Ionizable lipid for muscle-specific delivery

Abstract

The present invention provides an ionizable lipid for muscle-specific delivery, and specifically relates to a compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The present invention further provides a nanoparticle pharmaceutical composition comprising the compound, and a use of the compound and the composition thereof in muscle-specific nucleic acid delivery.

Description

Ionizable lipids for muscle-specific delivery

[0001] This application claims the rights of Chinese application No. CN202310720951.5 filed on June 16, 2023, Chinese application No. CN202310723466.3 filed on June 16, 2023, PCT application No. PCT / CN2023 / 143111 filed on December 29, 2023, Chinese application No. CN202410115561.X filed on January 26, 2024, and Chinese application No. The present application claims priority to Chinese application No. CN202410239117.9 filed on April 11, 2024, PCT application No. PCT / CN2024 / 087231 filed on April 11, 2024, PCT application No. PCT / CN2024 / 087436 filed on April 12, 2024, and PCT application No. PCT / CN2024 / 087429 filed on April 12, 2024, and the entireties of which are incorporated herein by reference. Technical Field

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

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

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

[0005] Currently, there are nearly a thousand known monogenic diseases that can cause muscle dysfunction, but the design of many LNPs may inadvertently lead to the expression of large amounts of mRNA in off-target tissues and organs (such as the liver, spleen, or heart), resulting in unwanted side effects. Therefore, there is an urgent need to design LNPs for muscle-specific mRNA delivery.

[0006] Summary of the Invention

[0007] The present invention has developed a class of ionizable cationic lipid compounds for muscle-specific delivery. These compounds can be used to deliver a variety of bioactive substances with high muscle-specific delivery efficiency. SM102 is widely recognized in the field of muscle delivery, and a muscle-deliverable LNP drug based on SM102 is already on the market. Surprisingly, the cationic lipids of the present invention exhibit even better in vivo muscle delivery specificity than SM102.

[0008] The present invention provides a compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009] Wherein, each group is as defined in the present invention.

[0010] In another aspect, the present invention provides a nanoparticle composition comprising a lipid component and, optionally, a cargo; wherein the lipid component comprises a compound of the present invention.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a nanoparticle composition of the present invention, and optionally a pharmaceutically acceptable excipient such as a carrier, adjuvant, or vehicle.

[0012] In another aspect, the present invention provides use of a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating, diagnosing, or preventing a disease. In one embodiment, the medicament for treating, diagnosing, or preventing a disease is a therapeutic or prophylactic mRNA vaccine.

[0013] In another aspect, the present invention provides use of a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention in the preparation of a medicament for delivering a cargo.

[0014] In another aspect, the present invention provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0015] In another aspect, the present invention provides a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention for use in the treatment, diagnosis, and / or prevention of a disease.

[0016] In another aspect, the present invention provides a method of delivering a cargo in a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0017] In another aspect, the present invention provides a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention for use in delivering a cargo.

[0018] In a specific embodiment, the cargo is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; preferably, the therapeutic agent, prophylactic agent or diagnostic agent is a nucleic acid.

[0019] In more specific embodiments, the nucleic acid is selected from one or more of ASO, RNA or 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), polyencoding nucleic acid (MCNA), polyencoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA) or ribozyme, preferably mRNA, more preferably modified mRNA.

[0021] definition

[0022] Chemical definition

[0023] Definitions of specific functional groups and chemical terms are described in more detail below.

[0024] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C5-6 alkyl.

[0025] “C 1-20 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms. In some embodiments, C 4-20 Alkyl, C 6-14 Alkyl, C 7-12 Alkyl, C 8-12 Alkyl, C 9-12 Alkyl, C 7-11 Alkyl, C 8-11 Alkyl, C 9-11 Alkyl, C 10-11 Alkyl, C 4-10 Alkyl, C 6-10 Alkyl, C 7-10 Alkyl, C 8-10 Alkyl, C 9-10 Alkyl, C 10 Alkyl, C 8-9 Alkyl, C 6-9 Alkyl, C 7-9 Alkyl, C 3-9 Alkyl, C 4-9 Alkyl, C9 alkyl, C 10 Alkyl, C 11 Alkyl, C 2-8 Alkyl, C 3-8 Alkyl, C 4-8 Alkyl, C 5-8 Alkyl, C 6-8 Alkyl, C 7-8 Alkyl, C8 alkyl, C 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 3-7 Alkyl, C 4-7 Alkyl, C 5-7 Alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 5-6 Alkyl, C 1-5 Alkyl, C 4-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C1-2 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). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, the alkyl group is preferably a straight chain alkyl group.

[0026] “C 2-13 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 13 carbon atoms and at least one carbon-carbon double bond. 4-20 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-14 Alkenyl, C 6-14 Alkenyl, C 7-12 Alkenyl, C 4-10 Alkenyl, C 2-10 Alkenyl, C 2-9 Alkenyl, C 2-6 Alkenyl and C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] “C 2-13 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 13 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds.4-20 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 4 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4-14 Alkynyl, C 6-14 Alkynyl, C 7-12 Alkynyl, C 4-10 Alkynyl, C 2-10 Alkynyl, C 2-9 Alkynyl, C 2-6 Alkynyl and C 2-4 Alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] “C 1-20 "Alkylene" refers to the removal of C 1-20 In some embodiments, C 4-20 Alkylene, C 6-14 Alkylene, C 7-12 Alkylene, C 8-12 Alkylene, C 4-10 Alkylene, C 7-11 Alkylene, C 8-11 Alkylene, C 8-10 Alkylene, C 9-10 Alkylene, C 8-9 Alkylene, C 4-9 Alkylene, C 6-9 Alkylene, C 7-9 Alkylene, C9 alkylene, C 2-8 Alkylene, C 5-8 Alkylene, C 7-8 Alkylene, C 4-6 Alkylene, C 1-20 Alkylene, C 1-14 Alkylene, C 2-14 Alkylene, C 1-13 Alkylene, C 1-12 Alkylene, C 1-10 Alkylene, C 1-9 Alkyl, C 1-8 Alkylene, C 1-7 Alkylene, C2-7 Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4 Alkylene, C 2-4 Alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1-2 Alkylene and methylene are preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0029] “C 2-13 "Alkenylene" refers to the removal of C 2-13 A divalent group is formed by the addition of another hydrogen atom to the alkenyl group and may be substituted or unsubstituted. 4-14 "Alkenylene" refers to the removal of C 4-14 In some embodiments, C 6-14 Alkenylene, C 4-10 Alkenylene, C 2-10 Alkenylene, C 2-9 Alkenylene, C 2-6 Alkenylene and C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0030] “C 2-13 "Alkynylidene" refers to the removal of C 2-13 The other hydrogen of the alkynyl group forms a divalent group, which may be substituted or unsubstituted. 4-14 "Alkynylidene" refers to the removal of C 4-14 In some embodiments, C 6-14 Alkynylidene, C 4-10 Alkynylidene, C 2-10 Alkynylidene, C 2-9 Alkynylidene, C 2-6 Alkynylidene and C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0031] “C 0-6 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-4 "Alkylene".

[0032] The term "the total length of variable A and variable B is x carbon atoms" means that the sum of the number of carbon atoms in the main chain of the group represented by variable A and the number of carbon atoms in the main chain of the group represented by variable B is x.

[0033] The term "R s There are x carbon atoms between the substitution site on R2 and M2", which means that the variable R2 is replaced by the variable R s The sum of the number of carbon atoms between the substituted site and M2 (including the N atom replaced by -NR'-), and so on for other cases. For example:

[0034] In compound 1, R s The substitution site on R2 is separated from M2 by one carbon atom.

[0035] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0036] Therefore, “C 1-10 "Haloalkyl" refers to the above-mentioned "C 1-10 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkyl, C 1-4 Halogenated alkyl, C 1-3 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0037] “C 3-14"Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2 or 3 double bonds or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl and 3- to 6-membered cycloalkyl are particularly preferred, more preferably 5- to 7-membered cycloalkyl, 4- to 6-membered cycloalkyl, 3- to 5-membered cycloalkyl, 3- to 4-membered cycloalkyl and 5- to 6-membered cycloalkyl, more preferably 5-membered cycloalkyl, more preferably 6-membered cycloalkyl, more preferably cyclopropyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to refer to the number of carbons in the cycloalkyl system. Cycloalkyl also includes cycloalkyl rings as described above in which the substituents on any non-adjacent carbon atoms are linked to form a bridge. Ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes the above-mentioned cycloalkyl ring, wherein the substituents on the same carbon atom are connected to form a ring, together forming a polycycloalkane sharing one carbon atom. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] “C 3-14 "Cycloalkylene" refers to the removal of C 3-14 In some embodiments, C 3-10 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene is particularly preferred, for example cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, with cyclopropylene being particularly preferred.

[0039] "3-14 membered heterocyclyl" or "3- to 14-membered heterocyclic group" refers to a saturated or unsaturated radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 3 to 10-membered heterocyclyl is preferably a 3 to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5 to 10-membered heterocyclyl is preferably a 5 to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3 to 8-membered heterocyclyl is preferably a 3 to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 3 to 7-membered heterocyclyl is preferably a 3 to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; 5 to 7-membered heterocyclyl is preferably a A 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 3- to 6-membered heterocyclyl, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 6-membered heterocyclyl, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 5-membered heterocyclyl, which is a 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 6-membered heterocyclyl, which is a 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes a heterocyclyl ring in which any substituents on non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes a heterocyclyl ring in which the substituents on the same carbon atom are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxirane, and thiidine. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups also include those in which the above-mentioned heterocyclyl groups share one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group to form a bridged or spirocyclic ring. The shared atoms may be carbon or nitrogen atoms, as valence permits. Heterocyclyl groups also include those in which the above-mentioned heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0040] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0041] "5-14 membered heteroaryl" or "5 to 14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl or pyridonyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepinyl, and thieptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0042] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups.

[0043] "Alkoxy" refers to the oxygen ether form of a straight or branched chain alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0044] "Optionally substituted..." means that the group may be substituted with a designated substituent or may be unsubstituted.

[0045] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0046] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0047] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NRbb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0048] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0049] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0050] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc)2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

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

[0052] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff)2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0053] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0054] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0055] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, 3-7 membered heterocyclic group, 5-10 membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0056] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa)2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0057] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and hybrid molecules thereof. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASOs). The nucleic acid may be further chemically modified, and the chemical modification is selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. The mRNA molecule contains a protein coding region and may further contain an expression regulatory sequence. Typical expression regulatory sequences include, but are not limited to, a 5' cap (5' cap), a 5' untranslated region (5' UTR), a 3' untranslated region (3' UTR), a polyadenylic acid sequence (PolyA), and a miRNA binding site.

[0058] "Cationic lipid" refers to a lipid molecule that is capable of being positively charged under physiological pH conditions. In some embodiments, the cationic lipid is an amino lipid.

[0059] "Neutral lipids" refer to lipid molecules that are uncharged under specific pH conditions, such as physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0060] "Structured lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentanylphenyl carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol.

[0061] "Polymer lipid" refers to a molecule comprising a polymer portion and a lipid portion. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. Other lipids that can reduce aggregation, such as compounds having uncharged, hydrophilic, steric barrier moieties coupled to lipids, can also be used.

[0062] "Lipid nanoparticles" refer to particles containing lipid components and having nanometer dimensions.

[0063] "Biodegradable groups" refer to functional groups containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can affect the elimination of compounds from the body. The biodegradable groups of the present invention are oriented from the head to the tail of the ionizable lipid molecule.

[0064] Other definitions

[0065] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0066] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0067] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0068] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0069] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0070] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0071] "Disease," "disorder," and "condition" are used interchangeably herein.

[0072] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0073] Generally, an "effective amount" of a pharmaceutical composition refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of the pharmaceutical composition of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount encompasses both a therapeutically effective amount and a prophylactically effective amount.

[0074] As used herein, unless otherwise specified, a "therapeutically effective amount" of a pharmaceutical composition is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a pharmaceutical composition refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0075] Unless otherwise specified, a "prophylactically effective amount" of a pharmaceutical composition as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a pharmaceutical composition refers to an amount of a therapeutic agent, when used alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0076] "Combination" and related terms refer to the simultaneous or sequential administration of a pharmaceutical composition of the present invention and other therapeutic agents. For example, a pharmaceutical composition of the present invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. DETAILED DESCRIPTION

[0077] Herein, "compounds of the present invention" refers to the following compounds, pharmaceutically acceptable salts, isotopic variations, tautomers or stereoisomers thereof.

[0078] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0079] In one embodiment, the present invention relates to a compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0080] in,

[0081] a = 1, 2, 3, 4, 5, or 6;

[0082] b = 4, 5, 6, 7, 8, 9, or 10;

[0083] c = 1, 2, 3, 4, 5, or 6;

[0084] d = 0, 1, 2, 3, 4, or 5;

[0085] c+d=3, 4, 5, 6, 7, 8, or 9;

[0086] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O )S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -;

[0087] Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR a -、-NR a C(O)NR' a -、-OC(O)S-、-OC(O)O-、-NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -、-C(O)NR a -、-NR a C(O)-、-NR a C(O)S-、-SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -、-NR a C(S)O-, -SS-, and -S(O) 0-2 -;

[0088] R a and R' a Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0089] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted by one or more R s substituted, and wherein one or more methylene units are optionally and independently replaced by -NR'-;

[0090] R s There are 0 to 12 carbon atoms between the substitution site on R1 or R2 and M1 or M2;

[0091] R and R' are each independently selected from H and C 1-20 alkyl;

[0092] R s Independently selected from H, C 1-20 Alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0093] L b independently selected from chemical bonds and C 1-20 alkylene;

[0094] R b and R' b Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0095] R3 is selected from CN, -OR c 、-C(O)R c 、-OC(O)R c 、-NR”C(O)R c 、-NR c R' c 、-NR”C(O)NR c R' c 、-NR”C(O)R c 、-NR”S(O)2R c 、-OC(O)NR c R' c 、-NR”C(O)OR c 、-N(OR c )C(O)R c 、-N(OR c )S(O)2R c 、-N(OR c )C(O)OR c 、-N(OR c )C(O)R c R' c , 3- to 14-membered heterocyclyl and 5- to 14-membered heteroaryl;

[0096] R c and R' c Independently selected from H, C 1-10 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0097] R" is independently selected from H and C 1-6 alkyl;

[0098] R4 and R5 are independently C 1-8 alkyl, optionally substituted with one or more R*;

[0099] Or R4, R5 together with the carbon atom to which they are attached form C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, optionally substituted with one or more R*;

[0100] R* is independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -OR d 、-L d-SR d and -L d -NR d R' d ;

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

[0102] R d and R' d Independently selected from H, C 1-8 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0103] a, b, c, and d

[0104] 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.

[0105] In a more specific embodiment, a=2, 3, 4, 5 or 6; in another more specific embodiment, a=2, 3, 4 or 5; in another more specific embodiment, a=2, 3 or 4; in another more specific embodiment, a=2 or 3; in another more specific embodiment, a=3 or 4.

[0106] In one embodiment, b is 4; in another embodiment, b is 5; in another embodiment, b is 6; in another embodiment, b is 7; in another embodiment, b is 8; in another embodiment, b is 9; and in another embodiment, b is 10.

[0107] In a more specific embodiment, b=4, 5, 6, 7, 8 or 9; in another more specific embodiment, b=5, 6, 7 or 8; in another more specific embodiment, b=5, 6 or 7; in another more specific embodiment, b=6, 7 or 8; in another more specific embodiment, b=5 or 7; in another more specific embodiment, b=6 or 7; in another more specific embodiment, b=6 or 8; in another more specific embodiment, b=7 or 8.

[0108] 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.

[0109] In a more specific embodiment, c=2, 3, 4, 5 or 6; in another more specific embodiment, c=2, 3, 5 or 6; in another more specific embodiment, c=3, 4, 5 or 6; in another more specific embodiment, c=2, 3, 4 or 5; in another more specific embodiment, c=3, 5 or 6; in another more specific embodiment, c=2, 4 or 5; in another more specific embodiment, c=2 or 4; in another more specific embodiment, c=2 or 6; in another more specific embodiment, c=5 or 6.

[0110] 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; in another embodiment, d is 5.

[0111] In a more specific embodiment, d=1, 2, 3, 4 or 5; in another more specific embodiment, d=0, 1, 2, 3 or 4; in another more specific embodiment, d=1, 2, 3 or 4; in another more specific embodiment, d=0, 1, 2 or 3; in another more specific embodiment, d=1, 2 or 4; in another more specific embodiment, d=0, 1 or 2; in another more specific embodiment, d=0 or 1; in another more specific embodiment, d=2 or 4; in another more specific embodiment, d=0 or 3.

[0112] 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.

[0113] In a more specific embodiment, c+d=4, 5 or 6; in another more specific embodiment, c+d=5, 6 or 7; in another more specific embodiment, c+d=6 or 7; in another more specific embodiment, c+d=5 or 6.

[0114] M1 and M2

[0115] In one embodiment, M1 is -C(O)O-; in another embodiment, M1 is -OC(O)-; in another embodiment, M1 is -O-; in another embodiment, M1 is -SC(O)O-; in another embodiment, M1 is -OC(O)NR-; in another embodiment, M1 is -NRC(O)NR-; in another embodiment, M1 is -OC(O)S-; in another embodiment, M1 is -OC(O)O-; in another embodiment, M1 is -NRC(O)O- In another embodiment, M1 is -SC(O)-; In another embodiment, M1 is -C(O)S-; In another embodiment, M1 is -NR-; In another embodiment, M1 is -C(O)NR-, for example, -C(O)NH-; In another embodiment, M1 is -NRC(O)-, for example, -NHC(O)-; In another embodiment, M1 is -NRC(O)S-; In another embodiment, M1 is -SC(O)NR-; In another embodiment, M1 is -C(O)-; In another embodiment, M1 is -OC(S)-; In another embodiment, M1 is -C(S)O-; In another embodiment, M1 is -OC(S)NR-; In another embodiment, M1 is -NRC(S)O-; In another embodiment, M1 is -SS-; In another embodiment, M1 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0116] In one embodiment, M2 is -C(O)O-; in another embodiment, M2 is -OC(O)-; in another embodiment, M2 is -O-; in another embodiment, M2 is -SC(O)O-; in another embodiment, M2 is -OC(O)NR-; in another embodiment, M2 is -NRC(O)NR-; in another embodiment, M2 is -OC(O)S-; in another embodiment, M2 is -OC(O)O-; in another embodiment, M2 is -NRC(O)O-; in another embodiment, M2 is -SC(O)-; in another embodiment, M2 is -C(O)S-; in another embodiment In another embodiment, M2 is -NR-; in another embodiment, M2 is -C(O)NR-; in another embodiment, M2 is -NRC(O)-; in another embodiment, M2 is -NRC(O)S-; in another embodiment, M2 is -SC(O)NR-; in another embodiment, M2 is -C(O)-; in another embodiment, M2 is -OC(S)-; in another embodiment, M2 is -C(S)O-; in another embodiment, M2 is -OC(S)NR-; in another embodiment, M2 is -NRC(S)O-; in another embodiment, M2 is -SS-; in another embodiment, M2 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0117] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -OC(O)O-, -C(O)NR- and -NRC(O)-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-.

[0118] Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; in another more specific embodiment, M1 and M2 are not both -OC(O)O-; in another more specific embodiment, M1 and M2 are not both -OC(O)-; in another more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -OC(O)-.

[0119] In a more specific embodiment, M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-; and M2 is -C(O)O-.

[0120] In a more specific embodiment, M1 is -OC(O)- or -SC(O)-; and M2 is -C(O)O- or -C(O)S-.

[0121] In a more specific embodiment, M1 is -OC(O)-; M2 is -C(O)O-.

[0122] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-;

[0123] In a more specific embodiment, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably -C(O)O- and -OC(O)-.

[0124] In a more specific embodiment, M1 is -OC(O)O-, and M2 is selected from -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-, preferably -C(O)O- and -OC(O)-.

