementation, R and R' are each independently selected from H and C. 1-20 Alkyl; in another, more specific embodiment, R and R' are each independently selected from H and C. 1-14 Alkyl; in another, more specific embodiment, R and R' are each independently selected from H and C. 1-9 Alkyl; in another, more specific embodiment, R and R' are each independently selected from H and C. 1-6 Alkyl; in another, more specific embodiment, R is H.

[0219] L c R c and R' c

[0220] In one implementation, L c For chemical bonds; in another embodiment, L c C 1-20 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene.

[0221] In a more specific implementation, L c Independently selected from chemical bonds and C 1-14 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-6 Alkylene.

[0222] In one implementation, R c 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.

[0223] In one implementation, R' c H; in another embodiment, R' c C1-20 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.

[0224] In a more specific implementation, R c and R' c Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R c and R' 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.

[0225] R3

[0226] In one implementation, R3 is CN; in another implementation, R3 is -OR. g For example, -OH; in another embodiment, R3 is -C(O)R g In another embodiment, R3 is -OC(O)R g In another embodiment, R3 is -NR”C(O)R g In another implementation, R3 is -NR g R' g For example, -N(CH3)2; in another embodiment, R3 is -NR”C(O)NR g R' g In another embodiment, R3 is -NR”C(O)R g In another embodiment, R3 is -NR”S(O)2R g In another embodiment, R3 is -OC(O)NR g R' g In another embodiment, R3 is -NR”C(O)OR g In another implementation, R3 is -N (OR g )C(O)R g In another implementation, R3 is -N (OR g )S(O)2R gIn another implementation, R3 is -N (OR g )C(O)OR g In another implementation, R3 is -N (OR g )C(O)R g R' g In another embodiment, R3 is a 3- to 14-membered heterocyclic group; in another embodiment, R3 is a 5- to 14-membered heteroaryl group.

[0227] In a more specific implementation, R3 is selected from CN, -OR g and -NR g R' g In another, more specific implementation, R3 is selected from -OR g and -NR g R' g In another, more specific embodiment, R3 is selected from -OH and -N(CH3)2; in another, more specific embodiment, R3 is -OR g In another, more specific embodiment, R3 is OH.

[0228] R g and R' g

[0229] In one implementation, R g H; in another embodiment, R g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, 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.

[0230] In one implementation, R' g H; in another embodiment, R' g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; 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.

[0231] In a more specific implementation, Rg and R' g Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R 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 Selected independently from H and Me.

[0232] R”

[0233] In one implementation, R” is H; in another implementation, R” is C. 1-6 Alkyl, preferably C 1-4 alkyl.

[0234] R4 and R5

[0235] In one implementation, 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 In another embodiment, R4 is not replaced.

[0236] In one implementation, 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 Rs. 4s In another implementation, R5 is not replaced.

[0237] In one implementation, R4, R5, together with the carbon atoms they are attached to, form C. 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C 3-6 Cycloalkylene compounds (e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene), preferably forming C 3-5 Cycloalkylene, preferably forming C 3-4The cycloalkyl group, preferably forming a cyclopropyl group, more preferably forming a cyclopentyl group; in another embodiment, R4, R5 together with the carbon atoms to which they are attached form a 3 to 14-membered heterocyclic group, preferably forming a 3 to 10-membered heterocyclic group, more preferably forming a 3 to 6-membered heterocyclic group; in another embodiment, the ring formed by R4, R5 together with the carbon atoms to which they are attached is optionally divided by one or more R 4s In another embodiment, the rings formed by R4, R5, and the carbon atoms they are attached to are optionally replaced by 1, 2, or 3 R atoms. 4s Substitution; in another embodiment, the rings formed by R4, R5 and the carbon atoms they are attached to are not substituted.

[0238] In a more specific embodiment, R4, R5, together with the carbon atoms they are bonded to, form C. 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups; in another more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene groups; in another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); in another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C14. 3-5 Cycloalkylene; in another more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form cyclopropylene or cyclopentylene; in another more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form cyclopropylene; in another more specific embodiment, R4, R5 and the carbon atoms to which they are attached do not form a ring.

[0239] R 4s

[0240] In one implementation, R 4s H; in another embodiment, R 4s It is a halogen; in another embodiment, R 4s It is cyano; in another embodiment, R 4s C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl; in another embodiment, R 4s C 1-8 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl groups, preferably C 1-3 Halogenated alkyl; in another embodiment, R 4s -L d -OR d In another implementation, R4s -L d -SR d In another implementation, R 4s -L d -NR d R' d .

[0241] In a more specific implementation, R 4s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d In another, more specific implementation, R 4s Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in another, more specific embodiment, R 4s Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0242] L d R d and R' d

[0243] In one implementation, L d For chemical bonds; in another embodiment, L d C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene.

[0244] In a more specific implementation, L d Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L d Independently selected from chemical bonds and C 1-3 Alkylene.

[0245] In one implementation, R d H; in another embodiment, R d C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R d C 3-14 Cycloalkyl, preferably C 3-10cycloalkyl; in another embodiment, R d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0246] In one implementation, R' d H; in another embodiment, R' d C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' d C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0247] In a more specific implementation, R d and R' d Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R d and R' d Independently selected from H and C 1-6 alkyl.

[0248] a, b, c, and d

[0249] In one implementation, a is 1; in another implementation, a is 2; in another implementation, a is 3; in another implementation, a is 4; in another implementation, a is 5; in another implementation, a is 6.

[0250] In one 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.

[0251] In one implementation, b is 4; in another implementation, b is 5; in another implementation, b is 6; in another implementation, b is 7; in another implementation, b is 8; in another implementation, b is 9; in another implementation, b is 10.

[0252] In one more specific embodiment, b = 5, 6, 7 or 8; in another more specific embodiment, b = 5, 6 or 7; in yet another more specific embodiment, b = 5 or 7; in yet another more specific embodiment, b = 6 or 7.

[0253] In one 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.

[0254] 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.

[0255] In one 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.

[0256] In one 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;

[0257] In one implementation, d is 0; in another implementation, d is 1; in another implementation, d is 2; in another implementation, d is 3; in another implementation, d is 4.

[0258] In one more specific embodiment, d = 0, 1, 2, or 4; in another more specific embodiment, d = 2, 3, or 4; in yet another more specific embodiment, d = 0 or 1.

[0259] In one 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;

[0260] 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.

[0261] In one more specific implementation, c+d = 4, 5, or 6; in another more specific implementation, c+d = 5 or 6.

[0262] In one 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.

[0263] 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 in 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, R g 、R' g R, R4, R5, R 4s L d R d 、R' d This invention refers to any combination of technical solutions a, b, c, and d, or any combination thereof. The invention aims to include combinations of all these technical solutions; however, due to space limitations, they are not listed individually.

[0264] 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:

[0265]

[0266] in,

[0267] G1 and G2 are independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, which are optionally surrounded by one or more R groups G1 replace;

[0268] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0269] R G1 Independently selected from H and C 1-14 Alkyl, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0270] G3 is selected from C 4-14 straight-chain alkylene, C 4-14 Straight-chain alkenyl groups and C 4-14 Straight-chain ynylene groups, which are optionally surrounded by one or more R groups G3 replace;

[0271] R G3 Independently selected from H, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0272] L a Independently selected from chemical bonds and C 1-14 Alkylene;

[0273] R a and R' a Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0274] G4 is selected from chemical bonds, C 1-6 Alkylene, C2-6 imide and C 2-6 Alynyl group, which is optionally surrounded by one or more R G4 replace;

[0275] R G4 Independently selected from H and C 1-6 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0276] L b Independently selected from chemical bonds and C 1-6 Alkylene;

[0277] R b and R' b Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0278] Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4g replace;

[0279] R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0280] L e Independently selected from chemical bonds and C 1-8 Alkylene;

[0281] R e and R' e Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0282] 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 -;

[0283] Q is selected from chemical bonds, -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 - Phenylidene and pyridylene, wherein the phenylene or pyridylene is optionally substituted with one or more R*;

[0284] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ;

[0285] L f Independently selected from chemical bonds and C 1-8 Alkylene;

[0286] R f and R' f Independently selected from H and C 1-10 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0287] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, which is optionally surrounded by one or more R groups 1s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-;

[0288] R 1s Independently selected from H and C 1-20 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ;

[0289] R and R' are each independently selected from H and C. 1-20 alkyl;

[0290] L c Independently selected from chemical bonds and C 1-20 Alkylene;

[0291] R c and R' c Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0292] R3 is selected from CN, -OR g -C(O)R g -OC(O)R g -NR”C(O)R g -NR g R' g 、-NR”C(O)NR g R' g -NR”C(O)R g -NR”S(O)2R g -OC(O)NR g R' g -NR”C(O)OR g -N(OR) g )C(O)R g -N(OR) g )S(O)2R g -N(OR) g )C(O)OR g -N(OR) g )C(O)R g R'g 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

[0293] R g and R' g Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0294] "R" is independently selected from H and C. 1-6 alkyl;

[0295] R4 and R5 are independently selected from C 1-8 Alkyl groups, which are optionally composed of one or more R groups 4s replace;

[0296] Or R4, R5, together with the carbon atoms they are attached to, form C. 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4s replace;

[0297] R 4s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0298] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0299] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups.

[0300] 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 chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain acetylenic group.

[0301] In a more specific implementation scheme, G1 is selected from C. 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6Straight-chain ynylene groups, preferably selected from C 1-6 Straight-chain alkylene groups, preferably selected from C 2-6 Straight-chain alkylene groups.

[0302] In a more specific implementation, G2 is selected from chemical bonds, C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynylene groups, preferably selected from chemical bonds and C 1-6 Straight-chain alkylene groups, preferably selected from chemical bonds and C 1-4 Straight-chain alkylene groups.

[0303] In a more specific embodiment, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably 4, 5 or 6 carbon atoms, more preferably 5 or 6 carbon atoms; preferably 5, 6 or 7 carbon atoms, more preferably 6 or 7 carbon atoms.

[0304] Preferably, G1 and G2 are optionally represented by 1, 2, 3 or 4 Rs G1 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 R G1 Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-6 alkyl.

[0306] 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 alkenyl groups and C 4-10 Straight-chain ynylene group; preferably selected from C 4-9 Straight-chain alkylene groups; preferably selected from C 5-8 Straight-chain alkylene groups.

[0307] In a more specific implementation, G3 is optionally represented by 1, 2, 3, or 4 Rs. G3 replace.

[0308] 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 a Independently selected from chemical bonds and C 1-10 Alkylenes, preferably selected from chemical bonds and C 1-6 Alkylene.

[0309] In a more specific implementation plan, R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 alkyl.

[0310] 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 imide and C 2-4 Alynyl group; preferably selected from C 2-4 Alkylene; preferably selected from C 2-3 Alkylene.

[0311] In a more specific implementation, G4 is optionally represented by 1, 2, 3, or 4 Rs. G4 replace.

[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 R G4 Independently selected from H and C 1-6 Alkyl; preferably selected from C 1-4 alkyl.

[0313] In a more specific implementation, two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups, preferably forming C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic alkylene group, optionally surrounded by 1, 2 or 3 R groups. 4g replace.

[0314] In a more specific implementation plan, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0315] 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.

[0316] In a more specific implementation plan, R b and R' b Independently selected from H and C 1-6 Alkyl, C3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0317] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein M1 and M2 are independently selected from -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-; and preferably selected from -C(O)O- and -OC(O)-.

[0318] In a more specific implementation, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-.

[0319] In a more specific implementation, 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)-.

[0320] In a more specific implementation, M1 is -OC(O)- or -SC(O)-, preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-.

[0321] In a more specific implementation, M1 is -C(O)O-, and M2 is -C(O)O- or -C(O)S-.

[0322] In a more specific implementation, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)- and -C(O)NH-.

[0323] In a more specific implementation, 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-.

[0324] 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)-.

[0325] In a more specific implementation, 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)-.

[0326] In a more specific implementation, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably selected from -C(O)O- and -OC(O-), more preferably -C(O)O-, and more preferably -OC(O-), and M2 is -OC(O)O-.

[0327] In a more specific implementation, M1 is -OC(O)O-, and M2 is -OC(O)- or -OC(O)-, preferably -OC(O)-.

[0328] In a more specific implementation, 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-.

[0329] 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 Alkyne group; preferably selected from C 6-14 Alkyl; preferably selected from C 7-12 Alkyl; preferably selected from C 8-12 alkyl.

[0330] In a more specific implementation, R1 and R2 are independently selected from C. 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group, preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12alkynyl group;

[0331] In a more specific implementation, R1 and R2 are optionally represented by 1, 2, 3, or 4 R... 1s Replace, preferably optionally by 1 R 1s replace.

[0332] In a 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,

[0333] In a 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)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,

[0334]

[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 R 1sIndependently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl groups; preferably selected from H and C. 1-6 Alkyl groups, preferably selected from H and C 1-4 alkyl.

[0336] 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 groups; preferably selected from H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl groups; preferably selected from H and C. 1-6 Alkyl group; preferably R is H.

[0337] 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.

[0338] In a more specific implementation plan, R c and R' c Independently selected from H and C 1-14 Alkyl groups; preferably selected from H and C. 1-10 Alkyl groups; preferably selected from H and C. 1-6 alkyl.

[0339] 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 Preferred selection from -OR g and -NR g R' g Preferred option: -OR g ; preferably OH.

[0340] In a more specific implementation, R3 is selected from -OH and -N(CH3)2.

[0341] In a more specific implementation plan, R g and R' g Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 Alkyl group; preferably selected from H and Me.

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

[0343] In a more specific implementation, R4 and R5 are optionally represented by 1, 2, or 3 R... 4s replace.

[0344] In a more specific implementation, R4, R5, together with the carbon atoms they are bonded to, form C. 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably cyclopropylene.

