Highly metabolizable lipid compounds

Abstract

This specification provides a class of highly metabolic lipid compounds, and in particular, compounds represented by formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. Also provided are nanoparticle pharmaceutical compositions containing the above compounds, as well as applications of the above compounds and their compositions for nucleic acid delivery. [C1] TIFF2026521611000342.tif25156

Description

[Technical Field]

[0001] This application claims priority to China Patent Application No. 202310720951.5, filed on 16 June 2023, China Patent Application No. 202310723466.3, filed on 16 June 2023, and China Patent Application No. 202410115561.X, filed on 26 January 2024. The aforementioned China patent applications are incorporated herein by reference as part of the disclosure of this application.

[0002] <Technical field> This disclosure relates to a novel class of ionizable cationic lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. The disclosure also relates to lipid nanoparticles and pharmaceutical compositions containing such compounds, as well as applications of such lipid nanoparticles in the delivery of biologically active substances such as nucleic acids (e.g., mRNA, siRNA, ASO, and DNA). [Background technology]

[0003] Gene therapy refers to the introduction of exogenous genes into target cells to repair or compensate for genetic defects or abnormalities within those cells in order to achieve therapeutic objectives. Over the past few decades, research into treating clinical diseases through gene therapy has attracted increasing attention. In particular, in recent years, the approval of siRNA-related drugs and mRNA vaccines for clinical use by the FDA has further stimulated research and related investment in the field of gene therapy.

[0004] Nucleic acid substances are readily degraded by nucleases in living organisms, and because nucleic acid substances themselves are negatively charged, it is difficult for them to enter cells through the cell membrane. Lipid nanoparticles (LNPs) are one of the most important nucleic acid delivery systems as nucleic acid delivery materials, possessing advantages such as ease of preparation, excellent biodegradability, non-immunogenicity, and high safety. The main components of LNPs include cationic lipids, cholesterol, neutral lipids, and polyethylene glycol-bound lipids. Among these, cationic lipid molecules form the core of the LNP delivery system, and their molecular structure plays a crucial role in the delivery efficiency, target directivity, and formulation stability of the entire liposome nanoparticle system.

[0005] Because different types of nucleic acid substances and delivery systems for specific delivery to various targets have different requirements, further development of novel lipid molecules is needed to meet the diverse needs in gene therapy. [Overview of the project] [Problems that the invention aims to solve]

[0006] This disclosure relates to the development of a novel class of ionizable cationic lipid compounds that can be used to deliver various biologically active substances with high delivery efficiency.

[0007] Our prior patent CN115850104A discloses a class of cationic lipid compounds having a pair of geminal dialkyl groups in each tail that exhibits high delivery efficiency. Surprisingly, further research has shown that when the geminal dialkyl structure is applied to cationic lipids containing a central nitrogen atom, these cationic lipids are slowly degraded in the liver, making them suitable for applications where slow degradation is required. In some application cases where accelerated in vivo metabolism is necessary, a novel class of ionizable lipid compounds has been developed. [Means for solving the problem]

[0008] This disclosure provides compounds of formula (I) or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. [ka] In the formula, each group is as defined herein.

[0009] In another embodiment, the Disclosure provides a nanoparticle composition comprising a lipid component and optionally a support, wherein the lipid component comprises a compound of the Disclosure.

[0010] US11246933B1 discloses that by incorporating biodegradable groups into the tail chains of lipid compounds in lipid nanoparticles, the metabolism and elimination of the lipids from the body are more rapid after the activator has been delivered to the target site. As a result, these lipids containing biodegradable groups are less toxic than similar lipids that do not contain biodegradable groups. The tail chains of the cationic lipid compounds in this disclosure have one or more biodegradable groups, thereby having a superior toxicity profile compared to similar lipids that do not contain biodegradable groups, such as DLin-MC3-DMA.

[0011] In other embodiments, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure or the nanoparticle compositions of the Disclosure, and optionally, pharmaceutically acceptable excipients such as carriers, adjuvants, or vehicles.

[0012] In other embodiments, the Disclosure provides the use of the Compounds of the Disclosure, the Nanoparticle Compositions of the Disclosure, or the Pharmaceutical Compositions of the Disclosure in the manufacture of agents for treating, diagnosing, or preventing diseases. In one embodiment, the agent for treating, diagnosing, or preventing diseases is a therapeutic or prophylactic mRNA vaccine.

[0013] In other embodiments, the Disclosure provides the use of the Compounds, Nanoparticle Compositions, or Pharmaceutical Compositions of the Disclosure in the preparation of agents for delivering a supported substance. In other embodiments, the Disclosure provides the use of the Compounds, Nanoparticle Compositions, or Pharmaceutical Compositions of the Disclosure in the manufacture of agents for delivering a supported substance.

[0014] In other embodiments, the Disclosure provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a compound of the Disclosure, a nanoparticle composition of the Disclosure, or a pharmaceutical composition of the Disclosure.

[0015] In other embodiments, the Disclosure provides compounds, nanoparticle compositions, or pharmaceutical compositions of the Disclosure for use in the treatment, diagnosis, and / or prevention of diseases.

[0016] In other embodiments, the Disclosure provides a method for delivering a supported substance to a subject, comprising administering to the subject a compound of the Disclosure, a nanoparticle composition of the Disclosure, or a pharmaceutical composition of the Disclosure.

[0017] In other embodiments, the Disclosure provides compounds of the Disclosure, nanoparticle compositions of the Disclosure, or pharmaceutical compositions of the Disclosure for use in the delivery of supported materials.

[0018] In specific embodiments, the supported substance is selected from one or more therapeutic agents, prophylactic agents, and diagnostic agents, or the therapeutic agent, prophylactic agent, or diagnostic agent is a nucleic acid.

[0019] In a more specific embodiment, the nucleic acid is selected from one or more of ASO, RNA, and DNA.

[0020] In a more specific embodiment, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), and ribozyme, or mRNA, or further modified mRNA.

[0021] Definition Chemical definition The definitions of specific functional groups and chemical terms are described in detail below.

[0022] When a range of values is recited, each value and sub-range within that range is intended to be encompassed. For example, "C 5-6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C<00,00015>, and C 5-6 alkyl.

[0023] "C 1-20 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1 to 20 carbon atoms. In some embodiments, C 4-20 alkyl, C 6-14 alkyl, C 7-12 alkyl, C 8-12 alkyl, C 9-12 alkyl, C 4-10 alkyl, C 7-11 alkyl, C 8-11 alkyl, C 9-11 alkyl, C 10-11Alkyl, C 6-10 Alkyl, C 7-10 Alkyl, C 8-10 Alkyl, C 9-10 Alkyl, C 10 Alkyl, C 8-9 Alkyl, C 4-9 Alkyl, C 6-9 Alkyl, C 7-9 Alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 2-8 Alkyl, C 4-8 Alkyl, C 5-8 Alkyl, C 6-8 Alkyl, C 7-8 Alkyl, C8 alkyl, C 6-7 Alkyl, C7 alkyl, C 4-6 Alkyl, C 1-20 Alkyl, C 1-14 Alkyl, C 2-14 Alkyl, C 1-13 Alkyl, C 1-12 Alkyl, C 1-10 Alkyl, C 1-9 Alkyl, C 1-8 Alkyl, C 1-7 Alkyl, C 2-7 Alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 1-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 Alkyl and Me are preferred. 1-6 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). 1-6The term "alkyl" also includes heteroalkyls in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). Alkyl alkyls may optionally be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyls 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 is preferably a linear alkyl.

[0024] "C 2-13 "Alkenyl" refers to a linear or branched hydrocarbon group having 2 to 13 carbon atoms and at least one carbon-carbon double bond. 4-20 "Alkenyl" refers to a linear or branched hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-14 Alkenil, C 6-14 Alkenil, C 7-12 Alkenil, C 4-10 Alkenil, C 2-10 Alkenil, C 2-9 Alkenil, C 2-6 Alkenyl and C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyls include etenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), and hexenyl (C6). 2-6 The term “alkenyl” also includes heteroalkenyls in which one or more carbon atoms (e.g., 1, 2, 3, or 4) are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). The alkenyl group may optionally be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0025] 「C 2-13 "C alkynyl" refers to a linear 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. "C 4-20 "C alkynyl" refers to a linear 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, C 6-14 alkynyl, C 7-12 alkynyl, C 4-10 alkynyl, C 2-10 alkynyl, C 2-9 alkynyl, C 2-6 alkynyl, and C 2-4 alkynyl are preferred. C 2-6 Examples of C alkynyl include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. "C 2-6 The term "C alkynyl" also includes heteroalkynyl in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). The alkynyl group may optionally be substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] 「C 1-20 "C alkylene" refers to a divalent group formed by removing another hydrogen of C 1-20 alkyl, which may or may not be substituted. 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 9-10Alkilen, C 8-9 Alkilen, C 4-9 Alkilen, C 6-9 Alkilen, C 7-9 Alkylene, C9 Alkylene, C 2-8 Alkilen, C 5-8 Alkilen, C 7-8 Alkilen, C 4-6 Alkilen, C 1-20 Alkilen, C 1-14 Alkilen, C 2-14 Alkilen, C 1-13 Alkilen, C 1-12 Alkilen, C 1-10 Alkilen, C 1-9 Alkyl, C 1-8 Alkilen, C 1-7 Alkilen, C 2-7 Alkilen, C 1-6 Alkilen, C 2-6 Alkilen, C 1-5 Alkylene, C5 Alkylene, C 1-4 Alkilen, C 2-4 Alkilen, C 1-3 Alkilen, C 2-3 Alkilen, C 1-2 Alkylenes and methylenes are preferred. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Examples of substituted alkylene groups, such as those substituted with one or more alkyl (methyl) groups, include substituted methylene (-CH(CH3)- and -C(CH3)2-), and substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)). 2- Examples include substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0027] "C 2-13 "Alkenylene" refers to C 2-13 This refers to a divalent group formed by removing another hydrogen atom from an alkenyl, and it may be substituted or unsubstituted. 4-14 "Alkenylene" refers to C 4-14 This refers to a divalent group formed by removing another hydrogen from an alkenyl, which may be substituted or unsubstituted. In some embodiments, C 6-14 Alkenylene, C 4-10 Alkenylene, C 2-10 Alkenylene, C 2-9 Alkenylene, C 2-6 Alkenylene and C 2-4 Alkenylenes are particularly preferred. Examples of unsubstituted forms of alkenylenes include ethynylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2- and -CH2-CH=CH-). Examples of substituted alkenylene groups, such as alkenylenes substituted with one or more alkyl (methyl) groups, include substituted ethynylene (-C(CH3)=CH- and -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-).

[0028] "C 2-13 "Alkynylene" is C 2-13 This refers to a divalent group formed by removing another hydrogen atom from an alkynyl group, and it may be substituted or unsubstituted. 4-14 "Alkynylene" is C 4-14 This refers to a divalent group formed by removing another hydrogen from an alkynyl group, which may be substituted or unsubstituted. In some embodiments, C 6-14 Alkinylene, C 4-10 Alkinylene, C 2-10 Alkinylene, C 2-9 Alkinylene, C 2-6Alkynylene and C 2-4 Alkynylene is particularly preferred. Examples of alkynylene groups include ethynylene (-C≡C-) and substituted or unsubstituted propynylene (-C≡CCH2-).

[0029] "C 0-6 "Alkylene" is a chemical bond and the above-mentioned "C 1-6 This refers to "alkylene". 0-4 "Alkylene" is a chemical bond and the above-mentioned "C 1-4 This refers to "alkylene".

[0030] The phrase "variable A and variable B have a total length of x carbon atoms" means that the total 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 are x.

[0031] "R on R2" 1s The phrase "the substitution position is x carbon atoms away from M2" means that the variable R2 is located on the variable R 1s This refers to the total number of carbon atoms (including the N atoms replaced by -NR'-) between the substituted position and the position itself, and is interpreted similarly in other cases. For example, [ka] In compound 11b, the variable R on R2 1s The substitution site is separated from M2 by three carbon atoms.

[0032] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0033] Therefore, "C 1-10 "Haloalkyl" refers to the above "C" which is substituted with one or more halogens. 1-10 This refers to "alkyl". In some embodiments, C 1-8 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Haloalkyl and C 1-3Haloalkyl is particularly preferred, and furthermore, C 1-2 Haloalkyl groups are preferred. Examples of haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, and 2,2,2-trifluoro-1,1-dimethylethyl. Haloalkyl groups may be substituted with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent at any bondable position.

[0034] "C 3-14"Cycloalkyl" or "3-14 membered cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and 0 heteroatoms, and optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, 3-10 membered cycloalkyls, 5-10 membered cycloalkyls, 3-8 membered cycloalkyls, 3-7 membered cycloalkyls, and 3-6 membered cycloalkyls are particularly preferred, and further, 5-7 membered cycloalkyls, 4-6 membered cycloalkyls, 3-5 membered cycloalkyls, 3-4 membered cycloalkyls, and 5-6 membered cycloalkyls, further, 5 membered cycloalkyls, further, 6 membered cycloalkyls, and further, cyclopropyls are preferred. Cycloalkyls also include ring systems in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, and the bond position is on the cycloalkyl ring, in which case the number of carbon atoms represents the number of carbon atoms in the cycloalkyl system. The cycloalkyl further comprises the above-mentioned cycloalkyl, wherein a substituent on any non-adjacent carbon atom is bonded to form a bridging ring, forming a polycyclic alkane that shares two or more carbon atoms together. The cycloalkyl further comprises the above-mentioned cycloalkyl, wherein a substituent on the same carbon atom is bonded to form a ring, forming a polycyclic alkane that shares one carbon atom together. Examples of cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptadienyl (C7), and cycloheptatrielinyl (C7). The cycloalkyl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] "C 3-14 "Cycloalkylene" refers to C 3-14This refers to a divalent group formed by removing another hydrogen atom from a cycloalkyl group, which may 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 is particularly preferred, and further, cyclopropylene is preferred.

[0036] A "3- to 14-membered heterocyclil" refers to a saturated or unsaturated group of a 3- to 14-membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms, where 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 heterocyclils containing one or more nitrogen atoms, the bond position may be a carbon atom or a nitrogen atom, within the limits of the valence. In some embodiments, a 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring radical having a ring carbon atom and 1-5 ring heteroatoms; in some embodiments, a 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring radical having a ring carbon atom and 1-5 ring heteroatoms; in some embodiments, a 3-8 membered heterocyclyl is preferred, which is a 3-8 membered non-aromatic ring radical having a ring carbon atom and 1-4 ring heteroatoms; in some embodiments, a 3-7 membered heterocyclyl is preferred, which is a 3-7 membered non-aromatic ring radical having a ring carbon atom and 1-4 ring heteroatoms; and a 5-7 membered heterocyclyl having a ring carbon atom and 1-3 ring heteroatoms Preferably, the non-aromatic ring radical is a 5-7 membered heterocycline; preferably, a 3-6 membered heterocycline having a ring carbon atom and 1-3 ring heteroatoms; preferably, a 4-6 membered heterocycline having a ring carbon atom and 1-3 ring heteroatoms; more preferably, a 5-6 membered heterocycline having a ring carbon atom and 1-3 ring heteroatoms; preferably, a 5 membered heterocycline having a ring carbon atom and 1-3 ring heteroatoms; preferably, a 6 membered heterocycline having a ring carbon atom and 1-3 ring heteroatoms.Heterocyclyls also include ring systems in which the above-described heterocyclyl is fused with one or more cycloalkyl groups, the bond site being on the heterocyclyl ring, or ring systems in which the above-described heterocyclyl is fused with one or more aryl or heteroaryl groups, the bond site being on the heterocyclyl ring, in which case the number of ring members represents the number of ring members in the heterocyclyl ring system. Heterocyclyls further include the above-described heterocyclyls in which substituents on any non-adjacent carbon or nitrogen atom bond to form a bridging ring, forming a polycyclic alkane that both share two or more carbon or nitrogen atoms. Heterocyclyls further include the above-described heterocyclyls in which substituents on the same carbon atom bond to form a ring, forming a polycyclic heteroalkane that both share one carbon atom. Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxyranyl, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinyl.Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of five-membered heterocyclyl groups fused with a C6 aryl ring (also referred herein as a 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused with a C6 aryl ring (also referred herein as a 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Heterocyclyls also include the aforementioned heterocyclyls that share one or two atoms with one cycloalkyl, heterocyclyl, aryl, or heteroaryl to form a bridging ring or spiro ring, where the shared atoms may be carbon or nitrogen atoms, to the extent permitted by their valence. The heterocyclil further includes the heterocyclil described above, which may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] "C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring radical having 6 to 10 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 shared π electrons in the cyclic arrangement). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl"). 10 The aryl group has an "aryl" (for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). The aryl group also includes a ring system in which the aforementioned aryl ring is condensed with one or more cycloalkyl or heterocyclyl groups, with the bond position located on the aryl ring, in which case the number of carbon atoms represents the number of carbon atoms in the aryl ring system. The aryl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] A "5-14 membered heteroaryl" refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring radical (for example, having 6, 10, or 14 shared π electrons in the cyclic arrangement) having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the bond position can be a carbon atom or a nitrogen atom, as long as the valence is within the acceptable range. A bicyclic heteroaryl system may contain one or more heteroatoms in one or two rings. Furthermore, heteroaryls also include ring systems in which the above-mentioned heteroaryl ring is condensed with one or more cycloalkyl or heterocyclyl groups, and the bond position is on the heteroaryl ring. In this case, the number of carbon atoms represents the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl groups, which are radicals of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, are used as substitutes. In other embodiments, 5-6 membered heteroaryl groups, which are radicals of a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, are used as further substitutes. Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and purinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolyl, isoquinolyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryls can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] "Hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups.

[0040] "Alkoxy" refers to the oxyether form of a linear or branched alkyl group, i.e., an -O-alkyl group. Similarly, "methoxy" refers to -O-CH3.

[0041] "Optionally substituted with..." means that the substituent may or may not be substituted with a specific substituent.

[0042] Divalent groups formed by removing another hydrogen from groups defined above, such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, are collectively called "ylenes." Ring-forming groups such as cycloalkyl, heterocyclyl, aryl, and heteroaryl are collectively called "cyclic groups."

[0043] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like as defined herein are optionally substituted groups.

[0044] Examples of substituents on carbon atoms include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa , -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR cc )2, -CO2R aa -OC(=O)R aa , -OCO2R aa -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -OC(=NR bb )R aa -OC(=NR bb )OR aa -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb)2, -SO2R aa , -SO2OR aa , -OSO2R aa -S(=O)R aa -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa , -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc Examples include, but are not limited to, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl compounds, each of which independently contains 0, 1, 2, 3, 4, or 5 R12s. dd Substituted with the base; Alternatively, two geminal hydrogen atoms on a carbon atom are =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 with the base; R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups bond to form a heterocyclyl ring or a heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R bb Each of these is independently hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc)2, selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb The groups bond to form a heterocyclyl ring or a heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups independently has 0, 1, 2, 3, 4, or 5 R groups. dd Replaced by; R cc Each of them is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups bond to form a heterocyclyl ring or a heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R dd These are, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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, selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by or two geminal R dd The substituents may bond to form =O or =S. R ee Each of these is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg Substituted with the base; Rff Each of them is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff The groups bond to form a heterocyclyl ring or a heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base; R gg Each of these is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 Alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6Alkyl)2,-NHC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3,-OSi(C 1-6 Alkyl)3,-C(=S)N(C 1-6 Alkyl)2, C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -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 alkynyl, C3-C7 cycloalkyl, C6-C 10 An aryl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, or two geminal Rs gg Substituents may bond to form =O or =S, X- It is a counterion.

[0045] Examples of substituents on a nitrogen atom include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are examples, but are not limited thereto, or two R bonded to a nitrogen atom cc The groups bond to form a heterocyclyl ring or a heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc , and R dd This is as stated above.

[0046] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules, and their heterozygous 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 may be further chemically modified, and the chemical modification group may be selected from one or a combination thereof from pseudouridine, N1-methyl-psoiduridine, 5-methoxyuridine, and 5-methylcytosine. mRNA molecules include a protein-coding region and may also include expression regulatory sequences. Typical expression regulatory sequences include, but are not limited to, the 5' cap, 5' untranslated region (5'UTR), 3' untranslated region (3'UTR), polyadenylate sequence (PolyA), and miRNA binding site.

[0047] "Cationic lipids" refer to lipid molecules that can acquire a positive charge at physiological pH. In some embodiments, cationic lipids are amino lipids.

[0048] "Neutral lipids" refer to lipid molecules that do not carry an electric charge at a specific pH, such as physiological pH. Examples of neutral lipids include 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POP C) Examples include, but are not limited to, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0049] "Structural lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, and generally include steroids. Steroids are compounds having a perhydrocyclopentanophenanthrene carbon skeleton. In alternative embodiments, the steroid is selected from cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, and campesterol.

[0050] A "polymer lipid" refers to a molecule containing both a polymer and a lipid portion. In some embodiments, the polymer lipid is polyethylene glycol (PEG) lipid. Other lipids that can reduce aggregation may be used, such as products of compounds having an uncharged, hydrophilic, sterically hindrance site bound to the lipid.

[0051] "Lipid nanoparticles" refer to particles containing lipid components on a nanoscale.

[0052] "Biodegradable group" refers to a functional group containing biodegradable bonds such as esters, disulfide bonds, and amides. Biodegradation can affect the process of removing compounds from the body. The biodegradable groups in this disclosure are oriented from head to tail in ionizable lipid molecules.

[0053] Other definitions As used herein, the term “to treat” relates to the disorder or condition to which the term applies, or to the reversal, reduction, suppression, or prevention of the progression of one or more symptoms of such disorder or condition. As used herein, the noun “treatment” relates to the verb “to treat,” which has the meaning defined immediately before it.

[0054] As used herein, the term “pharmaceutically acceptable salt” refers to carboxylate salts and amino acid addition salts of the compounds disclosed herein that are suitable for contact with patient tissue under reliable medical judgment and do not cause inappropriate toxicity, irritation, allergy, etc. They are commensurate with a reasonable benefit / risk ratio and are effective for the intended use. This term includes, where possible, the zwitterionic forms of the disclosed compounds.

[0055] pharmaceutically acceptable base addition salts are formed from metals or amines such as alkali metals and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0056] Base addition salts of acidic compounds can be prepared by conventional methods by contacting a free acid form with a desired base in sufficient quantities to form a salt. Free acids can be regenerated by contacting the salt form with the acid and then isolating the free acid by conventional methods. The free acid forms differ somewhat from their respective salt forms in terms of physical properties, such as solubility in polar solvents. However, for the purposes of this disclosure, these salts are equivalent to their respective free acids.

[0057] These salts can be prepared from inorganic acids, including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides. Examples of acids include 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, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalene, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate. These salts can also be prepared from organic acids, including aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. Typical salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberinate, sebacinate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthaleneate, besilate, tosilate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. Pharmaceutically acceptable salts include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium salts, quaternary ammonium salts, and amine cations (such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine). Salts of amino acids such as arginine salts, gluconates, and galacturonic acid salts are also included (see, for example, Berge SMet al., “Pharmaceutical Salts”, J.Pharm.Sci., 1977;66:1-19).

[0058] The "subjects" intended for administration include, but are not limited to, humans (e.g., males or females of all age groups, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, elderly adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus macaques, rhesus macaques, etc.), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. In this specification, the terms "human," "patient," and "subject" are used interchangeably.

[0059] In this specification, the terms "disease," "disorder," and "symptom" are used interchangeably.

[0060] Unless otherwise specified, the term “treatment” as used herein includes effects that reduce the severity of, or slow or inhibit the progression of, a particular disease, disorder, or condition in a subject suffering from such disease, disorder, or condition (“therapeutic treatment”). This term also includes effects that occur before the subject develops a particular disease, disorder, or condition (“preventive treatment”).

[0061] Generally, the “effective dose” of a pharmaceutical composition refers to an amount sufficient to elicit a target biological response. As those skilled in the art will understand, the effective dose of a pharmaceutical composition in this disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the dosage form, the age of the subject, their health status, and their symptoms. The effective dose includes the therapeutic effective dose and the prophylactic effective dose.

[0062] Unless otherwise specified, the “therapeutic dose” of a pharmaceutical composition as used herein means an amount sufficient to produce a therapeutic effect in the course of treating a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. The therapeutic dose of a pharmaceutical composition means the amount of the therapeutic agent that, when used alone or in combination with other therapies, produces a therapeutic effect in treating a disease, disorder, or condition. The term “therapeutic dose” includes amounts that improve overall treatment, reduce or avoid symptoms or causes of a disease or condition, or enhance the therapeutic effect of other therapeutic agents.

[0063] Unless otherwise specified, the “preventive effective dose” of a pharmaceutical composition as used herein means 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 the recurrence of a disease, disorder, or condition. The preventive effective dose of a pharmaceutical composition means the amount of a therapeutic agent that, when used alone or in combination with other agents, produces a preventive effect in preventing a disease, disorder, or condition. The term “preventive effective dose” includes amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0064] "Concomitant use" and related terms refer to the simultaneous or sequential administration of the pharmaceutical composition of this disclosure with other therapeutic agents. For example, the pharmaceutical composition of this disclosure may be administered in separate unit doses simultaneously or sequentially with other therapeutic agents, or in a single unit dose simultaneously with other therapeutic agents. [Modes for carrying out the invention]

[0065] In this specification, “compounds of the disclosure” means the following compounds, their pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers.

[0066] In this disclosure, compounds are named using standard nomenclature. For compounds with chiral centers, it should be understood that all optical isomers and mixtures thereof are included unless otherwise specified. Furthermore, unless otherwise specified, all isomer compounds and carbon-carbon double bonds included in this disclosure may exist in Z and E forms. For compounds with different tautomer forms, it is intended to encompass all tautomer forms, rather than being limited to any particular tautomer.

[0067] In one embodiment, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: [ka] During the ceremony, G1 and G2 are independently chemically bonded, C 1-13 Linear alkylene, C 2-13 Linear alkenylenes, and C 2-13 A selection of linear alkynylenes, each of which optionally contains one or more R G1 Replaced by; G1 and G2 have a total length with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R G1 H and C are independent of each other. 1-14 Alkyl, -L a -OR a , -L a -SR a , or -L a -NR a R' a and; G3 is C 4-14 Linear alkylene, C 4-14 Linear alkenylene, or C 4-14 It is a linear alkynylene, each of which optionally contains one or more R G3 Replaced by; R G3 These are independently H and -L a -OR a , -L a -SRa , or -L a -NR a R' a and; L a These are, independently, chemical bonds or C 1-14 It is alkylene; R a and R' a H and C are independent of each other. 1-14 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; G4 is a chemical bond, C 1-6 Alkilen, C 2-6 Alkenylene, or C 2-6 It is an alkynylene, and each of them can be optionally given one or more R G4 Replaced by; R G4 H and C are independent of each other. 1-6 Alkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; L b These are, independently, chemical bonds or C 1-6 It is alkylene; R b and R' b H and C are independent of each other. 1-6 Alkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines; Alternatively, two R atoms bonded to the same carbon atom. G4 Along with the carbon atoms to which they are bonded, C 3-14 They form cycloalkylenes or 3-14 member heterocyclenes, each of which optionally contains one or more R 4g Replaced by; R 4g These are independently H, halogen, cyano, and C. 1-8 Alkyl, C 1-8 Haloalkyl, -L e -OR e , -Le -SR e , or -L e -NR e R' e and; L e These are, independently, chemical bonds or C 1-8 It is alkylene; R e and R' e H and C are independent of each other. 1-8 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; M1 and M2 are independently -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 - Selected from; Q represents 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 - is selected from phenylene and pyridinylene, and phenylene or pyridinylene is optionally substituted with one or more R*; R* is independently H, halogen, cyano, C 1-10 Alkyl, C 1-10 Haloalkyl, -Lf -OR f , -L f -SR f , or -L f -NR f R' f and; L f These are, independently, chemical bonds or C 1-8 It is alkylene; R f and R' f H and C are independent of each other. 1-10 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; R1 and R2 are independent of C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Selected from alkinyl, each of which optionally contains one or more R 1s Substituted by -NR'-, and one or more methylene units are optionally and independently replaced by -NR'-; R 1s H and C are independent of each other. 1-20 Alkyl, -L c -OR c , -L c -SR c , or -L c -NR c R' c and; R and R' are independently H or C 1-20 It is alkyl; L c These are, independently, chemical bonds or C 1-20 It is alkylene; R c and R' c H and C are independent of each other. 1-20 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; R3 is 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 Selected from 3- to 14-membered heterocyclyls and 5- to 14-membered heteroaryls; R g and R' g H and C are independent of each other. 1-10 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; R'' is independently H or C 1-6 It is alkyl; R4 and R5 are independent of C 1-8 It is an alkyl group, and it optionally contains one or more R groups. 4s Replaced by; Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, are C 3-14 They form cycloalkylenes or 3-14 member heterocyclenes, each of which optionally contains one or more R 4s Replaced by; R 4s These are independently H, halogen, cyano, and C. 1-8 Alkyl, C 1-8 Haloalkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d and; L d These are, independently, chemical bonds or C 1-8 It is alkylene; R d and R' d H and C are independent of each other. 1-8 Alkyl, C 3-14 They are cycloalkyl or 3- to 14-membered heterocyclines.

[0068] In other embodiments, the disclosure relates to a compound of formula (I) having the structure of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: [ka] During the ceremony, 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; Other groups are as defined herein.

[0069] G1 and G2 In one embodiment, G1 is a chemical bond; in another embodiment, G1 is C 1-13 Linear alkylene, or C 1-9 Linear alkylene, or C 1-6 Linear alkylene, or C 2-6 It is a linear alkylene; in other embodiments, G1 is C 2-13 Linear alkenylenes, or C 2-9 Linear alkenylenes, or C 2-6 It is a linear alkenylene; in other embodiments, G1 is C 2-13 Linear alkynylene, or C 2-9 Linear alkynylene, or C 2-6 It is a linear alkynylene; in other embodiments, G1 is optionally one or more R G1 Replaced by; in other embodiments, G1 is optionally 1, 2, 3, or 4 R G1In other embodiments, G1 is replaced; however, G1 is not replaced.

[0070] In a more specific embodiment, G1 is a chemical bond, C 1-9 Linear alkylene, C 2-9 Linear alkenylene, or C 2-9 It is a linear alkynylene; in other more specific embodiments, G1 is C 1-6 Linear alkylene, C 2-6 Linear alkenylene, or C 2-6 It is a linear alkynylene; in other more specific embodiments, G1 is C 1-6 It is a linear alkylene; in other more specific embodiments, G1 is C 2-6 It is a linear alkylene.

[0071] In one embodiment, G2 is a chemical bond, and in another embodiment, G2 is C 1-13 Linear alkylene, or C 1-9 Linear alkylene, or C 1-6 Linear alkylene, or C 1-4 It is a linear alkylene; in other embodiments, G2 is C 2-13 Linear alkenylenes, or C 2-9 Linear alkenylenes, or C 2-6 It is a linear alkenylene; in other embodiments, G2 is C 2-13 Linear alkynylene, or C 2-9 Linear alkynylene, or C 2-6 It is a linear alkynylene; in other embodiments, G2 is optionally one or more R G1 Replaced by; in other embodiments, G2 is optionally 1, 2, 3, or 4 R G1 In other embodiments, G2 is replaced; however, G2 is not replaced.