[0125] In a more specific embodiment, M2 is -OC(O)O-, and M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-, preferably -C(O)O- and -OC(O)-.

[0126] Q

[0127] In one embodiment, Q is a chemical bond; in another embodiment, Q is -C(O)O-; in another embodiment, Q is -O-; in another embodiment, Q is -SC(O)O-; in another embodiment, Q is -OC(O)NR a -; In another embodiment, Q is -NR a C(O)NR' a -; in another embodiment, Q is -OC(O)S-; in another embodiment, Q is -OC(O)O-; in another embodiment, Q is -NR a C(O)O-; in another embodiment, Q is -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR a -; In another embodiment, Q is -C(O)NR a-; In another embodiment, Q is -NR a C(O)-; in another embodiment, Q is -NR a C(O)S-; in another embodiment, Q is -SC(O)NR a -; in another embodiment, Q is -C(O)-; in another embodiment, Q is -OC(S)-; in another embodiment, Q is -C(S)O-; in another embodiment, Q is -OC(S)NR a -; In another embodiment, Q is -NR a C(S)O-; in another embodiment, Q is -SS-; in another embodiment, Q is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-;.

[0128] In a more specific embodiment, Q is selected from a chemical bond, -OC(O)-, and -SC(O)-; in another more specific embodiment, Q is a chemical bond or -SC(O)-; in another more specific embodiment, Q is -SC(O)- or -OC(O)-.

[0129] R a and R' a

[0130] In one embodiment, R a is H; in another embodiment, R a C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R a C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R a It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0131] In one embodiment, R' a is H; in another embodiment, R' a C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' a C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R' a It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0132] In a more specific embodiment, R a and R' a Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3 to 10 membered heterocyclyl; in another more specific embodiment, R a and R' a Independently selected from H and C 1-6 Alkyl; in another more specific embodiment, R a and R' a Independently selected from H and C 1-4 alkyl.

[0133] R1 and R2

[0134] In one embodiment, R1 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 10 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, preferably C8 alkyl, preferably C 8-12 Straight chain alkyl, preferably C 7-11 Straight chain alkyl, preferably C 8-11 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl, preferably C 8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C 8-9 Straight chain alkyl, preferably C 11 Straight chain alkyl, preferably C 10 Straight chain alkyl, preferably C9 straight chain alkyl; in another embodiment, R1 is C 4-20 Alkenyl, preferably C 6-14 Alkenyl, preferably C 7-12 Alkenyl, preferably C 8-12 In another embodiment, R1 is C 4-20 Alkynyl, preferably C 6-14 Alkynyl, preferably C 7-12 Alkynyl, preferably C 8-12 Alkynyl; In another embodiment, R1 is optionally replaced by one or more R s In another embodiment, R1 is optionally replaced by 1, 2, 3 or 4 R s substituted, preferably optionally with 1 R sIn another embodiment, R1 is unsubstituted; in another embodiment, one or more methylene units in R1 are optionally and independently replaced by -NR'-, preferably one methylene unit in R1 is optionally replaced by -NR'-.

[0135] In one embodiment, R1 is -(CH2)7CH3; in another embodiment, R1 is -(CH2)8CH3; in another embodiment, R1 is -(CH2)9CH3; in another embodiment, R1 is -(CH2) 10 CH3; In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is In another embodiment, R1 is

[0136] In one embodiment, R2 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 10 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, preferably C8 alkyl, preferably C 8-12 Straight chain alkyl, preferably C 7-11 Straight chain alkyl, preferably C 8-11 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 10-11 Straight chain alkyl, preferably C8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C 8-9 Straight chain alkyl, preferably C 11 Straight chain alkyl, preferably C 10 Straight chain alkyl, preferably C9 straight chain alkyl; in another embodiment, R2 is C 4-20 Alkenyl, preferably C 6-14 Alkenyl, preferably C 7-12 Alkenyl, preferably C 8-12 In another embodiment, R2 is C 4-20 Alkynyl, preferably C 6-14 Alkynyl, preferably C 7-12 Alkynyl, preferably C 8-12 Alkynyl; In another embodiment, R2 is optionally replaced by one or more R s In another embodiment, R2 is optionally replaced by 1, 2, 3 or 4 R s substituted, preferably optionally with 1 R s In another embodiment, R2 is unsubstituted; in another embodiment, one or more methylene units in R2 are optionally and independently replaced by -NR'-, preferably one methylene unit in R2 is optionally replaced by -NR'-.

[0137] In one embodiment, R2 is -(CH2)7CH3; in another embodiment, R2 is -(CH2)8CH3; in another embodiment, R2 is -(CH2)9CH3; in another embodiment, R2 is -(CH2) 10 CH3; In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is In another embodiment, R2 is

[0138] In a more specific embodiment, R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 In another more specific embodiment, R1 and R2 are independently selected from C 8-10 Alkyl, C 8-10 Alkenyl and C 8-10 Alkynyl.

[0139] In a more specific embodiment, R1 and R2 are independently C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl.

[0140] In a more specific embodiment, R1 and R2 are independently selected from the following groups: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, In another more specific embodiment, R1 and R2 are independently selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3,

[0141] In one embodiment, R1 and R2 are not substituted at the same time; in another embodiment, one of R1 and R2 is substituted and the other is not substituted; in another embodiment, R1 is not substituted and R2 is substituted; in another embodiment, R1 is substituted and R2 is not substituted; in another embodiment, one of R1 and R2 is replaced by 1, 2, 3 or 4 (preferably 1) R s substituted, and the other is unsubstituted; in another embodiment, R1 is replaced by 1, 2, 3 or 4 (preferably 1) R s In another embodiment, R1 is unsubstituted and R2 is replaced by 1, 2, 3 or 4 (preferably 1) R s replace.

[0142] In a more specific embodiment, one of R1 and R2 is selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3 and -(CH2) 10CH3, preferably -(CH2)8CH3, -(CH2)9CH3 and -(CH2) 10 CH3; another selected from: Preferably selected from:

[0143] In a more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, In another more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[0144] In a more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, In another more specific embodiment, R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3,

[0145] In a more specific embodiment, one of R1 and R2 is selected from C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl, the other is selected from: Preferred

[0146] In a more specific embodiment, one of R1 and R2 is a C9 linear alkyl group, and the other is selected from: Preferred

[0147] In a more specific embodiment, R2 is selected from: In another more specific embodiment, R2 is selected from: In another more specific embodiment, R2 is selected from: In another more specific embodiment, R2 is selected from: In another more specific embodiment, R2 is selected from: Preferred In another more specific embodiment, R2 is selected from:

[0148] R and R'

[0149] In one embodiment, R is H; in another embodiment, R is C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 alkyl.

[0150] In one embodiment, R' is H; in another embodiment, R' is C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 alkyl.

[0151] In a more specific embodiment, R and R' are each independently selected from H and C 1-20 In another more specific embodiment, R and R' are each independently selected from H and C 1-14 In another more specific embodiment, R and R' are each independently selected from H and C 1-10 In another more specific embodiment, R and R' are each independently selected from H and C 1-6 In another more specific embodiment, R is H.

[0152] R s

[0153] In one embodiment, R s is H; in another embodiment, R s is H; in another embodiment, R s C 1-20 Alkyl; in another embodiment, R s -L b -OR b In another embodiment, R s -L b -SR b In another embodiment, R s -L b -NR b R' b .

[0154] In a more specific embodiment, R sIndependently selected from H, C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b In another more specific embodiment, R s Independently selected from H and C 1-14 Alkyl; in another more specific embodiment, R s Independently selected from H and C 1-12 Alkyl; in another more specific embodiment, R s Independently selected from H and C 1-10 Alkyl; in another more specific embodiment, R s Independently selected from H and C 1-9 Alkyl; in another more specific embodiment, R s Independently selected from H and C 3-9 Alkyl; in another more specific embodiment, R s Independently selected from H and C 1-8 Alkyl; in another more specific embodiment, R s Independently selected from H and C 3-8 Alkyl; in another more specific embodiment, R s Independently selected from H and C 4-8 Alkyl; in another more specific embodiment, R s Independently selected from H and C 5-8 Alkyl; in another more specific embodiment, R s Independently selected from H and C 6-8 Alkyl; in another more specific embodiment, R s Independently selected from H and C 1-7 Alkyl; in another more specific embodiment, R s Independently selected from H and C 3-7 Alkyl; in another more specific embodiment, R s Independently selected from H and C 4-7 Alkyl; in another more specific embodiment, R s Independently selected from H and C 5-7 Alkyl; in another more specific embodiment, R s Independently selected from H and C 1-6 Alkyl; in another more specific embodiment, R s Independently selected from H and C 5-6 Alkyl; in another more specific embodiment, R s Independently selected from H and C 1-5Alkyl; in another more specific embodiment, R s Independently selected from H and C 4-5 Alkyl; in another more specific embodiment, R s Independently selected from H and C5 alkyl.

[0155] In a more specific embodiment, R s Independently selected from C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b In another more specific embodiment, R s Independently C 1-14 Alkyl; in another more specific embodiment, R s Independently C 1-12 Alkyl; in another more specific embodiment, R s Independently C 1-10 Alkyl; in another more specific embodiment, R s Independently C 1-9 Alkyl; in another more specific embodiment, R s Independently C 3-9 Alkyl; in another more specific embodiment, R s Independently C 1-8 Alkyl; in another more specific embodiment, R s Independently C 3-8 Alkyl; in another more specific embodiment, R s Independently C 4-8 Alkyl; in another more specific embodiment, R s Independently C 5-8 Alkyl; in another more specific embodiment, R s Independently C 6-8 Alkyl; in another more specific embodiment, R s Independently C 1-7 Alkyl; in another more specific embodiment, R s Independently C 3-7 Alkyl; in another more specific embodiment, R s Independently C 4-7 Alkyl; in another more specific embodiment, R s Independently C 5-7 Alkyl; in another more specific embodiment, R s Independently C 1-6 Alkyl; in another more specific embodiment, Rs Independently C 5-6 Alkyl; in another more specific embodiment, R s Independently C 1-5 Alkyl; in another more specific embodiment, R s Independently C 4-5 Alkyl; in another more specific embodiment, R s are independently C9 alkyl; in another more specific embodiment, R s are independently C8 alkyl; in another more specific embodiment, R s are independently C7 alkyl; in another more specific embodiment, R s are independently C6 alkyl; in another more specific embodiment, R s are independently C5 alkyl.

[0156] In one embodiment, R s There is 0 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There is one carbon atom between the substitution site on R1 and M1; in another embodiment, R s There are 2 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 3 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 4 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 5 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 6 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 7 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 8 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 9 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 10 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 11 carbon atoms between the substitution site on R1 and M1; in another embodiment, R s There are 12 carbon atoms between the substitution site on R1 and M1.

[0157] In one embodiment, R sThere is 0 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There is one carbon atom between the substitution site on R2 and M2; in another embodiment, R s There are 2 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 3 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 4 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 5 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 6 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 7 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 8 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 9 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 10 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 11 carbon atoms between the substitution site on R2 and M2; in another embodiment, R s There are 12 carbon atoms between the substitution site on R2 and M2.

[0158] In a more specific embodiment, R s There are 0-12 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 0-10 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 0-6 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 0-5 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 0-4 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 0-3 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 0-2 carbon atoms between the substitution site on R1 and M1; R sThe substitution site on R1 is separated from M1 by at least 2 carbon atoms; in another more specific embodiment, R s There are 2-4 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 2-3 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 3-4 carbon atoms between the substitution site on R1 and M1; s There is at least one carbon atom between the substitution site on R1 and M1; in another more specific embodiment, R s There are 1 to 5 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 1 to 4 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 1-3 carbon atoms between the substitution site on R1 and M1; in another more specific embodiment, R s There are 3 carbon atoms between the substitution site on R1 and M1.

[0159] In a more specific embodiment, R s There are 0-12 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 0-10 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 0-6 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 0-5 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 0-4 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 0-3 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 0-2 carbon atoms between the substitution site on R2 and M2; s The substitution site on R2 is separated from M2 by at least 2 carbon atoms; in another more specific embodiment, R s There are 2-4 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 2-3 carbon atoms between the substitution site on R2 and M1; in another more specific embodiment, R sThere are 3-4 carbon atoms between the substitution site on R2 and M2; s The substitution site on R2 is separated from M2 by at least one carbon atom; in another more specific embodiment, R s There are 1 to 5 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 1-4 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 1-3 carbon atoms between the substitution site on R2 and M2; in another more specific embodiment, R s There are 3 carbon atoms between the substitution site on R2 and M2.

[0160] L b 、R b and R' b

[0161] In one embodiment, L b is a chemical bond; in another embodiment, L b C 1-20 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene.

[0162] In a more specific embodiment, L b independently selected from chemical bonds and C 1-14 Alkylene; in another more specific embodiment, L b independently selected from chemical bonds and C 1-10 Alkylene; in another more specific embodiment, L b independently selected from chemical bonds and C 1-6 Alkylene.

[0163] In one embodiment, R b is H; in another embodiment, R b C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R b C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R b It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0164] In one embodiment, R' bis H; in another embodiment, R' b C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' b C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R' b It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0165] In a more specific embodiment, R b and R' b Independently selected from H and C 1-14 Alkyl; in another more specific embodiment, R b and R' b Independently selected from H and C 1-10 Alkyl; in another more specific embodiment, R b and R' b Independently selected from H and C 1-6 alkyl.

[0166] R3

[0167] In one embodiment, R3 is CN; in another embodiment, R3 is -OR c , such as -OH; in another embodiment, R3 is -C(O)R c In another embodiment, R3 is -OC(O)R c In another embodiment, R3 is -NR"C(O)R c In another embodiment, R3 is -NR c R' c , such as -N(CH3)2; in another embodiment, R3 is -NR"C(O)NR c R' c In another embodiment, R3 is -NR"C(O)R c In another embodiment, R3 is -NR"S(O)2R c In another embodiment, R3 is -OC(O)NR c R' c In another embodiment, R3 is -NR"C(O)OR c In another embodiment, R3 is -N(OR c )C(O)R c In another embodiment, R3 is -N(OR c)S(O)2R c In another embodiment, R3 is -N(OR c )C(O)OR c In another embodiment, R3 is -N(OR c )C(O)R c R' c In another embodiment, R3 is a 3- to 14-membered heterocyclyl; in another embodiment, R3 is a 5- to 14-membered heteroaryl.

[0168] In a more specific embodiment, R3 is selected from CN, -OR c and -NR c R' c In another more specific embodiment, R3 is selected from -OR c and -NR c R' c ; In another more specific embodiment, R3 is selected from -OH and -N(CH3)2.

[0169] R c and R' c

[0170] In one embodiment, R c is H; in another embodiment, R c C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, such as Me; in another embodiment, R c C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R c It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0171] In one embodiment, R' c is H; in another embodiment, R' c C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, such as Me; in another embodiment, R' c C 3-10 Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R' c It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0172] In a more specific embodiment, R c and R' c Independently selected from H, C1-6 Alkyl, C 3-7 cycloalkyl and 3 to 7 membered heterocyclyl; in another more specific embodiment, R c and R' c Independently selected from H and C 1-6 Alkyl; in another more specific embodiment, R c and R' c Independently selected from H and C 1-4 Alkyl; in another more specific embodiment, R c and R' c Independently selected from H and Me.

[0173] R”

[0174] In one embodiment, R" is H; in another embodiment, R" is C 1-6 Alkyl, preferably C 1-4 alkyl.

[0175] R4 and R5

[0176] In one embodiment, R4 is C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl, preferably methyl; in another embodiment, R4 is optionally substituted with one or more R*; in another embodiment, R4 is optionally substituted with 1, 2 or 3 R*; in another embodiment, R4 is unsubstituted.

[0177] In one embodiment, R5 is C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl, preferably methyl; in another embodiment, R5 is optionally substituted with one or more R*; in another embodiment, R5 is optionally substituted with 1, 2 or 3 R*; in another embodiment, R5 is unsubstituted.

[0178] In one embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C 3-6 Cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene), preferably forming C 3-5 Cycloalkylene, preferably forming C 3-4In another embodiment, R4, R5 and the carbon atom to which they are attached form a 3- to 14-membered heterocyclylene, preferably a 3- to 10-membered heterocyclylene, preferably a 3- to 6-membered heterocyclylene; in another embodiment, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted by one or more R*; in another embodiment, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted by 1, 2 or 3 R*; in another embodiment, the ring formed by R4, R5 and the carbon atom to which they are attached is unsubstituted.

[0179] In a more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-10 In another more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-6 In another more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); in another more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-4 In another more specific embodiment, R4, R5 and the carbon atom to which they are attached together form a cyclopropylene group; in another more specific embodiment, R4, R5 and the carbon atom to which they are attached do not form a ring.

[0180] R*

[0181] In one embodiment, R* is H; in another embodiment, R* is halogen; in another embodiment, R* is cyano; in another embodiment, R* is C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl; in another embodiment, R* is C 1-8 Halogenated alkyl, preferably C 1-6 Halogenated alkyl, preferably C 1-3 haloalkyl; in another embodiment, R* is -L d -OR d In another embodiment, R* is -L d -SR d In another embodiment, R* is -L d -NR d R' d .

[0182] In a more specific embodiment, R* is independently selected from H, halogen, cyano, C1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -OR d 、-L d -SR d and -L d -NR d R' d In another more specific embodiment, R* is independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 In another more specific embodiment, R* is independently selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0183] L d 、R d and R' d

[0184] In one embodiment, L d is a chemical bond; in another embodiment, L d C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene.

[0185] In a more specific embodiment, L d independently selected from chemical bonds and C 1-6 Alkylene; in another more specific embodiment, L d independently selected from chemical bonds and C 1-3 Alkylene.

[0186] In one embodiment, R d is H; in another embodiment, R d C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R d C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl; in another embodiment, R d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0187] In one embodiment, R' d is H; in another embodiment, R' d C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' d C 3-14 Cycloalkyl, preferably C3-10 Cycloalkyl; in another embodiment, R' d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0188] In a more specific embodiment, R d and R' d Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3 to 10 membered heterocyclyl; in another more specific embodiment, R d and R' d Independently selected from H and C 1-6 alkyl.

[0189] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of G1 can be combined with M1, M2, Q, R a , R' a , R1, R2, R, R', R s 、L b 、R b , R' b , R3, R c , R' c , R”, R4, R5, R*, L d 、R d , R' d The present invention is intended to include combinations of all these technical solutions, which are not listed one by one due to space limitations.

[0190] In a more specific embodiment, the present invention provides a compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0191] in,

[0192] a = 1, 2, 3, 4, 5, or 6;

[0193] b = 4, 5, 6, 7, 8, 9, or 10;

[0194] c = 1, 2, 3, 4, 5, or 6;

[0195] d = 0, 1, 2, 3, 4, or 5;

[0196] c+d=3, 4, 5, 6, 7, 8, or 9;

[0197] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O )S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -;

[0198] Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR a -、-NR a C(O)NR' a -、-OC(O)S-、-OC(O)O-、-NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -、-C(O)NR a -、-NR a C(O)-、-NR a C(O)S-、-SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -、-NR a C(S)O-, -SS-, and -S(O) 0-2 -;

[0199] R a and R' a Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0200] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted by one or more R s substituted, and wherein one or more methylene units are optionally and independently replaced by -NR'-;

[0201] R s There are 0 to 12 carbon atoms between the substitution site on R1 or R2 and M1 or M2;

[0202] R and R' are each independently selected from H and C 1-20 alkyl;

[0203] R s Independently selected from H, C 1-20 Alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0204] L b independently selected from chemical bonds and C 1-20 alkylene;

[0205] R b and R' b Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0206] R3 is selected from CN, -OR c 、-C(O)R c 、-OC(O)R c 、-NR”C(O)R c 、-NR c R' c 、-NR”C(O)NR c R' c 、-NR”C(O)R c 、-NR”S(O)2R c 、-OC(O)NR c R' c 、-NR”C(O)OR c 、-N(OR c )C(O)R c 、-N(OR c )S(O)2R c 、-N(OR c )C(O)OR c 、-N(OR c )C(O)R c R' c , 3- to 14-membered heterocyclyl and 5- to 14-membered heteroaryl;

[0207] R c and R' c Independently selected from H, C 1-10 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0208] R" is independently selected from H and C 1-6 alkyl;

[0209] R4 and R5 are independently C1-8 alkyl, optionally substituted with one or more R*;

[0210] Or R4, R5 together with the carbon atom to which they are attached form C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, optionally substituted with one or more R*;

[0211] R* is independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -OR d 、-L d -SR d and -L d -NR d R' d ;

[0212] L d independently selected from chemical bonds and C 1-8 alkylene;

[0213] R d and R' d Independently selected from H, C 1-8 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0214] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5; preferably a=2, 3 or 4; preferably a=2 or 3; preferably a=3 or 4; preferably a=2; preferably a=3; preferably a=4.

