Lung-targeting lipid compound

Abstract

Provided is a lung-targeting lipid compound, specifically relating to a compound as shown in formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Also provided are a nanoparticle pharmaceutical composition comprising the compound, and a use of the compound and the composition thereof in lung targeted delivery of nucleic acids.

Description

Lung-targeting lipid compounds

[0001] This application claims priority to Chinese application 202411186955.0 filed on August 27, 2024, which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to a class of lung-targeting lipid compounds, or isotopic variants, tautomers, or stereoisomers thereof, or pharmaceutically acceptable salts thereof. The invention also relates to lipid nanoparticles comprising said compounds and pharmaceutical compositions, and the use of said lipid nanoparticles in the lung-targeted delivery of bioactive substances such as nucleic acids (e.g., mRNA, siRNA, ASO, DNA, etc.). Background Technology

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

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

[0005] Lung-related diseases pose a significant threat to human health, including COVID-19, influenza, cystic fibrosis, primary ciliary dyskinesia, alpha-1 antitrypsin deficiency, asthma, and lung cancer. However, traditional therapies often fail to cure these diseases due to limitations such as the lack of druggable therapeutic targets. With the development of various key technologies, nucleic acid drugs can not only treat diseases directly at the transcriptional level, but also rapidly develop new drugs simply by modifying the sequence of nucleic acid molecules, providing a completely new approach to curing lung diseases. However, current LNP delivery systems tend to accumulate in the liver; therefore, there is an urgent need to design LNPs for targeted delivery of nucleic acid molecules to the lungs. Summary of the Invention

[0006] This invention develops a class of lung-targeting lipid compounds that can be used to deliver various bioactive substances and have high lung-targeting delivery efficiency.

[0007] This invention provides compounds of formula (I), or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0008] Wherein, each group is as defined in this invention.

[0009] In another aspect, the present invention provides a nanoparticle composition comprising a lipid component and optionally a loading; wherein the lipid component contains a compound of the present invention.

[0010] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention or the nanoparticle compositions of the present invention, and optionally pharmaceutically acceptable excipients, such as carriers, adjuvants, or mediators.

[0011] In another aspect, the present invention provides the use of the compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention in the preparation of medicaments for treating, diagnosing, or preventing diseases. In one embodiment, the medicament for treating, diagnosing, or preventing diseases is a therapeutic or prophylactic mRNA vaccine.

[0012] In another aspect, the present invention provides the use of the compounds of the present invention, the nanoparticle compositions of the present invention, or the pharmaceutical compositions of the present invention in the preparation of a medicament for delivery of a loading.

[0013] In another aspect, the present invention provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0014] In another aspect, the present invention provides compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for the treatment, diagnosis, and / or prevention of diseases.

[0015] In another aspect, the present invention provides a method for delivering a payload to a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0016] In another aspect, the present invention provides compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for delivering payloads.

[0017] In a specific implementation, the application includes any one or a combination of local administration and systemic administration;

[0018] In a more specific embodiment, the administration includes inhalation, intravenous injection, arterial injection, or intraperitoneal injection, more preferably intravenous injection.

[0019] In a specific implementation plan, the drug used for treating, diagnosing, or preventing diseases is a nucleic acid.

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

[0021] In a more specific embodiment, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA, or DNA.

[0022] In a more specific embodiment, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified mRNA, long noncoding 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 ribozymes, preferably mRNA, siRNA, gRNA, or modified mRNA, more preferably modified mRNA.

[0023] In a more specific embodiment, 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), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0024] definition

[0025] Chemical definition

[0026] The definitions of specific functional groups and chemical terms are described in more detail below.

[0027] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C2-6 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.

[0028] “C 1-20 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. In some embodiments, C 4-20 Alkyl, C 8-20 Alkyl, C 1-14 Alkyl, C 2-14 Alkyl, C 4-14 Alkyl, C 6-14 Alkyl, C 1-13 Alkyl, C 1-12 Alkyl, C 4-12 Alkyl, C 6-12 Alkyl, C 7-12 Alkyl, C 8-12 Alkyl, C 9-12 Alkyl, C 7-11 Alkyl, C 8-11 Alkyl, C 9-11 Alkyl, C 10-11 Alkyl, C 11 Alkyl, C 1-10 Alkyl, C 4-10 Alkyl, C 5-10 Alkyl, C 6-10 Alkyl, C 7-10 Alkyl, C 8-10 Alkyl, C 9-10 Alkyl, C 10 Alkyl, C 1-9 Alkyl, C 3- 9-alkyl, C 4-9 Alkyl, C 5-9 Alkyl, C 6-9 Alkyl, C 7-9 Alkyl, C 8-9 Alkyl, C9 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 1-7 Alkyl, C 2-7 Alkyl, C 3-7 Alkyl, C 4-7 Alkyl, C 5-7Alkyl, C 6-7 Alkyl, C7 alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 4-6 Alkyl, C 5-6 Alkyl, C6 alkyl, C 1-5 Alkyl, C 4-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 Alkyl groups and Me are preferred. C 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "alkyl" also includes heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, the alkyl group is preferably a straight-chain alkyl group. For example, C 4-12 straight-chain alkyl, C 4-10 straight-chain alkyl, C 4-8 Straight-chain alkyl, C6 straight-chain alkyl.

[0029] “C 2-14 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 14 carbon atoms and at least one carbon-carbon double bond. 4-20 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-14 alkenyl, C 6-14 alkenyl, C 7-12 alkenyl, C 2-10 alkenyl, C 4-10 alkenyl, C 2-9 alkenyl, C 2-8 alkenyl, C 2-6 alkenyl and C 2-4 Alkenyl groups are preferred. C 2-6Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl group is preferably a straight-chain alkenyl group.

[0030] “C 2-14 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 14 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 4-20 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 4 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4-14 alkynyl group, C 6-14 alkynyl group, C 7-12 alkynyl group, C 2-10 alkynyl group, C 4-10 alkynyl group, C 2-9 alkynyl group, C 2-8 alkynyl group, C 2-6 alkynyl group and C 2-4 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkynyl is preferably a straight-chain alkynyl.

[0031] “C 1-20 "Alkylene" refers to the removal of C 1-20 The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 4-20 Alkylene, C 1-14 Alkylene, C 4-14 Alkylene, C 6-14 Alkylene, C 7-12 Alkylene, C 8-12 Alkylene, C4-10 Alkylene, C 7-11 Alkylene, C 8-11 Alkylene, C 8-10 Alkylene, C 9-10 Alkylene, C 1-9 Alkylene, C 4-9 Alkylene, C 6-9 Alkylene, C 7-9 Alkylene, C 8-9 Alkylene, C9 alkylene, C 1-8 Alkylene, C 2-8 Alkylene, C 5-8 Alkylene, C 7-8 Alkylene, C 4- 6-alkylene, C 1-20 Alkylene, C 1-14 Alkylene, C 2-14 Alkylene, C 1-13 Alkylene, C 1-12 Alkylene, C 1-10 Alkylene, C 1-7 Alkylene, C 2-7 Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C6 alkylene, C 1-5 Alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4 Alkylene, C 2-4 Alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1-2 Alkylenes and methylene groups are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0032] “C 2-14 "Alkenyl" refers to the group that has been de-carbonied. 2-114 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 4-14 imidene group, C 6-14 imidene group, C 2-10 imidene group, C 4-10 imidene group, C 2-8 imidene group, C 2-9 imidene group, C 2-6 imide and C 2-4 Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0033] “C 2-14 "Iso-ynyl group" refers to the group with the C group removed. 2-14 The other hydrogen atom of the alkynyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 4-14 Ethyne group, C 6-14 Ethyne group, C 2-10 Ethyne group, C 4-10 Ethyne group, C 2-8 Ethyne group, C 2-9 Ethyne group, C 2-6 etyne and C 2-4 The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0034] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene", "C" 0-4 "alkylene" refers to chemical bonds and the aforementioned "C" 1-4 "Alkylene". The same logic applies to other similar cases.

[0035] The term "the total length of variables A and B is x carbon atoms" means that the sum of the number of carbon atoms in the main chain of the group represented by variable A and the number of carbon atoms in the main chain of the group represented by variable B is x.

[0036] The term "R" s "x carbon atoms are spaced between the substitution site on R1 and M1" indicates that the variable R1 is affected by the variable R. s The sum of the number of carbon atoms (including N atoms replaced by -NR'-) between the substitution site and M1, and so on for other cases. For example:

[0037] In compound 1, R s The substitution site on R1 is separated from M1 by two carbon atoms.

[0038] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0039] Therefore, "C" 1-10 "Halogenated alkyl" refers to the above "C 1-10 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-8 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Haloalkyl groups, such as halomethyl groups. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The haloalkyl group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0040] “C 3-14"Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl, and 3- to 6-membered cycloalkyl are particularly preferred, more preferably 5- to 7-membered cycloalkyl, 4- to 6-membered cycloalkyl, 3- to 5-membered cycloalkyl, 3- to 4-membered cycloalkyl, and 5- to 6-membered cycloalkyl, more preferably 5-membered cycloalkyl, more preferably 6-membered cycloalkyl, and more preferably cyclopropyl. Cycloalkyl also includes a cyclic system in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system. Cycloalkyl also includes a cyclic system in which the aforementioned cycloalkyl ring, Substituents on any non-adjacent carbon atoms are linked together to form a bridged ring, forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups also include the aforementioned cycloalkyl rings, where substituents on the same carbon atom are linked together to form a ring, forming a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0041] “C 3-14 "Cycloalkylene" refers to the alkylene group after removing C24. 3-14 The cycloalkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 3-10 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene compounds are particularly preferred. Examples include cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, with cyclopropylene being especially preferred.

[0042] "3-14 membered heterocyclic group" or "3 to 14 membered heterocyclic group" refers to a saturated or unsaturated group having a 3 to 14 membered non-aromatic ring system with a cyclic carbon atom and 1 to 5 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 1, 2, or 3 double or triple bonds. In heterocyclic groups containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. In some embodiments, a 3- to 10-membered heterocyclic group is preferred, which is a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 5- to 10-membered heterocyclic group is preferred, which is a 5- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3- to 8-membered heterocyclic group is preferred, which is a 3- to 8-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; in some embodiments, a 3- to 7-membered heterocyclic group is preferred, which is a 3- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; preferably, a 5- to 7-membered heterocyclic group is preferred, which is a 3- to 10-membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms. A 5- to 7-membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 3- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 4- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; more preferably a 5- to 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 5-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; preferably a 6-membered heterocyclic group having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the heterocyclic ring; or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on the same carbon atom are linked to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolyl, dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclic groups also include those that share one or two atoms with a cycloalkyl, heterocyclic, aryl, or heteroaryl group to form a bridged or spirocyclic ring, wherein the shared atom may be a carbon or nitrogen atom, provided that the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] "3-14 membered heterocyclic group" refers to a divalent group formed by removing another hydrogen atom from a 3-14 membered heterocyclic group, and can be substituted or unsubstituted. In some embodiments, 3-10 membered heterocyclic groups, 3-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, 3-5 membered heterocyclic groups, and 3-4 membered heterocyclic groups are particularly preferred.

[0044] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10"Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0045] "5-14 membered heteroaryl" or "5 to 14 membered heteroaryl" refers to a 4n+2 aromatic ring system of a 5-14 membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6, 10, or 14 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryls containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryls also include ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryls are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having a ring carbon atom and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl or pyridoneyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, oxadiazinyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0046] "Hydroxyalkyl" refers to an alkyl group that has been replaced by one or more hydroxyl groups.

[0047] "Alkoxy" refers to the oxyether form of a straight-chain or branched alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0048] "Optionally replaced by..." means that it can be replaced by a specified substituent or not replaced.

[0049] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0050] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0051] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb OR aa -OC(=NR) bb )R aa -OC(=NR) bb OR aa -C(=NR) bb )N(R bb )2、-OC(=NRbb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0052] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

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

[0054] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0055] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0056] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff)2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0057] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0058] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0059] R gg Each of these is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C 1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1- 6-alkyl), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C) 1-6 Alkyl)3、-OSi(C 1-6 Alkyl)3, -C(=S)N(C 1-6 Alkyl)2、C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1- 6-alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, C6-C 10 aryl, 3-7 membered heterocyclic, 5-10 membered heteroaryl; or two geminal Rs gg Substituents can combine to form =O or =S; where X- is a counterion.

[0060] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa)2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0061] Nucleic acid refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their hybrid molecules. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASO). Nucleic acids can be further chemically modified, with modifications selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. mRNA molecules contain protein-coding regions and may further contain expression regulatory sequences, typical of which include, but are not limited to, a 5' cap (5'cap), a 5' untranslated region (5'UTR), a 3' untranslated region (3'UTR), a polyadenylated nucleotide sequence (PolyA), and a miRNA binding site.

[0062] "Ionizable lipids" refers to lipids that are ionizable, allowing them to exist in a positively charged or neutral form depending on pH. In some embodiments, ionizable lipids are aminolipids.

[0063] "Neutral lipids" refer to lipid molecules that are uncharged under specific pH conditions, such as physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearyl-sn-glycerol-3-phosphate choline (DSPC), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline (POPC), 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE), 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate ethanolamine (POPE), and 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE).

[0064] "Structural lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentane-polyhydrophenanthrene carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coccosterol, rock saponin, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol, or campesterol.

[0065] "Polymer lipid" refers to a molecule containing both a polymeric moiety and a lipid moiety. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. Other lipids capable of reducing aggregation, such as products of lipid coupling with compounds having uncharged, hydrophilic, or sterically barrier moieties, may also be used.

[0066] "Lipid nanoparticles" refer to particles containing lipid components and having a nanoscale size.

[0067] "Biodegradable groups" refer to functional groups containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can affect the process of clearing compounds from the body. In this invention, the orientation of the biodegradable groups is from the head to the tail of the ionizable lipid molecule.

[0068] Other definitions

[0069] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0071] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0072] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0073] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Salts of amino acids are also included, such as arginine salts, gluconates, and galacturonic acids (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19, incorporated herein by reference).

[0074] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0075] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0076] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0077] Generally, the "effective amount" of a pharmaceutical composition refers to a quantity sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the pharmaceutical compositions of the present invention can be varied depending on factors such as the biological target, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0078] Unless otherwise stated, the “therapeuticly effective amount” of a pharmaceutical composition as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a pharmaceutical composition refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeuticly effective amount” may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0079] Unless otherwise stated, the “preventive effective amount” of a pharmaceutical composition as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventive effective amount of a pharmaceutical composition refers to the amount of the therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventive effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0080] The term "combination" and related terms refer to the simultaneous or sequential administration of the pharmaceutical composition of the present invention and other therapeutic agents. For example, the pharmaceutical composition of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation Plan

[0081] In this document, “compounds of the present invention” refers to the following compounds, their isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof.