[0072] In a more specific embodiment, G2 is a chemical bond, C 1-9 Linear alkylene, C 2-9 Linear alkenylene, or C 2-9It is a linear alkynylene; in other more specific embodiments, G2 is a chemical bond, C 1-6 Linear alkylene, C 2-6 Linear alkenylene, or C 2-6 It is a linear alkynylene; in other more specific embodiments, G2 is a chemical bond or C 1-6 It is a linear alkylene; in other more specific embodiments, G2 is a chemical bond or C 1-4 It is a linear alkylene.

[0073] In one embodiment, G1 and G2 have a total length of 3 carbon atoms; in another embodiment, G1 and G2 have a total length of 4 carbon atoms; in another embodiment, G1 and G2 have a total length of 5 carbon atoms; in another embodiment, G1 and G2 have a total length of 6 carbon atoms; in another embodiment, G1 and G2 have a total length of 7 carbon atoms; in another embodiment, G1 and G2 have a total length of 8 carbon atoms; in another embodiment, G1 and G2 have a total length of 9 carbon atoms; in another embodiment, G1 and G2 have a total length of 10 carbon atoms; in another embodiment, G1 and G2 have a total length of 11 carbon atoms; in another embodiment, G1 and G2 have a total length of 12 carbon atoms; in another embodiment, G1 and G2 have a total length of 13 carbon atoms.

[0074] In a more specific embodiment, G1 and G2 have a total length of 3, 4, 5, 6, 7, 8, or 9 carbon atoms; in another more specific embodiment, G1 and G2 have a total length of 4, 5, or 6 carbon atoms; in another more specific embodiment, G1 and G2 have a total length of 5 or 6 carbon atoms; in another more specific embodiment, G1 and G2 have a total length of 5, 6, or 7 carbon atoms; in yet another more specific embodiment, G1 and G2 have a total length of 6 or 7 carbon atoms.

[0075] R G1 In one embodiment, R G1 H is; in other embodiments, RG1 C 1-14 Alkyl, or C 1-10 Alkyl, or C 1-6 It is alkyl; in other embodiments, R G1 is, -L a -OR a In other embodiments, R G1 is, -L a -SR a In other embodiments, R G1 is, -L a -NR a R' a That is the case.

[0076] In a more specific embodiment, R G1 H or C 1-10 It is alkyl; in other more specific embodiments, R G1 H or C 1-6 It is alkyl.

[0077] G3 In one embodiment, G3 is C 4-14 Linear alkylene, or C 4-10 Linear alkylene, or C 4-9 Linear alkylene, or C 5-8 It is a linear alkylene; in other embodiments, G3 is C 4-14 It is a linear alkenylene; in other embodiments, G3 is C 4-14 It is a linear alkynylene; in other embodiments, G3 is optionally one or more R G3 Replaced by; in other embodiments, G3 is optionally 1, 2, 3, or 4 R G3 In other embodiments, G3 is replaced; in other embodiments, G3 is not replaced.

[0078] In a more specific embodiment, G3 is C 4-10 Linear alkylene, C 4-10 Linear alkenylene, or C 4-10 It is a linear alkynylene; in other more specific embodiments, G3 is C 4-9It is a linear alkylene; in other more specific embodiments, G3 is C 5-8 It is a linear alkylene.

[0079] R G3 In one embodiment, R G3 H is; in other embodiments, R G3 is, -L a -OR a In other embodiments, R G3 is, -L a -SR a In other embodiments, R G3 is, -L a -NR a R' a That is the case.

[0080] L a , R a , and R' a In one embodiment, L a L is a chemical bond, and in other embodiments, L a C 1-14 Alkylene, or C 1-10 Alkylene, or C 1-6 It is alkylene.

[0081] In a more specific embodiment, L a These are, independently, chemical bonds or C 1-10 It is alkylene; in other more specific embodiments, L a is a chemical bond or C 1-6 It is alkylene.

[0082] In one embodiment, R a H is; in other embodiments, R a C 1-14 Alkyl, or C 1-10 Alkyl, or C 1-6 It is alkyl; in other embodiments, R a C 3-14 Cycloalkyl, or C 3-10It is cycloalkyl; in other embodiments, R a These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0083] In one embodiment, R' a H is; in other embodiments, R' a C 1-14 Alkyl, or C 1-10 Alkyl, or C 1-6 It is alkyl; in other embodiments, R' a C 3-14 Cycloalkyl, or C 3-10 It is cycloalkyl; in other embodiments, R' a These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0084] In a more specific embodiment, R a and R' a H and C are independent of each other. 1-10 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; in other more specific embodiments, R a and R' a H or C 1-6 It is alkyl.

[0085] G4 In one embodiment, G4 is a chemical bond; in another embodiment, G4 is C 1-6 Alkylene, or C 1-4 Alkylene, or C 2-4 Alkylene, or C 2-3 It is an alkylene; in other embodiments, G4 is C 2-6 It is an alkenylene; in other embodiments, G4 is C 2-6 It is an alkynylene; in other embodiments, G4 is optionally one or more R G4 In other embodiments, G4 is optionally replaced by 1, 2, 3, or 4 R G4 In other embodiments, G4 is replaced; however, G4 is not replaced.

[0086] In a more specific embodiment, G4 is C 1-4 Alkilen, C 2-4 Alkenylene, or C 2-4 It is an alkynylene; in other more specific embodiments, G4 is C 2-4 It is an alkylene; in other more specific embodiments, G4 is C 2-3 It is alkylene.

[0087] R G4 In one embodiment, R G4 H is; in other embodiments, R G4 C 1-6 Alkyl, or C 1-4 It is alkyl; in other embodiments, R G4 is, -L b -OR b In other embodiments, R G4 is, -L b -SR b In other embodiments, R G4 is, -L b -NR b R' b That is the case.

[0088] In a more specific embodiment, R G4 H or C 1-6 It is alkyl.

[0089] In one embodiment, two R atoms bonded to the same carbon atom G4 C 3-14 Cycloalkylene, or C 3-10 Cycloalkylene, or C 3-7 Forming a cycloalkylene; in another embodiment, two R atoms bonded to the same carbon atom G4 These, together with the carbon atoms to which they are bonded, form 3-14 membered heterocyclenes, or 3-10 membered heterocyclenes, or 3-7 membered heterocyclenes; in other embodiments, two R G4The ring formed by these atoms together with the carbon atoms to which they are bonded may optionally contain one or more R atoms. 4g Replaced by; in other embodiments, two R G4 The ring formed by these atoms together with the carbon atoms to which they are bonded can optionally consist of 1, 2, or 3 R atoms. 4g Replaced by; in other embodiments, two R G4 Furthermore, the ring formed by these atoms together with the carbon atoms to which they are bonded is not substituted.

[0090] In a more specific embodiment, two R atoms bonded to the same carbon atom G4 Along with the carbon atoms to which they are bonded, C 3-10 Forming cycloalkylene or 3-10 membered heterocyclene; in other more specific embodiments, two R bonded to the same carbon atom G4 Along with the carbon atoms to which they are bonded, C 3-7 It forms cycloalkylenes or 3- to 7-membered heterocyclenes.

[0091] L b , R b , and R' b In one embodiment, L b L is a chemical bond, and in other embodiments, L b C 1-6 Alkylene, or C 1-4 It is alkylene.

[0092] In a more specific embodiment, L b These are, independently, chemical bonds or C 1-4 It is alkylene.

[0093] In one embodiment, R b H is; in other embodiments, R b C 1-6 Alkyl, or C 1-4 It is alkyl; in other embodiments, R b C 3-10 Cycloalkyl, or C 3-7It is cycloalkyl; in other embodiments, R b These are heterocyclines with 3 to 10 members, or heterocyclines with 3 to 7 members.

[0094] In one embodiment, R' b H is, in other embodiments, R' b C 1-6 Alkyl, or C 1-4 It is alkyl; in other embodiments, R' b C 3-10 Cycloalkyl, or C 3-7 It is cycloalkyl; in other embodiments, R' b These are heterocyclines with 3 to 10 members, or heterocyclines with 3 to 7 members.

[0095] In a more specific embodiment, R b and R' b H and C are independent of each other. 1-6 Alkyl, C 3-7 It is a cycloalkyl or a 3- to 7-membered heterocycline; in other more specific embodiments, R b and R' b H or C 1-6 It is alkyl; in other more specific embodiments, R b and R' b H or C 1-4 It is alkyl.

[0096] R 4g In one embodiment, R 4g H is; in other embodiments, R 4g is a halogen; in other embodiments, R 4g is cyano; in other embodiments, R 4g C 1-8 Alkyl, or C 1-6 It is alkyl; in other embodiments, R 4g C 1-8 Haloalkyl, or C 1-6 It is a haloalkyl; in other embodiments, R 4gis, -L e -OR e In other embodiments, R 4g is, -L e -SR e In other embodiments, R 4g is, -L e -NR e R' e That is the case.

[0097] In a more specific embodiment, R 4g These are independently H, halogen, cyano, and C. 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0098] L e , R e , and R' e In one embodiment, L e L is a chemical bond, and in other embodiments, L e C 1-8 Alkylene, or C 1-6 Alkylene, or C 1-4 It is alkylene.

[0099] In a more specific embodiment, L e These are, independently, chemical bonds or C 1-6 It is alkylene; in other more specific embodiments, L a is a chemical bond or C 1-4 It is alkylene.

[0100] In one embodiment, R e H is; in other embodiments, R e C 1-8 Alkyl, or C 1-6 Alkylene, or C 1-4 It is an alkylene; in other embodiments, R e C 3-14 Cycloalkyl, or C 3-10 It is cycloalkyl; in other embodiments, R eThese are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0101] In one embodiment, R' e In other embodiments, R' e C 1-8 Alkyl, or C 1-6 Alkylene, or C 1-4 It is an alkylene; in other embodiments, R' e C 3-14 Cycloalkyl, or C 3-10 It is cycloalkyl; in other embodiments, R' e These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0102] In a more specific embodiment, R e and R' e H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; in other more specific embodiments, R e and R' e H or C 1-4 It is alkyl.

[0103] M1 and M2 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 other embodiments, M1 is -C(O)NR-, e.g., -C(O)NH-; in other embodiments, M1 is -NRC(O)-, e.g., -NHC(O)-; in other embodiments, M1 is -NRC(O)S-; in other embodiments, M1 is -SC(O)NR-; in other embodiments, M1 is -C(O)-; in other embodiments, M1 is -OC(S)-; in other embodiments, M1 is -C(S)O-; in other embodiments, M1 is -OC(S)NR-; in other embodiments, M1 is -NRC(S)O-; in other embodiments, M1 is -SS-; in other embodiments, M1 is -S(O) 0-2 -, for example, -S-, -S(O)-, and -S(O)2-.

[0104] 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 other embodiments, M2 is -NR-; in other embodiments, M2 is -C(O)NR-; in other embodiments, M2 is -NRC(O)-; in other embodiments, M2 is -NRC(O)S-; in other embodiments, M2 is -SC(O)NR-; in other embodiments, M2 is -C(O)-; in other embodiments, M2 is -OC(S)-; in other embodiments, M2 is -C(S)O-; in other embodiments, M2 is -OC(S)NR-; in other embodiments, M2 is -NRC(S)O-; in other embodiments, M2 is -SS-; in other embodiments, M2 is -S(O) 0-2 -, for example, -S-, -S(O)-, and -S(O)2-.

[0105] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in yet 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)-.

[0106] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -C(O)S-; in another more specific embodiment, M1 and M2 are -C(O)O-.

[0107] In a more specific embodiment, one of M1 and M2 is -C(O)O- or -C(O)S- and the other is -OC(O)- or -SC(O)-; in another more specific embodiment, one of M1 and M2 is -C(O)O- and the other is -OC(O)-.

[0108] In a more specific embodiment, M1 is -OC(O)- or -SC(O)-; in another more specific embodiment, M1 is -OC(O)-; in yet another more specific embodiment, M2 is -C(O)O- or -C(O)S-; and in yet another more specific embodiment, M2 is -C(O)O-.

[0109] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, and -C(O)NH-; in 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 In one embodiment, one of M1 and M2 is -C(O)O- or -C(O)S-, or -C(O)O-, and the other is -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)-, or -SC(O)-, or -C(O)O-, -C(O)S-, -C(O)NH-, or -OC(O)-, or -C(O)O-, -C(O)S-, -OC(O)-, or -SC(O)-, or -C(O)O-, -C(O)S-, or -OC(O)-; in other more specific embodiments, M One of 1 and M2 is -OC(O)O-, and the other is -C(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-, or -C(O)O- or -OC(O)-; in other more specific embodiments, M1 is -C(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-, or -C(O)O- or -OC(O)-, or -C(O)O-, or -OC(O)-, and M2 is -OC(O)O-; in other more specific embodiments, M1 is -O C(O)O-, and M2 is -OC(O)- or -C(O)O-, or -OC(O)-; in other more specific embodiments, M1 and M2 are independently -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, or -OC(O)O-; in other more specific embodiments, M1 and M2 are independently -C(O)O-, -OC(O)-, or -OC(O)O-; in other more specific embodiments, M1 and M2 are not simultaneously -OC(O)O-.

[0110] Q In one embodiment, Q is a chemical bond; in another more specific embodiment, Q is -C(O)O-; in yet another more specific embodiment, Q is -O-; in yet another more specific embodiment, Q is -SC(O)O-; in yet another more specific embodiment, Q is -OC(O)NR f -and; in other more specific embodiments, Q is -NR f C(O)NR f -and; in other more specific embodiments, Q is -OC(O)S-; in other more specific embodiments, Q is -OC(O)O-; and in other specific embodiments, Q is -NR f Q is C(O)O-; in other more specific embodiments, Q is -OC(O)-; in other more specific embodiments, Q is -SC(O)-; in other more specific embodiments, Q is -C(O)S-; in other more specific embodiments, Q is -NR f -and; in other more specific embodiments, Q is -C(O)NR f -and; in other more specific embodiments, Q is -NR f C(O)-; in other more specific embodiments, Q is -NR f C(O)S-; in other, more specific embodiments, Q is -SC(O)NR f -and; in other more specific embodiments, Q is -C(O)-; in other more specific embodiments, Q is -OC(S)-; in other more specific embodiments, Q is -C(S)O-; in other more specific embodiments, Q is -OC(S)NR f -and; in other more specific embodiments, Q is -NR f In other more specific embodiments, Q is C(S)O-; in other more specific embodiments, Q is -SS-; in other more specific embodiments, Q is -S(O) 0-2-and; in other more specific embodiments, Q is phenylene; in other more specific embodiments, Q is pyridinylene; in other more specific embodiments, if Q is phenylene, Q is optionally substituted with one or more R* or optionally substituted with one, two or three R*; in other more specific embodiments, Q is unsubstituted phenylene; in other more specific embodiments, if Q is pyridinylene, Q is optionally substituted with one or more R* or optionally substituted with one, two or three R*; in other more specific embodiments, Q is unsubstituted pyridinylene.

[0111] In other more specific embodiments, Q is a chemical bond, -OC(O)-, or -SC(O)-; in other more specific embodiments, Q is a chemical bond or -SC(O)-; and in other more specific embodiments, Q is phenylene or pyridinylene, which is optionally substituted with 1, 2, or 3 R*.

[0112] R* In one embodiment, R* is H; in another more specific embodiment, Q is halogen; in yet another more specific embodiment, R* is cyano; in yet another more specific embodiment, R* is C 1-10 Alkyl, or C 1-6 It is alkyl; in other more specific embodiments, R* is C 1-10 Haloalkyl, or C 1-6 It is a haloalkyl; in other more specific embodiments, R* is -L f -OR f And; in other more specific embodiments, R* is -L f -SR f And; in other more specific embodiments, R* is -L f -NR f R' f That is the case.

[0113] In a more specific embodiment, R* is independently H, halogen, cyano, C1-6 is alkyl or C 1-6 haloalkyl.

[0114] L f , R f , and R’ f In one embodiment, L f is a chemical bond; in other embodiments, L f is C 1-8 alkylene, or C 1-6 alkylene, or C 1-4 alkylene.

[0115] In more specific embodiments, L f is independently a chemical bond or C 1-6 alkylene; in other more specific embodiments, L f is independently a chemical bond or C 1-4 alkylene.

[0116] In one embodiment, R f is H; in other embodiments, R f is C 1-10 alkyl, or C 1-6 alkyl, or C 1-4 alkyl; in other embodiments, R f is C 3-14 cycloalkyl, or C 3-10 cycloalkyl; in other embodiments, R f is 3- to 14-membered heterocyclyl, or 3- to 10-membered heterocyclyl. [[ID=6Q]]

[0117] In one embodiment, R’ f is H; in other embodiments, R’ f is C 1-10 alkyl, or C 1-6 alkyl, or C 1-4 alkyl; in other embodiments, R’ f is C 3-14 cycloalkyl, or C 3-10 cycloalkyl; in other embodiments, R’f These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0118] In a more specific embodiment, R f and R' f H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; in other more specific embodiments, R f and R' f H or C 1-6 It is alkyl; in other more specific embodiments, R f and R' f H or C 1-4 It is alkyl.

[0119] R1 and R2 In one embodiment, R1 is C 4-20 Alkyl, or C 6-14 Alkyl, or C 7-12 Alkyl, or C 8-12 Alkyl, or C 8-11 Alkyl, or C 9-11 Alkyl, or C 8-10 Alkyl, or C 9-10 Alkyl, or C 8-9 Alkyl, or C9 alkyl, or C 8-12 Linear alkyl, or C 7-11 Linear alkyl, or C 8-11 Linear alkyl, or C 9-11 Linear alkyl, or C 10-11 Linear alkyl, or C 8-10 Linear alkyl, or C 9-10 Linear alkyl, or C 8-9 Linear alkyl, or C 11 Linear alkyl, or C 10 It is a linear alkyl or a C9 linear alkyl; in other embodiments, R1 is C 4-20 Alkenil, or C 6-14 Alkenil, or C 7-12 Alkenil; or C 8-12It is an alkenyl; in other embodiments, R1 is C 4-20 Alkinyl, or C 6-14 Alkinyl, or C 7-12 Alkinyl, or C 8-12 It is an alkynyl; in other embodiments, R1 is optionally one or more R 1s Replaced by; in other embodiments, R1 is optionally 1, 2, 3, or 4 R 1s Replaced by, or optionally, one R 1s In other embodiments, R1 is not replaced; in other embodiments, one or more methylene units in R1 are independently and optionally replaced with -NR'-, or R1 is independently and optionally replaced with -NR'-; in other embodiments, R1 is optionally replaced with one C 1-9 Alkyl (or C 6-9 Alkyl, or C 6-7 It is replaced with alkyl.

[0120] In one embodiment, R1 is -(CH2)5CH3; in another embodiment, R1 is -(CH2)6CH3; in another embodiment, R1 is -(CH2)7CH3; in another embodiment, R1 is -(CH2)8CH3; in another embodiment, R1 is -(CH2)9CH3; in another embodiment, R1 is -(CH2) 10 CH3 is; in other embodiments, R1 is -(CH2) 11In other embodiments, R1 is CH3; in other embodiments, R1 is -CH2-C≡C-(CH2)5CH3; in other embodiments, R1 is -CH2-C≡C-(CH2)6CH3; in other embodiments, R1 is -(CH2)2-C≡C-(CH2)5CH3; in other embodiments, R1 is -(CH2)4-C≡C-(CH2)3CH3; in other embodiments, R1 is -CH2-CH=CH-(CH2)5CH3; in other embodiments, R1 is -CH2-CH=CH-(CH2)6CH3; in other embodiments, R1 is -(CH2)2-CH=CH-(CH2)5CH3; in other embodiments, R1 is -(CH2)4-CH=CH-(CH2)3CH3; in other embodiments, R1 is -(CH2)5-CH=CH-CH2CH3; in other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] That is the case.

[0121] 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 [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [ka] In other embodiments, R1 is [Chemical formula] and; in other embodiments, R1 is [Chemical formula] and; in other embodiments, R1 is [Chemical formula] and; in other embodiments, R1 is [Chemical formula] and; in other embodiments, R1 is [Chemical formula] is.

[0122] In one embodiment, R2 is C 4-20 alkyl, or C 6-14 alkyl, or C 7-12 alkyl, or C 8-12 alkyl, or C 9-12 alkyl, or C 8-11 alkyl, or C 9-11 alkyl, or C 8-10 alkyl, or C <000878>alkyl, or C 10 alkyl, or C9 alkyl, or C 8-12 linear alkyl, or C 7-11 linear alkyl, or C 8-11 [[ID=​​​​​​​​​​​​​​​​8-12 It is an alkenyl; in other embodiments, R2 is C 4-20 Alkinyl, or C 6-14 Alkinyl, or C 7-12 Alkinyl, or C 8-12 It is an alkynyl; in other embodiments, R2 is optionally one or more R 1s Replaced by; in other embodiments, R2 is optionally 1, 2, 3, or 4 R 1s Replaced by, or optionally, one R 1s Replaced by, or optionally, one C 1-3 R2 is substituted with an alkyl group, or optionally substituted with a single methyl group; in other embodiments, R2 is unsubstituted; in other embodiments, one or more methylene units in R2 are optionally and independently replaced with -NR'-, or one methylene unit in R2 is optionally replaced with -NR'-.

[0123] In one embodiment, only one of R1 and R2 is replaced; in another embodiment, R1 is R 1s It is replaced by R2, 1s Not replaced by; in other embodiments, R2 is R 1s It is replaced by R1, 1s Not replaced by; In one embodiment, R2 is -(CH2)5CH3; in another embodiment, R2 is -(CH2)6CH3; in another embodiment, R2 is -(CH2)7CH3; in another embodiment, R2 is -(CH2)8CH3; in another embodiment, R2 is -(CH2)9CH3; in another embodiment, R2 is -(CH2) 10 CH3 is; in other embodiments, R2 is -(CH2) 11In other embodiments, R2 is CH3; in other embodiments, R2 is -CH2-C≡C-(CH2)5CH3; in other embodiments, R2 is -CH2-C≡C-(CH2)6CH3; in other embodiments, R2 is -(CH2)2-C≡C-(CH2)5CH3; in other embodiments, R2 is -(CH2)4-C≡C-(CH2)3CH3; in other embodiments, R2 is -CH2-CH=CH-(CH2)5CH3; in other embodiments, R2 is -CH2-CH=CH-(CH2)6CH3; in other embodiments, R2 is -(CH2)2-CH=CH-(CH2)5CH3; in other embodiments, R2 is -(CH2)4-CH=CH-(CH2)3CH3; in other embodiments, R2 is -(CH2)5-CH=CH-CH2CH3; in other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] That is the case.

[0124] 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 [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] In other embodiments, R2 is [ka] That is the case.

[0125] In a more specific embodiment, R1 and R2 are independently C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 Selected from alkynyl; in other more specific embodiments, R1 and R2 are independently C 7-12 Alkyl, C 7-12 Alkenyl and C 7-12 Selected from alkynyl; in other more specific embodiments, R1 and R2 are independently C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Selected from alkynyl; in other more specific embodiments, R1 and R2 are independently -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11CH3, -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, [ka] It is selected based on the following criteria.

[0126] In a more specific embodiment, R1 and R2 are independently C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-11 Alkyl, or C 9-10 Selected from alkyl groups, which optionally contain one R 1s It is replaced by; and only one of R1 or R2 is replaced.

[0127] In a more specific embodiment, R1 and R2 are independently -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, [ka] Selected from; in other more specific embodiments, R1 and R2 are independently -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, [ka] Selected from; in other more specific embodiments, R1 and R2 are independently -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2)11 CH3, [ka] Selected from.

[0128] In a more specific embodiment, R1 and R2 are independently -(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, [ka] Selected from; in other more specific embodiments, R1 and R2 are independently -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH 3、 -(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, [ka] Selected from; in other more specific embodiments, R1 and R2 are independently -(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, [ka] Selected from.

[0129] In a more specific embodiment, R1 and R2 are independently -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, [ka] Selected from; in other more specific embodiments, R1 and R2 are independently -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, [ka] Selected from.

[0130] In a more specific embodiment, R1 is [ka] Selected from; in other more specific embodiments, R1 is [ka] Selected from.

[0131] In a more specific embodiment, R1 is [ka] Selected from; in other more specific embodiments, R1 is [ka] Selected from; in other more specific embodiments, R1 is -(CH2)8CH3, -(CH2)9CH3, [ka] Selected from; in other more specific embodiments, R1 is [ka] Selected from; in other more specific embodiments, R1 is [ka] Selected from.

[0132] In a more specific embodiment, R2 is -(CH2)9CH3, -(CH2) 10 CH3, and [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from.

[0133] In a more specific embodiment, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from; in other more specific embodiments, R2 is [ka] Selected from.

[0134] R 1s In one embodiment, R 1s H is; in other embodiments, R 1s H is; in other embodiments, R 1s C 1-20 Alkyl, or C 1-14 Alkyl, or C 1-10 Alkyl, or C 1-9 Alkyl, or C 7-9 Alkyl, or C 8-9 Alkyl, or C1-6 Alkyl, or C 1-4 Alkyl, or C 7-11 Alkyl, or C 4-10 Alkyl, or C 6-10 Alkyl, or C 7-10 Alkyl, or C 9-10 Alkyl, or C 4-9 Alkyl, or C 6-9 Alkyl, or C 1-8 Alkyl, or C 4-8 Alkyl, or C 6-8 Alkyl, or C 7-8 Alkyl, or C 6-7 Alkyl, or C9 alkyl, or C8 alkyl, or C7 alkyl; in other embodiments, R 1s is, -L c -OR c In other embodiments, R 1s is, -L C -SR C In other embodiments, R 1s is, -L c -NR c R' c That is the case.

[0135] In one embodiment, R on R1 1s The substitution site is separated from M1 by 0 carbon atoms; in other embodiments, R on R1 1s The substitution site is separated from M1 by one carbon atom; in other embodiments, R on R1 1s The substitution site is located two carbon atoms away from M1; in other embodiments, R on R1 1s The substitution site is located three carbon atoms away from M1; in other embodiments, R on R1 1s The substitution site is located four carbon atoms away from M1; in other embodiments, R on R1 1s The substitution site is located five carbon atoms away from M1; in other embodiments, R on R1 1s The substitution site is located six carbon atoms away from M1; in other embodiments, R on R1 1sThe substitution site is located seven carbon atoms away from M1; in other embodiments, R on R1 1s The substitution site is located eight carbon atoms away from M1; in other embodiments, R on R1 1s The substitution site is located 9 carbon atoms away from M1; in other embodiments, R on R1 1s The substitution site is located 10 carbon atoms away from M1.

[0136] In one embodiment, R on R2 1s The substitution position is separated from M2 by 0 carbon atoms; in other embodiments, R on R2 1s The substitution site is separated from M2 by one carbon atom; in other embodiments, R on R2 1s The substitution site is located two carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located three carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located four carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located five carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located six carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located seven carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located eight carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located 9 carbon atoms away from M2; in other embodiments, R on R2 1s The substitution site is located 10 carbon atoms away from M2.

[0137] In a more specific embodiment, R 1s H and C are independent of each other. 1-14 Alkyl, -L c -OR c , or -L c -NR c R'c And; in other more specific embodiments, R 1s H or C 1-14 It is alkyl; in other more specific embodiments, R 1s H or C 1-10 It is alkyl; in other more specific embodiments, R 1s H or C 1-9 It is alkyl; in other more specific embodiments, R 1s H or C 1-6 It is alkyl; in other more specific embodiments, R 1s H or C 1-4 It is alkyl.

[0138] In a more specific embodiment, R on R1 or R2 1s The substitution position is separated from M1 or M2 by 0 to 10 carbon atoms; in other more specific embodiments, R on R1 or R2 1s The substitution position is separated from M1 or M2 by 0 to 6 carbon atoms; in other more specific embodiments, R on R1 or R2 1s The substitution position is separated from M1 or M2 by 0 to 4 carbon atoms; in other more specific embodiments, R on R1 or R2 1s The substitution position is separated from M1 or M2 by 0 to 2 carbon atoms; in other more specific embodiments, R on R1 or R2 1s The substitution site is separated from M1 or M2 by zero carbon atoms.

[0139] In a more specific embodiment, R on R1 or R2 1s The substitution site is separated from M1 or M2 by 1 to 10 carbon atoms; in other more specific embodiments, R on R1 or R2 1s The substitution position is separated by 1 to 6 carbon atoms from M1 or M2; in other more specific embodiments, R on R1 or R2 1s The substitution site is separated by 1 to 4 carbon atoms from M1 or M2; in other more specific embodiments, R on R1 or R21s The substitution position is separated by 1-2 carbon atoms from M1 or M2; in other more specific embodiments, R on R1 or R2 1s The substitution site is separated from M1 or M2 by 2 to 10 carbon atoms; in other more specific embodiments, R on R1 or R2 1s The substitution site is separated by 2 to 6 carbon atoms from M1 or M2; in other more specific embodiments, R on R1 or R2 1s The substitution site is located 2 to 4 carbon atoms away from M1 or M2.

[0140] In other, more specific embodiments, R1 is R 1s It is not replaced by R on R2. 1s The substitution site is separated from M2 by 0 to 10 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 2 carbon atoms; in other more specific embodiments, R1 is R 1s It is not replaced by R on R2. 1s The substitution site is separated from M2 by 0 to 10 carbon atoms, or 0 to 6 carbon atoms, or 0 to 4 carbon atoms, or 0 to 2 carbon atoms; or 0 carbon atoms; in other more specific embodiments, R1 is R 1s It is not replaced by R on R2. 1s The substitution site is located 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms away from M2.

[0141] R and R' In one embodiment, R is H; in another embodiment, R is C 1-20 Alkyl, or C 1-14 Alkyl, or C 1-9 Alkyl, or C 1-6 It is alkyl.

[0142] In one embodiment, R' is H; in another embodiment, R' is C 1-20 Alkyl, or C 1-14 Alkyl, or C 1-9Alkyl, or C 1-6 It is alkyl.

[0143] In a more specific embodiment, R and R' are independently H or C 1-20 It is alkyl; in other more specific embodiments, R and R' are each independently H or C 1-14 It is alkyl; in other more specific embodiments, R and R' are each independently H or C 1-9 It is alkyl; in other more specific embodiments, R and R' are each independently H or C 1-6 It is alkyl; in other more specific embodiments, R is H.

[0144] L c , R c , and R' c In one embodiment, L c is a chemical bond; in other embodiments, L is C 1-20 Alkylene, or C 1-14 Alkylene, or C 1-10 Alkylene, or C 1-6 It is alkylene.

[0145] In a more specific embodiment, L c These are, independently, chemical bonds or C 1-14 It is alkylene; in other more specific embodiments, L c These are, independently, chemical bonds or C 1-10 It is alkylene; in other more specific embodiments, L c These are, independently, chemical bonds or C 1-6 It is alkylene.

