Lipid compound containing cyclic urea structure

Abstract

The invention provides a lipid compound containing a cyclic urea structure, and particularly relates to a compound as shown in a formula (I), or an isotope variant, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt of the compound. The invention also provides a nanoparticle pharmaceutical composition containing the compound, and application of the compound and the composition thereof in muscle-specific delivery of nucleic acid. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a class of ionizable 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 said compounds, and the use of said lipid nanoparticles in the muscle-specific delivery of bioactive substances such as nucleic acids (e.g., mRNA, siRNA, ASO, DNA, etc.). Background Art

[0002] Gene therapy refers to the introduction of exogenous genes into target cells to correct or compensate for intracellular gene defects or abnormalities, thereby achieving a therapeutic purpose. In the past few decades, research on the treatment of clinical diseases by gene therapy has received increasing attention. Especially in recent years, siRNA-related drugs and mRNA vaccines have been approved by the FDA for clinical treatment, further promoting research and related investment in the field of gene therapy.

[0003] Nucleic acid substances are easily degraded in vivo under the action of nucleases, and nucleic acid substances themselves are negatively charged and it is difficult to enter cells through cell membranes. Lipid nanoparticles (LNPs), as a nucleic acid delivery material, have the advantages of simple preparation, good biodegradability, no immunogenicity, good safety, etc., and are one of the most important nucleic acid delivery systems at present. The main components of LNPs include ionizable lipid molecules, cholesterol, neutral lipids and polyethylene glycol-conjugated lipids. Among them, ionizable 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 nanoparticles.

[0004] Currently, nearly a thousand monogenic diseases that can cause muscle dysfunction are known, but the design of many LNPs may inadvertently lead to the expression of a large amount of mRNA in off-target tissues and organs (such as the liver, spleen or heart), resulting in unnecessary side effects. Therefore, there is an urgent need to design LNPs for muscle-specific mRNA delivery. Summary of the Invention

[0005] The present invention has developed a class of lipid compounds containing a cyclic urea structure, which can be used as ionizable lipids for muscle-specific delivery of LNPs to deliver various bioactive substances, and has high muscle-specific delivery efficiency. SM102 is widely recognized in the field of muscle delivery, and an LNP drug based on SM102 for muscle administration has been marketed. Unexpectedly, the ionizable lipids of the present invention have better in vivo muscle delivery specificity than SM102.

[0006] The present invention provides a compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] wherein each variable is as defined in the present invention.

[0009] In another aspect, the present invention provides a nanoparticle composition comprising a lipid component and optionally a payload; wherein the lipid component contains the compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

[0010] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of the present invention, and a pharmaceutically acceptable excipient.

[0011] In another aspect, the present invention provides the use of the compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention in the preparation of a drug for the treatment, diagnosis or prevention of a disease;

[0012] Preferably, the drug for the treatment, diagnosis or prevention of a disease is a nucleic acid drug;

[0013] Preferably, the drug for the treatment, diagnosis or prevention of a disease is a gene editing drug;

[0014] Preferably, the disease is a disease related to muscle dysfunction;

[0015] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA or DNA;

[0016] Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), poly-coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA), or ribozyme, preferably mRNA, siRNA, gRNA, modified mRNA, more preferably guide RNA (gRNA), mRNA, modified mRNA, and even more preferably modified mRNA and / or guide RNA (gRNA);

[0017] Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multi-copy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0018] In another aspect, the present invention provides the use of a compound of the present invention, or its isotope variant, tautomer, or stereoisomer, or its pharmaceutically acceptable salt, or the nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention in the preparation of a drug for delivering a payload, wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent;

[0019] Preferably, the drug is a drug for delivering a payload to muscle;

[0020] Preferably, the payload is a gene editing drug.

[0021] In another aspect, the present invention provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject the nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention;

[0022] Preferably, the method for treating, diagnosing, or preventing a disease is gene editing;

[0023] Preferably, the disease is a muscle dysfunction-related disease.

[0024] In another aspect, the present invention provides a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention, which is used for treating, diagnosing or preventing diseases; preferably for gene editing;

[0025] Preferably, the disease is a disease related to muscle dysfunction.

[0026] In another aspect, the present invention provides a method for delivering a payload to a subject, comprising administering to the subject the nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention;

[0027] wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent;

[0028] Preferably, the method is a method for delivering a payload to the muscle of a subject.

[0029] In another aspect, the present invention provides the method of the present invention, wherein the administration includes any one or a combination of local administration and systemic administration;

[0030] Preferably, the administration includes intramuscular injection, intravenous injection, intraperitoneal injection or arterial injection, preferably intramuscular injection.

[0031] In another aspect, the present invention provides a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention, which is used for delivering a payload;

[0032] wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent;

[0033] Preferably, it is used for delivering a payload to the muscle.

[0034] In another aspect, the present invention provides the nanoparticle composition of the present invention, or the use of the present invention, or the method of the present invention, or the compound or pharmaceutical composition or nanoparticle composition of the present invention, wherein the therapeutic agent, prophylactic agent or diagnostic agent is nucleic acid;

[0035] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA or DNA;

[0036] Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), poly-coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA), or ribozyme, preferably mRNA, siRNA, gRNA, or modified mRNA, more preferably guide RNA (gRNA), mRNA, and / or modified mRNA, even more preferably modified guide RNA (gRNA) and / or mRNA;

[0037] Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multi-copy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0038] In another aspect, the present invention provides a method for preparing a compound of formula (II), the method comprising:

[0039] Reacting a compound of formula (IIa) with a compound of formula (IIb) to obtain a compound of formula (II);

[0040]

[0041] wherein each variable is as defined in the present invention.

[0042] Definitions

[0043] Chemical definitions

[0044] The definitions of specific functional groups and chemical terms are described in more detail below.

[0045] When a numerical range is listed, it is intended to include each value and sub-ranges within the 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 C 5-6 alkyl group.

[0046] “C 1-20 alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon group having 1 to 20 carbon atoms. In some embodiments, C 4-20 alkyl, C 6-14 alkyl, C 7-12 alkyl, C 8-12 alkyl, C 9-12 alkyl, C 4-10 alkyl, C 7-11 alkyl, C 8-11 alkyl, C 9-11 alkyl, C 10-11 alkyl, C 6-10 alkyl, C 7-10 alkyl, C 8-10 alkyl, C 9-10 alkyl, C 10 alkyl, C 8-9 alkyl, C 6-9 alkyl, C 7-9 alkyl, C 4-9 alkyl, C 2-9 alkyl, C9 alkyl, C 10 alkyl, C 11 alkyl, C 1-8 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 3-7 alkyl, C 5-7 alkyl, C 6-7 alkyl, C7 alkyl, C 1-20 alkyl, C 1-14 alkyl, C 2-14 alkyl, C 1-13 alkyl, C 1-12 alkyl, C 1-10 alkyl, C 1-9 alkyl, C 1-8 alkyl, C 1-7 alkyl, C 2-7 alkyl, C 1-6 alkyl, C 2-6 alkyl, C 4-6 alkyl, C 1-5 alkyl, C5 alkyl, C 1-4 alkyl, C 2-4Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 Alkyl and Me are preferred. C 1-6 Examples of alkyl 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 heteroalkyls 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, e.g., 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 is preferably a straight-chain alkyl, e.g., C 6-14 Straight-chain alkyl, C 8-12 Straight-chain alkyl, e.g., C 8-10 Straight-chain alkyl, e.g., C 8-9 Straight-chain alkyl, e.g., C8 straight-chain alkyl, e.g., C9 straight-chain alkyl.

[0047] "C 4-20 alkenyl" refers to a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-14 Alkenyl, C 6-14 Alkenyl, C 7-12 Alkenyl, C 4-10 Alkenyl, C 2-10 Alkenyl, C 2-9 Alkenyl, C 5-8 Alkenyl, C 2-6 Alkenyl and C 2-4 Alkenyl are preferred. C 2-6 Examples of alkenyl include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C 2-6"Alkenyl" also includes heteroalkenyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, e.g., substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl is preferably a straight-chain alkenyl.

[0048] "C 4-20 "Alkynyl" refers to a straight-chain 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 5-8 alkynyl, C 2-6 alkynyl, and C 2-4 alkynyl are preferred. Examples of C 2-6 alkynyl 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, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted with one or more substituents, e.g., substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkynyl is preferably a straight-chain alkynyl.

[0049] "C 1-20 "Alkylene" refers to a divalent group formed by removing another hydrogen from C 1-20 alkyl, and may be substituted or unsubstituted. In some embodiments, C 4-20 alkylene, C 1-14 alkylene, C 4-14 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 2-8Alkylene, C 5-8 Alkylene, C 7-8 Alkylene, C 6-7 Alkylene, C 4-6 Alkylene, C 1-20 Alkylene, C 1-14 Alkylene, C 2-14 Alkylene, C 1-13 Alkylene, C 1-12 Alkylene, C 1-10 Alkylene, C 1-9 Alkyl, C 1-8 Alkylene, C 1-7 Alkylene, C 2-7 Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4 Alkylene, C 2-4 Alkylene, C 3-4 Alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1-2 Alkylene and methylene are preferred. The 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 alkylene, for example, the alkylene substituted by one or more alkyl groups (methyl), includes, but is 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. In some embodiments, the alkylene is preferably a straight-chain alkylene.

[0050] "C 2-6 Alkenylene" refers to a divalent group formed by removing another hydrogen from an alkenyl group, and may be substituted or unsubstituted. "C 2-6 Alkenylene" refers to a divalent group formed by removing another hydrogen from an alkenyl group, and may be substituted or unsubstituted. In some embodiments, C 4-14 Alkenylene" refers to a divalent group formed by removing another hydrogen from an alkenyl group, and may be substituted or unsubstituted. In some embodiments, C 4-14 Alkenylene" refers to a divalent group formed by removing another hydrogen from an alkenyl group, and may be substituted or unsubstituted. In some embodiments, C6-14 Vinylene, C 4-10 Vinylene, C 2-10 Vinylene, C 2-9 Vinylene, C 5-8 Vinylene, C 6-7 Vinylene, C 2-6 Vinylene, C 3-4 Vinylene and C 2-4 Vinylene is particularly preferred. Exemplary unsubstituted vinylene groups include, but are not limited to: vinylidene (-CH=CH-), and allylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted vinylene groups, e.g., vinylene groups substituted with one or more alkyl groups (methyl), include, but are not limited to: substituted vinylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted allylidene (-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. In some embodiments, the vinylene group is preferably a straight-chain vinylene group.

[0051] “C 2-6 Vinylidyne” refers to a divalent group formed by removing another hydrogen from a C 2-6 alkynyl group, and may be substituted or unsubstituted. “C 4-14 Vinylidyne” refers to a divalent group formed by removing another hydrogen from a C 4-14 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 6-14 Vinylidyne, C 4-10 Vinylidyne, C 2-10 Vinylidyne, C 2-9 Vinylidyne, C 5-8 Vinylidyne, C 6-7 Vinylidyne, C 2-6 Vinylidyne, C 3-4 Vinylidyne and C 2-4 Vinylidyne is particularly preferred. Exemplary vinylidyne groups include, but are not limited to: ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), and the like. In some embodiments, the vinylidyne group is preferably a straight-chain vinylidyne group.

[0052] “C 0-6 Alkylene” refers to a chemical bond and the above-mentioned “C 1-6 Alkylene”, “C 0-4 Alkylene” refers to a chemical bond and the above-mentioned “C 1-4 Alkylene”.

[0053] The term "R" s The substitution site on R1 is separated from M1 by x carbon atoms", which means the sum of the number of carbon atoms (including the N atom after being replaced by -NR'-) between the substitution site on the variable R1 substituted by the variable R s and so on for other cases. For example:

[0054] In Compound 2, R s The substitution site on R1 is separated from M1 by 1 carbon atom.

[0055] "Halogenated" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0056] 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 haloalkyl, C 1-6 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl are particularly preferred, and more preferably C 1-2 haloalkyl. Exemplary haloalkyls include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethylethyl, and the like. The haloalkyl group can be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0057] "C 3-14"Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic cycloaliphatic 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 cycloalkyl ring is fused to one or more aryl or heteroaryl groups, with the point of attachment on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes those in which the above cycloalkyl ring, where substituents on any non-adjacent carbon atoms are connected to form a bridged ring, together form a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes those in which the above cycloalkyl ring, where substituents on the same carbon atom are connected to form a ring, together form 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, substituted with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0058] "C 3-14 "Cycloalkylidene" refers to a divalent group formed by removing another hydrogen of the cycloalkyl other than C 3-14 and may be substituted or unsubstituted. In some embodiments, C 3-10 Cycloalkylidene, C 3-7 Cycloalkylidene, C 3-6 Cycloalkylidene, C 3-5 Cycloalkylidene and C 3-4 Cycloalkylidene are particularly preferred, especially preferably cyclopropylidene.

[0059] "3- to 14-membered heterocyclic group" or "3-14 membered heterocyclic group" refers to a saturated or unsaturated group 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 contains 1, 2, or 3 double bonds or triple bonds. In a heterocyclic group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, provided that the valence allows. In some embodiments, a 3- to 10-membered heterocyclic group is preferred, which is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 5- to 10-membered heterocyclic group is preferred, which is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3- to 8-membered heterocyclic group is preferred, which is a 3- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, a 3- to 7-membered heterocyclic group is preferred, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 5- to 7-membered heterocyclic group is preferred, which is a 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 3- to 6-membered heterocyclic group is preferred, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4- to 6-membered heterocyclic group is preferred, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 5- to 6-membered heterocyclic group is more preferred, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 5-membered heterocyclic group is preferred, which is a 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 6-membered heterocyclic group is preferred, which is a 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. The heterocyclic group also includes a ring system in which the above-mentioned heterocyclic group ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclic group ring, or a ring system in which the above-mentioned heterocyclic group ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic group ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic group ring system. The heterocyclic group also includes a case where the substituents on any non-adjacent carbon or nitrogen atoms of the above-mentioned heterocyclic group ring are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. The heterocyclic group also includes a case where the substituents on the same carbon atom of the above-mentioned heterocyclic group ring are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-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, dihydropyridyl, 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: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclic group also includes the above heterocyclic groups sharing one or two atoms with a cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group to form a bridged ring or spiro ring, and the shared atoms can be carbon or nitrogen atoms as long as the valence allows. The heterocyclic group also includes that the above heterocyclic groups can be optionally substituted by one or more substituents, for example, substituted by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0060] “C 3-14 subheterocyclylene” refers to a divalent group formed by removing another hydrogen of the C 3-14 heterocyclic group, and can be substituted or unsubstituted. In some embodiments, C 3-10 subheterocyclylene, C 3-7 subheterocyclylene, C 3-6 subheterocyclylene, C 3-5 subheterocyclylene, and C 3-4 subheterocyclylene are particularly preferred.

[0061] “C 6-10 aryl” refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having 6 or 10 π electrons shared in a cyclic arrangement). In some embodiments, the aryl has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, the aryl has ten ring carbon atoms (“C 10"aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0062] "5- to 14-membered heteroaryl" or "5-14-membered heteroaryl" means a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (e.g., having 6, 10, or 14 π electrons arranged in a cyclic array and shared), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In a heteroaryl containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, provided that the valence allows. The bicyclic heteroaryl system can include one or more heteroatoms in one or both rings. Heteroaryl also includes a ring system in which the above-described heteroaryl ring is fused to one or more cycloalkyl or heterocyclic 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- to 10-membered heteroaryl is preferred, which is a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl is particularly preferred, which is a 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to: pyrrolyl, furyl, 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: pyridyl or pyridone. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group can be optionally substituted by one or more substituents, e.g., by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0063] "Hydroxyalkyl" means an alkyl group substituted by one or more hydroxy groups.

[0064] "Alkoxy" refers to the oxygen ether form of a straight-chain or branched-chain alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0065] "Optionally substituted with ···" means that it can be substituted with the designated substituent or can be unsubstituted.

[0066] The divalent groups formed by removing another hydrogen from the groups such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl defined above are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclic group, aryl, and heteroaryl are collectively referred to as "ring groups".

[0067] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, etc. defined herein are optionally substituted groups.

[0068] Exemplary substituents on a carbon atom 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, heterocyclic group, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

[0069] alternatively, two geminal hydrogens on a carbon atom are substituted by the 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 groups;

[0070] Each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R aa groups combine to form a heterocyclic group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

[0071] Each R bb 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. An alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, or two R bb groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

[0072] Each R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R cc groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;

[0073] Each R dd 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, heterocyclic group, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may combine to form =O or =S;

[0074] Each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic group and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;

[0075] Each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R ff groups combine to form a heterocyclic group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;

[0076] Each R gg is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -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 haloalkyl, 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 - is a counterion.

[0077] Exemplary substituents on the nitrogen atom include but are not limited to: hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa)2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or two R groups attached to the nitrogen atom combine to form a heterocyclic group or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R groups, and wherein R cc groups are as described above. dd “Nucleic acid” refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their hybrid molecules. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASO), etc. Nucleic acids can be further chemically modified, and the chemical modifications are selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, 5-methylcytosine. The mRNA molecule contains a protein-coding region and may further contain expression regulatory sequences. Typical expression regulatory sequences include, but are not limited to, 5' cap, 5' untranslated region (5'UTR), 3' untranslated region (3'UTR), polyadenylation sequence (PolyA), miRNA binding site. aa “Ionizable lipid” refers to a lipid molecule that can carry a positive charge under physiological pH conditions. In some embodiments, the ionizable lipid is an amino lipid. bb “Neutral lipid” refers to a lipid molecule that is 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). cc dd

[0078]

[0079]

[0080] ​​​​​

[0081] "Structural lipid" refers to a lipid that enhances the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentanoperhydrophenanthrene carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coprosterol, saxisterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol.