[0082] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0083] 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:

[0084] in,

[0085] Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace;

[0086] n = 1, 2, 3, 4, 5 or 6;

[0087] R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g ;

[0088] L g Independently selected from chemical bonds and C 1-10 Alkylene;

[0089] R g and R' g Independently selected from H and C 1-10 Alkyl, C1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0090] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O )S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -;

[0091] W is selected from chemical bonds, C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR w -、-NR w C(O)NR w -、-OC(O)S-、-OC(O)O-、-NR w C(O)O-, -SC(O)-, -C(O)S-, -NR w -、-C(O)NR w -、-NR w C(O)-、-NR w C(O)S-、-SC(O)NR w -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR w -、-NR w C(S)O-, -SS-, and -S(O) 0- 2-;

[0092] R w Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0093] Q is selected from chemical bonds, -OC(O)-, -SC(O)-, -NR a C(O)-, -C(O)-, -OC(S)-, -S(O) 1-2 - Phenylidene and pyridylene, wherein the phenylene or pyridylene is optionally substituted with 1, 2, 3 or 4 R*.

[0094] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L a -ORa -L a -SR a and -L a -NR a R' a ;

[0095] L a Independently selected from chemical bonds and C 1-8 Alkylene;

[0096] R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0097] G1 is selected from C 4-14 Alkylene, C 4-14 imide and C 4-14 Alynyl group, which is optionally surrounded by one or more R G1 replace;

[0098] R G1 Independently selected from H and C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0099] L b Independently selected from chemical bonds and C 1-14 Alkylene;

[0100] R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0101] G2 and G3 are independently selected from chemical bonds, C 1-14 Alkylene, C 2-14 imide and C 2-14 Alynyl group, which is optionally surrounded by one or more R G2 replace;

[0102] R G2 Independently selected from H and C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NRb R' b ;

[0103] G4 is selected from chemical bonds, C 1-8 Alkylene, C 2-8 imide and C 2-8 Alynyl group, which is optionally surrounded by one or more R G4 replace;

[0104] R G4 Independently selected from H and C 1-8 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ;

[0105] L c Independently selected from chemical bonds and C 1-8 Alkylene;

[0106] R c and R' c Independently selected from H and C 1-8 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0107] Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4g replace;

[0108] R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0109] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0110] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0111] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, which is optionally surrounded by one or more R groups s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-;

[0112] R and R' are each independently selected from H and C. 1-20 alkyl;

[0113] R s Independently selected from H and C 1-20 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0114] L e Independently selected from chemical bonds and C 1-20 Alkylene;

[0115] R e and R' e Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0116] R3 is selected from CN, -OR f -C(O)R f -OC(O)R f -NR”C(O)R f -NR f R' f 、-NR”C(O)NR f R' f 、-NR”C(NR f )NR f R' f -NR”C(O)R f -NR”S(O)2R f -OC(O)NR f R' f -NR”C(O)OR f -N(OR) f )C(O)R f -N(OR) f )S(O)2R f -N(OR) f )C(O)OR f-N(OR) f )C(O)R f R' f 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

[0117] R f and R' f Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0118] "R" is independently selected from H and C. 1-6 alkyl.

[0119] In another embodiment, the compound of the present invention further has a structure of formula (II), formula (III), formula (III-1), formula (III-2), formula (III-3), formula (III-4) or formula (III-5):

[0120] in,

[0121] e = 0, 1, 2 or 3; preferably e = 0, 1 or 2; preferably e = 1 or 2;

[0122] f = 0, 1, 2 or 3; preferably f = 0, 1 or 2; preferably f = 1 or 2;

[0123] T1 and T2 are independently selected from CR A and N;

[0124] ring Randomly selected by n R A replace;

[0125] Other variables are as defined in this invention.

[0126] In another embodiment, the compound of the present invention further has the structure of formula (IV), formula (IV-1), formula (IV-2), formula (IV-3) or formula (IV-4):

[0127] in,

[0128] a = 1, 2, 3, 4, 5 or 6;

[0129] b = 3, 4, 5, 6, 7, 8, 9 or 10;

[0130] c = 1, 2, 3, 4, 5 or 6;

[0131] d = 1, 2, 3, 4, 5 or 6; preferably d = 1, 2, 3 or 4;

[0132] Other variables are as defined in this invention.

[0133] In the compounds of this invention, each group can be defined as follows.

[0134] Ring A

[0135] In one implementation, ring A is C. 3-10 Cycloalkylene; in another embodiment, ring A is a 3- to 10-membered heterocyclic alkylene group; in another embodiment, ring A is a C 3-7 Cycloalkylene; in another embodiment, ring A is a 3- to 7-membered heterocyclic group; in another embodiment, ring A is a 3- to 7-membered azeotropic heterocyclic group; in another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another embodiment, ring A is In another implementation, ring A is optionally divided by n R A Replacement; in another embodiment, ring A is not replaced.

[0136] In one implementation, ring A is In another implementation, Randomly selected by n R A Replace; in another implementation, It has not been replaced.

[0137] In one implementation, T1 is CR A In another implementation, T1 is N.

[0138] In one implementation, T2 is CR A In another implementation, T2 is N.

[0139] In a more specific implementation, T1 is N, and T2 is CR. A Or N; in another, more specific implementation, T1 is CR A Or N, T2 is N; in another more specific embodiment, T1 is N, T2 is N.

[0140] In one implementation, e is 0; in another implementation, e is 1; in yet another implementation, e is 2; and in still another implementation, e is 3.

[0141] In one implementation, f is 0; in another implementation, f is 1; in yet another implementation, f is 2; and in yet another implementation, f is 3.

[0142] In one more specific embodiment, e = 0, 1, 2, or 3; in another more specific embodiment, e = 0, 1, or 2; in yet another more specific embodiment, e = 1 or 2.

[0143] In one more specific embodiment, f = 0, 1, 2 or 3; in another more specific embodiment, f = 0, 1 or 2; in yet another more specific embodiment, f = 1 or 2.

[0144] In a more specific implementation, ring A is C. 3-7 Cycloalkylene or 3 to 7-membered heterocyclic cycloalkylene; in another more specific embodiment, ring A is...

[0145] In one implementation, n is 1; in another implementation, n is 2; in another implementation, n is 3; in another implementation, n is 4; in another implementation, n is 5; in another implementation, n is 6.

[0146] In one more specific embodiment, n = 1, 2, 3, 4, 5, or 6; in another more specific embodiment, n = 1, 2, 3, 4, or 5; in another more specific embodiment, n = 1, 2, 3, or 4; in another more specific embodiment, n = 1 or 2; in another more specific embodiment, n = 1.

[0147] R A

[0148] In one implementation, R A H; in another embodiment, R A For oxidation (=O); in another embodiment, R A It is cyano; in another embodiment, R A It is a halogen; in another embodiment, R A C 1-10 Alkyl, preferably C 1- 6-alkyl; in another embodiment, R A C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl; in another embodiment, R A -L g -OR g For example, -CH2-OR g For example, -OR g In another implementation, R A -L g -SRg For example -SR g In another implementation, R A -L g -NR g R' g For example, -CH2-NR g R' g For example, -CH2NH2, for example, -NR g R' g .

[0149] In a more specific implementation, R A Independently selected from H, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g In another, more specific implementation, R A Independently selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g In another, more specific implementation, R A Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g In another, more specific implementation, R A Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g and -L g -NR g R' g In another, more specific implementation, R A Independently selected from H, halogen, -L g -OR g and -Lg -NR g R' g .

[0150] L g

[0151] In one implementation, L g For chemical bonds; in another embodiment, L g C 1-10 Alkylene; in another embodiment, L g C 1-6 Alkylene; in another embodiment, L g C 1-4 Alkylene.

[0152] In a more specific implementation, L g Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L g Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L g Independently selected from chemical bonds and C 1- 4-alkylene compounds.

[0153] R g and R' g

[0154] In one implementation, R g H; in another embodiment, R g C 1-10 Alkyl, such as C 1-6 Alkyl; in another embodiment, R g C 1-10 Haloalkyl, such as C 1-6 Halogenated alkyl; in another embodiment, R g C 3-10 cycloalkyl, such as C 3-7 cycloalkyl; in another embodiment, R g It is a 3- to 10-membered heterocyclic group, such as a 3- to 7-membered heterocyclic group.

[0155] In one implementation, R' g H; in another embodiment, R' g C 1-10 Alkyl, such as C 1-6 Alkyl; in another embodiment, R' g C 1-10 Haloalkyl, such as C 1-6 Halogenated alkyl; in another embodiment, R'g C 3-10 cycloalkyl, such as C 3-7 cycloalkyl; in another embodiment, R' g It is a 3- to 10-membered heterocyclic group, such as a 3- to 7-membered heterocyclic group.

[0156] In a more specific implementation, R g Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R g Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0157] In a more specific implementation, R' g Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R' g Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0158] M1 and M2

[0159] 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... In one embodiment, M1 is -NR-; in another embodiment, M1 is -C(O)NR-; in another embodiment, M1 is -NRC(O)-; in another embodiment, M1 is -NRC(O)S-; in another embodiment, M1 is -SC(O)NR-; in another embodiment, M1 is -C(O)-; in another embodiment, M1 is -OC(S)-; in another embodiment, M1 is -C(S)O-; in another embodiment, M1 is -OC(S)NR-; in another embodiment, M1 is -NRC(S)O-; in another embodiment, M1 is -SS-; in another embodiment, M1 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-;

[0160] In one embodiment, M2 is -C(O)O-; in another embodiment, M2 is -OC(O)-; in another embodiment, M2 is -O-; in another embodiment, M2 is -SC(O)O-; in another embodiment, M2 is -OC(O)NR-; in another embodiment, M2 is -NRC(O)NR-; in another embodiment, M2 is -OC(O)S-; in another embodiment, M2 is -OC(O)O-; in another embodiment, M2 is -NRC(O)O-; in another embodiment, M2 is -SC(O)-; in another embodiment, M2 is -C(O)S-; in another embodiment... In one embodiment, M2 is -NR-; in another embodiment, M2 is -C(O)NR-; in another embodiment, M2 is -NRC(O)-; in another embodiment, M2 is -NRC(O)S-; in another embodiment, M2 is -SC(O)NR-; in another embodiment, M2 is -C(O)-; in another embodiment, M2 is -OC(S)-; in another embodiment, M2 is -C(S)O-; in another embodiment, M2 is -OC(S)NR-; in another embodiment, M2 is -NRC(S)O-; in another embodiment, M2 is -SS-; in another embodiment, M2 is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0161] In one more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; in another more specific embodiment, M1 is selected from -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in yet another more specific embodiment, M1 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-; in another more specific embodiment, M1 is selected from -OC(O)O-, -C(O)O-, and -C(O)S-; in another more specific embodiment, M1 is selected from -OC(O)O-, -C(O)O-, and -OC(O)-; in another more specific embodiment, M1 is selected from -OC(O)O- or -C(O)O-; in another more specific embodiment, M1 is -OC(O)O-.

[0162] In one more specific embodiment, M2 is selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; in another more specific embodiment, M2 is selected from -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in another more specific embodiment, M2 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-; in another more specific embodiment, M2 is selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in another more specific embodiment, M2 is -OC(O)-.

[0163] In a more specific implementation, M1 and M2 are not both -OC(O)O-.

[0164] W

[0165] In one embodiment, W is a chemical bond; in another embodiment, W is C(O)O-; in another embodiment, W is -OC(O)-; in another embodiment, W is -O-; in another embodiment, W is -SC(O)O-; in another embodiment, W is -OC(O)NR w -; In another implementation, W is -NR w C(O)NR w -; In another embodiment, W is -OC(O)S-; In another embodiment, W is -OC(O)O-; In another embodiment, W is -NR w C(O)O-; in another embodiment, W is -SC(O)-; in another embodiment, W is -C(O)S-; in another embodiment, W is -NR w -; In another embodiment, W is -C(O)NR w -; In another implementation, W is -NR w C(O)-; in another embodiment, W is -NR w C(O)S-; in another embodiment, W is -SC(O)NR w -; In another embodiment, W is -C(O)-; In another embodiment, W is -OC(S)-; In another embodiment, W is -C(S)O-; In another embodiment, W is -OC(S)NR w -; In another implementation, W is -NR wC(S)O-; in another embodiment, W is -SS-; in yet another embodiment, W is -S(O) 0-2 -, for example -S-, for example -S(O)-, for example -S(O)2-.

[0166] In a more specific embodiment, W is selected from chemical bonds, -C(O)-, -OC(O)-, -SC(O)-, -C(S)-, -OC(S)-, -NR w C(O)-, -OC(S)-, -NR w C(S)- and -S(O) 0-2 -; In another more specific embodiment, W is selected from chemical bonds, -C(O)- and -C(S)-; In another more specific embodiment, W is selected from chemical bonds and -C(O)-.

[0167] R w

[0168] In one implementation, R w H; in another embodiment, R w C 1-14 Alkyl; in another embodiment, R w C 1-10 Alkyl; in another embodiment, R w C 1-6 Alkyl; in another embodiment, R w C 3-14 cycloalkyl; in another embodiment, R w C 3-10 cycloalkyl; in another embodiment, R w C 3-7 cycloalkyl; in another embodiment, R w It is a 3- to 14-membered heterocyclic group; in another embodiment, R w It is a 3- to 10-membered heterocyclic group; in another embodiment, R w It consists of 3 to 7-membered heterocyclic groups.

[0169] In a more specific implementation, R w Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R w Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R w Independently selected from H and C 1-6 alkyl.

[0170] Q

[0171] In one embodiment, Q is a chemical bond; in another embodiment, Q is -OC(O)-; in yet another embodiment, Q is -SC(O)-; in still another embodiment, Q is -NR. a C(O)-; in another embodiment, Q is -C(O)-; in another embodiment, Q is -OC(S)-; in yet another embodiment, Q is -S(O)-. 1-2 -, for example -S(O)-, for example -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 with 1, 2, 3 or 4 R*; in another embodiment, when Q is pyridylene, it is optionally substituted with 1, 2, 3 or 4 R*; in another embodiment, Q is not substituted.

[0172] In a more specific embodiment, Q is selected from chemical bonds, -OC(O)-, -SC(O)-, -NR a C(O)-, -C(O)-, -OC(S)-, -S(O) 1-2 -; In another more specific embodiment, Q is selected from chemical bond, -OC(O)- and -SC(O)-; In another more specific embodiment, Q is selected from chemical bond and -SC(O)-.

[0173] R*

[0174] In one embodiment, R* is H; in another embodiment, R* is a halogen; in yet another embodiment, R* is a cyano group; in still another embodiment, R* is C. 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R* is C 1-10 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl; in another embodiment, R* is -L a -OR a For example, -OR a In another implementation, R* is -L a -SR a For example -SR a In another implementation, R* is -L a -NR a R' a For example -NR a R' a .