[0345] In a more specific implementation, the rings formed by R4, R5, and the carbon atoms connected to them are optionally separated by 1, 2, or 3 R atoms. 4s replace.

[0346] 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 Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d Preferably selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and C 1-3 Alkyl and C1-3 Halogenated alkyl groups.

[0347] 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.

[0348] In a more specific implementation plan, R d and R' d Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 alkyl.

[0349] 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.

[0350] In a more specific implementation plan, R e and R' e Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0351] 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 Q is selected from chemical bonds, -OC(O)- and -SC(O)-; preferably selected from chemical bonds and -SC(O)-.

[0352] In a more specific embodiment, when Q is phenylene or pyridylene, it is optionally substituted with 1, 2, or 3 R*.

[0353] In a more specific implementation, R* is independently selected from H, halogen, cyano, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0354] In a more specific implementation plan, L f Independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-4Alkylene.

[0355] In a more specific implementation plan, R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0356] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II) or (III):

[0357]

[0358] in,

[0359] a = 1, 2, 3, 4, 5 or 6;

[0360] b = 4, 5, 6, 7, 8, 9 or 10;

[0361] c = 1, 2, 3, 4, 5 or 6;

[0362] d = 0, 1, 2, 3 or 4;

[0363] c+d = 3, 4, 5, 6, 7, 8 or 9;

[0364] The remaining groups are as defined in this document.

[0365] In a more specific embodiment, the present invention provides compounds of formula (II) or formula (III) above, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof.

[0366]

[0367] Among them, R 1s The substitution sites on R1 or R2 are spaced 0-10 carbon atoms apart from M1 or M2, preferably 0-6 carbon atoms apart, preferably 0-4 carbon atoms apart, preferably 0-2 carbon atoms apart, and preferably 0 carbon atoms apart.

[0368] In a more specific implementation plan, R 1s The substitution site on R1 or R2 is spaced 1-10 carbon atoms from M1 or M2, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, and preferably 2-4 carbon atoms.

[0369] In a more specific implementation, there is no R on R1. 1s Replace, and R 1s The substitution site on R2 is spaced 0-10 carbon atoms from M2, preferably 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, and preferably 2-4 carbon atoms.

[0370] In a more specific implementation, R1 has R 1s Replacement, and there is no R on R2. 1s replace.

[0371] In a more specific implementation, R4 and R5, and the carbon atoms they connect to, do not form a ring.

[0372] In a more specific implementation, d is not 0.

[0373] 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.

[0374]

[0375] in,

[0376] a = 2, 3, 4, 5 or 6;

[0377] b = 4, 5, 6, 7, 8, 9 or 10;

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

[0379] d = 0, 1, 2, 3 or 4;

[0380] c+d = 3, 4, 5, 6, 7, 8 or 9; preferably c+d = 4, 5 or 6;

[0381] 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)-;

[0382] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[0383] R 1s Independently selected from H and C 1-14Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 alkyl;

[0384] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0385] R c and R' c Independently selected from H and C 1-14 alkyl;

[0386] R4 and R5 are independently selected from C 1-6 alkyl;

[0387] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0388] 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,

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

[0390] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7;

[0391] c = 2, 3, 4, 5 or 6;

[0392] d = 0, 1, 2, 3 or 4;

[0393] c+d = 5 or 6;

[0394] 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)-;

[0395] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl group, which is optionally marked with one R 1s replace;

[0396] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 alkyl;

[0397] R4 and R5 are independently selected from C 1-3alkyl;

[0398] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene; preferably forming C 3-5 Cycloalkylene.

[0399] 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,

[0400] a = 2, 3, or 4;

[0401] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7;

[0402] c = 2, 3, 4, 5 or 6;

[0403] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[0404] c+d = 5 or 6; c+d = 6 is preferred.

[0405] M1 and M2 are -C(O)O-;

[0406] Alternatively, one of M1 and M2 can be -C(O)O-, and the other can be -OC(O)-;

[0407] 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

[0408] R4 and R5 are methyl groups;

[0409] Alternatively, R4 and R5, along with their associated carbon atoms, can form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexylene; preferably, cyclopropyl or cyclopentylene; more preferably, cyclopropylene.

[0410] In a more specific implementation, only one of R1 and R2 has a substituent.

[0411] 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,

[0412] a = 2;

[0413] b = 5;

[0414] c = 2, 3, 4, 5 or 6; c = 6 is preferred;

[0415] d = 0, 1, 2, 3 or 4; preferred value is d = 0;

[0416] c+d = 5 or 6; preferably 6;

[0417] M1 and M2 are -C(O)O;

[0418] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0419] R 1s Independently selected from H and C 1-10 Alkyl groups; 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;

[0420] R2 is selected from C 7-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 11 Straight-chain alkyl group, optionally bounded by 1 C 1-3 Alkyl substitution, preferably optionally replaced by one methyl group;

[0421] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0422] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[0423] In a more specific implementation, R1 is selected from... Preferred selection

[0424] In a more specific implementation, R1 is selected from... Preferred selection

[0425] In a more specific implementation, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and

[0426] 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,

[0427] a = 2, 3, or 4; a = 2 is preferred.

[0428] b = 7;

[0429] c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2;

[0430] d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4;

[0431] c+d = 5 or 6; preferably 6;

[0432] M1 and M2 are -C(O)O;

[0433] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0434] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[0435] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 6-9 Alkyl; preferably selected from C 7-8 alkyl;

[0436] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0437] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[0438] In a more specific implementation, R2 is selected from... Preferred selection Preferred selection

[0439] 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,

[0440] a = 2;

[0441] b = 7;

[0442] c = 3 or 4; c = 4 is preferred.

[0443] d = 2;

[0444] M1 and M2 are -C(O)O;

[0445] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-10 Alkyl group, which is optionally marked with one R 1s replace;

[0446] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 alkyl;

[0447] R2 is selected from C 7-11 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0448] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0449] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[0450] 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,

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

[0452] b = 6 or 7; b = 7 is preferred.

[0453] c = 2, 3, 4, 5 or 6; preferably c = 5 or 6;

[0454] d = 0, 1, 2, 3 or 4; preferably d = 0 or 1;

[0455] c+d = 5 or 6; preferably 6;

[0456] M1 is -OC(O); M2 is -C(O)O;

[0457] R1 is selected from C 7-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl;

[0458] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Straight-chain alkyl group, optionally marked with one R 1s replace;

[0459] R 1s Selected independently from C 7-9 alkyl;

[0460] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0461] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[0462] In a more specific implementation, when a = 4, R4 and R5, as well as the carbon atoms they connect to, do not form a ring; preferably R 1s Selected independently from C 8-9 alkyl.

[0463] In a more specific implementation, R2 is selected from...

[0464] 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.

[0465]

[0466] in,

[0467] a = 2, 3, 4, 5 or 6;

[0468] b = 4, 5, 6, 7, 8, 9 or 10;

[0469] c = 1, 2, 3, 4, 5 or 6;

[0470] d = 0, 1, 2, 3 or 4;

[0471] c+d = 3, 4, 5, 6, 7, 8 or 9; preferably c+d = 4, 5, 6 or 7;

[0472] 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)-;

[0473] R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups 1s replace;

[0474] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 alkyl;

[0475] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0476] R c and R' c Independently selected from H and C 1-14 alkyl;

[0477] R4 and R5 are independently selected from C 1-6 alkyl;

[0478] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0479] 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,

[0480] a = 2, 3, or 4;

[0481] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7;

[0482] c = 2, 3, 4, 5 or 6;

[0483] d = 0, 1, 2, 3 or 4;

[0484] c+d = 5, 6 or 7;

[0485] 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-);

[0486] R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group, preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group, which is optionally surrounded by 1 R 1s replace;

[0487] R 1s Independently selected from H and C 1-10 alkyl;

[0488] R4 and R5 are independently selected from C 1-3 alkyl;

[0489] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene; preferably forming C 3-5 Cycloalkylene.

[0490] 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,

[0491] a = 2, 3, or 4;

[0492] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7;

[0493] c = 2, 3, 4, 5 or 6;

[0494] d = 0, 1, 2, 3 or 4;

[0495] c+d = 5, 6 or 7; c+d = 6 is preferred.

[0496] 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)-;

[0497] 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,

[0498] R4 and R5 are methyl groups;

[0499] Alternatively, R4 and R5, along with their associated carbon atoms, can form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexylene; preferably, cyclopropyl or cyclopentylene; more preferably, cyclopropylene.

[0500] In a more specific implementation, only one of R1 and R2 has a substituent.

[0501] 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,

[0502] a = 2;

[0503] b = 5;

[0504] c = 5 or 6; c = 6 is preferred.

[0505] d = 0 or 1; preferred is d = 0;

[0506] c+d = 5 or 6; preferably 6;

[0507] M1 is -C(O)O-, and M2 is -C(O)O- or -C(O)S-; preferably, M1 and M2 are -C(O)O-.

[0508] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0509] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 6-8 Alkyl; preferably selected from C 7-8 alkyl;

[0510] R2 is selected from C 7-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 11 Straight-chain alkyl group, optionally bounded by 1 C 1-3 Alkyl substitution, preferably optionally replaced by one methyl group;

[0511] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0512] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[0513] In a more specific implementation, R1 is selected from... Preferred selection

[0514] In a more specific implementation, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and

[0515] 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,

[0516] a = 2, 3, or 4; a = 2 is preferred.

[0517] b = 5, 6, or 7; b = 7 is preferred.

[0518] c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2;

[0519] d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4;

[0520] c+d = 5 or 6; preferably 6;

[0521] M1 and M2 are -C(O)O-;

[0522] 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 group, which is optionally marked with one R 1s Substitution; and only one of R1 and R2 has a substituent;

[0523] 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;

[0524] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0525] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably forming cyclopropylene; preferably not forming a ring;

[0526] In a more specific implementation, R1 is selected from C. 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl;

[0527] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s Replace; when R2 is C 10 When the chain is alkyl, R 1s Selected from C 9-10 Alkyl group, preferably C9 alkyl group.

[0528] In a more specific implementation, R2 is selected from... Preferred selection

[0529] 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,

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

[0531] b = 6;

[0532] c = 4, 5, or 6; preferably c = 5 or 6; preferably c = 5.

[0533] d = 1 or 2; preferred d = 1;

[0534] c+d = 6, 7 or 8; preferably 6 or 7; preferably 6;

[0535] M1 is -OC(O)-; M2 is -C(O)O-;

[0536] R1 is selected from C 7-12 Straight-chain alkyl, preferably C 8-11 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl;

[0537] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-12 Alkyl group, which is optionally marked with one R 1s replace;

[0538] R 1s Selected independently from C 7-11 Alkyl, preferably C 7-10 alkyl;

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

[0540] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene;

[0541] The condition is that when c = 4, a = 2 or 3.

[0542] In a more specific implementation, R2 is selected from...

[0543] In a more specific implementation, a = 2 or 4; b = 6; c = 5 or 6, preferably c = 5; d = 1;

[0544] R1 is selected from C 8-9 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0545] R2 is selected from C 9-10 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R 1s replace;

[0546] R 1s Selected independently from C 7-8 alkyl;

[0547] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0548] In a more specific implementation, a = 2, 3, or 4, preferably a = 2 or 4; b = 6; c = 5; d = 2;

[0549] R1 is selected from C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0550] R2 is selected from C 9-11 Alkyl group, which is optionally marked with one R 1s replace;

[0551] R 1s Selected independently from C 7-9 alkyl;

[0552] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0553] 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,

[0554] a = 2, 3, or 4; preferably a = 2 or 4.

[0555] b = 7;

[0556] c = 5 or 6; c = 5 is preferred.

[0557] d = 0 or 1; preferred d = 1;

[0558] c+d = 5 or 6; preferably 6;

[0559] M1 is -OC(O)-; M2 is -C(O)O-;

[0560] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl group, optionally bounded by 1 C 1-9 Alkyl (preferably C) 6-9 Alkyl, more preferably C6-7 Alkyl) substitution;

[0561] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[0562] R 1s Selected independently from C 7-9 alkyl;

[0563] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0564] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[0565] In a more specific implementation, R1 is selected from -(CH2)8CH3, -(CH2)9CH3,

[0566] R2 is selected from

[0567] In a more specific implementation, when a = 4,

[0568] R1 is selected from C 9-10 Straight-chain alkyl;

[0569] R2 is selected from C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[0570] R 1s Selected from C 8-9 alkyl;

[0571] R4 and R5, along with the carbon atoms they connect, do not form rings.

[0572] In a more specific implementation plan, when a = 2,

[0573] R1 is C 10 Straight-chain alkyl groups.

[0574] In a more specific implementation plan, R 1s Selected from C 8-9 Alkyl group, preferably C9 alkyl group.

[0575] 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,

[0576] a = 2, 3, or 4; preferably a = 2 or 4.

[0577] b = 7;

[0578] c = 4;

[0579] d = 2;

[0580] M1 is -OC(O)-; M2 is -C(O)O-;

[0581] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl;

[0582] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[0583] R 1s Selected independently from C 7-9 alkyl;

[0584] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0585] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene; preferably not cyclic.

[0586] In a more specific implementation, R2 is selected from...

[0587] 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,

[0588] a = 2, 3, or 4; a = 2 is preferred.

[0589] b = 8;

[0590] c = 5;

[0591] d = 1;

[0592] M1 is -OC(O)-; M2 is -C(O)O-;

[0593] R1 is selected from C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl;

[0594] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R1s replace;

[0595] R 1s Selected independently from C 7-9 Alkyl, preferably C 7-8 alkyl;

[0596] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0597] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene; preferably not cyclic.

[0598] In a more specific implementation, R2 is selected from...

