Rapidly metabolized lipid compound

Abstract

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

Description

Rapidly metabolized lipid compounds

[0001] This application claims priority to Chinese application 202411328869.9 filed on September 23, 2024, which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application relates to a new class of ionizable cationic lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof. The present application also relates to lipid nanoparticles and pharmaceutical compositions comprising said compounds, and the use of said lipid nanoparticles in the delivery of biologically active substances such as nucleic acids (e.g. mRNA, siRNA, ASO, DNA, etc.). BACKGROUND

[0003] Gene therapy refers to the introduction of exogenous genes into target cells to correct or compensate for genetic defects or abnormalities within cells, thereby achieving therapeutic purposes. In the past few decades, more and more attention has been paid to the research of treating clinical diseases through gene therapy. In particular, in recent years, siRNA-related drugs and mRNA vaccines have been approved by FDA for clinical treatment, further promoting the research and related investment in the field of gene therapy.

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

[0005] Because different types of nucleic acid substances and different target-specific deliveries have different requirements for delivery systems, in order to meet the different needs of gene therapy, new lipid molecules need to be further developed. SUMMARY

[0006] The present application has developed a new class of ionizable cationic lipid compounds, which can be used to deliver various biologically active substances and have high delivery efficiency.

[0007] The inventors’ prior patent CN115850104A discloses a class of cationic lipid compounds with double geminal dialkyl structures in both tail chains, which have high delivery efficiency. This indicates that increasing geminal dialkyl in the tail chain can significantly improve delivery efficiency. Unexpectedly, through further research, it was found that when the double geminal dialkyl structure is applied to cationic lipids containing a central nitrogen atom, the cationic lipids degrade slowly in the liver, which is suitable for slow degradation application scenarios. For some application scenarios that require accelerated in vivo metabolism, the inventors have developed a new class of ionizable cationic lipid compounds.

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

[0009] wherein the variables are as defined in the present application.

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

[0011] US11246933B1 discloses that in lipid nanoparticles, incorporating biodegradable groups into the tail chains of lipid compounds can accelerate metabolism and clear the lipids from the body after delivering active agents to target areas, making lipids containing biodegradable groups less toxic than similar lipids without biodegradable groups. The cationic lipid compounds of the present application have biodegradable groups in the tail chains, making them less toxic than similar lipids without biodegradable groups, such as DLin-MC3-DMA.

[0012] In another aspect, the present application provides a pharmaceutical composition containing a compound of the present application or a nanoparticle composition of the present application, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant, or vehicle.

[0013] In another aspect, the present application provides the use of a compound of the present application, a nanoparticle composition of the present application, or a pharmaceutical composition of the present application in the manufacture of a medicament for treating, diagnosing, or preventing a disease. In one embodiment, the medicament for treating, diagnosing, or preventing a disease is a nucleic acid, preferably a therapeutic or prophylactic mRNA vaccine.

[0014] In another aspect, the present application provides the use of a compound of the present application, a nanoparticle composition of the present application, or a pharmaceutical composition of the present application in the manufacture of a medicament for delivering a cargo.

[0015] In another aspect, the present application provides a method of treating, diagnosing or preventing a disease in a subject comprising administering to said subject a compound of the present application, a nanoparticle composition of the present application or a pharmaceutical composition of the present application.

[0016] In another aspect, the present application provides a compound of the present application, a nanoparticle composition of the present application or a pharmaceutical composition of the present application for use in the treatment, diagnosis and / or prevention of a disease.

[0017] In another aspect, the present application provides a method of delivering a payload in a subject comprising administering to said subject a compound of the present application, a nanoparticle composition of the present application or a pharmaceutical composition of the present application.

[0018] In another aspect, the present application provides a compound of the present application, a nanoparticle composition of the present application or a pharmaceutical composition of the present application for use in the delivery of a payload.

[0019] In particular embodiments, the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent; preferably, the therapeutic agent, prophylactic agent or diagnostic agent is a nucleic acid.

[0020] In more particular embodiments, the nucleic acid is selected from one or more of an ASO, an RNA or a DNA.

[0021] In more particular embodiments, the RNA is selected from one or more of a small interfering RNA (siRNA), a short hairpin RNA (shRNA), an antisense RNA (aRNA), a messenger RNA (mRNA), a long non-coding RNA (IncRNA), a microRNA (miRNA), a small activating RNA (saRNA), a multimeric coding nucleic acid (MCNA), a polymeric coding nucleic acid (PCNA), a guide RNA (gRNA), a CRISPR RNA (crRNA) or a ribozyme, preferably a mRNA, more preferably a modified mRNA.

[0022] Definitions

[0023] Chemical Definitions

[0024] The definitions of specific functional groups and chemical terms are described in more detail below.

[0025] When a range of values is listed, it is intended to include each value and sub-range within the range. For example, "C 1-6 "alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C2-3 , C 3-6 , C 3- 5, C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0026] "C 1-20 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having from 1 to 20 carbon atoms. In some embodiments, C 4-20 alkyl, C 6-14 alkyl, C 7-12 alkyl, C 8-12 alkyl, C 9-12 alkyl, C 4-10 alkyl, C 7-11 alkyl, C 8- 11 alkyl, C 9-11 alkyl, C 10-11 alkyl, C 6-10 alkyl, C 7-10 alkyl, C 8-10 alkyl, C 9-10 alkyl, C 10 alkyl, C 8-9 alkyl, C 6-9 alkyl, C 7-9 alkyl, C 4-9 alkyl, C9alkyl, C 10 alkyl, C 11 alkyl, C 2-8 alkyl, C 4-8 alkyl, C 5-8 alkyl, C 6-8 alkyl, C 7-8 alkyl, C8alkyl, C 5-7 alkyl, C 6-7 alkyl, C7alkyl, C 4-6 alkyl, C 1-20 alkyl, C 1-14 alkyl, C 2-14 alkyl, C 1-13 alkyl, C 1-12 alkyl, C 1-10 alkyl, C 1-9 alkyl, C 1-8 alkyl, C 1-7 alkyl, C 2-7 alkyl, C 1-6 alkyl, C 2-6 alkyl, C 1-5 alkyl, C5alkyl, C 1-4 alkyl, C 2-4 alkyl, C 1- 3alkyl, C 2-3 alkyl, C1-2 Alkyl and Me are preferred. C 1-6 Examples of alkyl groups include: methyl (Ci), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). The term "C 1- 6alkyl" also includes heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted by one or more substituents, e.g., by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2). In some embodiments, alkyl is preferably straight chain alkyl, e.g., C8straight chain alkyl, e.g., C9straight chain alkyl.

[0027] "C 2-13 Alkenyl" refers to a straight or branched chain hydrocarbon group having from 2 to 13 carbon atoms and at least one carbon-carbon double bond. "C 4-20 Alkenyl" refers to a straight or branched chain hydrocarbon group having from 4 to 20 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 4-14 Alkenyl, C 6-14 Alkenyl, C 7-12 Alkenyl, C 4-10 Alkenyl, C 2-10 Alkenyl, C 2-9 Alkenyl, C 2-6 Alkenyl and C 2-4 Alkenyl is preferred. C 2-6 Examples of alkenyl groups include: ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups can be optionally substituted by one or more substituents, e.g., by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, alkenyl is preferably straight chain alkenyl.

[0028] "C 2-13"Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 13 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4-20 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 4 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 4-14 "Alkynyl", C 6-14 "Alkynyl", C 7-12 "Alkynyl", C 4-10 "Alkynyl", C 2-10 "Alkynyl", C 2-9 "Alkynyl", C 2-6 "Alkynyl" and C 2-4 "Alkynyl" is preferred. 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), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted by one or more substituents, e.g., by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, alkynyl is preferably straight chain alkynyl.

[0029] "C 1-20 "Alkylene" refers to a divalent group formed by removing two hydrogens from a C 1-20 alkyl group and can be substituted or unsubstituted. In some embodiments, C 4-20 "Alkylene", C 4-14 "Alkylene", C 6-14 "Alkylene", C 7-12 "Alkylene", C 8-12 "Alkylene", C 4-10 "Alkylene", C 7-11 "Alkylene", C 8-11 "Alkylene", C 8-10 "Alkylene", C 9-10 "Alkylene", C 8-9 "Alkylene", C 4-9 "Alkylene", C 6-9 "Alkylene", C 7-9 "Alkylene", C9"Alkylene", C 2-8 "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", C1-12 Alkylene, C 1-10 Alkylene, C 1-9 Alkylene, C 1-8 Alkylene, C 1-7 Alkylene, C 2-7 Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4 Alkylene, C 2-4 Alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1- Alkylene and methylene are preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), etc. Exemplary substituted alkylene groups, 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. In some embodiments, the alkylene group is preferably a straight-chain alkylene group.

[0030] “C 2-13 "Alkenyl" refers to the group that has been de-carbonied. 2-13 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. "C 4-14 "Alkenyl" refers to the group that has been de-carbonied. 4-14 The other hydrogen atom of the alkenyl group forms a divalent group, which can be substituted or unsubstituted. In some embodiments, C 6-14 imidene group, C 4-10 imidene group, C 2-10 imidene group, C 2-9 imidene group, C 2-6 imide and C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted such alkenylenes include, but are not limited to: ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted such alkenylenes, e.g., alkenylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted ethenylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like. In some embodiments, alkenylene is preferably straight chain alkenylene.

[0031] "C 2-13 Alkynylene" refers to a divalent radical, which is formed by removing an additional hydrogen from a C 2-13 alkyl group, and can be substituted or unsubstituted. In some embodiments, C 4-14 alkynylene, C 4-14 alkynylene, C 6-14 alkynylene, C 4-10 alkynylene, C 2-10 alkynylene, C 2-9 alkynylene, C 2-6 alkynylene, and C 2-4 Alkynylene is particularly preferred. Exemplary such alkynylenes include, but are not limited to: ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), and the like. In some embodiments, alkynylene is preferably straight chain alkynylene.

[0032] "C 0-6 Alkylene" refers to a chemical bond and to the above "C 1-6 alkylene", "C 0-4 alkylene" refers to a chemical bond and to the above "C 1-4 alkylene".

[0033] The term "the total length of variable A and variable B is x carbon atoms" means that the sum of the number of carbon atoms in the main chain of the group represented by variable A and the number of carbon atoms in the main chain of the group represented by variable B is x.

[0034] The term "R 1s is x carbon atoms apart between the point of substitution on R1and M1" means that the distance between the point of substitution on variable R 1sThe sum of the number of carbon atoms between the substitution site and M1(including the N atom after replaced by -NR'-), and so on. For example:

[0035] In compound 1, R 1s The substitution site on R1is separated from M1by 3 carbon atoms.

[0036] "Halo" or "halogen" means fluoro (F), chloro (CI), bromo (Br), and iodo (I).

[0037] Thus, "C 1-10 "Haloalkyl" means "C 1-10 alkyl" as defined above, substituted by one or more halogen groups. In some embodiments, C 1-8 haloalkyl, C 1-6 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl is particularly preferred, more preferably C 1-2 haloalkyl. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCI3, -CH2CI, -CHCI2, 2,2,2-trifluoro-l,l-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] "C 3-14"Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic hydrocarbon radical of from 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double bonds or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl, and 3- to 6-membered cycloalkyl are particularly preferred, more preferred 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 preferred 5-membered cycloalkyl, more preferred 6-membered cycloalkyl, more preferred cyclopropyl. Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring is fused with one or more aryl or heteroaryl rings, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons refers to the number of carbons in the cycloalkyl ring system. Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring, wherein substituents on any non-adjacent carbon atoms are linked to form a bridged polycycloalkane together. Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring, wherein substituents on the same carbon atom are linked to form a bridged polycycloalkane together. Exemplary such 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), cycloheptatrienyl (C7), and the like. A cycloalkyl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] "C 3-14 "Cycloalkylidene" refers to a divalent radical formed by removing one hydrogen from a cycloalkyl group and can be substituted or unsubstituted. In some embodiments, C 3-14 "Cycloalkylidene" refers to a divalent radical formed by removing one hydrogen from a cycloalkyl group and can be substituted or unsubstituted. In some embodiments, C 3-10 "Cycloalkylidene" refers to a divalent radical formed by removing one hydrogen from a cycloalkyl group and can be substituted or unsubstituted. In some embodiments, C 3-7 "Cycloalkylidene" refers to a divalent radical formed by removing one hydrogen from a cycloalkyl group and can be substituted or unsubstituted. In some embodiments, C 3-6 "Cycloalkylidene" refers to a divalent radical formed by removing one hydrogen from a cycloalkyl group and can be substituted or unsubstituted. In some embodiments, C 3-5 "Cycloalkylidene" refers to a divalent radical formed by removing one hydrogen from a cycloalkyl group and can be substituted or unsubstituted. In some embodiments, C 3-4 "Cycloalkylidene" refers to a divalent radical formed by removing one hydrogen from a cycloalkyl group and can be substituted or unsubstituted. In some embodiments, C

[0040] "3-14 membered heterocyclyl" or "3 to 14 membered heterocyclyl" refers to a saturated or unsaturated radical of a 3 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, wherein optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. In some embodiments, 3 to 10 membered heterocyclyl is preferred, which is a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5 to 10 membered heterocyclyl is preferred, which is a 5 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3 to 8 membered heterocyclyl is preferred, which is a 3 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 3 to 7 membered heterocyclyl is preferred, which is a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; 5 to 7 membered heterocyclyl is preferred, which is a 5 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 3 to 6 membered heterocyclyl is preferred, which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 4 to 6 membered heterocyclyl is preferred, which is a 4 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 5 to 6 membered heterocyclyl is more preferred, which is a 5 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 5 membered heterocyclyl is preferred, which is a 5 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; 6 membered heterocyclyl is preferred, which is a 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused with one or more cycloalkyl rings, wherein the point of attachment is on the heterocyclyl ring, or with one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes ring systems in which the above heterocyclyl ring, wherein any non-adjacent carbon or nitrogen atoms on which substituents are attached form a bridge ring, together form a polycycloalkyl that shares two or more carbon or nitrogen atoms. Heterocyclyl also includes ring systems in which the above heterocyclyl ring, wherein substituents on the same carbon atom are connected to form a ring, together form a polycycloalkyl that shares one carbon atom. Exemplary 3 membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, thiorenyl. Exemplary 4 membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5 membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: 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.

[0041] "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.

[0042] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10"Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0043] "5-14 membered heteroaryl" or "5 to 14 membered heteroaryl" refers to a radical of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems wherein an above-described heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl rings, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms indicates the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. 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 pyridinone. 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 tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0044] "Heteroaralkyl" means an alkyl group substituted with one or more heteroaryl groups.

[0045] "Alkoxy" refers to the oxygen ether of straight chain or branched chain alkyl groups, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0046] "Optionally substituted" means that the group can be substituted with the indicated substituent or can be unsubstituted.

[0047] The divalent groups formed by removing a single hydrogen from the above defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are collectively referred to as "alkylene groups". The ring forming groups of cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are collectively referred to as "ring groups".

[0048] The above defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted groups.

[0049] Exemplary substituents on a carbon atom include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NRbb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc), alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

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

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

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

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

[0054] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ff OR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff)2, -NR ff C(=NR ff )2, -C(=NR ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be combined to form =O or =S;

[0055] each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0056] each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0057] each R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1- 6alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C1-6 alkyl, -SO2OC 1-6 alkyl, -OSO2C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1- 6alkyl, -SC(=S)SC 1-6 alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 alkyl)2, C 1-6 alkyl, C 1-6 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C6-C 10 aryl, 3-7 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg substituents can combine to form =O or =S; wherein X - is a counterion.

[0058] Exemplary substituents on a 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, heterocyclyl, aryl, and heteroaryl, or two R cc groups bound to a nitrogen atom combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc , and R dd are as described above.

[0059] “Nucleic acid” refers to a single- or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecule and hybrid molecules thereof. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASO), among others. The nucleic acid can be further chemically modified with a chemical modification selected from one of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, 5-methylcytosine, or a combination thereof. The mRNA molecule contains a protein coding region and can further contain expression regulatory sequences, typical expression regulatory sequences include, but are not limited to, 5’ cap, 5’ untranslated region (5’ UTR), 3’ untranslated region (3’ UTR), polyadenylation sequence (Poly A), miRNA binding site.

[0060] “Cationic lipid” refers to a lipid molecule that is positively charged under physiological pH conditions. In some embodiments, the cationic lipid is an amino lipid.

[0061] “Neutral lipid” refers to a lipid molecule that is not charged under certain pH conditions, for example, physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0062] "Structural lipid" refers to a lipid that enhances nanoparticle stability by filling the gaps between lipids, often seen with steroids. Steroids are compounds having a cyclopentanoperhydrophenanthrene class of carbon skeleton. In a preferred embodiment, the steroid is selected from the group consisting of cholesterol, sitosterol, coprostanol, stigmastanol, brassicasterol, ergosterol, tomatidine, ursolic acid, alpha-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol.

[0063] "Polymeric lipid" refers to a molecule that contains both a polymeric moiety and a lipid moiety. In some embodiments, the polymeric lipid is a polyethylene glycol (PEG) lipid. Other lipids that can reduce aggregation, such as the product of coupling a compound having no charge, hydrophilic, steric hindering moiety to a lipid, can also be used.

[0064] "Lipid nanoparticle" refers to a particle that contains a lipid component and has a nanoscale size.

[0065] "Biodegradable group" refers to a functional group that contains a biodegradable bond, such as ester, disulfide, amide, and the like. Biodegradation can affect the process of clearing a compound from the body. The direction of the biodegradable group of the present application is from the head to the tail of the ionizable lipid molecule. Common biodegradable groups include, but are not limited to, -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -S-S-, and -S(O) 0-2 -.

[0066] Other Definitions

[0067] The term "treatment" as used herein refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the act of treating as the term is defined immediately above.

[0068] The term "pharmaceutically acceptable salt" as used herein refers to those carboxylic acid salts, amino acid addition salts of the compounds of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without considerable toxic, irritating, allergic and like effects, commensurate with a reasonable benefit / risk ratio, effective for their intended use, including, where possible, the zwitterionic form of the compounds of the present application.

[0069] Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline-earth metals, and organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0070] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt. The free acid form can be regenerated by contacting the salt form with a sufficient amount of an acid to produce the free acid form. The free acid and base forms can differ slightly in certain physical properties, such as solubility in polar solvents, but are equivalent for the purposes of the present application. The base addition salts of the present application include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, ammonium, and tetramethylammonium, or any combination thereof.

[0071] Salts can be prepared from inorganic acids such as sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include the following: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurylsulphonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, sulfonic, phosphoric, and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals, for example, sodium, lithium, potassium, calcium, magnesium, and aluminum, and nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are salts of amino acids such as arginate, gluconate, galacturonate, and the like (see, e.g., Berge S.M. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0072] A "subject" for administration includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a bovine, a porcine, a equine, an ovine, a caprine, a rodent, a feline, and / or a canine. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0073] "Disease," "disorder," and "condition" are used interchangeably herein.

[0074] The term "treatment" as used herein includes an action that occurs while a subject is suffering from a particular disease, disorder, or condition, that reduces the severity of the disease, disorder, or condition, or retards or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), and also includes an action that occurs before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment"), unless otherwise indicated.

[0075] Generally, an "effective amount" of a pharmaceutical composition refers to an amount that is sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of a pharmaceutical composition of the application can vary depending on, for example, the biological target, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0076] A "therapeutically effective amount" of a pharmaceutical composition, as used herein, unless otherwise indicated, is an amount that is sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a pharmaceutical composition refers to the amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall prophylaxis, or enhances the therapeutic efficacy of another therapeutic agent.

[0077] A "prophylactically effective amount" of a pharmaceutical composition, as used herein, unless otherwise indicated, is an amount that is sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a pharmaceutical composition refers to the amount of therapeutic agent alone, or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis, or enhances the prophylactic efficacy of another prophylactic agent.

[0078] "Combination" and related terms mean simultaneous or sequential administration of a pharmaceutical composition of the present application and another therapeutic agent. For example, a pharmaceutical composition of the present application can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or administered simultaneously with another therapeutic agent in a single unit dosage form. Specific embodiments

[0079] Herein, "a compound of the present application" refers to a compound, an isotopologue, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0080] Herein, compounds are named using standard nomenclature. Compounds having asymmetric centers should be understood to include all optical isomers and mixtures thereof, unless otherwise indicated. In addition, unless otherwise indicated, all isomeric forms of a compound of the present application are embraced within the scope of this application, including those forms which can exist due to a carbon-carbon double bond in either the Z or E form. Where a compound exists in different tautomeric forms, a compound is not limited to any particular tautomer, but rather is intended to include all tautomeric forms.