[0146] In one embodiment, R c H is; in other embodiments, R c C 1-20 Alkyl, or C 1-14 Alkyl, or C 1-10 Alkyl, or C 1-6 It is alkyl; in other embodiments, Rc C 3-14 Cycloalkyl, or C 3-10 It is cycloalkyl; in other embodiments, R c These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0147] In one embodiment, R' c H is; in other embodiments, R' c C 1-20 Alkyl, or C 1-14 Alkyl, or C 1-10 Alkyl, or C 1-6 It is alkyl; in other embodiments, R' c C 3-14 Cycloalkyl, or C 3-10 It is cycloalkyl; in other embodiments, R' c These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0148] In a more specific embodiment, R c and R' c H or C 1-14 It is alkyl; in other more specific embodiments, R c and R' c H or C 1-10 It is alkyl; in other more specific embodiments, R c and R' c H or C 1-6 It is alkyl.

[0149] R3 In one embodiment, R3 is CN, and in another embodiment, R3 is -OR g For example, -OH; in other embodiments, R3 is -C(O)R g In other embodiments, R3 is -OC(O)R g In other embodiments, R3 is -NR''C(O)R g In other embodiments, R3 is -NR g R'g For example, -N(CH3)2; in other embodiments, R3 is -NR''C(O)NR g R' g In other embodiments, R3 is -NR''C(O)R g In other embodiments, R3 is -NR''S(O)2R g In other embodiments, R3 is -OC(O)NR g R' g In other embodiments, R3 is -NR''C(O)OR g In other embodiments, R3 is -N(OR g )C(O)R g In other embodiments, R3 is -N(OR g )S(O)2R g In other embodiments, R3 is -N(OR g )C(O)OR g In other embodiments, R3 is -N(OR g )C(O)R g R' g In other embodiments, R3 is a 3- to 14-membered heterocyclyl; in other embodiments, R3 is a 5- to 14-membered heteroaryl.

[0150] In a more specific embodiment, R3 is CN, -OR g , or -NR g R' g And; in other more specific embodiments, R3 is -OR g or -NR g R' g In other more specific embodiments, R3 is -OH or -N(CH3)2; and in other more specific embodiments, R3 is -OR g In other, more specific embodiments, R3 is -OH.

[0151] R g and R' g In one embodiment, R g H is; in other embodiments, Rg C 1-10 Alkyl, or C 1-6 Alkyl, or C 1-4 Alkyl, for example, methyl; in other embodiments, R g C 3-10 Cycloalkyl, or C 3-7 It is cycloalkyl; in other embodiments, R g These are heterocyclines with 3 to 10 members, or heterocyclines with 3 to 7 members.

[0152] In one embodiment, R' g H is; in other embodiments, R' g C 1-10 Alkyl, or C 1-6 Alkyl, or C 1-4 It is alkyl; in other embodiments, R' g C 3-10 Cycloalkyl, or C 3-7 It is cycloalkyl; in other embodiments, R' g These are heterocyclines with 3 to 10 members, or heterocyclines with 3 to 7 members.

[0153] In a more specific embodiment, R g and R' g H and C are independent of each other. 1-6 Alkyl, C 3-7 It is a cycloalkyl or a 3- to 7-membered heterocycline; in other more specific embodiments, R g and R' g H or C 1-6 It is alkyl; in other more specific embodiments, R g and R' g H or C 1-4 It is alkyl; in other more specific embodiments, R g and R' g It is independently either H or methyl.

[0154] R'' In one embodiment, R'' is H; in another embodiment, R'' is C1-6 Alkyl, or C 1-4 It is alkyl.

[0155] R4 and R5 In one embodiment, R4 is C 1-8 Alkyl, or C 1-6 Alkyl, or C 1-3 It is alkyl or methyl; in other embodiments, R4 is optionally one or more R 4s Replaced by; in other embodiments, R4 is optionally one, two, or three R 4s In other embodiments, R4 is replaced; however, R4 is not replaced.

[0156] In one embodiment, R5 is C 1-8 Alkyl, or C 1-6 Alkyl, or C 1-3 It is alkyl or methyl; in other embodiments, R5 is optionally one or more R 4s Replaced by; in other embodiments, R5 is optionally one, two, or three R 4s In other embodiments, R5 is replaced; however, R5 is not replaced.

[0157] In one embodiment, R4 and R5, along with the carbon atom to which they are bonded, are C 3-14 Cycloalkylene, or C 3-10 Cycloalkylene, or C 3-6 Cycloalkylenes (e.g., cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene), or C 3-5 Cycloalkylene, or C 3-4 In other embodiments, R4 and R5, together with the carbon atoms to which they are bonded, form a 3- to 14-membered heterocyclene, a 3- to 10-membered heterocyclene, or a 3- to 6-membered heterocyclene; in other embodiments, the ring formed by R4 and R5 together with the carbon atoms to which they are bonded optionally contains one or more R 4sSubstituted with; in other embodiments, the ring formed with the carbon atoms to which R4 and R5 are bonded may optionally consist of 1, 2, or 3 R 4s In other embodiments, the rings formed with the carbon atoms to which R4 and R5 are bonded are not substituted; however, in other embodiments, the rings formed together with the carbon atoms to which R4 and R5 are bonded are not substituted.

[0158] In a more specific embodiment, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-10 Forming cycloalkylenes or 3-10 membered heterocyclenes; in other more specific embodiments, R4 and R5, together with the carbon atom to which they are bonded, C 3-6 Forming cycloalkylenes or 3-6 membered heterocyclenes; in other more specific embodiments, R4 and R5, together with the carbon atom to which they are bonded, C 3-6 They form cycloalkylenes (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); in other more specific embodiments, R4 and R5, together with the carbon atoms to which they are bonded, C 3-5 They form a cycloalkylene; in other more specific embodiments, R4 and R5, together with the carbon atoms to which they are bonded, form a cyclopropylene or cyclopentylene; in other more specific embodiments, R4 and R5, together with the carbon atoms to which they are bonded, form a cyclopropylene; and in other more specific embodiments, R4 and R5, together with the carbon atoms to which they are bonded, do not form a ring.

[0159] R 4s In one embodiment, R 4s H is; in other embodiments, R 4s is a halogen; in other embodiments, R 4s is cyano; in other embodiments, R 4s C 1-8 Alkyl, or C 1-6 Alkyl, or C 1-3 It is alkyl; in other embodiments, R 4s C 1-8 Haloalkyl, or C1-6 Haloalkyl, or C 1-3 It is a haloalkyl; in other embodiments, R 4s is, -L d -OR d In other embodiments, R 4s is, -L d -SR d In other embodiments, R 4s is, -L d -NR d R' d That is the case.

[0160] In a more specific embodiment, R 4s These are independently H, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d And; in other more specific embodiments, R 4s These are independently H, halogen, cyano, and C. 1-6 Alkyl, or C 1-6 It is a haloalkyl; in other more specific embodiments, R 4s H and C are independent of each other. 1-3 Alkyl, or C 1-3 It is a haloalkyl group.

[0161] L d , R d , and R' d In one embodiment, L d is a chemical bond; in other embodiments, L d C 1-8 Alkylene, or C 1-6 Alkylene, or C 1-3 It is alkylene.

[0162] In a more specific embodiment, L d These are, independently, chemical bonds or C 1-6It is alkylene; in other more specific embodiments, L d These are, independently, chemical bonds or C 1-3 It is alkylene.

[0163] In one embodiment, R d H is; in other embodiments, R d C 1-8 Alkyl, or C 1-6 It is alkyl; in other embodiments, R d C 3-14 Cycloalkyl, or C 3-10 It is cycloalkyl; in other embodiments, R d These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0164] In one embodiment, R' d H is; in other embodiments, R' d C 1-8 Alkyl, or C 1-6 It is alkyl; in other embodiments, R' d C 3-14 Cycloalkyl, or C 3-10 It is cycloalkyl; in other embodiments, R' d These are heterocyclines with 3 to 14 members, or heterocyclines with 3 to 10 members.

[0165] In a more specific embodiment, R d and R' d H and C are independent of each other. 1-6 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; in other more specific embodiments, R d and R' d H or C 1-6 It is alkyl.

[0166] a, b, c, and d In one embodiment, a is 1; in another embodiment, a is 2; in another embodiment, a is 3; in another embodiment, a is 4; in another embodiment, a is 5; in another embodiment, a is 6.

[0167] In a more specific embodiment, a = 2, 3, 4, 5, or 6; in another more specific embodiment, a = 2, 3, or 4; in yet another more specific embodiment, a = 2 or 4; in yet another more specific embodiment, a = 2 or 3; in yet another more specific embodiment, a = 3 or 4.

[0168] In one embodiment, b is 4; in another embodiment, b is 5; in another embodiment, b is 6; in another embodiment, b is 7; in another embodiment, b is 8; in another embodiment, b is 9; in another embodiment, b is 10.

[0169] In a 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.

[0170] In a more specific embodiment, b = 4, 5, 6, 7, 8, 9, or 10; in another more specific embodiment, b = 4, 5, 6, 7, 8, or 9; in yet another more specific embodiment, b = 4, 5, 6, or 7; in yet another more specific embodiment, b = 5 or 6; in yet another more specific embodiment, b = 6, 7, or 8; in yet another more specific embodiment, b = 5, 6, 7, or 8.

[0171] 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.

[0172] In a more specific embodiment, c = 2, 3, 4, 5, or 6; in another more specific embodiment, c = 2, 3, or 4; in yet another more specific embodiment, c = 3 or 4; and in yet another more specific embodiment, c = 5 or 6.

[0173] In a more specific embodiment, c = 2, 4, 5, or 6; in another more specific embodiment, c = 4, 5, or 6; in yet another more specific embodiment, c = 4 or 6; in yet another more specific embodiment, c = 2, 3, 4, or 5; in yet another more specific embodiment, c = 2, 4, or 5; in yet another more specific embodiment, c = 2 or 5.

[0174] In one embodiment, d is 0; in another embodiment, d is 1; in another embodiment, d is 2; in another embodiment, d is 3; in another embodiment, d is 4.

[0175] In a more specific embodiment, d = 0, 1, 2, or 4; in another more specific embodiment, d = 2, 3, or 4; and in yet another more specific embodiment, d = 0 or 1.

[0176] In a more specific embodiment, d = 0, 1, 2, 3, or 4; in another more specific embodiment, d = 0, 1, or 2; in another more specific embodiment, d = 0 or 2; in another more specific embodiment, d is not 0; in another more specific embodiment, d = 1, 2, 3, or 4; in another more specific embodiment, d = 1 or 2; in another more specific embodiment, d = 1, 2, or 4; in another more specific embodiment, d = 1 or 4.

[0177] 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.

[0178] In a more specific embodiment, c+d=4, 5, or 6; in another more specific embodiment, c+d=5 or 6.

[0179] In a more specific embodiment, c+d=3, 4, 5, 6, 7, 8, or 9; in another more specific embodiment, c+d=4, 5, 6, or 7; in yet another more specific embodiment, c+d=4, 5, or 6; in yet another more specific embodiment, c+d=5, 6, or 7; in yet another more specific embodiment, c+d=6, 7, or 8; in yet another more specific embodiment, c+d=6 or 7.

[0180] Any particular embodiment of the above technical solutions, or any combination thereof, may be combined with any other particular embodiment of the technical solutions, or any combination thereof. For example, the technical solution of G1, or any combination thereof, may 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 may be combined with any of the technical solutions a, b, c, and d. This disclosure is intended to encompass all combinations of these technical solutions, but due to space limitations, not all of them are listed.

[0181] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer. [ka] During the ceremony, G1 and G2 are independently chemically bonded, C 1-13 Linear alkylene, C 2-13 Linear alkenylenes, and C 2-13 A selection of linear alkynylenes, each of which optionally contains one or more R G1 Replaced by; G1 and G2 have a total length with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R G1 H and C are independent of each other. 1-14 Alkyl, -L a -OR a , -L a -SR a , or -L a -NR a R' a and; G3 is C 4-14 Linear alkylene, C 4-14 Linear alkenylene, or C 4-14 It is a linear alkynylene, each of which optionally contains one or more R G3 Replaced by; R G3 These are independently H and -L a -OR a , -L a -SR a , or -L a -NRa R' a and; L a These are, independently, chemical bonds or C 1-14 It is alkylene; R a and R' a H and C are independent of each other. 1-14 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; G4 is a chemical bond, C 1-6 Alkilen, C 2-6 Alkenylene, or C 2-6 It is an alkynylene, and each of them can be optionally given one or more R G4 Replaced by; R G4 H and C are independent of each other. 1-6 Alkyl, -L b -OR b , -L b -SR b , or -L b -NR b R' b and; L b These are, independently, chemical bonds or C 1-6 It is alkylene; R b and R' b H and C are independent of each other. 1-6 Alkyl, C 3-10 Selected from cycloalkyls and 3- to 10-membered heterocyclines; Alternatively, two R atoms bonded to the same carbon atom. G4 Along with the carbon atoms to which they are bonded, C 3-14 They form cycloalkylenes or 3-14 member heterocyclenes, each of which optionally contains one or more R 4g Replaced by; R 4g These are independently H, halogen, cyano, and C. 1-8 Alkyl, C 1-8 Haloalkyl, -L e -OR e , -L e -SR e , or -Le -NR e R' e and; L e These are, independently, chemical bonds or C 1-8 It is alkylene; R e and R' e H and C are independent of each other. 1-8 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; M1 and M2 are independently -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 - Selected from; Q represents 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 - is selected from phenylene and pyridinylene, and phenylene or pyridinylene is optionally substituted with one or more R*; R* is independently H, halogen, cyano, C 1-10 Alkyl, C 1-10 Haloalkyl, -L f -OR f , -Lf -SR f , or -L f -NR f R' f and; L f These are, independently, chemical bonds or C 1-8 It is alkylene; R f and R' f H and C are independent of each other. 1-10 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; R1 and R2 are independent of C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Selected from alkinyl, each of which optionally contains one or more R 1s Substituted by -NR'-, and one or more methylene units are optionally and independently replaced by -NR'-; R 1s H and C are independent of each other. 1-20 Alkyl, -L c -OR c , -L c -SR c , or -L c -NR c R' c and; R and R' are independently H or C 1-20 It is alkyl; L c These are, independently, chemical bonds or C 1-20 It is alkylene; R c and R' c H and C are independent of each other. 1-20 Alkyl, C 3-14 Selected from cycloalkyl groups and 3- to 14-membered heterocyclines; R3 is 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 Selected from 3- to 14-membered heterocyclyls and 5- to 14-membered heteroaryls; R g and R' g H and C are independent of each other. 1-10 Alkyl, C 3-10 It is a cycloalkyl or a 3- to 10-membered heterocycline; R'' is independently H or C 1-6 It is alkyl; R4 and R5 are independent of C 1-8 It is an alkyl group, and it optionally contains one or more R groups. 4s Replaced by; Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, are C 3-14 They form cycloalkylenes or 3-14 member heterocyclenes, each of which optionally contains one or more R 4s Replaced by; R 4s These are independently H, halogen, cyano, and C. 1-8 Alkyl, C 1-8 Haloalkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d and; L d These are, independently, chemical bonds or C 1-8 It is alkylene; R d and R' dH and C are independent of each other. 1-8 Alkyl, C 3-14 They are cycloalkyl or 3- to 14-membered heterocyclines.

[0182] In more specific embodiments, the disclosure provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, where G1 and G2 are independently a chemical bond, C 1-9 Linear alkylene, C 2-9 Linear alkenylene, or C 2-9 It is a linear alkynylene.

[0183] In a more specific embodiment, G1 is C 1-6 Linear alkylene, C 2-6 Linear alkenylene, or C 2-6 Linear alkynylene, or C 1-6 Linear alkylene, or C 2-6 It is a linear alkylene.

[0184] In a more specific embodiment, G2 is a chemical bond, C 1-6 Linear alkylene, C 2-6 Linear alkenylene, or C 2-6 Linear alkynylene, or chemical bond or C 1-6 Linear alkylene, or chemical bond or C 1-4 It is a linear alkylene.

[0185] In a more specific embodiment, G1 and G2 have a total length of 3, 4, 5, 6, 7, 8, or 9 carbon atoms, or a total length of 4, 5, or 6 carbon atoms, or a total length of 5 or 6 carbon atoms, or a total length of 5, 6, or 7 carbon atoms, or a total length of 6 or 7 carbon atoms.

[0186] Alternatively, G1 and G2 may optionally have 1, 2, 3, or 4 R G1 It will be replaced with.

[0187] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein R G1 H or C 1-10 Alkyl, or H or C 1-6 It is alkyl.

[0188] In more specific embodiments, the present disclosure provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, where G3 is C 4-10 Linear alkylene, C 4-10 Linear alkenylene, or C 4-10 Linear alkynylene, or C 4-9 Linear alkylene, or C 5-8 It is a linear alkylene.

[0189] In a more specific embodiment, G3 optionally has 1, 2, 3, or 4 R G3 It will be replaced with.

[0190] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein L a These are, independently, chemical bonds or C 1-10 Alkylene, or chemical bond or C 1-6 It is alkylene.

[0191] In a more specific embodiment, R a and R' a H and C are independent of each other. 1-10 Alkyl, C 3-10 Cycloalkyl, or 3-10 membered heterocyclyl, or H or C 1-6 It is alkyl.

[0192] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, where G4 is C 1-4 Alkilen, C2-4 Alkenylene, or C 2-4 Alkynylene, or C 2-4 Alkylene, or C 2-3 It is alkylene.

[0193] In a more specific embodiment, G4 optionally has 1, 2, 3, or 4 R G4 It will be replaced with.

[0194] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein R G4 H or C 1-6 Alkyl, or C 1-4 It is alkyl.

[0195] In a more specific part, two R atoms bonded to the same carbon atom G4 C 3-10 They form cycloalkylenes or 3-10 membered heterocyclenes, or C 3-7 They form cycloalkylenes or 3- to 7-membered heterocyclenes, each of which optionally has 1, 2, or 3 R groups. 4g It has been replaced with.

[0196] In a more specific embodiment, R 4g These are independently H, halogen, cyano, and C. 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0197] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein L b These are, independently, chemical bonds or C 1-4 It is alkylene.

[0198] In a more specific embodiment, R b and R' b H and C are independent of each other.1-6 Alkyl, C 3-7 Cycloalkyl, or 3- to 7-membered heterocyclyl, or H or C 1-6 Alkyl, or H or C 1-4 It is alkyl.

[0199] In more specific embodiments, the present disclosure provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, where 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)-, or -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-, or -C(O)O- and -OC(O)-.

[0200] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, or -C(O)O-.

[0201] In a more specific embodiment, one of M1 and M2 is -C(O)O- or -C(O)S- or -C(O)O-, and the other is -OC(O)- or -SC(O)- or -OC(O)-.

[0202] In a more specific embodiment, M1 is -OC(O)- or -SC(O)- or -OC(O)-, and M2 is -C(O)O- or -C(O)S- or -C(O)O-.

[0203] In a more specific embodiment, M1 is -C(O)O- and M2 is -C(O)O- or -C(O)S-.

[0204] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-.

[0205] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, and -C(O)NH-, or -C(O)O-, -OC(O)-, and -C(O)S-.

[0206] In a more specific embodiment, one of M1 and M2 is -C(O)O- or -C(O)S-, or -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)-, and -SC(O)-, or -C(O)O-, -C(O)S-, -C(O)NH-, and -OC(O)-, or -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-, or -C(O)O-, -C(O)S-, and -OC(O)-.

[0207] In a more specific embodiment, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-, or -C(O)O- and -OC(O)-.

[0208] In a more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-, or -C(O)O- and -OC(O)-, or -C(O)O-, or -OC(O)-, and M2 is -OC(O)O-.

[0209] In a more specific embodiment, M1 is -OC(O)O-, and M2 is -OC(O)- or -C(O)O-, or -OC(O)-.

[0210] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-, or -C(O)O-, -OC(O)-, and -OC(O)O-, or M1 and M2 are not simultaneously -OC(O)O-. In more specific embodiments, the present disclosure provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, where R1 and R2 are independently C 6-14 Alkyl, C 6-14 Alkenyl, or C 6-14 Alkinyl, or C 6-14 Alkyl, or C 7-12 Alkyl, or C 8-12 It is alkyl.

[0211] In a more specific embodiment, R1 and R2 are independently C 7-12 Alkyl, C 7-12 Alkenyl, or C 7-12 Alkinyl, or C 8-12 Alkyl, C 8-12 Alkenyl, or C 8-12 It is alkinyl.

[0212] In a more specific embodiment, R1 and R2 are optionally 1, 2, 3, or 4 R 1s Replaced by, or optionally, one R 1s It will be replaced with.

[0213] In a more specific embodiment, R1 and R2 are independently -(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, [ka] It is selected based on the following criteria.

[0214] In a more specific embodiment, R1 and R2 are independently -(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, [ka] It is selected based on the following criteria.

[0215] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein R 1s H and C are independent of each other. 1-14 Alkyl, -L c -OR c , or -L c -NR c R' c , or H or C 1-14 Alkyl, or H or C 1-10 Alkyl, or H or C 1-9 Alkyl, or H or C 1-6 Alkyl, or H or C 1-4 It is alkyl.

[0216] In more specific embodiments, the present disclosure provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, where R and R' are independently H or C 1-20 Alkyl, or H or C1-14 Alkyl, or H or C 1-9 Alkyl, or H or C 1-6 It is alkyl; or, R is H.

[0217] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein L c These are, independently, chemical bonds or C 1-14 Alkylene, or chemical bond or C 1-10 Alkylene, or chemical bond or C 1-6 It is alkylene.

[0218] In a more specific embodiment, R c and R' c H or C 1-14 Alkyl, or H or C 1-10 Alkyl, or H or C 1-6 It is alkyl.

[0219] In more specific embodiments, the present disclosure provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, where R3 is CN, -OR g , or -NR g R' g , or -OR g or -NR g R' g , or -OR g , or -OH.

[0220] In a more specific embodiment, R3 is OH or -N(CH3)2.

[0221] In a more specific embodiment, R g and R' g H and C are independent of each other. 1-6 Alkyl, C 3-7 Cycloalkyl, or 3- to 7-membered heterocyclyl, or H or C 1-6 Alkyl, or H or C 1-4It is alkyl, or H, or methyl.

[0222] In more specific embodiments, the disclosure provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, wherein R4 and R5 are independently C 1-6 Alkyl, or C 1-3 It is alkyl or methyl.

[0223] In a more specific embodiment, R4 and R5 are optionally one, two, or three R 4s It will be replaced with.

[0224] In a more specific embodiment, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-10 Cycloalkylene or 3-10 member heterocyclene, or C 3-6 Cycloalkylene or 3-6 member heterocyclene, or C 3-6 Cycloalkylenes (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene), or C 3-5 It forms cycloalkylene, or cyclopropylene, or cyclopentylene, or cyclopropylene.

[0225] In a more specific embodiment, the ring formed with the carbon atoms to which R4 and R5 are bonded may optionally consist of 1, 2, or 3 R 4s It will be replaced with.

[0226] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein R 4s These are independently H, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -L d -OR d , -L d -SR d , or -L d -NR d R' d, or H, halogen, cyano, C 1-6 Alkyl, or C 1-6 Haloalkyl, or H, C 1-3 Alkyl, or C 1-3 It is a haloalkyl group.

[0227] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein L d These are, independently, chemical bonds or C 1-6 Alkylene, or chemical bond or C 1-3 It is alkylene.

[0228] In a more specific embodiment, R d and R' d H and C are independent of each other. 1-6 Alkyl, C 3-10 Cycloalkyl, or 3-10 membered heterocyclyl, or H or C 1-6 It is alkyl.

[0229] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein L e These are, independently, chemical bonds or C 1-6 Alkylene, or chemical bond or C 1-4 It is alkylene.

[0230] In a more specific embodiment, R e and R' e H and C are independent of each other. 1-6 Alkyl, C 3-10 Cycloalkyl, or 3-10 membered heterocyclyl, or H or C 1-6 Alkyl, or H or C 1-4 It is alkyl.

[0231] In more specific embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, where Q is a chemical bond, -OC(O)-, or -SC(O)-, or a chemical bond or -SC(O)-.

[0232] In a more specific embodiment, if Q is phenylene or pyridinylene, Q is optionally substituted with 1, 2, or 3 R*.

[0233] In a more specific embodiment, R* is independently H, halogen, cyano, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0234] In a more specific embodiment, L f These are, independently, chemical bonds or C 1-6 Alkylene, or chemical bond or C 1-4 It is alkylene.

[0235] In a more specific embodiment, R f and R' f H and C are independent of each other. 1-6 Alkyl, C 3-10 Cycloalkyl, or 3-10 membered heterocyclyl, or H or C 1-6 Alkyl, or H or C 1-4 It is alkyl.

[0236] In more specific embodiments, the present disclosure provides compounds of formula (I) having the structure of formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof: [ka] During the ceremony, 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; Other groups are as defined herein.

[0237] In more specific embodiments, the present disclosure provides compounds of formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. [ka] In the formula, R on R1 or R2 1s The substitution site is separated from M1 or M2 by 0 to 10 carbon atoms, 0 to 6 carbon atoms, 0 to 4 carbon atoms, 0 to 2 carbon atoms, or 0 carbon atoms.

[0238] In a more specific embodiment, R on R2 1s The substitution site is separated from M2 by 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 2 carbon atoms, or 2 to 10 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms.

[0239] In a more specific embodiment, R1 is R 1s It is not replaced by R on R2. 1s The substitution site is separated from M2 by 0 to 10 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 2 carbon atoms, or 2 to 10 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms.

[0240] In a more specific embodiment, R1 is R 1s It is replaced with R2, 1s It has not been replaced.

[0241] In a more specific embodiment, R4 and R5 do not form a ring with the carbon atoms to which they are bonded.

[0242] In a more specific embodiment, d is not 0.

[0243] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, [ka] During the ceremony, a = 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=3, 4, 5, 6, 7, 8, or 9; or c+d=4, 5, or 6; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; or M1 and M2 are independently selected from -C(O)O- and -C(O)S-; or one of M1 and M2 is -C(O)O- or -C(O)S-, and the other is -OC(O)- or -SC(O)-; R1 and R2 are independent of C 6-14 It is an alkyl group, and it optionally has 1, 2, 3, or 4 R atoms. 1s Replaced by; R 1s H and C are independent of each other. 1-14 Alkyl, -L c -OR c , or -L c -NR c R' c , or H or C 1-14 It is alkyl; L c These are, independently, chemical bonds or C 1-14 It is alkylene; R c and R' c H or C 1-14 It is alkyl; R4 and R5 are independent of C1-6 It is alkyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 They form cycloalkylenes or 3-6 member heterocyclenes.

[0244] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein in formula (II) a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or b = 5, 6, 7, or 8; or b = 5, 6, or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=5 or 6; M1 and M2 are independently -C(O)O- or -OC(O)-; or M1 and M2 are -C(O)O-; or one of M1 and M2 is -C(O)O- and the other is -OC(O)-; R1 and R2 are independent of C 7-12 Alkyl, or C 8-12 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s H or C 1-10 Alkyl, or H or C 1-9 It is alkyl; R4 and R5 are independent of C 1-3 It is alkyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 Forms cycloalkylenes, or C 3-5 It forms cycloalkylenes.

[0245] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein in formula (II) a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or b = 5, 6, 7, or 8; or b = 5 or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; or d = 0, 1, 2, or 4; c+d=5 or 6; or c+d=6; M1 and M2 are -C(O)O-; Alternatively, one of M1 and M2 is -C(O)O- and the other is -OC(O)-; R1 and R2 independently control -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, [ka] Selected from; or -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, [ka] Selected from; or -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, [ka] Selected from; R4 and R5 are methyl; Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, or cyclopropylene, cyclopentylene, or cyclopropylene.

[0246] In a more specific embodiment, only one of R1 and R2 is replaced.

[0247] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2; b=5; c = 2, 3, 4, 5, or 6; or c = 6; d = 0, 1, 2, 3, or 4; or d = 0; c+d=5 or 6, or 6; M1 and M2 are -C(O)O-; R1 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 8-9 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s H or C 1-10 Alkyl, or H or C 1-9 Alkyl, or C 5-8 Alkyl, or C 6-8 Alkyl, or C 7-8 It is alkyl; R2 is C 7-11 Linear alkyl, or C 10-11 Linear alkyl, or C 11 It is a linear alkyl group, which optionally contains one carbon atom. 1-3 Substituting with an alkyl group, or optionally substituted with a single methyl group; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It forms cycloalkylene or cyclopropylene.

[0248] In a more specific embodiment, R1 is [ka] And, or [ka] That is the case.

[0249] In a more specific embodiment, R1 is [ka] And, or [ka] That is the case.

[0250] In a more specific embodiment, R2 is -(CH2)9CH3, -(CH2) 10 CH3, or [ka] That is the case.

[0251] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; or a = 2; b=7; c=2, 3, 4, 5, or 6; or c=2, 3, or 4; or c=2; d = 0, 1, 2, 3, or 4; or d = 2, 3, or 4; or d = 4; c+d=5 or 6, or 6; M1 and M2 are -C(O)O-; R1 is C 8-11 Linear alkyl, or C 9-10 It is a linear alkyl or C9 linear alkyl; R2 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s H or C1-10 Alkyl, or H or C 1-9 Alkyl, or C 6-9 Alkyl, or C 7-8 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It forms cycloalkylene or cyclopropylene.

[0252] In a more specific embodiment, R2 is [ka] And, or [ka] And, or [ka] That is the case.

[0253] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2; b=7; c=3 or 4; or c=4; d=2; M1 and M2 are -C(O)O-; R1 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 8-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s H or C 1-10 Alkyl, or H or C 1-9 It is alkyl; R2 is C 7-11 It is a linear alkyl or C9 linear alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It forms cycloalkylene or cyclopropylene.

[0254] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; or a = 2 or 4; b = 6 or 7; or b = 7; c = 2, 3, 4, 5, or 6; or c = 5 or 6; d = 0, 1, 2, 3, or 4; or d = 0 or 1; c+d=5 or 6, or 6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 7-11 Linear alkyl, or C 9-10 It is a linear alkyl group; R2 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-10 It is a linear alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, C 7-9 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It forms cycloalkylene or cyclopropylene.

[0255] In a more specific embodiment, when a=4, R4 and R5 do not form a ring with the carbon atoms to which they are bonded; or, R 1s Independently, C 8-9It is alkyl.

[0256] In a more specific embodiment, R2 is [ka] That is the case.