[0599] 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,

[0600] a = 2;

[0601] b = 6, 7 or 8, with b = 7 being the preferred value;

[0602] c = 5;

[0603] d = 1;

[0604] M1 is -OC(O)-; M2 is -C(O)O-;

[0605] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0606] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0607] R 1s Independently selected from C7 alkyl groups;

[0608] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0609] In a more specific implementation, R2 is selected from... Preferred

[0610] 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,

[0611] a = 2 or 3, with a = 2 being the preferred value;

[0612] b = 7;

[0613] c = 3;

[0614] d = 3;

[0615] M1 is -OC(O)-; M2 is -C(O)O-;

[0616] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0617] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0618] R 1s Selected independently from C 6-7 Alkyl groups, preferably C7 alkyl groups;

[0619] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[0620] In a more specific implementation, R2 is selected from... Preferred

[0621] 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.

[0622]

[0623] in,

[0624] a = 2, 3, 4, 5 or 6;

[0625] b = 4, 5, 6, 7, 8, 9 or 10;

[0626] c = 1, 2, 3, 4, 5 or 6;

[0627] d = 0, 1, 2, 3 or 4;

[0628] c+d = 3, 4, 5, 6, 7, 8 or 9; preferably c+d = 4, 5 or 6;

[0629] 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-;

[0630] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[0631] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 alkyl;

[0632] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0633] R c and R' c Independently selected from H and C 1-14 alkyl;

[0634] R4 and R5 are independently selected from C 1-6 alkyl;

[0635] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0636] 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,

[0637] a = 2, 3, or 4;

[0638] b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6;

[0639] c = 2, 3, 4, 5 or 6; preferably c = 2, 4, 5 or 6;

[0640] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[0641] c+d = 5 or 6; c+d = 6 is preferred.

[0642] One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-;

[0643] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 9-11 Alkyl group, which is optionally marked with one R 1s replace;

[0644] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 4-10 alkyl;

[0645] R4 and R5 are independently selected from C 1-3 alkyl;

[0646] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene, preferably forming C 3-4 Cycloalkylene.

[0647] 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,

[0648] a = 2, 3, or 4;

[0649] b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6;

[0650] c = 2, 3, 4, 5 or 6; preferably c = 2, 4, 5 or 6;

[0651] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[0652] c+d = 5 or 6; c+d = 6 is preferred.

[0653] One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-;

[0654] R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3

[0655] R4 and R5 are methyl groups;

[0656] Alternatively, R4 and R5, along with their connecting carbon atoms, can form a cyclopropyl group.

[0657] In a more specific implementation, only one of R1 and R2 has a substituent.

[0658] In a more specific implementation, M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-, and M2 is -OC(O)O-.

[0659] In a more specific implementation, M1 is -OC(O)O-, and M2 is -OC(O)-.

[0660] 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,

[0661] a = 2;

[0662] b = 5 or 6; b = 6 is preferred.

[0663] c = 4, 5 or 6; preferably c = 4 or 6; preferably c = 6;

[0664] d = 0, 1, or 2; preferably d = 0 or 2;

[0665] c+d=6;

[0666] M1 is -C(O)O-, M2 is -OC(O)O-;

[0667] R1 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0668] R 1s Selected from C 7-9 Alkyl groups, preferably C7 alkyl groups;

[0669] R2 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0670] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0671] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic.

[0672] In a more specific implementation, R1 is selected from... Preferred

[0673] 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,

[0674] a = 2;

[0675] b = 6;

[0676] c = 4, 5, or 6; preferably c = 5 or 6; preferably c = 6;

[0677] d = 0, 1, or 2; preferably d = 0 or 1;

[0678] c+d=6;

[0679] M1 is -C(O)O-, M2 is -OC(O)O-;

[0680] R1 is selected from C 8-10 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0681] R2 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0682] R 1s Selected from C 6-7 Alkyl groups, preferably C7 alkyl groups;

[0683] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0684] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic.

[0685] In a more specific implementation, R2 is selected from... Preferred

[0686] 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,

[0687] a = 2;

[0688] b = 5 or 6; b = 6 is preferred.

[0689] c = 5;

[0690] d = 1;

[0691] M1 is -OC(O)-, M2 is -OC(O)O-;

[0692] R1 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0693] R 1s Selected from C 6-8 Alkyl, preferably C 6-7 alkyl;

[0694] R2 is selected from C 8-12 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl;

[0695] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0696] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic.

[0697] In a more specific implementation, R1 is selected from... Preferred

[0698] 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,

[0699] a = 2, 3, or 4; a = 2 is preferred.

[0700] b = 5, 6, 7 or 8; preferably b = 6 or 7; preferably b = 7;

[0701] c = 4, 5, or 6; c = 4 is preferred.

[0702] d = 0, 1, or 2; preferably d = 1;

[0703] c+d = 5 or 6; c+d = 5 is preferred.

[0704] M1 is -OC(O)O-, M2 is -OC(O)-;

[0705] R1 is selected from C 8-12 Alkyl groups, preferably selected from C 8-10 Alkyl group, which is optionally marked with one R 1s replace;

[0706] R 1s Selected from C 6-10 Alkyl groups, preferably selected from C 6-8 alkyl;

[0707] R2 is selected from C 8-12 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl;

[0708] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0709] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic.

[0710] In a more specific implementation plan, R1 is

[0711] 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.

[0712]

[0713] in,

[0714] Q is either -SC(O)- or -OC(O)-;

[0715] R g and R' g Selected independently from C 1-6 alkyl;

[0716] a = 2, 3, 4, 5 or 6, with a = 2, 3 or 4 being preferred;

[0717] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6 or 7;

[0718] c = 2, 3, 4, 5 or 6;

[0719] d = 0, 1, 2, 3 or 4;

[0720] c+d = 5 or 6;

[0721] M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-;

[0722] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[0723] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 alkyl;

[0724] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0725] R c and R' c Independently selected from H and C 1-14 alkyl;

[0726] R4 and R5 are independently selected from C 1-6 alkyl;

[0727] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0728] 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,

[0729] Q is either -SC(O)- or -OC(O)-;

[0730] R g and R' g Selected independently from C 1-3 alkyl;

[0731] a = 3 or 4;

[0732] b = 6 or 7;

[0733] c = 2, 3, 4 or 5; preferably 2 or 5;

[0734] d = 1, 2, 3 or 4; preferably 1 or 4;

[0735] c+d = 5 or 6;

[0736] 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-;

[0737] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-10 Alkyl group, which is optionally marked with one R 1s replace;

[0738] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 alkyl;

[0739] R4 and R5 are independently selected from C 1-3 alkyl;

[0740] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene.

[0741] 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,

[0742] Q is -SC(O)-;

[0743] R g and R' g It is methyl;

[0744] a = 3 or 4;

[0745] b = 6 or 7;

[0746] c = 2, 4, or 5; preferably 2 or 5;

[0747] d = 1, 2, or 4; preferably 1 or 4;

[0748] c+d=6;

[0749] 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-;

[0750] R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[0751] R4 and R5 are methyl groups;

[0752] Alternatively, R4 and R5, along with their connecting carbon atoms, can form a cyclopropyl sub-cyclopropane group, preferably without forming a ring.

[0753] In a more specific embodiment, only one of R1 and R2 has a substituent; preferably, R1 has no substituent and R2 has a substituent.

[0754] 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.

[0755]

[0756] Wherein, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-;

[0757] The remaining groups are as defined in this document.

[0758] 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.

[0759]

[0760] Among them, 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)-;

[0761] The remaining groups are as defined in this document.

[0762] In a more specific implementation plan, R 1s Independently selected from H and C 1-6 Alkyl groups, preferably selected from H and C 1-4 alkyl.

[0763] In a more specific implementation, M1 is -OC(O)- or -SC(O)-, preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, preferably -C(O)O-.

[0764] In a more specific implementation plan, R 1s Selected independently from C 1-8 Alkyl groups, preferably selected from C 4-8 Alkyl groups, preferably selected from C 6-8 Alkyl groups, preferably selected from C 7-8 Alkyl group, preferably C8 alkyl group.

[0765] 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:

[0766]

[0767] in,

[0768] Q is selected from chemical bonds, -SC(O)-, and -OC(O)-;

[0769] R g and R' g Selected independently from C 1-6 alkyl;

[0770] a = 2, 3, 4, 5 or 6;

[0771] b = 6 or 7;

[0772] c = 5 or 6;

[0773] d = 0 or 1;

[0774] c+d = 5 or 6;

[0775] M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-;

[0776] R1 and R2 are independently selected from C7-12 Alkyl, preferably C 8-12 Alkyl group, which is optionally marked with one R 1s replace;

[0777] R 1s Independently selected from H and C 1-10 alkyl;

[0778] R4 and R5 are independently selected from C 1-6 alkyl;

[0779] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene.

[0780] In a more specific embodiment, only one of R1 and R2 has a substituent; preferably, R1 has no substituent and R2 has a substituent.

[0781] In a more specific embodiment, the present invention provides the above-described formula (II) or compound (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein,

[0782] Q is -SC(O)- or -OC(O)-, preferably -SC(O)-;

[0783] R g and R' g Selected independently from C 1-3 Alkyl groups, preferably methyl groups;

[0784] a = 2, 3 or 4; preferably a = 2 or 4; more preferably a = 4;

[0785] b = 6 or 7; b = 7 is preferred.

[0786] c = 5 or 6; c = 5 is preferred.

[0787] d = 0 or 1; preferred d = 1;

[0788] c+d = 5 or 6; preferably 6;

[0789] M1 is -OC(O)-; M2 is -C(O)O-;

[0790] R1 is selected from C 7-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0791] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0792] R 1s Selected independently from C 1-9 Alkyl groups, preferably selected from C 1-8 Alkyl groups, preferably selected from C 4-9 Alkyl groups, preferably selected from C 4-8 alkyl;

[0793] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0794] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene compounds, preferably cyclopropylene compounds.

[0795] In a more specific implementation plan, R 1s The substitution sites on R1 or R2 are spaced 0-10 carbon atoms apart from M1 or M2, preferably 0-6 carbon atoms apart, preferably 0-4 carbon atoms apart, preferably 0-2 carbon atoms apart, and preferably 0 carbon atoms apart.

[0796] In a more specific implementation, there is no R on R1. 1s Replace, and R 1s The substitution site on R2 is spaced 0-10 carbon atoms from M2, preferably 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, and preferably 2-4 carbon atoms.

[0797] In a more specific implementation, R2 is selected from... Preferred selection Preferred selection Preferred

[0798] In a more specific implementation, R4 and R5, and the carbon atoms they connect to, do not form a ring.

[0799] 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).

[0800] Table (I)

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813] The present invention also provides 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);

[0814]

[0815] Where X is a halogen, and the other variables are as defined in this paper.

[0816] The present invention also provides 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);

[0817]

[0818] Where X is a halogen, and the other variables are as defined in this paper.

[0819] In one specific embodiment, the compound is selected from the following:

[0820]

[0821]

[0822]

[0823] In a more specific embodiment, the present invention provides a nanoparticle composition comprising a lipid component and optionally a loading; wherein the lipid component contains a compound of the present invention.

[0824] Optionally, the lipid component comprises the following components in molar percentage:

[0825] Ionizable cationic lipids 20 mol% - 85 mol%

[0826] Structural lipids: 10 mol% - 75 mol%;

[0827] Neutral lipids: 1.0 mol% - 30 mol%;

[0828] Polymer lipids: 0.25 mol% - 10 mol%;

[0829] Optionally, the lipid component comprises the following components in molar percentage:

[0830] 50 mol% of any of the compounds of the present invention mentioned above;

[0831] Neutral lipids 10 mol%;

[0832] Structural lipids 38.5 mol%;

[0833] Polymer lipid 1.5 mol%.

[0834] In a more specific embodiment, the present invention provides the above-described 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.

[0835] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the structural lipid is selected from one or more of cholesterol, sitosterol, coccosterol, lycopene, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol.

[0836] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the polymer lipid is a polyethylene glycol-modified lipid.

[0837] Optionally, the PEGylated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol.

[0838] Optionally, the PEGylated lipid contains a PEG portion of about 1000 Da to about 20 kDa, preferably a PEG portion of about 1000 Da to about 5000 Da.

[0839] 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.

[0840] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the loading is selected from one or more therapeutic agents, preventive agents, or diagnostic agents;

[0841] Preferably, the therapeutic agent, preventive agent, or diagnostic agent is a nucleic acid;

[0842] Preferably, the nucleic acid is selected from one or more of ASO, RNA, or DNA;

[0843] 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 noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozymes, preferably mRNA, and more preferably modified mRNA.

[0844] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0845] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. A tautomer is a special type of functional group isomer; a pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most prominent examples are enol and keto tautomers.

[0846] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (IV), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (IV) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes and / or the methods disclosed in the examples and preparation examples below.

[0847] This invention also provides pharmaceutical formulations 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 such forms are included in this invention.

[0848] Pharmaceutical Compositions and Kits

[0849] In another aspect, the present invention provides a pharmaceutical composition comprising the nanoparticle composition of the present invention and a pharmaceutically acceptable excipient, said nanoparticle composition comprising the compounds of the present invention.

[0850] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0851] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the nanoparticle composition of the present invention and / or other therapeutic, diagnostic, or preventative agents. In some embodiments, the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents provided in the first and second containers form a unit dosage form.