[0081] In one embodiment, the present application relates to a compound of Formula (I’), or an isotopologue, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0082] wherein,

[0083] Z is N or CN; preferably CH;

[0084] G1and G2are independently selected from a chemical bond, C 1-13 straight-chain alkenylene, and C 2-13 straight-chain alkenylene, and C 2-13 straight-chain alkynylene, optionally substituted with one or more R G1 ;

[0085] G1and G2have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms;

[0086] R G1 is independently selected from H, C 1-14 alkyl, -L a -OR a , -L a -SR a , and -L a -NR a R’ a ;

[0087] G3is selected from C 4-14 straight-chain alkenylene, and C 4-14 straight-chain alkenylene, and C4-14 straight-chain alkynylene, optionally substituted by one or more R G3 ;

[0088] R G3 is independently selected from H, -L a -OR a , -L a -SR a and -L a -NR a R’ a ;

[0089] L a is independently selected from a bond and C 1-14 alkylene;

[0090] R a and R’ a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl;

[0091] G4is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene and C 2-6 alkynylene, optionally substituted by one or more R G4 ;

[0092] R G4 is independently selected from H, C 1-6 alkyl, -L b -OR b , -L b -SR b and -L b -NR b R’ b ;

[0093] L b is independently selected from a bond and C 1-6 alkylene;

[0094] R b and R’ b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0095] or two R G4 on the same carbon atom, together with the carbon atom to which they are attached, form a C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, optionally substituted by one or more R 4g ;

[0096] R4g independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e , -L e -SR e and -L e -NR e R’ e ;

[0097] L e is independently selected from the group consisting of a bond and C 1-8 alkylene;

[0098] R e and R’ e are independently selected from the group consisting of H, C 1-8 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl;

[0099] M1and M2are independently selected from the group consisting of -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-;

[0100] Q is selected from the group consisting of a bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f -, -NR f C(O)NR f -, -OC(O)S-, -OC(O)O-, -NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -, -C(O)NR f -, -NR f C(O)-, -NR f C(O)S-, -SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -, -NR f C(S)O-, -S-S-, -S(O) 0-2- and -L

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

[0102] L f is independently selected from a bond and C 1-8 alkylene;

[0103] R f and R’ f are independently selected from H, C 1-10 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl;

[0104] R1and R2are independently selected from C 4-20 alkyl, C 4-20 alkenyl and C 4-20 alkynyl, which is optionally substituted with one or more R 1s , and wherein one or more methylene units are optionally and independently replaced with -NR’-;

[0105] R 1s is independently selected from H, C 1-20 alkyl, -L c -OR c , -L c -SR c and -L c -NR c R’ c ;

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

[0107] L c is independently selected from a bond and C 1-20 alkylene;

[0108] R c and R’ c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl;

[0109] R3is selected from CN, -OR g-C(O)R g -OC(O)R g -NR”C(O)R g -NR g R' g 、-NR”C(O)NR g R' g -NR”C(O)R g -NR”S(O)2R g -OC(O)NR g R' g -NR”C(O)OR g -N(OR) g )C(O)R g -N(OR) g )S(O)2R g -N(OR) g )C(O)OR g -N(OR) g )C(O)R g R' g 3 to 14-membered heterocyclic groups and 5 to 14-membered heteroaryl groups;

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

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

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

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

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

[0115] Ld independently selected from a chemical bond and C 1-8 alkylene;

[0116] R d and R' d independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl.

[0117] In another embodiment, the present application relates to the above compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a structure of Formula (III') or Formula (IV):

[0118] wherein,

[0119] a = 1, 2, 3, 4, 5 or 6;

[0120] b = 4, 5, 6, 7, 8, 9 or 10;

[0121] c = 1, 2, 3, 4, 5 or 6;

[0122] d = 0, 1, 2, 3 or 4;

[0123] c + d = 3, 4, 5, 6, 7, 8 or 9;

[0124] the remaining variables are as defined herein.

[0125] In the compounds of the present application, each variable can be as defined below.

[0126] Z

[0127] In one embodiment, Z is CH; in another embodiment, Z is N.

[0128] In a particular embodiment, Z is N or CN.

[0129] G1and G2

[0130] In one embodiment, G1is a chemical bond; in another embodiment, G1is C 1-13 straight-chain alkylene, preferably C 1-9 straight-chain alkylene, preferably C 1-6 straight-chain alkylene, preferably C 2-6 straight-chain alkylene; in another embodiment, G1is C 2-13 straight-chain alkenylene, preferably C 2-9 straight-chain alkenylene, preferably C 2-6 straight-chain alkenylene; in another embodiment, G1is C 2-13 straight-chain alkynylene, preferably C 2-9straight-chain alkynylene, preferably C 2-6 straight-chain alkynylene; in another more specific embodiment, G1is selected from the group consisting of a chemical bond, C G1 substituted; in another more specific embodiment, G1is optionally substituted with 1, 2, 3, or 4 R G1 substituted; in another more specific embodiment, G1is unsubstituted.

[0131] In a more specific embodiment, G1is selected from the group consisting of a chemical bond, C 1-9 straight-chain alkylene, preferably C 2-9 straight-chain alkenylene, preferably C 2- 9straight-chain alkynylene; in another more specific embodiment, G1is selected from the group consisting of a chemical bond, C 1-6 straight-chain alkylene, preferably C 2-6 straight-chain alkenylene, preferably C 2-6 straight-chain alkynylene; in another more specific embodiment, G1is selected from the group consisting of a chemical bond, C 1-6 straight-chain alkylene; in another more specific embodiment, G1is selected from the group consisting of a chemical bond, C 2-6 straight-chain alkylene.

[0132] In one embodiment, G2is a chemical bond; in another embodiment, G2is C 1-13 straight-chain alkylene, preferably C 1-9 straight-chain alkylene, preferably C 1-6 straight-chain alkylene, preferably C 1-4 straight-chain alkylene; in another embodiment, G2is C 2-13 straight-chain alkenylene, preferably C 2-9 straight-chain alkenylene, preferably C 2-6 straight-chain alkenylene; in another embodiment, G2is C 2-13 straight-chain alkynylene, preferably C 2-9 straight-chain alkynylene, preferably C 2-6 straight-chain alkynylene; in another embodiment, G2is optionally substituted with one or more R G1 substituted; in another embodiment, G2is optionally substituted with 1, 2, 3, or 4 R G1 substituted; in another embodiment, G2is unsubstituted.

[0133] In a more specific embodiment, G2is selected from the group consisting of a chemical bond, C 1-9 straight-chain alkylene, preferably C 2-9 straight-chain alkenylene, preferably C 2- 9straight-chain alkynylene; in another more specific embodiment, G2is selected from the group consisting of a chemical bond, C 1-6 straight-chain alkylene, preferably C 2-6 straight-chain alkenylene, preferably C 2-6 straight-chain alkynylene; in another more specific embodiment, G2is selected from the group consisting of a chemical bond, and C 1-6linear alkylene; in another more particular embodiment, G2is selected from the group consisting of a chemical bond and C 1-4 linear alkylene.

[0134] In one embodiment, the total length of G1and G2is 3 carbon atoms; in another embodiment, the total length of G1and G2is 4 carbon atoms; in another embodiment, the total length of G1and G2is 5 carbon atoms; in another embodiment, the total length of G1and G2is 6 carbon atoms; in another embodiment, the total length of G1and G2is 7 carbon atoms; in another embodiment, the total length of G1and G2is 8 carbon atoms; in another embodiment, the total length of G1and G2is 9 carbon atoms; in another embodiment, the total length of G1and G2is 10 carbon atoms; in another embodiment, the total length of G1and G2is 11 carbon atoms; in another embodiment, the total length of G1and G2is 12 carbon atoms; in another embodiment, the total length of G1and G2is 13 carbon atoms.

[0135] In one more particular embodiment, the total length of G1and G2is 3, 4, 5, 6, 7, 8, or 9 carbon atoms; in another more particular embodiment, the total length of G1and G2is 4, 5, or 6 carbon atoms; in another more particular embodiment, the total length of G1and G2is 5 or 6 carbon atoms; in another more particular embodiment, the total length of G1and G2is 5, 6, or 7 carbon atoms; in another more particular embodiment, the total length of G1and G2is 6 or 7 carbon atoms.

[0136] R G1

[0137] In one embodiment, R G1 is H; in another embodiment, R G1 is C 1-14 alkyl, preferably C 1-10 alkyl, preferably C 1-6 alkyl; in another embodiment, R G1 is -L a -OR a ; in another embodiment, R G1 is -L a -SR a ; in another embodiment, R G1 is -L a -NR a R’ a .

[0138] In one more particular embodiment, R G1 is independently selected from the group consisting of H and C 1-10alkyl; in another more specific embodiment, R G1 is independently selected from the group consisting of H and C 1-6 alkyl.

[0139] G3

[0140] In one embodiment, G3 is C 4-14 straight-chain alkylene, preferably C 4-10 straight-chain alkylene, preferably C 4-9 straight-chain alkylene, preferably C 5-8 straight-chain alkylene; in another embodiment, G3 is C 4-14 straight-chain alkenylene; in another embodiment, G3 is C 4-14 straight-chain alkynylene; in another embodiment, G3 is optionally substituted with one or more R G3 ; in another embodiment, G3 is optionally substituted with 1, 2, 3, or 4 R G3 ; in another embodiment, G3 is unsubstituted.

[0141] In one more specific embodiment, G3 is selected from the group consisting of C 4-10 straight-chain alkylene, C 4-10 straight-chain alkenylene, and C 4-10 straight-chain alkynylene; in another more specific embodiment, G3 is selected from the group consisting of C 4-9 straight-chain alkylene; in another more specific embodiment, G3 is selected from the group consisting of C 5-8 straight-chain alkylene; in another more specific embodiment, G3 is selected from the group consisting of C 6-7 straight-chain alkylene.

[0142] R G3

[0143] In one embodiment, R G3 is H; in another embodiment, R G3 is -L a -OR a ; in another embodiment, R G3 is -L a -SR a ; in another embodiment, R G3 is -L a -NR a R’ a .

[0144] L a , R a , and R’ a

[0145] In one embodiment, L a is a chemical bond; in another embodiment, La C 1-14 alkylene, preferably C 1- 10 alkylene, preferably C 1-6 alkylene.

[0146] In a more particular embodiment, L a is independently selected from the group consisting of a bond and C 1-10 alkylene; in another more particular embodiment, L a is independently selected from the group consisting of a bond and C 1-6 alkylene.

[0147] In one embodiment, R a is H; in another embodiment, R a C 1-14 alkyl, preferably C 1-10 alkyl, preferably C 1-6 alkyl; in another embodiment, R a C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R a is 3- to 14-membered heterocyclyl, preferably 3- to 10-membered heterocyclyl.

[0148] In one embodiment, R’ a is H; in another embodiment, R’ a C 1-14 alkyl, preferably C 1-10 alkyl, preferably C 1-6 alkyl; in another embodiment, R’ a C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R’ a is 3- to 14-membered heterocyclyl, preferably 3- to 10-membered heterocyclyl.

[0149] In one more particular embodiment, R a and R’ a are independently selected from the group consisting of H, C 1-10 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; in another more particular embodiment, R a and R’ a are independently selected from the group consisting of H and C 1-6 alkyl.

[0150] G4

[0151] In one embodiment, G4is a bond; in another embodiment, G4is C 1-6 alkylene, preferably C1- 4alkylene, preferably C 2-4 alkylene, preferably C 2-3 alkylene; in another embodiment, G4 is C 2-6 alkenylene, preferably C 2-4 alkenylene; in another embodiment, G4 is C 2-6 alkynylene, preferably C 2-4 alkynylene; in another embodiment, G4 is optionally substituted with one or more R G4 ; in another embodiment, G4 is optionally substituted with 1, 2, 3, or 4 R G4 ; in another embodiment, G4 is unsubstituted.

[0152] In a more particular embodiment, G4 is selected from C 1-4 alkylene, C 2-4 alkenylene, and C 2-4 alkynylene; in another more particular embodiment, G4 is selected from C 2-4 alkylene; in another more particular embodiment, G4 is selected from C 2-3 alkylene.

[0153] R G4

[0154] In one embodiment, R G4 is H; in another embodiment, R G4 is C 1-6 alkyl, preferably C 1-4 alkyl; in another embodiment, R G4 is -L b -OR b ; in another embodiment, R G4 is -L b -SR b ; in another embodiment, R G4 is -L b -NR b R' b .

[0155] In a more particular embodiment, R G4 is independently selected from H and C 1-6 alkyl.

[0156] In one embodiment, two R G4 attached to the same carbon atom together with the carbon atom to which they are attached form a C 3-14 cycloalkylene, preferably C 3-10 cycloalkylene, preferably C 3-7 cycloalkylene, preferably C 3-4Cycloalkylene, preferably cyclopropyl; in another embodiment, two R G4 together with the carbon atom to which they are attached form a 3- to 14- membered heterocyclylene, preferably a 3- to 10-membered heterocyclylene, preferably a 3- to 7-membered heterocyclylene; in another embodiment, two R G4 together with the carbon atom to which they are attached form a ring which is optionally substituted with one or more R 4g ; in another embodiment, two R G4 together with the carbon atom to which they are attached form a ring which is optionally substituted with 1, 2, or 3 R 4g ; in another embodiment, two R G4 together with the carbon atom to which they are attached form a ring which is unsubstituted.

[0157] In a more specific embodiment, two R G4 together with the carbon atom to which they are attached form a C 3-10 alkylene or a 3- to 10-membered heterocyclylene; in another more specific embodiment, two R G4 together with the carbon atom to which they are attached form a C 3-7 alkylene or a 3- to 7-membered heterocyclylene.

[0158] L b , R b , and R b

[0159] In one embodiment, L b is a bond; in another embodiment, L b is C 1-6 alkylene, preferably C 1- 4alkylene.

[0160] In a more specific embodiment, L b is independently selected from the group consisting of a bond and C 1-4 alkylene.

[0161] In one embodiment, R b is H; in another embodiment, R b is C 1-6 alkyl, preferably C 1-4 alkyl; in another embodiment, R b is C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R b is 3- to 10-membered heterocyclyl, preferably 3- to 7-membered heterocyclyl.

[0162] In one embodiment, R b is H; in another embodiment, R b is C 1-6 alkyl, preferably C 1-4 alkyl; in another embodiment, R b is C 3-10 cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R b is 3- to 10-membered heterocyclyl, preferably 3- to 7-membered heterocyclyl.

[0163] In one more specific embodiment, R b and R b are independently selected from the group consisting of H, C 1-6 alkyl, C 3-7 cycloalkyl, and 3- to 7-membered heterocyclyl; in another more specific embodiment, R b and R b are independently selected from the group consisting of H and C 1-6 alkyl; in another more specific embodiment, R b and R b are independently selected from the group consisting of H and C 1-4 alkyl.

[0164] R 4g

[0165] In one embodiment, R 4g is H; in another embodiment, R 4g is halogen; in another embodiment, R 4g is cyano; in another embodiment, R 4g is C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R 4g is C 1-8 haloalkyl, preferably C 1-6 haloalkyl; in another embodiment, R 4g is -L e -OR e ; in another embodiment, R 4g is -L e -SR e ; in another embodiment, R 4g is -L e -NR e R e .

[0166] In one more specific embodiment, R 4gIndependently selected from H, halogen, cyano, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0167] L e R e and R' e

[0168] In one implementation, L e For chemical bonds; in another embodiment, L e C 1-8 Alkylene, preferably C 1- 6-alkylene group, preferably C 1-4 Alkylene.

[0169] In a more specific implementation, L e Independently selected from chemical bonds and C 1-6 Alkylene; in another, more specific embodiment, L e Selected from independent chemical bonds and C 1-4 Alkylene.

[0170] In one implementation, R e H; in another embodiment, R e C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R e C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R e It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0171] In one implementation, R' e H; in another embodiment, R' e C 1-8 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' e C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' e It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0172] In a more specific implementation, R e and R' e Independently selected from H and C 1-6 Alkyl, C 3-10cycloalkyl and 3- to 10-membered heterocyclyl; in another more particular embodiment, R e and R' e are independently selected from the group consisting of H and C 1-6 alkyl; in another more particular embodiment, R e and R' e are independently selected from the group consisting of H and C 1-4 alkyl.

[0173] M1and M2

[0174] In one embodiment, M1is -C(O)O-; in another embodiment, M1is -OC(O)-; in another embodiment, M1is -O-; in another embodiment, M1is -SC(O)O-; in another embodiment, M1is -OC(O)NR-; in another embodiment, M1is -NRC(O)NR-; in another embodiment, M1is -OC(O)S-; in another embodiment, M1is -OC(O)O-; in another embodiment, M1is -NRC(O)O-; in another embodiment, M1is -SC(O)-; in another embodiment, M1is -C(O)S-; in another embodiment, M1is -NR-; in another embodiment, M1is -C(O)NR-, e.g., -C(O)NH-; in another embodiment, M1is -NRC(O)-, e.g., -NHC(O)-; in another embodiment, M1is -NRC(O)S-; in another embodiment, M1is -SC(O)NR-; in another embodiment, M1is -C(O)-; in another embodiment, M1is -OC(S)-; in another embodiment, M1is -C(S)O-; in another embodiment, M1is -OC(S)NR-; in another embodiment, M1is -NRC(S)O-; in another embodiment, M1is -S-S-; in another embodiment, M1is -S(O) 0-2 -, e.g., -S-, e.g., -S(O)-, e.g., -S(O)2-.

[0175] In one embodiment, M2is -C(O)O-; in another embodiment, M2is -OC(O)-; in another embodiment, M2is -O-; in another embodiment, M2is -SC(O)O-; in another embodiment, M2is -OC(O)NR-; in another embodiment, M2is -NRC(O)NR-; in another embodiment, M2is -OC(O)S-; in another embodiment, M2is -OC(O)O-; in another embodiment, M2is -NRC(O)O-; in another embodiment, M2is -SC(O)-; in another embodiment, M2is -C(O)S-; in another embodiment, M2is -NR-; in another embodiment, M2is -C(O)NR-; in another embodiment, M2is -NRC(O)-; in another embodiment, M2is -NRC(O)S-; in another embodiment, M2is -SC(O)NR-; in another embodiment, M2is -C(O)-; in another embodiment, M2is -OC(S)-; in another embodiment, M2is -C(S)O-; in another embodiment, M2is -OC(S)NR-; in another embodiment, M2is -NRC(S)O-; in another embodiment, M2is -S-S-; in another embodiment, M2is -S(O) 0-2 - such as -S-, such as -S(O)-, such as -S(O)2-.

[0176] In one more specific embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; in another more specific embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in another more specific embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in another more specific embodiment, M1and M2are independently selected from the group consisting of -C(O)O- and -OC(O)-.

[0177] In one more specific embodiment, M1and M2are independently selected from the group consisting of -C(O)O- and -C(O)S-; in another more specific embodiment, M1and M2are -C(O)O-.

[0178] In a more particular embodiment, one of M1and M2is -C(O)O- or -C(O)S-, the other is -OC(O)- or -SC(O)-; in another more particular embodiment, one of M1and M2is -C(O)O-, the other is -OC(O)-.

[0179] In a more particular embodiment, M1is -OC(O)- or -SC(O)-; in another more particular embodiment, M1is -OC(O)-; in another more particular embodiment, M2is -C(O)O- or -C(O)S-; in another more particular embodiment, M2is -C(O)O-.

[0180] In a more particular embodiment, M1is -C(O)O- or -C(O)S-; in another more particular embodiment, M1is -C(O)O-; in another more particular embodiment, M2is -OC(O)- or -SC(O)-; in another more particular embodiment, M2is -OC(O)-.

[0181] In a more particular embodiment, M1is -OC(O)-; M2is -C(O)O- or -OC(O)-, preferably -C(O)O-.

[0182] In a more particular embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)- and -C(O)NH-; in another more particular embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)S- and -C(O)NH-; in another more particular embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)- and -C(O)S-; in another more particular embodiment, one of M1and M2is -C(O)O- or -C(O)S-, preferably -C(O)O-, the other is selected from the group consisting of -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)- and -SC(O)-, preferably from the group consisting of -C(O)O-, -C(O)S-, -C(O)NH- and -OC(O)-, preferably from the group consisting of -C(O)O-, -C(O)S- and -OC(O)-; in another more particular embodiment, one of M1and M2is -OC(O)O-, the other is selected from the group consisting of -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably -C(O)O- or -OC(O)-; in another more particular embodiment, M1is selected from the group consisting of -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably from the group consisting of -C(O)O- and -OC(O)-, preferably -C(O)O-, preferably -OC(O)-, M2is -OC(O)O-; in another more particular embodiment, M1is -OC(O)O-, M2is -OC(O)- or -OC(O)-, preferably -OC(O)-; in another more particular embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)- and -OC(O)O-; in another more particular embodiment, M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)- and -OC(O)O-; in another more particular embodiment, M1and M2are not both -OC(O)O-.