[0257] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, [ka] During the ceremony, a = 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=3, 4, 5, 6, 7, 8, or 9; or c+d=4, 5, 6, or 7; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-, or selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; or one of M1 and M2 is -C(O)O- or -C(O)S- and the other is -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)-, or -SC(O)-, or -C(O)O-, -C(O)S-, -OC(O)-, or -SC(O)-; R1 and R2 are independently C 6-14 Alkyl, C 6-14 Alkenyl, or C 6-14 These are alkynyls, each of which can optionally contain 1, 2, 3, or 4 R 1s Replaced by; R 1s H and C are independent of each other. 1-14 Alkyl, -L c -OR c , or -L c -NRc R' c , or H or C 1-14 It is alkyl; L c These are, independently, chemical bonds or C 1-14 It is alkylene; R c and R' c H or C 1-14 It is alkyl; R4 and R5 are independent of C 1-6 It is alkyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 They form cycloalkylenes or 3-6 member heterocyclenes.

[0258] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9, or b = 5, 6, 7, or 8, or b = 5, 6, or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=5, 6, or 7; M1 and M2 are independently -C(O)O-, -OC(O)-, -C(O)S-, or -C(O)NH-, or -C(O)O-, -OC(O)-, or -C(O)S-; or one of M1 and M2 is -C(O)O-, and the other is -C(O)O-, -C(O)S-, -C(O)NH-, or -OC(O)-, or -C(O)O-, -C(O)S-, or -OC(O)-; R1 and R2 are independent of C 7-12 Alkyl, C 7-12 Alkenyl, or C 7-12 Alkinyl, or C 8-12 Alkyl, C 8-12 Alkenyl, or C 8-12 They are alkinyls, and each of them can be optionally one R1s Replaced by; R 1s H or C 1-10 It is alkyl; R4 and R5 are independent of C 1-3 It is alkyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 Forms cycloalkylenes, or C 3-5 It forms cycloalkylenes.

[0259] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or b = 5, 6, 7, or 8; or b = 5 or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=5, 6, or 7; or c+d=6; One of M1 and M2 is -C(O)O-, and the other is -C(O)O-, -C(O)S-, -C(O)NH-, or -OC(O)-, or -C(O)O-, -C(O)S-, or -OC(O)-; R1 and R2 independently control -(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, [ka] Selected from, or -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, [ka] Selected from; or -(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, [ka] Selected from; R4 and R5 are methyl; Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, may form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, or form cyclopropylene, cyclopentylene, or cyclopropylene; In a more specific embodiment, only one of R1 and R2 is replaced.

[0260] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2; b=5; c=5 or 6; or c=6; d=0 or 1; or d=0; c+d=5 or 6, or 6; M1 is -C(O)O-, and M2 is -C(O)O- or -C(O)S-; or M1 and M2 are -C(O)O-; R1 is C 7-12 Alkyl, or C 8-12 Alkyl, or C8-9 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s H or C 1-10 Alkyl, or H or C 1-9 Alkyl, or C 6-8 Alkyl, or C 7-8 It is alkyl; R2 is C 7-11 Linear alkyl, or C 10-11 Linear alkyl, or C 11 It is a linear alkyl group, which optionally contains one carbon atom. 1-3 Substituting with an alkyl group, or optionally substituted with a single methyl group; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 Forming cycloalkylene or cyclopropylene; In a more specific embodiment, R1 is [ka] And, or [ka] and; In a more specific embodiment, R2 is -(CH2)9CH3, -(CH2) 10 CH3, or [ka] That is the case.

[0261] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; or a = 2; b = 5, 6, or 7; or b = 7; c=2, 3, 4, 5, or 6; or c=2, 3, or 4; or c=2; d = 0, 1, 2, 3, or 4; or d = 2, 3, or 4; or d = 4; c+d=5 or 6, or 6; M1 and M2 are -C(O)O-; R1 and R2 are independently C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-11 Alkyl, or C 9-10 It is an alkyl group, and it optionally has one R 1s Replaced by; and only one of R1 and R2 is replaced; R 1s H or C 1-10 Alkyl, or C 6-10 Alkyl, or C 7-9 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 Forming or not forming cycloalkylene or cyclopropylene rings; In a more specific embodiment, R1 is C 8-12 Linear alkyl, or C 9-11 Linear alkyl, or C 9-10 It is a linear alkyl group; R2 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-11 Alkyl, or C 9-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R2 is C 10 If it is a linear alkyl group, R 1s C 9-10 It is alkyl, or C9 alkyl.

[0262] In a more specific embodiment, R2 is [ka] And, or [ka] That is the case.

[0263] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; b = 6; c=4, 5, or 6; or c=5 or 6; or c=5; d=1 or 2; or d=1; c+d=6, 7, or 8; or 6 or 7; or 6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 7-12 Linear alkyl, or C 8-11 Linear alkyl, or C 9-11 It is a linear alkyl group; R2 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-12 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, C 7-11 Alkyl, or C 7-10 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 Forming cycloalkylene or cyclopropylene; However, if c=4, then a=2 or 3.

[0264] In a more specific embodiment, R2 is [ka] That is the case.

[0265] In a more specific embodiment, a=2 or 4; b=6; c=5 or 6, or c=5; d=1; R1 is C 8-9 It is a linear alkyl or C9 linear alkyl; R2 is C 9-10 Alkyl, or C 10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, C 7-8 It is alkyl; R4 and R5 are independently C 1-3 It is alkyl or methyl.

[0266] In a more specific embodiment, a=2, 3, or 4, or 2 or 4; b=6; c=5; d=2; R1 is C 9-10 It is a linear alkyl or C9 linear alkyl; R2 is C 9-11 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, C 7-9 It is alkyl, R4 and R5 are independently C 1-3 It is alkyl or methyl.

[0267] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; or a = 2 or 4; b=7; c=5 or 6; or c=5; d=0 or 1; or d=1; c+d=5 or 6, or 6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 8-11 Linear alkyl, or C 9-10 It is a linear alkyl group, which optionally contains one carbon atom. 1-9 Alkyl (or C 6-9 Alkyl, or C 6-7 Substituted with alkyl; R2 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, C 7-9 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It forms cycloalkylene or cyclopropylene.

[0268] In a more specific embodiment, R1 is -(CH2)8CH3, -(CH2)9CH3, [ka] and; R2 is [ka] That is the case.

[0269] In a more specific embodiment, if a=4, R1 is C 9-10 It is a linear alkyl group; R2 is C 9-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s C 8-9 It is alkyl; R4 and R5 do not form a ring with the carbon atoms to which they are bonded.

[0270] In a more specific embodiment, if a=2, R1 is C 10 It is a linear alkyl group; Or R 1s C 8-9 It is alkyl, or C9 alkyl.

[0271] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; or a = 2 or 4; b=7; c=4; d=2; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 8-11 Linear alkyl, or C 9-10 It is a linear alkyl group; R2 is C 8-11 Alkyl, or C 9-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, C 7-9 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It does not form cycloalkylene or cyclopropylene rings.

[0272] In a more specific embodiment, R2 is [ka] That is the case.

[0273] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; or a = 2; b=8; c=5; d=1; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 8-12 Linear alkyl, or C 9-11 Linear alkyl, or C 10-11 It is a linear alkyl group; R2 is C 8-11 Alkyl, or C 9-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, C 7-9 Alkyl, or C 7-8 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It does not form cycloalkylene or cyclopropylene rings.

[0274] In a more specific embodiment, R2 is [ka] That is the case.

[0275] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2; b = 6, 7, or 8, or b = 7; c=5; d=1; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 8-11 Linear alkyl, or C 9-10 It is a linear alkyl or C9 linear alkyl; R2 is C 8-11 Alkyl, or C 9-10 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s It is independently a C7 alkyl; R4 and R5 are independently C 1-3 It is alkyl or methyl.

[0276] In a more specific embodiment, R2 is [ka] And, or [ka] That is the case.

[0277] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2 or 3, or a=2; b=7; c=3; d=3; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 8-11 Linear alkyl, or C 9-10 It is a linear alkyl or C9 linear alkyl; R2 is C 8-11 Alkyl, or C 9-10 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s Independently, C 6-7It is alkyl, or C7 alkyl; R4 and R5 are independently C 1-3 It is alkyl or methyl.

[0278] In a more specific embodiment, R2 is [ka] And, or [ka] That is the case.

[0279] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, [ka] During the ceremony, a = 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=3, 4, 5, 6, 7, 8, or 9, or c+d=4, 5, or 6; One of M1 and M2 is -OC(O)O-, and the other is -C(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-; R1 and R2 are independent of C 6-14 It is an alkyl group, and it optionally has 1, 2, 3, or 4 R atoms. 1s Replaced by; R 1s H and C are independent of each other. 1-14 Alkyl, -L c -OR c , or -L c -NR c R' c It is; or H or C 1-14 It is alkyl; L cThese are, independently, chemical bonds or C 1-14 It is alkylene; R c and R' c H or C 1-14 It is alkyl; R4 and R5 are independent of C 1-6 It is alkyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 They form cycloalkylenes or 3-6 member heterocyclenes.

[0280] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; b = 4, 5, 6, or 7, or b = 5 or 6, or b = 6; c = 2, 3, 4, 5, or 6; or c = 2, 4, 5, or 6; d = 0, 1, 2, 3, or 4; or d = 0, 1, 2, or 4; c+d=5 or 6, or c+d=6; One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-; R1 and R2 are independent of C 7-12 Alkyl, or C 9-11 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s Independently, H or C1- 10 Alkyl; or H or C4- 10 It is alkyl; R4 and R5 are independent of C 1-3 It is alkyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 Cycloalkylene, or C 3-4 It forms cycloalkylenes.

[0281] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; b = 4, 5, 6, or 7, or b = 5 or 6, or b = 6; c = 2, 3, 4, 5, or 6; or c = 2, 4, 5, or 6; d = 0, 1, 2, 3, or 4; or d = 0, 1, 2, or 4; c+d=5 or 6, or c+d=6; One of M1 and M2 is -OC(O)O-, and the other is -C(O)O- or -OC(O)-; R1 and R2 independently control -(CH2)8CH3, -(CH2)9CH3, and -(CH2) 10 CH3, [ka] Selected from; R4 and R5 are methyl; Alternatively, R4 and R5, together with the carbon atoms to which they are bonded, form cyclopropylene.

[0282] In a more specific embodiment, only one of R1 and R2 is replaced; In a more specific embodiment, M1 is -C(O)O- or -OC(O)- or -C(O)O-, and M2 is -OC(O)O-.

[0283] In a more specific embodiment, M1 is -OC(O)O- and M2 is -OC(O)-.

[0284] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2; b=5 or 6, or b=6; c=4, 5, or 6; or c=4 or 6; or c=6; d = 0, 1, or 2; or d = 0 or 2; c+d=6; M1 is -C(O)O-, and M2 is -OC(O)O-; R1 is C 8-11 Alkyl, or C 9-10 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s C 7-9 It is alkyl, or C7 alkyl; R2 is C 8-11 Linear alkyl, or C 9-10 It is a linear alkyl or C9 linear alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It may or may not form a cycloalkylene ring.

[0285] In a more specific embodiment, R1 is [ka] And, or [ka] That is the case.

[0286] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2; b = 6; c=4, 5, or 6; or c=5 or 6; or c=6; d = 0, 1, or 2; or d = 0 or 1; c+d=6; M1 is -C(O)O-, and M2 is -OC(O)O-; R1 is C 8-10 Linear alkyl, or C 9-10 It is a linear alkyl or C9 linear alkyl; R2 is C 8-10 Alkyl, or C 9-10 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s C 6-7 It is alkyl, or C7 alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It may or may not form a cycloalkylene ring.

[0287] In a more specific embodiment, R2 is [ka] And, or [ka] That is the case.

[0288] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a=2; b = 5 or 6; or b = 6; c=5; d=1; M1 is -OC(O)- and M2 is -OC(O)O-; R1 is C 8-10 Alkyl, or C 9-10 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s C6-8 Alkyl, or C 6-7 It is alkyl; R2 is C 8-12 Linear alkyl, or C 10-11 It is a linear alkyl group; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It may or may not form a cycloalkylene ring.

[0289] In a more specific embodiment, R1 is [ka] And, or [ka] That is the case.

[0290] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, a = 2, 3, or 4; or a = 2; b = 5, 6, 7, or 8; or b = 6 or 7; or b = 7; c=4, 5, or 6; or c=4; d = 0, 1, or 2; or d = 1; c+d=5 or 6; or c+d=5; M1 is -OC(O)O-, and M2 is -OC(O)-; R1 is C 8-12 Alkyl, or C 8-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s C 6-10 Alkyl, or C 6-8 It is alkyl; R2 is C 8-12Linear alkyl, or C 8-10 It is a linear alkyl group; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It may or may not form a cycloalkylene ring.

[0291] In a more specific embodiment, R1 is [ka] That is the case.

[0292] In more specific embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, [ka] During the ceremony, Q is either -SC(O)- or -OC(O)-; R g and R' g Independently, C 1-6 It is alkyl; a = 2, 3, 4, 5, or 6; or a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or a = 5, 6, or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=5 or 6; M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-; R1 and R2 are independent of C 6-14 It is an alkyl group, and it optionally has 1, 2, 3, or 4 R atoms. 1s Replaced by; R 1s H and C are independent of each other. 1-14 Alkyl, -L c-OR c , or -L c -NR c R' c It is; or H or C 1-14 It is alkyl; L c These are, independently, chemical bonds or C 1-14 It is alkylene; R c and R' c H or C 1-14 It is alkyl; R4 and R5 are independently C 1-6 Is it alkyl? Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 They form cycloalkylenes or 3-6 member heterocyclenes.

[0293] In more specific embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, Q is either -SC(O)- or -OC(O)-; R g and R' g Independently, C 1-3 It is alkyl; a = 3 or 4; b = 6 or 7; c = 2, 3, 4, or 5; or 2 or 5; d = 1, 2, 3, or 4; or 1 or 4; c+d=5 or 6; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, and -OC(O)O-; or, M1 and M2 cannot be -OC(O)O- at the same time; R1 and R2 are independent of C 7-12 Alkyl, or C 8-10 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s H or C 1-10 Alkyl, or H or C1-9 It is alkyl; R4 and R5 are independently C 1-3 Is it alkyl? Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 It forms cycloalkylenes.

[0294] In more specific embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, wherein, Q is -SC(O)-; R g and R' g It is methyl; a = 3 or 4; b = 6 or 7; c = 2, 4, or 5; or 2 or 5; d = 1, 2, or 4; or 1 or 4; c+d=6; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, and -OC(O)O-; or, M1 and M2 cannot be -OC(O)O- at the same time; R1 and R2 independently produce -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, [ka] and; R4 and R5 are methyl; Alternatively, R4 and R5 may form a cyclopropylene ring with the carbon atoms to which they are bonded, or they may not form a ring.

[0295] In a more specific embodiment, only one of R1 and R2 is substituted; or R1 is not substituted and R2 is substituted.

[0296] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, [ka] In the formula, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, or are -C(O)O-; Other groups are as defined herein.

[0297] In more specific embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, [ka] In the formula, one of M1 and M2 is -C(O)O- or -C(O)S- or -C(O)O-, and the other is -OC(O)- or -SC(O)- or -OC(O)-; Other groups are as defined herein.

[0298] In a more specific embodiment, R 1s H or C 1-6 Alkyl, or H or C 1-4 It is alkyl.

[0299] In a more specific embodiment, M1 is -OC(O)- or -SC(O)- or -OC(O)-, and M2 is -C(O)O- or -C(O)S- or -C(O)O-.

[0300] In a more specific embodiment, R 1s Independently, C 1-8 Alkyl, or C 4-8 Alkyl, or C 6-8 Alkyl, or C 7-8 Alkyl, or C8 alkyl; In more specific embodiments, the present disclosure provides compounds of formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. [ka] During the ceremony, Q is a chemical bond, -SC(O)- or -OC(O)-; R g and R' g Independently, C 1-6 It is alkyl; a = 2, 3, 4, 5, or 6; b = 6 or 7; c = 5 or 6; d = 0 or 1; c+d=5 or 6; M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-; R1 and R2 are independent of C 7-12 Alkyl, or C 8-12 It is an alkyl group, and it optionally has one R 1s Replaced by; R 1s H or C 1-10 It is alkyl; R4 and R5 are independently C 1-6 Is it alkyl? Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-6 It forms cycloalkylenes.

[0301] In a more specific embodiment, only one of R1 and R2 is substituted; or R1 is not substituted and R2 is substituted.

[0302] In more specific embodiments, the present disclosure provides compounds of formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof, wherein, Q is -SC(O)- or -OC(O)- or -SC(O)-; R g and R' g Independently, C 1-3 Alkyl or methyl; a = 2, 3, or 4; or a = 2 or 4; or a = 4; b = 6 or 7; or b = 7; c=5 or 6; or c=5; d=0 or 1; or d=1; c+d=5 or 6; or c+d=6; M1 is -OC(O)-; M2 is -C(O)O-; R1 is C 7-11 Linear alkyl, or C 9-10 It is a linear alkyl or C9 linear alkyl; R2 is C 7-12 Alkyl, or C 8-12 Alkyl, or C 9-10 It is an alkyl or C9 alkyl group, and it optionally contains one R 1s Replaced by; R 1s Independently, C 1-9 Alkyl, or C 1-8 Alkyl, or C 4-9 Alkyl, or C 4-8 It is alkyl; R4 and R5 are independent of C 1-3 Alkyl or methyl; Alternatively, R4 and R5, along with the carbon atoms to which they are bonded, are C 3-4 It forms cycloalkylene or cyclopropylene.

[0303] In a more specific embodiment, R on R1 or R2 1s The substitution site is separated from M1 or M2 by 0 to 10 carbon atoms, 0 to 6 carbon atoms, 0 to 4 carbon atoms, 0 to 2 carbon atoms, or 0 carbon atoms.

[0304] In a more specific embodiment, R1 is R 1s It is not replaced by R on R2. 1s The substitution sites are separated from M2 by 0 to 10 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 2 carbon atoms; or 2 to 10 carbon atoms, or 2 to 6 carbon atoms, 2 to 4 carbon atoms.

[0305] In a more specific embodiment, R2 is [ka] And, or [ka] And, or [ka] And, or [ka] and; In a more specific embodiment, R4 and R5 do not form a ring with the carbon atoms to which they are bonded.

[0306] In more specific embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, which is selected from the compounds in Table (I).

[0307] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0308] This disclosure further relates to a method for preparing a compound of formula (II), This includes reacting a compound of formula (IIA) with a compound of formula (IIB) to obtain a compound of formula (II), [ka] The present invention provides a method in which X is a halogen and the other variables are as defined herein.

[0309] This disclosure further relates to a method for preparing a compound of formula (II), This includes reacting a compound of formula (IIC) with a compound of formula (IID) to obtain a compound of formula (II), [ka] The present invention provides a method in which X is a halogen and the other variables are as defined herein.

[0310] In a particular embodiment, the compound is selected from the following formulas.

[0311] [Table 2-1] [Table 2-2] [Table 2-3]

[0312] In a more specific embodiment, the present disclosure provides a nanoparticle composition comprising a lipid component and optionally a supported material, wherein the lipid component comprises a compound of the present disclosure.

[0313] In a more specific embodiment, the present disclosure relates to the above-described nanoparticle composition, wherein the lipid component comprises the following components in molar percentage: 20 mol% to 85 mol% of ionizable cationic lipids; Structural lipids: 10 mol% to 75 mol%; Neutral lipids in an amount of 1.0 mol% to 30 mol%; High molecular weight lipids 0.25 mol% to 10 mol% include.

[0314] In a more specific embodiment, the present disclosure relates to the above-described nanoparticle composition, wherein the lipid component comprises the following components in molar percentage: 50 mol% of any of the aforementioned compounds in this disclosure; 10 mol% neutral lipids; Structural lipids: 38.5 mol%; 1.5 mol% high molecular weight lipids include.

[0315] In a more specific embodiment, the Disclosure relates to the above-described nanoparticle composition, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE, and DPPE, or is DSPC and / or DOPE.

[0316] In a more specific embodiment, the present disclosure provides a nanoparticle composition, wherein the structural lipid is one or more selected from cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, and campesterol, or is cholesterol and / or β-sitosterol, or is cholesterol.

[0317] In a more specific embodiment, the present disclosure provides a nanoparticle composition, wherein the polymer lipid is a polyethylene glycolated lipid.

[0318] In a more specific embodiment, the present disclosure provides a nanoparticle composition in which the polyethylene glycolated 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.

[0319] In a more specific embodiment, the present disclosure provides a nanoparticle composition, wherein the polyethylene glycolated lipid contains a PEG portion of about 1000 Da to about 20 kDa, or a PEG portion of about 1000 Da to about 5000 Da.

[0320] In a more specific embodiment, the present disclosure provides a nanoparticle composition in which the polyethylene glycolated lipid is selected from one or more of the following: DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, azide-PEG2000, DSPE-PEG2000-mannose, ceramide-PEG5000, and DSPE-PEG5000, or DMG-PEG2000.

[0321] In a more specific embodiment, the present disclosure provides a nanoparticle composition, wherein the supported material is selected from one or more therapeutic agents, prophylactic agents, and diagnostic agents.

[0322] In a more specific embodiment, the present disclosure provides a nanoparticle composition, wherein the therapeutic, prophylactic, or diagnostic agent is a nucleic acid.

[0323] In a more specific embodiment, the present disclosure provides a nanoparticle composition, wherein the nucleic acid is selected from one or more of ASO, RNA, and DNA.

[0324] In a more specific embodiment, the present disclosure provides a nanoparticle composition described above, wherein the RNA is selected from one or more of the following: interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymer coding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA), and nuclease, or is mRNA, and furthermore is modified mRNA.

[0325] Since the compounds of this disclosure may have one or more chiral centers, they may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this disclosure may be in the form of a single enantiomer, diastereomer, or geometric isomer (e.g., cis and trans isomers), or in the form of a racemic mixture or a mixture rich in one or more stereoisomers. The isomers can be separated from the mixture by methods well known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or other isomers can be prepared by asymmetric synthesis.

[0326] The compounds of this disclosure may exist in the form of tautomers. Tautomers are functional isomers resulting from the rapid movement of atoms between two positions within a molecule. Tautomers are special functional isomers, and a pair of tautomers are interconvertible but usually exist primarily as relatively stable isomers. The most important examples are enol tautomers and keto tautomers.

[0327] This disclosure also includes isotopically labeled compounds (isotopic variants) that are equivalent to the compounds represented by formula (IV), but in which one or more atoms are replaced with atoms having different atomic masses or mass numbers than those commonly found in nature. Examples of isotopes that can be introduced into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 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 36Examples include Cl. Compounds of the Disclosure containing the above-mentioned isotopes and / or isotopes of other atoms, their prodrugs, and pharmaceutically acceptable salts of the above-mentioned compounds or prodrugs are all included within the scope of the Disclosure. Certain isotope-labeled compounds of the Disclosure, for example, radioisotopes (e.g., 3 H and 14 Devices incorporating C) can be used to measure the distribution of drugs and / or substrates within tissues. 3 H is tritium and 14 Carbon-14, a 1C isotope, is useful as an alternative because it is easy to prepare and detect. Furthermore, 2 When replaced with heavier isotopes such as deuterium (H), this may offer therapeutic advantages due to improved metabolic stability, such as extended half-life in vivo and reduced required dose, and thus may be an alternative in some cases. The isotope-labeled compounds represented by formula (I) of this disclosure and their prodrugs can generally be prepared by replacing the isotope-unlabeled reagents with commercially available isotope-labeled reagents in the procedures disclosed in the following scheme and / or examples and preparation examples.

[0328] The Disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are included in the Disclosure.

[0329] Pharmaceutical compositions and kits In another embodiment, the Disclosure provides a pharmaceutical composition comprising a nanoparticle composition of the Disclosure and pharmaceutically acceptable excipients, wherein the nanoparticle composition comprises a compound of the Disclosure.

[0330] In this disclosure, pharmaceutically acceptable excipients refer to non-toxic carriers, adjuvants, or vehicles that do not impair the pharmacological activity of the compounds formulated together. Examples of pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol, and lanolin.

[0331] The Disclosure also includes kits (e.g., pharmaceutical packs). The kits provided may include the nanoparticle compositions, other therapeutic agents, or diagnostic or prophylactic agents of the Disclosure, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other materials) containing the nanoparticle compositions or other therapeutic agents, diagnostic or prophylactic agents of the Disclosure. In some embodiments, the kits provided may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the nanoparticle compositions and / or other therapeutic agents, diagnostic or prophylactic agents of the Disclosure. In some embodiments, the nanoparticle compositions of the Disclosure provided in the first container and the other therapeutic agents, diagnostic or prophylactic agents provided in the second container are combined to form a unit dose form.

[0332] Administration The pharmaceutical compositions provided herein can be administered by 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, implantation, or other means 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, intraventricular administration, intra-lesional administration, and intracranial injection or infusion techniques.

[0333] Generally, the pharmaceutical compositions provided herein are administered in effective doses. The actual amount of pharmaceutical composition administered is usually determined by a physician, taking into account the medical condition being treated or prevented, the chosen route of administration, the actual pharmaceutical composition being administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0334] When used to prevent a pre-existing condition of this disclosure, the pharmaceutical compositions provided herein are typically administered to subjects at risk of developing a medical condition, under the direction and supervision of a physician, at the dose levels described above. Subjects at risk of developing a particular medical condition generally include individuals with a family history of the condition or those identified as susceptible to the condition through genetic testing or screening.

[0335] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). "Chronic administration" means administering the compound or its pharmaceutical composition over a long period of time, including, for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or continuing indefinitely throughout the life of the subject. In certain embodiments, chronic administration is aimed at maintaining a constant blood concentration of the compound within the therapeutic concentration range over a long period of time.

[0336] The pharmaceutical compositions of this disclosure may be delivered by a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition may be administered, for example, as a bolus, to raise the blood concentration of the compound to an effective level. The site of administration of a bolus depends on the desired systemic level of the active ingredient throughout the body. For example, intramuscular or subcutaneous bolus administration allows for sustained release of the active ingredient, while direct intravenous (e.g., via IV infusion) bolus administration allows for more rapid delivery of the active ingredient and a rapid increase in blood concentration to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, to maintain a steady-state concentration of the active ingredient in the subject's body. Furthermore, in yet another embodiment, the pharmaceutical composition may be administered as a bolus first, followed by a continuous infusion.

[0337] Transdermal doses are generally selected to provide blood concentrations equivalent to or lower than those obtained by injection, and are typically in the range of about 0.01 to about 20% by weight, or about 0.1 to about 20% by weight, or about 0.1 to about 10% by weight, or even about 0.5 to about 15% by weight.

[0338] Injectable doses range from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour, and are administered over approximately 1 to 120 hours, particularly between 24 and 96 hours. To achieve an appropriate steady-state concentration, an initial loading bolus of approximately 0.1 mg / kg to 10 mg / kg or more may be administered. The maximum total dose is not expected to exceed approximately 2 g per day for human patients weighing 40-80 kg.

[0339] Injectable compositions are typically prepared based on sterile saline for injection, phosphate-buffered saline, or other injectable excipients known to those skilled in the art. As mentioned above, the active compound in such compositions is typically a trace component, often amounting to about 0.05 to 10% by weight, with the remainder often consisting of injectable excipients and the like.

[0340] Examples To make the technical solutions of this disclosure clearer and more specific, the disclosure will be described in more detail through the following examples. The following examples are intended to illustrate specific embodiments of this disclosure so that those skilled in the art can understand it, and are not intended to limit the scope of protection of this disclosure. Technical means or methods not specifically described in the specific embodiments of this disclosure are known technical means or methods in the art. Materials, reagents, etc. used in the examples are commercially available unless otherwise specified.

[0341] [Table 3]

[0342] Example 1: Synthesis of Compound 1a [ka] In a 500 mL three-necked round-bottom flask, 1-nonanol (15 g, 104.0 mmol, 1.0 equivalent), 8-bromooctanoic acid (25.5 g, 114.0 mmol, 1.1 equivalent), DMAP (2.54 g, 20.8 mmol, 0.2 equivalent), DIEA (40.3 g, 312.0 mmol, 3.0 equivalent), and EDCI (25.9 g, 135 mmol, 1.3 equivalent) were added at room temperature, and 250 mL of DCM was added. The reaction mixture was stirred at room temperature for 4 hours, and the completion of the reaction was monitored by TLC. The reaction mixture was poured into 200 mL of saturated ammonium chloride aqueous solution, and the mixture was extracted with 100 mL x 3 of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 21 g of the yellow oily compound 1a-2.

[0343] Compound 1a-2 (21 g, 60.1 mmol, 1.0 equivalent) and 2-aminoethanol (110 g, 1.80 mol, 30.0 equivalents) were added to a 250 mL three-necked round-bottom flask at room temperature, and the mixture was dissolved in 100 mL of methanol. The mixture was heated to 60 °C and stirred for 18 hours, after which it was concentrated to remove the reaction solvent. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to this, and the mixture was separated into layers and extracted. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 14 g of yellow oily compound 1a-3.

[0344] In a 250 mL three-necked round-bottom flask, 9-heptadecanol (9.8 g, 38.2 mmol, 1.0 equivalent) and triethylamine (15.5 g, 152.8 mmol, 4.0 equivalents) were added at room temperature, and the mixture was dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and 2-methylpropionyl chloride (9.8 g, 91.7 mmol, 2.4 equivalents) was slowly added. The mixture was warmed to room temperature and reacted overnight. After monitoring for completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 8.7 g of a yellow oily compound 1a-5.

[0345] Compound 1a-5 (8.7 g, 26.6 mmol, 1.0 equivalent) was added to a 250 mL three-necked round-bottom flask at room temperature, and the mixture was dissolved in 60 mL of THF. The reaction system was cooled to -40°C, and LDA (13.1 mL, 26.2 mmol, 0.98 equivalents) was slowly added dropwise. The mixture was stirred and reacted for 1 hour, after which 1,6-dibromohexane (9.03 g, 37.0 mmol, 1.39 equivalents) and DMPU (0.48 g, 3.73 mmol, 0.14 equivalents) were added to the reaction system. The mixture was warmed to room temperature and reacted overnight. After monitoring for completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride ice solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 10.1 g of the yellow oily compound 1a-6.

[0346] Compound 1a-6 (1.48 g, 3.04 mmol, 2.0 equivalents), compound 1a-3 (500 mg, 1.52 mmol, 1.0 equivalent), K2CO3 (628.2 mg, 4.55 mmol, 3.0 equivalents), KI (302.3 mg, 1.82 mmol, 1.2 equivalents), 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 reacted. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding saturated ammonium chloride ice solution, and the mixture was extracted by DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 96.98 mg of oily compound 1a.

[0347] 1H 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] + .

[0348] Example 2: Synthesis of Compound 2a [ka] In a 250 mL three-necked round-bottom flask, 1-nonanol (8.8 g, 61.0 mmol, 1.0 equivalent) and triethylamine (24.7 g, 244.0 mmol, 4.0 equivalents) were added at room temperature, and the mixture was dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and 2-methylpropionyl chloride (15.6 g, 146.4 mmol, 2.4 equivalents) was slowly added. The mixture was warmed to room temperature and allowed to react. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 10.8 g of a yellow oily compound 2a-2.