[0852] Dosage

[0853] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0854] Typically, an effective amount of the pharmaceutical composition of the present invention is administered. The amount of pharmaceutical composition actually administered may be determined by a physician, depending on relevant circumstances, including the condition being treated or prevented, the chosen route of administration, the actual amount of pharmaceutical composition administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0855] When used to prevent the conditions described in this invention, the pharmaceutical composition provided herein is administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0856] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0857] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0858] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0859] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0860] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0861] More specifically, the present invention provides the following technical solution:

[0862] Technical Solution 1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[0863]

[0864] in,

[0865] G1 and G2 are independently selected from chemical bonds, C 1-13 straight-chain alkylene, C 2-13 Straight-chain alkenyl groups and C 2-13 Straight-chain ynylene groups, which are optionally surrounded by one or more R groups G1 replace;

[0866] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0867] R G1 Independently selected from H and C 1-14 Alkyl, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0868] G3 is selected from C 4-14 straight-chain alkylene, C 4-14 Straight-chain alkenyl groups and C 4-14 Straight-chain ynylene groups, which are optionally surrounded by one or more R groups G3 replace;

[0869] R G3 Independently selected from H, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0870] L a Independently selected from chemical bonds and C 1-14 Alkylene;

[0871] R a and R' a Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0872] G4 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 imide and C 2-6 Alynyl group, which is optionally surrounded by one or more R G4 replace;

[0873] R G4 Independently selected from H and C 1-6 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0874] L b Independently selected from chemical bonds and C 1-6 Alkylene;

[0875] R b and R' b Independently selected from H and C 1-6 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0876] Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4g replace;

[0877] R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0878] L e Independently selected from chemical bonds and C 1-8 Alkylene;

[0879] R eand R' e Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0880] 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 -;

[0881] Q is selected from chemical bonds, -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 - Phenylidene and pyridylene, wherein the phenylene or pyridylene is optionally substituted with one or more R*;

[0882] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L f -OR f -L f -SR f and -L f -NR f R' f ;

[0883] L f Independently selected from chemical bonds and C 1-8 Alkylene;

[0884] R f and R' f Independently selected from H and C 1-10 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0885] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, which is optionally surrounded by one or more R groups 1s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-;

[0886] R 1s Independently selected from H and C 1-20 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ;

[0887] R and R' are each independently selected from H and C. 1-20 alkyl;

[0888] L c Independently selected from chemical bonds and C 1-20 Alkylene;

[0889] R c and R' c Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0890] 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)2Rg -N(OR) g )C(O)OR g -N(OR) g )C(O)R g R' g 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

[0891] R g and R' g Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0892] "R" is independently selected from H and C. 1-6 alkyl;

[0893] R4 and R5 are independently selected from C 1-8 Alkyl groups, which are optionally composed of one or more R groups 4s replace;

[0894] Or R4, R5, together with the carbon atoms they are attached to, form C. 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4s replace;

[0895] R 4s Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0896] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0897] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 Cycloalkyl and 3 to 14-membered heterocyclic groups.

[0898] Technical Solution 2. The compound of formula (I) of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein G1 and G2 are independently selected from chemical bonds, C 1-9 straight-chain alkylene, C 2-9 Straight-chain alkenyl groups and C 2-9 Straight-chain acetylenic group;

[0899] Preferably, G1 is selected from C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynylene groups, preferably selected from C 1-6 Straight-chain alkylene groups, preferably selected from C 2-6 Straight-chain alkylene;

[0900] Preferably, G2 is selected from chemical bonds, C 1-6 straight-chain alkylene, C 2-6 Straight-chain alkenyl groups and C 2-6 Straight-chain ynylene groups, preferably selected from chemical bonds and C 1-6 Straight-chain alkylene groups, preferably selected from chemical bonds and C 1-4 Straight-chain alkylene;

[0901] Preferably, the total length of G1 and G2 is 3, 4, 5, 6, 7, 8 or 9 carbon atoms, more preferably 4, 5 or 6 carbon atoms, more preferably 5 or 6 carbon atoms; more preferably 5, 6 or 7 carbon atoms, more preferably 6 or 7 carbon atoms.

[0902] Preferably, G1 and G2 are optionally represented by 1, 2, 3 or 4 Rs G1 replace.

[0903] Technical Solution 3. A compound of formula (I) of Technical Solution 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 groups; preferably selected from H and C. 1-6 alkyl.

[0904] Technical Solution 4. A compound of formula (I) from any one of Technical Solutions 1-3, 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 alkenyl groups and C 4-10 Straight-chain ynylene group; preferably selected from C 4-9 Straight-chain alkylene groups; preferably selected from C 5-8 Straight-chain alkylene;

[0905] Preferably, G3 is optionally divided by 1, 2, 3 or 4 R G3 replace.

[0906] Technical Solution 5. A compound of formula (I) from any one of Technical Solutions 1-4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L a Independently selected from chemical bonds and C 1-10 Alkylenes, preferably selected from chemical bonds and C1-6 Alkylene;

[0907] Preferably, R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 alkyl.

[0908] Technical Solution 6. A compound of formula (I) from any one of Technical Solutions 1-5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein G4 is selected from C 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group; preferably selected from C 2-4 Alkylene; preferably selected from C 2-3 Alkylene;

[0909] Preferably, G4 is optionally divided by 1, 2, 3 or 4 R G4 replace.

[0910] Technical Solution 7. A compound of formula (I) from any one of Technical Solutions 1-6, 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;

[0911] Preferably, the two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups, preferably forming C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic alkylene group, optionally surrounded by 1, 2 or 3 R groups. 4g replace;

[0912] Preferably, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0913] Technical Solution 8. A compound of formula (I) from any one of Technical Solutions 1-7, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L b Independently selected from chemical bonds and C 1-4 Alkylene;

[0914] Preferably, R b and R' b Independently selected from H and C 1-6 Alkyl, C3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0915] Technical Solution 9. A compound of formula (I) of any one of technical solutions 1-8, 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)-;

[0916] Preferably, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, and more preferably -C(O)O-;

[0917] 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)-;

[0918] Preferably, M1 is -OC(O)- or -SC(O)-, more preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, more preferably -C(O)O-;

[0919] Preferably, M1 is -C(O)O-, and M2 is -C(O)O- or -C(O)S-;

[0920] Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)- and -C(O)NH-;

[0921] Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S- and -C(O)NH-, and more preferably from -C(O)O-, -OC(O)- and -C(O)S-;

[0922] 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- and -OC(O)-;

[0923] 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)-;

[0924] Preferably, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, more preferably selected from -C(O)O- and -OC(O-), more preferably -C(O)O-, more preferably -OC(O-), and M2 is -OC(O)O-;

[0925] Preferably, M1 is -OC(O)O-, and M2 is -OC(O)- or -OC(O)-, preferably -OC(O)-;

[0926] 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 both -OC(O)O-.

[0927] Technical Solution 10. A compound of formula (I) from any one of technical solutions 1-9, 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 Alkyne group; preferably selected from C 6-14 Alkyl; preferably selected from C 7-12 Alkyl; preferably selected from C 8-12 alkyl;

[0928] Preferably, R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group, preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 alkynyl group;

[0929] Preferably, R1 and R2 are optionally represented by 1, 2, 3 or 4 R... 1s Replace, preferably optionally by 1 R 1s replace;

[0930] 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,

[0931] 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,

[0932] Technical Solution 11. A compound of formula (I) from any one of technical solutions 1-10, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -Lc -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl groups; preferably selected from H and C. 1-6 Alkyl groups, preferably selected from H and C 1-4 alkyl.

[0933] Technical Solution 12. A compound of formula (I) of any one of technical solutions 1-11, 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 groups; preferably selected from H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl groups; preferably selected from H and C. 1-6 Alkyl group; preferably R is H.

[0934] Technical Solution 13. A compound of formula (I) of any one of technical solutions 1-12, 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;

[0935] Preferably, R c and R' c Independently selected from H and C 1-14 Alkyl groups; preferably selected from H and C. 1-10 Alkyl groups; preferably selected from H and C. 1-6 alkyl.

[0936] Technical Solution 14. A compound of formula (I) of any one of technical solutions 1-13, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R3 is selected from CN, -OR g and -NR g R' g Preferred selection from -OR g and -NR g R' g Preferred option: -OR g ; preferably OH;

[0937] Preferably, R3 is selected from OH and -N(CH3)2;

[0938] Preferably, R g and R' g Independently selected from H and C1-6 Alkyl, C 3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 Alkyl group; preferably selected from H and Me.

[0939] Technical Solution 15. A compound of formula (I) of any one of technical solutions 1-14, 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;

[0940] Preferably, R4 and R5 are optionally represented by 1, 2, or 3 R... 4s replace;

[0941] Preferably, R4, R5, together with the carbon atoms they are bonded to, form C. 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably cyclopropylene;

[0942] Preferably, the rings formed by R4, R5 and the carbon atoms they are attached to are optionally bounded by 1, 2 or 3 R atoms. 4s replace.

[0943] Technical Solution 16. A compound of formula (I) of any one of technical solutions 1-15, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R 4s Independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d Preferably selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; preferably selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0944] Technical Solution 17. A compound of formula (I) from any one of technical solutions 1-16, 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;

[0945] Preferably, R d and R' d Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 alkyl.

[0946] Technical Solution 18. A compound of formula (I) of any one of technical solutions 1-17, 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;

[0947] Preferably, R e and R' e Independently selected from H and C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0948] Technical Solution 19. A compound of formula (I) of any one of technical solutions 1-18, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein Q is selected from chemical bonds, -OC(O)- and -SC(O)-; preferably selected from chemical bonds and -SC(O)-;

[0949] Preferably, when Q is phenylene or pyridylene, it is optionally substituted with 1, 2 or 3 R*.

[0950] Preferably, R* is independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0951] Preferably, L f Independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-4 Alkylene;

[0952] Preferably, R f and R' f Independently selected from H and C1-6 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably selected from H and C. 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0953] Technical Solution 20. A compound of formula (I) of any one of technical solutions 1-19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, having the structure of formula (II) or formula (III):

[0954]

[0955] in,

[0956] a = 1, 2, 3, 4, 5 or 6;

[0957] b = 4, 5, 6, 7, 8, 9 or 10;

[0958] c = 1, 2, 3, 4, 5 or 6;

[0959] d = 0, 1, 2, 3 or 4;

[0960] c+d = 3, 4, 5, 6, 7, 8 or 9;

[0961] The remaining groups are as defined in any one of technical solutions 1-19.

[0962] Technical Solution 21. A compound of formula (II) or formula (III) of Technical Solution 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0963]

[0964] Among them, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-4 carbon atoms, preferably 0-2 carbon atoms, and preferably 0 carbon atoms.

[0965] Preferably, R 1s The substitution site on R1 or R2 is spaced 1-10 carbon atoms from M1 or M2, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, preferably 2-4 carbon atoms.

[0966] Preferably, R1 has no R 1s Replace, and R 1sThe substitution site on R2 is spaced 0-10 carbon atoms from M2, preferably 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, and preferably 2-4 carbon atoms.

[0967] Preferably, R1 has R 1s Replacement, and there is no R on R2. 1s replace;

[0968] Preferably, R4 and R5, and the carbon atoms they connect to, do not form rings;

[0969] Preferably, d is not 0.

[0970] Technical Solution 22. A compound of formula (II) of technical solution 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[0971]

[0972] in,

[0973] a = 2, 3, 4, 5 or 6;

[0974] b = 4, 5, 6, 7, 8, 9 or 10;

[0975] c = 1, 2, 3, 4, 5 or 6;

[0976] d = 0, 1, 2, 3 or 4;

[0977] c+d = 3, 4, 5, 6, 7, 8 or 9; preferably c+d = 4, 5 or 6;

[0978] 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)-;

[0979] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[0980] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' cPreferred ingredients are H and C. 1-14 alkyl;

[0981] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0982] R c and R' c Independently selected from H and C 1-14 alkyl;

[0983] R4 and R5 are independently selected from C 1-6 alkyl;

[0984] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0985] Technical Solution 23. The compound of formula (II) of Technical Solution 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0986] a = 2, 3, or 4;

[0987] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7;

[0988] c = 2, 3, 4, 5 or 6;

[0989] d = 0, 1, 2, 3 or 4;

[0990] c+d = 5 or 6;

[0991] 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)-;

[0992] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl group, which is optionally marked with one R 1s replace;

[0993] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 alkyl;

[0994] R4 and R5 are independently selected from C 1-3 alkyl;

[0995] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene; preferably forming C 3-5Cycloalkylene.

[0996] Technical Solution 24. A compound of formula (II) of Technical Solution 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[0997] a = 2, 3, or 4;

[0998] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7;

[0999] c = 2, 3, 4, 5 or 6;

[1000] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[1001] c+d = 5 or 6; c+d = 6 is preferred.

[1002] M1 and M2 are -C(O)O-;

[1003] Alternatively, one of M1 and M2 can be -C(O)O-, and the other can be -OC(O)-;

[1004] 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

[1005] R4 and R5 are methyl groups;

[1006] Alternatively, R4 and R5, along with their connecting carbon atoms, can form a cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene; preferably, a cyclopropylene or cyclopentylene is formed; preferably, a cyclopropylene is formed.

[1007] Preferably, only one of R1 and R2 has a substituent.

[1008] Technical Solution 25. A compound of formula (II) of Technical Solution 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1009] a = 2;

[1010] b = 5;

[1011] c = 2, 3, 4, 5 or 6; c = 6 is preferred;

[1012] d = 0, 1, 2, 3 or 4; preferred value is d = 0;

[1013] c+d = 5 or 6; preferably 6;

[1014] M1 and M2 are -C(O)O-;

[1015] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1016] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 6-8 Alkyl; preferably selected from C 7-8 alkyl;

[1017] R2 is selected from C 7-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 11 Straight-chain alkyl group, optionally bounded by 1 C 1-3 Alkyl substitution, preferably optionally replaced by one methyl group;

[1018] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1019] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene;

[1020] Preferably, R1 is selected from Preferred selection

[1021] Preferably, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and

[1022] Technical Solution 26. The compound of formula (II) of Technical Solution 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1023] a = 2, 3, or 4; a = 2 is preferred.