[0183] Q

[0184] In one embodiment, Q is a bond; in another embodiment, Q is -C(O)O-; in another embodiment, Q is -O-; in another embodiment, Q is -SC(O)O-; in another embodiment, Q is -OC(O)NR f -; in another embodiment, Q is -NR f C(O)NR f-OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR f -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR 0-2 -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR

[0185] -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR

[0186] -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR

[0187] -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR -OC(O)-; in another embodiment, Q is -SC(O)-; in another embodiment, Q is -C(O)S-; in another embodiment, Q is -NR

[0188] In one embodiment, R* is H; in another embodiment, Q is halogen; in another embodiment, R* is cyano; in another embodiment, R* is C 1-10 alkyl, preferably C 1-6 alkyl; in another embodiment, R* is C 1-10 haloalkyl, preferably C 1-6 haloalkyl; in another embodiment, R* is -L f -OR f ; in another embodiment, R* is -L f -SR f ; in another embodiment, R* is -L f -NR f R’ f .

[0189] In a more specific embodiment, R* is independently selected from H, halogen, cyano, C 1-6 alkyl, and C 1-6 haloalkyl.

[0190] L f , R f , and R’ f

[0191] In one embodiment, L f is a bond; in another embodiment, L f is C 1-8 alkylene, preferably C 1- 6alkylene, preferably C 1-4 alkylene.

[0192] In a more specific embodiment, L f is independently selected from a bond and C 1-6 alkylene; in another more specific embodiment, L f is independently selected from a bond and C 1-4 alkylene.

[0193] In one embodiment, R f is H; in another embodiment, R f is C 1-10 alkyl, preferably C 1-6 alkyl, preferably C 1-4 alkyl; in another embodiment, R f is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R f is 3- to 14-membered heterocyclyl, preferably 3- to 10-membered heterocyclyl.

[0194] In one embodiment, R f is H; in another embodiment, R f is C 1-10 alkyl, preferably C 1-6 alkyl, preferably C 1-4 alkyl; in another embodiment, R f is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R f is 3- to 14-membered heterocyclyl, preferably 3- to 10-membered heterocyclyl.

[0195] In one more specific embodiment, R f and R f are independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclyl; in another more specific embodiment, R f and R f are independently selected from the group consisting of H and C 1-6 alkyl; in another more specific embodiment, R f and R f are independently selected from the group consisting of H and C 1-4 alkyl.

[0196] R1and R2

[0197] In one embodiment, R1is C 4-20 alkyl, preferably C 6-14 alkyl, preferably C 7-12 alkyl, preferably C 8-12 alkyl, preferably C 8-11 alkyl, preferably C 9-11 alkyl, preferably C 8-10 alkyl, preferably C 9-10 alkyl, preferably C 8-9 alkyl, preferably C9alkyl, preferably C 8-12 linear alkyl, preferably C 7-11 linear alkyl, preferably C 8-11 linear alkyl, preferably C 9-11 linear alkyl, preferably C 10-11 linear alkyl, preferably C 8-10 linear alkyl, preferably C 9-10 linear alkyl, preferably C 8-9 linear alkyl, preferably C 11 linear alkyl, preferably C 10 linear alkyl, preferably C9linear alkyl; in another embodiment, R1is C 4-20 alkenyl, preferably C 6-14 alkenyl, preferably C7-12 alkenyl, preferably C 8-12 alkenyl; in another embodiment, R1is C 4-20 alkynyl, preferably C 6-14 alkynyl, preferably C 7-12 alkynyl, preferably C 8-12 alkynyl; in another embodiment, R1is optionally substituted with one or more R 1s substituted; in another embodiment, R1is optionally substituted with 1, 2, 3, or 4 R 1s substituted, preferably optionally substituted with 1, 2, or 3 R 1s substituted, preferably optionally substituted with 1 or 2 R 1s substituted, preferably optionally substituted with 1 R 1s substituted; in another embodiment, R1is unsubstituted; in another embodiment, one or more (preferably 1, 2, or 3) methylene units in R1are optionally and independently replaced with -NR'-; in another embodiment, one methylene unit in R1is optionally replaced with -NR'-; in another embodiment, R1is optionally substituted with 1 C 1-9 alkyl (preferably C 6-9 alkyl, more preferably C 6-7 alkyl, preferably C 1-7 alkyl, more preferably C 5-7 alkyl) substituted; in another embodiment, R1is optionally substituted with 1 or 2 C 1-9 alkyl (preferably C 6-9 alkyl, more preferably C 6-7 alkyl, preferably C 1- 7alkyl, more preferably C 5-7 alkyl) substituted.

[0198] in another embodiment, R1is -(CH2)7CH3; in another embodiment, R1is -(CH2)8CH3; in another embodiment, R1is -(CH2)9CH3; in another embodiment, R1is -(CH2) 10 CH3; in another embodiment, R1is -(CH2) 11CH3; in another embodiment, R1is -CH2-C≡C-(CH2)5CH3; in another embodiment, R1is -CH2-C≡C-(CH2)6CH3; in another embodiment, R1is -(CH2)2-C≡C-(CH2)5CH3; in another embodiment, R1is -(CH2)4-C≡C-(CH2)3CH3; in another embodiment, R1is -CH2-CH=CH-(CH2)5CH3; in another embodiment, R1is -CH2-CH=CH-(CH2)6CH3; in another embodiment, R1is -(CH2)2-CH=CH-(CH2)5CH3; in another embodiment, R1is -(CH2)4-CH=CH-(CH2)3CH3; in another embodiment, R1is -(CH2)5-CH=CH-CH2CH3; in another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is

[0199] In another embodiment, R1is -(CH2)2-C≡C-(CH2)4CH3; in another embodiment, R1is -(CH2)3-C≡C-(CH2)3CH3; in another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is

[0200] In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is In another embodiment, R1is

[0201] In another embodiment, R2is C 4-20 alkyl, preferably C 6-14 alkyl, preferably C 7-12 alkyl, preferably C 8-12 alkyl, preferably C 9-12 alkyl, preferably C 8-11 alkyl, preferably C 9-11 alkyl, preferably C 8-10 alkyl, preferably C 9-10 alkyl, preferably C 10 alkyl, preferably C9alkyl, preferably C 8-12 straight chain alkyl, preferably C 7-11 straight chain alkyl, preferably C 8-11 straight chain alkyl, preferably C 10-11 straight chain alkyl, preferably C 11 straight chain alkyl, preferably C 10 straight chain alkyl, preferably C 8-10 straight chain alkyl, preferably C 9-10 straight chain alkyl, preferably C9straight chain alkyl; in another embodiment, R2is C 4-20 alkenyl, preferably C 6- 14 alkenyl, preferably C 7-12 alkenyl, preferably C 8-12 alkenyl; in another embodiment, R2is C4-20 Alkyne group, preferably C 6-14 Alkyne group, preferably C 7-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R2 is optionally surrounded by one or more R groups. 1s In another embodiment, R2 is optionally replaced by 1, 2, 3 or 4 Rs. 1s Instead, preferably optionally replaced by 1, 2 or 3 R 1s Instead, preferably optionally replaced by 1 or 2 R 1s Instead, preferably optionally replaced by 1 R 1s Replace, preferably, optionally, by 1 C 1-3 Alkyl substitution, preferably optionally substituted with one methyl group; in another embodiment, R2 is not substituted; in another embodiment, one or more (preferably 1, 2 or 3) methylene units in R2 are optionally and independently substituted with -NR'-, preferably one methylene unit in R2 is optionally substituted with -NR'-; in another embodiment, R2 is optionally substituted with one C 1-9 Alkyl (preferably C) 6-9 Alkyl, more preferably C 6-7 Alkyl, preferably C 1-7 Alkyl, more preferably C 5-7 Alkyl group substituted; in another embodiment, R2 is optionally replaced by one or two C atoms. 1-9 Alkyl (preferably C) 6- 9-alkyl, more preferably C 6-7 Alkyl, preferably C 1-7 Alkyl, more preferably C 5-7 Alkyl) substitution.

[0202] In one implementation, at least one of R1 and R2 is controlled by R. 1s replace.

[0203] In one embodiment, only one of R1 and R2 has a substituent; in another embodiment, R1 has R. 1s Replacement, and there is no R on R2. 1s Replacement; in another embodiment, R2 has R 1s Replacement, and there is no R on R1 1s replace.

[0204] In one embodiment, R2 is -(CH2)5CH3; in another embodiment, R2 is -(CH2)6CH3; in another embodiment, R2 is -(CH2)7CH3; in another embodiment, R2 is -(CH2)8CH3; in another embodiment, R2 is -(CH2)9CH3; in yet another embodiment, R2 is -(CH2) 10CH3; in another embodiment, R2 is -(CH2). 11 CH3; in another embodiment, R2 is -CH2-C≡C-(CH2)5CH3; in another embodiment, R2 is -CH2-C≡C-(CH2)6CH3; in another embodiment, R2 is -(CH2)2-C≡C-(CH2)5CH3; in another embodiment, R2 is -(CH2)4-C≡C-(CH2)3CH3; in another embodiment, R2 is -CH2-CH=CH-(CH2)5CH3; in another embodiment, R2 is -CH2-CH=CH-(CH2)6CH3; in another embodiment, R2 is -(CH2)2-CH=CH-(CH2)5CH3; in another embodiment, R2 is -(CH2)4-CH=CH-(CH2)3CH3; in another embodiment, R2 is -(CH2)5-CH=CH-CH2CH3; in another embodiment, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another embodiment, R2is In another embodiment, R2is

[0205] In another embodiment, R2is -(CH2)2-C≡C-(CH2)4CH3; in another embodiment, R2is -(CH2)3-C≡C-(CH2)3CH3; in another embodiment, R2is In another embodiment, R2is In another embodiment, R2is In another embodiment, R2is In another embodiment, R2is In another embodiment, R2is In another embodiment, R2is In another embodiment, R2is

[0206] In another embodiment, R2is In another embodiment, R2is In another embodiment, R2is In another embodiment, R2is

[0207] In another more specific embodiment, R1and R2are independently selected from the group consisting of C 6-14 alkyl, C 6-14 alkenyl, and C 6-14 alkynyl; in another more specific embodiment, R1and R2are independently selected from the group consisting of C 7-12 alkyl, C 7-12 alkenyl, and C 7-12 alkynyl; in another more specific embodiment, R1and R2are independently selected from the group consisting of C 8-12 alkyl, C 8-12 alkenyl, and C 8-12 alkynyl; in another more specific embodiment, R1and R2are independently selected from the group consisting of -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0208] In a more specific embodiment, R1and R2are independently selected from the group consisting of C 7-12 alkyl, preferably C 8-12 alkyl, preferably C 9-11 alkyl, preferably C 9-10 alkyl, preferably C9alkyl, optionally substituted with 1 or 2 R 1s ; and only one of R1and R2has a substituent.

[0209] In a more specific embodiment, R1and R2are independently selected from the group consisting of C 6-14 alkyl, preferably C 8-12 alkyl, preferably C 8-10 alkyl, preferably C 8-9 alkyl, preferably C9alkyl, optionally substituted with 1 or 2 R 1s ; and at least one of R1and R2is substituted with R 1s .

[0210] In a more specific embodiment, R1and R2are independently selected from the group consisting of: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, In another more specific embodiment, R1and R2are independently selected from the group consisting of: -(CH2)7CH3, -(CH2)8CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, In another more specific embodiment, R1and R2are independently selected from the group consisting of: -(CH2)8CH3, -(CH2) 10 CH3, -(CH2) 11 CH3,

[0211] In a more specific embodiment, R1 and R2 are independently selected from: -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, In another, more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, In another, more specific embodiment, R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3,

[0212] In a more specific implementation, R1 and R2 are independently selected from: -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3 In another, more specific embodiment, R1 and R2 are independently selected from: -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3,

[0213] In a more specific implementation, R1 is selected from... In another more specific embodiment, R1is selected from the group consisting of

[0214] In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of -(CH2)8CH3, -(CH2)9CH3, In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of

[0215] In another more specific embodiment, R1is selected from the group consisting of 10 CH3and In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of

[0216] In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of In another more specific embodiment, R1is selected from the group consisting of

[0217] In another more specific embodiment, R1and R2are independently selected from the group consisting of C8straight chain alkyl, C9straight chain alkyl, In another more specific embodiment, R1is selected from C9straight chain alkyl and R2is selected from C9straight chain alkyl, In another more specific embodiment, R1is selected from C8straight chain alkyl, C9straight chain alkyl and R2is selected from C9straight chain alkyl, preferably C9straight chain alkyl, In one embodiment, R 1s is H; in another embodiment, R 1s is C 1-20 straight chain alkyl, preferably C 1-14 straight chain alkyl, preferably C 1-10 straight chain alkyl, preferably C 1-9 straight chain alkyl, preferably C 7-9 straight chain alkyl, preferably C 8-9 straight chain alkyl, preferably C 1-6 straight chain alkyl, preferably C 1-4 straight chain alkyl, preferably C 7-11 straight chain alkyl, preferably C 4-10 straight chain alkyl, preferably C 6-10 straight chain alkyl, preferably C 7-10 straight chain alkyl, preferably C 9- 10 straight chain alkyl, preferably C 4-9 straight chain alkyl, preferably C 6-9 straight chain alkyl, preferably C 1-8 straight chain alkyl, preferably C 4-8 straight chain alkyl, preferably C 6-8 straight chain alkyl, preferably C 7-8 straight chain alkyl, preferably C 6-7 straight chain alkyl, preferably C9alkyl, preferably C8alkyl, preferably C7alkyl; in another embodiment, R 1s is -L c -OR c ; in another embodiment, R 1s is -L c -SR c ; in another embodiment, R 1s is -L c -NR c R' c .

[0218] In one embodiment, R 1s is separated by 0 carbon atoms between the point of substitution on R1and M1; in another embodiment, R 1s is separated by 1 carbon atom between the point of substitution on R1and M1; in another embodiment, R 1s ​0 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 3 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 4 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 5 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 6 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 7 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 8 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 9 carbon atoms apart from the site of substitution on R1and M1; in another embodiment, R 1s 10 carbon atoms apart from the site of substitution on R1and M1.

[0219] In one embodiment, R 1s 0 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 1 carbon atom apart from the site of substitution on R2and M2; in another embodiment, R 1s 2 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 3 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 4 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 5 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 6 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 7 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 8 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 9 carbon atoms apart from the site of substitution on R2and M2; in another embodiment, R 1s 10 carbon atoms apart from the site of substitution on R2and M2.

[0220] In one more specific embodiment, R 1s is independently selected from H, C 1-14alkyl, -L c -OR c and -L c -NR c R' c ; in another more specific embodiment, R 1s is independently selected from the group consisting of H and C 1-14 alkyl; in another more specific embodiment, R 1s is independently selected from the group consisting of H and C 1-10 alkyl; in another more specific embodiment, R 1s is independently selected from the group consisting of H and C 1-9 alkyl; in another more specific embodiment, R 1s is independently selected from the group consisting of H and C 1-6 alkyl; in another more specific embodiment, R 1s is independently selected from the group consisting of H and C 1-4 alkyl.

[0221] in another more specific embodiment, R 1s is spaced from M1 on R1 by 0-10 carbon atoms; in another more specific embodiment, R 1s is spaced from M1 on R1 by 0-6 carbon atoms; in another more specific embodiment, R 1s is spaced from M1 on R1 by 0-4 carbon atoms; in another more specific embodiment, R 1s is spaced from M1 on R1 by 0-2 carbon atoms; in another more specific embodiment, R 1s is spaced from M1 on R1 by 0 carbon atoms.

[0222] in another more specific embodiment, R 1s is spaced from M2 on R2 by 0-10 carbon atoms; in another more specific embodiment, R 1s is spaced from M2 on R2 by 0-6 carbon atoms; in another more specific embodiment, R 1s is spaced from M2 on R2 by 0-4 carbon atoms; in another more specific embodiment, R 1s is spaced from M2 on R2 by 0-2 carbon atoms; in another more specific embodiment, R 1s is spaced from M2 on R2 by 0 carbon atoms.

[0223] in another more specific embodiment, R 1sthe substituent site on R1is separated from M1by 1-10 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 1-6 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 1-4 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 1-3 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 1-2 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 2-10 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 2-6 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 3-4 carbon atoms; in another more specific embodiment R 1s the substituent site on R1is separated from M1by 2-4 carbon atoms.

[0224] in another more specific embodiment R 1s the substituent site on R2is separated from M2by 1-10 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 1-6 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 1-4 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 1-3 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 1-2 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 2-10 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 2-6 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 3-4 carbon atoms; in another more specific embodiment R 1s the substituent site on R2is separated from M2by 2-4 carbon atoms.

[0225] in another more specific embodiment R1is free of R 1s substitution, and R 1sthe substituent on R2is separated from M2by 0-10 carbons, preferably 1-10 carbons, preferably 1-6 carbons, preferably 1-4 carbons, preferably 1-2 carbons; in another more specific embodiment, R1is free of R 1s substituted, R 1s the substituent on R2is separated from M2by 0-10 carbons, preferably 0-6 carbons, preferably 0-4 carbons, preferably 0-2 carbons, preferably 0 carbons; in another more specific embodiment, R1is free of R 1s substituted, R 1s the substituent on R2is separated from M2by 2-10 carbons, preferably 2-6 carbons, preferably 2-4 carbons.

[0226] R and R'

[0227] In one embodiment, R is H; in another embodiment, R is C 1-20 alkyl, preferably C 1-14 alkyl, preferably C 1-9 alkyl, preferably C 1-6 alkyl.

[0228] In one embodiment, R' is H; in another embodiment, R' is C 1-20 alkyl, preferably C 1-14 alkyl, preferably C 1-9 alkyl, preferably C 1-6 alkyl.

[0229] In one more specific embodiment, R and R' are each independently selected from the group consisting of H and C 1-20 alkyl; in another more specific embodiment, R and R' are each independently selected from the group consisting of H and C 1-14 alkyl; in another more specific embodiment, R and R' are each independently selected from the group consisting of H and C 1-9 alkyl; in another more specific embodiment, R and R' are each independently selected from the group consisting of H and C 1-6 alkyl; in another more specific embodiment, R is H.

[0230] L c , R c and R' c

[0231] In one embodiment, L c is a bond; in another embodiment, L c is C 1-20 alkylene, preferably C 1- 14 alkylene, preferably C1-10 Alkylene, preferably C 1-6 Alkylene.

[0232] In a more specific implementation, L c Independently selected from chemical bonds and C 1-14 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-6 Alkylene.

[0233] In one implementation, R c H; in another embodiment, R c C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R c C 3-14 Cycloalkyl, preferably C 3- 10 cycloalkyl; in another embodiment, R c It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0234] In one implementation, R' c H; in another embodiment, R' c C 1-20 Alkyl, preferably C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' c C 3-14 Cycloalkyl, preferably C 3- 10 cycloalkyl; in another embodiment, R' c It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0235] In a more specific implementation, R c and R' c Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R c and R' c Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R c and R' c Independently selected from H and C 1-6alkyl.

[0236] R3

[0237] In one embodiment, R3is CN; in another embodiment, R3is -OR g , for example -OH; in another embodiment, R3is -C(O)R g ; in another embodiment, R3is -OC(O)R g ; in another embodiment, R3is -NR"C(O)R g ; in another embodiment, R3is -NR g R' g , for example -N(CH3)2; in another embodiment, R3is -NR"C(O)NR g R' g ; in another embodiment, R3is -NR"C(O)R g ; in another embodiment, R3is -NR"S(O)2R g ; in another embodiment, R3is -OC(O)NR g R' g ; in another embodiment, R3is -NR"C(O)OR g ; in another embodiment, R3is -N(OR g )C(O)R g ; in another embodiment, R3is -N(OR g )S(O)2R g ; in another embodiment, R3is -N(OR g )C(O)OR g ; in another embodiment, R3is -N(OR g )C(O)R g R' g ; in another embodiment, R3is a 3- to 14-membered heterocyclyl; in another embodiment, R3is a 5- to 14-membered heteroaryl.

[0238] In a more specific embodiment, R3is selected from CN, -OR g , and -NR g R' g ; in another more specific embodiment, R3is selected from -OR g , and -NR g R' g ; in another more specific embodiment, R3is selected from -OH and -N(CH3)2; in another more specific embodiment, R3is -OR g ; in another more specific embodiment, R3is OH.

[0239] R g and R' g

[0240] In one implementation, R g H; in another embodiment, R g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, preferably C 1-3 Alkyl, such as Me; in another embodiment, R g C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R g It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0241] In one implementation, R' g H; in another embodiment, R' g C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R' g C 3-10 Cycloalkyl, preferably C 3-7 cycloalkyl; in another embodiment, R' g It is a 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group.

[0242] In a more specific implementation, R g and R' g Independently selected from H and C 1-6 Alkyl, C 3-7 cycloalkyl groups and 3 to 7-membered heterocyclic groups; in another more specific embodiment, R g and R' g Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R g and R' g Independently selected from H and C 1-4 Alkyl; in another, more specific embodiment, R g and R' g Selected independently from H and Me.