[0175] In a more specific embodiment, R* is independently selected from H, cyano, halogen, C.1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a In another, more specific embodiment, R* is independently selected from H, halogens, C. 1-6 Alkyl, C 1- 6-Haloalkyl, -L a -OR a and -L a -NR a R' a In another, more specific embodiment, R* is independently selected from H, halogens, C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0176] L a

[0177] In one implementation, L a For chemical bonds; in another embodiment, L a C 1-8 Alkylene; in another embodiment, L a C 1-6 Alkylene; in another embodiment, L a C 1-4 Alkylene.

[0178] In a more specific implementation, L a Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L a Independently selected from chemical bonds and C 1-4 Alkylene.

[0179] R a and R' a

[0180] In one implementation, R a H; in another embodiment, R a C 1-10 Alkyl; in another embodiment, R a C 1-6 Alkyl; in another embodiment, R a C 3-14 cycloalkyl; in another embodiment, R a C 3-10 cycloalkyl; in another embodiment, Ra C 3-7 cycloalkyl; in another embodiment, R a It is a 3- to 14-membered heterocyclic group; in another embodiment, R a It is a 3- to 10-membered heterocyclic group; in another embodiment, R a It consists of 3 to 7-membered heterocyclic groups.

[0181] In one implementation, R' a H; in another embodiment, R' a C 1-10 Alkyl; in another embodiment, R' a C 1-6 Alkyl; in another embodiment, R' a C 3-14 cycloalkyl; in another embodiment, R' a C 3-10 cycloalkyl; in another embodiment, R' a C 3-7 cycloalkyl; in another embodiment, R' a It is a 3- to 14-membered heterocyclic group; in another embodiment, R' a It is a 3- to 10-membered heterocyclic group; in another embodiment, R' a It consists of 3 to 7-membered heterocyclic groups.

[0182] In a more specific implementation, R a Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R a Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R a Independently selected from H and C 1-6 alkyl.

[0183] In a more specific implementation, R' a Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R' a Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R' a Independently selected from H and C 1-6 alkyl.

[0184] G1

[0185] In one implementation, G1 is C 4-14 Alkylene; in another embodiment, G1 is C 4-14 alkenyl; in another embodiment, G1 is C 4-14 Ethyne group; in another embodiment, G1 is C 4-10 Alkylene, preferably C 4-10 Alkylene, preferably C 5-8 Alkylene, preferably C6 alkylene; in another embodiment, G1 is C6. 4-10 alkenyl; in another embodiment, G1 is C 4-10 Ethyne group; in another embodiment, G1 is optionally surrounded by one or more R groups. G1 In another embodiment, G1 is optionally replaced by 1, 2, 3 or 4 Rs. G1 Replacement; in another implementation, G1 is not replaced.

[0186] In a more specific implementation, G1 is selected from C. 4-10 Alkylene, C 4-10 imide and C 4-10 Ethyne group; in another, more specific embodiment, G1 is C 4-10 Alkylene; in another, more specific embodiment, G1 is C 5-8 Alkylene; in another, more specific embodiment, G1 is a C6 alkylene.

[0187] R G1

[0188] In one implementation, R G1 H; in another embodiment, R G1 C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl; in another embodiment, R G1 -L b -OR b For example, -OR b In another implementation, R G1 -L b -SR b For example -SR b In another implementation, R G1 -L b -NR b R' b For example -NR b R'b .

[0189] In a more specific implementation, R G1 Independently selected from H and C 1-10 Alkyl (preferably C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b In another, more specific implementation, R G1 Independently selected from H and C 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 alkyl).

[0190] L b

[0191] In one implementation, L b For chemical bonds; in another embodiment, L b C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0192] In a more specific implementation, L b Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L b Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L b Independently selected from chemical bonds and C 1- 4-alkylene compounds.

[0193] R b and R' b

[0194] In one implementation, R b H; in another embodiment, R b C 1-14 Alkyl; in another embodiment, R b C 1-10 Alkyl; in another embodiment, R b C 1-6 Alkyl; in another embodiment, R b C 3-14cycloalkyl; in another embodiment, R b C 3-10 cycloalkyl; in another embodiment, R b C 3-7 cycloalkyl; in another embodiment, R b It is a 3- to 14-membered heterocyclic group; in another embodiment, R b It is a 3- to 10-membered heterocyclic group; in another embodiment, R b It consists of 3 to 7-membered heterocyclic groups.

[0195] In one implementation, R' b H; in another embodiment, R' b C 1-14 Alkyl; in another embodiment, R' b C 1-10 Alkyl; in another embodiment, R' b C 1-6 Alkyl; in another embodiment, R' b C 3-14 cycloalkyl; in another embodiment, R' b C 3-10 cycloalkyl; in another embodiment, R' b C 3-7 cycloalkyl; in another embodiment, R' b It is a 3- to 14-membered heterocyclic group; in another embodiment, R' b It is a 3- to 10-membered heterocyclic group; in another embodiment, R' b It consists of 3 to 7-membered heterocyclic groups.

[0196] In a more specific implementation, R b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R b Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R b Independently selected from H and C 1-6 alkyl.

[0197] In a more specific implementation, R' b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; in another more specific embodiment, R' b Independently selected from H and C 1-6Alkyl, C 3-7 cycloalkyl and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R' b Independently selected from H and C 1-6 alkyl.

[0198] G2 and G3

[0199] In one embodiment, G2 is a chemical bond; in another embodiment, G2 is a C bond. 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 3-5 Alkylene, such as C3 alkylene, such as C4 alkylene, such as C5 alkylene; in another embodiment, G2 is C 2-14 Alkenyl group, preferably C 2-10 alkenyl; in another embodiment, G2 is C 2-14 Alynyl group, preferably C 2-10 Ethyne group; in another embodiment, G2 is optionally surrounded by one or more R groups. G2 In another embodiment, G2 is optionally replaced by 1, 2, 3 or 4 Rs. G2 In another implementation, G2 is not replaced.

[0200] In one embodiment, G3 is a chemical bond; in another embodiment, G3 is a C bond. 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-3 Alkylene, preferably C2 alkylene, for example -CH2CH2-; in another embodiment, G3 is C 2-14 Alkenyl group, preferably C 2-10 alkenyl; in another embodiment, G3 is C 2-14 Alynyl group, preferably C 2-10 Ethyne group; in another embodiment, G3 is optionally surrounded by one or more R groups. G2 In another embodiment, G3 is optionally replaced by 1, 2, 3 or 4 Rs. G2 In another implementation, G3 is not replaced.

[0201] In one embodiment, the total length of G2 and G3 is 4 carbon atoms; in another embodiment, the total length of G2 and G3 is 5 carbon atoms; in another embodiment, the total length of G2 and G3 is 6 carbon atoms; in another embodiment, the total length of G2 and G3 is 7 carbon atoms; in another embodiment, the total length of G2 and G3 is 8 carbon atoms; in another embodiment, the total length of G2 and G3 is 9 carbon atoms; in another embodiment, the total length of G2 and G3 is 10 carbon atoms; in another embodiment, the total length of G2 and G3 is 11 carbon atoms; in another embodiment, the total length of G2 and G3 is 12 carbon atoms; in another embodiment, the total length of G2 and G3 is 13 carbon atoms; in another embodiment, the total length of G2 and G3 is 14 carbon atoms.

[0202] In a more specific implementation, G2 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Alynyl group; in another, more specific embodiment, G2 is selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, G2 is C 1-10 Alkylene.

[0203] In a more specific implementation, G3 is selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Ethyne group; in another, more specific embodiment, G3 is selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, G3 is C 1-10 Alkylene.

[0204] In one more specific embodiment, the total length of G2 and G3 is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms; in another more specific embodiment, the total length of G2 and G3 is 4, 5, 6, 7, 8, 9, or 10 carbon atoms; in yet another more specific embodiment, the total length of G2 and G3 is 4, 5, 6, 7, or 8 carbon atoms; and in yet another more specific embodiment, the total length of G2 and G3 is 5, 6, or 7 carbon atoms.

[0205] R G2

[0206] In one implementation, R G2 H; in another embodiment, R G2 C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 Alkyl; in another embodiment, R G2 -L b -OR b For example, -OR b In another implementation, R G2 -L b -SR b For example -SR b In another implementation, R G2 -L b -NR b R' b For example -NR b R' b .

[0207] In a more specific implementation, R G2 Independently selected from H and C 1-10 Alkyl (preferably C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b In another, more specific implementation, R G2 Independently selected from H and C 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 alkyl).

[0208] G4

[0209] In one embodiment, G4 is a chemical bond; in another embodiment, G4 is a C bond. 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene, preferably C 2-4 Alkylene; in another embodiment, G4 is C 2-8 Alkenyl group, preferably C 2-6 Alkenyl group, preferably C 2-4 alkenyl; in another embodiment, G4 is C 2-8 Alynyl group, preferably C 2-6 Alynyl group, preferably C 2-4 Ethyne group; in another embodiment, G4 is optionally surrounded by one or more R groups. G4 Replace; in another embodiment, G4 is optionally replaced by 1, 2, 3 or 4 RG4 Replacement; in another implementation, G4 is not replaced.

[0210] In a more specific implementation, G4 is selected from C. 1-6 Alkylene, C 2-6 imide and C 2-6 Ethyne group; in another, more specific embodiment, G4 is selected from C 1-4 Alkylene, C 2-4 imide and C 2-4 Alynyl group.

[0211] R G4

[0212] In one implementation, R G4 H; in another embodiment, R G4 C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1- 4 alkyl; in another embodiment, R G4 -L c -OR c For example, -OR c In another implementation, R G4 -L c -SR c For example -SR c In another implementation, R G4 -L c -NR c R' c For example -NR c R' c .

[0213] In one implementation, two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkylene, preferably C 3-10 Cycloalkylene, preferably C 3-7 Cycloalkylene; in another embodiment, two R atoms attached to the same carbon atom G4 Together with the carbon atoms attached to them, they form 3 to 14-membered heterocyclic groups, preferably 3 to 10-membered heterocyclic groups, and more preferably 3 to 7-membered heterocyclic groups; in another embodiment, two R atoms attached to the same carbon atom G4 The rings formed together with the carbon atoms attached to them are optionally bounded by one or more R 4g Substitution; in another embodiment, two R atoms attached to the same carbon atom G4 The rings formed together with the carbon atoms attached to them are optionally bounded by 1, 2, or 3 R atoms.4g Substitution; in another embodiment, two R atoms attached to the same carbon atom G4 The ring formed together with the carbon atoms they are attached to is not replaced; in another embodiment, the two R atoms attached to the same carbon atom... G4 The carbon atoms bonded to them do not form rings.

[0214] In a more specific implementation, R G4 Independently selected from H and C 1-6 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c In another, more specific implementation, R G4 Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R G4 Independently selected from H and C 1-4 alkyl.

[0215] In a more specific embodiment, two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups; in another more specific embodiment, two R groups attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-7 Cycloalkyl or 3 to 7-membered heterocyclic groups.

[0216] L c

[0217] In one implementation, L c For chemical bonds; in another embodiment, L c C 1-8 Alkylene, preferably C 1-6 Alkylene, preferably C 1-4 Alkylene.

[0218] In a more specific implementation, L c Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-4 Alkylene.

[0219] R c and R' c

[0220] In one implementation, R c H; in another embodiment, R c C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R c C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R c It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0221] In one implementation, R' c H; in another embodiment, R' c C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' c C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' c It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0222] In a more specific implementation, R c Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R c Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R c Independently selected from H and C 1-4 alkyl.

[0223] In a more specific implementation, R' c Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R' c Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R' c Independently selected from H and C 1-4 alkyl.

[0224] R 4g

[0225] In one implementation, R 4g H; in another embodiment, R 4gIt is a halogen; in another embodiment, R 4g It is cyano; in another embodiment, R 4g C 1-8 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R 4g C 1-8 Halogenated alkyl groups, preferably C 1-6 Halogenated alkyl; in another embodiment, R 4g -L d -OR d For example, -OR d In another implementation, R 4g -L d -SR d For example -SR d In another implementation, R 4g -L d -NR d R' d For example -NR d R' d .

[0226] In a more specific implementation, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0227] L d

[0228] In one implementation, L d For chemical bonds; in another embodiment, L d C 1-8 Alkylene, preferably C 1-6 Alkyl, preferably C 1-4 alkyl.

[0229] In a more specific implementation, L d Independently selected from chemical bonds and C 1-6 Alkyl (preferably C) 1-4 (alkylene).

[0230] R d and R' d

[0231] In one implementation, R d H; in another embodiment, R d C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, Rd C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, and more preferably a 3- to 7-membered heterocyclic group.

[0232] In one implementation, R' d H; in another embodiment, R' d C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' d C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' d It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group, and more preferably a 3- to 7-membered heterocyclic group.

[0233] In a more specific implementation, R d Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in a more specific embodiment, R d Independently selected from H and C 1-6 Alkyl; in a more specific embodiment, R d Independently selected from H and C 1-4 alkyl.

[0234] In a more specific implementation, R' d Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; in a more specific embodiment, R' d Independently selected from H and C 1-6 Alkyl; in a more specific embodiment, R' d Independently selected from H and C 1-4 alkyl.

[0235] R1 and R2

[0236] In one implementation, R1 is C 4-20 Alkyl, preferably C 6-14 Alkyl, preferably C 8-20 Alkyl, preferably C 8-12 Alkyl, preferably C 8-10 Alkyl, preferably C9 alkyl; in another embodiment, R1 is C4-20 Alkenyl, preferably C 6-14 Alkenyl, preferably C 8-20 Alkenyl; in another embodiment, R1 is C 4-20 Alkyne group, preferably C 6-14 Alkyne group, preferably C 8-20 Alkyne group; in another embodiment, R1 is optionally surrounded by one or more R groups. s In another embodiment, R1 is optionally replaced by 1, 2, 3 or 4 (preferably 1, 2 or 3, preferably 1) R s In another embodiment, R1 is not substituted; in yet another embodiment, one or more (preferably 1, 2 or 3, preferably 1) methylene units in R1 are optionally and independently replaced by -NR'-.

[0237] In one implementation, R2 is C 4-20 Alkyl, preferably C 4-14 Alkyl, preferably C 4-12 Alkyl (e.g., C10) 4-12 Straight-chain alkyl groups, preferably C 4-10 Alkyl, preferably C 4-8 Alkyl, preferably C6 alkyl; in another embodiment, R2 is C 4-20 Alkenyl, preferably C 4-14 Alkenyl; in another embodiment, R2 is C 4-20 Alkyne group, preferably C 4-14 Alkyne group; in another embodiment, R2 is optionally surrounded by one or more R groups. s In another embodiment, R2 is optionally replaced by 1, 2, 3 or 4 (preferably 1, 2 or 3, preferably 1) R s In another embodiment, R2 is not substituted; in yet another embodiment, one or more (preferably 1, 2 or 3, preferably 1) methylene units in R2 are optionally and independently replaced by -NR'-.