[0349] Compound 2a-2 (4.8 g, 22.4 mmol, 1.0 equivalent) was added to a 250 mL three-necked round-bottom flask at room temperature, and the mixture was dissolved in 50 mL of THF. The reaction system was cooled to -40°C, and LDA (11.0 mL, 21.9 mmol, 0.98 equivalents) was slowly added dropwise. The mixture was stirred and reacted for 1 hour, after which 1,6-dibromohexane (7.59 g, 31.1 mmol, 1.39 equivalents) and DMPU (0.57 g, 4.48 mmol, 0.2 equivalents) were added to the reaction system. The mixture was warmed to room temperature and reacted overnight. After monitoring for completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride ice solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 4.6 g of the yellow oily compound 2a-3.

[0350] Compound 2a-3 (4.6 g, 12.2 mmol, 1.0 equivalent) and 2-aminoethanol (14.9 g, 244.0 mmol, 20.0 equivalents) were added to a 250 mL three-necked round-bottom flask at room temperature, and the mixture was dissolved in 50 mL of ethanol. The mixture was heated to 60 °C and stirred for 18 hours, after which it was concentrated to remove the reaction solvent. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to this, and the mixture was separated into layers and extracted. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 2.2 g of yellow oily compound 2a-4.

[0351] In a 20 mL round-bottom flask, compound 2a-4 (500 mg, 1.4 mmol, 1.0 equivalent), compound 1a-6 (1.37 g, 2.8 mmol, 2.0 equivalent), K2CO3 (579 mg, 4.2 mmol, 3.0 equivalent), KI (279 mg, 1.68 mmol, 1.2 equivalents), cyclopentyl methyl ether (7.5 mL), and acetonitrile (2.5 mL) were added. The mixture was heated to 80°C and reacted. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding saturated ammonium chloride ice solution, and the mixture was extracted by DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 137.9 mg of oily compound 2a.

[0352] 1 H NMR(400MHz,CDCl3)δ:4.83(m,1H),4.04(t,J=7.2Hz,2H),3.55(t,J=5.6Hz,2H),2.60(t,J=5.6Hz,2H),2.47(t, ESI-MS m / z:766.50[M+H] + .

[0353] Example 3: Synthesis of Compound 3a [ka] Compound 3a was prepared according to the method of Example 1, yielding 114.7 mg of the oily product.

[0354] 1H 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) m / z:738.55[M+H] + .

[0355] Example 4: Synthesis of Compound 4a [ka] Compound 4a was prepared according to the method of Example 1, yielding 112.1 mg of the oily product.

[0356] 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] + .

[0357] Example 5: Synthesis of Compound 5a [ka] Compound 5a was prepared according to the method of Example 1, yielding 150.8 mg of the oily product.

[0358] 1H 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] + .

[0359] Example 6: Synthesis of Compound 6a [ka] 15.0 g, 150.0 mmol, 1.0 equivalent of tert-butyl cyclopropanecarboxylic acid was dissolved in 150 mL of anhydrous tetrahydrofuran, and the mixture was cooled to -60°C. 150.0 mL, 300.0 mmol, 2.0 equivalents of LDA were added to the reaction mixture under a nitrogen atmosphere. The mixture was stirred and reacted at the same temperature for 1 hour, then 44.9 g, 225.0 mmol, 1.5 equivalents of 1-bromo-6-chlorohexane were added, and the mixture was stirred and reacted at room temperature for a further 3 hours. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted by DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 19 g of colorless oily compound 6a-1.

[0360] To a solution of compound 6a-1 (10.0 g, 38.3 mmol) in DCM (30.0 mL), 10.0 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The reaction solvent was removed by pressurized rotary evaporation to obtain the crude product, which was purified by silica gel column chromatography to obtain 6.9 g of colorless oily compound 6a-2.

[0361] Compound 6a-2 (500.0 mg, 2.45 mmol, 2.0 equivalents) was dissolved in DCM (5.0 mL), and 2-3 drops of DMF and oxalyl chloride (311.1 mg, 2.45 mmol, 2.0 equivalents) were added to the reaction system under an ice bath. After stirring the mixture for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain an acyl chloride intermediate. The obtained acyl chloride was dissolved in DCM (5.0 mL), and 9-heptadecanol (312.3 mg, 1.22 mmol, 1.0 equivalent) and triethylamine (247.5 mg, 2.45 mmol, 2.0 equivalents) were added, and the mixture was reacted at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into 50 mL of water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 240 mg of oily compound 6a-3.

[0362] To a solution of compound 6a-3 (200.0 mg, 0.45 mmol, 1.5 equivalents) in DMF (3.0 mL), potassium carbonate (124.2 mg, 0.90 mmol, 3.0 equivalents), sodium iodide (112.5 mg, 0.75 mmol, 2.5 equivalents), and compound 1a-3 (99.0 mg, 0.30 mmol, 1.0 equivalent) were added. The reaction mixture was heated to 80°C and stirred for 5 hours. After the reaction was complete, the reaction system was cooled to room temperature. The reaction was quenched with saturated sodium chloride aqueous solution, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by preparative liquid chromatography to obtain 75.2 mg of compound 6a. (Column model: XSelect C18 (19×150mm, 5μm), Mobile phase A: Water:Acetonitrile = 90:10 (10 mmol / L ammonium bicarbonate + 0.5% aqueous ammonia), Mobile phase B: Isopropanol:Acetonitrile = 90:10, Flow rate: 25 mL / min, Gradient: B is 75%-80% from 0 to 12 minutes, B is 90% after 12 minutes)

[0363] 1H 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] + .

[0364] Example 7: Synthesis of compound 7a [ka] Compound 7a was prepared according to the method of Example 1, yielding 102.4 mg of the oily product.

[0365] 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] + .

[0366] Example 8: Synthesis of Compound 8a [ka] Compound 8a was prepared according to the method of Example 1, yielding 44.9 mg of the oily product.

[0367] 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] +.

[0368] Example 9: Synthesis of compound 9a [ka] In a 250 mL round-bottom flask, 5-bromo-1-pentanol (30 g, 180.0 mmol, 1.0 equivalent) and imidazole (30.6 g, 449.0 mmol, 2.5 equivalents) were dissolved in 120 mL of DMF. The reaction system was kept in an ice bath, and TBSCl (29.8 g, 198 mmol, 1.1 equivalents) was added to the reaction system. The mixture was warmed to room temperature and reacted overnight. After monitoring the completion of the reaction by TLC, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 26 g of a pale yellow oily compound 9a-1.

[0369] In a 250 mL three-necked round-bottom flask, Mg (1.70 g, 70.1 mmol, 1.6 equivalents), I2 (0.01 g, 0.039 mmol), and 50 mL of anhydrous THF were added. The reaction system was warmed to 37 °C, and compound 9a-1 (18.5 g, 65.7 mmol, 1.5 equivalents) was slowly added within 30 minutes, and the mixture was reacted until the magnesium powder was almost completely gone to obtain the Grignard reagent. In a 250 mL three-necked round-bottom flask, CuBr (0.63 g, 4.38 mmol, 0.1 equivalent), LiCl (0.37 g, 8.76 mmol, 0.2 equivalents), and 50 mL of anhydrous THF were added under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes, and then methyl 3,3-dimethacrylate (5 g, 43.8 mmol, 1.0 equivalent) and TMSCl (7.14 g, 65.7 mmol, 1.5 equivalents) were added dropwise to the resulting lithium copper reagent solution. After the addition was complete, the mixture was stirred at 0°C for a further 30 minutes. The prepared Grignard reagent was slowly added dropwise to the reaction mixture, and after the addition was complete, the mixture was reacted for a further 2 hours. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 13 g of a pale yellow oily compound 9a-2.

[0370] To a THF solution of compound 9a-2 (13 g, 41.1 mmol, 1.0 equivalent), TBAF (21.5 g, 82.1 mmol, 2.0 equivalents) was added in several batches under an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product 9a-3, which was used directly in the next step without purification.

[0371] Compound 9a-3 (14 g, 69.2 mmol, 1.0 equivalent) and PPh3 (21.8 g, 83.0 mmol, 1.2 equivalents) were dissolved in 140 mL of dichloromethane. After cooling the reaction system to 0°C, CBr4 (25.3 g, 76.1 mmol, 1.1 equivalents) was added in several portions. The mixture was stirred at room temperature, and the completion of the reaction was monitored by TLC. The reaction was quenched with ice-saturated sodium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 7.6 g of pale yellow oily compound 9a-4.

[0372] To a 60 mL THF solution of compound 9a-4 (6 g, 22.6 mmol, 1 equivalent), TMSOK (4.35 g, 33.9 mmol, 1.5 equivalents) was added. The mixture was stirred at room temperature, and after monitoring for completion of the reaction 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 mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 2.5 g of pale yellow oily compound 9a-5.

[0373] Compound 9a was prepared according to the method of Example 1, yielding 81.7 mg of the oily product.

[0374] 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 ESI-MS m / z:738.65[M+H] + .

[0375] Example 10: Synthesis of Compound 10a [ka] In a 100 mL round-bottom flask, methyl 4-bromobutyrate (4 g, 22.1 mmol, 1.0 equivalent) was dissolved in 40 mL of MTBE. The reaction system was kept in an ice bath, and methylmagnesium bromide (22.1 mL, 66.3 mmol, 3.0 equivalents) was added to the reaction system. The mixture was warmed to room temperature, and after monitoring for completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with RINKAN. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 3.5 g of compound 10a-2.

[0376] In a 100 mL round-bottom flask, compound 10a-2 (3 g, 16.6 mmol, 1.0 equivalent), triethylchlorosilane (7.49 g, 49.7 mmol, 3.0 equivalent), zinc powder (3.25 g, 49.7 mmol, 3.0 equivalent), Cp*TiCl3 (519 mg, 1.80 mmol, 0.1 equivalent), and a 5A molecular sieve (2.4 g) were mixed under a nitrogen atmosphere, and then 24 mL of anhydrous THF was added. After heating the reaction system to 50 °C, ethyl acrylate (2.49 g, 24.9 mmol, 1.5 equivalent) was added to the reaction system. The mixture was heated to 60 °C and reacted for a further 12 hours. The reaction solution was cooled to room temperature, and the reaction was quenched by adding saturated sodium chloride aqueous solution. The mixture was then extracted with RINKAN. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 2.4 g of compound 10a-3.

[0377] In a 40 mL reaction flask, compound 10a-3 (1 g, 3.77 mmol, 1.0 equivalent) was dissolved in a mixed solution of 10 mL of ethanol and 2 mL of water, and then lithium hydroxide (0.27 g, 11.3 mmol, 3.0 equivalents) was added to the reaction system. The mixture was allowed to react at room temperature, and after monitoring for completion of the reaction by TLC, the organic solvent was removed by rotary evaporation, and the pH of the solution was adjusted to approximately 4 with 2.0 M dilute hydrochloric acid. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the mixture was extracted with EtOAC. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 800 mg of compound 10a-4.

[0378] Compound 10a was prepared according to the method of Example 1, yielding 93.4 mg of the oily product.

[0379] 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] + .

[0380] Example 11: Synthesis of compound 11a [ka] Compound 11a was prepared according to the method of Example 1, yielding 69.5 mg of the oily product.

[0381] 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] + .

[0382] Example 12: Synthesis of Compound 12a [ka] Compound 12a was prepared according to the method of Example 1, yielding 178.6 mg of the oily product.

[0383] 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] + .

[0384] Example 13: Synthesis of Compound 13a [ka] Compound 13a was prepared according to the method of Example 1, yielding 43.5 mg of the oily product.

[0385] 1H NMR(400MHz,CDCl3)δ:4.81(p,J=6.4Hz,1H),4.06(t,J=6.8Hz,2H),3.58(m,2H),2.58-2.36(m,6H),2.30(t,J=7.6Hz,2 ESI-MS m / z:736.60[M+H] + .

[0386] Example 14: Synthesis of Compound 14a [ka] Compound 14a was prepared according to the method of Example 1, yielding 56.3 mg of the oily product.

[0387] 1 H NMR(400MHz,CDCl3)δ:4.08(t,J=6.8Hz,2H),4.01(d,J=4.8Hz,2H),3.97(d,J=5.6Hz,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] + .

[0388] Example 15: Synthesis of Compound 15a [ka] Compound 15a was prepared according to the method of Example 1, yielding 120.3 mg of the oily product.

[0389] 1H 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) m / z:710.55[M+H] + .

[0390] Example 16: Synthesis of Compound 16a [ka] Compound 16a was prepared according to the method of Example 1, yielding 80.8 mg of the oily product.

[0391] 1 H NMR(400MHz,CDCl3)δ:4.07-3.92(m,4H),3.60(m,2H),2.66-2.46(m,6H),2.30(t,J=7.6H z,2H),1.68-1.44(m,12H),1.38-1.07(m,44H),1.05(s,6H),0.88(t,J=7.2Hz,9H) m / z:696.55[M+H] + .

[0392] Example 17: Synthesis of Compound 17a [ka] Compound 17a was prepared according to the method of Example 1, yielding 125.7 mg of the oily product.

[0393] 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] + .

[0394] Example 18: Synthesis of Compound 18a [ka] Compound 18a was prepared according to the method of Example 1, yielding 127.4 mg of the oily product.

[0395] 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 ESI-MS m / z:738.66[M+H] + .

[0396] Example 19: Synthesis of Compound 19a [ka] Compound 19a was prepared according to the method of Example 9, yielding 79.7 mg of the oily product.

[0397] 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) m / z:738.65[M+H] + .

[0398] Example 20: Synthesis of compound 20a [ka] Compound 20a was prepared according to the method of Example 10, yielding 74.5 mg of the oily product.

[0399] 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) m / z:738.45[M+H] + .

[0400] The compounds in Table 2 were synthesized using the methods described in the above examples or similar methods for the corresponding intermediates.

[0401] [Table 4]

[0402] Example 30: Synthesis of Compound 1b [ka] 9-Heptadecanol 1b-1 (200.0 mg, 0.78 mmol, 1.0 equivalent) was dissolved in DCM (2.0 mL), and 8-bromooctanoic acid (226.2 mg, 1.01 mmol, 1.3 equivalents), EDCI (179.4 mg, 0.94 mmol, 1.2 equivalents), and DMAP (42.9 mg, 1.17 mmol, 1.5 equivalents) were added to the solution. The reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was poured into 10 mL of saturated sodium chloride aqueous solution. The mixture was extracted with 3 × 20 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 300 mg of a yellow oily compound 1b-2.

[0403] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 equivalent) was dissolved in 200 mL of anhydrous THF, the mixture was cooled to 0°C, and LDA (205 mL, 410.0 mmol, 2.0 equivalents) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was heated to room temperature. After stirring for 30 minutes, 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 equivalent) was added. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with 3 × 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 30 g of a yellow oily compound 1b-4.

[0404] Compound 1b-4 (15.0 g, 40.0 mmol, 1.0 equivalent) was dissolved in 30 mL of THF, the mixture was cooled to 0°C, and borane-tetrahydrofuran solution (1 M, 100.0 mL) was added dropwise to the reaction system under a nitrogen atmosphere. The mixture was heated to 75°C and stirred for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with 3 × 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain crude product 1b-5 (13.6 g), which was used directly in the next step without purification.

[0405] Caprinoyl chloride (11.0 g, 58.0 mmol, 1.3 equivalents) was added to a solution of compound 1b-5 (10.0 g, 44.0 mmol, 1.0 equivalent) in DCM (100 mL), and triethylamine (13.5 g, 134.0 mmol, 3.0 equivalents) was added to the reaction system. The mixture was reacted at room temperature for 3 hours. The reaction solution was poured into 100 mL of water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 10 g of compound 1b-6.

[0406] Potassium carbonate (1.5 g, 11.1 mmol, 3.0 equivalents) and compound 1b-6 (1.4 g, 3.7 mmol, 1.0 equivalent) were added to a solution of ethanolamine (2.3 g, 37.2 mmol, 10.0 equivalents) in acetonitrile (15.0 mL). The mixture was heated to 70°C and stirred for 3 hours to allow the reaction to proceed. The reaction solution was poured into 30 mL of water, and the mixture was extracted using DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 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).

[0407] Compound 1b-2 (300.0 mg, 0.84 mmol, 1.0 equivalent) and Compound 1b-7 (503.4 mg, 1.09 mmol, 1.3 equivalents) were dissolved in DMF (3.0 mL). Then, potassium carbonate (289.9 mg, 2.1 mmol, 2.5 equivalents) and sodium iodide (314.4 mg, 2.1 mmol, 2.5 equivalents) were added, and the mixture was heated to 70°C and stirred for 2 hours to react. The reaction solution was poured into 20 mL of water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain Compound 1b (158.9 mg).

[0408] 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] +.

[0409] Example 31: Synthesis of Compound 2b [ka] Potassium carbonate (549.3 mg, 4.0 mmol, 3.0 equivalents) and compound 1b-6 (500.0 mg, 1.33 mmol, 1.0 equivalent) were added to a solution of 3-amino-1-propanol (1.0 g, 13.3 mmol, 10.0 equivalents) in acetonitrile (10.0 mL). The mixture was heated to 70°C and stirred for 3 hours to allow the reaction to proceed. The reaction solution was poured into 30 mL of water, and the mixture was extracted using DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 350 mg of colorless oily compound 2b-1.

[0410] Compound 1b-2 (565 mg, 1.22 mmol, 1.3 equivalents) and Compound 2b-1 (350 mg, 0.94 mmol, 1.0 equivalent) were dissolved in DMF (5.0 mL). Then, potassium carbonate (389 mg, 2.82 mmol, 3.0 equivalents) and sodium iodide (353 mg, 2.35 mmol, 2.5 equivalents) were added, and the mixture was heated to 70°C and stirred for 5 hours to react. The reaction solution was poured into 20 mL of water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain Compound 2b (160 mg).

[0411] 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] + .

[0412] Example 32: Synthesis of Compound 3b [ka] Potassium carbonate (549 mg, 4.0 mmol, 3.0 equivalents) and compound 1b-6 (500 mg, 1.33 mmol, 1.0 equivalent) were added to a solution of 4-amino-1-butanol (1.2 g, 13.3 mmol, 10.0 equivalents) in DMF (10.0 mL). The mixture was heated to 70°C and stirred for 3 hours to allow the reaction to proceed. The reaction solution was poured into 30 mL of water, and the mixture was extracted using DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 300 mg of colorless oily compound 3b-1.

[0413] Compound 1b-2 (462 mg, 1.0 mmol, 1.3 equivalents) and compound 3b-1 (297 mg, 0.77 mmol, 1.0 equivalent) were dissolved in DMF (5.0 mL). Then, potassium carbonate (269 mg, 1.9 mmol, 2.5 equivalents) and sodium iodide (285 mg, 1.9 mmol, 2.5 equivalents) were added, and the mixture was heated to 70°C and stirred for 5 hours to allow the reaction to proceed. The reaction solution was poured into 20 mL of water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain compound 3b (228 mg).

[0414] 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),2.2 4-2.37(m,4H),2.47-2.58(m,6H),3.56(s,2H),3.77(s,2H),4.81-4.88(m,1H);ESI-MSm / z:766.85[M+H] + .

[0415] Example 33: Synthesis of Compound 4b [ka] Methyl isobutyrate (21 g, 205 mmol, 1.0 equivalent) was dissolved in 200 mL of anhydrous THF, the mixture was cooled to 0°C, and LDA (205 mL, 410 mmol, 2.0 equivalents) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was heated to room temperature. After stirring for 30 minutes, 1,6-dibromohexane (50 g, 205 mmol, 1.0 equivalent) was added. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with 3 × 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 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).

[0416] Compound 4b-2 (10.0 g, 37.6 mmol, 1.0 equivalent) was added to an aqueous hydrobromic acid solution (50.0 mL). The reaction mixture was heated to 100°C and stirred for 24 hours. After the reaction was complete, the reaction system was cooled to room temperature. The reaction was quenched with a saturated aqueous sodium chloride solution, and the mixture was extracted using DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 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).

[0417] Compound 4b-3 (5.0 g, 19.9 mmol, 1.0 equivalent) was dissolved in DCM (50.0 mL), and DMF (291.0 mg, 3.98 mmol, 0.2 equivalents) and oxalyl chloride (5.1 g, 39.8 mmol, 2.0 equivalents) were added to the reaction system under an ice bath. After stirring the mixture for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain an acyl chloride intermediate. The obtained acyl chloride was dissolved in DCM (50.0 mL), and 9-heptadecanol (4.08 g, 15.9 mmol, 0.8 equivalents) and triethylamine (6.03 g, 59.7 mmol, 3.0 equivalents) were added, and the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into 300 mL of water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 4.3 g of the oily compound 4b-4.

[0418] Compound 4b-4 (492.9 mg, 1.0 mmol, 1.2 equivalents) was dissolved in DMF (3.0 mL) to which potassium carbonate (347.8 mg, 2.5 mmol, 3.0 equivalents), sodium iodide (314.4 mg, 2.1 mmol, 2.5 equivalents), and compound 1b-7 (300.0 mg, 0.8 mmol, 1.0 equivalent) were added. The reaction mixture was heated to 70°C and stirred for 2 hours. After the reaction was complete, the reaction system was cooled to room temperature. The reaction was quenched with saturated sodium chloride aqueous solution, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by preparative liquid chromatography to obtain 106 mg of compound 4b. (Column model: XBridge Shield RP18 OBD column 19×150mm, 5μm; Mobile phase A: Acetonitrile:Water (10 mmol / L ammonium bicarbonate + 0.05% aqueous ammonia), Mobile phase B: Isopropanol:Acetonitrile; Flow rate: 20 mL / min; Gradient: The proportion of mobile phase B was gradually increased from 75%B to 95%B within 9 minutes).

[0419] 1H 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] + .

[0420] Example 34: Synthesis of Compound 5b [ka] Compound 5b was prepared according to the method of Example 30, yielding 174 mg of the oily product.

[0421] 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] + .

[0422] Example 35: Synthesis of Compound 6b [ka] Compound 6b was prepared according to the method of Example 30, yielding 113 mg of the oily product.

[0423] 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),2.27-2.32 (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] + .

[0424] Example 36: Synthesis of Compound 7b [ka] Compound 7b was prepared according to the method of Example 30, yielding 91 mg of the oily product.

[0425] 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] + .

[0426] Example 37: Synthesis of Compound 8b [ka] Compound 8b was prepared according to the method of Example 30, yielding 124 mg of the oily product.

[0427] 1H 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] + .

[0428] Example 38: Synthesis of Compound 9b [ka] 15.0 g, 150.0 mmol, 1.0 equivalent of tert-butyl cyclopropanecarboxylic acid was dissolved in 150 mL of anhydrous tetrahydrofuran, and the mixture was cooled to -60°C. 150.0 mL, 300.0 mmol, 2.0 equivalents of LDA were added to the reaction mixture under a nitrogen atmosphere. The mixture was stirred and reacted at the same temperature for 1 hour, then 44.9 g, 225.0 mmol, 1.5 equivalents of 1-bromo-6-chlorohexane were added, and the mixture was stirred and reacted at room temperature for a further 3 hours. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with 3 × 300 mL of DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 19 g of a colorless oily compound 9b-1.

[0429] Compound 9b-1 (10.0 g, 38.3 mmol) was dissolved in DCM (30.0 mL), and 10.0 mL of trifluoroacetic acid was added to the solution. The mixture was stirred at room temperature for 3 hours. The reaction solvent was removed by pressurized rotary evaporation to obtain the crude product, which was purified by silica gel column chromatography to obtain 6.9 g of colorless oily compound 9b-2.

[0430] Compound 9b-2 (500.0 mg, 2.45 mmol, 2.0 equivalents) was dissolved in DCM (5.0 mL), and 2-3 drops of DMF and oxalyl chloride (311.1 mg, 2.45 mmol, 2.0 equivalents) were added to the reaction system under an ice bath. After stirring the mixture for 30 minutes, the solvent was removed by rotary evaporation under reduced pressure to obtain an acyl chloride intermediate. The obtained acyl chloride was dissolved in DCM (5.0 mL), and 9-heptadecanol (312.3 mg, 1.22 mmol, 1.0 equivalent) and triethylamine (247.5 mg, 2.45 mmol, 2.0 equivalents) were added, and the mixture was reacted at room temperature for 5 hours. After the reaction was complete, the reaction solution was poured into 50 mL of water, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 240 mg of oily compound 9b-3.

[0431] To a solution of compound 9b-3 (200 mg, 0.45 mmol, 1.5 equivalents) in DMF (3.0 mL), potassium carbonate (124.2 mg, 0.90 mmol, 3.0 equivalents), sodium iodide (112.5 mg, 0.75 mmol, 2.5 equivalents), and compound 6b-1 (99.0 mg, 0.30 mmol, 1.0 equivalent) were added. The reaction mixture was heated to 70°C and stirred for 5 hours. After the reaction was complete, the reaction system was cooled to room temperature. The reaction was quenched with saturated sodium chloride aqueous solution, and the mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by preparative liquid chromatography to obtain 85.4 mg of compound 9b. (Column model: XBridge Shield RP18 OBD column 19×150mm, 5μm; Mobile phase A: Acetonitrile:Water (10 mmol / L ammonium bicarbonate + 0.05% aqueous ammonia), Mobile phase B: Isopropanol:Acetonitrile; Flow rate: 20 mL / min; Gradient: From 75%B to 95%B in 9 minutes).

[0432] 1H 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] + .

[0433] Example 39: Synthesis of compound 10b [ka] Compound 10b was prepared according to the method of Example 30, yielding 128 mg of the oily product.

[0434] 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] + .

[0435] Example 40: Synthesis of compound 11b [ka] Compound 11b was prepared according to the method of Example 30, yielding 92 mg of an oily product.

[0436] 1H 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] + .

[0437] Example 41: Synthesis of compound 12b [ka] Compound 12b was prepared according to the method of Example 30, yielding 105 mg of the oily product.

[0438] 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 ESI-MS m / z:682.60[M+H] + .

[0439] The compounds in Table 3 were synthesized using the methods described in the above examples or similar methods for the corresponding intermediates.

[0440] [Table 5]

[0441] Example 54: Synthesis of Compound 30a [ka] In a 250 mL round-bottom flask, 9-heptadecanol (10.0 g, 39.0 mmol, 1.0 equivalent) and pyridine (6.17 g, 78.0 mmol, 2.0 equivalents) were dissolved in 100 mL of dichloromethane, and the reaction system was cooled to 0°C. Isobutyryl chloride (10.39 g, 97.5 mmol, 2.5 equivalents) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water at 0°C, and the mixture was extracted with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and then the solvent was removed by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to obtain a yellow oily compound 1a-5 (10.4 g).

[0442] Compound 1a-5 (10.0 g, 30.62 mmol, 1.0 equivalent) was dissolved in anhydrous THF (100 mL), the reaction system was cooled to -40°C, and LDA (15.3 mL, 30.6 mmol, 1.0 equivalent) was added to the reaction mixture under a nitrogen atmosphere. The mixture was stirred and reacted at -40°C for 1 hour, after which 1,6-dibromohexane (14.9 g, 61.2 mmol, 2.0 equivalents) and DMPU (471 mg, 3.7 mmol, 0.12 equivalents) were added at the same temperature. The reaction system was slowly warmed to room temperature and allowed to react overnight. After the reaction was complete, the reaction mixture was added to saturated NH4Cl solution, and the mixture was 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 was used directly in the next step without purification.

[0443] Compound 1a-6 (15 g, 30.6 mmol, 1.0 equivalent) and ethanolamine (37.4 g, 612.0 mmol, 20.0 equivalents) were dissolved in 80 mL of ethanol, and the reaction system was heated to 60°C and reacted for 2 hours. After the reaction was complete, the reaction system was cooled to room temperature, the ethanol solvent was removed by rotary evaporation, and the crude product was dissolved in ethyl acetate, after which saturated sodium chloride solution was added. After extraction, the organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and then the solvent was removed by rotary evaporation. The obtained crude product was purified by silica gel column chromatography to obtain a yellow oily compound 30a-1 (12.4 g).

[0444] In a 50 mL reaction flask, 6-bromo-1-hexanol (1.5 g, 8.3 mmol, 1.0 equivalent) and pyridine (1.31 g, 16.6 mmol, 2.0 equivalents) were dissolved in 15 mL of DCM. n-nonyl chloroformate (1.88 g, 9.1 mmol, 1.1 equivalents) was added dropwise within 15 minutes under ice bath conditions, and the mixture was left at room temperature overnight. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and then the solvent was removed by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to obtain a yellow oily compound 30a-4 (2.5 g).

[0445] In an 8 mL sealed tube, compound 30a-4 (200 mg, 0.57 mmol, 1.0 equivalent), compound 30a-1 (294.2 mg, 0.63 mmol, 1.1 equivalents), KI (113.4 mg, 0.68 mmol, 1.2 equivalents), K2CO3 (236.0 mg, 1.71 mmol, 3.0 equivalents), and 5.0 mL of anhydrous acetonitrile were added. The mixture was heated to 80°C, stirred, and reacted overnight. After cooling to room temperature, the mixture was filtered. The filtered cake was washed with acetonitrile, the organic phases were combined, and the solvent was removed by rotary evaporation to obtain the crude reaction product. The crude product was purified by preparative liquid chromatography to obtain compound 30a (87.9 mg).

[0446] 1H 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] + .

[0447] Example 55: Synthesis of Compound 31a [ka] Compound 31a was prepared according to the method of Example 54, yielding 80.7 mg of the oily product.

[0448] 1 H NMR(400MHz,CDCl3)δ:4.83(p,J=6.6Hz,1H),4.12(td,J=7.2,2.4Hz,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] + .

[0449] Example 56: Synthesis of Compound 32a [ka] Compound 32a was prepared according to the method of Example 54, yielding 93.9 mg of the oily product.

[0450] 1 H NMR(300MHz,CDCl3)δ:4.85(p,J=6.6Hz,1H),4.12(t,J=6.6Hz,4H),3.79(t,J=5.1Hz,2H),2.65(m,2H),2.42(m,4 ESI-MS m / z:754.60[M+H]+ .

[0451] Example 57: Synthesis of Compound 33a [ka] Compound 33a was prepared according to the method of Example 54, yielding 164.2 mg of the oily product.

[0452] 1 H NMR(400MHz,CDCl3)δ:4.12(t,J=6.8Hz,4H),3.95(d,J=5.6Hz,2H),3.54(t,J=5.2Hz,2H),2.59(t,J=5. ESI-MS m / z:726.50[M+H] + .

[0453] Example 58: Synthesis of Compound 34a [ka] Compound 34a was prepared according to the method of Example 54, yielding 150.1 mg of the oily product.

[0454] 1 H NMR(400MHz,CDCl3)δ:4.12(t,J=6.8Hz,4H),4.08(t,J=6.8Hz,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] + .

[0455] Example 59: Synthesis of Compound 35a [ka] Compound 35a was prepared according to the method of Example 54, yielding 217.9 mg of the oily product.

[0456] 1 H NMR(400MHz, CDCl3)δ:4.12(t,J=6.8Hz,4H),4.03(t,J=6.8Hz,2H),3.53(t,J=5.2Hz,2H),2.58(t,J=5.2Hz ,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] + .