[0243] R”

[0244] In one implementation, R” is H; in another implementation, R” is C. 1-6 Alkyl, preferably C 1-4 alkyl.

[0245] R4and R5

[0246] In one embodiment, R4is C 1-8 alkyl, preferably C 1-6 alkyl, preferably C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl; in another embodiment, R4is optionally substituted with one or more R 4s substituents; in another embodiment, R4is optionally substituted with 1, 2, or 3 R 4s substituents; in another embodiment, R4is unsubstituted.

[0247] In one embodiment, R5is C 1-8 alkyl, preferably C 1-6 alkyl, preferably C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl; in another embodiment, R5is optionally substituted with one or more R 4s substituents; in another embodiment, R5is optionally substituted with 1, 2, or 3 R 4s substituents; in another embodiment, R5is unsubstituted.

[0248] In one embodiment, R4, R5, together with the carbon atom to which they are attached, form a C 3-14 cycloalkylene, preferably forms a C 3-10 cycloalkylene, preferably forms a C 3-6 cycloalkylene (e.g., cyclopropylene, e.g., cyclobutylene, e.g., cyclopentylene, e.g., cyclohexylene), preferably forms a C 3-5 cycloalkylene, preferably forms a C 3-4 cycloalkylene, preferably forms a cyclopropylene, preferably forms a cyclopentylene; in another embodiment, R4, R5, together with the carbon atom to which they are attached, form a 3- to 14-membered heterocyclene, preferably a 3- to 10-membered heterocyclene, preferably a 3- to 6-membered heterocyclene; in another embodiment, the ring formed by R4, R5, together with the carbon atom to which they are attached, is optionally substituted with one or more R 4s substituents; in another embodiment, the ring formed by R4, R5, together with the carbon atom to which they are attached, is optionally substituted with 1, 2, or 3 R 4s substituents; in another embodiment, the ring formed by R4, R5, together with the carbon atom to which they are attached, is unsubstituted.

[0249] In one more specific embodiment, R4, R5, together with the carbon atom to which they are attached, form a C 3-10 cycloalkylene or a 3- to 10-membered heterocyclene; in another more specific embodiment, R4, R5, together with the carbon atom to which they are attached, form a C 3-6C3-C6-cycloalkylene or 3- to 6-membered heterocyclyl; in a further more specific embodiment, R4, R5together with the carbon atom to which they are attached form a C 3-6 C3-C6-cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene); in a further more specific embodiment, R4, R5together with the carbon atom to which they are attached form a C 3-5 C3-C6-cycloalkylene; in a further more specific embodiment, R4, R5together with the carbon atom to which they are attached form a C 3-4 C3-C6-cycloalkylene; in a further more specific embodiment, R4, R5together with the carbon atom to which they are attached form a C3-C6-cycloalkylene or 3- to 6-membered heterocyclyl; in a further more specific embodiment, R4, R5together with the carbon atom to which they are attached form a C

[0250] R 4s

[0251] In one embodiment, R 4s is H; in a further embodiment, R 4s is halogen; in a further embodiment, R 4s is cyano; in a further embodiment, R 4s is C 1-8 alkyl, preferably C 1-6 alkyl, preferably C 1-3 alkyl; in a further embodiment, R 4s is C 1-8 haloalkyl, preferably C 1-6 haloalkyl, preferably C 1-3 haloalkyl; in a further embodiment, R 4s is -L d -OR d ; in a further embodiment, R 4s is -L d -SR d ; in a further embodiment, R 4s is -L d -NR d R’ d .

[0252] In one embodiment, R 4s is independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L d -OR d , -L d -SR d and -L d -NR d R’d ; in another more specific embodiment, R 4s is independently selected from H, halo, cyano, C 1-6 alkyl and C 1-6 haloalkyl; in another more specific embodiment, R 4s is independently selected from H, C 1-3 alkyl and C 1-3 haloalkyl.

[0253] L d , R d and R' d

[0254] In one embodiment, L d is a chemical bond; in another embodiment, L d is C 1-8 alkylene, preferably C 1- 6alkylene, preferably C 1-3 alkylene.

[0255] In one more specific embodiment, L d is independently selected from a chemical bond and C 1-6 alkylene; in another more specific embodiment, L d is independently selected from a chemical bond and C 1-3 alkylene.

[0256] In one embodiment, R d is H; in another embodiment, R d is C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R d is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R d is 3- to 14-membered heterocyclyl, preferably 3- to 10-membered heterocyclyl.

[0257] In one embodiment, R' d is H; in another embodiment, R' d is C 1-8 alkyl, preferably C 1-6 alkyl; in another embodiment, R' d is C 3-14 cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' d is 3- to 14-membered heterocyclyl, preferably 3- to 10-membered heterocyclyl.

[0258] In one more specific embodiment, R dand R' d independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; in another more particular embodiment, R d and R' d independently selected from H and C 1-6 alkyl.

[0259] a, b, c and d

[0260] In one embodiment, a is 1 ; in another embodiment, a is 2; in another embodiment, a is 3; in another embodiment, a is 4; in another embodiment, a is 5; in another embodiment, a is 6.

[0261] In one more particular embodiment, a = 2, 3, 4, 5 or 6; in another more particular embodiment, a = 2, 3 or 4; in another more particular embodiment, a = 2 or 4; in another more particular embodiment, a = 2 or 3; in another more particular embodiment, a = 3 or 4.

[0262] In one embodiment, b is 4; in another embodiment, b is 5; in another embodiment, b is 6; in another embodiment, b is 7; in another embodiment, b is 8; in another embodiment, b is 9; in another embodiment, b is 10.

[0263] In one more particular embodiment, b = 4, 5, 6, 7 or 8; in another more particular embodiment, b = 5, 6, 7 or 8; in another more particular embodiment, b = 5, 6 or 7; in another more particular embodiment, b = 5 or 7; in another more particular embodiment, b = 6 or 7.

[0264] In one more particular embodiment, b = 4, 5, 6, 7, 8, 9 or 10; in another more particular embodiment, b = 4, 5, 6, 7, 8 or 9; in another more particular embodiment, b = 4, 5, 6 or 7; in another more particular embodiment, b = 5 or 6; in another more particular embodiment, b = 6, 7 or 8; in another more particular embodiment, b = 5, 6, 7 or 8;

[0265] 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.

[0266] In a more particular embodiment, c = 2, 3, 4, 5, or 6; in another more particular embodiment, c = 2, 3, 4, or 5; in another more particular embodiment, c = 2, 3, or 4; in another more particular embodiment, c = 3 or 4; in another more particular embodiment, c = 4, 5, or 6; in another more particular embodiment, c = 4 or 5; in another more particular embodiment, c = 5 or 6.

[0267] In a more particular embodiment, c = 2, 4, 5, or 6; in another more particular embodiment, c = 4, 5, or 6; in another more particular embodiment, c = 4 or 6; in another more particular embodiment, c = 2, 3, 4, or 5; in another more particular embodiment, c = 2, 4, or 5; in another more particular embodiment, c = 2 or 5.

[0268] In one embodiment, d is 0; in another embodiment, d is 1 ; in another embodiment, d is 2; in another embodiment, d is 3; in another embodiment, d is 4.

[0269] In a more particular embodiment, d = 0, 1, 2, or 4; in another more particular embodiment, d = 0, 1, or 2; in another more particular embodiment, d = 2, 3, or 4; in another more particular embodiment, d = 0 or 1.

[0270] In a more particular embodiment, d = 0, 1, 2, 3, or 4; in another more particular embodiment, d = 0, 1, or 2; in another more particular embodiment, d = 0 or 2; in another more particular embodiment, d is not 0; in another more particular embodiment, d = 1, 2, 3, or 4; in another more particular embodiment, d = 1 or 2; in another more particular embodiment, d = 1, 2, or 4; in another more particular embodiment, d = 1 or 4.

[0271] In one embodiment, c + d = 3; in another embodiment, c + d = 4; in another embodiment, c + d = 5; in another embodiment, c + d = 6; in another embodiment, c + d = 7; in another embodiment, c + d = 8; in another embodiment, c + d = 9.

[0272] In a more particular embodiment, c + d = 4, 5, or 6; in another more particular embodiment, c + d = 5 or 6.

[0273] In a more particular embodiment, c+d = 3, 4, 5, 6, 7, 8, or 9; in another more particular embodiment, c+d = 4, 5, 6, or 7; in another more particular embodiment, c+d = 4, 5, or 6; in another more particular embodiment, c+d = 5, 6, or 7; in another more particular embodiment, c+d = 5 or 6; in another more particular embodiment, c+d = 6, 7, or 8; in another more particular embodiment, c+d = 6 or 7.

[0274] Any of the technical solutions in any of the above embodiments, or any combination thereof, can be combined with any of the technical solutions in other embodiments, or any combination thereof. For example, any of the technical solutions of G1, or any combination thereof, can be combined with any of the technical solutions of G2, R G1 , G3, R G3 , L a , R a , R’ a , G4, R G4 , L b , R b , R’ b , R 4g , L e , R e , R’ e , M1, M2, Q, R*, L f , R f , R’ f , R1, R2, R 1s , R, R’, L c , R c , R’ c , R3, R g , R’ g , R”, R4, R5, R 4s , L d , R d , R’ d , a, b, c, and d, etc., or any combination thereof. The present application is intended to include all combinations of these technical solutions, which are not listed one by one due to the length of the article.

[0275] In more particular embodiments, the present application provides a compound of Formula (I’), or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0276] wherein,

[0277] Z is CH;

[0278] G1and G2are independently selected from a bond, C 1-13 straight-chain alkylene, C2-13 linear alkenylene, and C 2-13 linear alkynylene, optionally substituted with one or more R G1 substituents;

[0279] G1and G2have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms;

[0280] R G1 is independently selected from H, C 1-14 alkyl, -L a -OR a , -L a -SR a and -L a -NR a R’ a ;

[0281] G3is selected from C 4-14 linear alkylene, C 4-14 linear alkenylene, and C 4-14 linear alkynylene, optionally substituted with one or more R G3 substituents;

[0282] R G3 is independently selected from H, -L a -OR a , -L a -SR a and -L a -NR a R’ a ;

[0283] L a is independently selected from a bond and C 1-14 alkylene;

[0284] R a and R’ a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclyl;

[0285] G4is selected from a bond, C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, optionally substituted with one or more R G4 substituents;

[0286] R G4 is independently selected from H, C 1-6 alkyl, -L b -OR b , -L b -SR b and -Lb -NR b R’ b ;

[0287] L b independently selected from a bond and C 1-6 alkylene;

[0288] R b and R’ b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0289] or two R G4 on the same carbon atom, together with the carbon atom to which they are attached, form a C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, optionally substituted with one or more R 4g ;

[0290] R 4g is independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e , -L e -SR e and -L e -NR e R’ e ;

[0291] L e is independently selected from a bond and C 1-8 alkylene;

[0292] R e and R’ e are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl;

[0293] M1and M2are 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-;

[0294] Q is selected from a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f f C(O)NR f -, -OC(O)S-, -OC(O)O-, -NR f C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR f -, -C(O)NR f -, -NR f C(O)-, -NR f C(O)S-, -SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -, -NR f C(S)O-, -S-S-, -S(O) 0-2 -, phenylene and pyridinylene, wherein the phenylene or pyridinylene is optionally substituted with one or more R*;

[0295] R* is independently selected from H, halogen, cyano, C 1-10 alkyl, C 1-10 haloalkyl, -L f -OR f , -L f -SR f and -L f -NR f R’ f ;

[0296] L f is independently selected from a chemical bond and C 1-8 alkylene;

[0297] R f and R’ f are independently selected from H, C 1-10 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl;

[0298] R1and R2are independently selected from C 4-20 alkyl, C 4-20 alkenyl and C 4-20 alkynyl, which is optionally substituted with one or more R 1s , and wherein one or more methylene units are optionally and independently replaced with -NR’-;

[0299] R 1s is independently selected from H, C 1-20 alkyl, -L c -OR c , -L​c -SR c and -L c -NR c R’ c ;

[0300] R and R’ are each independently selected from H and C 1-20 alkyl;

[0301] L c is independently selected from a bond and C 1-20 alkylene;

[0302] R c and R’ c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclyl;

[0303] R3is selected from CN, -OR g , -C(O)R g , -OC(O)R g , -NR”C(O)R g , -NR g R’ g , -NR”C(O)NR g R’ g , -NR”C(O)R g , -NR”S(O)2R g , -OC(O)NR g R’ g , -NR”C(O)OR g , -N(OR g )C(O)R g , -N(OR g )S(O)2R g , -N(OR g )C(O)OR g , -N(OR g )C(O)R g R’ g , 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl;

[0304] R g and R’ g are independently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclyl;

[0305] R” is independently selected from H and C 1-6 alkyl;

[0306] R4and R5are independently selected from C 1-8alkyl, which is optionally substituted with one or more R 4s substituents;

[0307] or R4, R5, together with the carbon atom to which they are attached, form a C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, which is optionally substituted with one or more R 4s substituents;

[0308] R 4s is independently selected from the group consisting of H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L d -OR d , -L d -SR d and -L d -NR d R’ d ;

[0309] L d is independently selected from the group consisting of a bond and C 1-8 alkylene;

[0310] R d and R’ d are independently selected from the group consisting of H, C 1-8 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl.

[0311] In more particular embodiments, the present application provides the above-mentioned compounds, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is of the structure of Formula (III’) or Formula (IV):

[0312] wherein,

[0313] a = 1, 2, 3, 4, 5, or 6;

[0314] b = 4, 5, 6, 7, 8, 9, or 10;

[0315] c = 1, 2, 3, 4, 5, or 6;

[0316] d = 0, 1, 2, 3, or 4;

[0317] c + d = 3, 4, 5, 6, 7, 8, or 9;

[0318] and the remaining variables are as defined in the present application.

[0319] In more particular embodiments, the present application provides the above-mentioned compounds, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1sthe substituent on R1or R2is separated from M1or M2by 0-10 carbon atoms, preferably 0-6 carbon atoms, preferably 0-4 carbon atoms, preferably 0-2 carbon atoms, preferably 0 carbon atoms;

[0320] preferably R1is substituted with R 1s the substituent on R1or R2is separated from M1or M2by 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, preferably 2-4 carbon atoms;

[0321] preferably R1is substituted with R 1s and R2is not substituted with R 1s the substituent on R2is separated from M2by 0-10 carbon atoms, preferably 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, preferably 2-4 carbon atoms;

[0322] preferably at least one of R1and R2is substituted with R 1s ;

[0323] preferably R1is substituted with R 1s and R2is not substituted with R 1s ;

[0324] preferably R2is substituted with R 1s and R1is not substituted with R 1s ;

[0325] preferably R4and R5, together with the carbon atom to which they are attached, do not form a ring;

[0326] preferably d is not 0.

[0327] In more specific embodiments, the present application provides the above- described compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G1and G2are independently selected from a chemical bond, C 1-9 straight chain alkylene, C 2-9 straight chain alkenylene, and C 2-9 straight chain alkynylene.

[0328] In more specific embodiments, G1is selected from C 1-6 straight chain alkylene, C 2-6 straight chain alkenylene, and C 2-6 straight chain alkynylene, preferably selected from C 1-6 straight chain alkylene, preferably selected from C 2-6 straight chain alkylene.

[0329] In more particular embodiments, G2is selected from a chemical bond, C 1-6 straight-chain alkenylene, and C 2-6 straight-chain alkenylene, and C 2-6 straight-chain alkynylene, preferably selected from a chemical bond and C 1-6 straight-chain alkylene, preferably selected from a chemical bond and C 1-4 straight-chain alkylene.

[0330] In more particular embodiments, the total length of G1and G2is 3, 4, 5, 6, 7, 8, or 9 carbon atoms, preferably the total length is 4, 5, or 6 carbon atoms, preferably the total length is 5 or 6 carbon atoms; preferably the total length is 5, 6, or 7 carbon atoms, preferably the total length is 6 or 7 carbon atoms.

[0331] Preferably, G1and G2are optionally substituted with 1, 2, 3, or 4 R G1 .

[0332] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R G1 is independently selected from H and C 1-10 alkyl; preferably selected from H and C 1-6 alkyl.

[0333] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G3is selected from C 4-10 straight-chain alkylene, C 4-10 straight-chain alkenylene, and C 4-10 straight-chain alkynylene; preferably selected from C 4-9 straight-chain alkylene; preferably selected from C 5-8 straight-chain alkylene; preferably selected from C 6-7 straight-chain alkylene.

[0334] In more particular embodiments, G3is optionally substituted with 1, 2, 3, or 4 R G3 .

[0335] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L a is independently selected from a chemical bond and C 1-10 alkylene, preferably selected from a chemical bond and C 1-6 alkylene.

[0336] In more particular embodiments, R a and R’ aindependently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; preferably selected from H and C 1-6 alkyl.

[0337] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G4is selected from C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene; preferably selected from C 2-4 alkylene; preferably selected from C 2-3 alkylene.

[0338] In more particular embodiments, G4is optionally substituted with 1, 2, 3, or 4 R G4 groups.

[0339] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R G4 is independently selected from H and C 1-6 alkyl; preferably selected from C 1-4 alkyl.

[0340] In more particular embodiments, two R G4 groups attached to the same carbon atom, together with the carbon atom to which they are attached, form a C 3-10 cycloalkylene or 3- to 10-membered heterocyclylene, preferably a C 3-7 cycloalkylene or 3- to 7-membered heterocyclylene, optionally substituted with 1, 2, or 3 R 4g groups.

[0341] In more particular embodiments, R 4g is independently selected from H, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl.

[0342] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L b is independently selected from a chemical bond and C 1-4 alkylene.

[0343] In more particular embodiments, R b and R’ b are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl and 3- to 7-membered heterocyclyl; preferably selected from H and C 1-6alkyl; preferably selected from H and C 1-4 alkyl.

[0344] In more particular embodiments, the present application provides the above-mentioned compounds, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein M1and M2are independently selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR-, and -NRC(O)-; preferably from -C(O)O-, -OC(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; preferably from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; preferably from -C(O)O- and -OC(O)-.

[0345] In more particular embodiments, M1and M2are independently selected from -C(O)O- and -C(O)S-, preferably -C(O)O-.

[0346] In more particular embodiments, one of M1and M2is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is -OC(O)- or -SC(O)-, preferably -OC(O)-.

[0347] In more particular embodiments, M1is -OC(O)- or -SC(O)-, preferably -OC(O)-; and M2is -C(O)O- or -C(O)S-, preferably -C(O)O-.

[0348] In more particular embodiments, M1is -C(O)O- or -C(O)S-, preferably -C(O)O-; and M2is -OC(O)- or -SC(O)-, preferably M2is -OC(O)-.

[0349] In more particular embodiments, M1is -OC(O)-; and M2is -C(O)O- or -OC(O)-, preferably -C(O)O-.

[0350] In more particular embodiments, M1is -C(O)O-; and M2is -C(O)O- or -C(O)S-.

[0351] In more particular embodiments, M1and M2are independently selected from -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NHC(O)-, and -C(O)NH-.

[0352] In more particular embodiments, M1and M2are independently selected from -C(O)O-, -OC(O)-, -C(O)S-, and -C(O)NH-, preferably from -C(O)O-, -OC(O)-, and -C(O)S-.

[0353] In more particular embodiments, one of M1and M2is -C(O)O- or -C(O)S-, preferably -C(O)O-, and the other is selected from -C(O)O-, -C(O)S-, -C(O)NH-, -OC(O)-, and -SC(O)-, preferably from -C(O)O-, -C(O)S-, -C(O)NH-, and -OC(O)-, preferably from -C(O)O-, -C(O)S-, -OC(O)-, and -SC(O)-, preferably from -C(O)O-, -C(O)S-, and -OC(O)-.

[0354] In more particular embodiments, one of M1and M2is -OC(O)O-, and the other is selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-, preferably -C(O)O- or -OC(O)-.

[0355] In more particular embodiments, M1is selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-, preferably from -C(O)O- and -OC(O)-, preferably -C(O)O-, preferably -OC(O)-, and M2is -OC(O)O-.

[0356] In more particular embodiments, M1is -OC(O)O-, and M2is -OC(O)- or -OC(O)-, preferably -OC(O)-.

[0357] In more particular embodiments, M1and M2are independently selected from -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-, preferably from -C(O)O-, -OC(O)-, and -OC(O)O-; preferably, M1and M2are not both -OC(O)O-.

[0358] In more particular embodiments, the present application provides the above-mentioned compounds, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1and R2are independently selected from C 6-14 alkyl, C 6-14 alkenyl, and C 6-14 alkynyl; preferably from C 6-14 alkyl; preferably from C 7-12 alkyl; preferably from C 8-12 alkyl.