[0238] In a more specific implementation, R1 is selected from C. 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; in another, more specific embodiment, R1 is selected from C 8-20 Alkyl, C 8-20 alkenyl and C 8-20 Alkyne group.

[0239] In a more specific implementation, R2 is selected from C. 4-14 Alkyl, C 4-14 alkenyl and C 4-14 Alkyne group.

[0240] In a more specific implementation, R1 and R2 are independently selected from C. 4-20 Alkyl; in another, more specific embodiment, R1 is C 8-20 Alkyl group, R2 is C 4-14 Alkyl; in another, more specific embodiment, R1 is C 8-20 Alkyl group, R2 is C 4-12 Straight-chain alkyl groups.

[0241] In one implementation, R1 is replaced and R2 is not replaced; in another implementation, R1 is not replaced and R2 is replaced.

[0242] In a more specific implementation, R1 is one R s R2 was replaced, but not replaced.

[0243] R and R'

[0244] In one implementation, R is H; in another implementation, R is C. 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 alkyl.

[0245] In one implementation, R' is H; in another implementation, R' is C. 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 alkyl.

[0246] In a more specific implementation, 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.

[0247] In a more specific implementation, R' is independently selected from H and C. 1-14 Alkyl group; in another, more specific embodiment, R' is independently selected from H and C. 1-9 Alkyl group; in another, more specific embodiment, R' is independently selected from H and C. 1-6 alkyl.

[0248] R s

[0249] In one implementation, R s H; in another embodiment, R s C 1-20 Alkyl, preferably C1-14 Alkyl, preferably C 1- 10 Alkyl, preferably C 1-9 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R s -L e -OR e For example, -OR e In another implementation, R s -L e -SR e For example -SR e In another implementation, R s -L e -NR e R' e For example -NR e R' e .

[0250] In a more specific implementation, R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e In another, more specific implementation, R s Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R s Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R s Independently selected from H and C 1-9 Alkyl; in another, more specific embodiment, R s Independently selected from H and C 1-6 Alkyl, in another, more specific embodiment, R s Independently selected from H and C 1-4 alkyl.

[0251] In one implementation, R s The substitution site on R1 is separated from M1 by 0 carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by one carbon atom; in another embodiment, R s The substitution site on R1 is separated from M1 by two carbon atoms; in another embodiment, R s The substitution site on R1 is separated from M1 by three carbon atoms; in another embodiment, Rs The substitution site on R1 is spaced 4 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 5 carbon atoms away from M1; 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 spaced 7 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 8 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 9 carbon atoms apart from M1; in another embodiment, R s The substitution site on R1 is spaced 10 carbon atoms away from M1; in another embodiment, R s The substitution site on R1 is spaced 11 carbon atoms from M1; in another embodiment, R s The substitution site on R1 is separated from M1 by 12 carbon atoms.

[0252] In one implementation, R s The substitution site on R2 is separated from M2 by 0 carbon atoms; in another embodiment, R s The substitution site on R2 is separated from M2 by one carbon atom; in another embodiment, R s The substitution site on R2 is separated from M2 by two carbon atoms; in another embodiment, R s The substitution site on R2 is separated from M2 by three carbon atoms; in another embodiment, R s The substitution site on R2 is spaced 4 carbon atoms away from M2; in another embodiment, R s The substitution site on R2 is spaced 5 carbon atoms away from M2; in another embodiment, R s The substitution site on R2 is separated from M2 by 6 carbon atoms; in another embodiment, R s The substitution site on R2 is spaced 7 carbon atoms apart from M2; in another embodiment, R s The substitution site on R2 is spaced 8 carbon atoms apart from M2; in another embodiment, R s The substitution site on R2 is spaced 9 carbon atoms apart from M2; in another embodiment, R s The substitution site on R2 is spaced 10 carbon atoms away from M2; in another embodiment, R s The substitution site on R2 is spaced 11 carbon atoms from M2; in another embodiment, Rs The substitution site on R2 is separated from M2 by 12 carbon atoms.

[0253] In a more specific implementation, R s The substitution site on R1 is spaced 0-12 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-10 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-6 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-5 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-4 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is spaced 0-2 carbon atoms from M1; in another more specific embodiment, R s The substitution site on R1 is separated from M1 by two carbon atoms.

[0254] In a more specific implementation, R s The substitution site on R2 is spaced 0-12 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R2 is spaced 0-10 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R2 is spaced 0-6 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R2 is spaced 0-5 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R2 is spaced 0-4 carbon atoms from M2; in another more specific embodiment, R s The substitution site on R2 is separated from M2 by 0-2 carbon atoms; in another more specific embodiment, R s The substitution site on R2 is separated from M2 by two carbon atoms.

[0255] L e

[0256] In one implementation, L e For chemical bonds; in another embodiment, L e C 1-20 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C1-6 Alkylene.

[0257] In a more specific implementation, L e Independently selected from chemical bonds and C 1-14 Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L e Independently selected from chemical bonds and C 1-6 Alkylene.

[0258] R e and R' e

[0259] In one implementation, R e H; in another embodiment, R e C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1- 10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R e C 3-14 cycloalkyl; in another embodiment, R e It consists of 3 to 14-membered heterocyclic groups.

[0260] In one implementation, R' e H; in another embodiment, R' e C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' e C 3-14 cycloalkyl; in another embodiment, R' e It consists of 3 to 14-membered heterocyclic groups.

[0261] In a more specific implementation, R e and R' e Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R e and R' e Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R e and R' e Independently selected from H and C 1-6 alkyl.

[0262] R3

[0263] In one implementation, R3 is CN; in another implementation, R3 is -OR. f For example, -OH; in another embodiment, R3 is -C(O)R f In another embodiment, R3 is -OC(O)R f In another embodiment, R3 is -NR”C(O)R f In another implementation, R3 is -NR f R' f For example, -N(CH3)2; in another embodiment, R3 is -NR”C(O)NR f R' f In another embodiment, R3 is -NR”C(NR) f )NR f R' f In another embodiment, R3 is -NR”C(O)R f In another embodiment, R3 is -NR”S(O)2R f In another embodiment, R3 is -OC(O)NR f R' f In another embodiment, R3 is -NR”C(O)OR f In another implementation, R3 is -N (OR f )C(O)R f In another implementation, R3 is -N (OR f )S(O)2R f In another implementation, R3 is -N (OR f )C(O)OR f In another implementation, R3 is -N (OR f )C(O)R f R' f In another embodiment, R3 is a 3- to 14-membered heterocyclic group; in another embodiment, R3 is a 5- to 14-membered heteroaryl group.

[0264] In a more specific implementation, R3 is selected from CN, -OR f and -NR f R' f In another, more specific implementation, R3 is selected from -OR f and -NR f R' f In another, more specific embodiment, R3 is selected from OH and -N(CH3)2.

[0265] Rf and R' f

[0266] In one implementation, R f H; in another embodiment, R f C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl group, preferably Me; in another embodiment, R f C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R f It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0267] In one implementation, R' f H; in another embodiment, R' f C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1- 4 alkyl groups, preferably Me; in another embodiment, R' f C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' f It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0268] In a more specific implementation, R f Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in a more specific embodiment, R f Independently selected from H and C 1-6 Alkyl; in a more specific embodiment, R f Independently selected from H and C 1-4 Alkyl; in a more specific embodiment, R f Selected independently from H and Me.

[0269] In a more specific implementation, R' f Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; in a more specific embodiment, R' f Independently selected from H and C 1-6 Alkyl; in a more specific embodiment, R' f Independently selected from H and C 1-4 Alkyl; in a more specific embodiment, R' fSelected independently from H and Me.

[0270] R”

[0271] In one implementation, R” is H; in another implementation, R” is C. 1-6 alkyl.

[0272] a

[0273] In one implementation, a is 1; in another implementation, a is 2; in another implementation, a is 3; in another implementation, a is 4; in another implementation, a is 5; in another implementation, a is 6.

[0274] In one more specific embodiment, a = 1, 2, 3, 4, 5, or 6; in another more specific embodiment, a = 1, 2, 3, or 4; in another more specific embodiment, a = 2, 3, or 4; in yet another more specific embodiment, a = 2 or 4.

[0275] b

[0276] In one implementation, b is 3; in another implementation, b is 4; in another implementation, b is 5; in another implementation, b is 6; in another implementation, b is 7; in another implementation, b is 8; in another implementation, b is 9; in another implementation, b is 10.

[0277] In one more specific embodiment, b = 3, 4, 5, 6, 7, 8, 9, or 10; in another more specific embodiment, b = 4, 5, 6, 7, or 8; in yet another more specific embodiment, b = 5, 6, or 7.

[0278] c

[0279] In one embodiment, c is 1; in another embodiment, c is 2; in another embodiment, c is 3; in another embodiment, c is 4; in another embodiment, c is 5; in another embodiment, c is 6.

[0280] In one more specific embodiment, c = 1, 2, 3, 4, 5, or 6; in another more specific embodiment, c = 2, 3, 4, 5, or 6; in yet another more specific embodiment, c = 3, 4, or 5; in yet another more specific embodiment, c = 4 or 5.

[0281] d

[0282] In one implementation, d is 1; in another implementation, d is 2; in another implementation, d is 3; in another implementation, d is 4; in another implementation, d is 5; in another implementation, d is 6.

[0283] In one more specific embodiment, d = 1, 2, 3, 4, 5 or 6; in another more specific embodiment, d = 1, 2, 3 or 4; in yet another more specific embodiment, d = 1, 2 or 3.

[0284] 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 ring A can be combined with n, T1, T2, R A L g R g 、R' g M1, M2, W, R w Q, R*, L a R a 、R' a G1, R G1 L b R b 、R' b G2, G3, R G2 G4, R G4 L c R c 、R' c R 4g L d R d 、R' d R1, R2, R, R', R s L e R e 、R' e R3, R f 、R' f This invention may combine any technical solution or any combination thereof, such as R, a, b, c, d, e, and f. The invention aims to include combinations of all these technical solutions; however, due to space limitations, they will not be listed individually.

[0285] 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:

[0286] in,

[0287] Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups.A replace;

[0288] n = 1, 2, 3, 4, 5 or 6;

[0289] R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g ;

[0290] L g Independently selected from chemical bonds and C 1-10 Alkylene;

[0291] R g and R' g Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0292] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O )S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -;

[0293] W is selected from chemical bonds, C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR w -、-NR w C(O)NR w -、-OC(O)S-、-OC(O)O-、-NR w C(O)O-, -SC(O)-, -C(O)S-, -NR w -、-C(O)NR w -、-NR w C(O)-、-NR w C(O)S-、-SC(O)NR w-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR w -、-NR w C(S)O-, -SS-, and -S(O) 0- 2-;

[0294] R w Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0295] Q is selected from chemical bonds, -OC(O)-, -SC(O)-, -NR a C(O)-, -C(O)-, -OC(S)-, -S(O) 1-2 - Phenylidene and pyridylene, wherein the phenylene or pyridylene is optionally substituted with 1, 2, 3 or 4 R*.

[0296] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a ;

[0297] L a Independently selected from chemical bonds and C 1-8 Alkylene;

[0298] R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0299] G1 is selected from C 4-14 Alkylene, C 4-14 imide and C 4-14 Alynyl group, which is optionally surrounded by one or more R G1 replace;

[0300] R G1 Independently selected from H and C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0301] L b Independently selected from chemical bonds and C 1-14 Alkylene;

[0302] R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0303] G2 and G3 are independently selected from chemical bonds, C 1-14 Alkylene, C 2-14 imide and C 2-14 Alynyl group, which is optionally surrounded by one or more R G2 replace;

[0304] R G2 Independently selected from H and C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ;

[0305] G4 is selected from chemical bonds, C 1-8 Alkylene, C 2-8 imide and C 2-8 Alynyl group, which is optionally surrounded by one or more R G4 replace;

[0306] R G4 Independently selected from H and C 1-8 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ;

[0307] L c Independently selected from chemical bonds and C 1-8 Alkylene;

[0308] R c and R' c Independently selected from H and C 1-8 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0309] Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4g replace;

[0310] R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ;

[0311] L d Independently selected from chemical bonds and C 1-8 Alkylene;

[0312] R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0313] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, which is optionally surrounded by one or more R groups s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-;

[0314] R and R' are each independently selected from H and C. 1-20 alkyl;

[0315] R s Independently selected from H and C 1-20 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e ;

[0316] L e Independently selected from chemical bonds and C 1-20 Alkylene;

[0317] R e and R' e Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups;

[0318] R3 is selected from CN, -ORf -C(O)R f -OC(O)R f -NR”C(O)R f -NR f R' f 、-NR”C(O)NR f R' f 、-NR”C(NR f )NR f R' f -NR”C(O)R f -NR”S(O)2R f -OC(O)NR f R' f -NR”C(O)OR f -N(OR) f )C(O)R f -N(OR) f )S(O)2R f -N(OR) f )C(O)OR f -N(OR) f )C(O)R f R' f 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

[0319] R f and R' f Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups;

[0320] "R" is independently selected from H and C. 1-6 alkyl.

[0321] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic cycloalkylene groups;

[0322] Preferably, ring A is a 3- to 7-membered heterocyclic group, more preferably a 3- to 7-membered nitride heterocyclic group, for example...

[0323] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n = 1, 2, 3, 4 or 5; preferably n = 1, 2, 3 or 4; preferably n = 1 or 2; preferably n = 1.

[0324] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R A Independently selected from H, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g Preferred components include H, cyano, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g Preferred components include H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g Preferred components include H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g and -L g -NR g R' g Preferred components include H, halogens, and -L. g -OR g and -L g -NR g R' g .

[0325] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L g Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0326] Preferably, R g and R' g Independently selected from H and C 1-6 Alkyl, C 1-6Haloalkyl, C 3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0327] In a more specific embodiment, the present invention provides the above-described compound, 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)-, -OC(O)O-, -SC(O-, -C(O)S-, -C(O)NR-, and -NRC(O-), preferably -C(O)O-, -OC(O)O-, -OC(O-, -SC(O-), and -C(O)S-; preferably not simultaneously -OC(O)O-;

[0328] Preferably, M1 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, more preferably -OC(O)O-, -C(O)O- and -C(O)S-, more preferably -OC(O)O-, -C(O)O- and -OC(O-), more preferably -OC(O)O- or -C(O)O-, more preferably -OC(O)O-;

[0329] Preferably, M2 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, more preferably C(O)O-, -OC(O-, -SC(O- and -C(O)S-, more preferably -C(O)O- or -OC(O)-, more preferably -OC(O)-.