[1024] b = 7;

[1025] c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2;

[1026] d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4;

[1027] c+d = 5 or 6; preferably 6;

[1028] M1 and M2 are -C(O)O-;

[1029] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1030] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[1031] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 6-9 Alkyl; preferably selected from C 7-8 alkyl;

[1032] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1033] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene;

[1034] Preferably, R2 is selected from Preferred selection

[1035] Technical Solution 27. A compound of formula (II) of Technical Solution 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1036] a = 2;

[1037] b = 7;

[1038] c = 3 or 4; c = 4 is preferred.

[1039] d = 2;

[1040] M1 and M2 are -C(O)O-;

[1041] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-10 Alkyl group, which is optionally marked with one R 1s replace;

[1042] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 alkyl;

[1043] R2 is selected from C 7-11 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1044] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1045] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[1046] Technical Solution 28. A compound of formula (II) of Technical Solution 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1047] a = 2, 3, or 4; preferably a = 2 or 4.

[1048] b = 6 or 7; b = 7 is preferred.

[1049] c = 2, 3, 4, 5 or 6; preferably c = 5 or 6;

[1050] d = 0, 1, 2, 3 or 4; preferably d = 0 or 1;

[1051] c+d = 5 or 6; preferably 6;

[1052] M1 is -OC(O)-; M2 is -C(O)O-;

[1053] R1 is selected from C 7-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl;

[1054] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Straight-chain alkyl group, optionally marked with one R 1s replace;

[1055] R 1s Selected independently from C 7-9 alkyl;

[1056] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1057] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene;

[1058] Preferably, when a = 4, R4 and R5, as well as the carbon atoms they connect to, do not form rings; preferably R 1s Selected independently from C 8-9 alkyl;

[1059] Preferably, R2 is selected from

[1060] Technical Solution 29. A compound of formula (II) of Technical Solution 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[1061]

[1062] in,

[1063] a = 2, 3, 4, 5 or 6;

[1064] b = 4, 5, 6, 7, 8, 9 or 10;

[1065] c = 1, 2, 3, 4, 5 or 6;

[1066] d = 0, 1, 2, 3 or 4;

[1067] c+d = 3, 4, 5, 6, 7, 8 or 9; preferably c+d = 4, 5, 6 or 7;

[1068] 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)-;

[1069] R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups 1s replace;

[1070] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 alkyl;

[1071] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[1072] R c and R' c Independently selected from H and C 1-14 alkyl;

[1073] R4 and R5 are independently selected from C 1-6 alkyl;

[1074] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[1075] Technical Solution 30. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1076] a = 2, 3, or 4;

[1077] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5, 6 or 7;

[1078] c = 2, 3, 4, 5 or 6;

[1079] d = 0, 1, 2, 3 or 4;

[1080] c+d = 5, 6 or 7;

[1081] 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-);

[1082] R1 and R2 are independently selected from C 7-12 Alkyl, C7-12 alkenyl and C 7-12 Alkyne group, preferably C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group, which is optionally surrounded by 1 R 1s replace;

[1083] R 1s Independently selected from H and C 1-10 alkyl;

[1084] R4 and R5 are independently selected from C 1-3 alkyl;

[1085] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene; preferably forming C 3-5 Cycloalkylene.

[1086] Technical Solution 31. The compound of formula (II) of Technical Solution 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1087] a = 2, 3, or 4;

[1088] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 5 or 7;

[1089] c = 2, 3, 4, 5 or 6;

[1090] d = 0, 1, 2, 3 or 4;

[1091] c+d = 5, 6 or 7; c+d = 6 is preferred.

[1092] 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)-;

[1093] 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, -(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,

[1094] R4 and R5 are methyl groups;

[1095] Alternatively, R4 and R5, along with their connecting carbon atoms, can form a cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene; preferably, a cyclopropylene or cyclopentylene is formed; preferably, a cyclopropylene is formed.

[1096] Preferably, only one of R1 and R2 has a substituent.

[1097] Technical Solution 32. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1098] a = 2;

[1099] b = 5;

[1100] c = 5 or 6; c = 6 is preferred.

[1101] d = 0 or 1; preferred is d = 0;

[1102] c+d = 5 or 6; preferably 6;

[1103] M1 is -C(O)O-, and M2 is -C(O)O- or -C(O)S-; preferably, M1 and M2 are -C(O)O-.

[1104] R1 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-9 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1105] R 1sIndependently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 6-8 Alkyl; preferably selected from C 7-8 alkyl;

[1106] R2 is selected from C 7-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 11 Straight-chain alkyl group, optionally bounded by 1 C 1-3 Alkyl substitution, preferably optionally replaced by one methyl group;

[1107] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1108] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene;

[1109] Preferably, R1 is selected from Preferred selection

[1110] Preferably, R2 is selected from -(CH2)9CH3, -(CH2) 10 CH3 and

[1111] Technical Solution 33. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1112] a = 2, 3, or 4; a = 2 is preferred.

[1113] b = 5, 6, or 7; b = 7 is preferred.

[1114] c = 2, 3, 4, 5 or 6; preferably c = 2, 3 or 4; preferably c = 2;

[1115] d = 0, 1, 2, 3 or 4; preferably d = 2, 3 or 4; preferably d = 4;

[1116] c+d = 5 or 6; preferably 6;

[1117] M1 and M2 are -C(O)O-;

[1118] 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 group, which is optionally marked with one R 1s Substitution; and only one of R1 and R2 has a substituent;

[1119] 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;

[1120] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1121] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably forming cyclopropylene; preferably not forming a ring;

[1122] Preferably,

[1123] R1 is selected from C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl;

[1124] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s Replace; when R2 is C 10 When the chain is alkyl, R 1s Selected from C 9-10 Alkyl groups, preferably C9 alkyl groups;

[1125] Preferably, R2 is selected from Preferred selection

[1126] Technical Solution 34. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1127] a = 2, 3, or 4;

[1128] b = 6;

[1129] c = 4, 5, or 6; preferably c = 5 or 6; preferably c = 5.

[1130] d = 1 or 2; preferred d = 1;

[1131] c+d = 6, 7 or 8; preferably 6 or 7; preferably 6;

[1132] M1 is -OC(O)-; M2 is -C(O)O-;

[1133] R1 is selected from C 7-12 Straight-chain alkyl, preferably C 8-11 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl;

[1134] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-12 Alkyl group, which is optionally marked with one R 1s replace;

[1135] R 1s Selected independently from C 7-11 Alkyl, preferably C 7-10 alkyl;

[1136] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1137] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene;

[1138] The condition is that when c = 4, a = 2 or 3;

[1139] Preferably, R2 is selected from

[1140] Preferably,

[1141] a = 2 or 4; b = 6; c = 5 or 6, preferably c = 5; d = 1;

[1142] R1 is selected from C 8-9 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1143] R2 is selected from C 9-10 Alkyl, preferably C 10 Alkyl group, which is optionally marked with one R 1s replace;

[1144] R 1s Selected independently from C 7-8 alkyl;

[1145] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1146] Preferably,

[1147] a = 2, 3 or 4, preferably a = 2 or 4; b = 6; c = 5; d = 2;

[1148] R1 is selected from C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1149] R2 is selected from C 9-11 Alkyl group, which is optionally marked with one R 1s replace;

[1150] R 1s Selected independently from C 7-9 alkyl;

[1151] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably methyl group.

[1152] Technical Solution 35. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1153] a = 2, 3, or 4; preferably a = 2 or 4.

[1154] b = 7;

[1155] c = 5 or 6; c = 5 is preferred.

[1156] d = 0 or 1; preferred d = 1;

[1157] c+d = 5 or 6; preferably 6;

[1158] M1 is -OC(O)-; M2 is -C(O)O-;

[1159] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl group, optionally bounded by 1 C 1-9 Alkyl (preferably C) 6-9 Alkyl, more preferably C 6-7 Alkyl) substitution;

[1160] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[1161] R 1s Selected independently from C 7-9 alkyl;

[1162] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1163] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene;

[1164] Preferably, R1 is selected from -(CH2)8CH3, -(CH2)9CH3,

[1165] R2 is selected from

[1166] Preferably, when a = 4,

[1167] R1 is selected from C 9-10 Straight-chain alkyl;

[1168] R2 is selected from C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[1169] R 1s Selected from C 8-9 alkyl;

[1170] R4 and R5, and the carbon atoms they connect to, do not form rings;

[1171] Preferably, when a = 2,

[1172] R1 is C 10 Straight-chain alkyl;

[1173] Preferred R 1s Selected from C 8-9 Alkyl group, preferably C9 alkyl group.

[1174] Technical Solution 36. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1175] a = 2, 3, or 4; preferably a = 2 or 4.

[1176] b = 7;

[1177] c = 4;

[1178] d = 2;

[1179] M1 is -OC(O)-; M2 is -C(O)O-;

[1180] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl;

[1181] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[1182] R 1s Selected independently from C 7-9 alkyl;

[1183] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1184] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably forming cyclopropylene; preferably not forming a ring;

[1185] Preferably, R2 is selected from

[1186] Technical Solution 37. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1187] a = 2, 3, or 4; a = 2 is preferred.

[1188] b = 8;

[1189] c = 5;

[1190] d = 1;

[1191] M1 is -OC(O)-; M2 is -C(O)O-;

[1192] R1 is selected from C 8-12 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl;

[1193] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[1194] R 1s Selected independently from C 7-9 Alkyl, preferably C 7-8 alkyl;

[1195] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1196] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably forming cyclopropylene; preferably not forming a ring;

[1197] Preferably, R2 is selected from

[1198] Technical Solution 38. A compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1199] a = 2;

[1200] b = 6, 7 or 8, with b = 7 being the preferred value;

[1201] c = 5;

[1202] d = 1;

[1203] M1 is -OC(O)-; M2 is -C(O)O-;

[1204] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1205] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1206] R 1s Independently selected from C7 alkyl groups;

[1207] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1208] Preferably, R2 is selected from Preferred

[1209] Technical Solution 39. The compound of formula (II) of Technical Solution 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1210] a = 2 or 3, with a = 2 being the preferred value;

[1211] b = 7;

[1212] c = 3;

[1213] d = 3;

[1214] M1 is -OC(O)-; M2 is -C(O)O-;

[1215] R1 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1216] R2 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1217] R 1s Selected independently from C 6-7 Alkyl groups, preferably C7 alkyl groups;

[1218] R4 and R5 are independently selected from C 1-3Alkyl groups, preferably methyl groups;

[1219] Preferably, R2 is selected from Preferred

[1220] Technical solution 40. A compound of formula (II) of technical solution 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[1221]

[1222] in,

[1223] a = 2, 3, 4, 5 or 6;

[1224] b = 4, 5, 6, 7, 8, 9 or 10;

[1225] c = 1, 2, 3, 4, 5 or 6;

[1226] d = 0, 1, 2, 3 or 4;

[1227] c+d = 3, 4, 5, 6, 7, 8 or 9; preferably c+d = 4, 5 or 6;

[1228] 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-;

[1229] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[1230] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 alkyl;

[1231] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[1232] R c and R' c Independently selected from H and C 1-14 alkyl;

[1233] R4 and R5 are independently selected from C 1-6 alkyl;

[1234] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[1235] Technical Solution 41. A compound of formula (II) of Technical Solution 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1236] a = 2, 3, or 4;

[1237] b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6;

[1238] c = 2, 3, 4, 5 or 6; preferably c = 2, 4, 5 or 6;

[1239] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[1240] c+d = 5 or 6; c+d = 6 is preferred.

[1241] One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-;

[1242] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 9-11 Alkyl group, which is optionally marked with one R 1s replace;

[1243] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 4-10 alkyl;

[1244] R4 and R5 are independently selected from C 1-3 alkyl;

[1245] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene, preferably forming C 3-4 Cycloalkylene.

[1246] Technical solution 42. A compound of formula (II) of technical solution 40 or 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1247] a = 2, 3, or 4;

[1248] b = 4, 5, 6 or 7; preferably b = 5 or 6; preferably b = 6;

[1249] c = 2, 3, 4, 5 or 6; preferably c = 2, 4, 5 or 6;

[1250] d = 0, 1, 2, 3 or 4; preferably d = 0, 1, 2 or 4;

[1251] c+d = 5 or 6; c+d = 6 is preferred.

[1252] One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-;

[1253] R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3

[1254] R4 and R5 are methyl groups;

[1255] Or R4 and R5, along with their connecting carbon atoms, can form a cyclopropyl group;

[1256] Preferably, only one of R1 and R2 has a substituent;

[1257] Preferably, M1 is -C(O)O- or -OC(O)-, more preferably -C(O)O-, and M2 is -OC(O)O-;

[1258] Preferably, M1 is -OC(O)O- and M2 is -OC(O)-.

[1259] Technical Solution 43. The compound of formula (II) of Technical Solution 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1260] a = 2;

[1261] b = 5 or 6; b = 6 is preferred.

[1262] c = 4, 5 or 6; preferably c = 4 or 6; preferably c = 6;

[1263] d = 0, 1, or 2; preferably d = 0 or 2;

[1264] c+d=6;

[1265] M1 is -C(O)O-, M2 is -OC(O)O-;

[1266] R1 is selected from C 8-11 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1267] R 1s Selected from C 7-9 Alkyl groups, preferably C7 alkyl groups;

[1268] R2 is selected from C 8-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1269] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1270] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic;

[1271] Preferably, R1 is selected from Preferred

[1272] Technical Solution 44. A compound of formula (II) of Technical Solution 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1273] a = 2;

[1274] b = 6;

[1275] c = 4, 5, or 6; preferably c = 5 or 6; preferably c = 6;

[1276] d = 0, 1, or 2; preferably d = 0 or 1;

[1277] c+d=6;

[1278] M1 is -C(O)O-, M2 is -OC(O)O-;

[1279] R1 is selected from C 8-10 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1280] R2 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1281] R 1s Selected from C 6-7 Alkyl groups, preferably C7 alkyl groups;

[1282] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1283] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic;

[1284] Preferably, R2 is selected from Preferred

[1285] Technical Solution 45. A compound of formula (II) of Technical Solution 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1286] a = 2;

[1287] b = 5 or 6; b = 6 is preferred.