[0359] In more particular embodiments, R1and R2are independently selected from C 7-12 alkyl, C 7-12 alkenyl, and C 7-12 alkynyl, preferably C 8-12 alkyl, C8-12 alkenyl and C 8-12 alkynyl.

[0360] In more specific embodiments, R1and R2are independently selected from the group consisting of -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 1s substituted, preferably optionally substituted with 1, 2, or 3 R 1s substituted, preferably optionally substituted with 1, 2, or 3 R 1s substituted, preferably optionally substituted with 1, 2, or 3 R 1s substituted.

[0361] In more specific embodiments, R1and R2are independently selected from the group consisting of -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0362] In more specific embodiments, R1and R2are independently selected from the group consisting of -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0363] In more particular embodiments, R1and R2are independently selected from C8linear alkyl, C9linear alkyl,

[0364] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1s is independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably from H and C 1-14 alkyl; preferably from H and C 1-10 alkyl; preferably from H and C 1-9 alkyl; preferably from H and C 1-6 alkyl, preferably from H and C 1-4 alkyl.

[0365] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R and R’ are each independently selected from H and C 1-20 alkyl; preferably from H and C 1-14 alkyl; preferably from H and C 1-9 alkyl; preferably from H and C 1-6 alkyl; preferably R is H.

[0366] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L c is independently selected from a chemical bond and C 1-14 alkylene; preferably from a chemical bond and C 1-10 alkylene; preferably from a chemical bond and C 1-6 alkylene.

[0367] In more particular embodiments, R c and R’ c are independently selected from H and C 1-14 alkyl; preferably from H and C 1-10 alkyl; preferably from H and C 1-6 alkyl.

[0368] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R3is selected from CN, -OR g and -NR g R’ g; preferably -OR g and -NR g R' g ; preferably -OR g ; preferably OH.

[0369] In more particular embodiments, R3is selected from -OH and -N(CH3)2.

[0370] In more particular embodiments, R g and R' g are independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and 3- to 7-membered heterocyclyl; preferably from H and C 1-6 alkyl; preferably from H and C 1-4 alkyl; preferably from H and Me.

[0371] In more particular embodiments, R g and R' g are independently C 1-6 alkyl, preferably C 1-4 alkyl, preferably C 1-3 alkyl, e.g. Me.

[0372] In more particular embodiments, the present application provides a compound as described above, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4and R5are independently selected from C 1-6 alkyl; preferably from C 1-3 alkyl; preferably from C 1-2 alkyl; preferably methyl.

[0373] In more particular embodiments, R4and R5are optionally substituted with 1, 2, or 3 R 4s .

[0374] In more particular embodiments, R4, R5, together with the carbon atom to which they are attached, form C 3-10 cycloalkylene, or 3- to 10-membered heterocyclylene; preferably C 3-6 cycloalkylene, or 3- to 6-membered heterocyclylene; preferably C 3-6 cycloalkylene (e.g. cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably C 3-5 cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably C 3-4 cycloalkylene; preferably cyclopropylene.

[0375] In more particular embodiments, the ring formed by R4, R5, together with the carbon atom to which they are attached, is optionally substituted with 1, 2, or 3 R 4s .

[0376] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4s is independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L d -OR d , -L d -SR d and -L d -NR d R’ d ; preferably from H, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl; preferably from H, C 1-3 alkyl and C 1-3 haloalkyl.

[0377] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L d is independently selected from a chemical bond and C 1-6 alkylene; preferably from a chemical bond and C 1-3 alkylene.

[0378] In more particular embodiments, R d and R’ d are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; preferably from H and C 1-6 alkyl.

[0379] In more particular embodiments, the present application provides the aforementioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L e is independently selected from a chemical bond and C 1-6 alkylene; preferably from a chemical bond and C 1-4 alkylene.

[0380] In more particular embodiments, R e and R’ e are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; preferably from H and C 1-6 alkyl; preferably from H and C 1-4 alkyl.

[0381] In more particular embodiments, the present application provides the above-mentioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of a chemical bond, -OC(O)-, and -SC(O)-; preferably from the group consisting of a chemical bond and -SC(O)-; preferably from the group consisting of -C(O)O- or -C(O)S-; preferably from the group consisting of -C(O)O- or -SC(O)-; preferably -C(O)O-.

[0382] In more particular embodiments, Q is phenylene or pyridylene, optionally substituted with 1, 2, or 3 R*.

[0383] In more particular embodiments, R* is independently selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, and C 1-6 haloalkyl.

[0384] In more particular embodiments, L f is independently selected from the group consisting of a chemical bond and C 1-6 alkylene; preferably from the group consisting of a chemical bond and C 1- 4alkylene.

[0385] In more particular embodiments, R f and R’ f are independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclyl; preferably from the group consisting of H and C 1-6 alkyl; preferably from the group consisting of H and C 1-4 alkyl.

[0386] In more particular embodiments, the present application provides the above-mentioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is of the structure of Formula (III’):

[0387] wherein,

[0388] Z is N or CH; preferably CH;

[0389] Q is -C(O)O-, -C(O)S-, -SC(O)-, or -OC(O)-;

[0390] R g and R’ g are independently C 1-6 alkyl;

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

[0392] b = 4, 5, 6, 7, 8, or 9; b = 4, 5, 6, 7, or 8;

[0393] c = 2, 3, 4, 5, or 6;

[0394] d = 0, 1, 2, 3, or 4;

[0395] c + d = 5, 6, or 7;

[0396] M1and M2are independently selected from the group consisting of -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-;

[0397] R1and R2are independently C 6-14 alkyl, optionally substituted with 1, 2, 3, or 4 R 1s substituents;

[0398] R 1s are independently selected from the group consisting of H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably from the group consisting of H and C 1-14 alkyl;

[0399] L c is independently selected from the group consisting of a bond and C 1-14 alkylene;

[0400] R c and R’ c are independently selected from the group consisting of H and C 1-14 alkyl;

[0401] R4and R5are independently C 1-6 alkyl;

[0402] or R4and R5together with the carbon atom to which they are attached form a C 3-6 cycloalkylene or 3-6 membered heterocyclylene.

[0403] In more particular embodiments, the present application provides the above-mentioned compounds, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0404] Z is N or CH; preferably CH;

[0405] Q is -C(O)O- or -SC(O)-; preferably -C(O)O- or -C(O)S-;

[0406] R g and R’ g are independently C 1-3 alkyl;

[0407] a = 2, 3, or 4;

[0408] b = 5, 6 or 7; preferably b = 6 or 7;

[0409] c = 2, 3, 4 or 5;

[0410] d = 0, 1, 2, 3 or 4;

[0411] c + d = 5 or 6;

[0412] M1and M2are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; preferably, M1and M2are not -OC(O)O- at the same time;

[0413] R1and R2are independently C 8-12 alkyl, preferably C 8-10 alkyl, optionally substituted with 1, 2 or 3 R 1s substituents;

[0414] R 1s is independently C 1-12 alkyl, preferably C 1-10 alkyl, preferably C 1-9 alkyl;

[0415] R4and R5are independently C 1-3 alkyl, preferably methyl;

[0416] or R4and R5together with the carbon atom to which they are attached form a C 3-6 cycloalkylene, preferably C 3-4 cycloalkylene.

[0417] In more particular embodiments, the present application provides a compound as described above, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is of the structure of Formula (III’) or Formula (IV):

[0418] wherein,

[0419] Z is CH;

[0420] Q is -C(O)O-, -C(O)S-, -SC(O)- or -OC(O)-;

[0421] R g and R’ g are independently C 1-6 alkyl;

[0422] a = 2, 3, 4, 5 or 6;

[0423] b = 4, 5, 6, 7 or 8;

[0424] c = 2, 3, 4, 5 or 6;

[0425] d = 0, 1, 2, 3, or 4;

[0426] c + d = 5, 6, or 7;

[0427] M1and M2are independently selected from the group consisting of -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-; preferably -C(O)O-, -OC(O)-, and -OC(O)O-; preferably -C(O)O- and -OC(O)-;

[0428] R1and R2are independently C 6-14 alkyl, which is optionally substituted with 1, 2, or 3 R 1s substituents;

[0429] R 1s is independently selected from the group consisting of H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably from the group consisting of H and C 1-14 alkyl;

[0430] L c is independently selected from the group consisting of a bond and C 1-14 alkylene;

[0431] R c and R’ c are independently selected from the group consisting of H and C 1-14 alkyl;

[0432] R4and R5are independently C 1-3 alkyl;

[0433] or R4and R5together with the carbon atom to which they are attached form a C 3-6 cycloalkylene or 3-6 membered heterocyclylene.

[0434] In more specific embodiments, the present application provides the above-mentioned compounds, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (III’) or formula (IV),

[0435] Z is CH;

[0436] Q is -C(O)O- or -C(O)S-;

[0437] R g and R’ g are independently C 1-3 alkyl;

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

[0439] b = 5, 6 or 7; preferably 6 or 7;

[0440] c = 4, 5 or 6;

[0441] d = 0, 1 or 2;

[0442] c + d = 5, 6 or 7; preferably c + d = 5 or 6;

[0443] M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)- and -OC(O)O-; preferably -C(O)O- and -OC(O)-;

[0444] R1and R2are independently C 8-12 alkyl, preferably C 8-10 alkyl, optionally substituted with 1, 2 or 3 R 1s substituents;

[0445] R 1s is independently C 1-12 alkyl, preferably C 1-10 alkyl;

[0446] R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl;

[0447] or R4and R5together with the carbon atom to which they are attached form a C 3-6 cycloalkylene, preferably C 3-4 cycloalkylene.

[0448] In more particular embodiments, the present application provides the above-mentioned compounds, or an isotopic variant, a tautomer or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV),

[0449] R g and R' g are methyl;

[0450] a = 3;

[0451] b = 6 or 7;

[0452] c = 4 or 5;

[0453] d = 0 or 1;

[0454] c + d = 5 or 6;

[0455] M1and M2are independently selected from the group consisting of -C(O)O- and -OC(O)-;

[0456] R1and R2are independently C 8-9 alkyl, optionally substituted with 1 or 2 R 1s substituents;

[0457] R 1s independently C 1-7 alkyl;

[0458] R4and R5are methyl;

[0459] or R4and R5together with the carbon atom to which they are attached form a C 3-4 cycloalkylene; preferably not forming a ring;

[0460] Preferably, R1and R2are independently selected from C8straight chain alkyl, C9straight chain alkyl,

[0461] Preferably, at least one of R1and R2is substituted with R 1s

[0462] In more specific embodiments, the present application provides the above-mentioned compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV),

[0463] R g and R g are independently C 1-3 alkyl, preferably methyl;

[0464] a = 3;

[0465] b = 6;

[0466] c = 5;

[0467] d = 0;

[0468] M1and M2are -C(O)O-;

[0469] R1and R2are independently C 8-12 alkyl, preferably C 8-10 alkyl, preferably C9alkyl, optionally substituted with 1 or 2 R 1s

[0470] R 1s are independently C 1-10 alkyl; preferably C 1-7 alkyl; preferably C 1-5 alkyl;

[0471] R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl;

[0472] or R4and R5together with the carbon atom to which they are attached form a C 3-4 cycloalkylene; preferably not forming a ring;​​

[0473] Preferably, R1is selected from C9straight chain alkyl and

[0474] R2is selected from C9straight chain alkyl,

[0475] Preferably, at least one of R1and R2is substituted with R 1s

[0476] In more particular embodiments, the present application provides the above-mentioned compound, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV),

[0477] a = 3;

[0478] R g and R' g are independently C 1-3 alkyl, preferably methyl;

[0479] b = 7;

[0480] c = 5;

[0481] d = 0;

[0482] M1is -C(O)O-;

[0483] M2is -OC(O)-;

[0484] R1and R2are independently selected from C 8-12 alkyl, preferably C 8-10 alkyl, preferably C 8-9 alkyl; preferably, R1is selected from C9alkyl and R2is selected from C8alkyl; which are optionally substituted with 1 or 2 R 1s ;

[0485] R 1s is independently selected from C 1-10 alkyl; preferably C 1-7 alkyl, preferably C 5-7 alkyl;

[0486] R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl;

[0487] or R4and R5together with the carbon atom to which they are attached form a C 3-4 cycloalkylene; preferably no ring is formed;

[0488] Preferably, R1is selected from C9straight chain alkyl,

[0489] ​R2is selected from C8straight chain alkyl and

[0490] Preferably, at least one of R1and R2is R 1s substituted.

[0491] In a more specific embodiment, the present application provides the above compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV),

[0492] R g and R' g are independently C 1-3 alkyl, preferably methyl;

[0493] a = 3;

[0494] b = 6 or 7; preferably b = 6;

[0495] c = 4 or 5;

[0496] d = 0 or 1 ; preferably d = 1 ;

[0497] c + d = 5 or 6;

[0498] M1is -OC(O)-;

[0499] M2is -C(O)O- or -OC(O)-; preferably -C(O)O-;

[0500] R1and R2are independently C 8-12 alkyl, preferably C 8-10 alkyl; preferably C 8-9 alkyl; optionally substituted with 1 or 2 R 1s ;

[0501] R 1s is independently C 1-10 alkyl; preferably C 1-7 alkyl, preferably C 5-7 alkyl;

[0502] R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl;

[0503] or R4and R5together with the carbon atom to which they are attached form C 3-4 cycloalkylene; preferably no ring is formed;

[0504] Preferably, R1is selected from C8straight chain alkyl, C9straight chain alkyl and

[0505] R2is selected from C9straight chain alkyl, preferably C9 linear alkyl,

[0506] Preferably, at least one of R1and R2is R 1s substituted.

[0507] In more particular embodiments, the present application provides the above-mentioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1s The substitution site on R1or R2is spaced from M1or M2by 0-6 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 3-4 carbon atoms; preferably 1-3 carbon atoms.

[0508] In more particular embodiments, the present application provides the above-mentioned compound, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table (II).

[0509] Table (II)

[0510] The present application also provides a method of preparing a compound of Formula (IV), the method comprising:

[0511] reacting a compound of Formula (IVa) with a compound of Formula (IVb) to obtain a compound of Formula (IV);

[0512] wherein the variables are as defined in the present application.

[0513] In more particular embodiments, the present application provides a pharmaceutical composition comprising a compound of the present application, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0514] In more particular embodiments, the present application provides a nanoparticle composition comprising a lipid component, and optionally comprising a cargo; wherein the lipid component contains a compound of the present application, or an isotopic variant, a tautomer, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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

[0516] 20-85 mol% of any of the above-mentioned compounds of the present application:

[0517] 10-75 mol% of a structural lipid;

[0518] 1.0-30 mol% of a neutral lipid;

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

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

[0521] 50 mol% of any of the compounds of the application described above;

[0522] neutral lipid 10 mol%;

[0523] structural lipid 38.5 mol%;

[0524] polymeric lipid 1.5 mol%.

[0525] In more particular embodiments, the present application provides the above nanoparticle composition, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE, or DPPE, preferably DSPC and / or DOPE.

[0526] In more particular embodiments, the present application provides the above nanoparticle composition, wherein the structural lipid is a sterol; preferably, the sterol is selected from one or more of cholesterol, beta-sitosterol, coprostanol, desmosterol, brassicasterol, ergosterol, tomatidine, ursolic acid, alpha-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol, preferably cholesterol and / or beta-sitosterol, more preferably cholesterol.

[0527] In more particular embodiments, the present application provides the above nanoparticle composition, wherein the polymeric lipid is a pegylated lipid.

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

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

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

[0531] In more specific embodiments, the present application provides the above nanoparticle composition, wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent;

[0532] Preferably, the therapeutic agent, prophylactic agent, or diagnostic agent is a nucleic acid.

[0533] Preferably, the nucleic acid is selected from one or more of an ASO, an RNA, or a DNA.

[0534] Preferably, the RNA is selected from one or more of a small interfering RNA (siRNA), a short hairpin RNA (shRNA), an antisense RNA (aRNA), a messenger RNA (mRNA), a long non-coding RNA (IncRNA), a microRNA (miRNA), a small activating RNA (saRNA), a multimeric coding nucleic acid (MCNA), a polymeric coding nucleic acid (PCNA), a guide RNA (gRNA), a CRISPR RNA (crRNA), or a ribozyme, preferably a mRNA, more preferably a modified mRNA.

[0535] The compounds of the present application can include one or more asymmetric centers and can thus occur as various stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds of the present application can be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or the preferred isomer can be prepared by asymmetric synthesis.

[0536] The compounds of the present application can exist in tautomeric forms. Tautomers are functional group isomers that result from the rapid movement of an atom in a molecule to two positions. Tautomers are a special class of functional group isomers, a pair of which can interconvert, but usually one isomer predominates. The most common examples are the enol and keto tautomers.

[0537] The present application also includes isotopically-labeled compounds (isotopic variants) which are identical to those recited by Formula (I') but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be heteroatoms incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present application, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example, those into which radioactive isotopes such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of Formula (IV) of the present application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples and

[0538] The present application also provides pharmaceutical formulations including a therapeutically effective amount of a compound of Formula (I') or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient therefor. All such forms are within the present application.

[0539] Pharmaceutical compositions and kits

[0540] In another aspect, the present application provides pharmaceutical compositions comprising a nanoparticle composition of the present application comprising a compound of the present application and a pharmaceutically acceptable excipient.

[0541] Pharmaceutically acceptable excipients for use in the present application refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound with which it is co-administered. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0542] The present application also includes kits (e.g., pharmaceutical packs). The kits provided can include a nanoparticle composition of the present application and other therapeutic or diagnostic or prophylactic agents, as well as containers (e.g., vials, ampules, bottles, syringes, and / or dispensing containers or other suitable containers) filled with the nanoparticle composition of the present application and other therapeutic or diagnostic or prophylactic agents. In some embodiments, the kits provided can also optionally include a third container comprising a pharmaceutically-acceptable excipient that can be used to dilute or suspend the nanoparticle composition of the present application and / or other therapeutic or diagnostic or prophylactic agents. In some embodiments, the nanoparticle composition of the present application and other therapeutic or diagnostic or prophylactic agents provided in the first and second containers are combined to form a single unit dosage form.

[0543] Dosing

[0544] The pharmaceutical compositions provided by the present application can be administered by a variety of routes including, but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, administration via an implant, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0545] Generally, an effective amount of a pharmaceutical composition of the present application is administered. The amount of a pharmaceutical composition actually to be administered can be determined by a physician, in light of the relevant circumstances, including the condition(s) to be treated or prevented, the chosen route of administration, the actual pharmaceutical composition administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0546] When used to prevent a condition described herein, a pharmaceutical composition provided herein is administered to a subject at risk of developing the condition, typically on the advice and under the supervision of a physician, at a dosage level as described above. Subjects at risk of developing a particular condition include, generally, those who have a family history of the condition, or those who, through genetic testing or screening, are determined to be particularly susceptible to developing the condition.

[0547] A pharmaceutical composition provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound or a pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window, over an extended period of time.

[0548] Various methods of administration can be used to further deliver a pharmaceutical composition of the application. For example, in some embodiments, a pharmaceutical composition can be administered as a bolus, e.g., to raise the concentration of a compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose releases the active ingredient slowly, while a bolus delivered directly to a vein, e.g., by IV infusion, can deliver more rapidly, such that the concentration of the active ingredient in the blood rises quickly to an effective level. In other embodiments, a pharmaceutical composition can be administered as a continuous infusion, e.g., by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject. In still other embodiments, a bolus dose of a pharmaceutical composition can be administered first, followed by a continuous infusion.

[0549] To provide blood levels similar to, or lower than, those achieved using an injectable dose, transdermal doses are typically selected in amounts of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0550] Injectable dose levels range from about 0.1 mg / kg / hr to at least 10 mg / kg / hr for about 1 to about 120 hours, especially 24 to 96 hours. To achieve adequate steady state levels, a preloaded bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be administered. The maximum total dose for a 40 to 80 kg human patient should not exceed about 2 g / day.

[0551] Injectable compositions are typically based upon injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As before, in such compositions the active compound is typically the minor component, frequently about 0.05 to 10% by weight, with the remainder being the injectable excipient or the like.

[0552] Examples

[0553] In order to make the technical solutions of the present application clearer and more explicit, the present application is further described in detail through the following examples. The following examples are only used to illustrate the specific embodiments of the present application, so that those skilled in the art can understand the present application, but are not used to limit the protection scope of the present application. In the specific embodiments of the present application, the technical means or methods not specifically described are the conventional technical means or methods in the art. The materials, reagents and the like used in the examples, unless otherwise specified, can be obtained from commercial channels.