[0082] "Polymeric lipid" refers to a molecule containing a polymer moiety and a lipid moiety. In some embodiments, the polymeric lipid is a polyethylene glycol (PEG) lipid. Other lipids capable of reducing aggregation, such as products of coupling a compound with an uncharged, hydrophilic, steric hindrance moiety to a lipid, can also be used.

[0083] "Lipid nanoparticle" refers to a particle containing a lipid component and having a nanoscale size.

[0084] "Biodegradable group" refers to a functional group containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can affect the process of clearing compounds from the body. The direction of the biodegradable group in the present invention is from the head to the tail of the ionizable lipid molecule. Common biodegradable groups include, but are not limited to: -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -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 -.

[0085] Other definitions

[0086] As used herein, the term "treatment" refers to reversing, alleviating, inhibiting the progression of, or preventing a disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. As used herein, the noun "treatment" refers to the act of the verb treat, which is as defined just above.

[0087] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts and amino acid addition salts of the compounds of the present invention that are suitable, within the scope of sound medical judgment, for contact with the tissues of a patient and that do not produce undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio and that are effective for their intended use, including (where possible) the zwitterionic forms of the compounds of the present invention.

[0088] Pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0089] 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 in a conventional manner and separating the free acid. The free acid forms differ somewhat in certain physical properties, such as solubility in polar solvents, from their respective salt forms, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0090] Salts can be prepared from inorganic acids such as sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, etc. 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, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate, etc. Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids such as arginine salts, gluconates, galacturonates, etc. are also covered (see, for example, Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19, which is incorporated herein by reference).

[0091] "Subjects" to which administration is made 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 elderly adults)) and / or non-human animals, e.g., mammals, such as 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" may be used interchangeably herein.

[0092] The terms "disease", "disorder" and "condition" may be used interchangeably herein.

[0093] Unless otherwise indicated, the term "treatment" as used herein includes the effects that occur when a subject has a specific disease, disorder or condition, which reduce the severity of the disease, disorder or condition, or delay or slow the development of the disease, disorder or condition ("therapeutic treatment"), and also includes the effects that occur before a subject begins to have a specific disease, disorder or condition ("preventive treatment").

[0094] Generally, an "effective amount" of a pharmaceutical composition refers to an amount sufficient to cause a desired biological response. As will be understood by those of ordinary skill in the art, the effective amount of the pharmaceutical composition of the present invention may vary depending on factors such as, for example, 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. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0095] Unless otherwise indicated, a "therapeutically effective amount" of a pharmaceutical composition as used herein 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. The therapeutically effective amount of a pharmaceutical composition refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0096] Unless otherwise indicated, a "prophylactically effective amount" of a pharmaceutical composition as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with the disease, disorder or condition, or to prevent the recurrence of a disease, disorder or condition. The prophylactically effective amount of a pharmaceutical composition refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or enhances the prophylactic effect of other prophylactic agents.

[0097] "Combination" and related terms refer to the administration of the pharmaceutical composition of the present invention and other therapeutic agents either simultaneously or sequentially. For example, the pharmaceutical composition of the present invention can be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or administered simultaneously with other therapeutic agents in a single unit dosage form. Specific Embodiments

[0098] As used herein, "the compounds of the present invention" refers to compounds of formula (I), formula (II), formula (III), etc., their isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof.

[0099] As used herein, compounds are named using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise stated) all optical isomers and mixtures thereof are included. In addition, unless otherwise specified, all isomeric compounds included in the present invention may occur in the Z and E forms with respect to carbon-carbon double bonds. For compounds that exist in different tautomeric forms, a given compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.

[0100] 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:

[0101]

[0102] Wherein,

[0103] Z is CH or N; preferably CH;

[0104] n1 and n2 are independently 0, 1 or 2;

[0105] G1 and G2 are independently selected from C 4-14 alkylene, C 4-14 alkenylene and C 4-14 alkynylene, which is optionally substituted by one or more R G1 substituents;

[0106] R G1 is independently selected from H, C 1-14 alkyl, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0107] L a is independently selected from a chemical bond and C 1-14 alkylene;

[0108] R a and R' a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclic groups;

[0109] G3 is a chemical bond or -L-C 0-4 alkylene-Y-, where Y is connected to Q;

[0110] L is selected from a chemical bond, -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-;

[0111] Y is selected from C 6-10 arylene and 5- to 10-membered heteroarylene;

[0112] G4 is selected from a chemical bond, C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, which is optionally substituted by one or more R G4 substituents;

[0113] R G4 are independently selected from H, C 1-6 alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0114] L b are independently selected from a chemical bond and C 1-6 alkylene;

[0115] R b and R' b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic groups;

[0116] Or two R groups attached to the same carbon atom G4 together with the carbon atom to which they are attached form C 3-14 subcycloalkyl or 3- to 14-membered subheterocyclic groups, which are optionally substituted by one or more R 4g substituents;

[0117] R 4g are independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e, -L e , -SR e and -L e , -NR e R' e ;

[0118] L e is independently selected from a chemical bond and C 1-8 alkylene;

[0119] R e and R' e are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group;

[0120] Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f -, -NR f C(O)NR f -, -OC(O)S-, -OC(O)O-, -NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -, -C(O)NR f -, -NR f C(O)-, -NR f C(O)S-, -SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -, -NR f C(S)O-, -S-S-, -S(O) 0-2 -, phenylene, and pyridylene, wherein the phenylene or pyridylene is optionally substituted with one or more R*;

[0121] R* is independently selected from H, halogen, cyano, C 1-10 alkyl, C 1-10 haloalkyl, -L f -OR f , -L f , -SR f and -L f , -NR f R' f ;

[0122] L f is independently selected from a chemical bond and C 1-8 alkylene;

[0123] R f and R' f are independently selected from H, C1-10 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group;

[0124] 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-;

[0125] 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 substituents, and one or more of the methylene units therein are optionally and independently replaced by -NR'-;

[0126] R s is independently selected from H, C 1-20 alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0127] R and R' are each independently selected from H and C 1-20 alkyl;

[0128] L c is independently selected from a chemical bond and C 1-20 alkylene;

[0129] R c and R' c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group;

[0130] R3 is selected from CN, -OR d 、-C(O)R d 、-OC(O)R d 、-NR”C(O)R d 、-NR d R' d 、-NR”C(O)NR dR' d 、 -NR”C(O)R d 、 -NR”S(O)2R d 、 -OC(O)NR d R' d 、 -NR”C(O)OR d 、 -N(OR d )C(O)R d 、 -N(OR d )S(O)2R d 、 -N(OR d )C(O)OR d 、 -N(OR d )C(O)R d R' d 、 3 - to 14 - membered heterocyclic group and 5 - to 14 - membered heteroaryl group;

[0131] R d and R' d are independently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl and 3 - to 10 - membered heterocyclic group;

[0132] R” is independently selected from H and C 1-6 alkyl;

[0133] Provided that when both n1 and n2 are 0, Z is CH.

[0134] In another 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:

[0135]

[0136] Wherein,

[0137] Z is CH;

[0138] n1 and n2 are independently 1;

[0139] G1 and G2 are independently selected from C 4-14 alkylene, C 4-14 alkenylene and C 4-14 alkynylene, which is optionally substituted by one or more R G1 substituents;

[0140] R G1 is independently selected from H, C 1-14 alkyl, -L a -OR a 、 -L a -SR a and -L a -NRa R' a ;

[0141] L a is independently selected from a chemical bond and C 1-14 alkylene;

[0142] R a and R' a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic group;

[0143] G3 is a chemical bond or -L-C 0-4 alkylene-Y-, wherein Y is linked to Q;

[0144] L is selected from a chemical bond, -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0145] Y is selected from C 6-10 arylene and 5- to 10-membered heteroarylene;

[0146] G4 is selected from a chemical bond, C 1-6 alkylene, C 2-6 alkenylene and C 2-6 alkynylene, which is optionally substituted by one or more R G4 substituents;

[0147] R G4 is independently selected from H, C 1-6 alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0148] L b is independently selected from a chemical bond and C 1-6 alkylene;

[0149] R b and R' b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclic group;

[0150] Or two Rs attached to the same carbon atom G4 together with the carbon atom to which they are attached form C 3-14 subcycloalkyl or 3- to 14-membered heterocycloalkylene, which is optionally substituted by one or more R 4g substituents;

[0151] R 4g independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e 、-L e -SR e and -L e -NR e R' e ;

[0152] L e independently selected from a chemical bond and C 1-8 alkylene;

[0153] R e and R' e independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl and a 3- to 14-membered heterocyclic group;

[0154] Q is selected from a chemical bond, -C(O)O-, and -C(O)S-; preferably -C(O)O-;

[0155] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -C(O)NR-, -NRC(O)-, and -OC(O)O-;

[0156] 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 substituents, and one or more methylene units therein are optionally and independently replaced by -NR'-;

[0157] R s independently selected from H, C 1-20 alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0158] R and R' are each independently selected from H and C 1-20 alkyl;

[0159] L c independently selected from a chemical bond and C 1-20 alkylene;

[0160] R c and R' cIndependently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclic group;

[0161] R3 is -NR d R' d ;

[0162] R d and R' d are independently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic group.

[0163] In another embodiment, the present invention relates to the above compounds, or their isotopic variants, tautomers or stereoisomers, or their pharmaceutically acceptable salts, which have the structure of formula (II) or formula (III):

[0164]

[0165] wherein,

[0166] a = 1, 2, 3, 4, 5 or 6;

[0167] b = 4, 5, 6, 7, 8, 9 or 10;

[0168] c = 4, 5, 6, 7, 8, 9 or 10;

[0169] The remaining variables are as defined herein.

[0170] In the compounds of the present invention, each variable may be defined as follows.

[0171] Z

[0172] In one embodiment, Z is CH; in another embodiment, Z is N.

[0173] In a more specific embodiment, Z is CH or N.

[0174] In a more specific embodiment, when both n1 and n2 are 0, Z is CH.

[0175] n1 and n2

[0176] In one embodiment, n1 is 0; in another embodiment, n1 is 1; in another embodiment, n1 is 2.

[0177] In one embodiment, n2 is 0; in another embodiment, n2 is 1; in another embodiment, n2 is 2.

[0178] In a more specific embodiment, n1 is 0, 1 or 2; in another more specific embodiment, n1 is 0 or 1.

[0179] In a more specific embodiment, n2 is 0, 1 or 2; in another more specific embodiment, n2 is 0 or 1.

[0180] G1 and G2

[0181] In one embodiment, G1 is C 4-14 alkylene, preferably C 4-10 alkylene, preferably C 5-8 alkylene, preferably C 6-7 alkylene; in another embodiment, G1 is C 4-14 alkenylene, preferably C 4-10 alkenylene, preferably C 5-8 alkenylene; in another embodiment, G1 is C 4-14 alkynylene, preferably C 4-10 alkynylene, preferably C 5-8 alkynylene; in another embodiment, G1 is optionally substituted by one or more R G1 substituents; in another embodiment, G1 is optionally substituted by 1, 2, 3 or 4 R G1 substituents; in another embodiment, G1 is unsubstituted.

[0182] In one embodiment, G2 is C 4-14 alkylene, preferably C 4-10 alkylene, preferably C 5-8 alkylene, preferably C 6-7 alkylene; in another embodiment, G2 is C 4-14 alkenylene, preferably C 4-10 alkenylene, preferably C 5-8 alkenylene; in another embodiment, G2 is C 4-14 alkynylene, preferably C 4-10 alkynylene, preferably C 5-8 alkynylene; in another embodiment, G2 is optionally substituted by one or more R G1 substituents; in another embodiment, G2 is optionally substituted by 1, 2, 3 or 4 R G1 substituents; in another embodiment, G2 is unsubstituted.

[0183] In a more specific embodiment, G1 is selected from C 4-14 alkylene, C 4-14 alkenylene and C 4-14 alkynylene; in another more specific embodiment, G1 is selected from C 4-10 alkylene, C 4-10Alkenylene and C 4-10 alkynylene; in another more specific embodiment, G1 is selected from C 5-8 alkylene, C 5-8 alkenylene and C 5-8 alkynylene.

[0184] In a more specific embodiment, G2 is selected from C 4-14 alkylene, C 4-14 alkenylene and C 4-14 alkynylene; in another more specific embodiment, G2 is selected from C 4-10 alkylene, C 4-10 alkenylene and C 4-10 alkynylene; in another more specific embodiment, G2 is selected from C 5-8 alkylene, C 5-8 alkenylene and C 5-8 alkynylene.

[0185] R G1 、L a 、R a and R' a

[0186] In one embodiment, R G1 is H; in another embodiment, R G1 is C 1-14 alkyl, preferably C 1-10 alkyl, preferably C 1-6 alkyl; in another embodiment, R G1 is -L a -OR a ; in another embodiment, R G1 is -L a -SR a ; in another embodiment, R G1 is -L a -NR a R’ a .

[0187] In a more specific embodiment, R G1 is independently selected from H and C 1-10 alkyl; in another more specific embodiment, R G1 is independently selected from H and C 1-6 alkyl.

[0188] In one embodiment, L a is a chemical bond; in another embodiment, L a is C 1-14 alkylene, preferably C 1-10 alkylene, preferably C 1-6Alkylene.

[0189] In a more specific embodiment, L a is independently selected from a chemical bond and C 1-10 alkylene; in another more specific embodiment, L a is independently selected from a chemical bond and C 1-6 alkylene.

[0190] In one embodiment, R a is H; in another embodiment, R a is C 1-14 alkyl, preferably C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R a is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R a is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0191] In one embodiment, R' a is H; in another embodiment, R' a is C 1-14 alkyl, preferably C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R' a is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' a is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0192] In a more specific embodiment, R a is independently selected from H, C 1-10 alkyl (preferably C 1-6 alkyl), C 3-7 cycloalkyl and a 3- to 7-membered heterocyclic group; in another more specific embodiment, R a is independently selected from H and C 1-10 alkyl; in another more specific embodiment, R a is independently selected from H and C 1-6 alkyl.

[0193] In a more specific embodiment, R' a is independently selected from H, C 1-10 alkyl (preferably C1-6 alkyl), C 3-7 cycloalkyl, and 3- to 7-membered heteroaryl; in another more specific embodiment, R' a is independently selected from H and C 1-10 alkyl; in another more specific embodiment, R' a is independently selected from H and C 1-6 alkyl.

[0194] G3, L, and Y

[0195] In one embodiment, G3 is a chemical bond; in another embodiment, G3 is -L-C 0-4 alkylene-Y-, wherein Y is linked to Q; in another embodiment, G3 is -L-C 1-3 alkylene-Y-, wherein Y is linked to Q.

[0196] In a more specific embodiment, G3 is a chemical bond or -L-C 0-4 alkylene-Y-, wherein Y is linked to Q; in another more specific embodiment, G3 is a chemical bond or -L-C 1-3 alkylene-Y-, wherein Y is linked to Q.

[0197] In one embodiment, L is a chemical bond; in another embodiment, L is -C(O)O-; in another embodiment, L is -C(O)S-; in another embodiment, L is -OC(O)-; in another embodiment, L is -SC(O)-.

[0198] In a more specific embodiment, L is selected from a chemical bond, -C(O)O-, and -C(O)S-; in another more specific embodiment, L is selected from -C(O)O- and -OC(O)-.

[0199] In one embodiment, Y is C 6-10 arylene, preferably phenylene; in another embodiment, Y is 5- to 10-membered heteroarylene.

[0200] In a more specific embodiment, Y is selected from C 6-10 arylene and 5- to 10-membered heteroarylene; in another more specific embodiment, Y is selected from phenylene and 5- to 6-membered heteroarylene.

[0201] G4

[0202] In one embodiment, G4 is a chemical bond; in another embodiment, G4 is C 1-6 alkylene, preferably C 1-4 alkylene, preferably C 2-4 alkylene, preferably C 2-3Alkylene, preferably C 3-4 Alkylene; in another embodiment, G4 is C 2-6 Alkenylene, preferably C 2-4 In another embodiment, G4 is C 2-6 Alkyne, preferably C 2-4 Alkyne; In another embodiment, G4 is optionally substituted with one or more R G4 In another embodiment, G4 is optionally replaced by 1, 2, 3 or 4 R G4 substituted; in another embodiment, G4 is not substituted.

[0203] In a more specific embodiment, G4 is selected from C 1-4 Alkylene, C 2-4 Alkenylene and C 2-4 Alkyne group.

[0204] R G4 , L b , R b and R' b

[0205] In one embodiment, R G4 is H; in another embodiment, R G4 C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R G4 For -L b -OR b In another embodiment, R G4 For -L b -SR b In another embodiment, R G4 For -L b -NR b R' b .

[0206] In one embodiment, two R attached to the same carbon atom G4 Together with the carbon atom to which they are attached, they form C 3-14 Cycloalkylene, preferably forming C 3-10 Cycloalkylene, preferably forming C 3-7 Cycloalkylene, preferably forming C 3-4 Cycloalkylene, preferably cyclopropyl; in another embodiment, two R G4 Together with the carbon atom to which they are attached, they form a 3- to 14-membered heterocyclylene, preferably a 3- to 10-membered heterocyclylene, preferably a 3- to 7-membered heterocyclylene; in another embodiment, two R attached to the same carbon atom G4The ring formed together with the carbon atom to which they are attached is optionally substituted with one or more R 4g ; in another embodiment, two Rs attached to the same carbon atom G4 The ring formed together with the carbon atom to which they are attached is optionally substituted with 1, 2 or 3 Rs 4g ; in another embodiment, two Rs attached to the same carbon atom G4 The ring formed together with the carbon atom to which they are attached is unsubstituted.

[0207] In a more specific embodiment, R G4 is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R G4 is independently selected from H and C 1-4 alkyl.

[0208] In a more specific embodiment, two Rs attached to the same carbon atom G4 together with the carbon atom to which they are attached form a C 3-10 subcycloalkyl or a 3- to 10-membered heterocycloalkyl; in another more specific embodiment, two Rs attached to the same carbon atom G4 together with the carbon atom to which they are attached form a C 3-7 subcycloalkyl or a 3- to 7-membered heterocycloalkyl.