[1288] c = 5;

[1289] d = 1;

[1290] M1 is -OC(O)-, M2 is -OC(O)O-;

[1291] R1 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1292] R 1s Selected from C 6-8 Alkyl, preferably C 6-7 alkyl;

[1293] R2 is selected from C 8-12 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl;

[1294] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1295] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic;

[1296] Preferably, R1 is selected from Preferred

[1297] Technical Solution 46. A compound of formula (II) of Technical Solution 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1298] a = 2, 3, or 4; a = 2 is preferred.

[1299] b = 5, 6, 7 or 8; preferably b = 6 or 7; preferably b = 7;

[1300] c = 4, 5, or 6; c = 4 is preferred.

[1301] d = 0, 1, or 2; preferably d = 1;

[1302] c+d = 5 or 6; c+d = 5 is preferred.

[1303] M1 is -OC(O)O-, M2 is -OC(O)-;

[1304] R1 is selected from C 8-12 Alkyl groups, preferably selected from C 8-10 Alkyl group, which is optionally marked with one R 1s replace;

[1305] R 1s Selected from C 6-10 Alkyl groups, preferably selected from C 6-8 alkyl;

[1306] R2 is selected from C 8-12 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl;

[1307] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1308] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably non-cyclic;

[1309] Preferably, R1 is

[1310] Technical Solution 47. A compound of formula (III) of technical solution 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[1311]

[1312] in,

[1313] Q is either -SC(O)- or -OC(O)-;

[1314] R g and R' g Selected independently from C 1-6 alkyl;

[1315] a = 2, 3, 4, 5 or 6, with a = 2, 3 or 4 being preferred;

[1316] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6 or 7;

[1317] c = 2, 3, 4, 5 or 6;

[1318] d = 0, 1, 2, 3 or 4;

[1319] c+d = 5 or 6;

[1320] M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-;

[1321] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[1322] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 alkyl;

[1323] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[1324] R c and R' c Independently selected from H and C 1-14 alkyl;

[1325] R4 and R5 are independently selected from C 1-6 alkyl;

[1326] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[1327] Technical Solution 48. A compound of formula (III) of Technical Solution 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1328] Q is either -SC(O)- or -OC(O)-;

[1329] R g and R' g Selected independently from C 1-3 alkyl;

[1330] a = 3 or 4;

[1331] b = 6 or 7;

[1332] c = 2, 3, 4 or 5; preferably 2 or 5;

[1333] d = 1, 2, 3 or 4; preferably 1 or 4;

[1334] c+d = 5 or 6;

[1335] 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-;

[1336] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-10 Alkyl group, which is optionally marked with one R 1s replace;

[1337] R 1s Independently selected from H and C 1-10 Alkyl groups; preferably selected from H and C. 1-9 alkyl;

[1338] R4 and R5 are independently selected from C 1-3 alkyl;

[1339] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene.

[1340] Technical solution 49. A compound of formula (III) of technical solution 47 or 48, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1341] Q is -SC(O)-;

[1342] R g and R' g It is methyl;

[1343] a = 3 or 4;

[1344] b = 6 or 7;

[1345] c = 2, 4, or 5; preferably 2 or 5;

[1346] d = 1, 2, or 4; preferably 1 or 4;

[1347] c+d=6;

[1348] 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-;

[1349] R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[1350] R4 and R5 are methyl groups;

[1351] Alternatively, R4 and R5, along with their connecting carbon atoms, can form a cyclopropyl group, preferably without forming a ring;

[1352] Preferably, only one of R1 and R2 has a substituent; preferably, R1 does not have a substituent and R2 has a substituent.

[1353] Technical solution 50. A compound of formula (II) of technical solution 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[1354]

[1355] Wherein, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-;

[1356] The remaining groups are as defined in any of technical solutions 21-27 and 29-33.

[1357] Technical Solution 51. A compound of formula (II) of Technical Solution 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,

[1358]

[1359] Among them, 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)-;

[1360] The remaining groups are as defined in any one of technical solutions 21-24, 29-31 and 34-39;

[1361] Preferably, R 1s Independently selected from H and C 1-6 Alkyl groups, preferably selected from H and C 1-4 alkyl;

[1362] Preferably, R 1s Selected independently from C 1-8 Alkyl groups, preferably selected from C 4-8 Alkyl groups, preferably selected from C 6-8 Alkyl groups, preferably selected from C 7-8 Alkyl group, preferably C8 alkyl group.

[1363] Preferably, M1 is -OC(O)- or -SC(O)-, more preferably -OC(O)-; M2 is -C(O)O- or -C(O)S-, more preferably -C(O)O-.

[1364] Technical Solution 52. A compound of formula (II) or (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

[1365]

[1366] in,

[1367] Q is selected from chemical bonds, -SC(O)-, and -OC(O)-;

[1368] R g and R' g Selected independently from C 1-6 alkyl;

[1369] a = 2, 3, 4, 5 or 6;

[1370] b = 6 or 7;

[1371] c = 5 or 6;

[1372] d = 0 or 1;

[1373] c+d = 5 or 6;

[1374] M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-;

[1375] R1 and R2 are independently selected from C 7-12 Alkyl, preferably C 8-12 Alkyl group, which is optionally marked with one R 1s replace;

[1376] R 1s Independently selected from H and C 1-10 alkyl;

[1377] R4 and R5 are independently selected from C 1-6 alkyl;

[1378] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene;

[1379] Preferably, only one of R1 and R2 has a substituent; preferably, R1 does not have a substituent and R2 has a substituent.

[1380] Technical Solution 53. The compound of formula (II) or formula (III) of Technical Solution 52, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

[1381] Q is -SC(O)- or -OC(O)-, preferably -SC(O)-;

[1382] R g and R' g Selected independently from C 1-3 Alkyl groups, preferably methyl groups;

[1383] a = 2, 3 or 4; preferably a = 2 or 4; more preferably a = 4;

[1384] b = 6 or 7; b = 7 is preferred.

[1385] c = 5 or 6; c = 5 is preferred.

[1386] d = 0 or 1; preferred d = 1;

[1387] c+d = 5 or 6; preferably 6;

[1388] M1 is -OC(O)-; M2 is -C(O)O-;

[1389] R1 is selected from C 7-11 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[1390] R2 is selected from C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[1391] R 1s Selected independently from C 1-9 Alkyl groups, preferably selected from C 1-8 Alkyl groups, preferably selected from C 4-9 Alkyl groups, preferably selected from C 4-8 alkyl;

[1392] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[1393] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene groups, preferably cyclopropylene groups;

[1394] Preferably, R 1s The substitution site on R1 or R2 is separated from M1 or M2 by 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-4 carbon atoms, preferably 0-2 carbon atoms, and preferably 0 carbon atoms.

[1395] Preferably, R1 has no R 1s Replace, and R 1s The substitution site on R2 is spaced 0-10 carbon atoms from M2, preferably 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, and preferably 2-4 carbon atoms.

[1396] Preferably, R2 is selected from Preferred selection Preferred selection Preferred

[1397] Preferably, R4 and R5, and the carbon atoms they connect to, do not form rings.

[1398] Technical Solution 54. The compound of formula (I) of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein the compound is selected from the compounds in Table (I).

[1399] Technical Solution 55. A pharmaceutical composition comprising a compound of any one of Technical Solutions 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[1400] Technical Solution 56. A nanoparticle composition comprising a lipid component and optionally a loading agent; wherein the lipid component contains a compound of any one of technical solutions 1-54, or a pharmaceutically acceptable salt, isotope variant, tautomer, or stereoisomer thereof, and the loading agent is selected from one or more therapeutic agents, preventive agents, or diagnostic agents.

[1401] Technical Solution 57. Use of any compound of any one of Technical Solutions 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or the pharmaceutical composition of Technical Solution 55, or the nanoparticle composition of Technical Solution 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.

[1402] Use of a compound of any one of claims 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or the pharmaceutical composition of claim 55, or the nanoparticle composition of claim 56, in the preparation of a drug for delivery of a payload, said payload being selected from one or more therapeutic agents, preventive agents or diagnostic agents.

[1403] Technical Solution 59. A method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of Technical Solution 55, or the nanoparticle composition of Technical Solution 56.

[1404] Technical Solution 60. A compound of any one of Technical Solutions 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition of Technical Solution 55, or a nanoparticle composition of Technical Solution 56, for the treatment, diagnosis or prevention of disease.

[1405] Technical Solution 61. A method for delivering a payload into a subject, comprising administering to the subject the pharmaceutical composition of Technical Solution 55 or the nanoparticle composition of Technical Solution 56;

[1406] The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents.

[1407] Technical Solution 62. A compound of any one of Technical Solutions 1-54, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition of Technical Solution 55, or a nanoparticle composition of Technical Solution 56, for delivery of a payload.

[1408] The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents.

[1409] Technical solution 63. The nanoparticle composition of technical solution 56, or the use of technical solution 58 or 62, or the method of technical solution 61, wherein the therapeutic agent, preventive agent or diagnostic agent is a nucleic acid;

[1410] Preferably, the nucleic acid is selected from one or more of ASO, RNA, or DNA;

[1411] 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 noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozymes, preferably mRNA, and more preferably modified mRNA.

[1412] Technical Solution 64. A method for preparing a compound of formula (II), the method comprising:

[1413] The compound of formula (IIA) is reacted with the compound of formula (IIB) to obtain the compound of formula (II);

[1414]

[1415] Where X is a halogen, and the other variables are defined as in any of the technical solutions 20-46.

[1416] Technical Solution 65. A method for preparing a compound of formula (II), the method comprising:

[1417] The compound of formula (IIC) is reacted with the compound of formula (IID) to obtain the compound of formula (II);

[1418]

[1419] Where X is a halogen, and the other variables are defined as in any of the technical solutions 20-46.

[1420] Example

[1421] To make the technical solution of the present invention clearer and more explicit, the present invention will be further described in detail through the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art. Unless otherwise specified, the materials, reagents, etc., used in the embodiments can be obtained commercially.

[1422] Table 1

[1423]

[1424]

[1425] Example 1: Synthesis of compound 1a

[1426]

[1427] At room temperature, 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.) were added to a 500 mL three-necked round-bottom flask, followed by 250 mL of DCM. The reaction mixture was stirred at room temperature for 4 hours, and the reaction was monitored by TLC until complete. The reaction mixture was poured into 200 mL of saturated ammonium chloride aqueous solution and extracted with 3 x 100 mL DCM solutions. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 21 g of a yellow oily compound 1a-2.

[1428] Compound 1a-2 (21 g, 60.1 mmol, 1.0 eq.) and 2-aminoethanol (110 g, 1.80 mol, 30.0 eq.) were added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 100 mL of methanol. The mixture was heated to 60 °C and stirred for 18 hours. The reaction solvent was removed by concentration, and then saturated ammonium chloride aqueous solution and ethyl acetate were added. The mixture was extracted layer by layer, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 14 g of a yellow oily compound 1a-3.

[1429] 9-Heptadecyl alcohol (9.8 g, 38.2 mmol, 1.0 eq.) and triethylamine (15.5 g, 152.8 mmol, 4.0 eq.) were added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and then 2-methylpropionyl chloride (9.8 g, 91.7 mmol, 2.4 eq.) was slowly added. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution, 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 a crude product, which was purified by silica gel column chromatography to give 8.7 g of a yellow oily compound 1a-5.

[1430] Compound 1a-5 (8.7 g, 26.6 mmol, 1.0 eq.) was added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 60 mL THF. The reaction system was cooled to -40 °C, and then LDA (13.1 mL, 26.2 mmol, 0.98 eq.) was slowly added dropwise. The reaction was stirred for 1 hour, and then 1,6-dibromohexane (9.03 g, 37.0 mmol, 1.39 eq.) and DMPU (0.48 g, 3.73 mmol, 0.14 eq.) were added to the reaction system. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, 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 a crude product, which was purified by silica gel column chromatography to give 10.1 g of a yellow oily compound 1a-6.

[1431] 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 to a 20 mL round-bottom flask. The mixture was heated to 80 °C and the reaction was allowed to proceed. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to give 96.98 mg of oily compound 1a.

[1432] 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] + .

[1433] Example 2: Synthesis of compound 2a

[1434]

[1435] 1-Nonanol (8.8 g, 61.0 mmol, 1.0 eq.) and triethylamine (24.7 g, 244.0 mmol, 4.0 eq.) were added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and then 2-methylpropionyl chloride (15.6 g, 146.4 mmol, 2.4 eq.) was slowly added, and the mixture was allowed to rise to room temperature. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution, 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 a crude product, which was purified by silica gel column chromatography to give 10.8 g of a yellow oily compound 2a-2.

[1436] Compound 2a-2 (4.8 g, 22.4 mmol, 1.0 eq.) was added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 50 mL THF. The reaction system was cooled to -40 °C, and then LDA (11.0 mL, 21.9 mmol, 0.98 eq.) was slowly added dropwise. The reaction was stirred for 1 hour, and then 1,6-dibromohexane (7.59 g, 31.1 mmol, 1.39 eq.) and DMPU (0.57 g, 4.48 mmol, 0.2 eq.) were added to the reaction system. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, 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 a crude product, which was purified by silica gel column chromatography to give 4.6 g of a yellow oily compound 2a-3.