[0215] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; preferably b = 6, 7 or 8; preferably b = 6 or 7; preferably b = 6 or 8; preferably b = 7 or 8; preferably b = 7.

[0216] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein c = 2, 3, 4, 5 or 6; preferably c = 2, 3, 5 or 6; preferably c = 3, 4, 5 or 6; preferably c = 2, 3, 4 or 5; preferably c = 3, 5 or 6; preferably c = 2, 4 or 5; preferably c = 2 or 4; preferably c = 2 or 6; preferably c = 5 or 6; preferably c = 2; preferably c = 3; preferably c = 5; preferably c = 6.

[0217] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein d = 1, 2, 3, 4 or 5; preferably d = 0, 1, 2, 3 or 4; preferably d = 1, 2, 3 or 4; preferably d = 0, 1, 2 or 3; preferably d = 1, 2 or 4; preferably d = 0, 1 or 2; preferably d = 0 or 1; preferably d = 2 or 4; preferably d = 0 or 3; preferably d = 0; preferably d = 1; preferably d = 3; preferably d = 4.

[0218] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein c+d=5, 6 or 7; preferably c+d=6 or 7; preferably c+d=5 or 6; preferably c+d=6.

[0219] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -OC(O)O-, -C(O)NR- and -NRC(O)-; preferably selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-.

[0220] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably not simultaneously -OC(O)O-; preferably not simultaneously -OC(O)-; preferably selected from -C(O)O- and -OC(O)-.

[0221] In a more specific embodiment, M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-; and M2 is -C(O)O-.

[0222] In more specific embodiments, M1 is -OC(O)- or -SC(O)-; and M2 is -C(O)O- or -C(O)S-.

[0223] In a more specific embodiment, M1 is -OC(O)-; and M2 is -C(O)O-.

[0224] In a more specific embodiment, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-.

[0225] In a more specific embodiment, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably -C(O)O- and -OC(O)-; preferably M1 is selected from -C(O)O- and OC(O)-, preferably -C(O)O-, and M2 is -OC(O)O-.

[0226] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q is selected from a chemical bond, -OC(O)- and -SC(O)-; preferably a chemical bond or -SC(O)-; preferably -SC(O)- or -OC(O)-.

[0227] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R a and R' a Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

[0228] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl or C 6-14 Alkynyl; preferably selected from C 6-14 alkyl.

[0229] In a more specific embodiment, R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl, preferably C 8-10 Alkyl, C 8-10 Alkenyl and C 8-10 Alkynyl.

[0230] In more specific embodiments, R1 and R2 are independently C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl.

[0231] In more specific embodiments, R1 and R2 are optionally replaced by 1, 2, 3 or 4 R s substituted, preferably optionally with 1 R s replace.

[0232] In more specific embodiments, R1 and R2 are not substituted at the same time; preferably, one of R1 and R2 is substituted and the other is unsubstituted; preferably, R1 is unsubstituted and R2 is substituted; preferably, R1 is substituted and R2 is unsubstituted.

[0233] In more specific embodiments, R1 and R2 are independently selected from the following groups: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, Preferably selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3,

[0234] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R and R' are each independently selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 Alkyl; preferably R is H.

[0235] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R s Independently selected from H, C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably H and C 1-14 Alkyl; preferably H and C 1-12 Alkyl; preferably H and C 1-10 Alkyl; preferably H and C 1-9 Alkyl; preferably H and C 3-9 Alkyl; preferably H and C 1-8 Alkyl; preferably H and C 3-8 Alkyl; preferably H and C 4-8 Alkyl; preferably H and C 5-8 Alkyl; preferably H and C 6-8 Alkyl; preferably H and C 1-7Alkyl; preferably H and C 3-7 Alkyl; preferably H and C 4-7 Alkyl; preferably H and C 5-7 Alkyl; preferably H and C 1-6 Alkyl; preferably H and C 5-6 Alkyl; preferably H and C 1-5 Alkyl; preferably H and C 4-5 Alkyl; preferably H and C5 alkyl.

[0236] In a more specific embodiment, R s Independently preferably selected from C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably C 1-14 Alkyl, preferably C 1-12 Alkyl; preferably C 1-10 Alkyl; preferably C 1-9 Alkyl; preferably C 3-9 Alkyl; preferably C 1-8 Alkyl; preferably C 3-8 Alkyl; preferably C 4-8 Alkyl; preferably C 5-8 Alkyl; preferably C 6-8 Alkyl; preferably C 1-7 Alkyl; preferably C 3-7 Alkyl; preferably C 4-7 Alkyl; preferably C 5-7 Alkyl; preferably C 1-6 Alkyl; preferably C 5-6 Alkyl; preferably C 1-5 Alkyl; preferably C 4-5 Alkyl; preferably C5 alkyl.

[0237] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L b independently selected from chemical bonds and C 1-14 Alkylene; preferably selected from C 1-10 Alkylene; preferably selected from C 1-6 Alkylene.

[0238] In a more specific embodiment, R b and R' b Independently selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 alkyl.

[0239] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from CN, -OR c and -NR c R' c ; preferably selected from -OR c and -NR c R' c ; preferably -NR c R' c ; preferably -N(CH3)2; preferably -OR c ; preferably OH.

[0240] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R c and R' c Independently selected from H, C 1-10 Alkyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocyclic groups; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 Alkyl (eg, methyl).

[0241] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are independently C 1-6 Alkyl; preferably C 1-3 Alkyl; preferably C 1-2 Alkyl; preferably methyl.

[0242] In more specific embodiments, R4 and R5 are optionally substituted with 1, 2 or 3 R*.

[0243] In a more specific embodiment, R4, R5 together with the carbon atom to which they are attached form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-4 preferably forming a cyclopropylene group.

[0244] In more specific embodiments, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted with 1, 2 or 3 R*.

[0245] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L d -OR d 、-L d -SR d and -L d -NR d R' d ; preferably selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0246] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L d independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-3 Alkylene.

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

[0248] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R s The spacing between the substitution site on R1 or R2 and M1 or M2 is 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-5 carbon atoms, preferably 0-4 carbon atoms, preferably 0-3 carbon atoms, preferably 0-2 carbon atoms.

[0249] In a more specific embodiment, R s The substitution site on R1 or R2 is separated from M1 or M2 by at least 2 carbon atoms, preferably 2-4 carbon atoms, preferably 2-3 carbon atoms, and preferably 3-4 carbon atoms.

[0250] In a more specific embodiment, R sThe substitution site on R1 or R2 is separated from M1 or M2 by at least 1 carbon atom, preferably 1-5 carbon atoms, preferably 1-4 carbon atoms, preferably 1-3 carbon atoms, preferably 3 carbon atoms.

[0251] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0252] in,

[0253] a = 1, 2, 3, 4, 5, or 6;

[0254] b = 4, 5, 6, 7, 8, 9, or 10;

[0255] c = 1, 2, 3, 4, 5, or 6;

[0256] d = 1, 2, 3, 4, or 5;

[0257] c+d=3, 4, 5, 6, 7, 8, or 9;

[0258] M1 is -OC(O)- or -SC(O)-;

[0259] M2 is -C(O)O- or -C(O)S-;

[0260] Q is selected from a chemical bond, -OC(O)- or -SC(O)-;

[0261] R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 Alkynyl;

[0262] One of R1 and R2 is replaced by 1, 2, 3 or 4 R s replaced, the other was not replaced;

[0263] R s There is at least one carbon atom between the substitution site on R1 or R2 and M1 or M2;

[0264] R s Independently selected from C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably C 1-14 alkyl;

[0265] L b independently selected from chemical bonds and C 1-14 alkylene;

[0266] R b and R' b Independently selected from H and C 1-14 alkyl;

[0267] R3 is selected from -OR c and -NR c R' c ;

[0268] R c and R' c Independently selected from H and C 1-6 alkyl;

[0269] R4 and R5 are independently C 1-6 alkyl;

[0270] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

[0271] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0272] a = 2, 3, 4, or 5;

[0273] b = 5, 6, 7, or 8;

[0274] c = 1, 2, 3, 4, 5, or 6;

[0275] d = 1, 2, 3, 4, or 5;

[0276] c + d = 5, 6, or 7;

[0277] M1 is -OC(O)- or -SC(O)-;

[0278] M2 is -C(O)O- or -C(O)S-;

[0279] Q is selected from a chemical bond, -OC(O)-, and -SC(O)-;

[0280] R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl; preferably C 8-12 alkyl;

[0281] One of R1 and R2 is replaced by an R s replaced, the other was not replaced;

[0282] R s There is at least one carbon atom between the substitution site on R1 or R2 and M1 or M2;

[0283] R s C 1-12 alkyl;

[0284] R3 is selected from -OR c and -NR c R' c ;

[0285] R c and R' c Independently H and C 1-6 alkyl;

[0286] R4 and R5 are independently C 1-3 alkyl;

[0287] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene.

[0288] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0289] a = 2, 3, or 4;

[0290] b = 6, 7, or 8;

[0291] c = 2, 3, 4, 5, or 6;

[0292] d = 1, 2, 3, 4, or 5;

[0293] c + d = 6 or 7;

[0294] M1 is -OC(O)-; M2 is -C(O)O-;

[0295] Q is a chemical bond or -SC(O)-;

[0296] R1 and R2 are independently C 8-12 Alkyl; preferably C 8-11 Alkyl; preferably C 9-11 alkyl;

[0297] One of R1 and R2 is replaced by an R s replaced, the other was not replaced;

[0298] R s There is at least one carbon atom between the substitution site on R1 or R2 and M1 or M2; preferably 1-4 carbon atoms;

[0299] R s C 1-10 Alkyl; preferably C 1-8 Alkyl; preferably C3-8 Alkyl; preferably C 4-8 alkyl;

[0300] R3 is selected from -OR c and -NR c R' c ; Preferred -OH and -N(CH3)2;

[0301] R c and R' c Independently H and C 1-4 Alkyl; preferably H and methyl;

[0302] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0303] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-4 preferably forming a cyclopropylene group.

[0304] In more specific embodiments, one of R1 and R2 is selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3 and -(CH2) 10 CH3, preferably -(CH2)8CH3, -(CH2)9CH3 and -(CH2) 10 CH3; another selected from: Preferably selected from:

[0305] In a more specific embodiment, the present invention provides a compound of formula (I) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has a structure of formula (II) or formula (III):

[0306] Wherein, each variable is as defined in the present invention.

[0307] In a more specific embodiment, the present invention provides a compound of formula (II) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0308] in,

[0309] a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5;

[0310] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8;

[0311] c = 1, 2, 3, 4, 5, or 6;

[0312] d = 1, 2, 3, 4, or 5;

[0313] c + d = 5, 6, or 7;

[0314] M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0315] Q is -SC(O)- or -OC(O)-;

[0316] R1 and R2 are independently C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R s replace;

[0317] R s There are 0 to 5 carbon atoms between the substitution site on R1 or R2 and M1 or M2;

[0318] R s Independently selected from C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably C 1-14 alkyl;

[0319] L b independently selected from chemical bonds and C 1-14 alkylene;

[0320] R b and R' b Independently selected from H and C 1-14 alkyl;

[0321] R c and R' c Independently C 1-6 alkyl;

[0322] R4 and R5 are independently C 1-6 alkyl;

[0323] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

[0324] In a more specific embodiment, the present invention provides a compound of formula (II) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0325] a=3 or 4;

[0326] b = 6 or 7;

[0327] c=2, 3, 4 or 5; preferably c=2, 4 or 5;

[0328] d = 1, 2, 3 or 4; preferably d = 1, 2 or 4;

[0329] c+d=6;

[0330] M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably not simultaneously -OC(O)O-; preferably not simultaneously -OC(O)-; preferably selected from -C(O)O- and -OC(O)-;

[0331] Q is -SC(O)-;

[0332] R1 and R2 are independently C 8-12 Alkyl, preferably C 8-10 alkyl;

[0333] One of R1 and R2 is replaced by an R s replaced, the other was not replaced;

[0334] R s There are 0 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2;

[0335] R s C 1-12 Alkyl, preferably C 1-9 Alkyl, preferably C 3-9 Alkyl; preferably C 1-8 Alkyl, preferably C 5-8 alkyl;

[0336] R c and R' c Independently C 1-4 Alkyl; preferably methyl;

[0337] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0338] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, for example cyclopropylene.

[0339] In more specific embodiments, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, Preferably selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[0340] In a more specific embodiment, R1 is unsubstituted and R2 is substituted.

[0341] In a more specific embodiment, the present invention provides a compound of formula (II) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0342] a=3 or 4; preferably a=4;

[0343] b=6 or 7; preferably b=7;

[0344] c=2 or 4; preferably c=2;

[0345] d=2 or 4; preferably d=4;

[0346] c+d=6;

[0347] M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-; M2 is -C(O)O-;

[0348] Q is -SC(O)-;

[0349] R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-10 Straight chain alkyl;

[0350] R2 is selected from C 8-12 Alkyl, preferably C 9-10 Alkyl, which is replaced by 1 R s replace;

[0351] R s There are at least 2 carbon atoms between the substitution site on R2 and M2;

[0352] R s C 1-6 Alkyl, preferably C 5-6 Alkyl; preferably C 1-5 Alkyl, preferably C5 alkyl;

[0353] R c and R' c Independently C 1-4 Alkyl; preferably methyl;

[0354] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0355] Preferably, Rs The distance between the substitution site on R2 and M2 is 2 to 4 carbon atoms, preferably 3 to 4 carbon atoms.

[0356] In more specific embodiments, R2 is selected from: Preferred

[0357] In a more specific embodiment, the present invention provides a compound of formula (II) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0358] a=3 or 4; preferably a=4;

[0359] b=7;

[0360] c = 5;

[0361] d = 1;

[0362] M1 is -OC(O)-; M2 is -C(O)O-;

[0363] Q is -SC(O)-;

[0364] R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0365] R2 is selected from C 8-12 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace;

[0366] R s There are 0-3 carbon atoms between the substitution site on R2 and M2;

[0367] R s C 1-8 Alkyl, preferably C 5-8 alkyl;

[0368] R c and R' c Independently C 1-4 Alkyl; preferably methyl;

[0369] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0370] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-4 Cycloalkylene, for example cyclopropylene.

[0371] In more specific embodiments, R2 is selected from:

[0372] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0373] in,

[0374] a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5;

[0375] b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8;

[0376] c = 1, 2, 3, 4, 5, or 6;

[0377] d = 1, 2, 3, 4, or 5;

[0378] c + d = 5, 6, or 7;

[0379] M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-;

[0380] R1 and R2 are independently C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R s replace;

[0381] R s There is at least one carbon atom, preferably 1 to 5 carbon atoms, between the substitution site on R1 or R2 and M1 or M2;

[0382] R s Independently selected from H, C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably selected from H and C 1-14 alkyl;

[0383] L b independently selected from chemical bonds and C 1-14 alkylene;

[0384] R b and R' b Independently H and C 1-14 alkyl;

[0385] R4 and R5 are independently C 1-6 alkyl;

[0386] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6Cycloalkylene or 3-6 membered heterocyclylene.

[0387] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0388] a = 2, 3, or 4;

[0389] b = 6, 7, or 8;

[0390] c = 2, 3, 4, 5 or 6; preferably c = 2, 3, 5 or 6;

[0391] d = 1, 2, 3, or 4;

[0392] c + d = 6 or 7;

[0393] M1 is -OC(O)-; M2 is -C(O)O-;

[0394] R1 and R2 are independently C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 alkyl;

[0395] One of R1 and R2 is replaced by an R s replaced, the other was not replaced;

[0396] R s There are 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, between the substitution site on R1 or R2 and M1 or M2;

[0397] R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 3-8 Alkyl, preferably C 4-8 alkyl;

[0398] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0399] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, for example cyclopropylene.

[0400] In more specific embodiments, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, Preferably selected from -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3,

[0401] In a more specific embodiment, R1 is unsubstituted and R2 is substituted.

[0402] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0403] a=2, 3 or 4; preferably a=2 or 3;

[0404] b=6 or 7; preferably b=7;

[0405] c = 5;

[0406] d = 1;

[0407] M1 is -OC(O)-; M2 is -C(O)O-;

[0408] R1 and R2 are independently C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl;

[0409] One of R1 and R2 is replaced by an R s replaced, the other was not replaced;

[0410] R s There is at least one carbon atom between the substitution site on R1 or R2 and M1 or M2;

[0411] R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 Alkyl, preferably C 3-7 Alkyl, preferably C 4-7 Alkyl, preferably C 5-7 alkyl;

[0412] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0413] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably, R4 and R5 and the carbon atom to which they are attached do not form a ring.

[0414] In a more specific embodiment, R sThe distance between the substitution site on R1 or R2 and M1 or M2 is 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms.

[0415] In a more specific embodiment, one of R1 and R2 is selected from C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl, the other is selected from: Preferred

[0416] In a more specific embodiment, R1 is unsubstituted and R2 is substituted;

[0417] R1 is selected from C 8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0418] R2 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace.

[0419] In a more specific embodiment, R1 is substituted and R2 is unsubstituted;

[0420] R1 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace;

[0421] R2 is selected from C 8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl;

[0422] R s C 1-10 Alkyl, preferably C 1-5 Alkyl, preferably C 4-5 Alkyl, preferably C5 alkyl.

[0423] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0424] a=2, 3 or 4; preferably a=3 or 4;

[0425] b=6, 7 or 8; preferably b=6 or 8;

[0426] c = 5 or 6;

[0427] d = 1 or 2;

[0428] c+d=7;

[0429] M1 is -OC(O)-; M2 is -C(O)O-;

[0430] R1 is selected from C 8-12 Straight chain alkyl, preferably C 8-10 Straight chain alkyl, preferably C 8-9 Straight chain alkyl, preferably C9 straight chain alkyl;

[0431] R2 is selected from C 8-12 Alkyl, preferably C 9-11 Alkyl, which is replaced by 1 R s replace;

[0432] R s There are at least 2 carbon atoms between the substitution site on R1 or R2 and M1 or M2; preferably 2-3 carbon atoms;

[0433] R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 Alkyl, preferably C 6-7 alkyl;

[0434] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0435] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably R4 and R5 and the carbon atom to which they are attached do not form a ring;

[0436] Preferably, R2 is selected from:

[0437] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0438] a=2, 3 or 4; preferably a=3;

[0439] b=7 or 8; preferably b=7;

[0440] c = 3;

[0441] d = 3;

[0442] M1 is -OC(O)-; M2 is -C(O)O-;

[0443] R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl;

[0444] R2 is selected from C 8-12 Alkyl, preferably C 9-11 Alkyl, which is replaced by 1 R s replace;

[0445] R s There is at least one carbon atom between the substitution site on R2 and M2;

[0446] R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 6-8 alkyl;

[0447] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0448] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, for example cyclopropylene.

[0449] In a more specific embodiment, R s The substitution site on R2 is separated from M2 by 1 to 3 carbon atoms.