[0209] In one embodiment, L b is a chemical bond; in another embodiment, L b is a C 1-6 alkylene, preferably C 1-3 alkylene.

[0210] In a more specific embodiment, L b is independently selected from a chemical bond and C 1-3 alkylene.

[0211] In one embodiment, R b is H; in another embodiment, R b is C 1-6 alkyl, preferably C 1-3 alkyl; in another embodiment, R b is C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R b is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0212] In one embodiment, R' b is H; in another embodiment, R' b is C1-6 alkyl, preferably C 1-3 alkyl; in another embodiment, R' b is C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' b is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0213] In a more specific embodiment, R b is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic groups; in another more specific embodiment, R b is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R b is independently selected from H and C 1-3 alkyl.

[0214] In a more specific embodiment, R' b is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic groups; in another more specific embodiment, R' b is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R' b is independently selected from H and C 1-3 alkyl.

[0215] R 4g

[0216] In one embodiment, R 4g is H; in another embodiment, R 4g is a halogen; in another embodiment, R 4g is a cyano group; in another embodiment, R 4g is C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R 4g is C 1-8 haloalkyl, preferably C 1-6 haloalkyl; in another embodiment, R 4g is -L e -OR e ; in another embodiment, R 4g is -L e -SR e ; in another embodiment, R 4g is -L e -NR eR’ e 。

[0217] In a more specific embodiment, R 4g is independently selected from H, halogen, cyano, C 1-6 alkyl, and C 1-6 haloalkyl.

[0218] L e 、R e and R' e

[0219] In one embodiment, L e is a chemical bond; in another embodiment, L e is C 1-8 alkylene, preferably C 1-6 alkylene, preferably C 1-3 alkylene.

[0220] In one embodiment, R e is H; in another embodiment, R e is C 1-8 alkyl, preferably C 1-6 alkyl, preferably C 1-3 alkyl; in another embodiment, R e is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R e is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0221] In one embodiment, R' e is H; in another embodiment, R' e is C 1-8 alkyl, preferably C 1-6 alkylene, preferably C 1-3 alkylene; in another embodiment, R' e is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' e is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0222] In a more specific embodiment, L e is independently selected from a chemical bond and C 1-6 alkylene; in another more specific embodiment, L a is selected from a chemical bond and C 1-3 alkylene.

[0223] In a more specific embodiment, R eindependently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic group; in another more specific embodiment, R e is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R e is independently selected from H and C 1-3 alkyl.

[0224] In a more specific embodiment, R' e is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl and 3-7 membered heterocyclic group; in another more specific embodiment, R' e is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R' e is independently selected from H and C 1-3 alkyl.

[0225] Q

[0226] In one embodiment, Q is a chemical bond; in another embodiment, Q is -C(O)O-; in another embodiment, Q is -O-; in another embodiment, Q is -SC(O)O-; in another embodiment, Q is -OC(O)NR f -; in another embodiment, Q is -NR f C(O)NR f -; in another embodiment, Q is -OC(O)S-; in another embodiment, Q is -OC(O)O-; in another embodiment, Q is -NR f C(O)O-; in another embodiment, Q is -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -; in another embodiment, Q is -C(O)NR f -; in another embodiment, Q is -NR f C(O)-; in another embodiment, Q is -NR f C(O)S-; in another embodiment, Q is -SC(O)NR f -; in another embodiment, Q is -C(O)-; in another embodiment, Q is -OC(S)-; in another embodiment, Q is -C(S)O-; in another embodiment, Q is -OC(S)NR f -; in another embodiment, Q is -NR fC(S)O-; in another embodiment, Q is -S-S-; in another embodiment, Q is -S(O) 0-2 -, such as -S-, such as -S(O)-, such as -S(O)2-; in another embodiment, Q is phenylene; in another embodiment, Q is pyridylene; in another embodiment, when Q is phenylene, it is optionally substituted by one or more R*; in another embodiment, when Q is phenylene, it is optionally substituted by 1, 2 or 3 R*; in another embodiment, Q is unsubstituted phenylene; in another embodiment, when Q is pyridylene, it is optionally substituted by one or more R*; in another embodiment, when Q is pyridylene, it is optionally substituted by 1, 2 or 3 R*; in another embodiment, Q is unsubstituted pyridylene.

[0227] In a more specific embodiment, Q is selected from -C(O)O- and -C(O)S-.

[0228] R*

[0229] In one embodiment, R* is H; in another embodiment, Q is halogen; in another embodiment, R* is cyano; in another embodiment, R* is C 1-10 alkyl, preferably C 1-6 alkyl; in another embodiment, R* is C 1-10 haloalkyl, preferably C 1-6 haloalkyl; in another embodiment, R* is -L f -OR f ; in another embodiment, R* is -L f -SR f ; in another embodiment, R* is -L f -NR f R’ f .

[0230] In a more specific embodiment, R* is independently selected from H, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl.

[0231] L f 、R f and R' f

[0232] In one embodiment, L f is a chemical bond; in another embodiment, L f is C 1-8 alkylene, preferably C 1-6 alkylene, preferably C 1-4 alkylene.

[0233] In a more specific embodiment, L f is independently selected from a chemical bond and C 1-6 alkylene; in another more specific embodiment, L f is independently selected from a chemical bond and C 1-4 alkylene.

[0234] In one embodiment, R f is H; in another embodiment, R f is C 1-10 alkyl, preferably C 1-6 alkyl, preferably C 1-4 alkyl; in another embodiment, R f is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R f is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0235] In one embodiment, R' f is H; in another embodiment, R' f is C 1-10 alkyl, preferably C 1-6 alkyl, preferably C 1-4 alkyl; in another embodiment, R' f is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' f is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0236] In a more specific embodiment, R f is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and a 3- to 7-membered heterocyclic group; in another more specific embodiment, R f is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R f is independently selected from H and C 1-4 alkyl.

[0237] In a more specific embodiment, R' f is independently selected from H, C 1-6 alkyl, C 3-7Cycloalkyl and 3- to 7-membered heterocyclic group; in another more specific embodiment, R' f independently selected from H and C 1-6 alkyl; in another more specific embodiment, R' f independently selected from H and C 1-4 alkyl.

[0238] M1 and M2

[0239] 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-, such as -C(O)NH-; in another embodiment, M1 is -NRC(O)-, such as -NHC(O)-; in another embodiment, M1 is -NRC(O)S-; in another embodiment, M1 is -SC(O)NR-; in another embodiment, M1 is -C(O)-; in another embodiment, M1 is -OC(S)-; in another embodiment, M1 is -C(S)O-; in another embodiment, M1 is -OC(S)NR-; in another embodiment, M1 is -NRC(S)O-; in another embodiment, M1 is -S-S-; in another embodiment, M1 is -S(O) 0-2 -, such as -S-, such as -S(O)-, such as -S(O)2-.

[0240] 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, M2 is -NR-; in another embodiment, M2 is -C(O)NR-, such as -C(O)NH-; in another embodiment, M2 is -NRC(O)-, such as -NHC(O)-; in another embodiment, M2 is -NRC(O)S-; in another embodiment, M2 is -SC(O)NR-; in another embodiment, M2 is -C(O)-; in another embodiment, M2 is -OC(S)-; in another embodiment, M2 is -C(S)O-; in another embodiment, M2 is -OC(S)NR-; in another embodiment, M2 is -NRC(S)O-; in another embodiment, M2 is -S-S-; in another embodiment, M2 is -S(O) 0-2 -, such as -S-, such as -S(O)-, such as -S(O)2-.

[0241] In a more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -C(O)NR-, -NRC(O)- and -OC(O)O-; in another more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S- and -OC(O)O-; in another more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; in another more specific embodiment, M1 is selected from -C(O)O- and -C(O)S-; in another more specific embodiment, M1 is selected from -C(O)O- and -OC(O)-.

[0242] In a more specific embodiment, M2 is selected from --C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; in another more specific embodiment, M2 is selected from -C(O)O- and -C(O)S-; preferably -OC(O)- or -SC(O)-; in another more specific embodiment, M2 is selected from -C(O)O- and -OC(O)-.

[0243] In a more specific embodiment, M1 is -C(O)O- and M2 is -OC(O)-.

[0244] In a more specific embodiment, M1 is -OC(O)- and M2 is -C(O)O-.

[0245] In a more specific embodiment, M1 is -C(O)O- and M2 is -C(O)O-.

[0246] In a more specific embodiment, M1 is -OC(O)- and M2 is -OC(O)-.

[0247] In a more specific embodiment, M1 is -OC(O)O- and M2 is -OC(O)-.

[0248] R1 and R2

[0249] In one embodiment, R1 is C 4-20 alkyl, preferably C 6-14 alkyl, preferably C 8-12 alkyl, preferably C 8-10 alkyl, preferably C 8-9 alkyl, preferably C9 alkyl, preferably C 6-14 linear alkyl, preferably C 8-12 linear alkyl, preferably C 8-10 linear alkyl, preferably C 8-9 linear alkyl, preferably C8 linear alkyl, preferably C9 linear alkyl; in another embodiment, R1 is C 4-20 alkenyl, preferably C 6-14 alkenyl, preferably C 7-12 alkenyl, preferably C 8-12 alkenyl; in another embodiment, R1 is C 4-20 alkynyl, preferably C 6-14 alkynyl, preferably C 7-12 alkynyl, preferably C 8-12 alkynyl; in another embodiment, R1 is optionally substituted by one or more R s substituents; in another embodiment, R1 is optionally substituted by 1, 2, 3 or 4 R s substituents, preferably optionally substituted by 1, 2 or 3 R s substituents, preferably optionally substituted by 1 or 2 R s substituents, preferably optionally substituted by 1 R sSubstituted; in another embodiment, R1 is unsubstituted; in another embodiment, one or more methylene units in R1 are optionally and independently replaced by -NR'-; in another embodiment, 1, 2, 3, or 4 methylene units in R1 are optionally and independently replaced by -NR'-; preferably, one methylene unit in R1 is optionally replaced by -NR'

[0250] In one embodiment, R2 is C 4-20 alkyl, preferably C 6-14 alkyl, preferably C 8-12 alkyl, preferably C 8-10 alkyl, preferably C 8-9 alkyl, preferably C9 alkyl, preferably C 6-14 linear alkyl, preferably C 8-12 linear alkyl, preferably C 8-10 linear alkyl, preferably C 8-9 linear alkyl, preferably C8 linear alkyl, preferably C9 linear alkyl; in another embodiment, R2 is C 4-20 alkenyl, preferably C 6-14 alkenyl, preferably C 7-12 alkenyl, preferably C 8-12 alkenyl; in another embodiment, R2 is C 4-20 alkynyl, preferably C 6-14 alkynyl, preferably C 7-12 alkynyl, preferably C 8-12 alkynyl; in another embodiment, R2 is optionally substituted by one or more R s substituted; in another embodiment, R2 is optionally substituted by 1, 2, 3, or 4 R s substituted, preferably optionally substituted by 1, 2, or 3 R s substituted, preferably optionally substituted by 1 or 2 R s substituted, preferably optionally substituted by 1 R s substituted; in another embodiment, R2 is unsubstituted; in another embodiment, one or more methylene units in R2 are optionally and independently replaced by -NR'-; in another embodiment, 1, 2, 3, or 4 methylene units in R2 are optionally and independently replaced by -NR'-; preferably, one methylene unit in R2 is optionally replaced by -NR'

[0251] In a more specific embodiment, R1 and R2 are independently selected from C 6-14 alkyl, C 6-14 alkenyl, and C 6-14 alkynyl

[0252] In a more specific embodiment, R1 and R2 are independently selected from C8 linear alkyl, C9 linear alkyl,

[0253]

[0254] In a more specific embodiment, at least one of R1 and R2 is replaced by R s .

[0255] In a more specific embodiment, both R1 and R2 are replaced by R s .

[0256] In a more specific embodiment, R1 is replaced by R s , and R2 is not replaced.

[0257] In a more specific embodiment, R1 is not replaced, and R2 is replaced by R s .

[0258] R s

[0259] In one embodiment, R s is H; in another embodiment, R s is C 1-20 alkyl, preferably C 1-14 alkyl, preferably C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 2-9 alkyl, preferably C 4-9 alkyl, preferably C 7-9 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 3-7 alkyl, preferably C 1-6 alkyl, preferably C 4-6 alkyl, preferably C8 alkyl; in another embodiment, R s is -L c -OR c ; in another embodiment, R s is -L c -SR c ; in another embodiment, R s is -L c -NR c R’ c .

[0260] In one embodiment, the substitution site of R s on R1 is separated from M1 by 0 carbon atoms; in another embodiment, R sThe substitution site on R1 is separated from M1 by 1 carbon atom; in another embodiment, R s The substitution site on R1 is separated from M1 by 2 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 3 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 4 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 5 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 6 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 7 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 8 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 9 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by 10 carbon atoms.

[0261] In one embodiment, R s The substitution site on R2 is separated from ring A by 0 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 1 carbon atom; in another embodiment, R s The substitution site on R2 is separated from ring A by 2 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 3 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 4 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 5 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 6 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 7 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 8 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 9 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from ring A by 10 carbon atoms.

[0262] In a more specific embodiment, R s is independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; in another more specific embodiment, R s is independently selected from H and C 1-14 alkyl.

[0263] In a more specific embodiment, R s the substitution site on R1 is separated from M1 by 0-10 carbon atoms; in another more specific embodiment, R s the substitution site on R1 is separated from M1 by 0-6 carbon atoms; in another more specific embodiment, R s the substitution site on R1 is separated from M1 by 0-5 carbon atoms; in another more specific embodiment, R s the substitution site on R1 is separated from M1 by 0-4 carbon atoms; in another more specific embodiment, R s the substitution site on R1 is separated from M1 by 0-3 carbon atoms; in another more specific embodiment, R s the substitution site on R1 is separated from M1 by 0-2 carbon atoms; in another more specific embodiment, R s the substitution site on R1 is separated from M1 by 0-1 carbon atom; in another more specific embodiment, R s the substitution site on R1 is separated from M1 by 0 carbon atoms.

[0264] In a more specific embodiment, R s the substitution site on R2 is separated from ring A by 0-10 carbon atoms; in another more specific embodiment, R s the substitution site on R2 is separated from ring A by 0-6 carbon atoms; in another more specific embodiment, R s the substitution site on R2 is separated from ring A by 0-5 carbon atoms; in another more specific embodiment, R s the substitution site on R2 is separated from ring A by 0-4 carbon atoms; in another more specific embodiment, R s the substitution site on R2 is separated from ring A by 0-3 carbon atoms; in another more specific embodiment, R s the substitution site on R2 is separated from ring A by 0-2 carbon atoms; in another more specific embodiment, R sThe substitution site on R2 and ring A are separated by 0-1 carbon atoms; in another more specific embodiment, R s The substitution site on R2 and ring A are separated by 0 carbon atoms.

[0265] In a more specific embodiment, R s The substitution site on R1 and M1 are separated by at least 1 carbon atom; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 1-10 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 1-6 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 1-5 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 1-4 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 1-2 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by at least 2 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 2-10 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 2-6 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 2-5 carbon atoms; in another more specific embodiment, R s The substitution site on R1 and M1 are separated by 2-4 carbon atoms.

[0266] In a more specific embodiment, R s The substitution site on R2 and M1 are separated by at least 1 carbon atom; in another more specific embodiment, R s The substitution site on R2 and M1 are separated by 1-10 carbon atoms; in another more specific embodiment, R s The substitution site on R2 and M1 are separated by 1-6 carbon atoms; in another more specific embodiment, R s The substitution site on R2 and M1 are separated by 1-5 carbon atoms; in another more specific embodiment, R s The substitution site on R2 and M1 are separated by 1-4 carbon atoms; in another more specific embodiment, R sThe substitution site on R2 is separated from M1 by 1-2 carbon atoms; in another more specific embodiment, R s The substitution site on R2 is separated from M1 by at least 2 carbon atoms; in another more specific embodiment, R s The substitution site on R2 is separated from M1 by 2-10 carbon atoms; in another more specific embodiment, R s The substitution site on R2 is separated from M1 by 2-6 carbon atoms; in another more specific embodiment, R s The substitution site on R2 is separated from M1 by 2-5 carbon atoms; in another more specific embodiment, R s The substitution site on R2 is separated from M1 by 2-4 carbon atoms.

[0267] R and R'

[0268] In one embodiment, R is H; in another embodiment, R is C 1-20 alkyl, preferably C 1-14 alkyl, preferably C 1-9 alkyl, preferably C 1-6 alkyl.

[0269] In one embodiment, R' is H; in another embodiment, R' is C 1-20 alkyl, preferably C 1-14 alkyl, preferably C 1-9 alkyl, preferably C 1-6 alkyl.

[0270] In a more specific embodiment, R is independently selected from H and C 1-20 alkyl; in another more specific embodiment, R is independently selected from H and C 1-14 alkyl; in another more specific embodiment, R is independently selected from H and C 1-9 alkyl; in another more specific embodiment, R is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R is H.

[0271] In a more specific embodiment, R' is independently selected from H and C 1-20 alkyl; in another more specific embodiment, R' is independently selected from H and C 1-14 alkyl; in another more specific embodiment, R' is independently selected from H and C 1-9 alkyl; in another more specific embodiment, R' is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R' is H.

[0272] Lc , R c and R' c

[0273] In one embodiment, L c is a chemical bond; in another embodiment, L c is C 1-20 alkylene, preferably C 1-14 alkylene, preferably C 1-12 alkylene, preferably C 1-10 alkylene, preferably C 1-8 alkylene, preferably C 1-6 alkylene.

[0274] In a more specific embodiment, L c is independently selected from a chemical bond and C 1-14 alkylene (preferably C 1-12 alkylene, preferably C 1-10 alkylene, preferably C 1-8 alkylene, preferably C 1-6 alkylene).