[0457] Example 60: Synthesis of Compound 36a

change

[0458] 1 H 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] + .

[0459] Example 61: Synthesis of Compound 37a

change

[0460] 1H 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] + .

[0461] Example 62: Synthesis of Compound 38a [ka] Compound 38a was prepared according to the method of Example 54, yielding 44.8 mg of the oily product.

[0462] 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] + .

[0463] Example 63: Synthesis of Compound 39a [ka] Compound 39a was prepared according to the method of Example 54, yielding 105.4 mg of the oily product.

[0464] 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] + .

[0465] Example 64: Synthesis of Compound 40a [ka] In a 500 mL round-bottom flask, nonanoic acid (15.0 g, 94.8 mmol, 1.0 equivalent) and THF (150 mL) were added at room temperature under a nitrogen atmosphere. The reaction system was cooled to 0 °C, and NaH (3.64 g, 151.7 mmol, 1.6 equivalents) was added sequentially in several portions, followed by the dropwise addition of LDA (85.3 mL, 170.6 mmol, 1.8 equivalents, 2 M in THF). The mixture was stirred at room temperature for 1 hour, and 1-iodoheptane (23.6 g, 104.3 mmol, 1.1 equivalents) was added to the reaction system at 0 °C. The reaction system was stirred overnight at 80 °C. The reaction was monitored by TLC, and new spots of the product were discovered. The reactants were cooled to room temperature, the reaction was quenched with ice water, and the mixture was extracted three times using DCM. The organic phases were combined, washed once with saturated NaCl solution, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain yellow, oily 2-heptylnonanoic acid (16.36 g).

[0466] In a 250 mL round-bottom flask, 7.0 g of 2-heptyrnonanoic acid (27.3 mmol, 1.0 equivalent) was dissolved in 70 mL of anhydrous THF at room temperature. The reaction system was cooled to 0°C, and 16.38 mL of LiAlH4 (2.5 M in THF) was added dropwise over 30 minutes. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC to confirm that the conversion of the starting materials was complete. The reaction mixture was poured into a saturated sodium chloride solution to quench the reaction, the mixture was extracted with ethyl acetate, the organic phases were combined, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain a pale yellow oily 2-heptyrnonanol product (6.97 g).

[0467] In a 50 mL three-necked round-bottom flask, 2-heptyrnonanol (400 mg, 1.65 mmol, 1.0 equivalent), pyridine (261.0 mg, 3.30 mmol, 2.0 equivalents), DMAP (40.3 mg, 0.33 mmol, 0.2 equivalents), p-nitrophenyl chloroformate (399.0 mg, 1.98 mmol, 1.2 equivalents), and DCM (4 mL) were added at room temperature. The reaction system was stirred at room temperature for 1 hour. Then, 6-bromo-1-hexanol (896.2 mg, 4.95 mmol, 3.0 equivalents) and DIEA (639.7 mg, 4.95 mmol, 3.0 equivalents) were added to the reaction system. The system 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 obtain a pale yellow, oily carbonate intermediate compound 40a-4 (325 mg).

[0468] In an 8 mL sealed tube, compound 40a-4 (250 mg, 0.56 mmol, 1.0 equivalent), compound 2a-4 (179.0 mg, 0.50 mmol, 0.9 equivalents), potassium iodide (110.8 mg, 0.67 mmol, 1.2 equivalents), potassium carbonate (230.6 mg, 1.68 mmol, 3.0 equivalents), and acetonitrile (2.5 mL) were added at room temperature. The mixture was heated to 80°C and stirred and reacted overnight. The reaction was confirmed by LC-MS, and the reaction system was cooled to room temperature. The mixture was filtered, concentrated, and purified by preparative HPLC to obtain compound 40a (84.3 mg), a pale yellow oily product.

[0469] 1 H NMR(400MHz,CDCl3)δ:4.14(t,J=6.8Hz,2H),4.06(dd,J=8.0,6.0Hz,4H),3.60(m,2H),2.65-2 .53(m,6H),1.73-1.60(m,12H),1.42-1.22(m,46H),1.18(s,6H),0.90(t,J=6.8Hz,9H);ESI-MS m / z:726.50[M+H] + .

[0470] Example 65: Synthesis of Compound 41a [ka] Compound 41a was prepared according to the method of Example 64, yielding 113.3 mg of the oily product.

[0471] 1 H NMR(400MHz,CDCl3)δ:4.14(td,J=9.2,6.8Hz,4H),4.06(t,J=6.8Hz,2H),3.57(m,2H),2.62-2 .49(m,6H),1.71-1.63(m,6H),1.57-1.22(m,50H),1.17(s,6H),0.90(t,J=6.8Hz,9H);ESI-MS m / z:712.55[M+H] + .

[0472] Example 66: Synthesis of Compound 42a [ka] Compound 42a was prepared according to the method of Example 64, yielding 124.2 mg of the oily product.

[0473] 1 H NMR(300MHz,CDCl3)δ:4.12(td,J=6.6,4.8Hz,4H),4.04(t,J=6.6Hz,2H),3.55(t,J=5.7Hz,2H), 2.60-2.47(m,6H),1.72-1.62(m,6H),1.59-1.19(m,48H),1.15(s,6H),0.93-0.83(m,9H);ESI-MS m / z:698.55[M+H] + .

[0474] Example 67: Synthesis of Compound 43a [ka] Compound 43a was prepared according to the method of Example 64, yielding 97.7 mg of the oily product.

[0475] 1H NMR(400MHz,CDCl3)δ:4.15(td,J=6.8,1.6Hz,4H),4.06(t,J=6.8Hz,2H),3.64(m,2H),2.68 -2.56(m,6H),1.76-1.60(m,8H),1.54-1.22(m,44H),1.18(s,6H),0.96-0.86(m,9H);ESI-MS m / z:684.45[M+H] + .

[0476] Example 68: Synthesis of Compound 44a [ka] In a 20 mL round-bottom flask, compound 44a-1 (587.58 mg, 2.34 mmol, 1.2 equivalents), 2-heptylnonanol (500 mg, 1.95 mmol, 1.0 equivalent), EDCI (560.58 mg, 2.93 mmol, 1.5 equivalents), and DMAP (47.63 mg, 0.39 mmol, 0.2 equivalents) were dissolved in 5 mL of dichloromethane, and the mixture was reacted overnight at room temperature. After the reaction was complete, saturated sodium chloride aqueous solution was added to quench the reaction, the mixture was extracted with dichloromethane, the organic phases were combined, dried over Na2SO4, filtered, and concentrated to obtain 1 g of crude 44a-2, which was used directly in the next reaction.

[0477] Compound 44a was prepared according to the method of Example 54, yielding 165.3 mg of the oily product.

[0478] 1 H NMR(400MHz,CDCl3)δ:4.12(t,J=6.8Hz,4H),3.96(d,J=5.6Hz,2H),3.59(m,2H),2.53-2.42( m,6H),2.26-2.20(m,2H),1.70-1.63(m,7H),1.56-1.19(m,49H),0.92-0.83(m,15H);ESI-MS m / z:726.50[M+H] + .

[0479] Example 69: Synthesis of Compound 45a [ka] Compound 45a was prepared according to the method of Example 68, yielding 107.2 mg of the oily product.

[0480] 1 H NMR(300MHz,CDCl3)δ:4.12(t,J=6.6Hz,2H),4.04(t,J=6.6Hz,4H),3.57(m,2H),2.63-2.51(m, 6H), 2.18(s,2H),1.73-1.61(m,5H),1.59-1.21(m,51H),0.98(s,6H),0.93-0.83(m,9H) m / z:726.55[M+H] + .

[0481] Example 70: Synthesis of compound 46a [ka] Compound 46a was prepared according to the method of Example 68, yielding 116.7 mg of the oily product.

[0482] 1 H NMR(300MHz,CDCl3)δ:4.12(t,J=6.6Hz,2H),4.07-4.02(m,4H),3.58(m,2H),2.64-2.49(m ,6H),2.27-2.21(m,2H),1.73-1.60(m,5H),1.56-1.21(m,51H),0.93-0.82(m,15H);ESI-MS m / z:726.45[M+H] + .

[0483] Example 71: Synthesis of compound 47a [ka] Compound 47a was prepared according to the method of Example 68, yielding 24.2 mg of the oily product.

[0484] 1H NMR(400MHz,CDCl3)δ:4.12(t,J=6.8Hz,2H),4.07-4.02(m,4H),3.73(m,2H),2.81-2.63(m,6 ESI-MS m / z:726.55[M+H] + .

[0485] Example 72: Synthesis of Compound 48a [ka] Compound 48a was prepared according to the method of Example 54, yielding 258.1 mg of the oily product.

[0486] 1 H NMR(300MHz,CDCl3)δ:4.85(p,J=6.0Hz,1H),4.12(t,J=6.6Hz,4H),3.59(m,2H),2.65-2.5 2(m,6H),1.67-1.62(m,5H),1.49-1.20(m,60H),1.15(s,6H),0.88(t,J=6.6Hz,9H);ESI-MS m / z:782.72[M+H] + .

[0487] Example 73: Synthesis of Compound 49a [ka] Compound 49a was prepared according to the method of Example 54, yielding 27.9 mg of the oily product.

[0488] 1 H NMR(300MHz,CDCl3)δ:4.82(p,J=6.0Hz,1H),4.12(t,J=6.6Hz,4H),3.65(m,2H),2.73-2.6 1(m,6H),1.83-1.62(m,9H),1.51-1.19(m,64H),1.15(s,6H),0.89(t,J=6.6Hz,9H);ESI-MS m / z:824.70[M+H] + .

[0489] Example 74: Synthesis of Compound 50a [ka] Compound 50a was prepared according to the method of Example 68, yielding 75.9 mg of the oily product.

[0490] 1 H NMR(400MHz,CDCl3)δ:4.12(t,J=6.6Hz,2H),4.03(d,J=6.0Hz,2H),3.96(d,J=6.0Hz,2H),3.61(m,2H), 2.67-2.55(m,6H),2.32(t,J=7.2Hz,2H),1.72-1.54(m,10H),1.52-1.20(m,57H),0.89(m,18H);ESI-MS m / z:824.65[M+H] + .

[0491] Example 75: Synthesis of Compound 51a [ka] In a 250 mL reaction flask, methyl isobutyrate (3.5 g, 34.3 mmol, 1.0 equivalent) and THF (40 mL) were added under a nitrogen atmosphere, and the mixture was cooled to -40°C. LDA (17.2 mL, 34.3 mmol, 1.0 equivalent, 2 M in THF) was added dropwise within 10 minutes, and after the addition was complete, the mixture was allowed to react for a further 1.5 hours. Then, 1,4-dibromobutane (14.80 g, 68.5 mmol, 2.0 equivalent) and DMPU (0.88 g, 6.85 mmol, 0.2 equivalent) were added dropwise at the same temperature within 5 minutes, and the mixture was slowly warmed to room temperature and allowed to react overnight. After the reaction was complete, saturated aqueous ammonium chloride solution was added to quench the reaction, the mixture was extracted with ethyl acetate, the organic phases were combined, dried over Na2SO4, filtered, concentrated, and the organic solvent was removed by rotary evaporation to obtain 7.5 g of crude methyl 2,2-dimethyl-6-bromohexanoate compound.

[0492] In a 250 mL round-bottom flask, methyl 2,2-dimethyl-6-bromohexanoate (7.5 g, crude) was dissolved in 75 mL of anhydrous THF. After cooling the mixture to 0°C, LiAlH4 (10.12 mL, 25.3 mmol, 2.5 M in THF) was added dropwise. After the dropwise addition was complete, the mixture was reacted for a further 30 minutes. After the reaction was complete, saturated aqueous ammonium chloride solution was added to quench the reaction, the mixture was extracted with ethyl acetate, the organic phases were combined, dried over Na2SO4, filtered, concentrated, and the organic solvent was removed by rotary evaporation to obtain 7.5 g of crude product, which was purified by silica gel column chromatography to obtain 2.5 g of 2,2-dimethyl-6-bromohexanol compound.

[0493] Compound 51a was prepared according to the method of Example 64, yielding 205.5 mg of the oily product.

[0494] 1 H NMR(300MHz,CDCl3)δ:4.08-4.02(m,4H),3.85(s,2H),3.54(t,J=5.1Hz,2H),2.59(t,J=5.1Hz,2H),2.4 9-2.43(m,4H),2.29(t,J=7.5Hz,2H),1.66-1.57(m,6H),1.55-1.22(m,50H),0.92-0.83(m,15H);ESI-MS m / z:726.80[M+H] + .

[0495] Example 76: Synthesis of Compound 25b [ka] Compound 25b was prepared according to the method of Example 75, yielding 152.1 mg of the oily product.

[0496] 1H NMR(300MHz,CDCl3)δ:4.08-4.02(m,4H),3.85(s,2H),3.58(m,2H),2.64-2.51(m,6H),2 .29(t,J=7.5Hz,2H),1.79-1.59(m,6H),1.47-1.24(m,50H),0.95-0.85(m,15H);ESI-MS m / z:726.50[M+H] + .

[0497] Example 77: Synthesis of Compound 26b [ka] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 equivalent) was dissolved in 200 mL of anhydrous THF, the mixture was cooled to 0°C, and LDA (205 mL, 410.0 mmol, 2.0 equivalents) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was heated to room temperature. After stirring for 30 minutes, 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 equivalent) was added. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with DCM (3 × 300 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 30 g of methyl 2,2-dimethyl-7-bromoheptanoate, a yellow oily compound.

[0498] Methyl 2-dimethyl-7-bromoheptanoate (15.0 g, 40.0 mmol, 1.0 equivalent) was dissolved in 30 mL of THF, the mixture was cooled to 0°C, and lithium aluminum hydride solution (2 M, 50.0 mL) was added dropwise to the reaction system under a nitrogen atmosphere. The mixture was stirred for 3 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with DCM (3 × 300 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product 2,2-dimethyl-7-bromoheptanol (13.6 g), which was used directly in the next step without purification.

[0499] 2,2-dimethyl-7-bromoheptanol (500.0 mg, 2.24 mmol, 1.0 equivalent) was dissolved in DCM (10.0 mL), and 4-hexyldecanoic acid (746.2 mg, 2.91 mmol, 1.3 equivalents), EDCI (515.7 mg, 2.69 mmol, 1.2 equivalents), and DMAP (410.5 mg, 3.36 mmol, 1.5 equivalents) were added to the solution. The reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was poured into 10 mL of saturated sodium chloride aqueous solution. The mixture was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 858 mg of the yellow oily compound 26b-4.

[0500] Compound 26b was prepared according to the method of Example 64, yielding 99.0 mg of the oily product.

[0501] 1 H NMR(300MHz,MeOH-d4)δ:0.86-0.91(m,15H),1.21-1.40(m,50H),1.58-1.71(m,6H),2.32(t,J=7.5Hz,2H),2. 48-2.53(m,4H),2.62(t,J=6.6Hz,2H),3.61(t,J=6.3Hz,2H),3.80(s,2H),4.10(td,J=2.7,6.3Hz,4H);ESI-MS m / z:726.70[M+H] + .

[0502] Example 78: Synthesis of Compound 27b [ka] Compound 27b was prepared according to the method of Example 77, yielding 70.0 mg of the oily product.

[0503] 1H NMR(300MHz,MeOH-d4)δ:0.85-0.95(m,15H),1.25-1.55(m,48H),1.59-1.83(m,10H),2.25(d,J=6.6Hz,2H),2. 48-2.53(m,4H),2.62(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),3.79(s,2H),4.11(td,J=3.0,6.6Hz,4H);ESI-MS m / z:740.65[M+H] + .

[0504] Example 79: Synthesis of Compound 28b [ka] Compound 28b was prepared according to the method of Example 77, yielding 97.8 mg of the oily product.

[0505] 1 H NMR(300MHz,MeOH-d4)δ:0.85-0.95(m,15H),1.21-1.55(m,48H),1.60-1.84(m,10H),2.25(d,J=6.6Hz,2H),2. 47-2.53(m,4H),2.61(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),3.79(s,2H),4.11(td,J=4.5,6.3Hz,4H);ESI-MS m / z:740.80[M+H] + .

[0506] Example 80: Synthesis of Compound 29b [ka] Compound 29b was prepared according to the method of Example 77, yielding 107.7 mg of the oily product.

[0507] 1H NMR(300MHz,MeOH-d4)δ:0.85-0.95(m,15H),1.21-1.55(m,53H),1.60-1.84(m,5H),2.25(d,J=6.6Hz,2H),2. 50-2.55(m,4H),2.64(t,J=6.3Hz,2H),3.60(t,J=6.3Hz,2H),3.79(s,2H),4.11(td,J=1.8,6.6Hz,4H);ESI-MS m / z:740.60[M+H] + .

[0508] Example 81: Synthesis of compound 30b [ka] Compound 30b was prepared according to the method of Example 77, yielding 82.4 mg of the oily product.

[0509] 1 H NMR(300MHz,MeOH-d4)δ:0.87-0.92(m,15H),1.21-1.53(m,49H),1.55-1.83(m,13H),2.25(d,J=6. 9Hz,2H),2.46-2.52(m,6H),3.55(t,J=5.7Hz,2H),3.79(s,2H),4.11(td,J=3.0,6.6Hz,4H) m / z:768.70[M+H] + .

[0510] Example 82: Synthesis of Compound 31b [ka] Compound 31b was prepared according to the method of Example 77, yielding 107.7 mg of the oily product.

[0511] 1H NMR(300MHz,MeOH-d4)δ:0.86-0.92(m,15H),1.21-1.53(m,49H),1.55-1.83(m,13H),2.25(d,J=6.6 Hz,2H), 2.47-2.54(m,6H),3.55(t,J=5.7Hz,2H),3.79(s,2H),4.10(td,J=6.6,12.3Hz,4H) m / z:768.70[M+H] + .

[0512] Example 83: Synthesis of Compound 32b [ka] Compound 32b was prepared according to the method of Example 77, yielding 84.3 mg of the oily product.

[0513] 1 H NMR(300MHz,MeOH-d4)δ:0.88-0.93(m,15H),1.22-1.53(m,49H),1.56-1.83(m,13H),2.25(d,J=6. ESI-MS m / z:768.65[M+H] + .

[0514] Example 84: Synthesis of Compound 33b [ka] Compound 33b was prepared according to the method of Example 77, yielding 74.9 mg of the oily product.

[0515] 1H NMR(300MHz,MeOH-d4)δ:0.88-0.92(m,15H),1.22-1.53(m,51H),1.48-1.69(m,9H),2.33(t,J=7.5Hz,2H),2.50-2.55 (m,4H),2.63(t,J=6.3Hz,2H),3.62(t,J=6.6Hz,2H),3.80(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.6Hz,2H);ESI-MS m / z:754.60[M+H] + .

[0516] Example 85: Synthesis of Compound 34b

change

[0517] 1 H NMR(300MHz,MeOH-d4)δ:0.36-0.46(m,4H),0.88-0.92(m,9H),1.20-1.51(m,55H),1.56-1.69(m,5H),2.32(t,J=7.5Hz,2H),2. 51-2.55(m,4H),2.64(t,J=6.3Hz,2H),3.62(t,J=6.3Hz,2H),3.92(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.6Hz,2H);ESI-MS m / z:752.60[M+H] + .

[0518] Example 86: Synthesis of Compound 35b

change

[0519] 1H NMR(300MHz,MeOH-d4)δ:0.88-0.92(m,15H),1.24-1.72(m,64H),2.33(t,J=7.5Hz,2H),2.45-2.5 1(m,6H),3.55(t,J=6.0Hz,2H),3.80(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.3Hz,2H);ESI-MS m / z:782.65[M+H] + .

[0520] Example 87: Synthesis of Compound 36b

change

[0521] 1 H NMR(300MHz,MeOH-d4)δ:0.34-0.46(m,4H),0.87-0.92(m,9H),1.22-1.72(m,64H),2.32(t,J=7.2Hz,2H), 2.45-2.51(m,6H),3.55(t,J=5.7Hz,2H),3.92(s,2H),4.02(d,J=5.7Hz,2H),4.11(t,J=6.3Hz,2H);ESI-MS m / z:780.80[M+H] + .

[0522] Example 88: Synthesis of Compound 37b

change

[0523] 1H NMR(300MHz,MeOH-d4)δ:0.89-0.94(m,18H),1.24-1.69(m,67H),2.32(t,J=7.5Hz,2H),2.50-2.55(m ,4H),2.64(t,J=6.3Hz,2H),3.62(t,J=6.3Hz,2H),3.80(s,2H),4.11(td,J=6.3,14.7Hz,4H);ESI-MS m / z:824.70[M+H] + .

[0524] Example 89: Synthesis of Compound 52a

change

[0525] 1 H NMR(300MHz, CDCl3)δ:4.87-4.81(m,1H),3.59(m,2H),2.86(t,J=7.2Hz,2H),2.65-2.51(m,8H),1. 64-1.58(m,4H),1.57-1.43(m,11H),1.39-1.19(m,48H),1.15(s,6H),0.90(t,J=7.2Hz,9H);ESI-MS m / z:754.60[M+H] + .

[0526] Example 90: Synthesis of Compound 53a

change

[0527] 1 H NMR(300MHz, CDCl3)δ:4.90-4.78(m,1H),3.56(t,J=5.1Hz,2H),2.86(t,J=7.2Hz,2H ),2.63-2.48(m,8H),1.81-1.19(m,63H),1.16(s,6H),0.89(t,J=7.2Hz,9H);ESI-MS m / z:754.60[M+H] +.

[0528] Example 91: Synthesis of Compound 54a [ka] Compound 54a was prepared according to the method of Example 1, yielding 287.7 mg of the oily product.

[0529] 1 H NMR(300MHz,CDCl3)δ:4.89-4.79(m,1H),4.66(t,J=2.1Hz,2H),3.53(t,J=5.4Hz,2H),2.58(t,J=5.4Hz,2H),2.45(t, ESI-MS m / z:734.60[M+H] + .

[0530] Example 92: Synthesis of Compound 55a [ka] Compound 55a was prepared according to the method of Example 1, yielding 173.5 mg of the oily product.

[0531] 1 H NMR(300MHz,CDCl3)δ:4.89-4.78(m,1H),4.13(t,J=7.2Hz,2H),3.56(m,2H),2.63(m,2H),2.51-2.45( m,6H),2.31(t,J=7.2Hz,2H),2.16-2.10(m,2H),1.78-1.17(m,55H),1.15(s,6H),0.90(m,9H);ESI-MS m / z:734.50[M+H] + .

[0532] Example 93: Synthesis of Compound 56a [ka] Compound 56a was prepared according to the method of Example 1, yielding 112.2 mg of the oily product.

[0533] 1 H NMR(300MHz,CDCl3)δ:4.87-4.79(m,1H),4.16(t,J=6.6Hz,2H),3.60(m,2H),2.67-2.53(m,6H),2.32-2 .11(m,6H),2.32-2.11(m,6H),1.85-1.76(m,2H),1.66-1.18(m,53H),1.14(s,6H),0.88(m,9H);ESI-MS m / z:734.55[M+H] + .

[0534] Example 94: Synthesis of Compound 57a [ka] Compound 57a was prepared according to the method of Example 1, yielding 45.0 mg of the oily product.

[0535] 1 H NMR(400MHz,CDCl3)δ:5.68-5.49(m,2H),4.85-4.79(m,1H),4.63(d,J=6.8Hz,2H),3.84(m,2H),2.95-2. 76(m,6H),2.31(t,J=7.2Hz,2H),2.12-2.07(m,2H),1.66-1.18(m,57H),1.16(s,6H),0.88(m,9H);ESI-MS m / z:736.60[M+H] + .

[0536] Example 95: Synthesis of Compound 58a [ka] In a 50 mL round-bottom flask, the reactants 1-nonanamine (286.5 mg, 2.0 mmol, 1.0 equivalent), 8-bromooctanoic acid (535.5 mg, 2.4 mmol, 1.2 equivalents), NMM (202.3 mg, 2.0 mmol, 1.0 equivalent), and HATU (1.14 g, 3.0 mmol, 1.5 equivalents) were dissolved in a mixed solution of DMF (2.0 mL) and DCM (10.0 mL). The mixture was stirred at room temperature and allowed to react, and the completion of the reaction of 1-nonanamine was monitored by TLC. The reaction solution was added to 100 mL of saturated sodium chloride solution, and the mixture was extracted with DCM (30 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 610 mg of compound 58a-2.

[0537] Compound 58a was prepared according to the method of Example 1, yielding 104.0 mg of the oily product.

[0538] 1 H NMR(300MHz, CDCl3)δ:5.53(s,1H),4.87-4.79(m,1H),3.22(dd,J=6.9Hz,13.2Hz,2H),2.67-2. 52(m,6H),2.15(t,J=7.2Hz,2H),1.65-1.19(m,63H),1.15(s,6H),0.88(t,J=6.9Hz,9H);ESI-MS m / z:737.60[M+H] + .

[0539] Example 96: Synthesis of Compound 59a [ka] 4-dimethylamino-1-butanol (3.0 g, 25.5 mmol, 1.0 equivalent) and thiourea (8.4 g, 110.0 mmol, 4.3 equivalents) were added to a 100 mL sealed tube, then 60 mL of HBr aqueous solution (48%) was added, and the mixture was heated to 120°C and stirred overnight. The mixture was then used directly in the next step without purification.

[0540] The reaction system was cooled to 0°C, and NaOH (10.2 g, 255.0 mmol, 10.0 equivalents) was added in several batches. The mixture was heated to 120°C and reacted for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was removed to obtain 2.45 g of a colorless oily compound 59a-3.

[0541] In a 100 mL three-necked flask, compound 59a-6 (1.5 g, 5.8 mmol, 1.0 equivalent), 2-heptyl-1-nonanol (1.40 g, 5.8 mmol, 1.0 equivalent), EDCI (1.66 g, 8.7 mmol, 1.5 equivalent), and DMAP (0.35 g, 2.9 mmol, 0.5 equivalent) were dissolved in 20 mL of dichloromethane, and the mixture was stirred overnight at room temperature. The mixture was washed with water (3 × 15 mL). The organic phase was rotated and evaporated under reduced pressure, mixed directly with silica gel, and purified by silica gel column chromatography to obtain 3.3 g of compound 59a-7.

[0542] In a 100 mL three-necked flask, compound 59a-7 (2.8 g, 5.8 mmol, 1.0 equivalent) was dissolved in 20 mL of dichloromethane, and HCl / dioxane (4 M, 14 mL) was added. The mixture was stirred overnight at room temperature. The organic solvent was removed by rotary evaporation, and the reaction mixture was neutralized with saturated sodium bicarbonate aqueous solution. The mixture was extracted with DCM (3 × 20 mL). The organic phase was recovered and dried over anhydrous Na₂SO₄. The organic phase was purified by silica gel column chromatography to obtain 1.95 g of compound 8.

[0543] Compounds 59a-8 (680 mg, 1.8 mmol, 1.0 equivalent), KI (365 mg, 2.2 mmol, 1.2 equivalents), K2CO3 (745 mg, 5.4 mmol, 3.0 equivalents), and 59a-5 (668.9 mg, 1.8 mmol, 1.0 equivalent) were dissolved in 10 mL of acetonitrile in a 40 mL sealed tube. The mixture was heated to 80°C and stirred, and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtered cake was washed with acetonitrile (5 mL x 2). The filtrate was collected and concentrated to dryness by rotary evaporation. The residue was purified by column chromatography to obtain 580 mg of a yellow oily compound 59a-9.

[0544] In a 20 mL sealed tube, compound 59a-9 (200 mg, 0.29 mmol, 1.0 equivalent) was dissolved in 5 mL of DCM. After cooling the reaction system to 5°C, TEA (59.5 mg, 0.59 mmol, 2.0 equivalents) and BTC (87.3 mg, 0.29 mmol, 1.0 equivalent) were added dropwise. Maintaining the temperature at 5°C, the mixture was stirred and reacted for 1 hour, then concentrated to remove the DCM, and 5 mL of tetrahydrofuran was added. In another 20 mL sealed tube, compound 59a-3 (101.9 mg, 0.76 mmol, 2.6 equivalents) was dissolved in 5 mL of tetrahydrofuran. After cooling the mixture to 0°C, NaH (60%, 58.0 mg, 1.45 mmol, 5.0 equivalents) was added. After stirring at 0°C for 1 hour, the THF mixture solution prepared above was added dropwise, and the mixture was reacted for a further 1 hour. The reaction mixture was poured into 10 mL of ice water, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then the solvent was removed to obtain the crude product. The crude product was purified by preparative HPLC (column: XSelect C18 (30 × 150 mm, 5 μm); eluent A: H2O / ACN 60 / 40, 10 mM NH4HCO3 + 1%NH3·H2O; eluent B: IPA / ACN 90 / 10; flow rate: 60 mL / min; gradient program: 65%~85%B over 0~12 mins) to obtain 126.9 mg of pale yellow oily compound 59a.

[0545] 1H NMR(300MHz, CDCl3)δ:4.06(t,J=6.6Hz,2H),3.96(d,J=5.7Hz,2H),3.36-3.15(m,4H),2.90(t, J=6.9Hz,2H),2.41(s,2H),2.31-2.24(m,10H),1.64-1.16(m,61H),0.93-0.77(m,15H);ESI-MS m / z:839.65[M+H] + .

[0546] Example 97: Synthesis of Compound 60a

change

[0547] 1 H NMR(300MHz, CDCl3)δ:4.86(p,J=6.3Hz,1H),4.06(t,J=6.9Hz,2H),3.37-3.17(m,4H),2 .90(t,J=6.9Hz,2H),2.39-2.25(m,12H),1.79-1.18(m,70H),0.93-0.83(m,15H);ESI-MS m / z:895.80[M+H] + .

[0548] Example 98: Synthesis of Compound 61a

change

[0549] 1 H NMR(300MHz, CDCl3)δ:4.06(t,J=6.9Hz,2H),3.96(d,J=5.7Hz,2H),3.35-3.18(m,4H),2.91(t,J= 7.2Hz,2H),2.43-2.27(m,12H),1.87-1.77(m,2H),1.61-1.18(m,57H),0.93-0.84(m,15H);ESI-MS m / z:825.55[M+H] + .

[0550] Example 99: Synthesis of Compound 38b [ka] Compound 38b was prepared according to the method of Example 96, yielding 228 mg of the oily product.

[0551] 1 H NMR(300MHz,CDCl3)δ:4.86(p,J=6.3Hz,1H),3.78(s,2H),3.33-3.18(m,4H),2.90(t,J=6.6Hz ,2H),2.38-2.25(m,12H),1.69-1.44(m,16H),1.34-1.17(m,48H),0.90-0.85(m,15H);ESI-MS m / z:853.65[M+H] + .

[0552] Example 100: Synthesis of Compound 39b [ka] Compound 39b was prepared according to the method of Example 96, yielding 117.9 mg of the oily product.

[0553] 1 H NMR(300MHz,CDCl3)δ:4.86(p,J=6.3Hz,1H),3.78(s,2H),3.36-3.17(m,4H),2.92(t,J=7.2Hz,2H),2.46(t,J=7.2 ESI-MS m / z:881.65[M+H] + .