[0450] In more specific embodiments, R2 is selected from:

[0451] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0452] a=2, 3 or 4; preferably a=3;

[0453] b=7 or 8; preferably b=7;

[0454] c = 2;

[0455] d = 4;

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

[0457] R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 10 Straight chain alkyl;

[0458] R2 is selected from C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C10 Alkyl, which is replaced by 1 R s replace;

[0459] R s There is at least one carbon atom between the substitution site on R2 and M2;

[0460] R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 6-8 alkyl;

[0461] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0462] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably, R4 and R5 and the carbon atom to which they are attached do not form a ring.

[0463] In a more specific embodiment, R s The substitution site on R2 is separated from M2 by 1 to 3 carbon atoms.

[0464] In more specific embodiments, R2 is selected from: Preferred

[0465] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0466] in,

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

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

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

[0470] d = 0, 1, 2, 3, 4, or 5;

[0471] c + d = 5, 6, or 7;

[0472] M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-; or, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably -C(O)O- and -OC(O)-;

[0473] R1 and R2 are independently C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R s replace;

[0474] R s There are 0 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2;

[0475] R s Independently selected from H, C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably selected from H and C 1-14 alkyl;

[0476] L b independently selected from chemical bonds and C 1-14 alkylene;

[0477] R b and R' b Independently selected from H and C 1-14 alkyl;

[0478] R4 and R5 are independently C 1-6 alkyl;

[0479] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

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

[0481] a=2, 3 or 4; preferably a=2;

[0482] b = 5, 6 or 7; preferably b = 5 or 7;

[0483] c = 2, 3, 4, 5 or 6; preferably c = 2 or 6; preferably c = 6;

[0484] d = 0, 1, 2 or 3; preferably d = 0 or 3; preferably d = 0;

[0485] c+d=5 or 6; preferably c+d=6;

[0486] M1 and M2 are -C(O)O-;

[0487] R1 is selected from C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace;

[0488] R s There is at least one carbon atom between the substitution site on R1 and M1;

[0489] R2 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl;

[0490] R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-5 Alkyl, preferably C5 alkyl;

[0491] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0492] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably, R4 and R5 and the carbon atom to which they are attached do not form a ring.

[0493] In a more specific embodiment, R s The substitution site on R1 is separated from M1 by 1 to 3 carbon atoms, preferably 3 carbon atoms.

[0494] In a more specific embodiment, R1 is

[0495] In a more specific embodiment, the present invention provides a compound of formula (III) above, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0496] a=2, 3 or 4; preferably a=3 or 4;

[0497] b = 5, 6 or 7; preferably b = 6 or 7;

[0498] c = 3, 4, 5 or 6; preferably c = 3, 5 or 6; preferably c = 5 or 6; preferably c = 6;

[0499] d = 0, 1 or 2; preferably d = 0 or 1; preferably d = 0;

[0500] c+d=5 or 6; preferably c+d=6;

[0501] One of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O- and -OC(O)-; preferably, M1 is selected from -C(O)O- and OC(O)-, preferably -C(O)O-, and M2 is -OC(O)O-;

[0502] R1 and R2 are independently C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl;

[0503] One of R1 and R2 is replaced by an R s replaced, the other was not replaced;

[0504] R s There are 0 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2;

[0505] R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 6-8 alkyl;

[0506] R4 and R5 are independently C 1-3 Alkyl; preferably methyl;

[0507] Or R4 and R5 and the carbon atoms to which they are attached together form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably, R4 and R5 and the carbon atom to which they are attached do not form a ring.

[0508] In a more specific embodiment, R s The substitution site on R1 or R2 is separated from M1 or M2 by 0 to 3 carbon atoms, preferably 0 to 2 carbon atoms.

[0509] In a more specific embodiment, one of R1 and R2 is a C9 linear alkyl group, and the other is selected from: Preferred

[0510] In a more specific embodiment, the present invention provides a compound of the above formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1.

[0511] Table 1

[0512] In a more specific embodiment, the present invention also provides a pharmaceutical composition comprising a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0513] In a more specific embodiment, the present invention also provides a nanoparticle composition comprising a lipid component and, optionally, a load; wherein the lipid component contains a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the load is selected from one or more therapeutic agents, prophylactic agents or diagnostic agents.

[0514] In a more specific embodiment, the present invention provides a nanoparticle composition comprising a lipid component, and optionally a cargo; wherein the lipid component comprises a compound of the present invention.

[0515] Optionally, the lipid component comprises the following components in molar percentages:

[0516] 20 mol% to 85 mol% of any of the above compounds of the present invention:

[0517] Structural lipids 10 mol%-75 mol%;

[0518] Neutral lipids 1.0 mol%-30 mol%;

[0519] Polymer lipid 0.25mol%-10mol%;

[0520] Optionally, the lipid component comprises the following components in molar percentages:

[0521] 50 mol% of any of the above compounds of the present invention;

[0522] Neutral lipids 10 mol%;

[0523] structural lipids 38.5 mol%;

[0524] Polymer lipid 1.5 mol%.

[0525] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE, preferably DSPC and / or DOPE.

[0526] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the structured lipid is selected from one or more of cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol.

[0527] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the polymer lipid is a pegylated lipid.

[0528] Optionally, the PEGylated lipid is selected from one or more of: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol.

[0529] Optionally, the PEGylated lipid comprises a PEG moiety of about 1000 Da to about 20 kDa, preferably a PEG moiety of about 1000 Da to about 5000 Da.

[0530] Optionally, the PEGylated lipid is selected from one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000, preferably DMG-PEG2000.

[0531] In a more specific embodiment, the present invention also provides the use of a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, or a nanoparticle composition of the present invention in the preparation of a medicament for treating, diagnosing or preventing a disease; preferably, the medicament for treating, diagnosing or preventing a disease is a therapeutic or preventive mRNA vaccine.

[0532] In a more specific embodiment, the present invention also provides the use of a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, or a nanoparticle composition of the present invention in the preparation of a drug for delivering a load, wherein the load is selected from one or more therapeutic agents, prophylactic agents or diagnostic agents.

[0533] In a more specific embodiment, the present invention also provides a method for treating, diagnosing or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of the present invention, or the nanoparticle composition of the present invention.

[0534] In a more specific embodiment, the present invention also provides a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, or a nanoparticle composition of the present invention, for use in treating, diagnosing or preventing a disease.

[0535] In a more specific embodiment, the present invention also provides a method for delivering a load into a subject, comprising administering to the subject the pharmaceutical composition of the present invention or the nanoparticle composition of the present invention;

[0536] Wherein, the load is selected from one or more therapeutic agents, preventive agents or diagnostic agents.

[0537] In a more specific embodiment, the present invention also provides a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, or a nanoparticle composition of the present invention, for use in delivering a payload;

[0538] Wherein, the load is selected from one or more therapeutic agents, preventive agents or diagnostic agents.

[0539] In a more specific embodiment, the nanoparticle composition of the invention, or the use of the invention, or the method of the invention, wherein the therapeutic, prophylactic, or diagnostic agent is a nucleic acid;

[0540] Preferably, the nucleic acid is selected from one or more of ASO, RNA or DNA;

[0541] Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polyencoding nucleic acid (MCNA), polyencoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA) or ribozyme, preferably mRNA, more preferably modified mRNA.

[0542] In a more specific embodiment, the present invention also provides a method for preparing a compound of formula (II), which comprises:

[0543] reacting a compound of formula (IIA) with a compound of formula (IIB) to obtain a compound of formula (II);

[0544] Wherein, each variable is as defined in the present invention.

[0545] In a more specific embodiment, the present invention also provides a method for preparing a compound of formula (III), which comprises:

[0546] reacting a compound of formula (IIIA) with a compound of formula (IIB) to obtain a compound of formula (III);

[0547] Alternatively, the compound of formula (IIIC) is reacted with the compound of formula (IIID) to obtain the compound of formula (II);

[0548] Wherein, X is a halogen, and the remaining variables are as defined in the present invention.

[0549] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0550] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0551] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (IV) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P.32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (IV) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0552] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (IV) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0553] Pharmaceutical compositions and kits

[0554] In another aspect, the present invention provides a pharmaceutical composition comprising a nanoparticle composition of the present invention and a pharmaceutically acceptable excipient, wherein the nanoparticle composition comprises a compound of the present invention.

[0555] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0556] The present invention also includes kits (e.g., pharmaceutical packaging). The provided kits can include the nanoparticle composition of the present invention and other therapeutic, diagnostic, or prophylactic agents, as well as first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the nanoparticle composition of the present invention and the other therapeutic, diagnostic, or prophylactic agent. In some embodiments, the provided kits can also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the nanoparticle composition of the present invention and / or other therapeutic, diagnostic, or prophylactic agent. In some embodiments, the nanoparticle composition of the present invention and the other therapeutic, diagnostic, or prophylactic agent provided in the first and second containers are combined to form a unit dosage form.

[0557] Drug administration

[0558] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0559] Typically, an effective amount of the pharmaceutical composition of the present invention is administered. The amount of the pharmaceutical composition actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated or prevented, the route of administration selected, the pharmaceutical composition actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0560] When used to prevent the conditions described herein, the pharmaceutical compositions provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0561] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0562] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0563] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0564] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0565] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0566] Example

[0567] In order to make the technical solution of the present invention clearer and more specific, the present invention is further described in detail by the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the art. The materials, reagents, etc. used in the examples, unless otherwise specified, can be obtained from commercial sources.

[0568] Table 2

[0569] Example 1: Synthesis of Compound 1

[0570] In a 100 mL sealed tube, add 4-dimethylamino-1-butanol (3.0 g, 25.5 mmol, 1.0 eq.) and thiourea (8.4 g, 110.0 mmol, 4.3 eq.) and then add an aqueous solution of HBr (48%, 60 mL). Heat to 120°C and stir overnight to react. The product was directly used in the next step without purification.

[0571] The system was cooled to 0°C, and NaOH (10.2 g, 255.0 mmol, 10.0 eq.) was added portionwise. The mixture was heated to 120°C and reacted for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The solvent was removed to obtain 2.45 g of compound 1-3 as a colorless oil.

[0572] In a 100 mL three-necked flask, compound 1-4 (1.26 g, 5.0 mmol, 1.0 eq.), 1-nonanol (0.72 g, 5.0 mmol, 1.0 eq.), EDCI (1.44 g, 7.5 mmol, 1.5 eq.), and DMAP (0.31 g, 2.5 mmol, 0.5 eq.) were dissolved in 20 mL of dichloromethane and stirred at room temperature overnight. Extraction with dichloromethane was performed, followed by washing with water (3 x 20 mL). The combined organic phases were rotary evaporated under reduced pressure, mixed directly, and purified on a silica gel column to yield 1.6 g of compound 1-5.

[0573] In a 100 mL three-necked flask, compound 1-6 (1.5 g, 5.8 mmol, 1.0 eq.), 2-heptyl-1-nonanol (1.40 g, 5.8 mmol, 1.0 eq.), EDCI (1.66 g, 8.7 mmol, 1.5 eq.), and DMAP (0.35 g, 2.9 mmol, 0.5 eq.) were dissolved in 20 mL of dichloromethane and stirred at room temperature overnight. The mixture was washed with water (3 x 15 mL). The organic phase was then rotary evaporated under reduced pressure and directly mixed. Purification by silica gel column chromatography afforded 3.3 g of compound 1-7.

[0574] In a 100 mL three-necked flask, compound 1-7 (2.8 g, 5.8 mmol, 1.0 eq.) was dissolved in 20 mL of dichloromethane. HCl / dioxane (4 M, 14 mL) was added and stirred at room temperature overnight. The organic solvent was removed by rotary evaporation, and the reaction mixture was adjusted to neutral with saturated sodium bicarbonate solution and extracted with DCM (3 x 20 mL). The organic phase was collected and dried over anhydrous NaSO. Purification on a silica gel column afforded 1.95 g of compound 1-8.

[0575] In a 40 mL sealed tube, compound 1-8 (680 mg, 1.8 mmol, 1.0 eq.), KI (365 mg, 2.2 mmol, 1.2 eq.), KCO (745 mg, 5.4 mmol, 3.0 eq.), and compound 1-5 (668.9 mg, 1.8 mmol, 1.0 eq.) were dissolved in 10 mL of acetonitrile. The mixture was heated to 80°C and stirred overnight. After the reaction, the mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (2 x 5 mL). The filtrate was collected and dried. Purification by column chromatography afforded 580 mg of compound 1-9 as a yellow oil.

[0576] In a 20 mL sealed tube, compound 1-9 (200 mg, 0.29 mmol, 1.0 eq.) was dissolved in 5 mL of DCM. The reaction system was cooled to 5°C, and TEA (59.5 mg, 0.59 mmol, 2.0 eq.) and BTC (87.3 mg, 0.29 mmol, 1.0 eq.) were added dropwise. The reaction was stirred at 5°C for 1 hour. After concentration to remove the DCM, 5 mL of tetrahydrofuran was added. In another 20 mL sealed tube, compound 1-3 (101.9 mg, 0.76 mmol, 2.6 eq.) was dissolved in 5 mL of tetrahydrofuran. The reaction was cooled to 0°C, and NaH (60%, 58.0 mg, 1.45 mmol, 5.0 eq.) was added. After stirring at 0°C for 1 hour, the THF mixture prepared above was added dropwise, and the reaction was continued for 1 hour. The reaction solution was poured into 10 mL of ice water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The solvent was removed to obtain the crude product. The product was purified by Prep-HPLC (Column: XSelect C18 (30×150 mm, 5 μm); Eluent A: H2O / ACN 60 / 40, 10 mM NH4HCO3 + 1% NH3·H2O; Eluent B: IPA / ACN 90 / 10; Flow rate: 60 mL / min; Gradient program: 65%-85% B in 0-12 min) to give 126.9 mg of compound 1 as a light yellow oil.

[0577] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J = 6.6 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.36-3.15 (m, 4H), 2.90 (t, J=6.9Hz,2H),2.41(s,2H),2.31-2.24(m,10H),1.64-1.16(m,61H),0.93-0.77(m,15H); ESI-MS m / z:839.65[M+H] + .

[0578] Example 2: Synthesis of Compound 2

[0579] Compound 2 was prepared by referring to the method of Example 1 to obtain 157.3 mg of an oily product.

[0580] 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] + .

[0581] Example 3: Synthesis of Compound 3

[0582] Compound 3 was prepared by the method of Example 1 to obtain 184.0 mg of an oily product.

[0583] 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] + .

[0584] Example 4: Synthesis of Compound 4

[0585] Compound 4 was prepared by the method of Example 1 to obtain 103.2 mg of an oily product.

[0586] 1 H NMR (300MHz, CDCl3) δ: 4.07 (q, J=6.9Hz, 4H), 3.26 (m, 4H), 2.90 (t, J=6.9Hz, 2H), 2.54-2.42 (m, 5H), 2.30 (q, J = 7.8Hz, 5H), 1.74-1.52 (m, 16H), 1.42-1.22 (m, 45H), 0.93-0.83 (m, 15H); ESI-MS m / z:825.65[M+H] + .

[0587] Example 5: Synthesis of Compound 5

[0588] Compound 5 was prepared by referring to the method of Example 1 to obtain 82.3 mg of an oily product.

[0589] 1 H NMR (300MHz, CDCl3) δ: 4.05 (td, J=6.9, 5.4Hz, 4H), 3.26 (m, 4H), 2.97 -2.85 (m, 2H), 2.40-2.30(m,10H),1.60(m,14H),1.34-1.21(m,45H),0.94-0.83(m,15H); ESI-MS m / z:811.70[M+H] + .

[0590] Example 6: Synthesis of Compound 6

[0591] Compound 6 was prepared by the method of Example 1 to obtain 42.7 mg of an oily product.

[0592] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J = 6.9 Hz, 4H), 3.26 (m, 4H), 2.90 (t, J = 7.2 Hz, 2H), 2.62 (m, 6H), 2.30 (q, J=7.0Hz, 4H), 1.59 (m, 14H), 1.42-1.15 (m, 43H), 0.94-0.84 (m, 15H); ESI-MS m / z:797.65[M+H] + .

[0593] Example 7: Synthesis of Compound 7

[0594] Compound 7 was prepared by the method of Example 1 to obtain 145.3 mg of an oily product.

[0595] 1 H NMR (300MHz, CDCl3) δ: 4.05 (q, J = 6.6Hz, 4H), 3.26 (m, 4H), 2.95-2.85 (m, 2H), 2.42 -2.26(m,10H),1.64-1.59(m,14H),1.33-1.10(m,51H),0.93-0.83(m,15H); ESI-MS m / z:853.70[M+H] + .

[0596] Example 8: Synthesis of Compound 8

[0597] Compound 8 was prepared by referring to the method of Example 1 to obtain 125.4 mg of an oily product.

[0598] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J = 6.6 Hz, 4H), 3.26 (m, 4H), 2.90 (t, J = 6.6 Hz, 2H), 2.4 7-2.27(m,10H),1.68-1.60(m,16H),1.39-1.27(m,47H),0.94-0.83(m,15H); ESI-MS m / z:840.10[M+H] + .

[0599] Example 9: Synthesis of Compound 9

[0600] Compound 9 was prepared by referring to the method of Example 1 to obtain 120.4 mg of an oily product.

[0601] 1 H NMR (300MHz, CD3OD) δ: 4.06 (td, J=6.6, 3.6Hz, 4H), 3.31 (p, J=1.5Hz, 2H), 2.96-2.85 (m, 2H ),2.45-2.18(m,12H),1.65-1.58(m,14H),1.34-1.17(m,47H),0.95-0.85(m,15H); ESI-MS m / z:825.70[M+H] + .

[0602] Example 10: Synthesis of Compound 10

[0603] Compound 10 was prepared by the method of Example 1 to obtain 228 mg of an oily product.

[0604] 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] + .

[0605] Example 11: Synthesis of Compound 11

[0606] Compound 11 was prepared by referring to the method of Example 1 to obtain 117.9 mg of an oily product.

[0607] 1 H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 3.78 (s, 2H), 3.36-3.17 (m, 4H), 2.92 (t, J = 7.2Hz, 2H), 2.46 (t, J = 7.2 Hz,2H),2.34-2.22(m,10H),1.90-1.80(m,3H),1.62-1.49(m,14H),1.34-1.17(m,51H),0.93-0.86(m,15H); ESI-MS m / z:881.65[M+H] + .

[0608] Example 12: Synthesis of Compound 12

[0609] Compound 12 was prepared by referring to the method of Example 1 to obtain 75.3 mg of an oily product.

[0610] 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] + .

[0611] Example 13: Synthesis of Compound 13

[0612] Compound 13 was prepared by referring to the method of Example 1 to obtain 95.1 mg of an oily product.

[0613] 1H NMR (400MHz, CDCl3) δ: 4.86 (p, J = 6.4Hz, 1H), 4.09 (t, J = 7.6Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 7 .6Hz,2H),2.40-2.26(m,12H),1.63-1.50(m,21H),1.32-1.16(m,49H),0.90-0.86(m,15H); ESI-MS m / z:895.80[M+H] + .

[0614] Example 14: Synthesis of Compound 14

[0615] Compound 14 was prepared by referring to the method of Example 1 to obtain 63.6 mg of an oily product.

[0616] 1 H NMR (400MHz, CDCl3) δ: 4.09 (p, J = 7.6Hz, 2H), 3.96 (d, J = 6.0Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 7 .2Hz,2H),2.57-2.26(m,12H),1.67-1.43(m,20H),1.32-1.16(m,41H),0.90-0.86(m,15H); ESI-MS m / z:839.70[M+H] + .

[0617] Example 15: Synthesis of Compound 15

[0618] Compound 15 was prepared by referring to the method of Example 1 to obtain 70.5 mg of an oily product.

[0619] 1 H NMR(300MHz,CD3OD)δ:4.12(t,J=7.2Hz,2H),4.05(t,J=6.6Hz,2H),3.35(s,2H),2.90(t,J=6.6 Hz,2H),2.40-2.26(m,12H),1.62-1.56(m,16H),1.39-1.21(m,43H),0.98-0.84(m,15H); ESI-MS m / z:811.80[M+H] + .