[0275] In one embodiment, R c is H; in another embodiment, R c is C 1-20 alkyl, preferably C 1-14 alkyl, preferably C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R c is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R c is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0276] In one embodiment, R’ c is H; in another embodiment, R’ c is C 1-20 alkyl, preferably C 1-14 alkyl, preferably C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R’ c is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl, preferably C 3-7Cycloalkyl; in another embodiment, R' c is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0277] In a more specific embodiment, R c is independently selected from H, C 1-14 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic groups; in another more specific embodiment, R c is independently selected from H and C 1-14 alkyl; in another more specific embodiment, R c is independently selected from H and C 1-12 alkyl; in another more specific embodiment, R c is independently selected from H and C 1-10 alkyl; in another more specific embodiment, R c is independently selected from H and C 1-8 alkyl; in another more specific embodiment, R c is independently selected from H and C 1-6 alkyl.

[0278] In a more specific embodiment, R' c is independently selected from H, C 1-14 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic groups; in another more specific embodiment, R' c is independently selected from H and C 1-14 alkyl; in another more specific embodiment, R' c is independently selected from H and C 1-12 alkyl; in another more specific embodiment, R' c is independently selected from H and C 1-10 alkyl; in another more specific embodiment, R' c is independently selected from H and C 1-8 alkyl; in another more specific embodiment, R' c is independently selected from H and C 1-6 alkyl.

[0279] R3

[0280] In one embodiment, R3 is CN; in another embodiment, R3 is -OR d , such as -OH; in another embodiment, R3 is -C(O)R d ; in another embodiment, R3 is -OC(O)R d ; in another embodiment, R3 is -NR”C(O)R d; In another embodiment, R3 is -NR d R' d , such as -N(CH3)2, such as -N(CH2CH3)2; In another embodiment, R3 is -NR”C(O)NR d R' d ; In another embodiment, R3 is -NR”C(O)R d ; In another embodiment, R3 is -NR”S(O)2R d ; In another embodiment, R3 is -OC(O)NR d R' d ; In another embodiment, R3 is -NR”C(O)OR d ; In another embodiment, R3 is -N(OR d )C(O)R d ; In another embodiment, R3 is -N(OR d )S(O)2R d ; In another embodiment, R3 is -N(OR d )C(O)OR d ; In another embodiment, R3 is -N(OR d )C(O)R d R' d ; In another embodiment, R3 is a 3- to 14-membered heterocyclic group; In another embodiment, R3 is a 5- to 14-membered heteroaryl group.

[0281] In a more specific embodiment, R3 is selected from CN, -OR d and -NR d R' d ; In another more specific embodiment, R3 is selected from -OR d and -NR d R' d ; In another more specific embodiment, R3 is selected from OH and -N(CH3)2.

[0282] R d and R' d

[0283] In one embodiment, R d is H; In another embodiment, R d is C 1-10 alkyl, preferably C 1-6 alkyl, preferably C 1-4 alkyl, preferably C 1-3 alkyl, such as methyl, such as ethyl; In another embodiment, R d is C 3-10Cycloalkyl, preferably C 3-7 Cycloalkyl; in another embodiment, R d is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0284] In one embodiment, R' d is H; in another embodiment, R' d is C 1-10 alkyl, preferably C 1-6 alkyl, preferably C 1-4 alkyl, preferably C 1-3 alkyl, such as methyl, such as ethyl; in another embodiment, R' d is C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' d is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0285] In a more specific embodiment, R d is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic groups; in another more specific embodiment, R d is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R d is independently selected from H and C 1-4 alkyl; in another more specific embodiment, R d is independently selected from H and Me.

[0286] In a more specific embodiment, R' d is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic groups; in another more specific embodiment, R′ d is independently selected from H and C 1-6 alkyl; in another more specific embodiment, R' d is independently selected from H and C 1-4 alkyl; in another more specific embodiment, R′ d is independently selected from H and Me.

[0287] R”

[0288] In one embodiment, R” is H; in another embodiment, R” is C 1-6 alkyl, preferably C 1-4 alkyl.

[0289] a, b and c

[0290] 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.

[0291] In one embodiment, b is 4; in another embodiment, b is 5; in another embodiment, b is 6; in another embodiment, b is 7; in another embodiment, b is 8; in another embodiment, b is 9; in another embodiment, b is 10.

[0292] In one embodiment, c is 4; in another embodiment, c is 5; in another embodiment, c is 6; in another embodiment, c is 7; in another embodiment, c is 8; in another embodiment, c is 9; in another embodiment, c is 10.

[0293] In a more specific embodiment, a = 2, 3, 4, 5 or 6; in another more specific embodiment, a = 2, 3 or 4.

[0294] In a more specific embodiment, b = 4, 5, 6, 7 or 8; in another more specific embodiment, b = 5, 6 or 7; in another more specific embodiment, b = 6 or 7.

[0295] In a more specific embodiment, c = 4, 5, 6, 7 or 8; in another more specific embodiment, c = 5, 6 or 7; in another more specific embodiment, c = 6 or 7.

[0296] 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 Z can be combined with n1, n2, G1, G2, R G1 , L a , R a , R' a , G3, L, Y, G4, R G4 , L b , R b , R' b , R 4g , L e , R e , R' e , Q, R*, L f , R f , R' f , M1, M2, R1, R2, R s , R, R', Lc , R c , R' c , R3, R d , R' d , R'', a, b, and c, etc., or any combination of any technical solution or any combination thereof. The present invention is intended to include all such combinations of technical solutions, and due to space limitations, they are not listed one by one.

[0297] 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:

[0298]

[0299] Wherein,

[0300] Z is CH or N; preferably CH;

[0301] n1 and n2 are independently 0, 1, or 2;

[0302] G1 and G2 are independently selected from C 4-14 alkylene, C 4-14 alkenylene, and C 4-14 alkynylene, which is optionally substituted by one or more R G1 substituents;

[0303] R G1 is independently selected from H, C 1-14 alkyl, -L a -OR a , -L a -SR a and -L a -NR a R' a ;

[0304] L a is independently selected from a chemical bond and C 1-14 alkylene;

[0305] R a and R' a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group;

[0306] G3 is a chemical bond or -L-C 0-4 alkylene-Y-, wherein Y is connected to Q;

[0307] L is selected from a chemical bond, -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-;

[0308] Y is selected from C6-10 Arylene and 5- to 10-membered heteroarylene;

[0309] G4 is selected from a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylene, which is optionally substituted by one or more R G4 substituted;

[0310] R G4 is independently selected from H, C 1-6 alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0311] L b is independently selected from a chemical bond and C 1-6 alkylene;

[0312] R b and R' b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclic group;

[0313] Or two Rs attached to the same carbon atom G4 together with the carbon atom to which they are attached form C 3-14 subcycloalkyl or 3- to 14-membered subheterocyclic group, which is optionally substituted by one or more R 4g substituted;

[0314] R 4g is independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e 、-L e -SR e and -L e -NR e R' e ;

[0315] L e is independently selected from a chemical bond and C 1-8 alkylene;

[0316] R e and R' e are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic group;

[0317] Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f -, -NR f C(O)NR f -, -OC(O)S-, -OC(O)O-, -NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -, -C(O)NR f -, -NR f C(O)-, -NR f C(O)S-, -SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -, -NR f C(S)O-, -S-S-, -S(O) 0-2 -, phenylene and pyridylene, wherein the phenylene or pyridylene is optionally substituted by one or more R*;

[0318] R* is independently selected from H, halogen, cyano, C 1-10 alkyl, C 1-10 haloalkyl, -L f -OR f , -L f -SR f and -L f -NR f R' f ;

[0319] L f is independently selected from a chemical bond and C 1-8 alkylene;

[0320] R f and R' f are independently selected from H, C 1-10 alkyl, C 3-14 cycloalkyl and a 3- to 14-membered heterocyclic group;

[0321] 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-;

[0322] 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 substituents, and one or more of the methylene units therein are optionally and independently replaced by -NR'-;

[0323] R s is independently selected from H, C 1-20 alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0324] R and R' are each independently selected from H and C 1-20 alkyl;

[0325] L c is independently selected from a chemical bond and C 1-20 alkylene;

[0326] R c and R' c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group;

[0327] R3 is selected from CN, -OR d 、-C(O)R d 、-OC(O)R d 、-NR”C(O)R d 、-NR d R' d 、-NR”C(O)NR d R' d 、-NR”C(O)R d 、-NR”S(O)2R d 、-OC(O)NR d R' d 、-NR”C(O)OR d 、-N(OR d )C(O)R d 、-N(OR d )S(O)2R d 、-N(OR d )C(O)OR d 、-N(OR d )C(O)Rd R' d 、3- to 14-membered heterocyclic groups and 5- to 14-membered heteroaryl groups;

[0328] R d and R' d are independently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic groups;

[0329] R” is independently selected from H and C 1-6 alkyl;

[0330] provided that when both n1 and n2 are 0, Z is CH.

[0331] 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:

[0332]

[0333] wherein,

[0334] Z is CH;

[0335] n1 and n2 are independently 1;

[0336] G1 and G2 are independently selected from C 4-14 alkylene, C 4-14 alkenylene, and C 4-14 alkynylene, which is optionally substituted with one or more R G1 substituents;

[0337] R G1 is independently selected from H, C 1-14 alkyl, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0338] L a is independently selected from a chemical bond and C 1-14 alkylene;

[0339] R a and R' a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclic groups;

[0340] G3 is a chemical bond or -L-C 0-4 alkylene-Y-, wherein Y is linked to Q;

[0341] L is selected from a chemical bond, -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-;

[0342] Y is selected from C 6-10 arylene and 5- to 10-membered heteroarylene;

[0343] G4 is selected from a chemical bond, C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, which is optionally substituted by one or more R G4 substituents;

[0344] R G4 is independently selected from H, C 1-6 alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0345] L b is independently selected from a chemical bond and C 1-6 alkylene;

[0346] R b and R' b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic group;

[0347] Or two R G4 connected to the same carbon atom, together with the carbon atom to which they are attached, form C 3-14 cycloalkylene or 3- to 14-membered heteroarylene, which is optionally substituted by one or more R 4g substituents;

[0348] R 4g is independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e 、-L e -SR e and -L e -NR e R' e ;

[0349] L e is independently selected from a chemical bond and C 1-8 alkylene;

[0350] R e and R' e are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclic groups;

[0351] Q is selected from a chemical bond, -C(O)O-, and -C(O)S-; preferably -C(O)O-;

[0352] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -C(O)NR-, -NRC(O)-, and -OC(O)O-;

[0353] R1 and R2 are independently selected from C 4-20 alkyl, C 4-20 alkenyl, and C 4-20 alkynyl, which are optionally substituted by one or more R s substituents, and one or more methylene units therein are optionally and independently replaced by -NR'-;

[0354] R s is independently selected from H, C 1-20 alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0355] R and R' are each independently selected from H and C 1-20 alkyl;

[0356] L c is independently selected from a chemical bond and C 1-20 alkylene;

[0357] R c and R' c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclic groups;

[0358] R3 is -NR d R' d ;

[0359] R d and R' d are independently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic groups.

[0360] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein n1 and n2 are independently 0 or 1, preferably 1.

[0361] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein G1 and G2 are independently selected from C 4-10 alkylene, C 4-10 alkenylene and C 4-10 alkynylene; preferably C 5-8 alkylene, C 5-8 alkenylene and C 5-8 alkynylene; preferably C 4-10 alkylene, preferably C 5-8 alkylene, preferably C 6-7 alkylene;

[0362] Preferably, G1 and G2 are optionally substituted by 1, 2, 3 or 4 R G1 substituents.

[0363] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein R G1 is independently selected from H and C 1-10 alkyl; preferably H and C 1-6 alkyl;

[0364] Preferably, L a is independently selected from a chemical bond and C 1-10 alkylene; preferably a chemical bond and C 1-6 alkylene;

[0365] Preferably, R a and R' a are independently selected from H, C 1-10 alkyl (preferably C 1-6 alkyl), C 3-7 cycloalkyl and 3- to 7-membered heterocyclic group; preferably H and C 1-10 alkyl; preferably H and C 1-6 alkyl.

[0366] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein G3 is a chemical bond or -L-C 1-3 alkylene-Y-, wherein Y is connected to Q; preferably a chemical bond;

[0367] Preferably, L is selected from a chemical bond, -C(O)O-, and -C(O)S-; preferably -C(O)O- and -OC(O)-; more preferably -C(O)O-;

[0368] Preferably, Y is selected from C 6-10 arylene and 5- to 10-membered heteroarylene; preferably phenylene and 5- to 6-membered heteroarylene; more preferably phenylene.

[0369] In a more specific embodiment, the present invention provides the above compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G4 is selected from C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene; preferably C 2-4 alkylene; preferably C 2-3 alkylene; preferably C 3-4 alkylene;

[0370] Preferably, G4 is optionally substituted with 1, 2, 3 or 4 R G4 substituents.

[0371] In a more specific embodiment, the present invention provides the above compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R G4 is independently selected from H and C 1-6 alkyl; preferably H and C 1-4 alkyl;

[0372] Preferably, L b is independently selected from a chemical bond and C 1-3 alkylene;

[0373] Preferably, R b and R' b are independently H, C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic group; preferably H and C 1-3 alkyl;

[0374] Preferably, two Rs G4 attached to the same carbon atom together with the carbon atom to which they are attached form C 3-10 cycloalkylene or 3- to 10-membered heteroarylene, preferably forming C 3-7 cycloalkylene or 3- to 7-membered heteroarylene, which is optionally substituted with 1, 2 or 3 R 4g substituents;

[0375] Preferably, R 4g is independently selected from H, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl;

[0376] Preferably, L e is independently selected from a chemical bond and C 1-6 alkylene; preferably a chemical bond and C 1-3 alkylene;

[0377] Preferably, R e and R' e are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and a 3- to 7-membered heterocyclic group; preferably H and C 1-6 alkyl; preferably H and C 1-3 alkyl.

[0378] In a more specific embodiment, the present invention provides the above compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q is selected from -C(O)O- and -C(O)S-; preferably -C(O)O-;

[0379] Preferably, when Q is phenylene or pyridinylene, it is optionally substituted by 1, 2 or 3 R*;

[0380] Preferably, R* is independently selected from H, halogen, cyano, C 1-6 alkyl, and C 1-6 haloalkyl;

[0381] Preferably, L f is independently selected from a chemical bond and C 1-6 alkylene; preferably a chemical bond and C 1-4 alkylene;

[0382] Preferably, R f and R' f are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and a 3- to 7-membered heterocyclic group; preferably H and C 1-6 alkyl; preferably H and C 1-4 alkyl.

[0383] In more specific embodiments, the present invention provides the above compounds, or their isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, wherein M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -C(O)NR-, -NRC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -C(O)S-; preferably -C(O)O- and -OC(O)-; preferably -C(O)O-; preferably -OC(O)-;

[0384] Preferably,

[0385] M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -C(O)S-; preferably -C(O)O- and -OC(O)-; preferably -OC(O)-; preferably -C(O)O-;

[0386] M2 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O- and -C(O)S-; preferably -OC(O)- or -SC(O)-; preferably -C(O)O- and -OC(O)-; preferably -OC(O)-; preferably -C(O)O-; preferably -OC(O)O-;

[0387] Preferably,

[0388] M1 is -C(O)O-;

[0389] M2 is -OC(O)-;

[0390] Preferably,

[0391] M1 is -OC(O)-;

[0392] M2 is -C(O)O-;

[0393] Preferably,

[0394] M1 is -C(O)O-;

[0395] M2 is -C(O)O-;

[0396] Preferably,

[0397] M1 is -OC(O)-;

[0398] M2 is -OC(O)-;

[0399] Preferably,

[0400] M1 is -OC(O)O-;

[0401] M2 is -OC(O)-.

[0402] In a more specific embodiment, the present invention provides the above compound, or its isotope variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein R1 and R2 are independently selected from C 6-14 alkyl, C 6-14 alkenyl and C 6-14 alkynyl; preferably C 6-14 alkyl; preferably C 8-12 alkyl; preferably C 8-10 alkyl; preferably C 8-9 alkyl; preferably C9 alkyl; preferably C 6-14 linear alkyl; preferably C 8-12 linear alkyl; preferably C 8-10 linear alkyl; preferably C 8-9 linear alkyl, preferably C8 linear alkyl, preferably C9 linear alkyl.

[0403] Preferably, R1 and R2 are optionally substituted by 1, 2 or 3 R s substituents, preferably optionally substituted by 1 R s substituent;

[0404] Preferably, R1 and R2 are independently selected from C8 linear alkyl, C9 linear alkyl,

[0405] Preferably, at least one of R1 and R2 is substituted by R s substituent;

[0406] Preferably, both R1 and R2 are substituted by R s substituent;

[0407] Preferably, R1 is substituted by R s substituent and R2 is unsubstituted;

[0408] Preferably, R1 is unsubstituted and R2 is substituted by R s substituent.

[0409] In a more specific embodiment, the present invention provides the above compound, or its isotope variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein R s is independently selected from H, C 1-14 alkyl, -Lc -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl; preferably C 1-12 alkyl; preferably C 1-10 alkyl; preferably C 2-9 alkyl; preferably C 4-9 alkyl; preferably C 7-9 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 3-7 alkyl; preferably C 1-6 alkyl; preferably C 4-6 alkyl or C8 alkyl; preferably C8 alkyl;

[0410] Preferably, L c is independently selected from a chemical bond and C 1-14 alkylene (preferably C 1-12 alkylene, preferably C 1-10 alkylene, preferably C 1-8 alkylene, preferably C 1-6 alkylene);

[0411] R c and R' c are independently selected from H, C 1-14 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclic group; preferably H and C 1-14 alkyl (preferably C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 1-8 alkyl, preferably C 1-6 alkyl).