[0330] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein W is selected from chemical bonds, -C(O)-, -OC(O)-, -SC(O)-, -C(S)-, -OC(S)-, -NR w C(O)-, -OC(S)-, -NR w C(S)- and -S(O) 0-2 -; Preferred chemical bonds, -C(O)- and -C(S)-; Preferred chemical bonds and -C(O)-; Preferred chemical bonds; Preferred -C(O)-;

[0331] Preferably, R w Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

[0332] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein Q is selected from chemical bonds, -OC(O)-, -SC(O)-, -NR-. a C(O)-, -C(O)-, -OC(S)-, -S(O) 1-2 -; Preferred chemical bonds, -OC(O)- and -SC(O)-; Preferred chemical bonds and -SC(O)-;

[0333] Preferably, R* is independently selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a Preferred components include H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a and -L a -NR a R' a Preferred components include H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0334] Preferably, L a Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0335] Preferably, R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

[0336] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G1 is selected from C 4-10 Alkylene, C 4-10 imide and C 4-10 Alkyne group; preferably C 4-10 Alkylene; preferably C 5-8Alkylene; preferably C6 alkylene;

[0337] Preferably, G1 is optionally divided by 1, 2, 3 or 4 R G1 replace.

[0338] In a more specific embodiment, the present invention provides the above-described compound, 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 C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 alkyl);

[0339] Preferably, L b Independently selected from chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0340] Preferably, R b and R' b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

[0341] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein G2 and G3 are independently selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Alynyl group; preferred chemical bond and C 1-10 Alkylene; preferably C 1-10 Alkylene;

[0342] Preferably, G2 is selected from C 1-8 Alkylene; preferably C 1-6 Alkylene; preferably C 3-5 Alkylene;

[0343] Preferably, G3 is selected from C 1-8 Alkylene; preferably C 1-6 Alkylene; preferably C 1-3 Alkylene;

[0344] Preferably, the total length of G2 and G3 is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms; preferably 4, 5, 6, 7, 8, 9 or 10 carbon atoms; preferably 4, 5, 6, 7 or 8 carbon atoms; preferably 5, 6 or 7 carbon atoms.

[0345] Preferably, G2 and G3 are each optionally represented by 1, 2, 3 or 4 Rs. G2 replace.

[0346] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R G2 Independently selected from H and C 1-10 Alkyl (preferably C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 alkyl).

[0347] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G4 is selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 Alkyne group; preferably C 1-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; preferably C 1-4 Alkylene; preferably C 2-4 Alkylene;

[0348] Preferably, G4 is optionally divided by 1, 2, 3 or 4 R G4 replace.

[0349] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R G4 Independently selected from H and C1-6 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c H and C are preferred. 1-6 Alkyl groups, preferably H and C 1-4 alkyl;

[0350] Preferably, the two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups, preferably forming C 3-7 Cycloalkyl or 3 to 7-membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4g replace;

[0351] Preferably, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0352] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L c Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene;

[0353] Preferably, R c and R' c Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably selected from H and C 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0354] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L d Independently selected from chemical bonds and C 1-6 Alkyl (preferably C) 1-4 Alkylene);

[0355] Preferably, R d and R' d Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably selected from H and C 1-6Alkyl groups; preferably selected from H and C. 1-4 alkyl.

[0356] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; preferably C 8-20 Alkyl, C 8- 20 alkenyl and C 8-20 Alkyne group; preferably, R1 is C 4-20 Alkyl; preferably C 6-14 Alkyl; preferably C 8-20 Alkyl; preferably C 8-12 Alkyl; preferably C 8-10 Alkyl; preferably C9 alkyl;

[0357] Preferably, R2 is selected from C 4-14 Alkyl, C 4-14 alkenyl and C 4-14 Alkyne group; preferably, R2 is C 4-20 Alkyl; preferably C 4-14 Alkyl; preferably C 4-12 Alkyl (e.g., C10) 4-12 (linear alkyl); preferably C 4-10 Alkyl; preferably C 4-8 Alkyl; preferably C6 alkyl;

[0358] Preferably, R1 and R2 are each optionally represented by 1, 2, 3 or 4 R... s Instead, preferably optionally replaced by 1, 2 or 3 R s Replace, preferably optionally by 1 R s replace;

[0359] Preferably, R1 and R2 are independently selected from C 4-20 Alkyl; preferably, R1 is C 8-20 Alkyl group, R2 is C 4-14 Alkyl; preferably, R1 is C 8-20 Alkyl group, R2 is C 4-12 Straight-chain alkyl;

[0360] Preferably, R1 is substituted and R2 is not substituted;

[0361] Preferably, one, two, or three (preferably one) methylene units in R1 or R2 are optionally and independently replaced by -NR'-.

[0362] In a more specific embodiment, the present invention provides the above-described 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. 1-14 Alkyl groups; preferably H and C 1-9 Alkyl groups; preferably H and C 1-6 Alkyl group; preferably R is H.

[0363] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e Preferred ingredients are H and C. 1-14 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C 1-9 Alkyl groups; preferably H and C 1-6 Alkyl groups, preferably H and C 1-4 alkyl.

[0364] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L e Independently selected from chemical bonds and C 1-14 Alkylene; preferably chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-6 Alkylene;

[0365] Preferably, R e and R' e Independently selected from H and C 1-14 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C 1-6 alkyl.

[0366] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein R3 is selected from CN, -OR f and -NR f R' f Preferred - OR f and -NR f R' f Preferred option: -OR f ; preferably OH;

[0367] Preferably, R3 is selected from OH and -N(CH3)2;

[0368] Preferably, R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 Alkyl groups; preferably H and C 1-4 Alkyl groups; preferably H and Me.

[0369] In a more specific embodiment, the present invention provides the above-described compound, 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 spaced 0-12 carbon atoms from M1 or M2, preferably 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 2 carbon atoms.

[0370] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, having a structure of formula (II), (III), (III-1), (III-2), (III-3), (III-4) or (III-5):

[0371] in,

[0372] e = 0, 1, 2 or 3; preferably e = 0, 1 or 2; preferably e = 1 or 2;

[0373] f = 0, 1, 2 or 3; preferably f = 0, 1 or 2; preferably f = 1 or 2;

[0374] T1 and T2 are independently selected from CR A and N;

[0375] ring Randomly selected by n R A replace;

[0376] Other variables are as defined in this invention;

[0377] Preferably, T1 is N; preferably, T2 is N; preferably, T2 is CR A .

[0378] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, having the structure of formula (IV), (IV-1), (IV-2), (IV-3) or (IV-4):

[0379] in,

[0380] a = 1, 2, 3, 4, 5 or 6;

[0381] b = 3, 4, 5, 6, 7, 8, 9 or 10;

[0382] c = 1, 2, 3, 4, 5 or 6;

[0383] d = 1, 2, 3, 4, 5 or 6; preferably d = 1, 2, 3 or 4;

[0384] Other variables are as defined in this invention.

[0385] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV):

[0386] in,

[0387] a = 1, 2, 3, 4, 5 or 6;

[0388] b = 4, 5, 6, 7 or 8;

[0389] c = 2, 3, 4, 5 or 6;

[0390] d = 1, 2, 3 or 4;

[0391] e = 0, 1, 2 or 3;

[0392] f = 0, 1, 2 or 3;

[0393] T1 and T2 are independently selected from CR A and N;

[0394] ring Randomly selected by n R A replace;

[0395] n = 1, 2, 3, 4, 5 or 6;

[0396] R A Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g-L g -SR g and -L g -NR g R' g ;

[0397] L g Independently selected from chemical bonds and C 1-6 Alkylene;

[0398] R g and R' g Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups;

[0399] W represents a chemical bond, either -C(O)- or -C(S)-;

[0400] M1 is selected from -OC(O)O-, -C(O)O- and -OC(O)-;

[0401] M2 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O-)- and -SC(O)-;

[0402] R1 is C 6-12 Alkyl groups, optionally surrounded by 1, 2, or 3 R groups s replace;

[0403] R2 is C 4-12 Alkyl; preferably C 4-10 alkyl;

[0404] R s C 1-12 alkyl;

[0405] R3 is -OR f or -NR f R' f Preferred - OR f ;

[0406] R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl;

[0407] Preferably, R s The substitution site on R1 is spaced 0-12 carbon atoms away from M1.

[0408] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers, or stereoisomers, or pharmaceutically acceptable salts thereof, wherein...

[0409] a = 2, 3, or 4; preferably a = 2 or 4.

[0410] b = 5, 6, or 7; b = 6 is preferred.

[0411] c = 2, 3, 4, 5 or 6; preferably c = 3, 4 or 5;

[0412] d = 1, 2, or 3; preferred d = 2;

[0413] e = 1 or 2;

[0414] f = 1 or 2;

[0415] T1 is N;

[0416] T2 is selected from CR A and N;

[0417] ring Randomly selected by n R A replace;

[0418] n = 1, 2, 3 or 4;

[0419] R A Independently selected from H, halogen, -L g -OR g and -L g -NR g R' g H is preferred;

[0420] L g Independently selected from chemical bonds and C 1-6 Alkylene;

[0421] R g and R' g Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0422] W represents a chemical bond or -C(O)-;

[0423] M1 is -OC(O)O- or -C(O)O-; preferably -OC(O)O-;

[0424] M2 is -C(O)O- or -OC(O-); preferably -OC(O-);

[0425] R1 is C 8-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R s replace;

[0426] R2 is C 4-8 Alkyl; preferably C6 alkyl;

[0427] R s C 1-10 Alkyl; preferably C 1-6 Alkyl; preferably C6 alkyl;

[0428] R3 is -OR f Preferred -OH;

[0429] R f Selected from H and C 1-6 alkyl;

[0430] Preferably, R s The substitution site on R1 is spaced 0-10 carbon atoms from M1; preferably 0-5 carbon atoms; preferably 2 carbon atoms.

[0431] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, having the structure of formula (IV-1):

[0432] The variables are as defined in this invention;

[0433] Preferably,

[0434] a = 4;

[0435] b = 6;

[0436] c = 5;

[0437] d = 2;

[0438] W is -C(O)-;

[0439] Preferably,

[0440] a = 2;

[0441] b = 6;

[0442] c = 3;

[0443] d = 2;

[0444] W is -C(O)-;

[0445] Preferably,

[0446] a = 2, 3, or 4; preferably a = 2 or 4; preferably a = 2.

[0447] b = 6;

[0448] c = 4;

[0449] d = 2;

[0450] W represents a chemical bond.

[0451] In a more specific embodiment, the present invention provides the above-described compound, or its isotopic variants, tautomers or stereoisomers, or pharmaceutically acceptable salts thereof, having the structure of formula (IV-2):

[0452] The variables are as defined in this invention;

[0453] Preferably, c = 4 or 5;

[0454] Preferably, a = 2, 3, or 4; more preferably, a = 2 or 4.

[0455] b = 6;

[0456] c = 4;

[0457] d = 2;

[0458] W represents a chemical bond;

[0459] Preferably, a = 2;

[0460] b = 6;

[0461] c = 5;

[0462] d = 2;

[0463] W is -C(O)-.

[0464] In a more specific embodiment, the present invention provides the above-described compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table (I).

[0465] Table I

[0466] In a more specific embodiment, the present invention also provides pharmaceutical compositions comprising the compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0467] In a more specific embodiment, the present invention also provides a nanoparticle composition comprising a lipid component and optionally a loading; wherein the lipid component contains a compound of the present invention, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the loading is selected from one or more therapeutic agents, preventive agents or diagnostic agents.

[0468] Preferably, the lipid component contains the following components in molar percentage:

[0469] The compounds of this invention, 20 mol% - 85 mol%:

[0470] Structural lipids: 10 mol% - 75 mol%;

[0471] Neutral lipids: 1.0 mol% - 30 mol%;

[0472] Polymer lipids: 0.25 mol% - 10 mol%;

[0473] Preferably, the lipid component contains the following components in molar percentage:

[0474] The compounds of this invention, 25 mol%-60 mol%:

[0475] Structural lipids: 10 mol% - 50 mol%;

[0476] Neutral lipids: 5.0 mol% - 30 mol%;

[0477] Polymer lipids: 0.5 mol% - 5 mol%;

[0478] Preferably, the lipid component contains the following components in molar percentage:

[0479] 50 mol% of the compound of the present invention;

[0480] Neutral lipids 10 mol%;

[0481] Structural lipids 38.5 mol%;

[0482] Polymer lipid 1.5 mol%.

[0483] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the neutral lipid is a phospholipid; preferably, the phospholipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE, and more preferably DSPC and / or DOPE.

[0484] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the structural lipid is a steroid; preferably, the steroid is selected from one or more of cholesterol, sitosterol, coccosterol, lycopene, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol.

[0485] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the polymer lipid is a polyethylene glycol-modified lipid.

[0486] Optionally, the PEGylated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol.

[0487] Optionally, the PEGylated lipid contains a PEG portion of about 1000 Da to about 20 kDa, preferably a PEG portion of about 1000 Da to about 5000 Da.

[0488] Optionally, the PEGylated lipid is selected from one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000, preferably DMG-PEG2000.

[0489] In a more specific embodiment, the present invention also provides the use of the compounds of the present invention, or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, or nanoparticle compositions of the present invention, in the preparation of medicaments for treating, diagnosing or preventing diseases.

[0490] Preferably, the disease is a lung disease;

[0491] Preferably, the drug used for treating, diagnosing, or preventing the disease is a nucleic acid;

[0492] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA, or DNA;

[0493] 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 noncoding 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 ribozymes, preferably mRNA, siRNA, gRNA, or modified mRNA, more preferably modified mRNA;

[0494] Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), and more preferably from one or more of plasmid DNA (pDNA), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0495] In a more specific embodiment, the present invention also provides the use of the compounds of the present invention, or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, or nanoparticle compositions of the present invention, in the preparation of a medicament for delivery of a load, said load being selected from one or more therapeutic agents, preventive agents or diagnostic agents.

[0496] Preferably, the drug is a drug that delivers a load to the lungs.

[0497] In a more specific embodiment, the present invention also provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a pharmaceutical composition of the present invention, or a nanoparticle composition of the present invention;

[0498] Preferably, the disease is a lung disease.

[0499] In more specific embodiments, the present invention also provides compounds of the present invention, or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, or nanoparticle compositions of the present invention, for the treatment, diagnosis or prevention of diseases.

[0500] Preferably, the disease is a lung disease.

[0501] In a more specific embodiment, the present invention also provides a method for delivering a payload into a subject, comprising administering the pharmaceutical composition of the present invention or the nanoparticle composition of the present invention to the subject;

[0502] The load is selected from one or more of a therapeutic agent, a preventive agent, or a diagnostic agent;

[0503] Preferably, the method is a method of delivering a load to the lungs of a subject.