[0620] Example 16: Synthesis of Compound 16

[0621] Compound 16 was prepared by referring to the method of Example 1 to obtain 46.4 mg of an oily product.

[0622] 1 H NMR(400MHz,CD3OD)δ:4.12(t,J=7.2Hz,2H),4.07(t,J=6.4Hz,2H),3.35(m,2H),2.92-2.83(m ,2H),2.39-2.26(m,12H),1.64-1.51(m,16H),1.44-1.21(m,41H),0.95-0.86(m,15H); ESI-MS m / z:797.65[M+H] + .

[0623] Example 17: Synthesis of Compound 17

[0624] Compound 17 was prepared by referring to the method of Example 1 to obtain 34.8 mg of an oily product.

[0625] 1 H NMR(300MHz, CDCl3)δ:4.12-4.03(m,4H),3.31(m,4H),3.06-2.78(m,10H),2.32-2.25(m,4 H),2.00-1.95(m,2H),1.62-1.56(m,14H),1.44-1.21(m,37H),0.94-0.85(m,15H); ESI-MS m / z:783.60[M+H] + .

[0626] Example 18: Synthesis of Compound 18

[0627] 18-1 (5.0 g, 22.40 mmol, 1.0 eq.) and decanoic acid (5.0 g, 29.12 mmol, 1.3 eq.) were added to a DMF (50 mL) solution. Potassium carbonate (9.3 g, 67.21 mmol, 3.0 eq.) was added under nitrogen. Stirring was continued at 70°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with 100 mL of water. The mixture was then extracted with dichloromethane (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (3 x 300 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to yield the crude product. Purification by silica gel column chromatography afforded compound 18-2 (7.7 g) as a yellow oil.

[0628] 18-2 (7.7 g, 24.48 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (80 mL). Triphenylphosphine (25.6 g, 97.93 mmol, 4.0 eq.) and carbon tetrabromide (32.4 g, 97.93 mmol, 4.0 eq.) were added under nitrogen and stirred at room temperature for 5 hours. The mixture was filtered, diluted with 100 mL of water, and then extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride solution (3 x 300 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to yield the crude product. Purification on a silica gel column afforded compound 18-3 (8.9 g) as a pale yellow oil.

[0629] 18-3 (4.0 g, 10.59 mmol, 1.0 eq.) was dissolved in 40 mL of acetonitrile, and benzylamine (2.2 g, 21.19 mmol, 2.0 eq.) was added under an ice bath. The reaction was allowed to proceed at 50°C for 16 h under nitrogen. After completion, the reaction was cooled to room temperature and diluted with 50 mL of water. The mixture was then extracted with dichloromethane (3 x 100 mL). The combined organic phases were washed with saturated sodium chloride solution (3 x 100 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to afford the crude product. Purification on a silica gel column afforded compound 18-4 (3.1 g) as a colorless oil.

[0630] Compound 18-4 (1.0 g, 2.47 mmol, 1.0 eq.) was dissolved in 10.0 mL of DMF. Under nitrogen, compound 18-5 (1.2 g, 2.97 mmol, 1.2 eq.), potassium carbonate (1.0 g, 7.43 mmol, 3.0 eq.), and sodium iodide (0.9 g, 6.19 mmol, 2.5 eq.) were added sequentially. The mixture was stirred at 70°C for 5 hours. After completion, the mixture was cooled to room temperature, diluted with 10 mL of water, and extracted with dichloromethane (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to yield the crude product. Purification on a silica gel column afforded compound 18-6 (1.5 g) as a yellow oil.

[0631] 18-6 (1.5 g, 2.06 mmol, 1.0 eq.) was dissolved in 15 mL of ethanol, and palladium carbon (700.0 mg) was added at room temperature under hydrogen protection. The reaction was allowed to proceed at room temperature overnight under hydrogen atmosphere. The palladium carbon was removed by filtration, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification to obtain colorless oily compound 18-7 (1.1 g).

[0632] 18-7 (260 mg, 0.39 mmol, 1.0 eq.) was dissolved in 2 mL of dichloromethane, and triphosgene (81.07 mg, 0.27 mmol, 0.7 eq.) and triethylamine (118.49 mg, 1.17 mmol, 3.0 eq.) were added under ice-cooling conditions. The mixture was stirred at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure. The above concentrate, 4-dimethylamino-1-butanethiol (259.4 mg, 1.93 mmol, 5.0 eq.) were dissolved in 5 mL of tetrahydrofuran. Under ice bath conditions, sodium hydroxide (124.89 mg, 3.12 mmol, 8.0 eq.), pyridine (92.62 mg, 1.17 mmol, 3.0 eq.) and 4-dimethylaminopyridine (95.37 mg, 0.78 mmol, 2.0 eq.) were added sequentially and stirred at room temperature for 3 hours. After the reaction was completed, 10 mL of water was added to dilute the mixture, and then extracted with ethyl acetate (3x50 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (3x50 mL), dried over anhydrous sodium sulfate, and the organic phase was collected by filtration. The organic solvent was removed by rotary evaporation to obtain a crude product. The product was purified by HPLC (column: YMC-Actus Triart C820X150 mm, 5 μm; phase A: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water), phase B: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain compound 18 (71.4 mg) as a yellow oil.

[0633] 1 H NMR(400MHz,CD3OD)δ:0.86-0.95(m,15H),1.26-1.43(m,45H),1.59-1.61(m,14H),2.26(s, 6H),2.29-2.39(m,6H),2.90(t,J=6.8Hz,2H),3.29-3.32(m,4H),4.07-4.12(m,4H); ESI-MS m / z:825.70[M+H] + .

[0634] Example 19: Synthesis of Compound 19

[0635] Compound 19 was prepared by referring to the method of Example 18 to obtain 72.0 mg of an oily product.

[0636] 1H NMR(300MHz,CD3OD)δ:0.90-0.92(m,15H),1.28-1.34(m,41H),1.43-1.61(m,16H),2.25(s, 6H),2.29-2.39(m,6H),2.90(t,J=6.6Hz,2H),3.29-3.31(m,4H),4.03-4.11(m,4H); ESI-MS m / z:811.90[M+H] + .

[0637] Example 20: Synthesis of Compound 20

[0638] Compound 20 was prepared by referring to the method of Example 18 to obtain 74.5 mg of an oily product.

[0639] 1 H NMR(400MHz,CD3OD)δ:0.88-0.92(m,15H),1.21-1.35(m,40H),1.45-1.62(m,15H),2.27(s,6 H),2.29-2.40(m,6H),2.90(t,J=6.4Hz,2H),3.29-3.31(m,4H),4.08(q,J=6.8Hz,4H); ESI-MS m / z:797.70[M+H] + .

[0640] Example 21: Synthesis of Compound 21

[0641] Compound 21 was prepared by referring to the method of Example 18 to obtain 77.1 mg of an oily product.

[0642] 1 H NMR(300MHz, CDCl3)δ:0.82-0.95(m,15H),1.14-1.40(m,41H),1.45-1.85(m,18H),2. 26-2.69(m,12H),2.90(t,J=6.9Hz,2H),3.19-3.37(m,4H),4.03-4.09(m,4H); ESI-MS m / z:825.95[M+H] + .

[0643] Example 22: Synthesis of Compound 22

[0644] Compound 22 was prepared by referring to the method of Example 18 to obtain 98.9 mg of an oily product.

[0645] 1 H NMR(300MHz,CD3OD)δ:0.85-0.92(m,15H),1.21-1.62(m,61H),2.25(s,6H),2.29-2.38( m,6H),2.90(t,J=6.9Hz,2H),3.29-3.32(m,4H),4.07(dd,J=6.3Hz,11.7Hz,4H); ESI-MS m / z:839.95[M+H] + .

[0646] Example 23: Synthesis of Compound 23

[0647] Compound 23 was prepared by referring to the method of Example 18 to obtain 130.5 mg of an oily product.

[0648] 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] + .

[0649] Example 24: Synthesis of Compound 24

[0650] Compound 24 was prepared by referring to the method of Example 18 to obtain 79.4 mg of an oily product.

[0651] 1 H 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] + .

[0652] Example 25: Synthesis of Compound 25

[0653] Compound 25 was prepared by referring to the method of Example 18 to obtain 67.0 mg of an oily product.

[0654] 1 H NMR (300MHz, CD3OD) δ: 4.05 (t, J = 6.9 Hz, 2H), 3.92 (s, 2H), 3.32 (s, 2H), 2.92-2.88 (m, 2H), 2.41-2.25 (m,12H),1.71-1.48(m,14H),1.34-1.25(m,45H),0.98-0.83(m,9H),0.47(m,2H),0.39(m,2H); ESI-MS m / z:809.75[M+H] + .

[0655] Example 26: Synthesis of Compound 26

[0656] Compound 26 was prepared by referring to the method of Example 18 to obtain 33.5 mg of an oily product.

[0657] 1 H NMR(400MHz,CD3OD)δ:4.07(t,J=6.4Hz,2H),3.92(s,2H),3.34(s,2H),2.90(t,J=6.8Hz,2H),2.40-2.32(m,6H) ,2.27(s,6H),1.60(m,16H),1.40-1.18(m,41H),0.93-0.88(m,9H),0.48-0.46(m,2H),0.43-0.39(m,2H); ESI-MS m / z:795.70[M+H] + .

[0658] Example 27: Synthesis of Compound 27

[0659] Compound 27 was prepared by referring to the method of Example 18 to obtain 32.0 mg of an oily product.

[0660] 1 H NMR (300MHz, CDCl3) δ: 4.05 (t, J = 6.6 Hz, 2H), 3.90 (s, 2H), 3.24 (s, 4H), 2.96-2.75 (m, 8H), 2.30 (q, J = 7 .2Hz,4H),1.74-1.62(m,18H),1.32-1.18(s,37H),0.93-0.82(m,9H),0.46(m,2H),0.36(m,2H); ESI-MS m / z:781.65[M+H]+ .

[0661] Example 28: Synthesis of Compound 28

[0662] Compound 28 was prepared by referring to the method of Example 18 to obtain 41 mg of an oily product.

[0663] 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, 2 H),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] + .

[0664] Example 29: Synthesis of Compound 29

[0665] Compound 29 was prepared by referring to the method of Example 18 to obtain 68.8 mg of an oily product.

[0666] 1 H NMR(300MHz,CD3OD)δ:0.26(m,4H),0.86-0.96(m,9H),1.24-1.41(m,41H),1.61-1.74(m,16H),2. 27(s,6H),2.29-2.41(m,6H),2.90(t,J=6.6Hz,2H),3.32-3.41(m,4H),4.03-4.09(m,4H); ESI-MS m / z:809.65[M+H] + .

[0667] Example 30: Synthesis of Compound 30

[0668] Compound 30 was prepared by referring to the method of Example 18 to obtain 86.5 mg of an oily product.

[0669] 1H NMR(300MHz,CD3OD)δ:0.21-0.28(m,4H),0.86-0.95(m,9H),1.21-1.45(m,39H),1.61-1.74(m,16H) ,2.22(s,6H),2.25-2.39(m,6H),2.90(t,J=6.6Hz,2H),3.30-3.35(m,4H),4.04-4.11(m,4H); ESI-MS m / z:795.70[M+H] + .

[0670] Example 31: Synthesis of Compound 31

[0671] Compound 31 was prepared by the method of Example 18 to obtain 86.5 mg of an oily product.

[0672] 1 H NMR(300MHz,CD3OD)δ:0.27(m,4H),0.81-0.96(m,9H),1.27-1.34(m,37H),1.59-1.74(m,16H),2.2 5(s,6H),2.28-2.38(m,6H),2.90(t,J=6.6Hz,2H),3.31-3.35(m,4H),4.06(t,J=6.6Hz,4H); ESI-MS m / z:781.85[M+H] + .

[0673] Example 32: Synthesis of Compound 32

[0674] Under nitrogen, compound 1 (1.0 g, 4.60 mmol, 1.0 eq.), pyridine (0.74 mL, 9.2 mmol, 2.0 eq.), DMAP (112.4 mg, 0.92 mmol, 0.2 eq.), and p-nitrophenyl chloroformate (1.11 g, 5.52 mmol, 1.2 eq.) were dissolved in 20 mL of dichloromethane in a 100 mL three-necked round-bottom flask at room temperature. The reaction system was stirred at room temperature for 1 hour. 2-nonyl-1-decanol (3.93 g, 13.8 mmol, 3.0 eq.) and DIEA (2.40 mL, 13.8 mmol, 3.0 eq.) were then added to the reaction system. The reaction system was stirred at room temperature overnight. TLC monitoring revealed a new product. The solution was diluted with DCM (20 mL) and washed once with saturated sodium bicarbonate solution (10 mL). The organic phase was washed twice with saturated NaCl solution (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column to obtain compound 32-2 (1.68 g) as a light yellow oil.

[0675] Compound 32 was prepared by referring to the method of Example 1 to obtain 78.5 mg of an oily product.

[0676] 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] + .

[0677] Example 33: Synthesis of Compound 33

[0678] Compound 33 was prepared by the method of Example 32 to obtain 189.8 mg of an oily product.

[0679] 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 Hz,2H),2.47-2.30(m,10H),1.85-1.84(m,2H),1.66-1.40(m,7H),1.26-1.18(m,48H),0.93-0.88(m,15H); ESI-MS m / z:827.55[M+H] + .

[0680] Example 34: Synthesis of Compound 34

[0681] Compound 34 was prepared by the method of Example 32 to obtain 129.4 mg of an oily product.

[0682] 1H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.6 Hz, 2H), 4.02 (d, J = 5.7 Hz, 2H), 3.78 (s, 2H), 3.36-3.21 (m, 4H), 2.90 (t,J=6.9Hz,2H),2.36-2.26(m,10H),1.63-1.41(m,13H),1.26-1.18(m,46H),0.89-0.86(m,15H); ESI-MS m / z:841.65[M+H] + .

[0683] Example 35: Synthesis of Compound 35

[0684] Compound 35 was prepared by the method of Example 32 to obtain 135.6 mg of an oily product.

[0685] 1 H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.3Hz, 2H), 4.02 (d, J = 5.7Hz, 2H), 3.89 (s, 2H), 3.31-3.22 (m, 4H), 2.90 (t, J = 6.9 Hz,2H),2.34-2.26(m,10H),1.65-1.48(m,13H),1.27-1.19(m,46H),0.90-0.86(m,9H),0.45-0.35(m,4H); ESI-MS m / z:839.50[M+H] + .

[0686] Example 36: Synthesis of Compound 36

[0687] Compound 36 was prepared by the method of Example 32 to obtain 123.1 mg of an oily product.

[0688] 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=6.6Hz,2H),2.46-2.20(m,10H),1.84(m,2H),1.65-1.44(m,13H),1.27-1.19(m,46H), 0.92-0.86(m,15H); ESI-MS m / z:855.60[M+H] + .

[0689] Example 37: Synthesis of Compound 37

[0690] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0°C. LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction mixture under nitrogen. The reaction temperature was raised to room temperature and stirred for 30 minutes before the addition of 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.). The reaction was monitored by TLC until completion. The reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM (3 x 300 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to afford 30 g of compound 37-1 as a yellow oil.

[0691] Compound 37-1 (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0°C. Borane-tetrahydrofuran solution (1 M, 100.0 mL) was added dropwise to the reaction system under nitrogen. The temperature was raised to 75°C and stirred for 3 hours. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with DCM (3 x 300 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain crude product 37-2 (13.6 g), which was used directly in the next step without purification.

[0692] Decanoyl chloride (11.0 g, 58.0 mmol, 1.3 eq.) was added to a solution of compound 37-2 (10.0 g, 44.0 mmol, 1.0 eq.) in DCM (100 mL). Triethylamine (13.5 g, 134.0 mmol, 3.0 eq.) was then added to the reaction system and allowed to react at room temperature for 3 hours. The reaction solution was poured into 100 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to afford 10 g of compound 37-3.

[0693] Potassium carbonate (1.5 g, 11.1 mmol, 3.0 eq.) and compound 37-3 (1.4 g, 3.7 mmol, 1.0 eq.) were added to a solution of ethanolamine (2.3 g, 37.2 mmol, 10.0 eq.) in acetonitrile (15.0 mL). The mixture was heated to 70°C and stirred for 3 hours. The reaction solution was poured into 30 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 1.4 g of compound 37-4.

[0694] 37-5 (211.0 mg, 0.50 mmol, 1.2 eq.) and 37-4 (150.0 mg, 0.42 mmol, 1.0 eq.) were added to a solution of N,N-dimethylformamide (2 mL). Potassium carbonate (173.9 mg, 1.26 mmol, 3.0 eq.) and sodium iodide (157.5 mg, 1.05 mmol, 2.5 eq.) were added under nitrogen. The mixture was stirred at 70°C for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with 10 mL, and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was then removed by rotary evaporation to obtain a crude product. The product was purified by HPLC (Xselect CSH F-Phenyl OBD column, 19x250 mm, 5 μm; phase A: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water), phase B: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain 82 mg of compound 37 as a yellow oil.

[0695] 1 H NMR(300MHz, CDCl3)δ:0.83-0.94(m,15H),1.18-1.42(m,43H),1.48-1.67(m,10H),2.28-2.35(m,4H),2. 46-2.52(m,4H),2.61(t,J=6.6Hz,2H),3.61(t,J=6.6Hz,2H),3.80(s,2H),4.05(t,J=6.6Hz,2H); ESI-MS m / z:696.60[M+H] + .

[0696] Example 38 Synthesis of Compound 38

[0697] Referring to the method of Example 37, 138.0 mg of compound 38 was prepared as an oily product.

[0698] 1 H NMR (300MHz, CD3OD) δ: 0.86-0.94 (m, 15H), 1.18-1.42 (m, 45H), 1.49-1.74 (m, 13H), 2.33 (q, J = 7.5Hz, 4H), 2. 47(t,J=7.5Hz,4H),2.61(t,J=7.5Hz,2H),3.62(t,J=6.0Hz,2H),3.80(s,2H),4.10(t,J=6.6Hz,2H); ESI-MS m / z:724.75[M+H]+ .

[0699] Example 39 Synthesis of Compound 39

[0700] By referring to the method of Example 37, 113.5 mg of compound 39 was prepared as an oily product.

[0701] 1 H NMR(300MHz,CD3OD)δ:0.88-0.97(m,15H),1.12-1.41(m,52H),1.50-1.63(m,14H),2.30-2.3 5(m,4H),2.48-2.53(m,6H),3.55(t,J=6.0Hz,2H),3.80(s,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:780.80[M+H] + .

[0702] Example 40 Synthesis of Compound 40

[0703] Referring to the method of Example 37, 90 mg of compound 40 was prepared as an oily product.

[0704] 1 H NMR(300MHz,CD3OD)δ:0.89-0.98(m,15H),1.22-1.34(m,40H),1.48-1.63(m,10H),2.32(q,J=7.5Hz,4H),2. 50(q,J=7.5Hz,4H),2.62(t,J=6.6Hz,2H),3.62(t,J=6.6Hz,2H),3.80(s,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:668.70[M+H] + .

[0705] Example 41 Synthesis of Compound 41

[0706] With reference to the method of Example 37, 174 mg of compound 41 was prepared as an oily product.

[0707] 1H NMR(400MHz,CD3OD)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] + .

[0708] Example 42 Synthesis of Compound 42

[0709] Referring to the method of Example 37, 93.6 mg of compound 42 was prepared as an oily product.

[0710] 1 H NMR(300MHz, CDCl3)δ:0.88-0.94(m,15H),1.18-1.43(m,42H),1.51-1.65(m,14 H),2.28-2.32(m,4H),2.56-2.69(m,6H),3.62(m,2H),4.02-4.12(m,4H); ESI-MS m / z:710.70[M+H] + .