[0412] In a more specific embodiment, the present invention provides the above compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R and R' are each independently selected from H and C 1-20 alkyl; preferably H and C 1-14 alkyl; preferably H and C 1-9 alkyl; preferably H and C 1-6 alkyl; preferably R is H.

[0413] In a more specific embodiment, the present invention provides the above compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from CN, -OR dand -NR d R' d ; preferably -OR d and -NR d R' d ; preferably -OR d ; preferably OH;

[0414] Preferably, R3 is selected from OH and -N(CH3)2; preferably -N(CH3)2;

[0415] Preferably, R d and R' d are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and 3- to 7-membered heterocyclic group; preferably H and C 1-6 alkyl; preferably selected from H and C 1-4 alkyl; preferably H and Me.

[0416] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein the substitution site of R s 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 0-2 carbon atoms; preferably 0 carbon atoms; preferably 1 carbon atom; preferably 2 carbon atoms; preferably 3 carbon atoms; preferably 4 carbon atoms; preferably 5 carbon atoms;

[0417] Preferably, the substitution site of R s on R1 or R2 is separated from M1 or M2 by 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-5 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, preferably 2-5 carbon atoms, preferably 2-4 carbon atoms.

[0418] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, which has the structure of formula (Ⅱ) or formula (Ⅲ):

[0419]

[0420] wherein,

[0421] a = 1, 2, 3, 4, 5 or 6;

[0422] b = 4, 5, 6, 7, 8, 9 or 10;

[0423] c = 4, 5, 6, 7, 8, 9 or 10;

[0424] The remaining variables are as defined herein.

[0425] In a more specific embodiment, the present invention provides the above compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (II):

[0426]

[0427] wherein,

[0428] R d and R' d are independently C 1-6 alkyl;

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

[0430] b = 4, 5, 6, 7 or 8;

[0431] c = 4, 5, 6, 7 or 8;

[0432] M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-;

[0433] M2 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-;

[0434] R1 and R2 are independently C 6-14 alkyl, which is optionally substituted by 1, 2 or 3 R s substituents;

[0435] R s is independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl;

[0436] L c is independently selected from a chemical bond and C 1-14 alkylene;

[0437] R c and R’ c are independently selected from H and C 1-14 alkyl;

[0438] Preferably, M1 and M2 are not both -OC(O)O- at the same time.

[0439] In a more specific embodiment, the present invention provides the above compound, or its isotope variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein,

[0440] R d and R' d are independently C 1-3 alkyl; preferably methyl;

[0441] a = 2, 3 or 4; preferably a = 3;

[0442] b = 5, 6, 7 or 8; preferably b = 6 or 7;

[0443] c = 5, 6, 7 or 8; preferably c = 6 or 7;

[0444] M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)- and -OC(O)O-;

[0445] M2 is selected from -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -OC(O)-;

[0446] R1 and R2 are independently C 8-12 alkyl, preferably C 8-10 alkyl, preferably C 8-9 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s substituents;

[0447] R s is independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 1-8 alkyl, preferably C 3-8 alkyl;

[0448] Preferably, R1 and R2 are independently selected from C8 straight-chain alkyl, C9 straight-chain alkyl,

[0449] Preferably, at least one of R1 and R2 is substituted by R s substituents.

[0450] In a more specific embodiment, the present invention provides the above compound, or its isotope variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, which has the structure of formula (II):

[0451]

[0452] Wherein,

[0453] R d and R' d are independently C 1-6 alkyl;

[0454] a = 2, 3, 4, 5 or 6;

[0455] b = 4, 5, 6, 7 or 8;

[0456] c = 4, 5, 6, 7 or 8;

[0457] M1 and M2 are independently -C(O)O- or -C(O)S-;

[0458] R1 and R2 are independently C 6-14 alkyl, optionally substituted by 1, 2 or 3 R s substituents;

[0459] R s is independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl;

[0460] L c is independently selected from a chemical bond and C 1-14 alkylene;

[0461] R c and R’ c are independently selected from H and C 1-14 alkyl.

[0462] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein,

[0463] R d and R' d are independently C 1-3 alkyl;

[0464] a = 2, 3 or 4; preferably a = 3;

[0465] b = 5, 6, 7 or 8; preferably b = 6 or 7;

[0466] c = 5, 6, 7 or 8; preferably c = 6 or 7;

[0467] M1 and M2 are independently -C(O)O- or -C(O)S-; preferably -C(O)O-;

[0468] R1 and R2 are independently C 8-12 alkyl, preferably C 8-10 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s substituted;

[0469] R s is independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 2-9 alkyl;

[0470] Preferably, at least one of R1 and R2 is substituted by R s substituted.

[0471] In a more specific embodiment, the present invention provides the above compound, or its isotope variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein,

[0472] R d and R' d are methyl;

[0473] a = 3;

[0474] b = 6 or 7; preferably b = 6;

[0475] c = 6 or 7; preferably c = 6;

[0476] M1 and M2 are -C(O)O-;

[0477] R1 and R2 are independently C 8-9 alkyl, preferably C9 alkyl, which is optionally substituted by 1 R s substituted;

[0478] R s is independently C 1-8 alkyl, preferably C 3-8 alkyl;

[0479] Preferably, R1 and R2 are independently selected from C9 straight-chain alkyl

[0480] Preferably, at least one of R1 and R2 is substituted by R s substituted.

[0481] In a more specific embodiment, the present invention provides the above compound, or its isotope variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, which has the structure of formula (II):

[0482]

[0483] Among them,

[0484] R d and R' d are independently C 1-3 alkyl; preferably methyl;

[0485] a = 2, 3 or 4; preferably a = 3;

[0486] b = 5, 6 or 7; preferably b = 6;

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

[0488] M1 and M2 are -C(O)O-;

[0489] R1 is C 8-10 alkyl, preferably C9 alkyl, which is optionally substituted by one R s substituted; preferably R1 is substituted by one R s substituted;

[0490] R2 is C 8-10 linear alkyl, preferably C9 linear alkyl;

[0491] R s is independently C 1-8 alkyl, preferably C 3-8 alkyl, preferably C 4-6 alkyl or C8 alkyl;

[0492] Preferably, R1 is selected from C9 linear alkyl, Preferably

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

[0494]

[0495] Among them,

[0496] R d and R' d are independently C 1-3 alkyl; preferably methyl;

[0497] a = 2, 3 or 4; preferably a = 3;

[0498] b = 5, 6 or 7; preferably b = 6;

[0499] c = 5, 6 or 7; preferably c = 6;

[0500] M1 and M2 are -C(O)O-;

[0501] R1 is C 8-10 alkyl, preferably C9 alkyl, which is substituted by one R s substituted;

[0502] R2 is C 8-10 alkyl, preferably C9 alkyl, which is substituted by one R s substituted;

[0503] R s is independently C 1-8 alkyl, preferably C 3-8 alkyl, preferably C 4-8 alkyl; preferably C 3-7 alkyl;

[0504] Preferably, R1 and R2 are independently selected from

[0505] Preferably

[0506] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, which has the structure of formula (II):

[0507]

[0508] wherein,

[0509] R d and R' d are independently C 1-6 alkyl;

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

[0511] b = 4, 5, 6, 7 or 8;

[0512] c = 4, 5, 6, 7 or 8;

[0513] M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-;

[0514] M2 is -OC(O)-, -C(O)O-, -SC(O)-, -SC(O)- or -OC(O)O-; preferably -OC(O)- or -SC(O)-;

[0515] R1 and R2 are independently C 6-14 alkyl, which is optionally substituted by 1, 2 or 3 R s substituted;

[0516] R s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl;

[0517] L c independently selected from a chemical bond and C 1-14 alkylene;

[0518] R c and R’ c independently selected from H and C 1-14 alkyl;

[0519] Preferably, at least one of R1 and R2 is substituted by R s ;

[0520] Preferably, M1 and M2 are not both -OC(O)O-.

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

[0522] R d and R' d are independently C 1-3 alkyl;

[0523] a = 2, 3 or 4;

[0524] b = 5, 6 or 7;

[0525] c = 5, 6 or 7;

[0526] M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)- and -OC(O)O-;

[0527] M2 is -OC(O)- or -SC(O)-; preferably -OC(O)-;

[0528] R1 and R2 are independently C 8-12 alkyl, preferably C 8-10 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s ;

[0529] R s is independently C 1-12 alkyl, preferably C1-10 Alkyl, preferably C 4-9 alkyl;

[0530] Preferably, at least one of R1 and R2 is substituted by R s substituted;

[0531] Preferably,

[0532] M1 is -C(O)O-;

[0533] M2 is -OC(O)-;

[0534] R1 is C 8-12 alkyl, preferably C 8-10 alkyl, which is substituted by one R s substituted;

[0535] R2 is C 8-12 linear alkyl, preferably C 8-10 linear alkyl;

[0536] R s independently is C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 7-9 alkyl;

[0537] Preferably,

[0538] M1 is -OC(O)O-;

[0539] M2 is -OC(O)-;

[0540] R1 is C 6-14 linear alkyl, C 8-12 linear alkyl, preferably C 8-10 linear alkyl;

[0541] R2 is C 6-14 alkyl, C 8-12 alkyl, preferably C 8-10 alkyl, which is substituted by one R s substituted;

[0542] R s independently is C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 7-9 alkyl.

[0543] In a more specific embodiment, the present invention provides the above compounds, or their isotopic variants, tautomers or stereoisomers, or their pharmaceutically acceptable salts, wherein,

[0544] R d and R' d are methyl;

[0545] a = 3;

[0546] b = 6;

[0547] c = 6;

[0548] M1 is selected from -C(O)O-, -OC(O)-, and -OC(O)O-;

[0549] M2 is -OC(O)- or -C(O)O-; preferably -OC(O)-;

[0550] R1 and R2 are independently C 8-9 alkyl, which is optionally substituted by one R s substituted;

[0551] R s is independently C 1-8 alkyl, preferably C 5-8 alkyl;

[0552] Preferably, R1 and R2 are independently selected from C8 linear alkyl, C9 linear alkyl,

[0553] Preferably, at least one of R1 and R2 is substituted by R s substituted;

[0554] Preferably,

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

[0556] M2 is -OC(O)-;

[0557] R1 is C 8-9 alkyl, preferably C9 alkyl, which is substituted by one R s substituted;

[0558] R2 is C 8-9 linear alkyl, preferably C9 linear alkyl;

[0559] R s is independently C 1-8 alkyl, preferably C8 alkyl;

[0560] Preferably,

[0561] M1 is -OC(O)O-;

[0562] M2 is -OC(O)-;

[0563] R1 is C 8-9 linear alkyl, preferably C8 linear alkyl;

[0564] R2 is C 8-9An alkyl group, preferably a C9 alkyl group, which is substituted by one R s substituted;

[0565] R s is independently a C 1-8 alkyl group, preferably a C8 alkyl group.

[0566] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein,

[0567] R d and R' d are independently a C 1-3 alkyl group; preferably a methyl group;

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

[0569] b = 5, 6 or 7; preferably b = 6;

[0570] c = 5, 6 or 7; preferably c = 6;

[0571] M1 is -C(O)O- or -OC(O)-; preferably -OC(O)-;

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

[0573] R1 is a C 8-10 alkyl group, preferably a C9 alkyl group, which is substituted by one R s substituted;

[0574] R2 is a C 8-10 alkyl group, preferably a C9 alkyl group, which is substituted by one R s substituted;

[0575] R s is independently a C 6-8 alkyl group;

[0576] Preferably, R1 and R2 are independently selected from

[0577] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, which has the structure of formula (Ⅲ):

[0578]

[0579] wherein,

[0580] R d and R' d are independently a C 1-6 alkyl group;

[0581] a = 2, 3, 4, 5 or 6;

[0582] b = 4, 5, 6, 7 or 8;

[0583] c = 4, 5, 6, 7 or 8;

[0584] M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -C(O)S-;

[0585] M2 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -C(O)S-;

[0586] R1 and R2 are independently C 6-14 alkyl, which is optionally substituted by 1, 2 or 3 R s substituents;

[0587] R s is independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl;

[0588] L c is independently selected from a chemical bond and C 1-14 alkylene;

[0589] R c and R’ c are independently selected from H and C 1-14 alkyl;

[0590] Preferably, both R1 and R2 are substituted by R s substituents;

[0591] Preferably, M1 and M2 are not both -OC(O)O-.

[0592] In a more specific embodiment, the present invention provides the above compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0593] R d and R' d are independently C 1-3 alkyl; preferably methyl;

[0594] a = 2, 3 or 4; preferably a = 3;

[0595] b = 5, 6 or 7; preferably b = 6;

[0596] c = 5, 6 or 7; preferably c = 6;

[0597] M1 and M2 are independently -C(O)O- or -C(O)S-; preferably -C(O)O-;

[0598] R1 and R2 are independently C 8-12 alkyl, preferably C 8-10 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s substituents;

[0599] R s is independently C 1-12 alkyl, preferably C 1-10 alkyl;

[0600] Preferably, both R1 and R2 are substituted by R s substituents.

[0601] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein the substitution site of R s on R1 or R2 is separated from M1 or M2 by 0 - 6 carbon atoms, preferably 0 - 5 carbon atoms, preferably 0 carbon atoms; preferably 1 carbon atom; preferably 2 carbon atoms; preferably 3 carbon atoms; preferably 4 carbon atoms; preferably 5 carbon atoms.

[0602] In a more specific embodiment, the present invention provides the above compound, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, wherein the compound is selected from the following structures:

[0603]

[0604]

[0605] In a more specific embodiment, the present invention provides a nanoparticle composition, which contains a lipid component and optionally contains a payload; wherein the lipid component contains the compound of the present invention, or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, and the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

[0606] Optionally, the lipid component contains the following components in mole percentages:

[0607] 20 mol% - 85 mol% of any of the above-described compounds of the present invention:

[0608] 10 mol% - 75 mol% of a structured lipid;

[0609] 1.0 mol% - 30 mol% of a neutral lipid;

[0610] 0.25 mol% - 10 mol% of a polymeric lipid;

[0611] Optionally, the lipid component contains components in the following molar percentages:

[0612] 50 mol% of any of the above-described compounds of the present invention;

[0613] 10 mol% of a neutral lipid;

[0614] 38.5 mol% of a structured lipid;

[0615] 1.5 mol% of a polymeric lipid.

[0616] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE, or DPPE, preferably DSPC and / or DOPE.

[0617] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the structured lipid is a steroid; preferably, the steroid is selected from one or more of cholesterol, sitosterol, coprosterol, saxisterol, brassicasterol, ergosterol, tomatidine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol, more preferably cholesterol and / or β-sitosterol, and even more preferably cholesterol.

[0618] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the polymeric lipid is a polyethylene glycolated lipid.

[0619] Optionally, the polyethylene glycolated lipid is selected from one or more of: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol.

[0620] Optionally, the polyethylene glycolated lipid contains a PEG moiety of about 1000 Da to about 20 kDa, preferably contains a PEG moiety of about 1000 Da to about 5000 Da.

[0621] Optionally, the polyethylene glycolated 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, DSPE-PEG5000, preferably DMG-PEG2000.

[0622] In a more specific embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a nanoparticle composition of the present invention, and a pharmaceutically acceptable excipient.

[0623] Preferably, the therapeutic, prophylactic or diagnostic agent is a nucleic acid;

[0624] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA or DNA;

[0625] Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA) or ribozyme, preferably mRNA, siRNA, gRNA or modified mRNA, preferably guide RNA (gRNA), mRNA and / or modified mRNA, more preferably modified guide RNA (gRNA) and / or mRNA;

[0626] Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multi-copy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

[0627] The present invention also provides a method for preparing a compound of formula (II), the method comprising:

[0628] reacting a compound of formula (IIa) with a compound of formula (IIb) to obtain a compound of formula (II);

[0629]

[0630] wherein each variable is as defined herein.

[0631] The compounds of the present invention may include one or more asymmetric centers and thus may exist in various stereoisomeric forms, for example, enantiomeric and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis.

[0632] The compounds of the present invention may exist in tautomeric forms. Tautomers are functional group isomers resulting from the rapid movement of a particular atom within a molecule between two locations. Tautomers are a special type of functional group isomers, and a pair of tautomers can interconvert, but usually one relatively stable isomer predominates. The most common examples are keto-enol tautomers.

[0633] The present invention also includes isotopically labeled compounds (isotope variants) which are equivalent to those described by formula (I), but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36Cl. The compounds of the invention containing the above isotopes and / or other isotopes of other atoms, their prodrugs, and the pharmaceutically acceptable salts of said compounds or said prodrugs all fall within the scope of the invention. Certain isotopically labeled compounds of the invention, for example those incorporating radioactive isotopes (such as 3 H and 14 C), can be used for drug and / or substrate tissue distribution assays. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred because they are readily prepared and detected. Furthermore, substitution with heavier isotopes, such as deuterium, i.e., 2 H, can provide therapeutic benefits, such as extended in vivo half-life or reduced dosage requirements, due to higher metabolic stability and may thus be preferred in some cases. The isotopically labeled compounds of formula (I) of the invention and their prodrugs can generally be prepared by substituting the readily available isotopically labeled reagents for the non-isotopically labeled reagents when carrying out the procedures and / or the processes disclosed in the following schemes and / or examples and preparation examples.

[0634] The invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient. All such forms fall within the scope of the invention.

[0635] Pharmaceutical Compositions and Kits

[0636] In another aspect, the invention provides a pharmaceutical composition comprising the nanoparticle composition of the invention and a pharmaceutically acceptable excipient, said nanoparticle composition comprising a compound of the invention.

[0637] The pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants, or vehicles that do not destroy the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides 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, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene-block polymers, polyethylene glycol, and lanolin.

[0638] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the nanoparticle composition of the present invention and other therapeutic, diagnostic, or prophylactic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other suitable containers) containing the nanoparticle composition of the present invention and other therapeutic, diagnostic, or prophylactic agents. In some embodiments, the provided kit may 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 agents. In some embodiments, the nanoparticle composition of the present invention and other therapeutic, diagnostic, or prophylactic agents provided in the first and second containers combine to form a unit dosage form.