[0554] Table 1

[0555] Example 1: Synthesis of compound 1

[0556] Sodium hydride (50.0 g, 2.08 mol, 3.0 eq.) was added to THF (1000 mL) solution and cooled to 0°C, 7-bromo-1-heptanol (135.1 g, 0.69 mol, 1.0 eq.) was slowly added dropwise under nitrogen protection, and after the dropwise addition was completed, the reaction was continued to stir for 10 minutes at 0°C. Bromobenzene (175.6 g, 1.04 mol, 1.5 eq.) was slowly added dropwise at 0°C. The reaction was stirred at room temperature for 12 hours, and after the reaction was completed, the reaction system was quenched with saturated aqueous ammonium chloride solution (50 mL), diluted with water (500 mL), extracted with DCM (3x500 mL), and the combined organic phase was washed with saturated aqueous sodium chloride solution (3x500 mL) and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporator to obtain the crude product, which was purified by silica gel column separation to obtain 141.8 grams of colorless oil compound 1-1.

[0557] 1-1 (30.0 g, 70.10 mmol, 1.0 eq.) was dissolved in anhydrous THF (200 mL), and under dry nitrogen protection, a magnesium strip (2.2 g, 91.20 mmol, 1.3 eq.) and iodine (1.77 g, 7.00 mmol, 0.1 eq.) were added. The reaction system was stirred at room temperature for 3 hours under dry nitrogen protection to obtain a THF solution of compound 1-2, which was directly used in the subsequent reaction without additional treatment.

[0558] Compound 1-3 (40.0 g, 150.84 mmol, 1.0 eq.) was dissolved in DMSO (400 mL) solution, under nitrogen protection, potassium carbonate (20.8 g, 150.84 mmol, 1.0 eq.) and sodium iodide (45.5 g, 301.67 mmol, 2.0 eq.) were added in turn. The reaction was stirred at 85 °C for 5 hours. After the reaction was completed, it was cooled to room temperature, water (500 mL) was added to dilute the reaction, DCM (3 x 500 mL) was extracted, the organic phase was combined, washed with saturated sodium chloride aqueous solution (3 x 500 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by silica gel column to obtain compound 1-4 (16.8 g) as a yellow oil.

[0559] Compound 1-4 (15.0 g, 75.00 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (150 mL) solution, and the solution was cooled to -78 °C. Compound 1-2 was slowly added dropwise to the reaction system under nitrogen protection. The reaction was stirred at -78 °C for 3 hours. After the reaction was completed, the reaction system was quenched with saturated ammonium chloride (50 mL) aqueous solution, diluted with water (300 mL), extracted with DCM (3 x 300 mL), and the organic phase was combined, washed with saturated sodium chloride aqueous solution (3 x 300 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by silica gel column separation to obtain compound 1-5 (14.7 g) as a yellow oil.

[0560] Compound 1-5 (14.0 g, 34.43 mmol, 1.0 eq.) was dissolved in DCM (140 mL) solution, under nitrogen protection, tert-butyl diphenylchlorosilane (14.2 g, 51.65 mmol, 1.5 eq.) and imidazole (4.7 g, 68.86 mmol, 2 eq.) were added in turn. The reaction was stirred at room temperature for 6 hours. After the reaction was completed, water (300 mL) was added to dilute the reaction, DCM (3 x 300 mL) was extracted, and the organic phase was combined, washed with saturated sodium chloride aqueous solution (3 x 300 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by silica gel column separation to obtain compound 1-6 (15.6 g) as a yellow oil.

[0561] Compound 1-6 (15.0 g, 23.26 mmol, 1.0 eq.) was dissolved in a mixture solution of THF (30 mL), water (30 mL) and methanol (30 mL), and lithium hydroxide (2.78 g, 116.28 mmol, 5.0 eq.) was added under nitrogen protection. The reaction was stirred at 60 °C for 16 h. The reaction was cooled to room temperature, and diluted with water (300 mL). The pH was adjusted to 5 by adding dilute hydrochloric acid (1 M). The mixture was extracted with DCM (3 x 300 mL), and the combined organic phase was washed with saturated aqueous sodium chloride (3 x 300 mL) and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation to give a crude product. The crude product was purified by silica gel column chromatography to give compound 1-7 (12.4 g) as a yellow oil.

[0562] Compound 1-7 (9.0 g, 14.26 mmol, 1.0 eq.) was dissolved in DCM (90 mL), and compound 1-8 (3.1 g, 14.26 mmol, 1.0 eq.), EDCI (4.10 g, 21.39 mmol, 1.5 eq.) and DMAP (3.5 g, 28.53 mmol, 2.0 eq.) were added sequentially under nitrogen protection. The reaction was stirred at room temperature for 12 h. The reaction was diluted with water (300 mL) after completion of the reaction, and the mixture was extracted with DCM (3 x 300 mL). The combined organic phase was washed with saturated aqueous sodium chloride (3 x 300 mL) and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation to give a crude product. The crude product was purified by silica gel column chromatography to give compound 1-9 (8.9 g) as a yellow oil.

[0563] Compound 1-9 (5.0 g, 6.04 mmol, 1.0 eq.) was dissolved in ethanol (50 mL), and anhydrous palladium on carbon (500 mg) was added. The reaction was stirred at room temperature for 12 h under hydrogen atmosphere. The reaction was filtered through celite, and the filter cake was washed with DCM (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate. The organic solvent was removed by rotary evaporation to give compound 1-10 (3.4 g) as a colorless oil, which was used directly in the next reaction.

[0564] Compound 1-10 (1.5 g, 2.04 mmol, 1.0 eq.) was dissolved in acetone (15 mL) and cooled to 0 °C, and Jones reagent (3.10 mL, 6.12 mmol, 3.0 eq.) was added under nitrogen protection. The reaction was stirred at room temperature for 3 h. The reaction was diluted with water (30 mL) after completion of the reaction, and the mixture was extracted with DCM (3 x 30 mL). The combined organic phase was washed with saturated aqueous sodium chloride (3 x 30 mL) and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation to give a crude product. The crude product was purified by silica gel column chromatography to give compound 1-11 (1.2 g) as a yellow oil.

[0565] Compound 1-11 (700.0 mg, 0.93 mmol, 1.0 eq.) was dissolved in DCM (7 mL) solution, under nitrogen protection, 1-nonyl alcohol (161.3 mg, 1.12 mmol, 1.2 eq.), EDCI (268.4 mg, 1.40 mmol, 1.5 eq.) and DMAP (227.7 mg, 1.86 mmol, 2.0 eq.) were added successively. The reaction was stirred at room temperature for 6 hours, after the reaction was completed, diluted with water (30 mL), extracted with DCM (3 x 30 mL), combined organic phase, washed with saturated aqueous sodium chloride solution (3 x 30 mL), dried over anhydrous sodium sulfate. The organic phase was collected by filtration, the organic solvent was removed by rotary evaporator to obtain the crude product, purified by silica gel column separation to obtain compound 1-12 (450 mg) as yellow oil.

[0566] Compound 1-12 (400.0 mg, 0.46 mmol, 1.0 eq.) was dissolved in THF (4 mL) solution, cooled to 0 °C, under nitrogen protection, triethylamine hydrofluoric acid complex (367.4 mg, 2.28 mmol, 5.0 eq.) was added. The reaction was stirred at room temperature for 12 hours, after the reaction was completed, diluted with water (30 mL), extracted with DCM (3 x 30 mL), combined organic phase, washed with saturated aqueous sodium chloride solution (3 x 30 mL), dried over anhydrous sodium sulfate. The organic phase was collected by filtration, the organic solvent was removed by rotary evaporator to obtain the crude product, purified by silica gel column separation to obtain compound 1-13 (238 mg) as yellow oil.

[0567] Compound 1-13 (210.0 mg, 0.33 mmol, 1.0 eq.) was dissolved in DCM (2 mL) solution, under nitrogen protection, 4-dimethylaminobutyric acid (51.7 mg, 0.39 mmol, 1.2 eq.), EDCI (66.2 mg, 0.35 mmol, 1.2 eq.) and DMAP (111.6 mg, 0.86 mmol, 3.0 eq.) were added successively. The reaction was stirred at room temperature for 12 hours, after the reaction was completed, diluted with water (30 mL), extracted with DCM (3 x 30 mL), combined organic phase, washed with saturated aqueous sodium chloride solution (3 x 30 mL), dried over anhydrous sodium sulfate. The organic phase was collected by filtration, the organic solvent was removed by rotary evaporator to obtain the crude product, purified by high performance liquid chromatography (column: YMC-Actus Triart C8 20X150mm, 5μm; A phase: acetonitrile / water (10mmol / L ammonium bicarbonate + 0.05% ammonia water), B phase: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain compound 1 (114.7 mg) as yellow oil.

[0568] 1H NMR (300 MHz, CDC13): δ ppm 0.85-0.92 (m, 9H), 1.15 (s, 6H), 1.17-1.43 (m, 41H), 1.46-1.84 (m, 16H), 2.24 (s, 6H), 2.26-2.35 (m, 6H), 4.00-4.07 (m, 4H), 4.82-4.86 (m, 1H); ESI-MS m / z: 752.85 [M+H] + .

[0569] Example 2: Synthesis of compound 2

[0570] Cyclopentanone (10.0 g, 99.88 mmol, 1.0 eq.) was dissolved in ether (100 mL) and cooled to -78 °C, under nitrogen protection, n-butyllithium (3.2 g, 49.94 mmol, 0.5 eq.) was added dropwise slowly. Stirring at -78 °C for 1 hour, after the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction at -78 °C, diluted with water (100 mL), extracted with DCM (3 x 200 mL), combined organic phase, washed with saturated aqueous sodium chloride solution (3 x 200 mL), dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the filtrate was concentrated by rotary evaporator to obtain a crude product, which was purified by silica gel column separation to obtain compound 2-1 (6.0 g) as yellow oil.

[0571] Dimethylzinc (7.3 g, 75.83 mmol, 2.0 eq.) was dissolved in DCM (60 mL) and cooled to -30 °C, under nitrogen protection, titanium tetrachloride (14.4 g, 75.83 mmol, 2.0 eq.) was added slowly, stirring at -30 °C for 30 minutes, then 2-1 (6.0 g, 37.92 mmol, 1.0 eq.) was added, the reaction system was warmed to room temperature, and stirring was continued for 5 hours. After the reaction was completed, it was diluted with water (200 mL), extracted with DCM (3 x 200 mL), combined organic phase, washed with saturated aqueous sodium chloride solution (3 x 200 mL), dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the filtrate was concentrated by rotary evaporator to obtain a crude product, which was purified by silica gel column separation to obtain compound 2-2 (3.5 g) as yellow oil.

[0572] Reference Example 1 was prepared according to the method of Reference Example 1 to give the product as an oil, 70.6 mg.

[0573] 1H NMR (300 MHz, Methanol-d4): δ ppm 0.80 (s, 6H), 0.85-0.95 (m, 9H), 1.28 (s, 6H), 1.31-1.49 (m, 41H), 1.52-1.60 (m, 12H), 1.78-1.81 (m, 2H), 2.26 (s, 6H), 2.29-2.38 (m, 6H), 4.02-4.09 (m, 4H), 4.85-4.87 (m, 1H); ESI-MS m / z: 780.85 [M+H] + .

[0574] Example 3: Synthesis of compound 3

[0575] Compound 1-10 (500.0 mg, 0.68 mmol, 1.0 eq.) was dissolved in DCM (5 ml) and cooled to 0 °C, under nitrogen protection, n-nonanoyl chloride (143.8 mg, 0.81 mmol, 1.2 eq.) and triethylamine (137.4 mg, 1.36 mmol, 2.0 eq.) were added slowly dropwise in turn. The reaction was stirred at room temperature for 3 hours, after the reaction was completed, water (30 mL) was added to dilute the reaction solution, DCM (3 x 100 mL) was extracted, the organic phase was combined and washed with saturated aqueous sodium chloride solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporator to obtain a crude product, which was purified by silica gel column to obtain compound 3-1 (400 mg) as yellow oil.

[0576] Reference to the method of Example 1, compound 3 was prepared to obtain oil product 108.1 mg.

[0577] 1 H NMR (300 MHz, CDCl3): δ ppm 0.80-0.90 (m, 9H), 1.09 (s, 6H), 1.12-1.28 (m, 43H), 1.46-1.62 (m, 12H), 1.78-1.88 (m, 2H), 2.26-2.38 (m, 12H), 4.00-4.06 (m, 4H), 4.81-4.89 (m, 1H); ESI-MS m / z: 752.65 [M+H] + .

[0578] Example 4: Synthesis of compound 4

[0579] Reference to the method of Example 3, compound 4 was prepared to obtain oil product 95.0 mg.

[0580] 1H NMR (300 MHz, CDC13): δ ppm 0.83-0.94 (m, 9H), 1.13 (s, 6H), 1.18-1.46 (m, 47H), 1.54-1.62 (m, 12H), 1.75-1.85 (m, 2H), 2.25 (s, 6H), 2.28-2.38 (m, 6H), 3.96 (d, J=5.4 Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 4.81-4.89 (m, 1H); ESI-MS m / z: 780.85 [M+H] + .

[0581] Example 5: Synthesis of compound 5

[0582] Compound 5 was prepared according to the procedure of Reference Example 1 to give the product as an oil, 111.8 mg.

[0583] 1 H NMR (400 MHz, CDC13): δ ppm 0.88-0.93 (m, 9H), 1.15 (s, 6H), 1.23-1.32 (m, 43H), 1.46-1.63 (m, 12H), 1.74-1.84 (m, 2H), 2.01 (s, 6H), 2.30-2.35 (m, 6H), 4.04 (t, J=6.6 Hz, 4H), 4.81-4.89 (m, 1H); ESI-MS m / z: 752.90 [M+H] + .

[0584] Example 6: Synthesis of compound 6

[0585] Compound 6 was prepared according to the procedure of Reference Example 1 to give the product as an oil, 64.0 mg.

[0586] 1 H NMR (400 MHz, Methanol-d4): δ ppm 0.85-0.95 (m, 9H), 1.15 (s, 6H), 1.20-1.40 (m, 43H), 1.54-1.64 (m, 12H), 1.77-1.81 (m, 2H), 2.25 (s, 6H), 2.27-2.37 (m, 6H), 4.03-4.07 (m, 4H), 4.81-4.89 (m, 1H); ESI-MS m / z: 752.65 [M+H] + .

[0587] Example 7: Synthesis of compound 7

[0588] Compound 7-1 (5.0 g, 13.25 mmol, 1.0 eq.) was dissolved in DMSO (50 mL) and potassium carbonate (1.8 g, 13.25 mmol, 1.0 eq.) and sodium iodide (4.0 g, 26.50 mmol, 2.0 eq.) were added sequentially under nitrogen protection at room temperature. The reaction was stirred at 85 °C for 5 hours. After the reaction was completed, the reaction solution was reduced to room temperature, diluted with water (100 mL), extracted with DCM (3 x 200 mL), and the organic phases were combined and washed with saturated aqueous sodium chloride solution (3 x 200 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was collected. The organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 7-2 (1.7 g) as a yellow oil.

[0589] Compound 7-2 (1.3 g, 4.16 mmol, 1.0 eq.) was dissolved in THF (15.0 mL) and cooled to -78 °C. 1-2 (1.93 g, 6.24 mmol, 1.5 eq.) was added dropwise under nitrogen protection. The reaction was stirred at -78 °C for 3 hours. After the reaction was completed, the reaction system was quenched with saturated aqueous ammonium chloride solution (10 mL), extracted with DCM (3 x 100 mL), and the organic phases were combined and washed with saturated aqueous sodium chloride solution (3 x 100 mL), dried over anhydrous sodium sulfate. The organic phase was collected, and the organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 7-3 (1.4 g) as a yellow oil.

[0590] Compound 7-3 (1.2 g, 2.31 mmol, 1.0 eq.) was dissolved in DCM (12.0 mL) and 4-dimethylaminobutyric acid (455.1 mg, 3.47 mmol, 1.5 eq.), EDCI (666.2 mg, 3.47 mmol, 1.5 eq.), and DMAP (896.8 mg, 6.94 mmol, 3.0 eq.) were added sequentially under nitrogen protection at room temperature. The reaction was stirred for 6 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with DCM (3 x 100 mL), and the organic phases were combined and washed with saturated aqueous sodium chloride solution (3 x 100 mL), dried over anhydrous sodium sulfate. The organic phase was collected, and the organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 7-4 (1.1 g) as a yellow oil.

[0591] Compound 7-4 (800.0 mg, 1.27 mmol, 1.0 eq.) was dissolved in ethyl acetate (10.0 mL) and palladium on carbon (200 mg) was added. The reaction was stirred for 3 hours under a hydrogen atmosphere, filtered after the reaction was completed, the filter cake was washed with DCM (3 x 50 mL), and the filtrate was concentrated to obtain compound 7-5 (615 mg) as a yellow oil, which was used directly in the next reaction.

[0592] Compound 7-5 (240 mg, 0.44 mmol, 1.0 eq.) was dissolved in acetone (10.0 mL), cooled to 0 °C, and Jones reagent (0.7 mL, 1.32 mmol, 3.0 eq.) was added to the reaction solution under nitrogen protection. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to dilute the reaction solution, and DCM (3 x 100 mL) was used to extract the reaction solution. The organic phase was combined and washed with saturated aqueous sodium chloride solution (3 x 100 mL) and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 7-6 (180 mg) in the form of yellow oil.

[0593] Compound 7-6 (160.0 mg, 0.29 mmol, 1.0 eq.) was dissolved in DCM (3.0 mL), and 4-pentyl-1-nonanol (74.1 mg, 0.35 mmol, 1.2 eq.), EDCI (66.2 mg, 0.35 mmol, 1.2 eq.), and DMAP (111.6 mg, 0.86 mmol, 3.0 eq.) were sequentially added to the reaction solution under nitrogen protection. The reaction solution was stirred for 3 hours. After the reaction was completed, water (100 mL) was added to dilute the reaction solution, and DCM (3 x 100 mL) was used to extract the reaction solution. The organic phase was combined and washed with saturated aqueous sodium chloride solution (3 x 100 mL) and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by a rotary evaporator to obtain a crude product, which was purified by high performance liquid chromatography (column: YMC-Actus Triart C8 20X150 mm, 5 μm; A phase: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water), B phase: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain compound 7 (94.7 mg) in the form of yellow oil.

[0594] 1 H NMR (300 MHz, CDCl3): δ ppm 0.88-0.92 (m, 15H), 1.23-1.37 (m, 43H), 1.50-1.61 (m, 10H), 1.81-1.88 (m, 2H), 2.26-2.38 (m, 14H), 3.77 (s, 2H), 4.04 (t, J = 6.6 Hz, 2H), 4.81-4.89 (m, 1H); ESI-MS m / z: 752.65 [M+H] + .

[0595] Example 8: Synthesis of compound 8

[0596] Compound 8 was prepared according to the method of Reference Example 7 to obtain 84.3 mg of product in the form of oil.

[0597] 1 H NMR (400 MHz, CDC13): δ ppm 0.88-0.90 (m, 15H), 1.04-1.27 (m, 43H), 1.50-1.60 (m, 10H), 1.77-1.86 (m, 2H), 2.27-2.37 (m, 14H), 3.77 (s, 2H), 4.05 (t, J = 6.6 Hz, 2H), 4.81-4.89 (m, 1H); ESI-MS m / z: 752.85 [M+H] + .

[0598] Example 9: Synthesis of compound 9

[0599] Following the procedure of Reference Example 7, compound 9 was prepared to give the product as an oil, 79.9 mg.

[0600] 1 H NMR (400 MHz, CDC13): δ ppm 0.88-0.90 (m, 15H), 1.04-1.27 (m, 43H), 1.50-1.60 (m, 10H), 1.77-1.86 (m, 2H), 2.27-2.37 (m, 14H), 3.77 (s, 2H), 4.05 (t, J = 6.6 Hz, 2H), 4.81-4.89 (m, 1H); ESI-MS m / z: 752.85 [M+H] + .

[0601] Example 10: Synthesis of compound 10

[0602] Following the procedure of Reference Example 7, compound 10 was prepared to give the product as an oil, 105.0 mg.

[0603] 1 H NMR (300 MHz, Methanol-d4): δ ppm 0.85-0.90 (m, 15H), 1.30-1.43 (m, 48H), 1.50-1.64 (m, 9H), 1.80-1.85 (m, 2H), 2.25 (s, 6H), 2.29-2.41 (m, 8H), 3.79 (s, 2H), 3.98 (t, J = 5.7 Hz, 2H), 4.82-4.90 (m, 1H); ESI-MS m / z: 780.70 [M+H] + .

[0604] Example 11: Synthesis of compound la

[0605] Into a 500 mL three-necked round-bottom flask was placed 1-nonyl alcohol (15 g, 104.0 mmol, 1.0 eq.), 8-bromooctanoic acid (25.5 g, 114.0 mmol, 1.1 eq.), DMAP (2.54 g, 20.8 mmol, 0.2 eq.), DIEA (40.3 g, 312.0 mmol, 3.0 eq.), and EDCI (25.9 g, 135 mmol, 1.3 eq.) in 250 mL DCM at room temperature. The reaction was stirred at room temperature for 4 h, and the reaction was monitored by TLC. The reaction was poured into 200 mL saturated aqueous ammonium chloride solution, extracted with 3 * 100 mL DCM, and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to give a crude product, which was purified by silica gel column chromatography to give 21 g of compound la-2 as a yellow oil.