[0504] In a more specific embodiment, the present invention provides the above method, wherein the application includes any one or a combination of local administration and systemic administration;

[0505] Preferably, the administration includes inhalation, intravenous injection, arterial injection, or intraperitoneal injection, more preferably intravenous injection.

[0506] In more specific embodiments, the present invention also provides compounds, or isotopic variants, tautomers or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, or nanoparticle compositions of the present invention, for delivering payloads.

[0507] The load is selected from one or more of a therapeutic agent, a preventive agent, or a diagnostic agent;

[0508] Preferably, it is used to deliver a load to the lungs.

[0509] In more specific embodiments, the present invention also provides the above-mentioned compounds, pharmaceutical compositions, nanoparticle compositions, methods, or uses, wherein the therapeutic agent, preventive agent, or diagnostic agent is a nucleic acid;

[0510] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASO), RNA, or DNA;

[0511] 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 noncoding 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 ribozymes, preferably mRNA, siRNA, gRNA, or modified mRNA, more preferably mRNA or modified mRNA;

[0512] Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), and more preferably from one or more of plasmid DNA (pDNA), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

[0513] In a more specific embodiment, the present invention also provides a method for preparing a compound of formula (II), the method comprising:

[0514] The compound of formula (IIA) is reacted with the compound of formula (IIB) to give the compound of formula (II);

[0515] Alternatively, the compound of formula (IIA) may be reacted with the compound of formula (IIC) to obtain the compound of formula (II);

[0516] Wherein, X is a halogen, and the other groups are as defined in this invention.

[0517] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0518] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. A tautomer is a special type of functional group isomer; a pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most prominent examples are enol and keto tautomers.

[0519] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H,13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0520] The present 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 thereof. All such forms are subject to the present invention.

[0521] Pharmaceutical Compositions and Kits

[0522] In another aspect, the present invention provides a pharmaceutical composition comprising the nanoparticle composition of the present invention and a pharmaceutically acceptable excipient, said nanoparticle composition comprising the compounds of the present invention.

[0523] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0524] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the nanoparticle composition of the present invention and / or other therapeutic, diagnostic, or preventative agents. In some embodiments, the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents provided in the first and second containers form a unit dosage form.

[0525] Dosage

[0526] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0527] Typically, an effective amount of the pharmaceutical composition of the present invention is administered. The amount of pharmaceutical composition actually administered may be determined by a physician, depending on relevant circumstances, including the condition being treated or prevented, the chosen route of administration, the actual amount of pharmaceutical composition administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0528] When used to prevent the conditions described in this invention, the pharmaceutical composition provided herein is administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0529] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0530] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0531] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0532] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0533] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0534] Example

[0535] To make the technical solution of the present invention clearer and more explicit, the present invention will be further described in detail through the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art. Unless otherwise specified, the materials, reagents, etc., used in the embodiments can be obtained commercially.

[0536] Table 1

[0537] Example 1: Synthesis of Compound 1

[0538] Compound 1-1 (1.90 g, 4.36 mmol, 1.0 eq.) and 4-hydroxybutylamine (0.78 g, 8.72 mmol, 2.0 eq.) were dissolved in ethanol (19 mL) at room temperature in a 40 mL sealed tube. The mixture was heated to 70 °C and reacted for 3 h. The system was cooled to room temperature, and the reaction was monitored by TLC and LCMS until the starting material was almost completely converted. The reaction system was concentrated, redissolved in ethyl acetate (100 mL), backwashed with water (3 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give a yellow oily compound 1-2 (998 mg).

[0539] Compound 1-3 (5 g, 21.80 mmol, 1.0 eq.), n-heptanoic acid (3.12 g, 23.98 mmol, 1.1 eq.), EDCI (5.08 g, 32.70 mmol, 1.5 eq.), DMAP (0.53 g, 4.36 mmol, 0.2 eq.), and DCM (50 mL) were added to a 250 mL single-necked round-bottom flask at room temperature. The mixture was stirred at room temperature for 18 h, and the reaction was monitored by TLC. The starting material was essentially completely converted. The mixture was concentrated under reduced pressure, redissolved in ethyl acetate (300 mL), and extracted with saturated ammonium chloride (50 mL). The mixture was separated, and the organic phase was washed with saturated sodium chloride (500 mL), dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a colorless oily compound 1-4 (6.98 g).

[0540] Compound 1-4 (6.98 g, 20.44 mmol, 1.0 eq.) was dissolved in DCM (35 mL) in a 100 mL single-necked round-bottom flask at room temperature. After the system was cooled to 0 °C, a 1,4-dioxane solution of hydrogen chloride (35 mL, 4 M in THF) was added dropwise. After the addition was complete, the system was warmed back to room temperature and the reaction was continued for 1 h. The reaction was monitored by TLC. The starting material was basically completely converted. The crude compound 1-5 (6.22 g) was concentrated under reduced pressure and used directly in subsequent reactions without purification.

[0541] Compound 1-5 (2.2 g, 7.92 mmol, 1.0 eq.), bromide 1-6 (2.33 g, 8.71 mmol, 1.1 eq.), K₂CO₃ (3.28 g, 23.76 mmol, 3.0 eq.), KI (1.58 g, 9.50 mmol, 1.2 eq.), CPME (15 mL), and ACN (5 mL) were added to a 40 mL sealed tube. The system was heated to 80 °C and reacted for 18 h. The reaction was monitored by LCMS until the starting material was almost completely reacted. The system was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (3 x 5 mL). The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a brown oily compound 1-7 (3.21 g).

[0542] Compound 1-7 (3.21 g, 7.50 mmol, 1.0 eq.) and THF (32 mL) were added to a 100 mL single-necked round-bottom flask. The system was cooled to 0 °C, and a tetrahydrofuran solution of TBAF (1 M, 9 mL, 9.0 mmol, 1.2 eq) was added dropwise. After the addition was complete, the system was warmed to room temperature and reacted for 2 h. The mixture was extracted with ethyl acetate (2 x 100 mL), separated, and the organic phases were combined and washed with saturated NaCl (100 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain crude yellow oily compound 1-8 (3.1 g).

[0543] Oxaloyl chloride (0.69 g, 5.42 mmol, 1.7 eq.) and DCM (10 mL) were added to a 100 mL three-necked round-bottom flask. The system was cooled to -78 °C, and DMSO (0.62 g, 7.98 mmol, 2.5 eq.) was added dropwise. After the addition was complete, the system was warmed to -60 °C and stirred for 10 min. The system was then warmed to -55 °C, and compound 1-8 (1 g, 3.19 mmol, 1.0 eq.) was added dropwise over 10 min. After the addition was complete, the reaction was continued at -55 °C for 1 h. Et3N (1.87 g, 18.50 mmol, 5.8 eq.) was then added dropwise over 5 min. After the addition was complete, the mixture was allowed to return to room temperature and the reaction continued for another 10 min. The reaction was quenched at 0 °C with 100 mL of water, extracted with DCM (1 x 100 mL), separated, and the organic phases were combined and washed with saturated NaCl (1 x 100 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain crude yellow oily compound 1-9 (181.3 mg).

[0544] Compounds 1-2 (106.84 mg, 0.24 mmol, 1.0 eq.), 1-9 (90.00 mg, 0.29 mmol, 1.2 eq.), and THF (4 mL) were added to a 40 mL sealed tube. After reacting at room temperature for 18 h, sodium triacetoxyborohydride (153.10 mg, 0.72 mmol, 3.0 eq.) was added, and the reaction was continued at room temperature for another 3 h. The reaction system was quenched at 0 °C with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The liquid and liquid phases were combined, washed with saturated NaCl (1 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was sent for preparation to obtain yellow oily compound 1 (68.9 mg).

[0545] 1 H NMR(300MHz, CDCl3)δ:4.33-4.09(m,6H),3.55(m,2H),2.99(m,2H),2.46-2. 26(m,10H),2.05-2.00(m,2H),1.74-1.23(m,55H),0.93-0.86(m,9H); ESI-MS m / z:739.55[M+H] + .

[0546] Example 2: Synthesis of Compound 2

[0547] Compound 2 was prepared according to the method of Example 1, yielding 59.4 mg of an oily product.

[0548] 1H NMR(300MHz, CDCl3)δ:4.31-4.08(m,6H),3.54(t,J=5.1Hz,2H),2.96-2.93(m,2H),2 .60-2.26(m,10H),1.94-1.85(m,2H),1.72-1.25(m,51H),0.94-0.86(m,9H); ESI-MS m / z:711.50[M+H] + .

[0549] Example 3: Synthesis of Compound 3

[0550] Compound 1-5 (880 mg, 3.17 mmol, 1.0 eq.), 6-bromohexanoic acid (679.60 mg, 3.48 mmol, 1.1 eq.), EDCI (737.59 mg, 4.75 mmol, 1.5 eq.), DMAP (386.96 mg, 3.17 mmol, 1.0 eq.), and DCM (8.8 mL) were added to a 25 mL single-necked flask. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was monitored by TLC until the starting material was completely converted. The mixture was concentrated under reduced pressure, redissolved in dichloromethane (30 mL), and extracted with saturated ammonium chloride (50 mL). The mixture was separated, and the organic phase was washed with saturated sodium chloride (50 mL), dried, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a colorless oily compound 3-1 (1.1 g).

[0551] Compounds 1-2 (200 mg, 0.45 mmol, 1.0 eq.), 3-1 (207.46 mg, 0.50 mmol, 1.1 eq.), potassium carbonate (186.88 mg, 1.35 mmol, 3.0 eq.), potassium iodide (89.79 mg, 0.54 mmol, 1.2 eq.), CPME (6 mL), and acetonitrile (2 mL) were added to a 40 mL sealed tube. The reaction was heated to 80 °C for 18 h, and the reaction was monitored by LCMS until the starting materials were almost completely reacted. After the system cooled to room temperature, it was filtered, and the filter cake was washed with ethyl acetate (2 x 5 mL). The filtrate was concentrated to obtain the crude product. The crude product was sent for preparation to obtain a pale yellow oily compound 3 (164.8 mg).

[0552] 1H NMR (300MHz, CDCl3) δ: 4.59 (d, J = 12.9Hz, 1H), 4.16-4.09 (m, 6H), 3.82 (d, J = 12.9Hz, 1H), 3.55 (s ,2H),2.98(t,J=12.3Hz,1H),2.57-2.27(m,11H),1.79--1.10(m,57H),0.90-0.86(m,9H); ESI-MS m / z:781.50[M+H] + .

[0553] Example 4: Synthesis of Compound 4

[0554] Compound 4 was prepared according to the method of Example 3, yielding 130.8 mg of an oily product.

[0555] 1 H NMR (300MHz, CDCl3) δ: 4.59 (d, J = 12.9Hz, 1H), 4.17-4.09 (m, 6H), 3.82 (d, J = 12.9Hz, 1H), 3.55 (s ,2H),2.98(t,J=12.0Hz,1H),2.62-2.27(m,11H),1.79-1.11(m,53H),0.90-0.86(m,9H); ESI-MS m / z:753.50[M+H] + .

[0556] Example 5: Synthesis of Compound 5

[0557] Compound 5 was prepared according to the method of Example 3, yielding 130.8 mg of an oily product.

[0558] 1 H NMR(300MHz,CD3OD)δ:4.49(d,J=12.6Hz,1H),4.16-4.10(m,6H),3.94(d,J=12.6Hz,1H),3.61(t,J=6 .3Hz,2H),3.06(t,J=12.3Hz,1H),2.64-2.28(m,11H),1.84-1.11(m,49H),0.93-0.88(m,9H); ESI-MS m / z:725.65[M+H] + .

[0559] Example 6: Synthesis of Compound 6

[0560] In a 50 mL three-necked flask, N-Boc-piperazine (1.9 g, 10.20 mmol, 1.0 eq.), 4-bromobutanol (1.72 g, 11.22 mmol, 1.1 eq.), potassium iodide (2.03 g, 12.24 mmol, 1.2 eq.), potassium carbonate (4.23 g, 30.60 mmol, 3.0 eq.), and acetonitrile (19 mL) were added at room temperature. The reaction system was heated to 80 °C and stirred overnight. The reaction system was cooled to room temperature, and the reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined and washed with saturated NaCl aqueous solution (15 mL). The organic phases were dried over anhydrous Na2SO4, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oily compound 6-2 (1.1 g).

[0561] Oxaloyl chloride (0.84 g, 6.58 mmol, 1.7 eq.) and DCM (10 mL) were added to a 50 mL three-necked flask at room temperature. DMSO (0.76 g, 9.68 mmol, 2.5 eq.) was added dropwise to the system at -78 °C, and the reaction mixture was stirred at -78 °C for 10 minutes. Compound 6-2 (1 g, 3.87 mmol, 1.0 eq.) was added to the system again at -60 °C, and the reaction mixture was stirred at -55 °C for 1 hour. Triethylamine (2.27 g, 22.45 mmol, 5.8 eq.) was then added, and the reaction mixture was allowed to return to room temperature and stirred overnight. The reaction was quenched with water (10 mL), extracted with dichloromethane (2 x 10 mL), the organic phase was washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oily compound 6-3 (525 mg).

[0562] Compound 6-3 (150 mg, 0.59 mmol, 1.0 eq.), compound 1-2 (259.64 mg, 0.59 mmol, 1.0 eq.), and THF (5 mL) were added to a 20 mL sealed tube at room temperature. The reaction system was stirred overnight at room temperature. Sodium triacetoxyborohydride (372.05 mg, 1.77 mmol, 3.0 eq.) was added to the system at room temperature. After stirring for 3 hours, water (4 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (2 x 5 mL). The organic phase was washed with saturated NaHCO3 aqueous solution (2 mL) and dried over anhydrous Na2SO4. The mixture was filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oily compound 6-4 (245 mg).

[0563] Compound 6-4 (245 mg, 0.36 mmol, 1.0 eq.) and hydrogen chloride (1,4-dioxane solution) (4.9 mL) were added to a 50 mL single-necked round-bottom flask at room temperature. The reaction system was stirred at room temperature for 1 hour. The reaction system was then concentrated under reduced pressure to obtain crude compound 6-5 (195 mg). The crude product can be used directly in the next step.

[0564] Compound 6-5 (210 mg, 0.36 mmol, 1.0 eq.), compound 6-6 (85.28 mg, 0.36 mmol, 1.0 eq.), potassium iodide (71.64 mg, 0.43 mmol, 1.2 eq.), potassium carbonate (149.11 mg, 1.08 mmol, 3.0 eq.), and acetonitrile (4 mL) were added to an 8 mL sealed tube at room temperature. The system was heated to 80 °C and reacted overnight, with the reaction monitored by LC-MS. The reaction system was cooled to room temperature, filtered, concentrated, and the crude product was purified by HPLC to obtain a pale yellow oily compound 6 (98 mg).