[0711] Example 43 Synthesis of Compound 43

[0712] Referring to the method of Example 37, 185.7 mg of compound 43 was prepared as an oily product.

[0713] 1 H NMR(300MHz,CD3OD)δ:0.89-0.96(m,15H),1.24-1.43(m,46H),1.57-1.61(m,14H),2.26-2.32(m ,4H),2.48-2.53(m,4H),2.62(t,J=6.3Hz,2H),3.61(t,J=6.6Hz,2H),4.08-4.14(m,4H); ESI-MS m / z:738.75[M+H] + .

[0714] Example 44 Synthesis of Compound 44

[0715] With reference to the method of Example 37, 177.7 mg of compound 44 was prepared as an oily product.

[0716] 1H NMR (300MHz, CD3OD) δ: 0.89-0.95 (m, 15H), 1.23-1.73 (m, 62H), 2.30 (dt, J = 4.2Hz, 7.5Hz, 4H ),2.43-2.56(m,4H),2.61(t,J=6.9Hz,2H),3.62(t,J=6.0Hz,2H),4.08-4.14(m,4H); ESI-MS m / z:752.70[M+H] + .

[0717] Example 45 Synthesis of Compound 45

[0718] Dimethyl carbonate (10.7 g, 118.86 mmol, 3.0 eq.) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. Under nitrogen, sodium hydride (2.8 g, 118.86 mmol, 3.0 eq.) was added. The reaction was stirred at 0°C for 1 hour. 4,4-Dimethylcyclohexanone (5.0 g, 39.62 mmol, 1.0 eq.) was then added. The reaction was stirred at reflux for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with 100 mL of water, and extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 100 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to obtain the crude product. Purification by silica gel column chromatography afforded compound 45-1 (5.0 g) as a yellow oil.

[0719] 45-1 (5.0 g, 27.139 mmol, 1.0 eq.) was dissolved in methanol (50 mL) and sodium methoxide (4.4 g, 81.417 mmol, 3.0 eq.) was added under nitrogen. The reaction was stirred at reflux for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with dichloromethane (3 x 200 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain compound 45-2 (5.0 g) as a yellow oil.

[0720] Dissolve 45-2 (5.0 g, 23.12 mmol, 1.0 eq.) in tetrahydrofuran (50 mL). Add borane tetrahydrofuran solution (50.0 mL) under nitrogen. Stir and react at 75°C for 3 hours. After completion, cool to 0°C and quench with methanol (10 mL). Remove the organic solvent using a rotary evaporator to obtain the crude product, which is then purified on a silica gel column to afford compound 45-3 (2.5 g) as a yellow oil.

[0721] 45-3 (1.5 g, 9.36 mmol, 1.0 eq.) was dissolved in dichloromethane (15 mL). Under nitrogen, decanoic acid (1.8 g, 10.29 mmol, 1.1 eq.), EDCI (2.7 g, 14.04 mmol, 1.5 eq.), and N,N-dimethylaminopyridine (1.7 g, 14.04 mmol, 1.5 eq.) were added sequentially. The reaction was stirred at room temperature for 12 hours. After completion, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 50 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain the crude product, which was purified on a silica gel column to obtain compound 45-4 (1.5 g) as a yellow oil.

[0722] 45-4 (1.5 g, 4.77 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (15 mL) and triphenylphosphine (3.7 g, 14.31 mmol, 3.0 eq.) and carbon tetrabromide (4.7 g, 14.31 mmol, 3.0 eq.) were added under nitrogen. The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 50 mL), and dried over anhydrous sodium sulfate. The organic phases were collected by filtration and the organic solvent was removed by rotary evaporation to obtain the crude product, which was purified on a silica gel column to obtain compound 45-5 (1.5 g) as a yellow oil.

[0723] Referring to the method of Example 37, 95 mg of compound 45 was prepared as an oily product.

[0724] 1 H NMR(300MHz,DMSO-d6)δ:0.89-0.98(m,15H),1.18-1.55(m,46H),1.57-1.61(m,8H),2 .28-2.33(m,4H),2.45-2.64(m,6H),3.59(t,J=6.6Hz,2H),4.02-4.12(m,4H); ESI-MS m / z:696.65[M+H] + .

[0725] Example 46 Synthesis of Compound 46

[0726] Referring to the method of Example 45, 99.3 mg of compound 46 was prepared as an oily product.

[0727] 1H NMR(400MHz,CD3OD)δ:0.89-0.96(m,15H),1.22-1.41(m,40H),1.46-1.63(m,12H),2.30(t,J=7.5 Hz,4H),2.44-2.52(m,4H),2.61(t,J=6.6Hz,2H),3.61(t,J=6.6Hz,2H),4.02-4.07(m,4H); ESI-MS m / z:682.65[M+H] + .

[0728] Example 47 Synthesis of Compound 47

[0729] Referring to the method of Example 45, 92.2 mg of compound 47 was prepared as an oily product.

[0730] 1 H NMR (400MHz, CD3OD) δ: 0.91-0.99 (m, 15H), 1.17-1.70 (m, 56H), 2.30-2.34 (m, 4H), 2.42-2.63 (m, 6H), 3.63 (t, J = 6.6Hz, 2H), 4.03-4.13 (m, 4H); ESI-MS m / z:710.65[M+H] + .

[0731] Example 48 Synthesis of Compound 48

[0732] Referring to the method of Example 45, 94 mg of compound 48 was prepared as an oily product.

[0733] 1 H NMR (400MHz, CD3OD) δ: 0.93-0.99 (m, 15H), 1.19-1.64 (m, 56H), 2.29-2.34 (m, 4H), 2.42-2.51 (m, 6H), 3.55 (t, J = 5.7Hz, 2H), 4.02-4.08 (m, 4H); ESI-MS m / z:710.75[M+H] + .

[0734] Example 49 Synthesis of Compound 49

[0735] Isopropylidene diethyl malonate (10.0 g, 49.94 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (50 mL) and cuprous chloride (500 mg, 5.0 mmol, 0.1 eq.) and 3-butenyl magnesium bromide (76.0 mL, 74.92 mmol, 1.5 eq.) were added at -30°C under nitrogen. The reaction was stirred at room temperature for 12 hours. After completion of the reaction, ammonium chloride (100 mL) was added to the reaction solution for dilution and extraction with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain a crude product, which was purified on a silica gel column to obtain compound 49-2 (8.0 g) as a yellow oil.

[0736] Compound 49-2 (8.0 g, 31.21 mmol, 1.0 eq.) was dissolved in a mixture of dimethyl sulfoxide (100 mL) and water (1 mL). Lithium chloride (130.0 mg, 3.12 mmol, 0.1 eq.) was added under nitrogen. The reaction mixture was stirred at 180°C for 8 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phases were collected by filtration and the organic solvent was removed by rotary evaporation to obtain the crude product, which was then purified on a silica gel column to obtain compound 49-3 (4.2 g) as a yellow oil.

[0737] 49-3 (3.9 g, 21.16 mmol, 1.0 eq.) was dissolved in n-heptane (40 mL). Under nitrogen, hydrobromic acid and acetic acid solution (10.3 g, 42.33 mmol, 2.0 eq.) were added at 0°C. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phases were collected by filtration and the organic solvent was removed by rotary evaporation to obtain the crude product, which was purified on a silica gel column to obtain compound 49-4 (3.1 g) as a yellow oil.

[0738] Dissolve 49-4 (3.0 g, 11.31 mmol, 1.0 eq.) in tetrahydrofuran (10 mL). Under nitrogen, add borane tetrahydrofuran solution (30.0 mL) at 0°C. Heat to 75°C and stir for 5 hours. After completion, cool to 0°C and quench with methanol (30 mL). Remove the organic solvent using a rotary evaporator to obtain compound 49-5 (2.0 g) as a yellow oil.

[0739] 49-5 (2.0 g, 8.96 mmol, 1.0 equiv.) was dissolved in DMF (20.0 mL). Potassium carbonate (3.7 g, 26.88 mmol, 3.0 eq.) and undecanoic acid (1.83 g, 9.85 mmol, 1.1 eq.) were added under nitrogen. The mixture was stirred at 70°C for 2 hours. After completion, the reaction was cooled to room temperature and diluted with 50 mL of water. The mixture was then extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to yield the crude product. Purification by silica gel column chromatography afforded compound 49-6 (2.4 g) as a yellow oil.

[0740] Referring to the method of Example 45, 91 mg of compound 49 was prepared as an oily product.

[0741] 1 H NMR (300MHz, CD3OD) δ: 0.88-0.94 (m, 15H), 1.22-1.74 (m, 64H), 2.30 (t, J = 7.2Hz, 4H), 2. 49-2.52(m,4H),2.60(t,J=7.2Hz,2H),3.62(t,J=6.0Hz,2H),4.06-4.12(m,4H); ESI-MS m / z:766.70[M+H] + .

[0742] Example 50 Synthesis of Compound 50

[0743] Referring to the method of Example 49, 77 mg of compound 50 was prepared as an oily product.

[0744] 1 H NMR (300MHz, CD3OD) δ: 0.87-0.93 (m, 15H), 1.21-1.63 (m, 52H), 2.28-2.34 (m, 4H), 2.50-2.66 (m, 6H), 3.62 (t, J = 6.3Hz, 2H), 4.04-4.10 (m, 4H); ESI-MS m / z:682.70[M+H] + .

[0745] Example 51 Synthesis of Compound 51

[0746] Referring to the method of Example 49, 90 mg of compound 51 was prepared as an oily product.

[0747] 1H NMR (400MHz, CD3OD) δ: 0.90-0.96 (m, 15H), 1.22-1.63 (m, 56H), 2.29-2.33 (m, 4H), 2.46-2.52 (m, 6H), 3.55 (t, J = 6.0Hz, 2H), 4.04-4.10 (m, 4H); ESI-MS m / z:710.90[M+H] + .

[0748] Example 52 Synthesis of Compound 52

[0749] Referring to the method of Example 49, 95.1 mg of compound 52 was prepared as an oily product.

[0750] 1 H NMR(400MHz,CD3OD)δ:0.90-0.94(m,15H),1.25-1.36(m,47H),1.40-1.73(m,19H),2.30-2.35(m,4H),2.48-2 .54(m,4H),2.63(t,J=7.2Hz,2H),3.64(t,J=6.0Hz,2H),4.00(d,J=5.6Hz,2H),4.10(t,J=6.4Hz,2H); ESI-MS m / z:780.95[M+H] + .

[0751] Example 53 Synthesis of Compound 53

[0752] Referring to the method of Example 49, 76 mg of compound 53 was prepared as an oily product.

[0753] 1 H NMR (300MHz, CD3OD) δ: 0.88-0.93 (m, 15H), 1.21-1.63 (m, 66H), 2.30 (t, J = 7.5Hz, 4H), 2. 46-2.53(m,6H),3.55(t,J=6.0Hz,2H),4.00(d,J=5.6Hz,2H),4.06-4.12(m,4H); ESI-MS m / z: 780.80[M+H] + .

[0754] Example 54 Synthesis of Compound 54

[0755] Referring to the method of Example 49, 90.5 mg of compound 54 was prepared as an oily product.

[0756] 1H NMR(300MHz,CD3OD)δ:0.88-0.93(m,15H),1.21-1.63(m,66H),2.28-2.33(m,4H) ,2.50-2.66(m,6H),3.63(t,J=6.3Hz,2H),4.10(dd,J=6.6Hz,12.6Hz,4H); ESI-MS m / z:780.75[M+H] + .

[0757] Example 55 Synthesis of Compound 55

[0758] Referring to the method of Example 49, 75.7 mg of compound 55 was prepared as an oily product.

[0759] 1 H NMR(300MHz,CD3OD)δ:0.89-0.97(m,15H),1.23-1.63(m,70H),2.28-2.33(m,4H) ,2.46-2.53(m,6H),3.55(t,J=5.7Hz,2H),4.10(dd,J=6.3Hz,12.6Hz,4H); ESI-MS m / z:808.75[M+H] + .

[0760] Example 56 Synthesis of Compound 56

[0761] Referring to the method of Example 49, 94.1 mg of compound 56 was prepared as an oily product.

[0762] 1 H NMR(400MHz,CD3OD)δ:0.88-0.92(m,15H),1.23-1.69(m,62H),2.29-2.33(m,4H),2.46-2.52 (m,4H),2.61(t,J=7.2Hz,2H),3.62(t,J=6.0Hz,2H),4.07(dd,J=6.4Hz,12.0Hz,4H); ESI-MS m / z:752.90[M+H] + .

[0763] Example 57 Synthesis of Compound 57

[0764] 1,1-Cyclopropane dimethanol (6.0 g, 58.75 mmol, 1.0 eq.) was dissolved in dichloromethane (60 mL). Dess-Martin reagent (74.8 g, 176.24 mmol, 3.0 eq.) was added at 0°C under nitrogen. The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL), the pH was adjusted to 7 with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain compound 57-1 (3.5 g) as a yellow oil.

[0765] A solution of sodium hydride (2.6 g, 61.2 mmol, 3.0 eq.) in tetrahydrofuran (30 mL) was cooled to 0°C. Under nitrogen, triethyl phosphinoacetate (13.7 g, 61.2 mmol, 3.0 eq.) was slowly added and stirred at room temperature for 1 hour. The reaction system was then cooled to 0°C, and compound 57-1 (2.0 g, 20.4 mmol, 1.0 eq.) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 hours. After completion, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phases were collected by filtration and the organic solvent was removed by rotary evaporation to obtain the crude product, which was purified on a silica gel column to obtain compound 57-2 (2.4 g) as a yellow oil.

[0766] 57-2 (2.4 g, 10.08 mmol, 1.0 eq.) was dissolved in ethanol (20 mL). Cobalt chloride hexahydrate (476.4 mg, 2.01 mmol, 0.2 eq.) and sodium borohydride (1.5 g, 40.34 mmol, 4.0 eq.) were added at 0°C under nitrogen. The reaction was stirred at room temperature for 2 hours. After completion, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 50 mL), and dried over anhydrous sodium sulfate. The organic phases were collected by filtration and the organic solvent was removed by rotary evaporation to obtain the crude product, which was purified on a silica gel column to obtain compound 57-3 (1.8 g) as a yellow oil.

[0767] Dissolve 57-3 (1.8 g, 7.43 mmol, 1 eq.) in tetrahydrofuran (10 mL). Under nitrogen, add borane tetrahydrofuran solution (18.0 mL) at 0°C. Stir and react at 75°C for 3 hours. After completion, cool to room temperature and quench with methanol (10 mL). Remove the organic solvent using a rotary evaporator to obtain compound 57-4 (1.0 g, 85%) as a yellow oil.

[0768] Compound 57-4 (500.0 mg, 3.16 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL). Under nitrogen, decanoic acid (653.2 mg, 3.79 mmol, 1.2 eq.), EDCI (908.6 mg, 4.74 mmol, 1.5 eq.), and DMPA (579.0 mg, 4.74 mmol, 1.5 eq.) were added sequentially. The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 50 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain a crude product, which was purified on a silica gel column to obtain compound 57-5 (500 mg) as a yellow oil.

[0769] Referring to the method of Example 45, 77.7 mg of compound 57 was prepared as an oily product.

[0770] 1 H NMR(400MHz,CD3OD)δ:0.16(m,4H),0.79-0.82(m,9H),1.13-1.38(m,46H),1.40-1.64(m,12H),2.18-2.24(m,4H),2 .37-2.52(m,4H),2.51(t,J=6.4Hz,2H),3.51(t,J=6.4Hz,2H),3.89(d,J=5.6Hz,2H),4.00(t,J=6.4Hz,2H); ESI-MS m / z:722.45[M+H] + .

[0771] Example 58 Synthesis of Compound 58

[0772] Referring to the method of Example 57, 85 mg of compound 58 was prepared as an oily product.

[0773] 1 H NMR(300MHz,CD3OD)δ:0.24-0.26(m,4H),0.91-0.97(m,9H),1.24-1.75(m,60H),2.27-2.34(m,4H),2.43-2. 50(m,4H),2.60(t,J=7.5Hz,2H),3.62(t,J=6.0Hz,2H),3.98(d,J=5.4Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:736.65[M+H] + .

[0774] Example 59 Synthesis of Compound 59

[0775] Referring to the method of Example 57, 90.2 mg of compound 59 was prepared as an oily product.

[0776] 1 H NMR(300MHz,CD3OD)δ:0.22(m,4H),0.89-0.96(m,9H),1.22-1.75(m,62H),2.28-2.34(m,4H), 2.43-2.50(m,6H),3.55(t,J=6.3Hz,2H),3.98(d,J=5.7Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:750.55[M+H] + .

[0777] Example 60 Synthesis of Compound 60

[0778] Referring to the method of Example 57, 80 mg of compound 60 was prepared as an oily product.

[0779] 1 H NMR (300MHz, CD3OD) δ: 0.26-0.28 (m, 4H), 0.91-0.97 (m, 9H), 1.22-1.75 (m, 64H), 2.32 (dt, J = 5.1Hz, 7.8Hz, 4H), 2. 47-2.53(m,4H),2.62(t,J=6.6Hz,2H),3.61(t,J=6.6Hz,2H),3.98(d,J=5.7Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:764.75[M+H] + .

[0780] Example 61 Synthesis of Compound 61

[0781] Referring to the method of Example 57, 85 mg of compound 61 was prepared as an oily product.

[0782] 1H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.91-0.94(m,9H),1.26-1.37(m,52H),1.50-1.74(m,14H),2.31-2.36(m,4H) ),2.47-2.51(m,4H),2.63(t,J=7.0Hz,2H),3.65(t,J=6.5Hz,2H),4.01(d,J=5.5Hz,2H),4.10(t,J=6.5Hz,2H); ESI-MS m / z:778.70[M+H] + .

[0783] Example 62 Synthesis of Compound 62

[0784] Referring to the method of Example 57, 90 mg of compound 62 was prepared as an oily product.

[0785] 1 H NMR(300MHz,CD3OD)δ:0.24-0.26(m,4H),0.88-0.92(m,9H),1.25-1.41(m,52H),1.52-1.73(m,16H),2.28- 2.34(m,4H),2.48-2.54(m,6H),3.55(t,J=6.0Hz,2H),4.00(d,J=5.7Hz,2H),4.07(t,J=6.6Hz,2H); ESI-MS m / z:792.65[M+H] + .

[0786] Example 63 Synthesis of Compound 63

[0787] Referring to the method of Example 57, 89.6 mg of compound 63 was prepared as an oily product.

[0788] 1 H NMR(400MHz,CD3OD)δ:0.25-0.26(m,4H),0.88-0.92(m,9H),1.23-1.34(m,41H),1.40-1.72(m,15H),2.30( t,J=7.6Hz,4H),2.47-2.52(m,4H),2.61(t,J=6.4Hz,2H),3.61(t,J=6.4Hz,2H),4.05-4.11(m,4H); ESI-MS m / z:708.75[M+H] + .

[0789] Example 64 Synthesis of Compound 64

[0790] Referring to the method of Example 57, 79.7 mg of compound 64 was prepared as an oily product.

[0791] 1 H NMR(400MHz, CD3OD)δ:0.25-0.26(m,4H),0.88-0.92(m,9H),1.23-1.72(m,58H),2.28-2.32(dt,J=1.6H z,7.6Hz,4H),2.44-2.49(m,4H),2.60(t,J=7.2Hz,2H),3.62(t,J=6.0Hz,2H),4.05-4.12(m,4H); ESI-MS m / z:722.70[M+H] + .

[0792] Example 65 Synthesis of Compound 65

[0793] Referring to the method of Example 57, 101.4 mg of compound 65 was prepared as an oily product.

[0794] 1 H NMR(300MHz,CD3OD)δ:0.25-0.26(m,4H),0.88-0.92(m,9H),1.23-1.75(m,60H),2.30 (t,J=7.2Hz,4H),2.44-2.50(m,6H),3.55(t,J=6.0Hz,2H),4.04-4.12(m,4H); ESI-MS m / z:736.85[M+H] + .