[0639] Administration

[0640] The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, administration by implant, or other administration methods. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial cavity administration, intra-sternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion techniques.

[0641] Generally, an effective amount of the pharmaceutical composition of the present invention is administered. Depending on the circumstances, including the disorder being treated or prevented, the selected route of administration, the actual pharmaceutical composition being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc., the amount of the pharmaceutical composition actually administered can be determined by a physician.

[0642] When used to prevent the disorders described in the present invention, the pharmaceutical composition provided herein is administered to a subject at risk of developing the disorder, typically on the advice of a physician and under the supervision of a physician, at a dosage level as described above. Subjects at risk of developing a specific disorder generally include those with a family history of the disorder, or those determined to be particularly sensitive to developing the disorder through genetic testing or screening.

[0643] The pharmaceutical composition provided herein can also be administered for a long period of time (“long-term administration”). Long-term administration refers to the administration of a compound or its pharmaceutical composition over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be administered 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 a long period of time, e.g., within a therapeutic window.

[0644] A variety of administration methods can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for example, 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 in the body. For example, a bolus dose administered intramuscularly or subcutaneously results in a slow release of the active ingredient, while a bolus injection directly into the vein (e.g., by IV infusion) enables a more rapid delivery, causing the concentration of the active ingredient in the blood to quickly rise to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, by IV infusion, to provide a steady-state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0645] To provide blood levels similar to or lower than those obtained with an injectable dose, a transdermal dose is typically selected in the range of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0646] The injection dose level ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for from about 1 to about 120 hours, especially 24 to 96 hours. To obtain a sufficient steady-state level, a preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be administered. For a human patient weighing 40 to 80 kg, the maximum total dose should not exceed about 2 g / day.

[0647] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically the minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0648] Examples

[0649] To make the technical solutions of the present invention clearer and more definite, the present invention is further described in detail through 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 used to limit the protection scope 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, etc. The materials, reagents, etc. used in the examples can be obtained from commercial sources without special instructions.

[0650] Table 1

[0651] Abbreviation of Chemical Substance Name Full Name THF Tetrahydrofuran DCM Dichloromethane NMP N-Methylpyrrolidone <![CDATA[CDCl3]]> Deuterated Chloroform Imidazole Imidazole TBSCl tert-Butyldimethylchlorosilane NaH Sodium Hydride NaCl Sodium Chloride NaI Sodium Iodide <![CDATA[Na2SO4]]> Sodium Sulfate TBAF Tetrabutylammonium Fluoride EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride DMAP 4-Dimethylaminopyridine TEA Triethylamine

[0652] Example 1: Synthesis of Compound 1

[0653]

[0654] 1,3-Diamino-2-propanol (50.0 g, 544.8 mmol, 1.0 eq.), diethyl carbonate (64.4 g, 544.8 mmol, 1.0 eq.) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (3.79 g, 27.24 mmol, 0.05 eq.) were added to a round-bottom flask equipped with a water separator. The mixture was heated under reflux with stirring overnight, and ethanol produced during the reaction was removed. After the reaction was completed, the solvent in the reaction system was removed by rotary evaporation under reduced pressure. The resulting solid compound was slurried with petroleum ether and filtered, and the collected solid was dried to obtain 58.1 g of Compound 1-3.

[0655] Compound 1-3 (20.0 g, 172.2 mmol, 1.0 eq.) and imidazole (35.2 g, 516.6 mmol, 3.0 eq.) were dissolved in 250 mL of dichloromethane in a round-bottom flask. TBSCl (31.1 g, 206.6 mmol, 1.2 eq.) was added to the reaction system, and the reaction was stirred at room temperature. After the reaction was completed, the reaction solution was poured into 300 mL of saturated sodium chloride aqueous solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the collected filtrate was concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 33.4 g of Compound 1-4.

[0656] Under nitrogen protection, Compound 1-4 (500 mg, 2.17 mmol, 1.0 eq.) was added to a reaction flask, and NMP (5 mL) was added. Sodium hydride (261 mg, 6.51 mmol, 3.0 eq., 60%) was added in batches, and the mixture was stirred at room temperature for 40 min. Then, NaI (65.1 mg, 0.43 mmol, 0.2 eq.) and Bromide 1-5 (1.82 g, 5.43 mmol, 2.5 eq.) were added, and the reaction solution was heated to 65 °C and stirred overnight. After the reaction was completed, the reaction system was cooled to room temperature, 10 mL of ice water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL × 1), and the collected organic phase was dried over anhydrous sodium sulfate and filtered. The obtained filtrate was concentrated by rotary evaporation. The obtained crude product was purified by silica gel column chromatography to obtain Compound 1-6 (180 mg).

[0657] Dissolve compound 1-6 (180 mg, 0.244 mmol, 1.0 eq.) in 4 mL of tetrahydrofuran, then add TBAF (127 mg, 0.488 mmol, 2.0 eq.), stir at room temperature for 3 h. After the reaction is completed, add saturated brine to quench the reaction, extract with ethyl acetate (10 mL x 3), combine the organic phases and wash with brine (10 mL x 1), collect the organic phase and dry it over anhydrous sodium sulfate, filter the obtained filtrate and concentrate it by rotary evaporation. The obtained crude product is purified by silica gel column chromatography to obtain compound 1-7 (90 mg).

[0658] In a reaction flask at room temperature, dissolve compound 1-7 (90 mg, 0.144 mmol, 1.0 eq.), triethylamine (72.9 mg, 0.72 mmol, 5.0 eq.) in 2 mL of dichloromethane, then add DMAP (17.6 mg, 0.144 mmol, 1.0 eq.), EDCI (82.8 mg, 0.432 mmol, 3.0 eq.) and 4-(dimethylamino)butyric acid (37.8 mg, 0.288 mmol, 2.0 eq.), stir at room temperature until the reaction is complete. After the reaction is completed, add saturated brine to quench the reaction, extract with ethyl acetate (10 mL x 3), combine the organic phases and wash with brine (10 mL x 1), collect the organic phase and dry it over anhydrous sodium sulfate, filter the obtained filtrate and concentrate it by rotary evaporation. The obtained crude product is purified by silica gel column chromatography to obtain yellow oily compound 1 (20.4 mg).

[0659] 1 H NMR (300 MHz, CDCl3) δ: 5.11 (m, 1H), 4.03 (t, J = 6.9 Hz, 4H), 3.52 (dd, J = 3.3 Hz, 12.0 Hz, 2H), 3.30 - 3.25 (m, 6H), 2.37 - 2.32 (m, 6H), 2.21 (t, J = 7.5 Hz, 4H), 1.89 - 1.83 (m, 2H), 1.54 - 1.43 (m, 16H), 1.26 - 1.20 (m, 32H), 0.89 - 0.83 (m, 6H); ESI-MS m / z: 738.65 [M+H] + 。

[0660] Example 2: Synthesis of Compound 2

[0661]

[0662] Refer to the method of Example 1 to prepare Compound 2, and obtain 107.9 mg of an oily product.

[0663] 11H NMR (300 MHz, CDCl3) δ: 5.12 - 5.08 (m, 1H), 3.97 (d, J = 6.0 Hz, 4H), 3.52 (dd, J = 3.0 Hz, 12.0 Hz, 2H), 3.33 - 3.24 (m, 6H), 2.37 (t, J = 7.2 Hz, 2H), 2.32 - 2.26 (m, 6H), 2.23 (s, 6H), 1.83 - 1.78 (m, 2H), 1.65 - 1.58 (m, 6H), 1.53 - 1.43 (m, 4H), 1.38 - 1.27 (m, 48H), 0.90 - 0.85 (m, 12H); ESI-MS m / z: 878.70 [M+H] + 。

[0664] Example 3: Synthesis of Compound 3

[0665]

[0666] Referring to the method of Reference Example 1, Compound 3 was prepared to obtain 100.4 mg of an oily product.

[0667] 1 1H NMR (400 MHz, CDCl3) δ: 5.12 - 5.08 (m, 1H), 4.85 (p, J = 6.0 Hz, 2H), 3.54 (dd, J = 3.2 Hz, 12.0 Hz, 2H), 3.38 - 3.23 (m, 6H), 2.37 (t, J = 7.2 Hz, 2H), 2.32 - 2.25 (m, 6H), 2.23 (s, 6H), 1.83 - 1.75 (m, 2H), 1.65 - 1.57 (m, 4H), 1.50 - 1.43 (m, 12H), 1.38 - 1.26 (m, 58H), 0.89 - 0.86 (m, 12H); ESI-MS m / z: 962.70 [M+H] + 。

[0668] Example 4: Synthesis of Compound 4

[0669]

[0670] Referring to the method of Reference Example 1, Compound 4 was prepared to obtain 79.9 mg of an oily product.

[0671] 11H NMR (400 MHz, CDCl3) δ: 5.13 - 5.09 (m, 1H), 4.88 (p, J = 6.0 Hz, 2H), 3.54 (dd, J = 3.2 Hz, 12.4 Hz, 2H), 3.35 - 3.26 (m, 6H), 2.40 (t, J = 7.2 Hz, 2H), 2.32 - 2.26 (m, 12H), 1.88 - 1.84 (m, 2H), 1.66 - 1.60 (m, 4H), 1.52 - 1.41 (m, 12H), 1.38 - 1.28 (m, 60H), 0.89 - 0.86 (m, 12H); ESI-MS m / z: 990.85 [M + H] + 。

[0672] Example 5: Synthesis of Compound 5

[0673]

[0674] Referring to the method of Reference Example 1, Compound 5 was prepared to obtain 120.3 mg of an oily product.

[0675] 1 1H NMR (300 MHz, CDCl3) δ: 5.13 - 5.09 (m, 1H), 3.95 (d, J = 6.0 Hz, 4H), 3.53 (dd, J = 3.0 Hz, 12.3 Hz, 2H), 3.36 - 3.26 (m, 6H), 2.64 - 2.39 (m, 10H), 2.29 (t, J = 7.5 Hz, 4H), 1.94 - 1.92 (m, 2H), 1.64 - 1.43 (m, 12H), 1.38 - 1.25 (m, 58H), 0.89 - 0.86 (m, 12H); ESI-MS m / z: 935.10 [M + H] + 。

[0676] Example 6: Synthesis of Compound 6

[0677]

[0678] Referring to the method of Reference Example 1, Compound 6 was prepared to obtain 126.3 mg of an oily product.

[0679] 11H NMR (400 MHz, CDCl3) δ: 5.13 - 5.09 (m, 1H), 4.07 (t, J = 7.2 Hz, 4H), 3.53 (dd, J = 3.2 Hz, 12.0 Hz, 2H), 3.35 - 3.23 (m, 6H), 2.64 - 2.42 (m, 6H), 2.28 (t, J = 7.2 Hz, 4H), 1.96 - 1.92 (m, 2H), 1.64 - 1.47 (m, 14H), 1.41 - 1.24 (m, 52H), 0.89 - 0.86 (m, 12H); ESI-MS m / z: 906.70 [M + H] + 。

[0680] Example 7: Synthesis of Compound 7

[0681]

[0682] Refer to the method of Reference Example 1 to prepare Compound 7, obtaining 42.6 mg of an oily product.

[0683] 1 1H NMR (400 MHz, CDCl3) δ: 5.11 - 5.09 (m, 1H), 4.03 (t, J = 6.8 Hz, 4H), 3.52 (dd, J = 3.2 Hz, 12.4 Hz, 2H), 3.34 - 3.25 (m, 6H), 2.44 - 2.26 (m, 14H), 1.88 - 1.85 (m, 2H), 1.72 - 1.43 (m, 14H), 1.38 - 1.23 (m, 48H), 0.96 - 0.88 (m, 12H); ESI-MS m / z: 878.60 [M + H] + 。

[0684] Example 8: Synthesis of Compound 8

[0685]

[0686] Refer to the method of Reference Example 1 to prepare Compound 8, obtaining 26.8 mg of an oily product.

[0687] 11H NMR (300 MHz, CDCl3) δ: 5.12 - 5.09 (m, 1H), 4.05 (t, J = 6.6 Hz, 4H), 3.53 (dd, J = 3.3 Hz, 12.3 Hz, 2H), 3.37 - 3.21 (m, 6H), 2.54 - 2.39 (m, 6H), 2.29 (t, J = 7.8 Hz, 4H), 1.94 - 1.89 (m, 2H), 1.66 - 1.49 (m, 14H), 1.36 - 1.23 (m, 44H), 0.91 - 0.87 (m, 12H); ESI-MS m / z: 850.65 [M+H] + 。

[0688] Example 9: Synthesis of Compound 9

[0689]

[0690] Referring to the method of Reference Example 1, Compound 9 was prepared to obtain 55.0 mg of an oily product.

[0691] 1 1H NMR (300 MHz, CDCl3) δ: 5.12 - 5.09 (m, 1H), 4.05 (t, J = 6.6 Hz, 4H), 3.53 (dd, J = 3.0 Hz, 12.6 Hz, 2H), 3.32 - 3.24 (m, 6H), 2.51 - 2.26 (m, 12H), 1.89 - 1.85 (m, 2H), 1.66 - 1.47 (m, 12H), 1.41 - 1.22 (m, 40H), 0.90 - 0.85 (m, 12H); ESI-MS m / z: 822.60 [M+H] + 。

[0692] Example 10: Synthesis of Compound 10

[0693]

[0694] Referring to the method of Reference Example 1, Compound 10 was prepared to obtain 50.0 mg of an oily product.

[0695] 1 1H NMR (300 MHz, CDCl3) δ: 5.12 - 5.10 (m, 1H), 4.05 (t, J = 6.9 Hz, 4H), 3.54 (dd, J = 3.3 Hz, 12.3 Hz, 2H), 3.38 - 3.22 (m, 6H), 2.47 - 2.27 (m, 10H), 1.91 - 1.88 (m, 2H), 1.67 - 1.22 (m, 74H), 0.90 - 0.86 (m, 12H); ESI-MS m / z: 962.75 [M+H]+ .

[0696] Example 11: Synthesis of Compound 11

[0697]

[0698] Referring to the method of Reference Example 1, Compound 11 was prepared to obtain 110.9 mg of an oily product.

[0699] 1 H NMR (400 MHz, CDCl3) δ: 8.01 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 5.42 - 5.38 (m, 1H), 5.19 (s, 2H), 4.88 - 4.83 (m, 2H), 3.68 (dd, J = 2.8 Hz, 12.4 Hz, 2H), 3.45 (dd, J = 2.8 Hz, 12.4 Hz, 2H), 3.36 (t, J = 7.2 Hz, 4H), 2.49 (t, J = 7.2 Hz, 4H), 2.34 (s, 6H), 2.25 (t, J = 7.6 Hz, 4H), 1.94 - 1.90 (m, 2H), 1.61 - 1.50 (m, 14H), 1.31 - 1.23 (m, 58H), 0.90 - 0.85 (m, 12H); ESI-MS m / z: 1097.10 [M+H] + .

[0700] Example 12: Synthesis of Compound 12

[0701]

[0702] In a round-bottom flask, 7-bromoheptanoic acid 12-1 (3.0 g, 14.3 mmol, 1.0 eq.), EDCI (4.9 g, 25.7 mmol, 1.8 eq.), and DMAP (0.35 g, 2.86 mmol, 0.2 eq.) were dissolved in 100 mL of dichloromethane. Then, 9-heptadecanol (3.67 g, 14.3 mmol, 1.0 eq.) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 300 mL of saturated sodium chloride aqueous solution to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 5.9 g of Compound 12-2.

[0703] Under nitrogen protection, compound 1-4 (2.0 g, 8.68 mmol, 1.0 eq.) and the reaction solvent NMP (20 mL) were added to the reaction flask. NaH (382 mg, 9.55 mmol, 1.1 eq., 60%) was added in portions. The mixture was stirred at room temperature for 40 min, and then bromide 12-2 (4.27 g, 9.55 mmol, 1.1 eq.) was added. The reaction solution was heated to 65 °C and stirred overnight. After the reaction was completed, it was cooled to room temperature, quenched with 50 mL of ice water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with brine (80 mL × 1). The organic phase was collected, dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain compound 12-3 (800 mg).

[0704] Under nitrogen protection, compound 12-3 (800 g, 1.34 mmol, 1.0 eq.) and the reaction solvent NMP (5 mL) were added to the reaction flask. NaH (59 mg, 1.47 mmol, 1.1 eq., 60%) was added in portions. The mixture was stirred at room temperature for 40 min, and then bromide 1-5 (493 mg, 1.47 mmol, 1.1 eq.) was added. The reaction solution was heated to 65 °C and stirred overnight. After the reaction was completed, it was cooled to room temperature, quenched with 20 mL of ice water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with brine (50 mL × 1). The organic phase was collected, dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain compound 12-4 (600 mg).

[0705] Referring to the method of Reference Example 1, compound 12 was prepared to obtain 65.3 mg of an oily product.

[0706] 1 H NMR (400 MHz, CDCl3) δ: 5.12 - 5.09 (p, J = 3.6 Hz, 1H), 4.85 (p, J = 6.0 Hz, 1H), 4.04 (t, J = 6.8 Hz, 2H), 3.53 (dd, J = 3.2 Hz, 12.0 Hz, 2H), 3.34 - 3.25 (m, 6H), 2.51 - 2.25 (m, 12H), 1.91 - 1.87 (m, 2H), 1.65 - 1.50 (m, 14H), 1.47 - 1.23 (m, 46H), 0.93 - 0.88 (m, 9H); ESI-MS m / z: 850.90 [M + H] + 。

[0707] Example 13: Synthesis of Compound 13

[0708]

[0709] Referring to the method of Reference Example 12, Compound 13 was prepared to obtain 87.9 mg of an oily product.