[0565] 1 H NMR (400MHz, CDCl3) δ: 4.20 (t, J = 5.6Hz, 2H), 4.13 (dt, J = 7.2Hz, 11.2Hz, 4H), 3.65 (s, 2H), 2.66-2.4 3(m,18H),2.31(t,J=7.2Hz,2H),1.78-1.58(m,16H),1.42-1.22(m,32H),0.91-0.84(m,9H); ESI-MS m / z:740.65[M+H] + .

[0566] Example 7: Synthesis of Compound 7

[0567] Compound 7 was prepared according to the method of Example 6, yielding 68.1 mg of an oily product.

[0568] 1 H NMR(300MHz,CD3OD)δ:4.20(t,J=5.6Hz,2H),4.13(dt,J=6.8Hz,10.4Hz,4H),3.87(s,2H),3.01-2.6 7(m,16H),2.31(t,J=7.6Hz,2H),1.76-1.60(m,12H),1.42-1.25(m,34H),0.91-0.84(m,9H); ESI-MS m / z:712.65[M+H] + .

[0569] Example 8: Synthesis of Compound 8

[0570] In a 250 mL reaction flask, compound 8-1 (5 g, 21.71 mmol, 1.0 eq.), n-heptanoic acid (3.11 g, 23.88 mmol, 1.1 eq.), EDCI (6.24 g, 32.57 mmol, 1.5 eq.), and DMAP (2.652 g, 21.71 mmol, 1.0 eq.) were dissolved in DCM (50 mL). The mixture was reacted overnight at room temperature. Water (2 x 50 mL) was added, and the mixture was extracted. The organic phase was washed with salt (1 x 50 mL), dried over Na2SO4, and evaporated to dryness. The residue was filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain a colorless oily compound 8-2 (6.8 g).

[0571] Compound 8-2 (6.8 g, 29.53 mmol, 1.0 eq.), HCl (4 M in Dioxane) (25 mL) and DCM (5 mL) were added to a 250 mL round-bottom flask. The mixture was reacted at room temperature for 1 h. The organic solvent was removed by rotary evaporation under reduced pressure to obtain crude product 8-3, which was used directly in the next step of the reaction.

[0572] Compound 8-3 (500 mg, 2.06 mmol, 1.0 eq.), 6-bromohexanoic acid (402.40 mg, 2.06 mmol, 1.0 eq.), EDCI (480.41 mg, 3.10 mmol, 1.5 eq.), DMAP (252.04 mg, 2.06 mmol, 1.0 eq.), and DCM (15 mL) were added to a 20 mL sealed tube. The mixture was reacted overnight at room temperature. 5 mL of water was added, and the mixture was extracted with DCM (2 x 5 mL). The extract was washed with organic phase brine (1 x 15 mL), dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain a yellow oily compound 8-4 (840 mg).

[0573] Compounds 8-4 (207.95 mg, 0.50 mmol, 1.1 eq.), 1-2 (200 mg, 0.45 mmol, 1.0 eq.), KI (89.79 mg, 0.54 mmol, 1.2 eq.), K2CO3 (186.88 mg, 1.35 mmol, 3.0 eq.), and ACN (4 mL) were added to an 8 mL sealing tube. The mixture was reacted overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with acetonitrile (2 x 4 mL). The filtrates were combined and evaporated to dryness. The mixture was then purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.5% NH3·H2O) / ACN = 6:4, Mobile Phase B: ACN / IPA = 1:9; Flow rate: 60 mL / min; Gradient: 45%) B to 75% B in 0-12 min), yielding yellow oily compound 8 (165.1 mg).

[0574] 1 H NMR (300MHz, CD3OD) δ: 4.23 (t, J = 5.7Hz, 2H), 4.16-4.09 (m, 4H), 3.60-3.55 (m, 6H), 2.68-2.31 (m, 16H), 1.69-1.25 (m, 50H), 0.92-0.86 (m, 9H); ESI-MS m / z:782.55[M+H] + .

[0575] Example 9: Synthesis of Compound 9

[0576] Compound 9 was prepared according to the method of Example 8, yielding 144.8 mg of an oily product.

[0577] 1 H NMR (300MHz, CD3OD) δ: 4.22 (t, J = 5.7Hz, 2H), 4.16-4.08 (m, 4H), 3.64-3.54 (m, 6H), 2.68-2.31 (m, 16H), 1.69-1.27 (m, 46H), 0.95-0.88 (m, 9H); ESI-MS m / z:754.65[M+H] + .

[0578] Pharmacological experiments

[0579] Experimental Example 1: Preparation of Nanoparticles

[0580] Materials used for assembling lipid nanoparticles include: (1) ionizable lipid compounds: such as the compounds designed and synthesized in this invention or Lipid5 (commercially available); (2) structural lipids: such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids: such as DSPC, which is 1,2-distearyl-SN-glycerol-3-phosphocholine (purchased from AVT); (4) polyethylene glycol-modified lipid compounds: such as DMG-PEG2000, which is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (purchased from AVT); (5) effective components of nucleic acid fragments: such as Luciferase mRNA, siRNA, CRISPR Cas 9 mRNA, etc. (self-made or commercially available). The names and structural formulas of lipid nanoparticle assembly materials are detailed in Table 1, and the ionizable lipids designed and synthesized in this invention are shown in Table 2.

[0581] Table 1

[0582] Table 2. Structural formulas of compounds

[0583] Preparation method of lipid nanoparticles: (1) Ionizable lipid compounds (the compounds provided in this invention or control compounds (Lipid5, etc.), cholesterol, phospholipids (DSPC) and polyethylene glycol-modified lipids (DMG-PEG2000) are dissolved and mixed in ethanol in sequence at (molar percentage) 50%, 38.5%, 10% and 1.5%. (2) Dissolve the mRNA active ingredient in 25mM sodium citrate solution (pH=4.0-4.5); (3) Use an automated high-throughput microfluidic system to mix the organic phase containing the dissolved lipid mixture and the aqueous phase containing the dissolved mRNA at a flow rate ratio of 1:1 to 1:4, with a mixing speed of 10mL / min to 18mL / min; (4) Dilute the prepared lipid nanoparticles (N / P ratio of 6) with phosphate buffer solution and ultrafilter the nanoparticle solution to the original preparation volume using an ultrafiltration tube with a molecular weight cutoff of 100kDa (purchased from Millipore); (5) After sterilization by filtration through a 0.2μm sterile filter membrane, store the obtained nanoparticles in a sealed glass bottle at low temperature.

[0584] Lipid nanoparticles can be prepared using microfluidic mixing systems, but are not limited to this method; other methods include T-type mixers and ethanol injection.

[0585] Experimental Example 2: Characterization of the physical properties of lipid nanoparticles

[0586] The particle size and particle size distribution (PDI) of the prepared lipid nanoparticles were measured using a Zetasizer Pro (purchased from Malvern Instruments Ltd) and a DynaPro NanoStar (purchased from Wyatt). The lipid nanoparticle samples were diluted in PB buffer, and the surface potential (Zeta potential) of the prepared lipid nanoparticles was measured using a Zetasizer Pro (purchased from Malvern Instruments Ltd).

[0587] The degree to which lipid nanoparticles encapsulate RNA is characterized by encapsulation efficiency (%), a coefficient reflecting the degree of binding between lipid nanoparticles and RNA fragments. This coefficient is derived from Quant-it... TM The RiboGreen RNA Assay (purchased from Invitrogen) method was used for measurement. Lipid nanoparticle samples were diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.5), and a portion of the sample solution was added to 0.5% Triton X-100 and incubated at 37°C for 30 minutes. Immediately after the reaction, the fluorescence values ​​were read using a Varioskan LUX multi-functional microplate reader (purchased from Thermofisher) at an absorption wavelength of 485 nm and an emission wavelength of 528 nm to obtain the encapsulation loading rate. The physical characterization information is detailed in Table 3.

[0588] Experiment Example 3: Animal Experiment

[0589] The delivery efficiency and safety of nanoparticles loaded with luciferase mRNA (Trilink, L-7202) in mice were evaluated. SPF-grade C57BL / 6 mice, female, 6-8 weeks old, weighing 18-22g, were purchased from Beijing Spefol Biotechnology Co., Ltd. All animals underwent acclimatization for at least 7 days prior to the experiment, with free access to food and water, 12 / 12h light / dark cycles, an indoor temperature of 20-26℃, and a humidity of 40-70%. Mice were randomly assigned to groups. The prepared lipid nanoparticles loaded with luciferase mRNA were injected intravenously into mice at a single dose according to the dosage listed in Table 3. Six hours after administration, the mice were dissected and organs were removed. Bioluminescence detection of the mouse organs was performed using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer). The specific procedures for detection were as follows: a 15 mg / mL D-luciferin solution was prepared with physiological saline, and the substrate was administered to each mouse via intraperitoneal injection. Seven minutes after administration of the substrate, mice were euthanized by cervical dragging, and organs were dissected and removed. The removed mouse organs were placed in IVIS for fluorescence imaging, and data were collected and analyzed from areas of concentrated fluorescence distribution.

[0590] The organ distribution of lipid nanoparticle carriers delivered in vivo is expressed as the average fluorescence intensity and total photon count of different animal organs within the same test group, as shown in Table 3. Higher values ​​for fluorescence intensity and total photon count indicate higher delivery efficiency of the lipid nanoparticles for the mRNA fragment in that organ (liver or lung).

[0591] Table 3 Physical characteristics and organ distribution of LNPs in vivo

[0592] While the invention has been fully described through its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims.

Claims

1. A compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Ring A is C 3-10 Cycloalkyl or 3 to 10-membered heterocyclic groups, optionally surrounded by n R groups. A replace; n = 1, 2, 3, 4, 5 or 6; R A Independently selected from H, oxo, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g ; L g Independently selected from chemical bonds and C 1-10 Alkylene; R g and R' g Independently selected from H and C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; 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 -; W is selected from a chemical bond, C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR w -, -NR w C(O)NR w -, -OC(O)S-, -OC(O)O-, -NR w C(O)O-, -SC(O)-, -C(O)S-, -NR w -, -C(O)NR w -, -NR w C(O)-, -NR w C(O)S-, -SC(O)NR w -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR w -, -NR w C(S)O-, -S-S- and -S(O) 0- 2-; R w Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; Q is selected from chemical bonds, -OC(O)-, -SC(O)-, -NR a C(O)-, -C(O)-, -OC(S)-, -S(O) 1-2 - Phenylidene and pyridylene, wherein the phenylene or pyridylene is optionally substituted with 1, 2, 3 or 4 R*. R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a ; L a Independently selected from chemical bonds and C 1-8 Alkylene; R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; G1 is selected from C 4-14 Alkylene, C 4-14 imide and C 4-14 Alynyl group, which is optionally surrounded by one or more R G1 replace; R G1 Independently selected from H and C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ; L b Independently selected from chemical bonds and C 1-14 Alkylene; R b and R' b Independently selected from H and C 1-14 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; G2 and G3 are independently selected from chemical bonds, C 1-14 Alkylene, C 2-14 imide and C 2-14 Alynyl group, which is optionally surrounded by one or more R G2 replace; R G2 Independently selected from H and C 1-14 Alkyl, -L b -OR b -L b -SR b and -L b -NR b R' b ; G4 is selected from chemical bonds, C 1-8 Alkylene, C 2-8 imide and C 2-8 Alynyl group, which is optionally surrounded by one or more R G4 replace; R G4 Independently selected from H and C 1-8 Alkyl, -L c -OR c -L c -SR c and -L c -NR c R' c ; L c Independently selected from chemical bonds and C 1-8 Alkylene; R c and R' c Independently selected from H and C 1-8 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; Or two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-14 Cycloalkyl or 3 to 14-membered heterocyclic group, optionally surrounded by one or more R 4g replace; R 4g Independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups, -L d -OR d -L d -SR d and -L d -NR d R' d ; L d Independently selected from chemical bonds and C 1-8 Alkylene; R d and R' d Independently selected from H and C 1-8 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 alkenyl and C 4-20 Alkyne group, which is optionally surrounded by one or more R groups s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-; R and R' are each independently selected from H and C. 1-20 alkyl; R s Independently selected from H and C 1-20 Alkyl, -L e -OR e -L e -SR e and -L e -NR e R' e ; L e Independently selected from chemical bonds and C 1-20 Alkylene; R e and R' e Independently selected from H and C 1-20 Alkyl, C 3-14 cycloalkyl groups and 3 to 14-membered heterocyclic groups; R3 is selected from CN, -OR f -C(O)R f -OC(O)R f -NR”C(O)R f -NR f R' f 、-NR”C(O)NR f R' f 、-NR”C(NR f )NR f R' f -NR”C(O)R f -NR”S(O)2R f -OC(O)NR f R' f -NR”C(O)OR f -N(OR) f )C(O)R f -N(OR) f )S(O)2R f -N(OR) f )C(O)OR f -N(OR) f )C(O)R f R' f 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups; R f and R' f Independently selected from H and C 1-10 Alkyl, C 3-10 cycloalkyl groups and 3 to 10-membered heterocyclic groups; "R" is independently selected from H and C. 1-6 alkyl.

2. The compound of claim 1, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is C 3-7 Cycloalkylene or 3 to 7-membered heterocyclic cycloalkylene groups; Preferably, ring A is a 3- to 7-membered heterocyclic group, more preferably a 3- to 7-membered nitride heterocyclic group, for example...

3. The compound of claim 1 or 2, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, n = 1, 2, 3, 4 or 5; preferably n = 1, 2, 3 or 4; preferably n = 1 or 2; preferably n = 1.

4. The compound of any one of claims 1-3, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R A Independently selected from H, cyano, halogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g Preferred components include H, cyano, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g Preferred components include H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g Preferred components include H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g and -L g -NR g R' g Preferred components include H, halogens, and -L. g -OR g and -L g -NR g R' g .

5. The compound of any one of claims 1-4, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L g Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R g and R' g Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl groups and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

6. The compound of any one of claims 1-5, 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)-, -OC(O)O-, -SC(O-, -C(O)S-, -C(O)NR- and -NRC(O-), preferably -C(O)O-, -OC(O)O-, -OC(O-, -SC(O-) and -C(O)S-; preferably not both of them are -OC(O)O-; Preferably, M1 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, more preferably -OC(O)O-, -C(O)O- and -C(O)S-, more preferably -OC(O)O-, -C(O)O- and -OC(O-), more preferably -OC(O)O- or -C(O)O-, more preferably -OC(O)O-; Preferably, M2 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O)- and -SC(O)-, more preferably C(O)O-, -OC(O-, -SC(O- and -C(O)S-, more preferably -C(O)O- or -OC(O)-, more preferably -OC(O)-.