[0795] Example 66 Synthesis of Compound 66

[0796] Referring to the method of Example 57, 106.4 mg of compound 66 was prepared as an oily product.

[0797] 1 H NMR(300MHz,CD3OD)δ:0.28-0.29(m,4H),0.89-0.93(m,9H),1.26-1.75(m,62H),2.30(t,J=7.5Hz,4H),2.48- 2.54(m,4H),2.63(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),4.08(t,J=6.6Hz,2H),4.10(t,J=6.6Hz,2H); ESI-MS m / z:750.70[M+H] + .

[0798] Example 67 Synthesis of Compound 67

[0799] Referring to the method of Example 57, 85 mg of compound 67 was prepared as an oily product.

[0800] 1 H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.91-0.94(m,9H),1.26-1.74(m,64H),2.32(dt,J=2.5Hz,7.5Hz,4H),2. 48-2.52(m,4H),2.64(t,J=7.5Hz,2H),3.65(t,J=7.0Hz,2H),4.09(t,J=6.5Hz,2H),4.12(t,J=6.5Hz,2H); ESI-MS m / z:764.65[M+H] + .

[0801] Example 68 Synthesis of Compound 68

[0802] Referring to the method of Example 57, 86.8 mg of compound 68 was prepared as an oily product.

[0803] 1 H NMR(400MHz,CD3OD)δ:0.25-0.26(m,4H),0.91-0.94(m,9H),1.24-1.74(m,66H),2.30(dt ,J=1.6Hz,7.6Hz,4H),2.45-2.50(m,6H),3.55(t,J=5.6Hz,2H),4.05-4.12(m,4H); ESI-MS m / z:778.80 [M+H] + .

[0804] Example 69 Synthesis of Compound 69

[0805] Referring to the method of Example 57, 80 mg of compound 69 was prepared as an oily product.

[0806] 1H NMR(300MHz,CD3OD)δ:0.25-0.26(m,4H),0.89-0.94(m,9H),1.26-1.73(m,68H),2.30(t,J=7.5H z,4H),2.47-2.54(m,4H),2.62(t,J=6.6Hz,2H),3.61(t,J=6.3Hz,2H),4.04-4.12(m,4H); ESI-MS m / z:792.80[M+H] + .

[0807] Example 70 Synthesis of Compound 70

[0808] Referring to the method of Example 57, 87 mg of compound 70 was prepared as an oily product.

[0809] 1 H NMR(300MHz,CD3OD)δ:0.26-0.27(m,4H),0.88-0.92(m,9H),1.26-1.73(m,70H),2.30(t,J=7.5H z,4H),2.43-2.49(m,4H),2.59(t,J=7.5Hz,2H),3.62(t,J=6.0Hz,2H),4.04-4.12(m,4H); ESI-MS m / z:806.80[M+H] + .

[0810] Example 71 Synthesis of Compound 71

[0811] Referring to the method of Example 57, 97 mg of compound 71 was prepared as an oily product.

[0812] 1 H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.94-0.98(m,9H),1.29-1.75(m,60H),2.33(dt,J=5.5Hz,7. 5Hz,4H),2.50-2.54(m,4H),2.64(t,J=6.5Hz,2H),3.63(t,J=6.5Hz,2H),4.07(q,J=6.5Hz,4H); ESI-MS m / z:736.70[M+H] + .

[0813] Example 72 Synthesis of Compound 72

[0814] Referring to the method of Example 57, 83.3 mg of compound 72 was prepared as an oily product.

[0815] 1 H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.91-0.94(m,9H),1.26-1.38(m,47H),1.50-1.73(m,15H),2.31- 2.35(m,4H),2.46-2.50(m,4H),2.62(t,J=7.0Hz,2H),3.65(t,J=6.0Hz,2H),4.08(q,J=7.0Hz,4H); ESI-MS m / z:750.65[M+H] + .

[0816] Example 73 Synthesis of Compound 73

[0817] Referring to the method of Example 57, 99 mg of compound 73 was prepared as an oily product.

[0818] 1 H NMR(400MHz,CD3OD)δ:0.26-0.27(m,4H),0.88-0.92(m,9H),1.16-1.40(m,46H),1.45-1.74(m, 18H),2.28-2.33(m,4H),2.44-2.49(m,6H),3.55(t,J=5.6Hz,2H),4.06(q,J=6.4Hz,4H); ESI-MS m / z:765.00[M+H] + .

[0819] Example 74 Synthesis of Compound 74

[0820] Referring to the method of Example 57, 80 mg of compound 74 was prepared as an oily product.

[0821] 1 H NMR(300MHz,CD3OD)δ:0.26-0.28(m,4H),0.91-0.97(m,9H),1.23-1.75(m,62H),2.31(dt,J=4.2Hz,7.2Hz,4H),2. 47-2.53(m,4H),2.62(t,J=6.3Hz,2H),3.61(t,J=6.6Hz,2H),4.00(d,J=6.0Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:750.75[M+H] + .

[0822] Example 75 Synthesis of Compound 75

[0823] Referring to the method of Example 57, 83 mg of compound 75 was prepared as an oily product.

[0824] 1 H NMR(300MHz,CD3OD)δ:0.26-0.27(m,4H),0.91-0.94(m,9H),1.22-1.40(m,50H),1.45-1.75(m,14H),2.27-2.34(m,4H) ),2.45-2.51(m,4H),2.61(t,J=6.9Hz,2H),3.63(t,J=6.0Hz,2H),3.98(d,J=5.4Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:764.70[M+H] + .

[0825] Example 76 Synthesis of Compound 76

[0826] Referring to the method of Example 57, 100.4 mg of compound 76 was prepared as an oily product.

[0827] 1 H NMR(400MHz,CD3OD)δ:0.28-0.29(m,4H),0.93-0.97(m,9H),1.25-1.42(m,50H),1.47-1.74(m,16H),2.28- 2.33(m,4H),2.49-2.52(m,6H),3.55(t,J=6.0Hz,2H),3.98(d,J=5.6Hz,2H),4.06(t,J=6.8Hz,2H); ESI-MS m / z:778.80[M+H] + .

[0828] Example 77 Synthesis of Compound 77

[0829] In a 250 mL round-bottom flask, 9-heptadecanol (10.0 g, 39.0 mmol, 1.0 eq.) and pyridine (6.17 g, 78.0 mmol, 2.0 eq.) were dissolved in 100 mL of dichloromethane. The reaction system was then cooled to 0°C and isobutyryl chloride (10.39 g, 97.5 mmol, 2.5 eq.) was slowly added to the reaction solution. The mixture was then stirred at room temperature for 2 hours. The reaction was quenched by adding water at 0°C and extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na2SO4. The desiccant was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified on a silica gel column to afford Compound 77-2 (10.4 g) as a yellow oil.

[0830] Compound 77-2 (10.0 g, 30.62 mmol, 1.0 eq.) was dissolved in anhydrous THF (100 mL). The reaction system was cooled to -40°C. LDA (15.3 mL, 30.6 mmol, 1.0 eq.) was added to the reaction solution under a nitrogen atmosphere. The reaction was stirred at -40°C for 1 hour. 1,6-Dibromohexane (14.9 g, 61.2 mmol, 2.0 eq.) and DMPU (471 mg, 3.7 mmol, 0.12 eq.) were then added at the same temperature. The reaction system was slowly warmed to room temperature and allowed to react overnight. After completion of the reaction, the reaction solution was added to a saturated NH₄Cl solution and extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na₂SO₄. The desiccant was filtered and the solvent was removed by rotary evaporation to obtain crude compound 77-3, which was used directly in the next step without purification.

[0831] Compound 77-3 (15 g, 30.6 mmol, 1.0 eq.) and 3-hydroxypropylamine (45.0 g, 612.0 mmol, 20.0 equiv.) were dissolved in 80 ml of ethanol and the reaction system was heated to 60°C for 2 hours. After the reaction, the reaction system was cooled to room temperature and the ethanol solvent was removed by rotary evaporation. The crude product was dissolved in ethyl acetate and then added with saturated sodium chloride solution. After extraction, the organic phases were combined and dried over anhydrous Na2SO4. The desiccant was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified on a silica gel column to obtain compound 77-4 (12.6 g) as a yellow oil.

[0832] In a 50 mL reaction flask, 6-bromo-1-hexanol (1.5 g, 8.3 mmol, 1.0 eq.) and pyridine (1.31 g, 16.6 mmol, 2.0 eq.) were dissolved in 15 mL of dichloromethane. Nonyl chloroformate (1.88 g, 9.1 mmol, 1.1 equiv) was added dropwise over 15 minutes under an ice bath and allowed to stand overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic phases were dried over anhydrous NaSO, the desiccant was filtered, and the solvent was removed by rotary evaporation. The crude product was purified on a silica gel column to afford Compound 77-7 (2.5 g) as a yellow oil.

[0833] To an 8 mL sealed tube, compound 77-7 (200 mg, 0.57 mmol, 1.0 eq.), compound 77-4 (304.8 mg, 0.63 mmol, 1.1 eq.), KI (113.4 mg, 0.68 mmol, 1.2 eq.), KCO (236.0 mg, 1.71 mmol, 3.0 eq.), and 5.0 mL of anhydrous acetonitrile were added. The mixture was heated to 80°C and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile. The organic phases were combined and the solvent was removed by rotary evaporation to obtain the crude product. Purification by preparative liquid chromatography afforded 77 (93.9 mg).

[0834] 1 H NMR (300MHz, CDCl3) δ: 4.85 (p, J = 6.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 4H), 3.79 (t, J = 5.1 Hz, 2H), 2.65 (m, 2H), 2.42 (m, 4 H),1.77-1.64(m,6H),1.51(t,J=6.0Hz,10H),1.28(d,J=4.5Hz,47H),1.17(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:754.60[M+H] + .

[0835] The compounds in Table 3 were synthesized using the methods of the above examples, or similar methods using the corresponding intermediates.

[0836] Table 3

[0837] Pharmacological experiments

[0838] Experimental Example 1: Nanoparticle Preparation

[0839] The materials used for lipid nanoparticle assembly include: (1) ionizable lipid compounds, such as the ionizable lipids designed and synthesized in the present invention or SM102 (purchased from AVT / MCE) as a control group; (2) structural lipids, such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids, such as DSPC (distearoylphosphatidylcholine, purchased from AVT); (4) PEGylated lipid compounds, such as DSPE-PEG2000 (distearoylphosphoethanolamine-PEG2000, purchased from AVT / SINOPEG); and (5) nucleic acid fragment active ingredients, such as luciferase mRNA (Trilink, L-7202). The names and structural formulas of the lipid nanoparticle assembly materials are detailed in Table 4.

[0840] Table 4

[0841] Preparation method of lipid nanoparticles: (1) ionizable lipid compound, cholesterol, phospholipid and PEGylated lipid are dissolved and mixed in ethanol in the order of (molar percentage) 50%, 38.5%, 10% and 1.5% respectively; (2) mRNA active ingredient is dissolved in 10mM-25mM citric acid buffer solution (pH=4.0-4.5); (3) an automated high-throughput microfluidic system is used to mix the organic phase containing the lipid mixture and the aqueous phase containing the mRNA component at a flow rate ratio of 1:3, and the mixing speed is between 5mL / min and 20mL / min; (4) the prepared lipid nanoparticles are diluted with phosphate buffered saline solution, and the nanoparticle solution is ultrafiltered to the original preparation volume using an ultrafiltration tube with a molecular weight cutoff of 100kDa (purchased from Millipore); (5) the obtained nanoparticles are stored at 4°C in a sealed EP tube.

[0842] Experimental Example 2: Characterization of physical properties of lipid nanoparticles

[0843] 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 (EE%), which reflects the degree of binding between lipid nanoparticles and RNA fragments. This coefficient is measured by Quant-it TM The lipid nanoparticle sample was diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH = 7.5), and a portion of the sample solution was added with 0.5% Triton X-100 and allowed to stand at 37°C for 30 minutes. Immediately after the reaction, the fluorescence value was read on a Varioskan LUX multifunctional microplate reader (purchased from Thermofisher) at an absorption wavelength of 485 nm and an emission wavelength of 528 nm to obtain the encapsulation efficiency value.

[0844] Experimental Example 3: Animal Experiment

[0845] The delivery effect and safety of nanoparticles loaded with luciferase mRNA in mice were evaluated. The experimental mice were SPF-grade C57BL / 6 female mice, 6-8 weeks old, weighing 18-22g, purchased from Beijing Sibeifu Biotechnology Co., Ltd. All animals were acclimated for more than 7 days before the experiment. During the experiment, they had free access to food and water, and the light was alternating between 12 / 12 hours. The room temperature was Humidity is The mice were randomly divided into groups. The lipid nanoparticles loaded with luciferase mRNA prepared above were injected intravenously into mice at a single dose of 2 mg / kg mRNA, n=3, and the mice were subjected to in vivo bioluminescence detection using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer) 6 hours after administration. The hair and skin were shaved before imaging. The specific operation steps of the detection are as follows: a 20 mg / mL concentration of D-luciferin solution was prepared with normal saline, and 3 mice were given the substrate by intraperitoneal injection. Ten minutes after the substrate was administered, the mice were placed in an anesthesia box and anesthetized with 2.5% isoflurane. The anesthetized mice were placed in IVIS and fluorescence imaging was performed to obtain in vivo muscle signals. After in vivo imaging, the mice were killed by cervical dislocation, and the livers were collected from each mouse for ex vivo imaging to obtain ex vivo liver signals.

[0846] The in vivo delivery efficiency of the lipid nanoparticle carrier is expressed as the average photon flux [p / s / cm2 / sr] of the fluorescence intensity of different animals in the same test group, as shown in Table 5. The designated region of interest (ROI) was divided using IVIS software, with the leg muscle representing muscle expression, the leg muscle circled, and the isolated liver circled, and the average value was calculated. The higher the value of the average photon number, the higher the in vivo delivery efficiency of the lipid nanoparticle for the mRNA fragment. The data show that the lipid nanoparticles containing the cationic lipids of the present invention have good in vivo muscle-specific delivery efficiency.

[0847] Table 5

[0848] Although the present invention has been fully described through its embodiments, it is noteworthy that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, a=1, 2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5 or 6; d = 0, 1, 2, 3, 4 or 5; c+d=3, 4, 5, 6, 7, 8 or 9; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -S-S- and -S(O) 0-2 -; Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR a -, -NR a C(O)NR’ a -, -OC(O)S-, -OC(O)O-, -NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)S-, -SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -, -NR a C(S)O-, -S-S- and -S(O) 0-2 -; R a and R' a Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted with one or more R s substituted, and one or more methylene units therein are optionally and independently replaced by -NR'-; R s There are 0 to 12 carbon atoms between the substitution site on R1 or R2 and M1 or M2; R and R' are each independently selected from H and C 1-20 alkyl; R s Independently selected from H, C 1-20 Alkyl, -L b -OR b , -L b -SR b and -L b -NR b R' b ; L b Independently selected from chemical bonds and C 1-20 Alkylene; R b and R' b Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; R3 is selected from CN, -OR c 、-C(O)R c 、-OC(O)R c 、-NR”C(O)R c 、-NR c R' c 、-NR”C(O)NR c R' c 、-NR”C(O)R c 、-NR”S(O)2R c 、-OC(O)NR c R' c 、-NR”C(O)OR c 、-N(OR c )C(O)R c 、-N(OR c )S(O)2R c 、-N(OR c )C(O)OR c 、-N(OR c )C(O)R c R' c , 3- to 14-membered heterocyclyl and 5- to 14-membered heteroaryl; R c and R' c Independently selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and 3- to 10-membered heterocyclyl; R" is independently selected from H and C 1-6 alkyl; R4 and R5 are independently C 1-8 alkyl, optionally substituted with one or more R*; Or R4, R5 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, optionally substituted with one or more R*; R* is independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl, -L d -OR d , -L d -SR d and -L d -NR d R' d ; L d Independently selected from chemical bonds and C 1-8 Alkylene; R d and R' d Independently selected from H, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl.

2. The compound of formula (I) according to claim 1, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5; preferably a=2, 3 or 4; preferably a=2 or 3; preferably a=3 or 4; preferably a=2; preferably a=3; preferably a=4.

3. A compound of formula (I) according to claim 1 or 2, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: b=4, 5, 6, 7, 8 or 9; preferably b=5, 6, 7 or 8; preferably b=6, 7 or 8; preferably b=6 or 7; preferably b=6 or 8; preferably b=7 or 8; preferably b=7.

4. A compound of formula (I) according to any one of claims 1 to 3, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: c=2, 3, 4, 5 or 6; preferably c=2, 3, 5 or 6; preferably c=3, 4, 5 or 6; preferably c=2, 3, 4 or 5; preferably c=3, 5 or 6; preferably c=2, 4 or 5; preferably c=2 or 4; preferably c=2 or 6; preferably c=5 or 6; preferably c=2; preferably c=3; preferably c=5; preferably c=6.

5. A compound of formula (I) according to any one of claims 1 to 4, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: d=1, 2, 3, 4 or 5; preferably d=0, 1, 2, 3 or 4; preferably d=1, 2, 3 or 4; preferably d=0, 1, 2 or 3; preferably d=1, 2 or 4; preferably d=0, 1 or 2; preferably d=0 or 1; preferably d=2 or 4; preferably d=0 or 3; preferably d=0; preferably d=1; preferably d=3; preferably d=4.

6. A compound of formula (I) according to any one of claims 1 to 5, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: c+d=5, 6 or 7; preferably c+d=6 or 7; preferably c+d=5 or 6; preferably c+d=6.

7. A compound of formula (I) according to any one of claims 1 to 6, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, -OC(O)O-, -C(O)NR- and -NRC(O)-; preferably selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably not simultaneously -OC(O)O-; preferably not simultaneously -OC(O)-; preferably selected from -C(O)O- and -OC(O)-; Preferably, M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-; M2 is -C(O)O-; Preferably, M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-; Preferably, M1 is -OC(O)-; M2 is -C(O)O-; Preferably, M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-; Preferably, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably -C(O)O- and -OC(O)-; preferably M1 is selected from -C(O)O- and OC(O)-, preferably -C(O)O-, and M2 is -OC(O)O-.

8. A compound of formula (I) according to any one of claims 1 to 7, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Q is selected from a chemical bond, -OC(O)- and -SC(O)-; preferably a chemical bond or -SC(O)-; preferably -SC(O)- or -OC(O)-.

9. A compound of formula (I) according to any one of claims 1 to 8, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R a and R' a Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 alkyl.

10. A compound of formula (I) according to any one of claims 1 to 9, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl or C 6-14 Alkynyl; preferably selected from C 6-14 alkyl; Preferably, R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl, preferably C 8-10 Alkyl, C 8-10 Alkenyl and C 8-10 Alkynyl; Preferably, R1 and R2 are independently C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl; Preferably, R1 and R2 are optionally replaced by 1, 2, 3 or 4 R s substituted, preferably optionally with 1 R s replace; Preferably, R1 and R2 are not substituted at the same time; preferably, one of R1 and R2 is substituted and the other is not substituted; preferably, R1 is not substituted and R2 is substituted; preferably, R1 is substituted and R2 is not substituted; Preferably, R1 and R2 are independently selected from the following groups: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, Preferably selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, 、 11. A compound of formula (I) according to any one of claims 1 to 10, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R and R' are each independently selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 Alkyl; preferably R is H.