[0710] 1 H NMR (300 MHz, CDCl3) δ: 5.11 (p, J = 3..6 Hz, 1H), 4.04 (t, J = 6.9 Hz, 4H), 3.53 (dd, J = 3.3 Hz, 12.3 Hz, 2H), 3.38 - 3.22 (m, 6H), 2.50 - 2.26 (m, 11H), 1.94 - 1.90 (m, 2H), 1.71 - 1.23 (m, 60H), 0.92 - 0.87 (m, 9H); ESI-MS m / z: 850.55 [M+H] + 。

[0711] Example 14: Synthesis of Compound 14

[0712]

[0713] Referring to the method of Reference Example 12, Compound 14 was prepared to obtain 81.0 mg of an oily product.

[0714] 1 H NMR (300 MHz, CDCl3) δ: 5.11 (p, J = 3..6 Hz, 1H), 4.85 (p, J = 6.0 Hz, 1H), 4.04 (t, J = 6.9 Hz, 2H), 3.53 (dd, J = 3.3 Hz, 12.6 Hz, 2H), 3.35 - 3.22 (m, 6H), 2.52 - 2.24 (m, 12H), 1.93 - 1.89 (m, 2H), 1.70 - 1.42 (m, 14H), 1.38 - 1.23 (m, 46H), 0.91 - 0.85 (m, 9H); ESI-MS m / z: 850.60 [M+H] + 。

[0715] Example 15: Synthesis of Compound 15

[0716]

[0717] Referring to the method of Reference Example 12, Compound 15 was prepared to obtain 22.8 mg of an oily product.

[0718] 11H NMR (300 MHz, CDCl3) δ: 5.12 (m, 1H), 4.12 (t, J = 6.9 Hz, 4H), 4.11 (t, J = 6.9 Hz, 2H), 3.62 - 3.20 (m, 12H), 2.60 (m, 2H), 2.54 (t, J = 6.9 Hz, 1H), 2.47 (t, J = 6.9 Hz, 1H), 2.32 - 1.98 (m, 14H), 1.68 - 1.25 (m, 47H), 0.89 - 0.86 (m, 9H); ESI-MS m / z: 852.65 [M + H] + 。

[0719] Example 16: Synthesis of Compound 16

[0720]

[0721] Referring to the method of Reference Example 12, Compound 16 was prepared to obtain 35.2 mg of an oily product.

[0722] 1 1H NMR (300 MHz, CDCl3) δ: 5.11 (p, J = 3.6 Hz, 1H), 4.07 - 4.02 (m, 4H), 3.53 (dd, J = 3.0 Hz, 12.3 Hz, 2H), 3.34 - 3.24 (m, 6H), 2.46 - 2.20 (m, 14H), 1.88 - 1.81 (m, 4H), 1.64 - 1.49 (m, 10H), 1.39 - 1.26 (m, 45H), 0.90 - 0.86 (m, 9H); ESI-MS m / z: 836.60 [M + H] + 。

[0723] Example 17: Synthesis of Compound 17

[0724]

[0725] Referring to the method of Reference Example 12, Compound 17 was prepared to obtain 116.2 mg of an oily product.

[0726] 11H NMR (300 MHz, CDCl3) δ: 5.11 (p, J = 3.6 Hz, 1H), 4.05 (t, J = 6.9 Hz, 2H), 3.95 (d, J = 5.7 Hz, 2H), 3.53 (dd, J = 3.3 Hz, 12.3 Hz, 2H), 3.34 - 3.24 (m, 6H), 2.41 - 2.26 (m, 14H), 1.88 - 1.81 (m, 2H), 1.64 - 1.56 (m, 12H), 1.42 - 1.21 (m, 43H), 0.90 - 0.86 (m, 9H); ESI-MS m / z: 836.65 [M+H] + 。

[0727] Example 18: Synthesis of Compound 18

[0728]

[0729] Referring to the method of Reference Example 12, Compound 18 was prepared to obtain 22.0 mg of an oily product.

[0730] 1 1H NMR (300 MHz, CDCl3) δ: 5.11 (p, J = 3.6 Hz, 1H), 4.09 - 4.02 (m, 4H), 3.53 (dd, J = 2.4 Hz, 12.0 Hz, 2H), 3.43 - 3.18 (m, 6H), 2.53 - 2.26 (m, 14H), 1.88 - 1.83 (m, 2H), 1.63 - 1.24 (m, 53H), 0.90 - 0.86 (m, 9H); ESI-MS m / z: 822.70 [M+H] + 。

[0731] Example 19: Synthesis of Compound 19

[0732]

[0733] Referring to the method of Reference Example 12, Compound 19 was prepared to obtain 41.5 mg of an oily product.

[0734] 1 1H NMR (300 MHz, CDCl3) δ: 5.11 (m, 1H), 4.07 - 4.01 (m, 4H), 3.53 (dd, J = 3.0 Hz, 12.3 Hz, 2H), 3.29 - 3.21 (m, 6H), 2.41 - 2.26 (m, 14H), 1.86 - 1.82 (m, 2H), 1.64 - 1.22 (m, 51H), 0.96 - 0.89 (m, 9H); ESI-MS m / z: 808.65 [M+H] + 。

[0735] Example 20: Synthesis of Compound 20

[0736]

[0737] Referring to the method of Reference Example 12, Compound 20 was prepared to obtain 56.4 mg of an oily product.

[0738] 1 H NMR (300 MHz, CDCl3) δ: 5.11 (m, 1H), 4.07 - 4.02 (m, 4H), 3.53 (dd, J = 3.3 Hz, 12.3 Hz, 2H), 3.37 - 3.24 (m, 6H), 2.48 - 2.26 (m, 14H), 1.86 - 1.80 (m, 2H), 1.64 - 1.19 (m, 49H), 0.96 - 0.89 (m, 9H); ESI-MS m / z: 794.65 [M+H] + 。

[0739] Example 21: Synthesis of Compound 21

[0740]

[0741] Referring to the method of Reference Example 12, Compound 21 was prepared to obtain 69.6 mg of an oily product.

[0742] 1 H NMR (300 MHz, CDCl3) δ: 5.11 (m, 1H), 4.05 (t, J = 6.9 Hz, 4H), 3.53 (dd, J = 3.0 Hz, 12.3 Hz, 2H), 3.36 - 3.24 (m, 6H), 2.38 (t, J = 7.5 Hz, 4H), 2.31 - 2.26 (m, 10H), 1.88 - 1.81 (m, 2H), 1.64 - 1.19 (m, 47H), 0.95 - 0.88 (m, 9H); ESI-MS m / z: 780.55 [M+H] + 。

[0743] Example 22: Synthesis of Compound 22

[0744]

[0745] Referring to the method of Reference Example 12, Compound 22 was prepared to obtain 87.8 mg of an oily product.

[0746] 11H NMR (400 MHz, CDCl3) δ: 5.11 (m, 1H), 4.09 - 4.02 (m, 4H), 3.53 (dd, J = 2.8 Hz, 12.4 Hz, 2H), 3.36 - 3.21 (m, 6H), 2.42 - 2.24 (m, 14H), 1.88 - 1.83 (m, 2H), 1.66 - 1.25 (m, 62H), 0.90 - 0.86 (m, 12H); ESI-MS m / z: 906.65 [M+H] + 。

[0747] Example 23: Synthesis of Compound 23

[0748]

[0749] Refer to the method of Reference Example 12 to prepare Compound 23, obtaining 93.9 mg of an oily product.

[0750] 1 1H NMR (400 MHz, CDCl3) δ: 5.11 (m, 1H), 4.03 (dd, J = 6.8 Hz, 12.0 Hz, 4H), 3.53 (dd, J = 2.8 Hz, 12.4 Hz, 2H), 3.33 - 3.25 (m, 6H), 2.38 (t, J = 7.2 Hz, 4H), 2.30 - 2.25 (m, 10H), 1.87 - 1.81 (m, 2H), 1.65 - 1.47 (m, 12H), 1.39 - 1.23 (m, 46H), 0.90 - 0.87 (m, 12H); ESI-MS m / z: 878.65 [M+H] + 。

[0751] Pharmacological Experiments

[0752] Experimental Example 1: Preparation of Nanoparticles

[0753] Materials for lipid nanoparticle assembly include: (1) Ionizable lipid compounds: such as the ionizable lipids designed and synthesized in the present invention; (2) Structural lipids: such as Cholesterol (purchased from Sigma-Aldrich); (3) Phospholipids: such as DSPC which is 1,2-distearoyl-sn-glycero-3-phosphocholine (Distearoylphosphatidylcholine, purchased from AVT); (4) PEGylated lipid compounds: such as DMG-PEG 2000 which is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (purchased from AVT); (5) Active ingredients of nucleic acid fragments: such as Luciferase mRNA, siRNA, CRISPR Cas 9mRNA, etc. (purchased commercially or prepared in-house). The names and structural formulas of the lipid nanoparticle assembly materials are shown in Table 2 in detail.

[0754] Table 2

[0755]

[0756] Preparation method of lipid nanoparticles: (1) Dissolve and mix the ionizable lipid compound, cholesterol, phospholipid, and PEGylated lipid in ethanol in sequence according to (mole percentage) 50%, 38.5%, 10%, and 1.5%; (2) Dissolve the active ingredient of mRNA in 25 mM citrate buffer (pH = 4); (3) Use an automated high-throughput microfluidic system to mix the organic phase containing the lipid mixture and the aqueous phase containing the mRNA component at a flow rate ratio in the range of 1:1 to 1:4, and the mixing speed is 10 - 18 mL / min; (4) Dilute the prepared lipid nanoparticles (N / P = 6) with phosphate buffer solution, and ultrafilter the nanoparticle solution with an ultrafiltration tube with a molecular weight cut-off of 10 kDa (purchased from Millipore) to the original preparation volume; (5) Filter and sterilize the obtained nanoparticle solution through a 0.22 μm sterile filter membrane and store it sealed at low temperature in an EP tube.

[0757] The preparation methods of lipid nanoparticles include, but are not limited to, the microfluidic mixing method, and also include T / Y-type mixers, ethanol injection methods, thin film hydration methods, nanoprecipitation methods, etc.

[0758] Experimental Example 2: Characterization of the physical properties of lipid nanoparticles

[0759] The particle size and particle size distribution coefficient (PDI) of the prepared lipid nanoparticles were measured using a Zetasizer Pro (purchased from Malvern Instruments Ltd) and a DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instrument. The encapsulation degree of RNA by the lipid nanoparticles was characterized by the encapsulation efficiency (Encapsulation Efficiency%), which reflects the binding degree between the lipid nanoparticles and RNA fragments. This parameter was measured by the method of Quant-it TM RiboGreen RNA Assay (purchased from Invitrogen). 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 taken and 0.5% Triton X-100 was added, and it was left standing at 37 °C for 30 minutes. After adding the reaction solution, the fluorescence value was immediately read on a Varioskan LUX multimode microplate reader (purchased from Thermofisher) at an absorption wavelength of 485 nm and an emission wavelength of 528 nm to obtain the encapsulation rate value.

[0760] Experimental Example 3: Animal Experiment

[0761] The delivery effect and safety of nanoparticles encapsulating luciferase mRNA (Trilink, L-7202) in mice were evaluated. The test mice were SPF-grade C57BL / 6 mice, female, 6-8 weeks old, weighing 18-22 g, purchased from Beijing Speyford Biotechnology Co., Ltd. All animals were acclimated for more than 7 days before the experiment, and were allowed to eat and drink freely during the experiment. The light was alternated between light and dark for 12 / 12 h, the indoor temperature was 20-26 °C, and the humidity was 40-70%.

[0762] The mice were randomly grouped, and the prepared lipid nanoparticles encapsulating luciferase mRNA were injected into the mice by intramuscular injection at a single dose of 0.1 mg / kg mRNA (the dosage of the lipid nanoparticles encapsulating luciferase mRNA prepared with lipid molecules 1-4 and SM102 (purchased from AVT) was 0.5 mg / kg mRNA) (n = 3). At 6 hours after administration, in vivo bioluminescence detection of the mice was performed using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer).

[0763] The specific operation steps for detection are as follows: Prepare a D-luciferin solution with a concentration of 20 mg / mL using phosphate buffer, and administer the substrate to each mouse by intraperitoneal injection at a dose of 0.1 mL. Nine minutes after administering the substrate, place the mouse in an anesthesia chamber and anesthetize it with isoflurane at a concentration of 2.5%. Place the anesthetized mouse supine in the IVIS, perform fluorescence imaging, and collect and analyze data on the sites where fluorescence is concentrated.

[0764] The in vivo delivery efficiency of the lipid nanoparticle carrier to different organs is represented by the fluorescence intensity and total photon count of different animals within the same test group, as shown in Table 3. The data indicate that the lipid nanoparticles containing the ionizable lipid compound of the present invention have good in vivo muscle-specific delivery efficiency.

[0765] Table 3

[0766]

[0767] Although the present invention has been fully described by its embodiments, it should be noted 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: Wherein, Z is CH; n1 and n2 are independently 1; G1 and G2 are independently selected from C 4-14 alkylene, C 4-14 alkenylene and C 4-14 alkynylene, which is optionally substituted by one or more R G1 substituents; R G1 independently selected from H, C 1-14 alkyl, -L a -OR a , -L a -SR a and -L a -NR a R' a ; L a independently selected from a chemical bond and C 1-14 alkylene; R a and R' a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group; G3 is a chemical bond or -L-C 0-4 an alkylene group -Y-, where Y is connected to Q; L is selected from a chemical bond, -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; Y is selected from C 6-10 arylene and 5- to 10-membered heteroarylene; G4 is selected from a chemical bond, C 1-6 an alkylene group, C 2-6 an alkenylene group, and C 2-6 an alkynylene group, which is optionally substituted by one or more R G4 substituents; R G4 independently selected from H, C 1-6 alkyl, -L b -OR b , -L b -SR b and -L b -NR b R' b ; L b independently selected from a chemical bond and C 1-6 alkylene; R b and R' b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, and a 3- to 10-membered heterocyclic group; or two Rs attached to the same carbon atom G4 together with the carbon atom to which they are attached form a C 3-14 subcycloalkyl or 3- to 14-membered heterocycloalkyl, which is optionally substituted by one or more Rs 4g substituted; R 4g independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e 、-L e -SR e and -L e -NR e R' e ; L e independently selected from a chemical bond and C 1-8 alkylene; R e and R' e are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group; Q is selected from a chemical bond, -C(O)O- and -C(O)S-; preferably -C(O)O-; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -C(O)NR-, -NRC(O)- and -OC(O)O-; 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 substituents, and one or more of the methylene units therein are optionally and independently replaced by -NR'-; R s independently selected from H, C 1-20 alkyl, -L c -OR c , -L c -SR c and -L c -NR c R′ c ; R and R' are each independently selected from H and C 1-20 alkyl; L c independently selected from a chemical bond and C 1-20 alkylene; R c and R' c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl, and a 3- to 14-membered heterocyclic group; R3 is -NR d R' d ; R d and R' d are independently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic groups.

2. The compound of claim 1, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, n1 and n2 are independently 0 or 1, preferably 1.

3. A compound according to claim 1 or 2, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G1 and G2 are independently selected from C 4-10 alkylene, C 4-10 alkenylene and C 4-10 alkynylene; preferably C 5-8 alkylene, C 5-8 alkenylene and C 5-8 alkynylene; preferably C 4-10 alkylene, preferably C 5-8 alkylene, preferably C 6-7 alkylene; Preferably, G1 and G2 are optionally substituted by 1, 2, 3 or 4 Rs G1 substituted.

4. A compound according to any one of claims 1-3, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R G1 independently selected from H and C 1-10 alkyl; preferably H and C 1-6 alkyl; Preferably, L a is independently selected from a chemical bond and C 1-10 alkylene; preferably a chemical bond and C 1-6 alkylene; Preferably, R a and R' a are independently selected from H, C 1-10 alkyl (preferably C 1-6 alkyl), C 3-7 cycloalkyl, and 3- to 7-membered heterocyclic groups; preferably H and C 1-10 alkyl; preferably H and C 1-6 alkyl.

5. A compound according to any one of claims 1-4, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G3 is a chemical bond or -L-C 1-3 an alkylene -Y-, where Y is linked to Q; preferably a chemical bond; Preferably, L is selected from a chemical bond, -C(O)O- and -C(O)S-; preferably -C(O)O- and -OC(O)-; preferably -C(O)O-; Preferably, Y is selected from C 6-10 arylene and 5- to 10-membered heteroarylene; preferably phenylene and 5- to 6-membered heteroarylene; preferably phenylene.

6. A compound according to any one of claims 1-5, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G4 is selected from C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene; preferably C 2-4 alkylene; preferably C 2-3 alkylene; preferably C 3-4 alkylene; Preferably, G4 is optionally substituted by 1, 2, 3 or 4 R G4 groups.

7. A compound according to any one of claims 1-6, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R G4 independently selected from H and C 1-6 alkyl; preferably H and C 1-4 alkyl; Preferably, L b is independently selected from a chemical bond and C 1-3 alkylene; Preferably, R b and R' b are independently H, C 1-6 alkyl, C 3-7 cycloalkyl, and a 3- to 7-membered heterocyclic group; preferably H and C 1-3 alkyl; Preferably, two Rs attached to the same carbon atom G4 together with the carbon atom to which they are attached form a C 3-10 subcycloalkyl or a 3- to 10-membered heterocycloalkylidene, preferably forming a C 3-7 subcycloalkyl or a 3- to 7-membered heterocycloalkylidene, which is optionally substituted by 1, 2 or 3 Rs 4g substituted; Preferably, R 4g is independently selected from H, halogen, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; Preferably, L e is independently selected from a chemical bond and C 1-6 alkylene; preferably a chemical bond and C 1-3 alkylene; Preferably, R e and R' e are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and 3- to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl; preferably H and C 1-3 alkyl.