7. The compound of any one of claims 1-6, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, W is selected from chemical bonds, -C(O)-, -OC(O)-, -SC(O)-, -C(S)-, -OC(S)-, -NR w C(O)-, -OC(S)-, -NR w C(S)- and -S(O) 0-2 -; Preferred chemical bonds, -C(O)- and -C(S)-; Preferred chemical bonds and -C(O)-; Preferred chemical bonds; Preferred -C(O)-; Preferably, R w Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

8. The compound of 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 chemical bonds, -OC(O)-, -SC(O)-, -NR a C(O)-, -C(O)-, -OC(S)-, -S(O) 1-2 -; Preferred chemical bonds, -OC(O)- and -SC(O)-; Preferred chemical bonds and -SC(O)-; Preferably, R* is independently selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a -L a -SR a and -L a -NR a R' a Preferred components include H, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L a -OR a and -L a -NR a R' a Preferred components include H, halogens, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Preferably, L a Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R a and R' a Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

9. The compound of any one of claims 1-8, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G1 is selected from C 4-10 Alkylene, C 4-10 imide and C 4-10 Alkyne group; preferably C 4-10 Alkylene; preferably C 5-8 Alkylene; preferably C6 alkylene; Preferably, G1 is optionally divided by 1, 2, 3 or 4 R G1 replace.

10. The compound of any one of claims 1-9, 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 C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 alkyl); Preferably, L b Independently selected from chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R b and R' b Independently selected from H and C 1-10 Alkyl, C 3-10 Cycloalkyl groups and 3 to 10-membered heterocyclic groups; preferably H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl.

11. The compound of any one of claims 1-10, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G2 and G3 are independently selected from chemical bonds, C 1-10 Alkylene, C 2-10 imide and C 2-10 Alynyl group; preferred chemical bond and C 1-10 Alkylene; preferably C 1-10 Alkylene; Preferably, G2 is selected from C 1-8 Alkylene; preferably C 1-6 Alkylene; preferably C 3-5 Alkylene; Preferably, G3 is selected from C 1-8 Alkylene; preferably C 1-6 Alkylene; preferably C 1-3 Alkylene; Preferably, the total length of G2 and G3 is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms; preferably 4, 5, 6, 7, 8, 9 or 10 carbon atoms; preferably 4, 5, 6, 7 or 8 carbon atoms; preferably 5, 6 or 7 carbon atoms. Preferably, G2 and G3 are each optionally represented by 1, 2, 3 or 4 Rs. G2 replace.

12. The compound of any one of claims 1-11, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R G2 Independently selected from H and C 1-10 Alkyl (preferably C) 1-6 alkyl), -L b -OR b -L b -SR b and -L b -NR b R' b H and C are preferred. 1-10 Alkyl (preferably C) 1-6 Alkyl, preferably C 1-3 Alkyl, preferably C 1-2 alkyl).

13. The compound of any one of claims 1-12, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, G4 is selected from C 1-6 Alkylene, C 2-6 imide and C 2-6 Alkyne group; preferably C 1-4 Alkylene, C 2-4 imide and C 2-4 Alkyne group; preferably C 1-4 Alkylene; preferably C 2-4 Alkylene; Preferably, G4 is optionally divided by 1, 2, 3 or 4 R G4 replace.

14. The compound of any one of claims 1-13, 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, -L c -OR c -L c -SR c and -L c -NR c R' c H and C are preferred. 1-6 Alkyl groups, preferably H and C 1-4 alkyl; Preferably, the two R atoms attached to the same carbon atom G4 Together with the carbon atoms they are attached to, they form C 3-10 Cycloalkylene or 3 to 10-membered heterocyclic alkylene groups, preferably forming C 3-7 Cycloalkyl or 3 to 7-membered heterocyclic group, optionally surrounded by 1, 2 or 3 R groups. 4g replace; Preferably, R 4g Independently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

15. The compound of any one of claims 1-14, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L c Independently selected from chemical bonds and C 1-6 Alkylene; preferably chemical bonds and C 1-4 Alkylene; Preferably, R c and R' c Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably selected from H and C 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

16. The compound of any one of claims 1-15, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L d Independently selected from chemical bonds and C 1-6 Alkyl (preferably C) 1-4 Alkylene); Preferably, R d and R' d Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably selected from H and C 1-6 Alkyl groups; preferably selected from H and C. 1-4 alkyl.

17. The compound of any one of claims 1-16, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from C 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; preferably C 8-20 Alkyl, C 8-20 alkenyl and C 8-20 Alkyne group; preferably, R1 is C 4-20 Alkyl; preferably C 6-14 Alkyl; preferably C 8-20 Alkyl; preferably C 8-12 Alkyl; preferably C 8-10 Alkyl; preferably C9 alkyl; Preferably, R2 is selected from C 4-14 Alkyl, C 4-14 alkenyl and C 4-14 Alkyne group; preferably, R2 is C 4-20 Alkyl; preferably C 4-14 Alkyl; preferably C 4-12 Alkyl (e.g., C10) 4-12 (linear alkyl); preferably C 4-10 Alkyl; preferably C 4-8 Alkyl; preferably C6 alkyl; Preferably, R1 and R2 are each optionally represented by 1, 2, 3 or 4 R... s Instead, preferably optionally replaced by 1, 2 or 3 R s Instead, preferably optionally replaced by 1 R s replace; Preferably, R1 is substituted and R2 is not substituted; Preferably, one, two, or three (preferably one) methylene units in R1 or R2 are optionally and independently replaced by -NR'-.

18. The compound of any one of claims 1-17, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R and R' are each independently selected from H and C. 1-14 Alkyl groups; preferably H and C 1-9 Alkyl groups; preferably H and C 1-6 Alkyl group; preferably R is H.

19. The compound of any one of claims 1-18, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R s Independently selected from H and C 1-14 Alkyl, -L e -OR e and -L e -NR e R' e Preferred ingredients are H and C. 1-14 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C 1-9 Alkyl groups; preferably H and C 1-6 Alkyl groups, preferably H and C 1-4 alkyl.

20. The compound of any one of claims 1-19, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, L e Independently selected from chemical bonds and C 1-14 Alkylene; preferably chemical bonds and C 1-10 Alkylene; preferably chemical bonds and C 1-6 Alkylene; Preferably, R e and R' e Independently selected from H and C 1-14 Alkyl groups; preferably H and C 1-10 Alkyl groups; preferably H and C 1-6 alkyl.

21. The compound of any one of claims 1-20, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from CN, -OR f and -NR f R' f Preferred - OR f and -NR f R' f Preferred option: -OR f ; preferably OH; Preferably, R3 is selected from OH and -N(CH3)2; Preferably, R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 Alkyl groups; preferably H and C 1-4 Alkyl groups; preferably H and Me.

22. The compound of any one of claims 1-21, 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 spaced 0-12 carbon atoms from M1 or M2, preferably 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 2 carbon atoms.

23. The compound of any one of claims 1-22, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having a structure of formula (II), (III), (III-1), (III-2), (III-3), (III-4), or (III-5): in, e = 0, 1, 2 or 3; preferably e = 0, 1 or 2; preferably e = 1 or 2; f = 0, 1, 2 or 3; preferably f = 0, 1 or 2; preferably f = 1 or 2; T1 and T2 are independently selected from CR A and N; ring Randomly selected by n R A replace; Other variables are defined as described in any one of claims 1-22; Preferably, T1 is N; preferably, T2 is N; preferably, T2 is CR A .

24. The compound of any one of claims 1-23, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV), (IV-1), (IV-2), (IV-3), or (IV-4): in, a = 1, 2, 3, 4, 5 or 6; b = 3, 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5 or 6; d = 1, 2, 3, 4, 5 or 6; preferably d = 1, 2, 3 or 4; Other variables are defined as described in any one of claims 1-23.

25. The compound of claim 24, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV): in, a = 1, 2, 3, 4, 5 or 6; b = 4, 5, 6, 7 or 8; c = 2, 3, 4, 5 or 6; d = 1, 2, 3 or 4; e = 0, 1, 2 or 3; f = 0, 1, 2 or 3; T1 and T2 are independently selected from CR A and N; ring Randomly selected by n R A replace; n = 1, 2, 3, 4, 5 or 6; R A Independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -L g -OR g -L g -SR g and -L g -NR g R' g ; L g Independently selected from chemical bonds and C 1-6 Alkylene; R g and R' g Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; W represents a chemical bond, either -C(O)- or -C(S)-; M1 is selected from -OC(O)O-, -C(O)O- and -OC(O)-; M2 is selected from -OC(O)O-, -C(O)O-, -C(O)S-, -OC(O-)- and -SC(O)-; R1 is C 6-12 Alkyl groups, optionally surrounded by 1, 2, or 3 R groups s replace; R2 is C 4-12 Alkyl; preferably C 4-10 alkyl; R s C 1-12 alkyl; R3 is -OR f or -NR f R' f Preferred - OR f ; R f and R' f Independently selected from H and C 1-6 Alkyl, C 3-7 Cycloalkyl and 3 to 7-membered heterocyclic groups; preferably H and C 1-6 alkyl; Preferably, R s The substitution site on R1 is spaced 0-12 carbon atoms away from M1.

26. The compound of claim 25, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, a = 2, 3, or 4; preferably a = 2 or 4. b = 5, 6, or 7; b = 6 is preferred. c = 2, 3, 4, 5 or 6; preferably c = 3, 4 or 5; d = 1, 2, or 3; preferred d = 2; e = 1 or 2; f = 1 or 2; T1 is N; T2 is selected from CR A and N; ring Randomly selected by n R A replace; n = 1, 2, 3 or 4; R A Independently selected from H, halogen, -L g -OR g and -L g -NR g R' g H is preferred; L g Independently selected from chemical bonds and C 1-6 Alkylene; R g and R' g Independently selected from H and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; W represents a chemical bond or -C(O)-; M1 is -OC(O)O- or -C(O)O-; preferably -OC(O)O-; M2 is -C(O)O- or -OC(O-); preferably -OC(O-); R1 is C 8-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R s replace; R2 is C 4-8 Alkyl; preferably C6 alkyl; R s C 1-10 Alkyl; preferably C 1-6 Alkyl; preferably C6 alkyl; R3 is -OR f Preferred -OH; R f Selected from H and C 1-6 alkyl; Preferably, R s The substitution site on R1 is spaced 0-10 carbon atoms from M1; preferably 0-5 carbon atoms; preferably 2 carbon atoms.

27. The compound of claim 25, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV-1): in, Each variable is defined as described in claim 25 or 26; Preferably, a＝4； b＝6； c＝5； d＝2； W is -C(O)-; Preferably, a＝2； b＝6； c＝3； d＝2； W is -C(O)-; Preferably, a = 2, 3, or 4; preferably a = 2 or 4; preferably a = 2. b＝6； c＝4； d＝2； W represents a chemical bond.

28. The compound of claim 25, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV-2): in, Each variable is defined as described in claim 25 or 26; Preferably, c = 4 or 5; Preferably, a = 2, 3, or 4; more preferably, a = 2 or 4. b＝6； c＝4； d＝2； W represents a chemical bond; Preferably, a = 2; b＝6； c＝5； d＝2； W is -C(O)-.

29. The compound of claim 1, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from the compounds in Table (I).

30. A pharmaceutical composition comprising a compound of any one of claims 1-29, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

31. A nanoparticle composition comprising a lipid component and optionally a loading component; wherein, The lipid component contains a compound of any one of claims 1-29, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the loading is selected from one or more therapeutic agents, preventive agents, or diagnostic agents. Preferably, the lipid component contains the following components in molar percentage: 20 mol% to 85 mol% of the compound according to any one of claims 1-29: Structural lipids: 10 mol% - 75 mol%; Neutral lipids: 1.0 mol% - 30 mol%; Polymer lipids: 0.25 mol% - 10 mol%; Preferably, the lipid component contains the following components in molar percentage: 25 mol% to 60 mol% of the compound according to any one of claims 1-29: Structural lipids: 10 mol% - 50 mol%; Neutral lipids: 5.0 mol% - 30 mol%; Polymer lipids: 0.5 mol% - 5 mol%; Preferably, the lipid component contains the following components in molar percentage: 50 mol% of the compound according to any one of claims 1-29; Neutral lipids 10 mol%; Structural lipids 38.5 mol%; Polymer lipid 1.5 mol%.

32. The use of any compound of claims 1-29, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, or the nanoparticle composition of claim 31, in the preparation of a medicament for the treatment, diagnosis or prevention of a disease. Preferably, the disease is a lung disease; Preferably, the drug used for treating, diagnosing, or preventing the disease 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 noncoding 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 ribozymes, preferably mRNA, siRNA, gRNA, or modified mRNA, more preferably modified mRNA; Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), and more preferably from one or more of plasmid DNA (pDNA), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

33. Use of any compound of claims 1-29, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, or the nanoparticle composition of claim 31, in the preparation of a medicament for delivery of a load, said load being selected from one or more therapeutic agents, preventive agents or diagnostic agents. Preferably, the drug is a drug that delivers a load to the lungs.

34. A method of treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 30, or the nanoparticle composition of claim 31; Preferably, the disease is a lung disease.

35. The compound of any one of claims 1-29, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, or the nanoparticle composition of claim 31, for the treatment, diagnosis or prevention of disease. Preferably, the disease is a lung disease.

36. A method of delivering a payload into a subject, comprising administering to the subject the pharmaceutical composition of claim 30 or... The nanoparticle composition of claim 31; in, The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents; Preferably, the method is a method of delivering a load to the lungs of a subject.

37. The method of claim 36, wherein the administration comprises any one or a combination of local administration and systemic administration; Preferably, the administration includes inhalation, intravenous injection, arterial injection, or intraperitoneal injection, more preferably intravenous injection.

38. A compound of any one of claims 1-29, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, or a nanoparticle composition of claim 31, for delivery of a payload; in, The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents; Preferably, it is used to deliver a load to the lungs.

39. The nanoparticle composition of claim 31, or the method of claim 36 or 37, or the use of claim 38, wherein, The therapeutic, preventative, 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 noncoding 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 ribozymes, preferably mRNA, siRNA, gRNA, or modified mRNA, more preferably mRNA or modified mRNA; Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA) or double-stranded DNA (dsDNA), and more preferably from one or more of plasmid DNA (pDNA), microcircular DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA), or ribosomal DNA (rDNA).

40. A method for preparing a compound of formula (II), the method comprising: The compound of formula (IIA) is reacted with the compound of formula (IIB) to give the compound of formula (II); Alternatively, the compound of formula (IIA) may be reacted with the compound of formula (IIC) to obtain the compound of formula (II); Wherein, X is a halogen, and the other groups are as defined in any one of claims 1-28.

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