[0606] Into a 250 mL three-necked round-bottom flask was placed compound la-2 (21 g, 60.1 mmol, 1.0 eq.) and 2-aminoethanol (110 g, 1.80 mol, 30.0 eq.) in 100 mL methanol at room temperature. The reaction was stirred at 60 °C for 18 h, and the solvent was removed by concentration. Saturated aqueous ammonium chloride solution and ethyl acetate were added, and the layers were separated. The organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to give a crude product, which was purified by silica gel column chromatography to give 14 g of compound la-3 as a yellow oil.

[0607] Into a 250 mL three-necked round-bottom flask was placed 9-heptadecanol (9.8 g, 38.2 mmol, 1.0 eq.) and triethylamine (15.5 g, 152.8 mmol, 4.0 eq.) in 100 mL DCM at room temperature. The reaction was cooled in an ice bath, and 2-methylpropanoyl chloride (9.8 g, 91.7 mmol, 2.4 eq.) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was monitored by TLC, and saturated aqueous ammonium chloride solution was added to quench the reaction. The reaction was extracted with DCM, and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to give a crude product, which was purified by silica gel column chromatography to give 8.7 g of compound la-5 as a yellow oil.

[0608] Into a 250 mL three-necked round bottom flask was added compound 1a-5 (8.7 g, 26.6 mmol, 1.0 eq.) and dissolved in 60 mL THF at room temperature. The reaction was cooled to -40 °C, then LDA (13.1 mL, 26.2 mmol, 0.98 eq.) was added slowly dropwise, the reaction was stirred for 1 h, then 1,6-dibromohexane (9.03 g, 37.0 mmol, 1.39 eq.) and DMPU (0.48 g, 3.73 mmol, 0.14 eq.) were added to the reaction. The reaction was allowed to warm to room temperature overnight. The reaction was monitored by TLC, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to give the crude product, which was purified by silica gel column to give compound 1a-6 as yellow oil, 10.1 g.

[0609] Into a 20 mL round bottom flask was added compound 1a-6 (1.48 g, 3.04 mmol, 2.0 eq.), compound 1a-3 (500 mg, 1.52 mmol, 1.0 eq.), K2CO3 (628.2 mg, 4.55 mmol, 3.0 eq.), KI (302.3 mg, 1.82 mmol, 1.2 eq.), cyclopentyl methyl ether (7.5 mL), and acetonitrile (2.5 mL). The reaction was allowed to warm to 80 °C. The reaction was monitored by TLC, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution, extracted with DCM, the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to give the crude product, which was purified by silica gel column to give compound 1a as oil, 96.98 mg.

[0610] 1 H NMR (400 MHz, CDC13) δ: 4.86-4.80 (m, 1H), 4.04 (t, J = 7.2 Hz, 2H), 3.57 (m, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.49 (t, J = 7.2 Hz, 4H), 2.29 (t, J = 7.2 Hz, 2H), 1.62 (m, 4H), 1.51-1.45 (m, 10H), 1.38-1.23 (m, 49H), 1.15 (s, 6H), 0.88 (t, J = 7.2 Hz, 9H); ESI-MS m / z: 738.60 [M+H] + .

[0611] Example 12: Synthesis of compound 4a

[0612] Following the procedure of Reference Example 11, compound 4a was prepared to give the product as oil, 112.1 mg.

[0613] 1H NMR (400 MHz, CDC13) δ: 4.83 (m, 1H), 4.05 (t, J = 7.2 Hz, 2H), 3.80 (t, J = 5.4 Hz, 2H), 2.51-2.73 (m, 6H), 2.29 (t, J = 7.2 Hz, 2H), 1.65-1.44 (m, 16H), 1.26 (m, 49H), 1.15 (s, 6H), 0.93-0.82 (m, 9H); ESI-MS m / z: 752.70 [M+H] + .

[0614] Example 13: Synthesis of compound 56a

[0615] Referring to the method of Example 11, compound 56a was prepared to give product 112.2 mg as an oil.

[0616] 1 H NMR (300 MHz, CDC13) δ: 4.87-4.79 (m, 1H), 4.16 (t, J = 6.6 Hz, 2H), 3.60 (m, 2H), 2.67-2.53 (m, 6H), 2.32-2.11 (m, 6H), 2.32-2.11 (m, 6H), 1.85-1.76 (m, 2H), 1.66-1.18 (m, 53H), 1.14 (s, 6H), 0.88 (m, 9H); ESI-MS m / z: 734.55 [M+H] + .

[0617] Example 14: Synthesis of compound 30a

[0618] In a 250 mL round-bottom flask, 9-heptadecanol (10.0 g, 39.0 mmol, 1.0 eq.) and pyridine (6.17 g, 78.0 mmol, 2 eq.) were dissolved in 100 mL of dichloromethane, then the reaction system was cooled to 0 °C, and isobutyryl chloride (10.39 g, 97.5 mmol, 2.5 eq.) was slowly added to the reaction solution, then stirred at room temperature for 2 hours. Quench the reaction with water at 0 °C, extract with DCM, combine the organic phases, dry over anhydrous Na2SO4, filter to remove the drying agent and rotary evaporate the solvent. The obtained crude product was purified by silica gel column to give compound 1a-5 (10.4 g) as a yellow oil.

[0619] Compound 1a-5 (10.0 g, 30.62 mmol, 1.0 eq.) was dissolved in anhydrous THF (100 mL), the reaction system was cooled to -40 °C, and LDA (15.3 mL, 30.6 mmol, 1 eq.) was added to the reaction solution under a nitrogen atmosphere. After stirring at -40 °C for 1 h, 1,6-dibromohexane (14.9 g, 61.2 mmol, 2.0 eq.) and DMPU (471 mg, 3.7 mmol, 0.12 eq.) were added at the same temperature. The reaction system was slowly warmed to room temperature and then reacted overnight. After the reaction was completed, the reaction solution was added to a saturated NH4Cl solution, extracted with DCM, and the organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and the solvent was removed by rotary evaporation to obtain crude compound 1a-6, which was used directly in the next step without purification.

[0620] Compound 1a-6 (15 g, 30.6 mmol, 1.0 eq.) and ethanolamine (37.4 g, 612.0 mmol, 20.0 eq.) were dissolved in 80 mL of ethanol, and the reaction system was heated to 60 °C for 2 h. After the reaction was completed, the reaction system was cooled to room temperature, the ethanol solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate, and then a saturated sodium chloride solution was added. After extraction, the organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and the solvent was removed by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to obtain compound 30a-1 (12.4 g) as a yellow oil.

[0621] In a 50 mL reaction bottle, 6-bromo-1-hexanol (1.5 g, 8.3 mmol, 1.0 eq.) and pyridine (1.31 g, 16.6 mmol, 2.0 eq.) were dissolved in 15 mL of DCM, and n-nonyl chloroformate (1.88 g, 9.1 mmol, 1.1 eq.) was added dropwise over 15 min under ice bath conditions. After overnight reaction at room temperature, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction was extracted with DCM. The organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and the solvent was removed by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to obtain compound 30a-4 (2.5 g) as a yellow oil.

[0622] In a 8 mL sealed tube, compound 30a-4 (200 mg, 0.57 mmol, 1.0 eq.), compound 30a-1 (294.2 mg, 0.63 mmol, 1.1 eq.), KI (113.4 mg, 0.68 mmol, 1.2 eq.), K2CO3 (236.0 mg, 1.71 mmol, 3.0 eq.), and 5.0 mL of anhydrous acetonitrile were added. After stirring overnight at 80 °C, the reaction was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile. The organic phases were combined, and the solvent was removed by rotary evaporation to obtain the crude reaction product. Purification by preparative liquid chromatography yielded compound 30a (87.9 mg).

[0623] 1 H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.12 (t, J = 6.6Hz, 4H), 3.61 (m, 2H), 2.62 (m, 6H), 1. 70–1.63(m,4H),1.50(m,8H),1.26(m,49H),1.15(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:740.55[M+H] + .

[0624] Example 15: Synthesis of Compound 1b

[0625] 9-Heptadecyl 1b-1 (200.0 mg, 0.78 mmol, 1.0 eq.) was dissolved in DCM (2.0 mL). 8-Bromooctanoic acid (226.2 mg, 1.01 mmol, 1.3 eq.), EDCI (179.4 mg, 0.94 mmol, 1.2 eq.), and DMAP (42.9 mg, 1.17 mmol, 1.5 eq.) were added to the solution. The reaction mixture was stirred at room temperature for 3 hours. The solution was then poured into 10 mL of saturated sodium chloride aqueous solution and extracted with 3 x 20 mL DCM solutions. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 300 mg of a yellow oily compound 1b-2.

[0626] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0 °C. Under nitrogen protection, LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction solution. The reaction temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Then, 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.) was added. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 30 g of a yellow oily compound 1b-4.

[0627] Compound 1b-4 (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0 °C. Under nitrogen protection, a borane-tetrahydrofuran solution (1 M, 100.0 mL) was added dropwise to the reaction system. The temperature was raised to 75 °C, and the reaction was stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain crude product 1b-5 (13.6 g), which was used directly in the next reaction without further purification.

[0628] Compound 1b-5 (10.0 g, 44.0 mmol, 1.0 eq.) was dissolved in DCM (100 mL), and then capryloyl chloride (11.0 g, 58.0 mmol, 1.3 eq.) was added to the reaction system, and triethylamine (13.5 g, 134.0 mmol, 3.0 eq.) was added to the reaction system, and the reaction was carried out at room temperature for 3 hours. The reaction solution was poured into 100 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column to obtain 10 g of compound 1b-6.

[0629] Compound 1b-6 (1.4 g, 3.7 mmol, 1.0 eq.) was added to a solution of ethanolamine (2.3 g, 37.2 mmol, 10.0 eq.) in acetonitrile (15.0 mL), and heated to 70°C, and stirred for 3 hours. The reaction solution was poured into 30 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column to obtain 1.4 g of compound 1b-7. 1 H NMR (300 MHz, CD3Cl) δ: 0.85-0.89 (m, 9H), 1.20-1.26 (m, 21H), 1.59-1.62 (m, 4H), 2.29-2.34 (m, 2H), 2.73-2.76 (m, 2H), 2.87-2.91 (m, 2H), 3.72-3.77 (m, 3H).

[0630] Compound 1b-2 (300.0 mg, 0.84 mmol, 1.0 eq.) and compound 1b-7 (503.4 mg, 1.09 mmol, 1.3 eq.) were dissolved in DMF (3.0 mL), and then potassium carbonate (289.9 mg, 2.1 mmol, 2.5 eq.) and sodium iodide (314.4 mg, 2.1 mmol, 2.5 eq.) were added, and the reaction was carried out at 70°C for 2 hours. The reaction solution was poured into 20 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column to obtain compound 1b (158.9 mg).

[0631] 1H NMR (400 MHz, Methanol-d4) δ: 0.85-0.95 (m, 15H), 1.17-1.34 (m, 48H), 1.52-1.59 (m, 8H), 1.62-1.64 (m, 4H), 2.27-2.35 (m, 4H), 2.48-2.53 (m, 4H), 2.63 (t, J = 6.3 Hz, 2H), 3.61 (t, J = 6.3 Hz, 2H), 3.80 (s, 2H), 4.84-4.89 (m, 1H); ESI-MS m / z: 738.65 [M+H] + .

[0632] Example 16: Synthesis of compound 3b

[0633] Potassium carbonate (549 mg, 4.0 mmol, 3.0 eq.) and compound 1b-6 (500 mg, 1.33 mmol, 1.0 eq.) were added to a solution of 4-amino-1-butanol (1.2 g, 13.3 mmol, 10.0 eq.) in DMF (10.0 mL), heated to 70 °C, and stirred for 3 h. The reaction was poured into 30 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to give a crude product, which was purified by silica gel column to give 300 mg of compound 3b-1 as colorless oil.

[0634] Compound 1b-2 (462 mg, 1.0 mmol, 1.3 eq.) and compound 3b-1 (297 mg, 0.77 mmol, 1.0 eq.) were dissolved in DMF (5.0 mL), and then potassium carbonate (269 mg, 1.9 mmol, 2.5 eq.) and sodium iodide (285 mg, 1.9 mmol, 2.5 eq.) were added. The reaction was heated to 70 °C and stirred for 5 h. The reaction was poured into 20 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to give a crude product, which was purified by silica gel column to give compound 3b (228 mg).

[0635] 1 H NMR (400 MHz, CDCl3) δ: 0.80-0.90 (m, 15H), 1.25-1.40 (m, 48H), 1.49-1.66 (m, 8H), 1.74-1.81 (m, 8H), 2.24-2.37 (m, 4H), 2.47-2.58 (m, 6H), 3.56 (s, 2H), 3.77 (s, 2H), 4.81-4.88 (m, 1H); ESI-MS m / z: 766.85 [M+H] + .

[0636] Example 17: Synthesis of compound 10b

[0637] Compound 10b was prepared according to the procedure of Reference Example 15 to give the product as an oil, 128 mg.

[0638] Example 18: Synthesis of compound 12b

[0639] Compound 12b was prepared according to the procedure of Reference Example 15 to give the product as an oil, 105 mg.

[0640] 1 H NMR (400 MHz, CDC13) δ: 0.85-0.95 (m, 15H), 1.19-1.34 (m, 41H), 1.42-1.58 (m, 4H), 1.59-1.63 (m, 6H), 2.23 (q, J = 7.6 Hz, 4H), 2.53 (q, J = 7.6 Hz, 4H), 2.62 (q, J = 7.6 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.80 (s, 2H), 4.07 (t, J = 6.4 Hz, 2H); ESI-MS m / z: 682.60 [M+H] + .

[0641] 1 H NMR (300 MHz, CDC13) δ: 0.85-0.95 (m, 15H), 1.12-1.36 (m, 43H), 1.40-1.63 (m, 12H), 2.26-2.31 (m, 4H), 2.42-2.65 (m, 6H), 3.50-3.54 (m, 2H), 3.78 (s, 2H), 4.08 (t, J = 7.2 Hz, 2H); ESI-MS m / z: 710.80 [M+H] + .

[0642] The compounds of Table 2 were synthesized according to the procedures of the above examples, or by analogous procedures using the corresponding intermediates.

[0643] Table 2

[0644] Example 21: Synthesis of compound 26b

[0645] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0 °C, LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction under nitrogen protection. The reaction temperature was raised to room temperature and stirred for 30 minutes, then 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.) was added, TLC monitoring until the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with 3*300 mL of DCM, the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate to dryness gave 30 g of crude compound 2,2-dimethyl-7-bromoheptanoic acid methyl ester.

[0646] Methyl 2-dimethyl-7-bromoheptanoate (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0 °C, lithium aluminum hydride solution (2 M, 50.0 mL) was added dropwise to the reaction under nitrogen protection. The reaction was stirred for 3 hours, after the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with 3*300 mL of DCM, the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate to dryness gave crude 2,2-dimethyl-7-bromoheptanol (13.6 g), which was used directly in the next step without purification.

[0647] 2,2-Dimethyl-7-bromoheptanol (500.0 mg, 2.24 mmol, 1.0 eq.) was dissolved in DCM (10.0 mL), 4-hexyldecanoic acid (746.2 mg, 2.91 mmol, 1.3 eq.), EDCI (515.7 mg, 2.69 mmol, 1.2 eq.) and DMAP (410.5 mg, 3.36 mmol, 1.5 eq.) were added to the solution. The reaction was stirred at room temperature for 3 hours, the reaction was poured into 10 mL of saturated aqueous sodium chloride solution, extracted with DCM, the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate to dryness gave 858 mg of crude compound 26b-4 which was purified by silica gel column to give yellow oil.

[0648] Reference to the method of Example 64, compound 26b was prepared to give 99.0 mg of product as an oil.

[0649] 1H NMR (300 MHz, MeOH-d4) δ: 0.86-0.91 (m, 15H), 1.21-1.40 (m, 50H), 1.58-1.71 (m, 6H), 2.32 (t, J = 7.5 Hz, 2H), 2.48-2.53 (m, 4H), 2.62 (t, J = 6.6 Hz, 2H), 3.61 (t, J = 6.3 Hz, 2H), 3.80 (s, 2H), 4.10 (td, J = 2.7, 6.3 Hz, 4H); ESI-MS m / z: 726.70 [M+H] + .

[0650] Example 22: Synthesis of compound 59a

[0651] In a 100 mL sealed tube, add 4-dimethylamino-1-butanol (3.0 g, 25.5 mmol, 1.0 eq.) and thiourea (8.4 g, 110.0 mmol, 4.3 eq.) then add HBr aqueous solution (48%, 60 mL), heat to 120 °C and stir overnight. No purification, directly used in next step.

[0652] Cool the above system to 0 °C, add NaOH (10.2 g, 255.0 mmol, 10.0 eq.) in batches, heat to 120 °C and react for 2 hours. Cool to room temperature, extract with dichloromethane, combine the organic phase, dry over anhydrous sodium sulfate, filter to remove the drying agent, and remove the solvent to obtain 2.45 g of compound 59a-3 as colorless oil.

[0653] In a 100 mL three-necked flask, dissolve compound 59a-6 (1.5 g, 5.8 mmol, 1.0 eq.), 2-heptyl-1-nonanol (1.40 g, 5.8 mmol, 1.0 eq.), EDCI (1.66 g, 8.7 mmol, 1.5 eq.) and DMAP (0.35 g, 2.9 mmol, 0.5 eq.) in 20 mL of dichloromethane, stir at room temperature overnight. Wash with water 3*15 mL, dry the organic phase under reduced pressure, then directly purify by silica gel column chromatography to obtain 3.3 g of compound 59a-7.

[0654] In a 100 mL three-necked flask, dissolve compound 59a-7 (2.8 g, 5.8 mmol, 1.0 eq.) in 20 mL of dichloromethane, add HCl / dioxane (4M, 14 mL), stir at room temperature overnight. Remove the organic solvent by rotary evaporation, adjust the reaction solution to neutral with saturated sodium bicarbonate solution, extract with DCM 3*20 mL. Collect the organic phase, dry over anhydrous Na2SO4. Purify by silica gel column chromatography to obtain 1.95 g of compound 8.

[0655] In a 40 mL sealed tube, compound 59a-8 (680 mg, 1.8 mmol, 1.0 eq.), KI (365 mg, 2.2 mmol, 1.2 eq.), K2CO3(745 mg, 5.4 mmol, 3.0 eq.), 59a-5 (668.9 mg, 1.8 mmol, 1.0 eq.) were dissolved in 10 mL acetonitrile. The reaction was stirred at 80 °C overnight. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with 5 mL*2 ACN. The filtrate was collected and rotary evaporated. Purification by column chromatography gave 580 mg of compound 59a-9 as yellow oil.

[0656] In a 20 mL sealed tube, compound 59a-9 (200 mg, 0.29 mmol, 1.0 eq.) was dissolved in 5 mL DCM, and the reaction was cooled to 5 °C before adding TEA (59.5 mg, 0.59 mmol, 2.0 eq.) and BTC (87.3 mg, 0.29 mmol, 1.0 eq.). The reaction was stirred at 5 °C for 1 h, and then 5 mL tetrahydrofuran was added after the DCM was removed by concentration. In another 20 mL sealed tube, compound 59a-3 (101.9 mg, 0.76 mmol, 2.6 eq.) was dissolved in 5 mL tetrahydrofuran, and NaH (60%, 58.0 mg, 1.45 mmol, 5.0 eq.) was added after the reaction was cooled to 0 °C. After stirring at 0 °C for 1 h, the above prepared THF mixture was added dropwise, and the reaction was continued for 1 h. The reaction was poured into 10 mL ice water, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then the solvent was removed to give a crude product. Purification by Prep-HPLC (Column: XSelect C18 (30*150 mm, 5 μm); Eluent A: H2O / ACN 60 / 40, 10 mM NH4HCO3+1% NH3·H2O; Eluent B: IPA / ACN 90 / 10; Flow rate: 60 mL / min; Gradient program: 65%-85% B in 0-12 min) gave 126.9 mg of compound 59a as light yellow oil.

[0657] 1 H NMR (300 MHz, CDCl3) δ: 4.06 (t, J = 6.6 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.36-3.15 (m, 4H), 2.90 (t, J = 6.9 Hz, 2H), 2.41 (s, 2H), 2.31-2.24 (m, 10H), 1.64-1.16 (m, 61H), 0.93-0.77 (m, 15H); ESI-MS m / z: 839.65 [M+H] + .