[0554] Example 101: Synthesis of compound 40b [ka] Compound 40b was prepared according to the method of Example 96, yielding 75.3 mg of the oily product.

[0555] 1 H NMR(300MHz, CDCl3)δ:4.86(p,J=6.3Hz,1H),3.78(s,2H),3.36-3.17(m,4H),2.91(t,J=6.6Hz ,2H),2.48-2.28(m,12H),1.89-1.60(m,10H),1.51-1.16(m,60H),0.93-0.87(m,15H);ESI-MS m / z:895.70[M+H] + .

[0556] Example 102: Synthesis of Compound 41b [ka] Compound 41b was prepared according to the method of Example 96, yielding 95.1 mg of the oily product.

[0557] 1 H NMR(400MHz,CDCl3)δ:4.86(p,J=6.4Hz,1H),4.09(t,J=7.6Hz,2H),3.31-3.24(m,4H),2.90(t,J=7 ESI-MS m / z:895.80[M+H] + .

[0558] Example 103: Synthesis of Compound 42b [ka] Compound 42b was prepared according to the method of Example 96, yielding 63.6 mg of the oily product.

[0559] 1H NMR(400MHz,CDCl3)δ:4.09(p,J=7.6Hz,2H),3.96(d,J=6.0Hz,2H),3.31-3.24(m,4H),2.90(t,J=7 ESI-MS m / z:839.70[M+H] + .

[0560] Example 104: Synthesis of Compound 43b [ka] Compound 43b was prepared according to the method of Example 96, yielding 130.5 mg of the oily product.

[0561] 1 H NMR(300MHz,CDCl3)δ:3.96(d,J=6.0Hz,2H),3.89(s,2H),3.35-3.18(m,4H),2.91(t,J=7.2Hz,2H),2.44-2.28( m,12H),1.87-1.79(m,2H),1.77-1.60(m,10H),1.34-1.17(m,47H),0.90-0.85(m,9H),0.52-0.32(m,4H);ESI-MS m / z:823.60[M+H] + .

[0562] Example 105: Synthesis of Compound 44b [ka] Compound 44b was prepared according to the method of Example 96, yielding 79.4 mg of the oily product.

[0563] 1H NMR(300MHz, CDCl3)δ:3.95(d,J=5.7Hz,2H),3.90(s,2H),3.35-3.19(m,4H),2.90(t,J=7.2Hz,2H),2.67(s, 4H),2.34-2.27(m,4H),1.72-1.51(m,16H),1.29-1.21(m,49H),0.90-0.83(m,9H),0.46-0.36(m,4H);ESI-MS m / z:837.75[M+H] + .

[0564] Example 106: Synthesis of Compound 45b

change

[0565] 1 H NMR(400MHz, CDCl3)δ:4.13(s,2H),3.96(d,J=6.0Hz,2H),3.31-3.24(m,4H),2.90(t,J=6.8Hz,2H),2. 54-2.26(m,10H),1.67-1.45(m,18H),1.29-1.21(m,45H),0.90-0.82(m,9H),0.32-0.29(m,4H);ESI-MS m / z:837.70[M+H] + .

[0566] Example 107: Synthesis of Compound 46b

change

[0567] Compound 46b was prepared according to the method of Example 96, yielding 78.5 mg of the oily product.

[0568] 1 H NMR(300MHz,CDCl3)δ:4.68(p,J=6.0Hz,1H),4.11(t,J=6.6Hz,2H),3.78(s,2H),3.36-3.22(m,4H),2.90 (t,J=6.9Hz,2H),2.47-2.29(m,10H),1.70-1.56(m,18H),1.29-1.21(m,50H),0.90-0.86(m,15H);ESI-MS m / z:897.70[M+H] + .

[0569] Example 108: Synthesis of Compound 47b [ka] Compound 47b was prepared according to the method of Example 107, yielding 189.8 mg of the oily product.

[0570] 1 H NMR(400MHz,CDCl3)δ:4.12(t,J=6.4Hz,2H),4.02(d,J=5.6Hz,2H),3.78(s,2H),3.32-3.24(m,4H),2.92(t,J=7.2 ESI-MS m / z:827.55[M+H] + .

[0571] Example 109: Synthesis of Compound 48b [ka] Compound 48b was prepared according to the method of Example 107, yielding 129.4 mg of the oily product.

[0572] 1 H NMR(300MHz,CDCl3)δ:4.12(t,J=6.6Hz,2H),4.02(d,J=5.7Hz,2H),3.78(s,2H),3.36-3.21(m,4H),2.90 (t,J=6.9Hz,2H),2.36-2.26(m,10H),1.63-1.41(m,13H),1.26-1.18(m,46H),0.89-0.86(m,15H);ESI-MS m / z:841.65[M+H] + .

[0573] Example 110: Synthesis of Compound 49b [ka] Compound 49b was prepared according to the method of Example 107, yielding 135.6 mg of the oily product.

[0574] 1H NMR(300MHz,CDCl3)δ:4.12(t,J=6.3Hz,2H),4.02(d,J=5.7Hz,2H),3.89(s,2H),3.31-3.22(m,4H),2.90(t,J=6.9 ESI-MS m / z:839.50[M+H] + .

[0575] Example 111: Synthesis of compound 50b [ka] Compound 50b was prepared according to the method of Example 107, yielding 123.1 mg of the oily product.

[0576] 1 H NMR(300MHz,CDCl3)δ:4.12(t,J=6.6Hz,2H),4.02(t,J=6.6Hz,2H),3.84(s,2H),3.34-3.19(m,4H),2.90(t,J=6 ESI-MS m / z:855.60[M+H] + .

[0577] The compounds listed in the table below were synthesized using the methods of the above examples or similar methods for the corresponding intermediates.

[0578] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6]

[0579] Compounds 1c to 283c were synthesized using the methods described in the above examples, or similar methods using the corresponding intermediates.

[0580] Pharmacological experiments Assay Example 1: Preparation of Nanoparticles The materials used in the lipid nanoparticle composition include: (1) ionized lipid compounds, e.g., ionized lipids designed and synthesized in this disclosure, or DLin-MC3-DMA as a control (purchased from AVT); (2) structural lipids, e.g., cholesterol (purchased from Sigma-Aldrich); (3) phospholipids, e.g., DSPC, i.e., 1,2-distearoyl-SN-glycero-3-phosphocholine (distearoylphosphatidylcholine, purchased from AVT); (4) polyethylene glycolated lipids, e.g., DMG-PEG2000, i.e., dimyristoylglycero-polyethylene glycol 2000 (1,2-dimiristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, purchased from AVT); and (5) active ingredients of nucleic acid fragments, e.g., luciferase mRNA, siRNA, CRISPR-Cas9 mRNA, etc. (manufactured in-house). The material names and structural formulas of the lipid nanoparticle assemblies are shown in Table 4.

[0581] [Table 7]

[0582] Lipid nanoparticles are prepared by (1) dissolving and mixing ionized lipid compounds, cholesterol, phospholipids, and polyethylene glycolated lipids in ethanol at concentrations of 50%, 38.5%, 10%, and 1.5% (molar percentages), respectively; (2) dissolving the mRNA active ingredient in a 25 mM sodium acetate solution (pH=4.5); (3) mixing the organic phase containing the lipid mixture and the aqueous phase containing the mRNA component using an automated high-throughput microfluidic system at a flow rate ratio of 1:1 to 1:4 and a mixing rate of 10 mL / min to 18 mL / min; (4) diluting the prepared lipid nanoparticles (N / P ratio=6) in phosphate buffer and ultrafiltration to the initial preparation volume using an ultrafiltration tube with a fractional molecular weight of 30 kDa (purchased from Millipore); and (5) filtering the resulting nanoparticles through a sterile 0.2 μm filter and then storing them at low temperatures in a sealed glass vial.

[0583] Methods for preparing lipid nanoparticles include, but are not limited to, microfluidic mixing systems, and also include T-mixer methods and ethanol injection methods.

[0584] Assay Example 2: Physical Characterization of Lipid Nanoparticles The particle size and particle size dispersion index (PDI) of the prepared lipid nanoparticles were measured using Zetasizer Pro (purchased from Malvern Instruments Ltd) and DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instruments. The degree of RNA encapsulation by lipid nanoparticles is characterized by the encapsulation efficiency %, which reflects the degree to which the lipid nanoparticles bind to the RNA fragment. This parameter is Quant-it TMThe measurement was performed using the RiboGreen RNA Assay (purchased from Invitrogen). Lipid nanoparticle samples were diluted with TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH=7.5). A portion of the sample solution was taken, 0.5% Triton (Triton X-100) was added, and the solution was allowed to stand at 37°C for 30 minutes. Immediately after adding the RIBOGREEN® reaction solution, the fluorescence value was measured using a Varioskan LUX (purchased from Thermofisher) multifunctional microplate reader at absorption 485 nm and fluorescence emission 528 nm to obtain the encapsulation efficiency.

[0585] Test Example 3: Animal Experiments The efficacy and safety of delivery nanoparticles containing luciferase mRNA (Trilink, L-7202) to mice were evaluated. The test mice were SPF-grade C57BL / 6 mice (female, 6-8 weeks old, 18-22g body weight) purchased from SPF (Beijing) Biotechnology Co., Ltd. All animals underwent a 7-day acclimatization period before the start of the experiment and were allowed free feeding and drinking during the experiment. Conditions included a 12 / 12-hour light-dark cycle, room temperature of 20°C-26°C, and humidity of 40-70%. Mice were randomly assigned to groups. Lipid nanoparticles containing the prepared luciferase mRNA were administered intravenously to mice at a single dose of 0.5 mg / kg of mRNA. Six hours after administration, in vivo bioluminescence assays were performed on the mice using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer). The assay was performed by preparing a D-luciferin solution at a concentration of 15 mg / mL in physiological saline and administering the substrate to each mouse intraperitoneally. Ten minutes after substrate administration, the mice were anesthetized in an anesthesia room using 2.5% isoflurane. Fluorescence imaging was performed by placing the anesthetized mice in an IVIS (Intravascular Isolation Spectroscopy), and data were acquired and analyzed in areas of concentrated fluorescence distribution.

[0586] The in vivo delivery efficiency of lipid nanoparticle carriers is expressed as the average values ​​of fluorescence intensity and total photon count in different animals within the same test group, and is shown in Tables 5 to 11. Higher values ​​for fluorescence intensity and total photon count indicate higher in vivo delivery efficiency of the mRNA fragment by lipid nanoparticles. The lipid nanoparticles containing cationic lipids of this disclosure exhibit good in vivo delivery efficiency.

[0587] [Table 8]

[0588] [Table 9]

[0589] [Table 10]

[0590] [Table 11]

[0591] [Table 12]

[0592] [Table 13]

[0593] [Table 14-1] [Table 14-2] [Table 14-3]

[0594] Test Example 4: Evaluation of delivery efficiency and safety in vitro The delivery efficacy and safety of luciferase mRNA-encapsulated nanoparticles were evaluated at the cellular level in vitro. The cells used in the assay were human embryonic kidney-derived cells 293 (HEK293T cells) cultured at room temperature (37°C) and 5% CO2 concentration in DMEM (Dulbecco's Modified Eagle Medium) (purchased from Thermo Fisher) with 10% fetal bovine serum and 5% penicillin-streptomycin dual antibiotics. The cells were uniformly dispersed and seeded in 48-well plates and cultured in an incubator for 24 hours. Next, a solution of lipid nanoparticles encapsulating luciferase mRNA was added. After 24 hours, the cells were lysed, and the intracellular luciferase expression intensity and relative luminescence (RLU) of various lipid nanoparticles were measured using a luciferase detection reagent (purchased from Promega). Higher expression intensity indicates higher cellular delivery efficiency of the lipid material. Meanwhile, a cytotoxicity test was performed 24 hours later on a parallel group of lipid nanoparticle-treated cells using the CCK-8 reagent (purchased from DOJINDO). In this test, the cell group treated with PBS alone was used as the negative control. The procedure was as follows: After adding the CCK-8 solution, the cells were left to stand in a 37°C incubator for 4 hours. Absorbance values ​​were measured using a multi-functional microplate reader at an absorption wavelength of 450 nm. The ratio of the absorbance value of the nanoparticle-treated cells to the absorbance value of the negative control was used as an indicator of cell viability.

[0595] Table 12 shows the in vitro delivery efficacy and toxicity data of nanoparticles at the cellular level.

[0596] [Table 15]

[0597] Assay Example 5: Evaluation of in vivo clearance rate of ionized lipids Three female C57WT mice aged 6-8 weeks were administered 100 μL of unencapsulated LNP (0.1 mg / mL) containing ionized lipids, cholesterol, DSPC, and DMG-PEG2000 in a ratio of 50:38.5:10:1.5 via tail vein. At 24 and 72 hours after administration, the animals were killed by removing the cervical vertebrae, and their livers were extracted. Liver tissue from untreated animals of the same lot was used as a blank control. The liver samples were homogenized with water to precipitate proteins. The ionized lipid content in the samples was quantitatively analyzed by LC-MS / MS using a calibration standard prepared from matched blank liver tissue.

[0598] Table 13 shows the clearance rate data for ionized lipids.

[0599] [Table 16]

[0600] The structure of the control compound is as follows: [ka]

[0601] The data in Table 13 shows that in the control group, the geminal dialkyl compound was slowly degraded in the liver, with approximately 90% remaining in the liver even 72 hours after administration. The compound of the present invention is rapidly degraded and can be degraded in the liver in approximately 72 hours.

[0602] While this disclosure has been described in detail using its embodiments, it should be noted that various modifications and variations will be obvious to those skilled in the art. All such modifications and variations should be included in the claims attached to this disclosure.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, 【Chemistry 1】 During the ceremony, G １ and G ２ These are, independently, chemical bonds, C １－１３ Linear alkylene, C ２－１３ Linear alkenylenes, and C ２－１３ A selection of linear alkynylenes, each of which optionally contains one or more R Ｇ１ Replaced by; G １ and G ２ It has a total length with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R Ｇ１ is, independently, H, C １－１４ alkyl, -L ａ -OR ａ 、-L ａ -SR ａ 、or -L ａ -NR ａ R' ａ wherein; G ３ C ４－１４ Linear alkylene, C ４－１４ Linear alkenylene, or C ４－１４ It is a linear alkynylene, each of which optionally contains one or more R Ｇ３ Replaced by; R Ｇ３ These are H and -L independently. ａ -OR ａ , -L ａ -SR ａ , or -L ａ -NR ａ R' ａ And; L ａ These are, independently, chemical bonds or C １－１４ It is alkylene; R ａ and R' ａ H and C are independent of each other. １－１４ Alkyl, C ３－１４ Selected from cycloalkyls and 3- to 14-membered heterocyclines; G ４ is a chemical bond, C １－６ Alkylene, C ２－６ Alkenylene, or C ２－６ It is an alkynylene, and each of them can be optionally given one or more R Ｇ４ Replaced by; R Ｇ４ H and C are independent of each other. １－６ Alkyl, -L ｂ -OR ｂ , -L ｂ -SR ｂ , or -L ｂ -NR ｂ R' ｂ And; L ｂ These are, independently, chemical bonds or C １－６ It is alkylene; R ｂ and R' ｂ H and C are independent of each other. １－６ Alkyl, C ３－１０ Selected from cycloalkyls and 3- to 10-membered heterocyclines; Alternatively, two R atoms bonded to the same carbon atom. Ｇ４ C ３－１４ They form cycloalkylenes or 3- to 14-membered heterocyclenes, each of which optionally contains one or more R ４ｇ Replaced by; R ４ｇ These are independently H, halogen, cyano, and C. １－８ Alkyl, C １－８ Haloalkyl, -L ｅ -OR ｅ , -L ｅ -SR ｅ , or -L ｅ -NR ｅ R' ｅ And; L ｅ These are, independently, chemical bonds or C １－８ It is alkylene; R ｅ and R' ｅ H and C are independent of each other. １－８ Alkyl, C ３－１４ Selected from cycloalkyls and 3- to 14-membered heterocyclines; M １ and M ２ These are independently -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 - Selected from; 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-, -S-S-, -S(O) ０－２ -, and is selected from phenylene and pyridinylene, where phenylene or pyridinylene is optionally substituted with one or more R*; R* is independently H, halogen, cyano, C １－１０ alkyl, C １－１０ haloalkyl, -L ｆ -OR ｆ 、-L ｆ -SR ｆ 、or -L ｆ -NR ｆ R’ ｆ ; L ｆ These are, independently, chemical bonds or C １－８ It is alkylene; R ｆ and R' ｆ H and C are independent of each other. １－１０ Alkyl, C ３－１４ Selected from cycloalkyls and 3- to 14-membered heterocyclines; R １ and R ２ Independently, C ４－２０ Alkyl, C ４－２０ Alkenyl and C ４－２０ Selected from the alkinyls, each of which optionally contains one or more Rs. １ｓ Substituted by, and one or more methylene units are optionally and independently replaced by -NR'-; R １ｓ H and C are independent of each other. １－２０ Alkyl, -L ｃ -OR ｃ , -L ｃ -SR ｃ , or -L ｃ -NR ｃ R' ｃ And; R and R' are independently H or C １－２０ It is alkyl; L ｃ These are, independently, chemical bonds or C １－２０ It is alkylene; R ｃ and R' ｃ H and C are independent of each other. １－２０ Alkyl, C ３－１４ Selected from cycloalkyls and 3- to 14-membered heterocyclines; R ３ is 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 Selected from 3- to 14-membered heterocyclyls and 5- to 14-membered heteroaryls; R ｇ and R' ｇ H and C are independent of each other. １－１０ Alkyl, C ３－１０ It is a cycloalkyl or a 3- to 10-membered heterocycline; R'' is independently H or C １－６ It is alkyl; R ４ and R ５ Independently, C １－８ It is an alkyl group, and it optionally contains one or more R groups. ４ｓ Replaced by; Or, R ４ and R ５ C ３－１４ They form cycloalkylenes or 3- to 14-membered heterocyclenes, each of which optionally contains one or more R ４ｓ Replaced by; R ４ｓ These are independently H, halogen, cyano, and C. １－８ Alkyl, C １－８ Haloalkyl, -L ｄ -OR ｄ , -L ｄ -SR ｄ , or -L ｄ -NR ｄ R' ｄ And; L ｄ These are, independently, chemical bonds or C １－８ It is alkylene; R ｄ and R' ｄ H and C are independent of each other. １－８ Alkyl, C ３－１４ It is a cycloalkyl or a 3- to 14-membered heterocycline. A compound of formula (I), or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer.

2. G １ and G ２ These are, independently, chemical bonds, C １－９ Linear alkylene, C ２－９ Linear alkenylene, or C ２－９ It is a linear alkynylene; Or, G １ C １－６ Linear alkylene, C ２－６ Linear alkenylene, or C ２－６ Linear alkynylene, or C １－６ Linear alkylene, or C ２－６ It is a linear alkylene; Or, G ２ is a chemical bond, C １－６ Linear alkylene, C ２－６ Linear alkenylene, or C ２－６ Linear alkynylene, or chemical bond or C １－６ Linear alkylene, or chemical bond or C １－４ It is a linear alkylene; Or, G １ and G ２ This has a total length of 3, 4, 5, 6, 7, 8, or 9 carbon atoms, or a total length of 4, 5, or 6 carbon atoms, or a total length of 5 or 6 carbon atoms, or a total length of 5, 6, or 7 carbon atoms, or a total length of 6 or 7 carbon atoms; Or, G １ and G ２ This is 1, 2, 3, or 4 R Ｇ１ It is optionally replaced by A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

3. R Ｇ１ H or C １－１０ Alkyl, or H or C １－６ It is alkyl. A compound of formula (I) as described in claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

4. G ３ C ４－１０ Linear alkylene, C ４－１０ Linear alkenylene, or C ４－１０ Linear alkynylene, or C ４－９ Linear alkylene, or C ５－８ It is a linear alkylene; Or, G ３ This is an optional selection of 1, 2, 3, or 4 R's. Ｇ３ Replaced by, A compound of formula (I) as described in claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

5. L ａ These are, independently, chemical bonds or C １－１０ Alkylene, or chemical bond or C １－６ It is alkylene; R ａ and R' ａ H and C are independent of each other. １－１０ Alkyl, C ３－１０ Cycloalkyl, or 3- to 10-membered heterocyclyl, or H or C １－６ It is alkyl. A compound of formula (I) as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

6. G ４ C １－４ Alkylene, C ２－４ Alkenylene, or C ２－４ Alkynylene, or C ２－４ Alkylene, or C ２－３ It is alkylene; Or, G ４ This is an optional selection of 1, 2, 3, or 4 R's. Ｇ４ Replaced by, A compound of formula (I) as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

7. R Ｇ４ H or C １－６ Alkyl, or C １－４ It is alkyl; Alternatively, two R atoms bonded to the same carbon atom. Ｇ４ C ３－１０ They form cycloalkylenes or 3- to 10-membered heterocyclenes, or C ３－７ They form cycloalkylenes or 3- to 7-membered heterocyclenes, each of which optionally has 1, 2, or 3 R groups. ４ｇ Replaced by; Or, R ４ｇ These are independently H, halogen, cyano, and C. １－６ Alkyl, or C １－６ It is a haloalkyl, A compound of formula (I) as described in any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

8. L ｂ These are, independently, chemical bonds or C １－４ It is alkylene; Or, R ｂ and R' ｂ H and C are independent of each other. １－６ Alkyl, C ３－７ Cycloalkyl, or 3- to 7-membered heterocyclyl, or H or C １－６ Alkyl, or H or C １－４ It is alkyl. A compound of formula (I) as described in any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

9. M １ and M ２ These are independently -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; or -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; or -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; or -C(O)O- and -OC(O)- selected; Or, M １ and M ２ It is independently selected from -C(O)O- and -C(O)S-, or is -C(O)O-; Or, M １ and M ２ One of them is -C(O)O- or -C(O)S- or -C(O)O-, and the other is -OC(O)- or -SC(O)- or -OC(O)-; Or, M １ is -OC(O)- or -SC(O)- or -OC(O)-, M ２ is -C(O)O- or -C(O)S- or -C(O)O-; Or, M １ is -C(O)O-, and M ２ is -C(O)O- or -C(O)S-; Or, M １ and M ２ These are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-; Or, M １ and M ２ These are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, and -C(O)NH-, or -C(O)O-, -OC(O)-, and -C(O)S-; Or, M １ and M ２ One of them is -C(O)O- or -C(O)S- or -C(O)O-, and the other is -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- or -SC(O)-, or -C(O)O-, -C(O)S-, -C(O)NH- or -OC(O)-, or -C(O)O-, -C(O)S-, -OC(O)- or -SC(O)-, or -C(O)O-, -C(O)S- or -OC(O)-; Or, M １ and M ２ One of them is -OC(O)O-, and the other is -C(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-, or -C(O)O- or -OC(O)-; Or, M １ is -C(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-, or -C(O)O- or -OC(O)-, or -C(O)O-, or -OC(O)-, M ２ is -OC(O)O-; Or, M １ is -OC(O)O-, and M ２ is -OC(O)- or -C(O)O- or -OC(O)-; Or, M １ and M ２ independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-, or -C(O)O-, -OC(O)-, and -OC(O)O-; or M １ and M ２ It is not possible for -OC(O)O- to occur simultaneously. A compound of formula (I) as described in any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

10. R １ and R ２ Independently, C ６－１４ Alkyl, C ６－１４ Alkenyl, or C ６－１４ Alkinyl, or C ６－１４ Alkyl, or C ７－１２ Alkyl, or C ８－１２ It is alkyl; Or, R １ and R ２ C is independent ７－１２ Alkyl, C ７－１２ Alkenyl, or C ７－１２ Alkinyl, or C ８－１２ Alkyl, C ８－１２ Alkenyl, or C ８－１２ It is alkinyl; Or, R １ and R ２ This is an optional selection of 1, 2, 3, or 4 R's. １ｓ Replaced by, or optionally, one R １ｓ Replaced by; Or, R １ and R ２ are, independently, -(CH ２ ) ５ CH ３ , -(CH ２ ) ６ CH ３ , -(CH ２ ) ７ CH ３ , -(CH ２ ) ８ CH ３ , -(CH ２ ) ９ CH ３ , -(CH ２ ) １０ CH ３ , -(CH ２ ) １１ CH ３ , -CH ２ -C≡C-(CH ２ ) ５ CH ３ , -CH ２ -C≡C-(CH ２ ) ６ CH ３ , -(CH ２ ) ２ -C≡C-(CH ２ )<( ５ CH ３ , -(CH ２ ) ２ -C≡C-(CH ２ ) ４ CH ３ , -(CH ２ )<( ３ -C≡C-(CH ２ ) ３ CH ３ , -(CH ２ ) ４ -C≡C-(CH ２ ) ３ CH ３ , -CH ２ -CH=CH-(CH ２ ) ５ CH ３ , -CH ２ -CH=CH-(CH ２ ) ６ CH ３ , -(CH<0000-CH=CH-(CH ２ ) ５ CH ３ 、-(CH ２ ) ４ -CH=CH-(CH ２ ) ３ CH ３ 、-(CH ２ ) ５ -CH=CH-CH ２ CH ３ 、 【Chemistry 2】 Selected from the basis; Alternatively, R １ and R ２ are each independently -(CH ２ ) ５ CH ３ -(CH ２ ) ６ CH ３ -(CH ２ ) ７ CH ３ -(CH ２ ) ８ CH ３ -(CH ２ ) ９ CH[[ID=!33]] ３ -(CH ２ ) １０ CH ３ -(CH ２ ) １１ CH ３ -CH ２ -C≡C-(CH ２ ) ５ CH ３ -CH ２ -C≡C-(CH ２ ) ６ CH ３ -(CH ２ ) ２ -C≡C-(CH ２ ) ５ CH ３ -(CH ２ ) ４ -C≡C-(CH ２ ) ３ CH ３ -CH ２ -CH=CH-(CH ２ ) ５ CH ３ -CH ２ -CH=CH-(CH ２ ) ６ CH ３ -(CH ２ ) ２ -CH=CH-(CH ２ ) ５ CH ３ -(CH ２ ) ４ -CH=CH-(CH ２ ) [[ID=1!15]] ３ CH ３ -(CH ２ ) ５ -CH=CH-CH ２ CH ３ 、 【Transformation 3】 Selected from the basis, A compound of formula (I) as described in any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

11. R １ｓ H and C are independent of each other. １－１４ Alkyl, -L ｃ -OR ｃ , or -L ｃ -NR ｃ R' ｃ , or H or C １－１４ Alkyl, or H or C １－１０ Alkyl, or H or C １－９ Alkyl, or H or C １－６ Alkyl, or H or C １－４ It is alkyl. A compound of formula (I) as described in any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

12. R and R' are each independently H or C １－２０ Alkyl, or H or C １－１４ Alkyl, or H or C １－９ Alkyl, or H or C １－６ It is alkyl; or, R is H. A compound of formula (I) as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

13. L ｃ These are, independently, chemical bonds or C １－１４ Alkylene, or chemical bond or C １－１０ Alkylene, or chemical bond or C １－６ It is alkylene; Or, R ｃ and R' ｃ H or C １－１４ Alkyl, or H or C １－１０ Alkyl, or H or C １－６ It is alkyl. A compound of formula (I) as described in any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

14. R ３ is CN, -OR ｇ , or -NR ｇ R' ｇ , or -OR ｇ or -NR ｇ R' ｇ , or -OR ｇ , or -OH; Or, R ３ is -OH or -N(CH ３ ) ２ And; Or, R ｇ and R' ｇ H and C are independent of each other. １－６ Alkyl, C ３－７ Cycloalkyl, or 3- to 7-membered heterocyclyl, or H or C １－６ Alkyl, or H or C １－４ Alkyl, or H or methyl, A compound of formula (I) as described in any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

15. R ４ and R ５ Independently, C １－６ Alkyl, or C １－３ Alkyl or methyl; Or, R ４ and R ５ This is an optional selection of 1, 2, or 3 R ４ｓ Replaced by; Or, R ４ and R ５ C ３－１０ Cycloalkylene or 3- to 10-membered heterocyclene, or C ３－６ Cycloalkylene or 3-6 member heterocyclene, or C ３－６ Cycloalkylenes (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene), or C ３－５ Forms cycloalkylene, or cyclopropylene, or cyclopentylene, or cyclopropylene; Or, R ４ and R ５ The ring formed with the bonded carbon atom may optionally consist of 1, 2, or 3 R atoms. ４ｓ Replaced by, A compound of formula (I) as described in any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

16. R ４ｓ These are independently H, halogen, cyano, and C. １－６ Alkyl, C １－６ Haloalkyl, -L ｄ -OR ｄ , -L ｄ -SR ｄ , or -L ｄ -NR ｄ R' ｄ , or H, halogen, cyano, C １－６ Alkyl, or C １－６ Haloalkyl, or H, C １－３ Alkyl, or C １－３ It is a haloalkyl, A compound of formula (I) as described in any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

17. L ｄ These are, independently, chemical bonds or C １－６ Alkylene, or chemical bond or C １－３ It is alkylene; Or, R ｄ and R' ｄ H and C are independent of each other. １－６ Alkyl, C ３－１０ Cycloalkyl, or 3- to 10-membered heterocyclyl, or H or C １－６ It is alkyl. A compound of formula (I) as described in any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

18. L ｅ These are, independently, chemical bonds or C １－６ Alkylene, or chemical bond or C １－４ It is alkylene; Or, R ｅ and R' ｅ H and C are independent of each other. １－６ Alkyl, C ３－１０ Cycloalkyl, or 3- to 10-membered heterocyclyl, or H or C １－６ Alkyl, or H or C １－４ It is alkyl. A compound of formula (I) as described in any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

19. Q is a chemical bond, -OC(O)-, or -SC(O)-; or a chemical bond or -SC(O)-; Alternatively, if Q is phenylene or pyridinylene, it may be optionally substituted with one, two, or three R*; Alternatively, R* can independently be H, halogen, cyano, or C. １－６ Alkyl, or C １－６ It is a haloalkyl; Or, L ｆ These are, independently, chemical bonds or C １－６ Alkylene, or chemical bond or C １－４ It is alkylene; Or, R ｆ and R' ｆ H and C are independent of each other. １－６ Alkyl, C ３－１０ Cycloalkyl, or 3- to 10-membered heterocyclyl, or H or C １－６ Alkyl, or H or C １－４ It is alkyl. A compound of formula (I) as described in any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