[1437] 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 to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 50 mL of ethanol. The mixture was heated to 60 °C and stirred for 18 hours. The reaction solvent was removed by concentration, and then saturated ammonium chloride aqueous solution and ethyl acetate were added. The mixture was extracted by layer-by-layer extraction, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 2.2 g of a yellow oily compound 2a-4.

[1438] 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) were added to a 20 mL round-bottom flask. The mixture was heated to 80 °C and the reaction was allowed to proceed. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 137.9 mg of oily compound 2a.

[1439] 1H 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] + .

[1440] Example 3: Synthesis of compound 3a

[1441]

[1442] Compound 3a was prepared according to the method of Example 1, yielding 114.7 mg of an oily product.

[1443] 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] + .

[1444] Example 4: Synthesis of compound 4a

[1445]

[1446] Compound 4a was prepared according to the method of Example 1, yielding 112.1 mg of an oily product.

[1447] 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] + .

[1448] Example 5: Synthesis of compound 5a

[1449]

[1450] Compound 5a was prepared according to the method of Example 1, yielding 150.8 mg of an oily product.

[1451] 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] + .

[1452] Example 6: Synthesis of compound 6a

[1453]

[1454] 15.0 g (150.0 mmol, 1.0 eq.) of tert-butyl cyclopropionate was dissolved in 150 mL of anhydrous tetrahydrofuran and cooled to -60 °C. Under nitrogen protection, LDA (150.0 mL, 300.0 mmol, 2.0 eq.) was added to the reaction solution. After stirring for 1 hour at the same temperature, 1-bromo-6-chlorohexane (44.9 g, 225.0 mmol, 1.5 eq.) was added, and the reaction was continued at room temperature with stirring for another 3 hours. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, 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 a crude product, which was purified by silica gel column chromatography to give 19 g of a colorless oily compound 6a-1.

[1455] 10.0 mL of trifluoroacetic acid was added to a DCM (30.0 mL) solution of compound 6a-1 (10.0 g, 38.3 mmol), stirred at room temperature for 3 hours, and the reaction solvent was removed by rotary evaporation under pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 6.9 g of colorless oily compound 6a-2.

[1456] Compound 6a-2 (500.0 mg, 2.45 mmol, 2.0 eq.) was dissolved in DCM (5.0 mL). Under ice bath conditions, 2-3 drops of DMF and oxaloyl chloride (311.1 mg, 2.45 mmol, 2.0 eq.) were added to the reaction system. After stirring for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain the acyl chloride intermediate. The obtained acyl chloride was dissolved in DCM (5.0 mL), and then 9-heptadecyl alcohol (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 carried out at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water, 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 by silica gel column chromatography to give 240 mg of the oily compound 6a-3.

[1457] 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.) were added to a DMF (3.0 mL) solution of compound 6a-3 (200.0 mg, 0.45 mmol, 1.5 eq.). The reaction solution was heated to 80 °C and stirred for 5 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction was quenched with saturated sodium chloride aqueous solution, 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 a crude product, which was purified by preparative liquid chromatography to give 75.2 mg of compound 6a. (Column type: XSelect C18 (19×150mm, 5μm); Mobile phase A: water: acetonitrile = 90:10 (10mmol / L ammonium bicarbonate + 0.5% ammonia), Mobile phase B: isopropanol: acetonitrile = 90:10; Flow rate: 25mL / min; Gradient: B proportion is 75%-80% within 0-12 minutes, and B proportion is 90% after 12 minutes).

[1458] 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] + .

[1459] Example 7: Synthesis of compound 7a

[1460]

[1461] Compound 7a was prepared according to the method of Example 1, yielding 102.4 mg of an oily product.

[1462] 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] + .

[1463] Example 8: Synthesis of compound 8a

[1464]

[1465] Compound 8a was prepared according to the method of Example 1, yielding 44.9 mg of an oily product.

[1466] 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] + .

[1467] Example 9: Synthesis of compound 9a

[1468]

[1469] 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 mixture was placed in an ice bath, and then TBSCl (29.8 g, 198 mmol, 1.1 eq.) was added. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated sodium bicarbonate solution, 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 a crude product, which was purified by silica gel column chromatography to give 26 g of a pale yellow oily compound 9a-1.

[1470] In a 250 mL three-necked round-bottom flask, Mg (1.70 g, 70.1 mmol, 1.6 eq.), I2 (0.01 g, 0.039 mmol), and 50 mL of anhydrous THF were added. The reaction system was heated to 37 °C, and then compound 9a-1 (18.5 g, 65.7 mmol, 1.5 eq.) was slowly added over 30 minutes. The reaction proceeded until the magnesium powder was almost completely eliminated, thus preparing the Grignard reagent. Under nitrogen protection, 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 were added to a 250 mL three-necked round-bottom flask. The mixture was stirred at 0 °C for 30 minutes. Then, methyl 3,3-dimethacrylate (5 g, 43.8 mmol, 1.0 eq.) and TMSCl (7.14 g, 65.7 mmol, 1.5 eq.) were added dropwise to the resulting copper-lithium reagent solution. After the addition was complete, stirring was continued at 0 °C for another 30 minutes. The prepared Grignard reagent was then slowly added dropwise to the reaction solution, and the reaction was continued for 2 hours after the addition was complete. The reaction was monitored by TLC until complete. 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 a crude product, which was purified by silica gel column chromatography to give 13 g of a pale yellow oily compound 9a-2.

[1471] TBAF (21.5 g, 82.1 mmol, 2.0 eq.) was added in portions to a THF solution of compound 9a-2 (13 g, 41.1 mmol, 1.0 eq.) under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. 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 crude product 9a-3, which was used directly in the next reaction without further purification.

[1472] 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 mixture was cooled to 0 °C, and then CBr4 (25.3 g, 76.1 mmol, 1.1 eq.) was added in portions. The reaction mixture was stirred at room temperature until complete as monitored by TLC. The reaction was quenched with ice-cold 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 a crude product, which was purified by silica gel column chromatography to give 7.6 g of a pale yellow oily compound 9a-4.

[1473] TMSOK (4.35 g, 33.9 mmol, 1.5 eq.) was added to 60 mL of a THF solution of compound 9a-4 (6 g, 22.6 mmol, 1 eq.). The mixture was stirred at room temperature until complete as monitored by TLC. The pH of the reaction system was adjusted to 4.0 with 2.0 M hydrochloric acid, and the mixture was 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 a crude product, which was purified by silica gel column chromatography to give 2.5 g of a pale yellow oily compound 9a-5.

[1474] Following the method of Example 1, compound 9a was prepared to obtain 81.7 mg of an oily product.

[1475] 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] + .

[1476] Example 10: Synthesis of compound 10a

[1477]

[1478] In a 100 mL round-bottom flask, methyl 4-bromo-butyrate (4 g, 22.1 mmol, 1.0 eq.) was dissolved in 40 mL MTBE. The reaction mixture was placed in an ice bath. Then, magnesium methyl bromide (22.1 mL, 66.3 mmol, 3.0 eq.) was added to the reaction mixture. The mixture was brought to room temperature and allowed to react until complete as monitored by TLC. The reaction was quenched with saturated ammonium chloride solution, 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 a crude product, which was purified by silica gel column chromatography to give 3.5 g of compound 10a-2.

[1479] Under nitrogen protection, compound 10a-2 (3 g, 16.6 mmol, 1.0 eq.), triethylchlorosilane (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 sieve (2.4 g) were added to a 100 mL round-bottom flask, followed by 24 mL of anhydrous THF. The reaction mixture was heated to 50 °C, and then 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 mixture was cooled to room temperature, and the reaction was quenched with saturated sodium chloride aqueous solution. The mixture 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 a crude product, which was purified by silica gel column chromatography to give 2.4 g of compound 10a-3.

[1480] 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 ethanol and 2 mL water. Lithium hydroxide (0.27 g, 11.3 mmol, 3.0 eq.) was then added to the reaction mixture. The reaction was allowed to proceed at room temperature until complete as monitored by TLC. The organic solvent was removed by rotary evaporation, and the pH of the solution was adjusted to approximately 4 using 2.0 M dilute hydrochloric acid. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture 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 a crude product, which was then purified by silica gel column chromatography to yield 800 mg of compound 10a-4.

[1481] Following the method of Example 1, compound 10a was prepared, yielding 93.4 mg of an oily product.

[1482] 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] + .

[1483] Example 11: Synthesis of compound 11a

[1484]

[1485] Compound 11a was prepared according to the method of Example 1, yielding 69.5 mg of an oily product.

[1486] 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] + .

[1487] Example 12: Synthesis of compound 12a

[1488]

[1489] Compound 12a was prepared according to the method of Example 1, yielding 178.6 mg of an oily product.

[1490] 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] + .

[1491] Example 13: Synthesis of compound 13a

[1492]

[1493] Compound 13a was prepared according to the method of Example 1, yielding 43.5 mg of an oily product.

[1494] 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 H),1.70-1.51(m,16H),1.48-1.16(m,47H),1.14(t,J=4.0Hz,2H),0.88(t,J=7.2Hz,9H),0.64(t,J=4.0Hz,2H); ESI-MS m / z:736.60[M+H] + .

[1495] Example 14: Synthesis of compound 14a

[1496]

[1497] Compound 14a was prepared according to the method of Example 1, yielding 56.3 mg of an oily product.

[1498] 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] + .

[1499] Example 15: Synthesis of compound 15a

[1500]

[1501] Compound 15a was prepared according to the method of Example 1, yielding 120.3 mg of an oily product.

[1502] 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] + .

[1503] Example 16: Synthesis of compound 16a

[1504]

[1505] Compound 16a was prepared according to the method of Example 1, yielding 80.8 mg of an oily product.

[1506] 1H 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] + .

[1507] Example 17: Synthesis of compound 17a

[1508]

[1509] Compound 17a was prepared according to the method of Example 1, yielding 125.7 mg of an oily product.

[1510] 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] + .

[1511] Example 18: Synthesis of compound 18a

[1512]

[1513] Compound 18a was prepared according to the method of Example 1, yielding 127.4 mg of an oily product.

[1514] 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] + .

[1515] Example 19: Synthesis of compound 19a

[1516]

[1517] Compound 19a was prepared according to the method of Example 9, yielding 79.7 mg of an oily product.

[1518] 1 H 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] + .

[1519] Example 20: Synthesis of compound 20a

[1520]

[1521] Compound 20a was prepared according to the method of Example 10, yielding 74.5 mg of an oily product.

[1522] 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] + .

[1523] The compounds in Table 2 were synthesized using the methods described in the above examples, or using similar methods with the corresponding intermediates.

[1524] Table 2

[1525]

[1526] Example 30: Synthesis of Compound 1b

[1527]

[1528] 9-Heptadecyl 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 mixture was stirred at room temperature for 3 hours. The solution was then poured into 10 mL of saturated sodium chloride aqueous solution and extracted with 3 x 20 mL DCM solutions. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 300 mg of a yellow oily compound 1b-2.

[1529] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0 °C. Under nitrogen protection, LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction solution. The reaction temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Then, 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.) was added. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 30 g of a yellow oily compound 1b-4.

[1530] Compound 1b-4 (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0 °C. Under nitrogen protection, a borane-tetrahydrofuran solution (1 M, 100.0 mL) was added dropwise to the reaction system. The temperature was raised to 75 °C, and the reaction was stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with 3 x 300 mL DCM, and 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 reaction without further purification.

[1531] Decanoyl chloride (11.0 g, 58.0 mmol, 1.3 eq.) was added to a DCM solution of compound 1b-5 (10.0 g, 44.0 mmol, 1.0 eq.) in 100 mL. Triethylamine (13.5 g, 134.0 mmol, 3.0 eq.) was then added to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. The reaction solution was poured into 100 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 10 g of compound 1b-6.

[1532] 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, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to give 1.4 g of compound 1b-7. 1 H 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).

[1533] 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), followed by the addition of potassium carbonate (289.9 mg, 2.1 mmol, 2.5 eq.) and sodium iodide (314.4 mg, 2.1 mmol, 2.5 eq.). The mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was then poured into 20 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give compound 1b (158.9 mg).

[1534] 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] + .

[1535] Example 31: Synthesis of compound 2b

[1536]

[1537] 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, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 350 mg of a colorless oily compound 2b-1.

[1538] 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), followed by the addition of potassium carbonate (389 mg, 2.82 mmol, 3.0 eq.) and sodium iodide (353 mg, 2.35 mmol, 2.5 eq.). The mixture was heated to 70 °C and stirred for 5 hours. The reaction solution was then poured into 20 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give compound 2b (160 mg).

[1539] 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] + .

[1540] Example 32: Synthesis of compound 3b

[1541]

[1542] 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 DMF (10.0 mL) solution of 4-amino-1-butanol (1.2 g, 13.3 mmol, 10.0 eq.). The mixture was heated to 70 °C and stirred for 3 hours. The reaction solution was poured into 30 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 300 mg of a colorless oily compound 3b-1.

[1543] 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), followed by the addition of potassium carbonate (269 mg, 1.9 mmol, 2.5 eq.) and sodium iodide (285 mg, 1.9 mmol, 2.5 eq.). The mixture was heated to 70 °C and stirred for 5 hours. The reaction solution was poured into 20 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give compound 3b (228 mg).

[1544] 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] + .

[1545] Example 33: Synthesis of compound 4b

[1546]

[1547] Methyl isobutyrate (21 g, 205 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0 °C. Under nitrogen protection, LDA (205 mL, 410 mmol, 2.0 eq.) was added to the reaction mixture. The reaction temperature was raised to room temperature and stirred for 30 minutes. Then, 1,6-dibromohexane (50 g, 205 mmol, 1.0 eq.) was added. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 34 g of a yellow oily compound 4b-2. 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).