[0658] Example 23: Synthesis of compound 39b

[0659] Referring to the method of Example 22, compound 39b was prepared to obtain product 117.9 mg in oil form.

[0660] 1 H NMR (300 MHz, CDC13) δ: 4.86 (p, J = 6.3 Hz, 1H), 3.78 (s, 2H), 3.36-3.17 (m, 4H), 2.92 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.34-2.22 (m, 10H), 1.90-1.80 (m, 3H), 1.62-1.49 (m, 14H), 1.34-1.17 (m, 51H), 0.93-0.86 (m, 15H); ESI-MS m / z: 881.65 [M+H] + .

[0661] Pharmacological experiments

[0662] Experimental Example 1: Nanoparticle preparation

[0663] The materials used for the assembly of the lipid nanoparticles are: (1) ionizable lipid compounds: ionizable lipids designed and synthesized according to the present application or DLin-MC3-DMA (MC3, purchased from AVT) as a control group; (2) structural lipids: such as Cholesterol (purchased from Sigma-Aldrich); (3) phospholipids: such as 1,2-distearoyl-SN-glycero-3-phosphocholine (DSPC, purchased from AVT); (4) polyethylene glycol lipid compounds: such as dimyristoylglycerol-polyethylene glycol 2000 (DMG-PEG 2000, purchased from AVT); (5) nucleic acid fragment active ingredients: such as Luciferase mRNA, siRNA, CRISPR Cas 9 mRNA, etc. (self-made nucleic acid fragments). The names and structural formulas of the components of the lipid nanoparticles are shown in Table 3.

[0664] Table 3

[0665] The preparation method of the lipid nanoparticles is as follows: (1) ionizable lipid compounds, cholesterol, phospholipids and polyethylene glycol lipids are respectively dissolved and mixed in ethanol according to the molar percentage of 50%, 38.5%, 10% and 1.5%; (2) the mRNA active ingredient is dissolved in a 25 mM sodium acetate solution (pH = 4.5); (3) the organic phase dissolved with the lipid mixture and the aqueous phase dissolved with the mRNA ingredient are mixed at a flow rate ratio ranging from 1:1 to 1:4 using an automated high-throughput microfluidic system, and the mixing speed is 10-18 mL / min; (4) the prepared lipid nanoparticles (N / P is 6) are diluted with a phosphate buffered saline solution, and then the nanoparticle solution is ultrafiltered to the original preparation volume using an ultrafiltration tube with a molecular weight cutoff of 30 kDa (purchased from Millipore); (5) the obtained nanoparticles are filtered and sterilized through a 0.2 μm sterile filter membrane, and then stored in a sealed glass bottle at low temperature.

[0666] The preparation method of the lipid nanoparticles includes a microfluidic mixing system, but is not limited to this method, and also includes a T-type mixer and an ethanol injection method.

[0667] Experimental Example 2: Physical property characterization of lipid nanoparticles

[0668] The particle size and particle size dispersion index (PDI) of the prepared lipid nanoparticles are measured using a Zetasizer Pro (purchased from Malvern Instruments Ltd) and a DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instrument. The encapsulation degree of the lipid nanoparticles for RNA is characterized by the encapsulation efficiency (%), which reflects the degree of combination of the lipid nanoparticles and the RNA fragments. The coefficient is measured by the method of Quant-it RiboGreen RNA Assay (purchased from Invitrogen). The lipid nanoparticle sample is diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH = 7.5), and part of the sample solution is added with 0.5% Triton X-100 and then placed at 37°C for 30 minutes. The fluorescence value is read immediately after the addition of the reaction solution using a Varioskan LUX multifunctional enzyme label instrument (purchased from Thermofisher) at an absorption light wavelength of 485 nm and an emission light wavelength of 528 nm to obtain the encapsulation efficiency value. TM

[0669] Experimental Example 3: Animal experiment

[0670] ​​The delivery effect and safety of the nanoparticles loaded with luciferase mRNA (purchased from Trilink, L-7202) in mice were evaluated. The test mice were SPF C57BL / 6 mice, female, 6-8 weeks old, weighing 18-22 g, purchased from Beijing Sbielof Biotechnology Co., Ltd. All animals were adaptively fed for more than 7 days before the test, and free access to food and water during the test, 12 / 12h light and dark alternation, indoor temperature of 20-26℃, humidity of 40-70%. The mice were randomly divided into groups.

[0671] The above prepared lipid nanoparticles loaded with luciferase mRNA were injected into the mice at a single dose of 0.5 mg / kg mRNA by intravenous administration, and the mice were detected by small animal living imaging system (IVIS LUMINA III, purchased from PerkinElmer) at 6 hours after administration. The specific operation steps of detection are as follows: D-luciferin solution with a concentration of 15 mg / mL was prepared with normal saline, and each mouse was given the substrate by intraperitoneal injection. After 10 minutes of substrate administration, the mice were placed in the anesthesia box for anesthesia with 2.5% isoflurane. The anesthetized mice were placed in IVIS for fluorescence imaging, and the data of the fluorescence concentrated distribution were collected and analyzed.

[0672] The in vivo delivery efficiency of the lipid nanoparticle carrier was represented by the average value of the fluorescence intensity and the total photon number of different animals in the same test group, as shown in Table 4. The higher the values of fluorescence intensity and total photon number, the higher the in vivo delivery efficiency of the lipid nanoparticle for the mRNA fragment. The lipid nanoparticles containing the ionizable lipids of the application have good in vivo delivery efficiency.

[0673] Table 4

[0674] Experimental Example 4: In vitro delivery efficiency and safety evaluation

[0675] The delivery efficiency and safety of nanoparticles encapsulating luciferase mRNA (purchased from Trilink, L-7202) at the in vitro cell level were evaluated. The cells used in the experiment were human embryonic kidney 293 (HEK293T cells) cultured in DMEM Dulbecco's Modified Eagle Medium (purchased from Thermofisher) containing 10% fetal bovine serum and 5% penicillin-streptomycin double antibody, and the culture environment was room temperature at 37°C and carbon dioxide concentration was 5%. The cells were evenly dispersed and plated in a 48-well plate, and after 24 hours of incubation in the incubator, the luciferin mRNA-encapsulated lipid nanoparticle solution was added. After 24 hours of incubation, the cells were broken and the luciferase detection reagent (purchased from Promega) was used to detect the intensity of luciferase expression in the cells mediated by each lipid nanoparticle and the relative light unit (RLU). The higher the expression intensity, the higher the delivery efficiency of the lipid material at the cell level. At the same time, 24 hours later, CCK-8 reagent (purchased from DOJINDO) was used to test the cytotoxicity of the parallel lipid nanoparticle-treated cell group. In the experiment, the cell group with only PBS added was used as a negative control. The specific steps are as follows: after adding CCK-8 solution to the cells, incubate at 37°C in the cell incubator for 4 hours, and use a multifunctional enzyme label instrument to read the absorbance at an absorbance wavelength of 450 nm. The ratio of the absorbance value of the cells treated with nanoparticles to the absorbance value of the negative control is used as a parameter to represent the cell survival rate.

[0676] The delivery efficiency and toxicity data of the nanoparticles at the in vitro cell level are shown in Table 5.

[0677] Table 5

[0678] Experimental Example 5: In vivo clearance rate experiment of ionizable liposomes

[0679] 100 uL of empty LNP (0.1 mg / mL) formed by ionizable lipids, cholesterol, DSPC and DMG-PEG 2000 in a ratio of 50:38.5:10:1.5 was injected into the tail vein of 6-8 week old C57 WT female mice (n=3), and the experimental animals were decapitated and dissected to remove the liver 72 h after administration. The liver samples were homogenized with water, and the protein was precipitated. The calibration standard prepared by matching the blank liver tissue was used for quantitative analysis of the ionizable lipid content in the sample using LC-MS / MS.

[0680] The in vivo clearance rate data of ionizable liposomes are shown in Table 6.

[0681] Table 6

[0682] The structures of the control compounds are as follows:

[0683] As can be seen from the data in Table 5, the bis-gem-dimethyl compounds of the control group degrade slowly in the liver, about 10-20% at 72 h; while the mono-gem-dimethyl compounds degrade rapidly in the liver, completely at 72 h. Since the in vivo degradation of the lipid compounds is mainly through hydrolysis of the ester bond of the two tail chains, this indicates that the bis-gem-dimethyl has an inhibitory effect on the hydrolysis of the ester bond of the tail chain, while the mono-gem-dimethyl eliminates the inhibitory effect.

[0684] While the application has been described in full detail and pictorially demonstrated by the drawings accompanying the detailed description above, it is not to be limited to what is illustrated and described, but is to only be limited as described by the claims.

Claims

1. A compound of Formula (I): or an isotopolog, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: wherein Z is CH; G1and G2are independently selected from a chemical bond, C 1-13 straight-chain alkenylene, and C 2-13 straight-chain alkenylene, and C 2-13 straight-chain alkynylene, which is optionally substituted by one or more R G1 substituents; the total length of G1and G2is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms; R G1 independently selected from H, C 1-14 alkyl, -L a -OR a , -L a -SR a and -L a -NR a R’ a ; G3is selected from C 4-14 straight-chain alkenylene, C 4-14 straight-chain alkenylene, and C 4-14 straight-chain alkynylene, which is optionally substituted by one or more R G3 substituents; R G3 independently selected from H, -L a -OR a , -L a -SR a and -L a -NR a R’ a ; L a independently selected from a chemical bond and C 1-14 alkylene; R a and R' a are independently selected from H, C 1-14 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl; G4is selected from the group consisting of a chemical bond, C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, optionally substituted with one or more R G4 ; R G4 independently selected from H, C 1-6 alkyl, -L b -OR b , -L b -SR b and -L b -NR b R’ b ; L b independently selected from a chemical bond and C 1-6 alkylene; R b and R' b are independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; or two R connected to the same carbon atom G4 with the carbon atom to which they are attached to form a C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, optionally substituted with one or more R 4g substituents; R 4g independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e , -L e -SR e and -L e -NR e R’ e ; L e independently selected from a chemical bond and C 1-8 alkylene; R e and R' e are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl; M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O)S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -S-S-, and -S(O) 0- 2-; Q is selected from the group consisting of a chemical bond, -C(O)O-, -O-, -SC(O)O-, -OC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR f -SC(O)NR 0-2 -SC(O)NR -SC(O)NR R*is independently selected from H, halogen, cyano, C 1-10 alkyl, C 1-10 haloalkyl, -L f -OR f , -L f -SR f and -L f -NR f R’ f ; L f independently selected from a chemical bond and C 1-8 alkylene; R f and R' f are independently selected from H, C 1-10 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl; R1and R2are independently selected from C 4-20 alkyl, C 4-20 alkenyl and C 4-20 alkynyl, optionally substituted with one or more R 1s and wherein one or more methylene units are optionally and independently replaced with -NR'-; R 1s independently selected from H, C 1-20 alkyl, -L c -OR c , -L c -SR c and -L c -NR c R’ c ; R and R' are each independently selected from H and C 1-20 alkyl; L c independently selected from a chemical bond and C 1-20 alkylene; R c and R' c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl; R3is selected from the group consisting of CN, -OR g , -C(O)R g , -OC(O)R g , -NR"C(O)R g , -NR g R' g , -NR"C(O)NR g R' g , -NR"C(O)R g , -NR"S(O)2R g , -OC(O)NR g R' g , -NR"C(O)OR g , -N(OR g )C(O)R g , -N(OR g )S(O)2R g , -N(OR g )C(O)OR g , -N(OR g )C(O)R g R' g , 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl; R g and R' g are independently selected from H, C 1-10 alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; R" is independently selected from H and C 1-6 alkyl; R4and R5are independently selected from C 1-8 alkyl, optionally substituted with one or more R 4s substituents; or R4, R5 together with the carbon atom to which they are attached form C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, which is optionally substituted by one or more R 4s substituents; R 4s independently selected from H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L d -OR d , -L d -SR d and -L d -NR d R’ d ; L d independently selected from a chemical bond and C 1-8 alkylene; R d and R' d are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclyl.

2. The compound of claim 1, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having a structure of formula (III') or (IV): wherein a = 1, 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 3, 4, 5, 6, 7, 8, or 9; the remaining variables are as defined in claim 1.

3. The compound of claim 1 or 2, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1s the substituent site on R1or R2is separated from M1or M2by 0-10 carbon atoms, preferably by 0-6 carbon atoms, preferably by 0-4 carbon atoms, preferably by 0-2 carbon atoms, preferably by 0 carbon atoms; Preferably, R 1s the substituent site on R1or R2is spaced from M1or M2by 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, preferably 2-4 carbon atoms; Preferably, R1 is free of R 1s substituted, and R 1s The substituent on R2 is spaced from M2 by 0-10 carbon atoms, preferably 1-10 carbon atoms, preferably 1-6 carbon atoms, preferably 1-4 carbon atoms, preferably 1-2 carbon atoms, preferably 2-10 carbon atoms, preferably 2-6 carbon atoms, preferably 2-4 carbon atoms; Preferably, at least one of R1and R2is substituted with R 1s substituted; Preferably, R1 has R 1s substituted, and R2 has no R 1s substituted; Preferably, R2 has R 1s substituted, and R1 has no R 1s substituted; Preferably, R4and R5, together with the carbon atom to which they are attached, do not form a ring; Preferably, d is not 0.

4. The compound of claim 2, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having a structure of formula (III') or (IV): wherein Z is CH; Q is -C(O)O-, -C(O)S-, -SC(O)-, or -OC(O)-; R g and R' g are independently C 1-6 alkyl; a = 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, or 8; c = 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c + d = 5, 6, or 7; M1and M2are independently selected from the group consisting of -C(O)O-, -C(O)S-, -OC(O)-, -SC(O)-, and -OC(O)O-; preferably -C(O)O-, -OC(O)-, and -OC(O)O-; preferably -C(O)O- and -OC(O)-; R1and R2are independently C 6-14 alkyl, optionally substituted with 1, 2, or 3 R 1s substituents; R 1s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably from H and C 1-14 alkyl; L c independently selected from a chemical bond and C 1-14 alkylene; R c and R' c are independently selected from H and C 1-14 alkyl; R4and R5are independently C 1-3 alkyl; or R4and R5together with the carbon atom to which they are attached form C 3-6 cycloalkylene or 3-6 membered heterocyclylene.

5. The compound of claim 4, or an isotopolog, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (III’) or formula (IV), Z is CH; Q is -C(O)O- or -C(O)S-; R g and R' g are independently C 1-3 alkyl; a = 2, 3, or 4; b = 5, 6, or 7; preferably 6 or 7; c = 4, 5, or 6; d = 0, 1, or 2; c + d = 5, 6, or 7; preferably c + d = 5 or 6; M1and M2are independently selected from the group consisting of -C(O)O-, -OC(O)-, and -OC(O)O-; preferably -C(O)O- and -OC(O)-; R1and R2are independently C 8-12 alkyl, preferably C 8-10 alkyl, optionally substituted with 1, 2, or 3 R 1s substituents; R 1s independently C 1-12 alkyl, preferably C 1-10 alkyl; R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl; or R4and R5together with the carbon atom to which they are attached form C 3-6 cycloalkylidene, preferably C 3-4 cycloalkylidene.

6. The compound of claim 5, or an isotopolog, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV), R g and R' g is methyl; a＝3； b = 6 or 7; c = 4 or 5; d = 0 or 1; c + d = 5 or 6; M1and M2are independently selected from the group consisting of -C(O)O- and -OC(O)-; R1and R2are independently C 8-9 alkyl, optionally substituted with 1 or 2 R 1s substituents; R 1s independently C 1-7 alkyl; R4and R5are methyl; or R4and R5together with the carbon atom to which they are attached form C 3-4 cycloalkylene; preferably not forming a ring; Preferably, R1and R2are independently selected from C8linear alkyl, C9linear alkyl, Preferably, at least one of R1and R2is substituted with R 1s substituted.

7. The compound of claim 4, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV), R g and R' g are independently C 1-3 alkyl, preferably methyl; a＝3； b＝6； c＝5； d＝0； M1and M2are -C(O)O-; R1and R2are independently C 8-12 alkyl, preferably C 8-10 alkyl, preferably C9alkyl, optionally substituted with 1 or 2 R 1s substituents; R 1s independently C 1-10 alkyl; preferably C 1-7 alkyl; preferably C 1-5 alkyl; R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl; or R4and R5together with the carbon atom to which they are attached form C 3-4 cycloalkylene; preferably not forming a ring; Preferably, R1is selected from C9straight chain alkyl and R2is selected from C9straight chain alkyl, Preferably, at least one of R1and R2is substituted with R 1s substituted.

8. The compound of claim 4, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV), a＝3； R g and R' g are independently C 1-3 alkyl, preferably methyl; b＝7； c＝5； d＝0； M1is -C(O)O-; M2is -OC(O)-; R1and R2are independently selected from C 8-12 alkyl, preferably C 8-10 alkyl, preferably C 8-9 alkyl; preferably, R1is selected from C9alkyl and R2is selected from C8alkyl; which is optionally substituted by 1 or 2 R 1s substituents; R 1s independently selected from C 1-10 alkyl; preferably C 1-7 alkyl, preferably C 5-7 alkyl; preferably C R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl; or R4and R5together with the carbon atom to which they are attached form C 3-4 cycloalkylene; preferably not forming a ring; Preferably, R1is selected from C9straight chain alkyl, R2is selected from C8straight chain alkyl and Preferably, at least one of R1and R2is substituted with R 1s substituted.

9. The compound of claim 4, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, in formula (IV), R g and R' g are independently C 1-3 alkyl, preferably methyl; a＝3； b = 6 or 7; preferably b = 6; c = 4 or 5; d = 0 or 1; preferably d = 1; c + d = 5 or 6; M1is -OC(O)-; M2is -C(O)O- or -OC(O)-; preferably -C(O)O-; R1and R2are independently C 8-12 alkyl, preferably C 8-10 alkyl; preferably C 8-9 alkyl; optionally substituted with 1 or 2 R 1s substituents; R 1s independently C 1-10 alkyl; preferably C 1-7 alkyl, preferably C 5-7 alkyl; preferably C R4and R5are independently C 1-3 alkyl, preferably C 1-2 alkyl, preferably methyl; or R4and R5together with the carbon atom to which they are attached form C 3-4 cycloalkylene; preferably not forming a ring; Preferably, R1is selected from C8linear alkyl, C9linear alkyl and R2is selected from C9straight chain alkyl, preferably C9 linear alkyl, Preferably, at least one of R1and R2is substituted with R 1s substituted.

10. The compound of any one of claims 4-9, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1s The substituent sites on R1or R2are spaced 0-6 carbon atoms apart, preferably 1-6 carbon atoms apart, preferably 1-4 carbon atoms apart, preferably 3-4 carbon atoms apart; preferably 1-3 carbon atoms apart, from M1or M2.

11. The compound of claim 1, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, the compound is selected from the group consisting of the compounds of Table (II).

12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or an isotopologue, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. A nanoparticle composition comprising a lipid component, and optionally a payload; wherein, the lipid component comprises a compound of any one of claims 1-11, or an isotopologue, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the payload is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent.

14. Use of a compound of any one of claims 1-11, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12, or a nanoparticle composition of claim 13, for the manufacture of a medicament for the treatment, diagnosis, or prevention of a disease; preferably, the medicament for the treatment, diagnosis, or prevention of a disease is a nucleic acid, preferably a therapeutic or prophylactic mRNA vaccine.

15. Use of a compound of any one of claims 1-11, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12, or a nanoparticle composition of claim 13, for the manufacture of a delivery vehicle for a payload selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent.

16. A compound of any one of claims 1-11, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12, or a nanoparticle composition of claim 13, for use in the treatment, diagnosis, or prevention of a disease.

17. A compound of any one of claims 1-11, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 12, or a nanoparticle composition of claim 13, for use in the delivery of a payload; wherein the payload is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent.

18. The nanoparticle composition of claim 15, or the use of claim 15, or the compound, pharmaceutical composition, or nanoparticle composition of claim 17, wherein, the therapeutic agent, prophylactic agent, or diagnostic agent is a nucleic acid; preferably, the nucleic acid is selected from one or more of an ASO, an RNA, or a DNA; preferably, the RNA is selected from one or more of a small interfering RNA (siRNA), a short hairpin RNA (shRNA), an antisense RNA (aRNA), a messenger RNA (mRNA), a long non-coding RNA (IncRNA), a microRNA (miRNA), a small activating RNA (saRNA), a multimeric coding nucleic acid (MCNA), a polymeric coding nucleic acid (PCNA), a guide RNA (gRNA), a CRISPR RNA (crRNA), or a ribozyme, preferably an mRNA, more preferably a modified mRNA.

19. A method of preparing a compound of formula (IV), the method comprising: reacting a compound of formula (IVa) with a compound of formula (IVb) to give a compound of formula (IV); wherein the variables are as defined in any one of claims 1-10.

Images