12. A compound of formula (I) according to any one of claims 1 to 11, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R s Independently selected from H, C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; H and C are preferred 1-14 Alkyl; preferably H and C 1-12 Alkyl; preferably H and C 1-10 Alkyl; preferably H and C 1-9 Alkyl; preferably H and C 3-9 Alkyl; preferably H and C 1-8 Alkyl; preferably H and C 3-8 Alkyl; preferably H and C 4-8 Alkyl; preferably H and C 5-8 Alkyl; preferably H and C 6-8 Alkyl; preferably H and C 1-7 Alkyl; preferably H and C 3-7 Alkyl; preferably H and C 4-7 Alkyl; preferably H and C 5-7 Alkyl; preferably H and C 1-6 Alkyl; preferably H and C 5-6 Alkyl; preferably H and C 1-5 Alkyl; preferably H and C 4-5 Alkyl; preferably H and C5 alkyl; Preferably, R s Preferably independently selected from C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably C 1-14 Alkyl, preferably C 1-12 Alkyl; preferably C 1-10 Alkyl; preferably C 1-9 Alkyl; preferably C 3-9 Alkyl; preferably C 1-8 Alkyl; preferably C 3-8 Alkyl; preferably C 4-8 Alkyl; preferably C 5-8 Alkyl; preferably C 6-8 Alkyl; preferably C 1-7 Alkyl; preferably C 3-7 Alkyl; preferably C 4-7 Alkyl; preferably C 5-7 Alkyl; preferably C 1-6 Alkyl; preferably C 5-6 Alkyl; preferably C 1-5 Alkyl; preferably C 4-5 Alkyl; preferably C5 alkyl.

13. A compound of formula (I) according to any one of claims 1 to 12, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: L b Independently selected from chemical bonds and C 1-14 Alkylene; preferably selected from C 1-10 Alkylene; preferably selected from C 1-6 Alkylene; Preferably, R b and R' b Independently selected from H and C 1-14 Alkyl; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 alkyl.

14. A compound of formula (I) according to any one of claims 1 to 13, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from CN, -OR c and-NR c R' c ; preferably selected from -OR c and-NR c R' c ; preferably -NR c R' c ; preferably -N(CH3)2; preferably -OR c ; preferably OH.

15. A compound of formula (I) according to any one of claims 1 to 14, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R c and R' c Independently selected from H, C 1-10 Alkyl, C 3-7 Cycloalkyl and 3 to 7 membered heterocyclic group; preferably selected from H and C 1-10 Alkyl; preferably selected from H and C 1-6 Alkyl; preferably selected from H and C 1-4 Alkyl (eg, methyl).

16. A compound of formula (I) according to any one of claims 1 to 15, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R4 and R5 are independently C 1-6 Alkyl; preferably C 1-3 Alkyl; preferably C 1-2 Alkyl; preferably methyl; Preferably, R4 and R5 are optionally substituted with 1, 2 or 3 R*; Preferably, R4, R5 together with the carbon atom to which they are attached form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene); preferably forming C 3-4 Preferably, it forms a cyclopropylene group; Preferably, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted by 1, 2 or 3 R*.

17. A compound of formula (I) according to any one of claims 1 to 16, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -L d -OR d , -L d -SR d and -L d -NR d R' d ; preferably selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 preferably selected from H, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

18. A compound of formula (I) according to any one of claims 1 to 17, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: L d Independently selected from chemical bonds and C 1-6 Alkylene; preferably selected from chemical bonds and C 1-3 Alkylene; Preferably, R d and R' d Independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic group; preferably selected from H and C 1-6 alkyl.

19. A compound of formula (I) according to any one of claims 1 to 18, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R s The substitution site on R1 or R2 is separated from M1 or M2 by 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-5 carbon atoms, preferably 0-4 carbon atoms, preferably 0-3 carbon atoms, preferably 0-2 carbon atoms; Preferably, R s The substitution site on R1 or R2 is separated from M1 or M2 by at least 2 carbon atoms, preferably 2-4 carbon atoms, preferably 2-3 carbon atoms, preferably 3-4 carbon atoms; Preferably, R s The substitution site on R1 or R2 is separated from M1 or M2 by at least 1 carbon atom, preferably 1-5 carbon atoms, preferably 1-4 carbon atoms, preferably 1-3 carbon atoms, preferably 3 carbon atoms.

20. A compound of formula (I) according to any one of claims 1 to 19, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, a=1, 2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5 or 6; d = 1, 2, 3, 4 or 5; c+d=3, 4, 5, 6, 7, 8 or 9; M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-; Q is selected from a chemical bond, -OC(O)- or -SC(O)-; R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 Alkenyl and C 6-14 Alkynyl; One of R1 and R2 is replaced by 1, 2, 3 or 4 R s replaced, the other not replaced; R s There is at least one carbon atom between the substitution site on R1 or R2 and M1 or M2; R s Independently selected from C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably C 1-14 alkyl; L b Independently selected from chemical bonds and C 1-14 Alkylene; R b and R' b Independently selected from H and C 1-14 alkyl; R3 is selected from -OR c and-NR c R' c ; R c and R' c Independently selected from H and C 1-6 alkyl; R4 and R5 are independently C 1-6 alkyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

21. The compound of formula (I) according to claim 20, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3, 4 or 5; b = 5, 6, 7 or 8; c = 1, 2, 3, 4, 5 or 6; d = 1, 2, 3, 4 or 5; c+d=5, 6 or 7; M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-; Q is selected from a chemical bond, -OC(O)- and -SC(O)-; R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 Alkenyl and C 8-12 Alkynyl; preferably C 8-12 alkyl; One of R1 and R2 is replaced by an R s replaced, the other not replaced; R s There is at least one carbon atom between the substitution site on R1 or R2 and M1 or M2; R s C 1-12 alkyl; R3 is selected from -OR c and-NR c R' c ; R c and R' c Independently for H and C 1-6 alkyl; R4 and R5 are independently C 1-3 alkyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene.

22. A compound of formula (I) according to claim 20 or 21, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; b = 6, 7 or 8; c = 2, 3, 4, 5 or 6; d = 1, 2, 3, 4 or 5; c+d=6 or 7; M1 is -OC(O)-; M2 is -C(O)O-; Q is a chemical bond or -SC(O)-; R1 and R2 are independently C 8-12 Alkyl; preferably C 8-11 Alkyl; preferably C 9-11 alkyl; One of R1 and R2 is replaced by an R s replaced, the other not replaced; R s There is at least 1 carbon atom between the substitution site on R1 or R2 and M1 or M2; preferably 1-4 carbon atoms; R s C 1-10 Alkyl; preferably C 1-8 Alkyl; preferably C 3-8 Alkyl; preferably C 4-8 alkyl; R3 is selected from -OR c and-NR c R' c ; Preferred are -OH and -N(CH3)2; R c and R' c Independently for H and C 1-4 Alkyl; preferably H and methyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-4 Preferably, it forms a cyclopropylene group; Preferably, one of R1 and R2 is selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3 and -(CH2) 10 CH3, preferably -(CH2)8CH3, -(CH2)9CH3 and -(CH2) 10 CH3; another selected from: Preferably selected from:

23. A compound of formula (I) according to any one of claims 1 to 22, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is of formula (II) or formula (III): in, The variables are defined in any one of claims 1-22.

24. A compound of formula (II) according to claim 23, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; c = 1, 2, 3, 4, 5 or 6; d = 1, 2, 3, 4 or 5; c+d=5, 6 or 7; M1 and M2 are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; Q is -SC(O)- or -OC(O)-; R1 and R2 are independently C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R s replace; R s There are 0 to 5 carbon atoms between the substitution site on R1 or R2 and M1 or M2; R s Independently selected from C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably C 1-14 alkyl; L b Independently selected from chemical bonds and C 1-14 Alkylene; R b and R' b Independently selected from H and C 1-14 alkyl; R c and R' c Independently for C 1-6 alkyl; R4 and R5 are independently C 1-6 alkyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

25. The compound of formula (II) according to claim 24, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=3 or 4; b = 6 or 7; c=2, 3, 4 or 5; preferably c=2, 4 or 5; d = 1, 2, 3 or 4; preferably d = 1, 2 or 4; c+d=6; M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably not simultaneously -OC(O)O-; preferably not simultaneously -OC(O)-; preferably selected from -C(O)O- and -OC(O)-; Q is -SC(O)-; R1 and R2 are independently C 8-12 Alkyl, preferably C 8-10 alkyl; One of R1 and R2 is replaced by an R s replaced, the other not replaced; R s There are 0 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2; R s C 1-12 Alkyl, preferably C 1-9 Alkyl, preferably C 3-9 Alkyl; preferably C 1-8 Alkyl, preferably C 5-8 alkyl; R c and R' c Independently for C 1-4 Alkyl; preferably methyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; Preferably, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, Preferably selected from -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, Preferably, R1 is unsubstituted and R2 is substituted.

26. The compound of formula (II) according to claim 24, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=3 or 4; preferably a=4; b=6 or 7; preferably b=7; c=2 or 4; preferably c=2; d=2 or 4; preferably d=4; c+d=6; M1 is -C(O)O- or -OC(O)-, preferably -C(O)O-; M2 is -C(O)O-; Q is -SC(O)-; R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-10 Straight chain alkyl; R2 is selected from C 8-12 Alkyl, preferably C 9-10 Alkyl, which is replaced by 1 R s replace; R s There are at least 2 carbon atoms between the substitution site on R2 and M2; R s C 1-6 Alkyl, preferably C 5-6 Alkyl; preferably C 1-5 Alkyl, preferably C5 alkyl; R c and R' c Independently for C 1-4 Alkyl; preferably methyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Preferably, R s The substitution site on R2 is separated from M2 by 2-4 carbon atoms, preferably 3-4 carbon atoms; Preferably, R2 is selected from: Best 27. The compound of formula (II) according to claim 24, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=3 or 4; preferably a=4; b＝7； c＝5； d＝1； M1 is -OC(O)-; M2 is -C(O)O-; Q is -SC(O)-; R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 8-12 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace; R s There are 0-3 carbon atoms between the substitution site on R2 and M2; R s C 1-8 Alkyl, preferably C 5-8 alkyl; R c and R' c Independently for C 1-4 Alkyl; preferably methyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-4 Cycloalkylene, such as cyclopropylene; Preferably, R2 is selected from:

28. A compound of formula (III) according to claim 23, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; c = 1, 2, 3, 4, 5 or 6; d = 1, 2, 3, 4 or 5; c+d=5, 6 or 7; M1 is -OC(O)- or -SC(O)-; M2 is -C(O)O- or -C(O)S-; R1 and R2 are independently C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R s replace; R s There is at least 1 carbon atom, preferably 1 to 5 carbon atoms, between the substitution site on R1 or R2 and M1 or M2; R s Independently selected from H, C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably selected from H and C 1-14 alkyl; L b Independently selected from chemical bonds and C 1-14 Alkylene; R b and R' b Independently for H and C 1-14 alkyl; R4 and R5 are independently C 1-6 alkyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

29. The compound of formula (III) according to claim 28, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; b = 6, 7 or 8; c=2, 3, 4, 5 or 6; preferably c=2, 3, 5 or 6; d = 1, 2, 3 or 4; c+d=6 or 7; M1 is -OC(O)-; M2 is -C(O)O-; R1 and R2 are independently C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 alkyl; One of R1 and R2 is replaced by an R s replaced, the other not replaced; R s The substitution site on R1 or R2 is separated from M1 or M2 by 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms; R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 3-8 Alkyl, preferably C 4-8 alkyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; Preferably, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, Preferably selected from -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, Preferably, R1 is unsubstituted and R2 is substituted.

30. The compound of formula (III) according to claim 28, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; preferably a=2 or 3; b=6 or 7; preferably b=7; c＝5； d＝1； M1 is -OC(O)-; M2 is -C(O)O-; R1 and R2 are independently C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl; One of R1 and R2 is replaced by an R s replaced, the other not replaced; R s There is at least one carbon atom between the substitution site on R1 or R2 and M1 or M2; R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 Alkyl, preferably C 3-7 Alkyl, preferably C 4-7 Alkyl, preferably C 5-7 alkyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably R4 and R5 and the carbon atoms to which they are attached do not form a ring; Preferably, R s There are 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, between the substitution site on R1 or R2 and M1 or M2; Preferably, one of R1 and R2 is selected from C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl, the other is selected from: Best Preferably, R1 is unsubstituted, R2 is substituted; R1 is selected from C 8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace; Preferably, R1 is substituted, R2 is unsubstituted; R1 is selected from C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace; R2 is selected from C 8-10 Straight chain alkyl, preferably C 9-10 Straight chain alkyl, preferably C9 straight chain alkyl; R s C 1-10 Alkyl, preferably C 1-5 Alkyl, preferably C 4-5 Alkyl, preferably C5 alkyl.

31. The compound of formula (III) of claim 28, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; preferably a=3 or 4; b=6, 7 or 8; preferably b=6 or 8; c = 5 or 6; d = 1 or 2; c+d=7; M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-12 Straight chain alkyl, preferably C 8-10 Straight chain alkyl, preferably C 8-9 Straight chain alkyl, preferably C9 straight chain alkyl; R2 is selected from C 8-12 Alkyl, preferably C 9-11 Alkyl, which is replaced by 1 R s replace; R s There are at least 2 carbon atoms between the substitution site on R1 or R2 and M1 or M2; preferably 2-3 carbon atoms; R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-7 Alkyl, preferably C 6-7 alkyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably R4 and R5 and the carbon atoms to which they are attached do not form a ring; Preferably, R2 is selected from:

32. The compound of formula (III) of claim 28, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; preferably a=3; b=7 or 8; preferably b=7; c＝3； d＝3； M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl; R2 is selected from C 8-12 Alkyl, preferably C 9-11 Alkyl, which is replaced by 1 R s replace; R s There is at least one carbon atom between the substitution site on R2 and M2; R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 6-8 alkyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; Preferably, R s There are 1 to 3 carbon atoms between the substitution site on R2 and M2; Preferably, R2 is selected from:

33. The compound of formula (III) of claim 28, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; preferably a=3; b=7 or 8; preferably b=7; c＝2； d＝4； M1 is -OC(O)-; M2 is -C(O)O-; R1 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl, preferably C 10 Straight chain alkyl; R2 is selected from C 8-12 Alkyl, preferably C 9-11 Alkyl, preferably C 10 Alkyl, which is replaced by 1 R s replace; R s There is at least one carbon atom between the substitution site on R2 and M2; R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 6-8 alkyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably R4 and R5 and the carbon atoms to which they are attached do not form a ring; Preferably, R s There are 1 to 3 carbon atoms between the substitution site on R2 and M2; Preferably, R2 is selected from: Best 34. A compound of formula (III) according to claim 23, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, a=2, 3, 4, 5 or 6; preferably a=2, 3 or 4; b = 4, 5, 6, 7, 8 or 9; preferably b = 5, 6, 7 or 8; c = 1, 2, 3, 4, 5 or 6; d = 0, 1, 2, 3, 4 or 5; c+d=5, 6 or 7; M1 and M2 are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-; or, one of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, preferably -C(O)O- and -OC(O)-; R1 and R2 are independently C 6-14 Alkyl, which is optionally substituted by 1, 2, 3 or 4 R s replace; R s There are 0 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2; R s Independently selected from H, C 1-14 Alkyl, -L b -OR b and -L b -NR b R' b ; preferably selected from H and C 1-14 alkyl; L b Independently selected from chemical bonds and C 1-14 Alkylene; R b and R' b Independently selected from H and C 1-14 alkyl; R4 and R5 are independently C 1-6 alkyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene or 3-6 membered heterocyclylene.

35. The compound of formula (III) of claim 34, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; preferably a=2; b=5, 6 or 7; preferably b=5 or 7; c=2, 3, 4, 5 or 6; preferably c=2 or 6; preferably c=6; d = 0, 1, 2 or 3; preferably d = 0 or 3; preferably d = 0; c+d=5 or 6; preferably c+d=6; M1 and M2 are -C(O)O-; R1 is selected from C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl, which is replaced by 1 R s replace; R s There is at least one carbon atom between the substitution site on R1 and M1; R2 is selected from C 8-12 Straight chain alkyl, preferably C 9-11 Straight chain alkyl; R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-5 Alkyl, preferably C5 alkyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably R4 and R5 and the carbon atoms to which they are attached do not form a ring; Preferably, R s The substitution site on R1 is separated from M1 by 1 to 3 carbon atoms, preferably 3 carbon atoms; Preferably, R1 is 36. The compound of formula (III) of claim 34, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a=2, 3 or 4; preferably a=3 or 4; b=5, 6 or 7; preferably b=6 or 7; c=3, 4, 5 or 6; preferably c=3, 5 or 6; preferably c=5 or 6; preferably c=6; d = 0, 1 or 2; preferably d = 0 or 1; preferably d = 0; c+d=5 or 6; preferably c+d=6; One of M1 and M2 is -OC(O)O-, and the other is selected from -C(O)O- and -OC(O)-; preferably M1 is selected from -C(O)O- and OC(O)-, preferably -C(O)O-, and M2 is -OC(O)O-; R1 and R2 are independently C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C9 alkyl; One of R1 and R2 is replaced by an R s replaced, the other not replaced; R s There are 0 to 4 carbon atoms between the substitution site on R1 or R2 and M1 or M2; R s C 1-12 Alkyl, preferably C 1-10 Alkyl, preferably C 1-8 Alkyl, preferably C 6-8 alkyl; R4 and R5 are independently C 1-3 Alkyl; preferably methyl; Or R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkylene, preferably C 3-4 Cycloalkylene, such as cyclopropylene; preferably R4 and R5 and the carbon atoms to which they are attached do not form a ring; Preferably, R s There are 0-3 carbon atoms, preferably 0-2 carbon atoms, between the substitution site on R1 or R2 and M1 or M2; Preferably, one of R1 and R2 is a C9 straight chain alkyl group, and the other is selected from: Best 37. A compound of formula (I) according to claim 1, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compounds in Table 1.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

39. A nanoparticle composition comprising a lipid component and, optionally, a load; wherein: The lipid component contains a compound according to any one of claims 1 to 37, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the cargo is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; Preferably, the lipid component comprises the following components in molar percentage: 20 mol% to 85 mol% of a compound according to any one of claims 1 to 37: Structural lipids 10 mol%-75 mol%; Neutral lipids 1.0 mol%-30 mol%; Polymer lipid 0.25mol%-10mol%; Preferably, the lipid component comprises the following components in molar percentage: 50 mol% of a compound according to any one of claims 1 to 37; Neutral lipids 10 mol%; structural lipids 38.5 mol%; Polymer lipid 1.5 mol%.

40. Use of a compound of any one of claims 1-37, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38, or a nanoparticle composition of claim 39 in the preparation of a medicament for treating, diagnosing or preventing a disease; preferably, the medicament for treating, diagnosing or preventing a disease is a therapeutic or preventive mRNA vaccine.

41. Use of a compound of any one of claims 1 to 37, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38, or a nanoparticle composition of claim 39 in the preparation of a medicament for delivering a load selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

42. A method of treating, diagnosing or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 38, or the nanoparticle composition of claim 39.

43. A compound of any one of claims 1-37, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38, or a nanoparticle composition of claim 39, for use in treating, diagnosing or preventing a disease.

44. A method of delivering a payload into a subject, comprising administering to the subject the pharmaceutical composition of claim 38 or the nanoparticle composition of claim 39; in, The cargo is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

45. A compound according to any one of claims 1 to 37, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, or a nanoparticle composition according to claim 39, for use in delivering a cargo; in, The cargo is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

46. ​​The nanoparticle composition of claim 39, or the use of claim 41 or 45, or the method of claim 44, wherein The therapeutic, prophylactic or diagnostic agent is a nucleic acid; Preferably, the nucleic acid is selected from one or more of ASO, RNA or DNA; Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), micro RNA (miRNA), small activating RNA (saRNA), polycoding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA) or ribozyme, preferably mRNA, more preferably modified mRNA.

47. A method for preparing a compound of formula (II), the method comprising: reacting a compound of formula (IIA) with a compound of formula (IIB) to obtain a compound of formula (II); wherein the variables are as defined in any one of claims 1-37.

48. A method for preparing a compound of formula (II), the method comprising: The compound of formula (IIIA) is reacted with the compound of formula (IIB) to obtain the compound of formula (III); Alternatively, the compound of formula (IIIC) is reacted with the compound of formula (IIID) to obtain the compound of formula (II); wherein X is halogen, and the remaining variables are as defined in any one of claims 1 to 37.

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