[1548] Compound 4b-2 (10.0 g, 37.6 mmol, 1.0 eq.) was added to an aqueous solution of hydrobromic acid (50.0 mL). The reaction mixture was heated to 100 °C and stirred for 24 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction was quenched with a saturated sodium chloride aqueous solution, 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 a crude product, which was purified by silica gel column chromatography to give 7.4 g of a yellow oily compound 4b-3. 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).

[1549] 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 mixture under ice bath conditions. After stirring for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain the acyl chloride intermediate. The obtained acyl chloride was dissolved in DCM (50.0 mL), and then 9-heptadecyl alcohol (4.08 g, 15.9 mmol, 0.8 eq.) and triethylamine (6.03 g, 59.7 mmol, 3.0 eq.) were added. The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was poured into 300 mL of water, 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 by silica gel column chromatography to give 4.3 g of the oily compound 4b-4.

[1550] 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.) were added to a DMF (3.0 mL) solution of compound 4b-4 (492.9 mg, 1.0 mmol, 1.2 eq.). The reaction mixture was heated to 70 °C and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction was quenched with saturated sodium chloride aqueous solution, 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 a crude product, which was then purified by preparative liquid chromatography to give 106 mg of compound 4b. (Column type: XBridge Shield RP18 OBD Column 19x150 mm, 5μm; Mobile phase A: Acetonitrile: Water (10 mmol / L ammonium bicarbonate + 0.05% ammonia), Mobile phase B: Isopropanol: Acetonitrile; Flow rate: 20 mL / min; Gradient: The proportion of mobile phase B is gradually increased from 75% B to 95% B over 9 minutes).

[1551] 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] + .

[1552] Example 34: Synthesis of compound 5b

[1553]

[1554] Compound 5b was prepared according to the method of Example 30, yielding 174 mg of an oily product.

[1555] 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] + .

[1556] Example 35: Synthesis of compound 6b

[1557]

[1558] Compound 6b was prepared according to the method of Example 30, yielding 113 mg of an oily product.

[1559] 1H 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] + .

[1560] Example 36: Synthesis of compound 7b

[1561]

[1562] Compound 7b was prepared according to the method of Example 30, yielding 91 mg of an oily product.

[1563] 1 H 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] + .

[1564] Example 37: Synthesis of compound 8b

[1565]

[1566] Compound 8b was prepared according to the method of Example 30, yielding 124 mg of an oily product.

[1567] 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] + .

[1568] Example 38: Synthesis of compound 9b

[1569]

[1570] 15.0 g (150.0 mmol, 1.0 eq.) of tert-butyl cyclopropionate was dissolved in 150 mL of anhydrous tetrahydrofuran and cooled to -60 °C. Under nitrogen protection, LDA (150.0 mL, 300.0 mmol, 2.0 eq.) was added to the reaction solution. After stirring at the same temperature for 1 hour, 1-bromo-6-chlorohexane (44.9 g, 225.0 mmol, 1.5 eq.) was added, and the reaction was continued at room temperature with stirring for another 3 hours. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 19 g of a colorless oily compound 9b-1.

[1571] 10.0 mL of trifluoroacetic acid was added to a DCM (30.0 mL) solution of compound 9b-1 (10.0 g, 38.3 mmol), stirred at room temperature for 3 hours, and the reaction solvent was removed by rotary evaporation under pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 6.9 g of colorless oily compound 9b-2.

[1572] Compound 9b-2 (500.0 mg, 2.45 mmol, 2.0 eq.) was dissolved in DCM (5.0 mL). Under ice bath conditions, 2-3 drops of DMF and oxaloyl chloride (311.1 mg, 2.45 mmol, 2.0 eq.) were added to the reaction system. After stirring for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain the acyl chloride intermediate. The obtained acyl chloride was dissolved in DCM (5.0 mL), and then 9-heptadecyl alcohol (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 carried out at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water, 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 by silica gel column chromatography to give 240 mg of the oily compound 9b-3.

[1573] 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.) were added to a DMF (3.0 mL) solution of compound 9b-3 (200.0 mg, 0.45 mmol, 1.5 eq.). The reaction mixture was heated to 70 °C and stirred for 5 hours. After the reaction was completed, the reaction system was cooled to room temperature, the reaction was quenched with saturated sodium chloride aqueous solution, 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 a crude product, which was then purified by preparative liquid chromatography to give 85.4 mg of compound 9b. (Column type: XBridge Shield RP18 OBDColumn 19x150 mm, 5μm; Mobile phase A: acetonitrile:water (10mmol / L ammonium bicarbonate + 0.05% ammonia), Mobile phase B: isopropanol:acetonitrile; Flow rate: 20mL / min; Gradient: 75% B to 95% B in 9min).

[1574] 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] + .

[1575] Example 39: Synthesis of Compound 10b

[1576]

[1577] Compound 10b was prepared according to the method of Example 30, yielding 128 mg of an oily product.

[1578] 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]+ .

[1579] Example 40: Synthesis of compound 11b

[1580]

[1581] Compound 11b was prepared according to the method of Example 30, yielding 92 mg of an oily product.

[1582] 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] + .

[1583] Example 41: Synthesis of compound 12b

[1584]

[1585] Compound 12b was prepared according to the method of Example 30, yielding 105 mg of an oily product.

[1586] 1 H 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] + .

[1587] The compounds in Table 3 were synthesized using the methods described in the above examples, or using similar methods with the corresponding intermediates.

[1588] Table 3

[1589]

[1590]

[1591] Example 54: Synthesis of compound 30a

[1592]

[1593] In a 250 mL round-bottom flask, 9-heptadecyl alcohol (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. Isobutyryl chloride (10.39 g, 97.5 mmol, 2.5 eq.) was slowly added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at 0 °C, extracted with DCM, and 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 by silica gel column chromatography to give a yellow oily compound 1a-5 (10.4 g).

[1594] Compound 1a-5 (10.0 g, 30.62 mmol, 1.0 eq.) was dissolved in anhydrous THF (100 mL). The reaction system was cooled to -40 °C, and LDA (15.3 mL, 30.6 mmol, 1 eq.) was added to the reaction solution under a nitrogen atmosphere. After stirring at -40 °C for 1 hour, 1,6-dibromohexane (14.9 g, 61.2 mmol, 2.0 eq.) and DMPU (471 mg, 3.7 mmol, 0.12 eq.) were added at the same temperature. The reaction system was slowly raised to room temperature and then allowed to react overnight. After the reaction was completed, the reaction solution was added to a saturated NH4Cl solution and extracted with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and the solvent was removed by rotary evaporation to obtain crude compound 1a-6, which could be used directly in the next reaction without purification.

[1595] 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. The reaction system was heated to 60 °C and reacted for 2 hours. After the reaction was completed, 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 a saturated sodium chloride solution was added. After extraction, the organic phases were combined and dried with anhydrous Na₂SO₄. The drying agent was removed by filtration, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography to give a yellow oily compound 30a-1 (12.4 g).

[1596] 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 min in an ice bath, and the mixture was left to stand overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, extracted with DCM, and 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 by silica gel column chromatography to give a yellow oily compound 30a-4 (2.5 g).

[1597] 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.), K₂CO₃ (236.0 mg, 1.71 mmol, 3.0 eq.), and 5.0 mL of anhydrous acetonitrile were added to an 8 mL sealed tube. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with acetonitrile. The organic phases were combined, and the solvent was removed by rotary evaporation to obtain the crude product. Compound 30a (87.9 mg) was purified by preparative liquid chromatography.

[1598] 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] + .

[1599] Example 55: Synthesis of compound 31a

[1600]

[1601] Compound 31a was prepared according to the method of Example 54, yielding 80.7 mg of an oily product.

[1602] 1H 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] + .

[1603] Example 56: Synthesis of compound 32a

[1604]

[1605] Compound 32a was prepared according to the method of Example 54, yielding 93.9 mg of an oily product.

[1606] 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] + .

[1607] Example 57: Synthesis of compound 33a

[1608]

[1609] Compound 33a was prepared according to the method of Example 54, yielding 164.2 mg of an oily product.

[1610] 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] + .

[1611] Example 58: Synthesis of compound 34a

[1612]

[1613] Compound 34a was prepared according to the method of Example 54, yielding 150.1 mg of an oily product.

[1614] 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] + .

[1615] Example 59: Synthesis of compound 35a

[1616]

[1617] Compound 35a was prepared according to the method of Example 54, yielding 217.9 mg of an oily product.

[1618] 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] + .

[1619] Example 60: Synthesis of compound 36a

[1620]

[1621] Compound 36a was prepared according to the method of Example 54, yielding 169.7 mg of an oily product.

[1622] 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] + .

[1623] Example 61: Synthesis of compound 37a

[1624]

[1625] Compound 37a was prepared according to the method of Example 54, yielding 59.4 mg of an oily product.

[1626] 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] + .

[1627] Example 62: Synthesis of compound 38a

[1628]

[1629] Compound 38a was prepared according to the method of Example 54, yielding 44.8 mg of an oily product.

[1630] 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] + .

[1631] Example 63: Synthesis of compound 39a

[1632]

[1633] Compound 39a was prepared according to the method of Example 54, yielding 105.4 mg of an oily product.

[1634] 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] + .

[1635] Example 64: Synthesis of compound 40a

[1636]

[1637] In 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 protection. The system was cooled to 0 °C, and NaH (3.64 g, 151.7 mmol, 1.6 eq.) was added in portions, followed by dropwise addition of LDA (85.3 mL, 170.6 mmol, 1.8 eq., 2 M in THF). The mixture was stirred at room temperature for 1 hour, and then 1-iodoheptane (23.6 g, 104.3 mmol, 1.1 eq.) was added to the system at 0 °C. The mixture was stirred overnight at 80 °C. The reaction was monitored by TLC, and a new product was identified. The reaction 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 by silica gel column chromatography to obtain a yellow oily 2-heptylnonanoic acid (16.36 g).

[1638] In a 250 mL round-bottom flask, 7.0 g (27.3 mmol, 1.0 eq.) of 2-heptylnonanoic acid 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 brought back to room temperature and stirred for 2 hours. The reaction was monitored by TLC, and the starting material was completely converted. The reaction solution was quenched by pouring it into a saturated sodium chloride solution. The organic phases were extracted with ethyl acetate and combined, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give a pale yellow oily product, 2-heptylnonanol (6.97 g).

[1639] In 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 mixture was stirred at room temperature for 1 hour. Then, 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. The mixture was stirred at room temperature overnight. The mixture 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 chromatography to give a pale yellow oily carbonate intermediate compound 40a-4 (325 mg).

[1640] 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) obtained in the previous step were added to an 8 mL sealed tube at room temperature. The mixture was heated to 80 °C and stirred overnight. The reaction was monitored by LC-MS, and the reaction system was cooled to room temperature. The mixture was f...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: in, G 1 and G 2 independently selected from chemical bonds, 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; G 1 and G 2 has a total length of 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 ; G 3 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; G 4 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; M 1 and M 2 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; R 1 and R 2 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; R 3 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) 2 R g 、-OC(O)NR g R' g 、-NR”C(O)OR g 、-N(OR g )C(O)R g 、-N(OR g )S(O) 2 R 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; R 4 and R 5 Independently selected from C 1-8 Alkyl, which is optionally substituted by one or more R 4s replace; or R 4 , R 5 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 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, which is 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 claim 1.

3. A compound of formula (II) or (III) according to claim 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, R 1s In R 1 or R 2 The substitution site on M 1 or M 2 There are 0-10 carbon atoms between them, preferably 0-6 carbon atoms between them, preferably 0-4 carbon atoms between them, preferably 0-2 carbon atoms between them, and preferably 0 carbon atoms between them; Preferably, R 1s In R 1 or R 2 The substitution site on M 1 or M 2 There are 1-10 carbon atoms between them, preferably 1-6 carbon atoms between them, preferably 1-4 carbon atoms between them, preferably 1-2 carbon atoms between them, preferably 2-10 carbon atoms between them, preferably 2-6 carbon atoms between them, preferably 2-4 carbon atoms between them; Preferably, R 1 No R 1s Replace, and R 1s In R 2 The substitution site on M 2 There are 0-10 carbon atoms between them, preferably 1-10 carbon atoms between them, preferably 1-6 carbon atoms between them, preferably 1-4 carbon atoms between them, preferably 1-2 carbon atoms between them, preferably 2-10 carbon atoms between them, preferably 2-6 carbon atoms between them, preferably 2-4 carbon atoms between them; Preferably, R 1 There is R 1s Replace, and R 2 No R 1s replace; Preferably, R 4 and R 5 and they connect carbon atoms without forming a ring; Preferably, d is not zero.

4. A compound of formula (II) or formula (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; M 1 -OC(O)- or -SC(O)-; M 2 is -C(O)O- or -C(O)S-; R 1 and R 2 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; R 4 and R 5 Independently selected from C 1-6 alkyl; or R 4 and R 5 and they join carbon atoms together to form C 3-6 Cycloalkylene; Preferably, R 1 and R 2 Only one of them has a substituent; preferably, R 1 No substituent, R 2 Has a substituent.

5. A pharmaceutical composition comprising the compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient.

6. A nanoparticle composition comprising a lipid component and, optionally, a cargo; in, The lipid component contains the compound according to any one of claims 1 to 4, 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.

7. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 5, or a nanoparticle composition according to claim 6 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.

8. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 5, or a nanoparticle composition according to claim 6 in the preparation of a drug for delivering a load selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

9. A method for preparing a compound of formula (II), the method include: 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 2-4.

10. A method for preparing a compound of formula (II), the method comprising: include: 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 2-4.

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