20. Having the structure of formula (II) or formula (III), 【Chemistry 4】 During the ceremony, 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; Other bases are as defined in any one of claims 1 to 19. A compound of formula (I) as described in any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. 【Request Item 21】 【Chemistry 5】 During the ceremony, R １ or R ２ Upper R １ｓ The substitution position is M １ or M ２ It is separated from by 0 to 10 carbon atoms, or 0 to 6 carbon atoms, or 0 to 4 carbon atoms, or 0 to 2 carbon atoms, or 0 carbon atoms; Or, R １ or R ２ Upper R １ｓ The substitution position is M １ or M ２ It is separated from it by 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 2 carbon atoms; or 2 to 10 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms; Or, R １ R １ｓ It is not replaced by R ２ Upper R １ｓ The substitution position is M ２ It is separated from by 0 to 10 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 2 carbon atoms; or 2 to 10 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms; Or, R １ R １ｓ It is replaced with R ２ R １ｓ It has not been replaced; Or, R ４ and R ５ They do not form a ring with the carbon atoms to which they are bonded; Alternatively, d is not 0. A compound of formula (II) or formula (III) as described in claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. 【Request Item 22】 【Chemistry 6】 During the ceremony, a = 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 3, 4, 5, 6, 7, 8, or 9; or c + d = 4, 5, or 6; M １ and M ２ These are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; or, M １ and M ２ These are independently selected from -C(O)O- and -C(O)S-; or, M １ and M ２ One of them is -C(O)O- or -C(O)S-, and the other is -OC(O)- or -SC(O)-; R １ and R ２ Independently, C ６－１４ It is an alkyl group, and it optionally has 1, 2, 3, or 4 R atoms. １ｓ Replaced by; R １ｓ H and C are independent of each other. １－１４ Alkyl, -L ｃ -OR ｃ , or -L ｃ -NR ｃ R' ｃ , or H or C １－１４ It is alkyl; L ｃ These are, independently, chemical bonds or C １－１４ It is alkylene; R ｃ and R' ｃ H or C １－１４ It is alkyl; R ４ and R ５ Independently, C １－６ It is alkyl; Or, R ４ and R ５ C ３－６ Forming cycloalkylenes or 3-6 member heterocyclenes, A compound of formula (II) as described in claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

23. During the ceremony, a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or b = 5, 6, 7, or 8; or b = 5, 6, or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 5 or 6; M １ and M ２ Independently, -C(O)O- or -OC(O)-; or, M １ and M ２ is -C(O)O-; or, M １ and M ２ One of them is -C(O)O-, and the other is -OC(O)-; R １ and R ２ Independently, C ７－１２ Alkyl, or C ８－１２ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ Alkyl, or H or C １－９ It is alkyl; R ４ and R ５ Independently, C １－３ It is alkyl; Or, R ４ and R ５ C ３－６ Cycloalkylene, or C ３－５ Forms cycloalkylenes, A compound of formula (II) as described in claim 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

24. During the ceremony, a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or b = 5, 6, 7, or 8; or b = 5 or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; or d = 0, 1, 2, or 4; c + d = 5 or 6; or c + d = 6; M １ and M ２ is -C(O)O-; Or, M １ and M ２ One of them is -C(O)O-, and the other is -OC(O)-; R １ and R ２ It is independently, - (CH ２ ) ６ CH ３ ,-(CH ２ ) ７ CH ３ ,-(CH ２ ) ８ CH ３ ,-(CH ２ ) ９ CH ３ ,-(CH ２ ) １０ CH ３ ,-(CH ２ ) １１ CH ３ , 【Transformation 7】 Selected from; or - (CH ２ ) ７ CH ３ ,-(CH ２ ) ８ CH ３ ,-(CH ２ ) ９ CH ３ ,-(CH ２ ) １０ CH ３ ,-(CH ２ ) １１ CH ３ , 【Transformation 8】 Selected from; or -(CH2) ８ CH ３ ,-(CH ２ ) ９ CH ３ ,-(CH ２ ) １０ CH ３ ,-(CH ２ ) １１ CH ３ , 【Chemistry 9】 Selected from; R ４ and R ５ It is methyl; Or, R ４ and R ５ They, together with the carbon atoms to which they are bonded, form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, or form cyclopropylene, cyclopentylene, or cyclopropylene; Or, R １ and R ２ Only one of them has been replaced. A compound of formula (II) as described in claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

25. During the ceremony, a = 2; b = 5; c = 2, 3, 4, 5, or 6; or c = 6; d = 0, 1, 2, 3, or 4; or d = 0; c + d = 5 or 6, or 6; M １ and M ２ is -C(O)O-; R １ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ８－９ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ Alkyl, or H or C １－９ Alkyl, or C ６－８ Alkyl, or C ７－８ It is alkyl; R ２ C ７－１１ Linear alkyl, or C １０－１１ Linear alkyl, or C １１ It is a linear alkyl group, which optionally contains one carbon atom. １－３ Substituting with an alkyl group, or optionally substituted with a single methyl group; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene; Or, R １ teeth, 【Chemistry 10】 And, or 【Chemistry 11】 And; Or, R ２ is, -(CH ２ ) ９ CH ３ ,-(CH ２ ) １０ CH ３ , or 【Chemistry 12】 That is, A compound of formula (II) as described in claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

26. During the ceremony, a = 2, 3, or 4; or a = 2; b = 7; c = 2, 3, 4, 5, or 6; or c = 2, 3, or 4; or c = 2; d = 0, 1, 2, 3, or 4; or d = 2, 3, or 4; or d = 4; c + d = 5 or 6, or 6; M １ and M ２ is -C(O)O-; R １ C ８－１１ Linear alkyl, or C ９－１０ Linear alkyl, or C ９ It is a linear alkyl group; R ２ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ９－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ Alkyl, or H or C １－９ Alkyl, or C ６－９ Alkyl, or C ７－８ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene; Or, R ２ teeth, 【Chemistry 13】 And, or 【Chemistry 14】 That is, A compound of formula (II) as described in claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

27. During the ceremony, a = 2; b = 7; c = 3 or 4; or c = 4; d = 2; M １ and M ２ is -C(O)O-; R １ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ８－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ Alkyl, or H or C １－９ It is alkyl; R ２ C ７－１１ Linear alkyl, or C ９ It is a linear alkyl group; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forms cycloalkylene or cyclopropylene. A compound of formula (II) as described in claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

28. During the ceremony, a = 2, 3, or 4; or a = 2 or 4; b = 6 or 7; or b = 7; c = 2, 3, 4, 5, or 6; or c = 5 or 6; d = 0, 1, 2, 3, or 4; or d = 0 or 1; c + d = 5 or 6, or 6; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ７－１１ Linear alkyl, or C ９－１０ It is a linear alkyl group; R ２ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ９－１０ It is a linear alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７－９ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene; Alternatively, if a = 4, R ４ and R ５ They do not form a ring with the carbon atoms to which they are bonded; or, R １ｓ Independently, C ８－９ It is alkyl; Or, R ２ teeth, 【Chemistry 15】 That is, A compound of formula (II) as described in claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. 【Request Item 29】 【Chemistry 16】 During the ceremony, a = 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 3, 4, 5, 6, 7, 8, or 9; or c + d = 4, 5, 6, or 7; M １ and M ２ independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-, or selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; or, M １ and M ２ One of them is -C(O)O- or -C(O)S-, and the other is -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- or -SC(O)-, or -C(O)O-, -C(O)S-, -OC(O)- or -SC(O)-; R １ and R ２ C is independent ６－１４ Alkyl, C ６－１４ Alkenyl, or C ６－１４ These are alkynyls, each of which can optionally contain 1, 2, 3, or 4 Rs. １ｓ Replaced by; R １ｓ H and C are independent of each other. １－１４ Alkyl, -L ｃ -OR ｃ , or -L ｃ -NR ｃ R' ｃ , or H or C １－１４ It is alkyl; L ｃ These are, independently, chemical bonds or C １－１４ It is alkylene; R ｃ and R' ｃ H or C １－１４ It is alkyl; R ４ and R ５ Independently, C １－６ It is alkyl; Or, R ４ and R ５ C ３－６ Forming cycloalkylenes or 3-6 member heterocyclenes, A compound of formula (II) as described in claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

30. During the ceremony, a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9, or b = 5, 6, 7, or 8, or b = 5, 6, or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 5, 6, or 7; M １ and M ２ independently, -C(O)O-, -OC(O)-, -C(O)S- or -C(O)NH-, or -C(O)O-, -OC(O)-, or -C(O)S-; or M １ and M ２ One of them is -C(O)O-, and the other is -C(O)O-, -C(O)S-, -C(O)NH-, or -OC(O)-, or -C(O)O-, -C(O)S-, or -OC(O)-; R １ and R ２ Independently, C ７－１２ Alkyl, C ７－１２ Alkenyl, or C ７－１２ Alkinyl, or C ８－１２ Alkyl, C ８－１２ Alkenyl, or C ８－１２ They are alkinyls, and each of them can be optionally given one R １ｓ Replaced by; R １ｓ H or C １－１０ It is alkyl; R ４ and R ５ Independently, C １－３ It is alkyl; Or, R ４ and R ５ C ３－６ Cycloalkylene, or C ３－５ Forms cycloalkylenes, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

31. During the ceremony, a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or b = 5, 6, 7, or 8; or b = 5 or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 5, 6, or 7; or c + d = 6; M １ and M ２ One of them is -C(O)O-, and the other is -C(O)O-, -C(O)S-, -C(O)NH-, or -OC(O)-, or -C(O)O-, -C(O)S-, or -OC(O)-; R １ and R ２ are, independently, -(CH ２ ) ６ CH ３ -(CH ２ ) ７ CH ３ -(CH ２ ) ８ CH ３ -(CH ２ ) ９ CH ３ -(CH ２ ) １０ CH ３ -(CH ２ ) １１ CH ３ -CH ２ -CH=CH-(CH ２ ) ５ CH ３ -CH ２ -C≡C-(CH ２ ) ５ CH ３ -(CH ２ ) ２ -C≡C-(CH ２ ) ４ CH ３ -(CH ２ ) ３ -C≡C-(CH ２ ) ３ CH ３ , 【Chemistry 17】 Selected from, or -(CH ２ ) ７ CH ３ ,-(CH ２ ) ８ CH ３ ,-(CH ２ ) ９ CH ３ ,-(CH ２ ) １０ CH ３ ,-(CH ２ ) １１ CH ３ ien-CH ２ -CH=CH-(CH ２ ) ５ CH ３ ien-CH ２ -C≡C-(CH ２ ) ５ CH ３ ,-(CH ２ ) ２ -C≡C-(CH ２ ) ４ CH ３ ,-(CH ２ ) ３ -C≡C-(CH ２ ) ３ CH ３ , [Chemistry 18] selected from; or, -(CH ２ ) ８ CH ３ 、-(CH ２ ) ９ CH ３ 、-(CH ２ ) １０ CH ３ 、-(CH ２ ) １１ CH ３ 、-CH ２ -CH=CH-(CH ２ ) ５ CH ３ 、-CH ２ -C≡C-(CH ２ ) ５ CH ３ 、-(CH ２ ) ２ -C≡C-(CH ２ ) ４ CH ３ 、-(CH ２ ) ３ -C≡C-(CH ２ ) ３ CH ３ 、 【Chemistry 19】 Selected from; R ４ and R ５ It is methyl; Or, R ４ and R ５ They, together with the carbon atoms to which they are bonded, form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, or form cyclopropylene, cyclopentylene, or cyclopropylene; Or, R １ and R ２ Only one of them has been replaced. A compound of formula (II) as described in claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

32. During the ceremony, a = 2; b = 5; c = 5 or 6; or c = 6; d = 0 or 1; or d = 0; c + d = 5 or 6, or 6; M １ is -C(O)O-, and M ２ is -C(O)O- or -C(O)S-; or M １ and M ２ is -C(O)O-; R １ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ８－９ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ Alkyl, or H or C １－９ Alkyl, or C ６－８ Alkyl, or C ７－８ It is alkyl; R ２ C ７－１１ Linear alkyl, or C １０－１１ Linear alkyl, or C １１ It is a linear alkyl group, which optionally contains one carbon atom. １－３ Substituting with an alkyl group, or optionally substituted with a single methyl group; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene; Or, R １ teeth, 【Chemistry 20】 And, or 【Chemistry 21】 And; Or, R ２ is, -(CH ２ ) ９ CH ３ ,-(CH ２ ) １０ CH ３ , or 【Chemistry 22】 That is, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

33. During the ceremony, a = 2, 3, or 4; or a = 2; b = 5, 6, or 7; or b = 7; c = 2, 3, 4, 5, or 6; or c = 2, 3, or 4; or c = 2; d = 0, 1, 2, 3, or 4; or d = 2, 3, or 4; or d = 4; c + d = 5 or 6, or 6; M １ and M ２ is -C(O)O-; R １ and R ２ C is independent ７－１２ Alkyl, or C ８－１２ Alkyl, or C ９－１１ Alkyl, or C ９－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; and R １ and R ２ Only one of them is replaced; R １ｓ H or C １－１０ Alkyl, or C ６－１０ Alkyl, or C ７－９ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene, or not forming a ring; Or, R １ is a C ８－１２ linear alkyl, or a C ９－１１ linear alkyl, or a C ９－１０ linear alkyl; R ２ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ９－１１ Alkyl, or C ９－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R ２ C １０ If it is a linear alkyl group, R １ｓ C ９－１０ Alkyl, or C ９ It is alkyl; Or, R ２ teeth, 【Chemistry 23】 And, or 【Chemistry 24】 That is, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

34. During the ceremony, a = 2, 3, or 4; b = 6; c = 4, 5, or 6; or c = 5 or 6; or c = 5; d = 1 or 2; or d = 1; c + d = 6, 7, or 8; or 6 or 7; or 6; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ７－１２ Linear alkyl, or C ８－１１ Linear alkyl, or C ９－１１ It is a linear alkyl group; R ２ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ９－１２ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７－１１ Alkyl, or C ７－１０ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene; However, if c = 4, then a = 2 or 3; Or, R ２ teeth, 【Chemistry 25】 And; Or, a = 2 or 4; b = 6; c = 5 or 6, or c = 5; d = 1; R １ C ８－９ Linear alkyl, or C ９ It is a linear alkyl group; R ２ C ９－１０ Alkyl, or C １０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７－８ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, a = 2, 3, or 4, or 2 or 4, b = 6, c = 5, d = 2; R １ C ９－１０ Linear alkyl, or C ９ It is a linear alkyl group; R ２ C ９－１１ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７－９ It is alkyl, R ４ and R ５ C is independent １－３ Alkyl or methyl, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

35. During the ceremony, a = 2, 3, or 4; or a = 2 or 4; b = 7; c = 5 or 6; or c = 5; d = 0 or 1; or d = 1; c + d = 5 or 6, or 6; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ８－１１ Linear alkyl, or C ９－１０ It is a linear alkyl group, which optionally contains one carbon atom. １－９ Alkyl (or C ６－９ Alkyl, or C ６－７ Substituted with alkyl; R ２ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ９－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７－９ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene; Or, R １ is, -(CH ２ ) ８ CH ３ ,-(CH ２ ) ９ CH ３ , 【Chemistry 26】 And; R ２ teeth, 【Chemistry 27】 And; Alternatively, if a = 4, R １ C ９－１０ It is a linear alkyl group; R ２ C ９－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ C ８－９ It is alkyl; R ４ and R ５ They do not form a ring with the carbon atoms to which they are bonded; Alternatively, if a = 2, R １ C １０ It is a linear alkyl group; Or R １ｓ C ８－９ Alkyl, or C ９ It is alkyl. A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

36. During the ceremony, a = 2, 3, or 4; or a = 2 or 4; b = 7; c = 4; d = 2; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ８－１１ Linear alkyl, or C ９－１０ It is a linear alkyl group; R ２ C ８－１１ Alkyl, or C ９－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７－９ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene, or not forming a ring; Or, R ２ teeth, 【Chemistry 28】 That is, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

37. During the ceremony, a = 2, 3, or 4; or a = 2; b = 8; c = 5; d = 1; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ８－１２ Linear alkyl, or C ９－１１ Linear alkyl, or C １０－１１ It is a linear alkyl group; R ２ C ８－１１ Alkyl, or C ９－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７－９ Alkyl, or C ７－８ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene, or not forming a ring; Or, R ２ teeth, 【Chemistry 29】 That is, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

38. During the ceremony, a = 2; b = 6, 7, or 8, or b = 7; c = 5; d = 1; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ８－１１ Linear alkyl, or C ９－１０ Linear alkyl, or C ９ It is a linear alkyl group; R ２ C ８－１１ Alkyl, or C ９－１０ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ７ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ２ teeth, 【Transformation 30】 And, or 【Chemistry 31】 That is, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

39. During the ceremony, a = 2 or 3, or a = 2; b = 7; c = 3; d = 3; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ８－１１ Linear alkyl, or C ９－１０ Linear alkyl, or C ９ It is a linear alkyl group; R ２ C ８－１１ Alkyl, or C ９－１０ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C ６－７ Alkyl, or C ７ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ２ teeth, 【Chemistry 32】 And, or 【Transformation 33】 That is, A compound of formula (II) as described in claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. 【Request Item 40】 【Chemistry 34】 During the ceremony, a = 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 3, 4, 5, 6, 7, 8, or 9, or c + d = 4, 5, or 6; M １ and M ２ One of them is -OC(O)O-, and the other is -C(O)O-, -OC(O)-, -SC(O)-, or -C(O)S-; R １ and R ２ Independently, C ６－１４ It is an alkyl group, and it optionally has 1, 2, 3, or 4 R atoms. １ｓ Replaced by; R １ｓ H and C are independent of each other. １－１４ Alkyl, -L ｃ -OR ｃ , or -L ｃ -NR ｃ R' ｃ It is; or H or C １－１４ It is alkyl; L ｃ These are, independently, chemical bonds or C １－１４ It is alkylene; R ｃ and R' ｃ H or C １－１４ It is alkyl; R ４ and R ５ Independently, C １－６ It is alkyl; Or, R ４ and R ５ C ３－６ Forming cycloalkylenes or 3-6 member heterocyclenes, A compound of formula (II) as described in claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

41. During the ceremony, a = 2, 3, or 4; b = 4, 5, 6, or 7, or b = 5 or 6, or b = 6; c = 2, 3, 4, 5, or 6; or c = 2, 4, 5, or 6; d = 0, 1, 2, 3, or 4; or d = 0, 1, 2, or 4; c + d = 5 or 6, or c + d = 6; M １ and M ２ One of them is -OC(O)O-, and the other is -C(O)O- or -OC(O)-; R １ and R ２ Independently, C ７－１２ Alkyl, or C ９－１１ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ Alkyl; or H or C ４－１０ It is alkyl; R ４ and R ５ Independently, C １－３ It is alkyl; Or, R ４ and R ５ C ３－６ Cycloalkylene, or C ３－４ Forms cycloalkylenes, A compound of formula (II) as described in claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

42. During the ceremony, a = 2, 3, or 4; b = 4, 5, 6, or 7, or b = 5 or 6, or b = 6; c = 2, 3, 4, 5, or 6; or c = 2, 4, 5, or 6; d = 0, 1, 2, 3, or 4; or d = 0, 1, 2, or 4; c + d = 5 or 6, or c + d = 6; M １ and M ２ One of them is -OC(O)O-, and the other is -C(O)O- or -OC(O)-; R １ and R ２ It is independently, - (CH ２ ) ８ CH ３ ,-(CH ２ ) ９ CH ３ ,-(CH ２ ) １０ CH ３ , 【Chemistry 35】 Selected from; R ４ and R ５ It is methyl; Or, R ４ and R ５ They, together with the carbon atoms to which they are bonded, form cyclopropylene; Or, R １ and R ２ Only one of them has been replaced; Or, M １ is -C(O)O- or -OC(O)- or -C(O)O-, M ２ is -OC(O)O-; Or, M １ is -OC(O)O-, and M ２ is -OC(O)- A compound of formula (II) as described in claim 40 or 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

43. During the ceremony, a = 2; b = 5 or 6, or b = 6; c = 4, 5, or 6; or c = 4 or 6; or c = 6; d = 0, 1, or 2; or d = 0 or 2; c + d = 6; M １ is -C(O)O-, and M ２ is -OC(O)O-; R １ C ８－１１ Alkyl, or C ９－１０ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ C ７－９ Alkyl, or C ７ It is alkyl; R ２ C ８－１１ Linear alkyl, or C ９－１０ Linear alkyl, or C ９ It is a linear alkyl group; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylenes or not forming rings; Or, R １ teeth, 【Transformation 36】 And, or 【Chemistry 37】 That is, A compound of formula (II) as described in claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

44. During the ceremony, a = 2; b = 6; c = 4, 5, or 6; or c = 5 or 6; or c = 6; d = 0, 1, or 2; or d = 0 or 1; c + d = 6; M １ is -C(O)O-, and M ２ is -OC(O)O-; R １ C ８－１０ Linear alkyl, or C ９－１０ Linear alkyl, or C ９ It is a linear alkyl group; R ２ C ８－１０ Alkyl, or C ９－１０ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ C ６－７ Alkyl, or C ７ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylenes or not forming rings; Or, R ２ teeth, 【Transformation 38】 And, or 【Chemistry 39】 That is, A compound of formula (II) as described in claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

45. During the ceremony, a = 2; b = 5 or 6; or b = 6; c = 5; d = 1; M １ is -OC(O)-, and M ２ is -OC(O)O-; R １ C ８－１０ Alkyl, or C ９－１０ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ C ６－８ Alkyl, or C ６－７ It is alkyl; R ２ C ８－１２ Linear alkyl, or C １０－１１ It is a linear alkyl group; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylenes or not forming rings; Or, R １ teeth, 【Chemistry 40】 And, or 【Chemistry 41】 That is, A compound of formula (II) as described in claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

46. During the ceremony, a = 2, 3, or 4; or a = 2; b = 5, 6, 7, or 8; or b = 6 or 7; or b = 7; c = 4, 5, or 6; or c = 4; d = 0, 1, or 2; or d = 1; c + d = 5 or 6; or c + d = 5; M １ is -OC(O)O-, and M ２ is -OC(O)-; R １ C ８－１２ Alkyl, or C ８－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ C ６－１０ Alkyl, or C ６－８ It is alkyl; R ２ C ８－１２ Linear alkyl, or C ８－１０ It is a linear alkyl group; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylenes or not forming rings; Or, R １ teeth, 【Chemistry 42】 That is, A compound of formula (II) as described in claim 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. 【Request Item 47】 【Chemistry 43】 During the ceremony, Q is either -SC(O)- or -OC(O)-; R ｇ and R' ｇ Independently, C １－６ It is alkyl; a = 2, 3, 4, 5, or 6; or a = 2, 3, or 4; b = 4, 5, 6, 7, 8, or 9; or a = 5, 6, or 7; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 5 or 6; M １ and M ２ These are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-; R １ and R ２ Independently, C ６－１４ It is an alkyl group, and it optionally has 1, 2, 3, or 4 R atoms. １ｓ Replaced by; R １ｓ H and C are independent of each other. １－１４ Alkyl, -L ｃ -OR ｃ , or -L ｃ -NR ｃ R' ｃ It is; or H or C １－１４ It is alkyl; L ｃ These are, independently, chemical bonds or C １－１４ It is alkylene; R ｃ and R' ｃ H or C １－１４ It is alkyl; R ４ and R ５ C is independent １－６ Is it alkyl? Or, R ４ and R ５ C ３－６ Forming cycloalkylenes or 3-6 member heterocyclenes, A compound of formula (III) as described in claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

48. During the ceremony, Q is either -SC(O)- or -OC(O)-; R ｇ and R' ｇ Independently, C １－３ It is alkyl; a = 3 or 4; b = 6 or 7; c = 2, 3, 4, or 5; or 2 or 5; d = 1, 2, 3, or 4; or 1 or 4; c + d = 5 or 6; M １ and M ２ These are independently selected from -C(O)O-, -OC(O)-, and -OC(O)O-; or, M １ and M ２ It is not possible for it to simultaneously become -OC(O)O-; R １ and R ２ Independently, C ７－１２ Alkyl, or C ８－１０ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ Alkyl, or H or C １－９ It is alkyl; R ４ and R ５ C is independent １－３ Is it alkyl? Or, R ４ and R ５ C ３－６ Forms cycloalkylenes, A compound of formula (III) as described in claim 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

49. During the ceremony, Q is -SC(O)-; R ｇ and R' ｇ It is methyl; a = 3 or 4; b = 6 or 7; c = 2, 4, or 5; or 2 or 5; d = 1, 2, or 4; or 1 or 4; c + d = 6; M １ and M ２ These are independently selected from -C(O)O-, -OC(O)-, and -OC(O)O-; or, M １ and M ２ It is not possible for it to simultaneously become -OC(O)O-; R １ and R ２ It is independently, - (CH ２ ) ７ CH ３ ,-(CH ２ ) ８ CH ３ ,-(CH ２ ) ９ CH ３ , 【Chemistry 44】 And; R ４ and R ５ It is methyl; Or, R ４ and R ５ They either form a cyclopropylene ring with the carbon atoms to which they are bonded, or they do not form a ring; Or, R １ and R ２ Only one of them is replaced; or, R １ It is not substituted, and R ２ It has been replaced. A compound of formula (III) as described in claim 47 or 48, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. [Request Item 50] [Chemistry 45] In the formula, M １ and M ２ It is independently -C(O)O- or -C(O)S- or -C(O)O-; Other bases are as defined in any one of claims 21-27 and 29-33. A compound of formula (II) as described in claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. 【Request Item 51】 【Chemistry 46】 In the formula, M １ and M ２ One of them is -C(O)O- or -C(O)S- or -C(O)O-, and the other is -OC(O)- or -SC(O)- or -OC(O)-; Other groups are as defined in any one of claims 21-24, 29-31, and 34-39; Or, R １ｓ H or C １－６ Alkyl; or H or C １－４ It is alkyl; Or, R １ｓ Independently, C １－８ Alkyl, or C ４－８ Alkyl, or C ６－８ Alkyl, or C ７－８ Alkyl, or C ８ It is alkyl; Or, M １ is -OC(O)- or -SC(O)- or -OC(O)-, M ２ is -C(O)O- or -C(O)S- or -C(O)O- A compound of formula (II) as described in claim 20 or 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

52. A compound of formula (II) or formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, 【Chemistry 47】 During the ceremony, Q is a chemical bond, -SC(O)- or -OC(O)-; R ｇ and R' ｇ Independently, C １－６ It is 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 is -OC(O)- or -SC(O)-; M ２ is -C(O)O- or -C(O)S-; R １ and R ２ Independently, C ７－１２ Alkyl, or C ８－１２ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ H or C １－１０ It is alkyl; R ４ and R ５ C is independent １－６ Is it alkyl? Or, R ４ and R ５ C ３－６ Forms cycloalkylenes; Or, R １ and R ２ Only one of them is replaced; or, R １ It is not substituted, R ２ It has been replaced. Compounds of formula (II) or formula (III), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof.

53. During the ceremony, Q is -SC(O)- or -OC(O)- or -SC(O)-; R ｇ and R' ｇ Independently, C １－３ Alkyl or methyl; a = 2, 3, or 4; or a = 2 or 4; or a = 4; b = 6 or 7; or b = 7; c = 5 or 6; or c = 5; d = 0 or 1; or d = 1; c + d = 5 or 6; or c + d = 6; M １ is -OC(O)-; M ２ is -C(O)O-; R １ C ７－１１ Linear alkyl, or C ９－１０ Linear alkyl, or C ９ It is a linear alkyl group; R ２ C ７－１２ Alkyl, or C ８－１２ Alkyl, or C ９－１０ Alkyl, or C ９ It is an alkyl group, and it optionally has one R １ｓ Replaced by; R １ｓ Independently, C １－９ Alkyl, or C １－８ Alkyl, or C ４－９ Alkyl, or C ４－８ It is alkyl; R ４ and R ５ Independently, C １－３ Alkyl or methyl; Or, R ４ and R ５ C ３－４ Forming cycloalkylene or cyclopropylene; Or, R １ or R ２ Upper R １ｓ The substitution position is M １ or M ２ It is separated from by 0 to 10 carbon atoms, or 0 to 6 carbon atoms, or 0 to 4 carbon atoms, or 0 to 2 carbon atoms, or 0 carbon atoms; Or, R １ R １ｓ It is not replaced by R ２ Upper R １ｓ The substitution position is M ２ It is separated from by 0 to 10 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 2 carbon atoms; or 2 to 10 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms; Or, R ２ teeth, 【Chemistry 48】 And, or 【Chemistry 49】 And, or [Transformation 50] And, or 【Chemistry 51】 And; Or, R ４ and R ５ They do not form a ring with the carbon atoms to which they are bonded. A compound of formula (II) or formula (III) as described in claim 52, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

54. The aforementioned compound is selected from the compounds in Table (I). A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

55. A compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient(s), Pharmaceutical composition.

56. A nanoparticle composition comprising a lipid component and optionally a support material, wherein the lipid component comprises a compound described in any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, isotopic variant, tautomer, or stereoisomer, and the support material is selected from one or more therapeutic agents, prophylactic agents, and diagnostic agents. Nanoparticle composition.

57. Uses of a compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutical composition according to claim 55, or a nanoparticle composition according to claim 56, in the manufacture of a drug for the treatment, diagnosis, or prevention of a disease, or the drug for the treatment, diagnosis, or prevention of a disease is a therapeutic or preventive mRNA vaccine. Use.

58. Uses of a compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutical composition according to claim 55, or a nanoparticle composition according to claim 56, in the manufacture of a drug for delivering a supported substance, wherein the supported substance is selected from one or more of therapeutic agents, prophylactic agents, and diagnostic agents. Use.

59. A method for treating, diagnosing, or preventing a disease in a subject, comprising administering the pharmaceutical composition described in claim 55 or the nanoparticle composition described in claim 56 to the subject. method.

60. A compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, isotope variant, tautomer, or stereoisomer, or a pharmaceutical composition according to claim 55, or a nanoparticle composition according to claim 56, for use in the treatment, diagnosis, or prevention of a disease.

61. A method for delivering a supported substance to a subject, The process includes administering the pharmaceutical composition according to claim 55 or the nanoparticle composition according to claim 56 to the subject, The aforementioned carrier substance is selected from one or more of the following: therapeutic agents, prophylactic agents, and diagnostic agents. method.

62. A compound according to any one of claims 1 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutical composition according to claim 55, or a nanoparticle composition according to claim 56, for use in delivering a carrier selected from one or more therapeutic agents, prophylactic agents, and diagnostic agents.

63. The aforementioned therapeutic agent, prophylactic agent, or diagnostic agent is nucleic acid; Alternatively, the nucleic acid may be selected from one or more of ASO, RNA, and DNA; Alternatively, the nanoparticle composition according to claim 56, or the use according to claim 58 or 62, or the method according to claim 61, wherein the RNA is selected from one or more of the following: small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimer coding nucleic acid (MCNA), polymer coding nucleic acid (PCNA), guide RNA (gRNA), CRISPRRNA (crRNA), and nuclease, or mRNA, or modified mRNA.

64. A method for preparing the compound of formula (II), This includes reacting a compound of formula (IIA) with a compound of formula (IIB) to obtain a compound of formula (II), 【Chemistry 52】 In the formula, X is a halogen, and the other variables are as defined in any one of claims 20 to 46. method.

65. A method for preparing the compound of formula (II), This includes reacting a compound of formula (IIC) with a compound of formula (IID) to obtain a compound of formula (II), 【Chemistry 53】 In the formula, X is a halogen, and the other variables are as defined in any one of claims 20 to 46. method.

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