8. A compound according to any one of claims 1 - 7, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Q is selected from -C(O)O- and -C(O)S-; preferably -C(O)O-; Preferably, when Q is phenylene or pyridinylene, it is optionally substituted by 1, 2 or 3 R*; Preferably, R* is independently selected from H, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl; Preferably, L f is independently selected from a chemical bond and C 1-6 alkylene; preferably a chemical bond and C 1-4 alkylene; Preferably, R f and R' f are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and 3- to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl; preferably H and C 1-4 alkyl.

9. A compound according to any one of claims 1-8, 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-, -OC(O)-, -SC(O)-, -C(O)S-, -C(O)NR-, -NRC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -C(O)S-; preferably -C(O)O- and -OC(O)-; preferably -C(O)O-; preferably -OC(O)-; Preferably, M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -C(O)S-; preferably -C(O)O- and -OC(O)-; preferably -OC(O)-; preferably -C(O)O-; M2 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O- and -C(O)S-; preferably -OC(O)- or -SC(O)-; preferably -C(O)O- and -OC(O)-; preferably -OC(O)-; preferably -C(O)O-; preferably -OC(O)O-; Preferably, M1 is -C(O)O-; M2 is -OC(O)-; Preferably, M1 is -OC(O)-; M2 is -C(O)O-; Preferably, M1 is -C(O)O-; M2 is -C(O)O-; Preferably, M1 is -OC(O)-; M2 is -OC(O)-; Preferably, M1 is -OC(O)O-; M2 is -OC(O)-.

10. A compound according to any one of claims 1-9, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R1 and R2 are independently selected from C 6-14 alkyl, C 6-14 alkenyl and C 6-14 alkynyl; preferably C 6-14 alkyl; preferably C 8-12 alkyl; preferably C 8-10 alkyl; preferably C 8-9 alkyl; preferably C9 alkyl; preferably C 6-14 linear alkyl; preferably C 8-12 linear alkyl; preferably C 8-10 linear alkyl; preferably C 8-9 linear alkyl, preferably C8 linear alkyl, preferably C9 linear alkyl. Preferably, R1 and R2 are optionally substituted by 1, 2 or 3 R s substitutions, preferably optionally substituted by 1 R s substitution; Preferably, R1 and R2 are independently selected from a C8 straight-chain alkyl group, a C9 straight-chain alkyl group, Preferably, at least one of R1 and R2 is substituted by R s substituted; Preferably, both R1 and R2 are replaced by R s substituted; Preferably, R1 is substituted by R s and R2 is unsubstituted; Preferably, R1 is unsubstituted and R2 is substituted by R s substituted.

11. A compound according to any one of claims 1 - 10, 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 c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl; preferably C 1-12 alkyl; preferably C 1-10 alkyl; preferably C 2-9 alkyl; preferably C 4-9 alkyl; preferably C 7-9 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 3-7 alkyl; preferably C 1-6 alkyl; preferably C 4-6 alkyl or C8 alkyl; preferably C8 alkyl; Preferably, L c is independently selected from a chemical bond and C 1-14 alkylene (preferably C 1-12 alkylene, preferably C 1-10 alkylene, preferably C 1-8 alkylene, preferably C 1-6 alkylene); R c and R' c are independently selected from H, C 1-14 alkyl, C 3-7 cycloalkyl, and 3- to 7-membered heterocyclic groups; preferably H and C 1-14 alkyl (preferably C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 1-8 alkyl, preferably C 1-6 alkyl).

12. A compound according to any one of claims 1-11, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R and R' are each independently selected from H and C 1-20 alkyl; preferably H and C 1-14 alkyl; preferably H and C 1-9 alkyl; preferably H and C 1-6 alkyl; preferably R is H.

13. A compound according to any one of claims 1-12, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from CN, -OR d and -NR d R' d ; preferably -OR d and -NR d R′ d ; preferably -OR d ; preferably OH; Preferably, R3 is selected from OH and -N(CH3)2; preferably -N(CH3)2; Preferably, R d and R' d are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and 3- to 7-membered heterocyclic group; preferably H and C 1-6 alkyl; preferably selected from H and C 1-4 alkyl; preferably H and Me.

14. A compound according to any one of claims 1-13, 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 0-2 carbon atoms; preferably 0 carbon atoms; preferably 1 carbon atom; preferably 2 carbon atoms; preferably 3 carbon atoms; preferably 4 carbon atoms; preferably 5 carbon atoms; Preferably, R s The substitution site on R1 or R2 is spaced from M1 or M2 by 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, preferably 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, preferably 2 to 5 carbon atoms, preferably 2 to 4 carbon atoms.

15. A compound according to any one of claims 1 - 14, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (Ⅱ) or formula (Ⅲ): Wherein, a = 1, 2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 4, 5, 6, 7, 8, 9 or 10; The remaining variables are as defined in any one of claims 1 - 15.

16. A compound according to claim 15, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (Ⅱ): Wherein, R d and R' d are each independently C 1-6 alkyl; a = 2, 3, 4, 5 or 6; b = 4, 5, 6, 7 or 8; c = 4, 5, 6, 7 or 8; M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; M2 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; R1 and R2 are independently C 6-14 alkyl, which is optionally substituted by 1, 2 or 3 R s substituents; R s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl; L c independently selected from a chemical bond and C 1-14 alkylene; R c and R' c are independently selected from H and C 1-14 alkyl; Preferably, M1 and M2 are not both -OC(O)O- at the same time.

17. A compound according to claim 16, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R d and R' d independently is C 1-3 alkyl; preferably methyl; a = 2, 3 or 4; preferably a = 3; b = 5, 6, 7 or 8; preferably b = 6 or 7; c = 5, 6, 7 or 8; preferably c = 6 or 7; M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)- and -OC(O)O-; M2 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 8-12 alkyl, preferably C 8-10 alkyl, preferably C 8-9 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s substituents; R s independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 1-8 alkyl, preferably C 3-8 alkyl; Preferably, R1 and R2 are independently selected from a C8 straight-chain alkyl group, a C9 straight-chain alkyl group, Preferably, at least one of R1 and R2 is substituted by R s substituted.

18. A compound according to claim 15 or 16, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (Ⅱ): Wherein, R d and R' d are independently C 1-6 alkyl; a = 2, 3, 4, 5 or 6; b = 4, 5, 6, 7 or 8; c = 4, 5, 6, 7 or 8; M1 and M2 are independently -C(O)O- or -C(O)S-; R1 and R2 are independently C 6-14 alkyl, which is optionally substituted by 1, 2 or 3 R s substituents; R s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl; L c independently selected from a chemical bond and C 1-14 alkylene; R c and R' c are independently selected from H and C 1-14 alkyl groups.

19. A compound according to claim 18, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R d and R' d are independently C 1-3 alkyl; a = 2, 3 or 4; preferably a = 3; b = 5, 6, 7 or 8; preferably b = 6 or 7; c = 5, 6, 7 or 8; preferably c = 6 or 7; M1 and M2 are independently -C(O)O- or -C(O)S-; preferably -C(O)O-; R1 and R2 are independently C 8-12 alkyl, preferably C 8-10 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s substituents; R s independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 2-9 alkyl; Preferably, at least one of R1 and R2 is substituted by R s substituted.

20. A compound according to claim 18 or 19, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R d and R' d are methyl; a＝3； b = 6 or 7; preferably b = 6; c = 6 or 7; preferably c = 6; M1 and M2 are -C(O)O-; R1 and R2 are independently C 8-9 alkyl, preferably C9 alkyl, which is optionally substituted by one R s substituent; R s independently C 1-8 alkyl, preferably C 3-8 alkyl; Preferably, R1 and R2 are independently selected from C9 linear alkyl groups, Preferably, at least one of R1 and R2 is substituted by R s substituted.

21. The compound of claim 15 or 16, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (II): Wherein, R d and R' d are independently C 1-3 alkyl; preferably methyl; a = 2, 3 or 4; preferably a = 3; b = 5, 6 or 7; preferably b = 6; c = 5, 6 or 7; preferably c = 6; M1 and M2 are -C(O)O-; R1 is C 8-10 alkyl, preferably C9 alkyl, which is optionally substituted by one R s substitution; preferably R1 is substituted by one R s substitution; R2 is C 8-10 a straight-chain alkyl group, preferably a C9 straight-chain alkyl group; R s independently C 1-8 alkyl, preferably C 3-8 alkyl, preferably C 4-6 alkyl or C8 alkyl; Preferably, R1 is selected from a C9 linear alkyl group, Preferably 22. The compound of claim 15 or 16, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (II): Wherein, R d and R' d are independently C 1-3 alkyl; preferably methyl; a = 2, 3 or 4; preferably a = 3; b = 5, 6 or 7; preferably b = 6; c = 5, 6 or 7; preferably c = 6; M1 and M2 are -C(O)O-; R1 is C 8-10 alkyl, preferably C9 alkyl, which is substituted by one R s substituent; R2 is C 8-10 alkyl, preferably C9 alkyl, which is substituted by one R s substituent; R s independently C 1-8 alkyl, preferably C 3-8 alkyl, preferably C 4-8 alkyl; preferably C 3-7 alkyl; Preferably, R1 and R2 are independently selected from Preferably 23. The compound of claim 15 or 16, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (II): Wherein, R d and R' d are each independently C 1-6 alkyl; a = 2, 3, 4, 5 or 6; b = 4, 5, 6, 7 or 8; c = 4, 5, 6, 7 or 8; M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; M2 is -OC(O)-, -C(O)O-, -SC(O)-, -SC(O)- or -OC(O)O-; preferably -OC(O)- or -SC(O)-; R1 and R2 are independently C 6-14 alkyl, which is optionally substituted by 1, 2 or 3 R s substituents; R s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl; L c independently selected from a chemical bond and C 1-14 alkylene; R c and R' c are independently selected from H and C 1-14 alkyl; Preferably, at least one of R1 and R2 is substituted by R s substituted; Preferably, M1 and M2 are not both -OC(O)O- at the same time.

24. The compound of claim 23, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R d and R' d are independently C 1-3 alkyl; a = 2, 3 or 4; b = 5, 6 or 7; c = 5, 6 or 7; M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -OC(O)- and -OC(O)O-; M2 is -OC(O)- or -SC(O)-; preferably -OC(O)-; R1 and R2 are independently C 8-12 alkyl, preferably C 8-10 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s substituents; R s independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 4-9 alkyl; Preferably, at least one of R1 and R2 is substituted by R s ; Preferably, M1 is -C(O)O-; M2 is -OC(O)-; R1 is C 8-12 alkyl, preferably C 8-10 alkyl, which is substituted by one R s substituent; R2 is C 8-12 a straight-chain alkyl group, preferably C 8-10 a straight-chain alkyl group; R s independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 7-9 alkyl; Preferably, M1 is -OC(O)O-; M2 is -OC(O)-; R1 is C 6-14 a straight-chain alkyl group, C 8-12 a straight-chain alkyl group, preferably C 8-10 a straight-chain alkyl group; R2 is C 6-14 alkyl, C 8-12 alkyl, preferably C 8-10 alkyl, which is substituted by one R s substituted; R s independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 7-9 alkyl.

25. The compound of claim 23 or 24, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R d and R' d are methyl; a＝3； b＝6； c＝6； M1 is selected from -C(O)O-, -OC(O)- and -OC(O)O-; M2 is -OC(O)- or -C(O)O-; preferably -OC(O)-; R1 and R2 are independently C 8-9 alkyl, which is optionally substituted by one R s substituent; R s independently C 1-8 alkyl, preferably C 5-8 alkyl; Preferably, R1 and R2 are independently selected from C8 straight-chain alkyl, C9 straight-chain alkyl, Preferably, at least one of R1 and R2 is substituted by R s substituted; Preferably, M1 is -C(O)O-; M2 is -OC(O)-; R1 is C 8-9 alkyl, preferably C9 alkyl, which is substituted by one R s substituent; R2 is C 8-9 a straight-chain alkyl group, preferably a C9 straight-chain alkyl group; R s independently C 1-8 alkyl, preferably C8 alkyl; Preferably, M1 is -OC(O)O-; M2 is -OC(O)-; R1 is C 8-9 a straight-chain alkyl group, preferably a C8 straight-chain alkyl group; R2 is C 8-9 alkyl, preferably C9 alkyl, which is substituted by one R s substituent; R s independently C 1-8 alkyl, preferably C8 alkyl.

26. The compound of claim 23, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R d and R' d are independently C 1-3 alkyl; preferably methyl; a = 2, 3 or 4; preferably a = 3; b = 5, 6 or 7; preferably b = 6; c = 5, 6 or 7; preferably c = 6; M1 is -C(O)O- or -OC(O)-; preferably -OC(O)-; M2 is -OC(O)-; R1 is C 8-10 alkyl, preferably C9 alkyl, which is substituted by one R s substituent; R2 is C 8-10 alkyl, preferably C9 alkyl, which is substituted by one R s substituent; R s independently C 6-8 alkyl; Preferably, R1 and R2 are independently selected from The compound of claim 15, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (III): Wherein, R d and R' d are each independently C 1-6 alkyl; a = 2, 3, 4, 5 or 6; b = 4, 5, 6, 7 or 8; c = 4, 5, 6, 7 or 8; M1 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -C(O)S-; M2 is selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; preferably -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-; preferably -C(O)O- and -C(O)S-; R1 and R2 are independently C 6-14 alkyl, which is optionally substituted by 1, 2 or 3 R s substituents; R s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably H and C 1-14 alkyl; L c independently selected from a chemical bond and C 1-14 alkylene; R c and R' c are independently selected from H and C 1-14 alkyl; Preferably, both R1 and R2 are substituted by R s substituted; Preferably, M1 and M2 are not both -OC(O)O-. The compound of claim 27, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R d and R' d are independently C 1-3 alkyl; preferably methyl; a = 2, 3 or 4; preferably a = 3; b = 5, 6 or 7; preferably b = 6; c = 5, 6 or 7; preferably c = 6; M1 and M2 are independently -C(O)O- or -C(O)S-; preferably -C(O)O-; R1 and R2 are independently C 8-12 alkyl, preferably C 8-10 alkyl, which is optionally substituted by 1, 2 or 3 (preferably 1) R s substituents; R s independently C 1-12 alkyl, preferably C 1-10 alkyl; Preferably, both R1 and R2 are replaced by R s substituted.

29. A compound according to any one of claims 16 - 28, 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 0-6 carbon atoms, preferably 0-5 carbon atoms, preferably 0 carbon atoms; preferably 1 carbon atom; preferably 2 carbon atoms; preferably 3 carbon atoms; preferably 4 carbon atoms; preferably 5 carbon atoms.

30. The compound of claim 1, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the following structures:

31. A nanoparticle composition comprising a lipid component and optionally a payload; wherein, The lipid component contains the compound of any one of claims 1-30, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; Preferably, the lipid component contains the following components in mole percentages: The compound of any one of claims 1-30: 20 mol% - 85 mol%; Structural lipid: 10 mol% - 75 mol%; Neutral lipid: 1.0 mol% - 30 mol%; Polymeric lipid: 0.25 mol% - 10 mol%; Preferably, the lipid component contains the following components in mole percentages: The compound of any one of claims 1-30: 50 mol%; Neutral lipid: 10 mol%; Structural lipid: 38.5 mol%; Polymeric lipid: 1.5 mol%.

32. A pharmaceutical composition comprising the compound of any one of claims 1-30, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of claim 31, and a pharmaceutically acceptable excipient.

33. Use of the compound of any one of claims 1-30, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of claim 31, or the pharmaceutical composition of claim 32 in the preparation of a drug for the treatment, diagnosis or prevention of a disease; Preferably, the drug for the treatment, diagnosis or prevention of a disease is a nucleic acid drug; Preferably, the drug for the treatment, diagnosis or prevention of a disease is a gene editing drug; Preferably, the disease is a disease related to muscle dysfunction; Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA or DNA; Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA) or ribozyme, preferably mRNA, siRNA, gRNA, modified mRNA, preferably guide RNA (gRNA), mRNA, modified mRNA, more preferably modified mRNA and / or guide RNA (gRNA); Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multi-copy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

34. Use of a compound according to any one of claims 1-30, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of claim 31, or the pharmaceutical composition of claim 32 in the preparation of a drug for delivering a payload, wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; Preferably, the drug is a drug for delivering a payload to muscle; Preferably, the payload is a gene editing drug.

35. A method for treating, diagnosing or preventing a disease in a subject, comprising administering to the subject the nanoparticle composition of claim 31, or the pharmaceutical composition of claim 32; Preferably, the method for treating, diagnosing or preventing a disease is gene editing; Preferably, the disease is a muscle dysfunction-related disease.

36. A compound according to any one of claims 1-30, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition of claim 31, or the pharmaceutical composition of claim 32, for treating, diagnosing or preventing a disease; preferably for gene editing; Preferably, the disease is a muscle dysfunction-related disease.

37. A method for delivering a payload to a subject, comprising administering to the subject the nanoparticle composition of claim 31, or the pharmaceutical composition of claim 32; Among them, The payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; Preferably, the method is a method for delivering a payload to the muscle of a subject.

38. The method according to claim 35 or 37, wherein the administration comprises any one or a combination of topical administration and systemic administration; Preferably, the administration comprises intramuscular injection, intravenous injection, intraperitoneal injection or arterial injection, preferably intramuscular injection.

39. A compound according to any one of claims 1-30, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the nanoparticle composition according to claim 31, or the pharmaceutical composition according to claim 32, for delivering a payload; Among them, The payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; Preferably, for delivering the payload to muscle. The nanoparticle composition of claim 31, or the use of claim 34, or the method of claim 37 or 38, or the compound or pharmaceutical composition or nanoparticle composition of claim 39, wherein, The therapeutic agent, prophylactic agent or diagnostic agent is a nucleic acid; Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA or DNA; Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multi-coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA) or ribozyme, preferably mRNA, siRNA, gRNA or modified mRNA, preferably guide RNA (gRNA), mRNA and / or modified mRNA, more preferably modified guide RNA (gRNA) and / or mRNA; Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multi-copy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

41. 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 each variable is defined as in any one of claims 1-30.

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