Three-cluster galactose-based compounds, conjugates, methods for their preparation, and uses

Abstract

The present invention relates to compounds of formula (I), conjugates of said compounds linked to drug molecules, methods for preparing said compounds, and uses of said compounds and conjugates in the preparation of medicaments for treating or preventing diseases associated with the expression or overexpression of genes in liver cells. [Case 1] JPEG2025527979000461.jpg50170

Description

[Technical Field]

[0001] The present invention relates to the field of biotechnology, specifically to a gel formulation of three-cluster galactose-based compounds and conjugates. The present invention also relates to a method for preparing said compounds and the use of said compounds and conjugates in the preparation of a medicament for treating or preventing diseases associated with the expression or overexpression of genes in liver cells. [Background technology]

[0002] The asialoglycoprotein receptor (ASGPR) is an endocytic receptor for numerous heterogeneous oligomers, primarily present on the plasma membrane surface of hepatocytes facing the sinusoidal cavity. It specifically recognizes carbohydrates. Various glycoproteins undergo enzymatic or acidolysis to remove terminal sialic acid, leaving the exposed secondary termini with galactose residues. Therefore, the carbohydrate-binding specificity of ASGPR is actually due to galactosylation, and therefore ASGPR is also known as the galactose-specific receptor. ASGPR is primarily distributed in hepatocytes, and its abundance in other cells is low, making it an ideal receptor for liver-directed transport.

[0003] Glycoproteins bearing either non-reducing galactose (Gal) or N-acetylgalactosamine (GalNAc) residues at their termini are recognized by ASGPR. The binding affinity of GalNAc for ASGPR is approximately 50-fold higher than that of Gal (Lobst ST et al., J Biol Chem, 1996, 271 (12): 6686-6693). In vitro experiments have shown that clustered sugar residues can simultaneously occupy receptor binding sites, thereby enabling much higher receptor affinity than non-clustered sugar residues.

[0004] ASGPR receptor-mediated liver-targeting oligonucleotides represents a new breakthrough in the field of innovative nucleic acid drug discovery research. Among these, GalNAc (N-acetylgalactosamine) modification is currently the most commonly used small molecule nucleic acid drug delivery system. Currently, all GalNAc-related conjugate structures are triantennary GalNAc structures, specifically, a trivalent GalNAc is covalently attached to the 3' or 5' end of the sense strand of a different siRNA sequence to form a polysaccharide-siRNA monoconjugate. This achieves specific delivery to hepatocytes, allowing the drug to enter and function in the cells through endocytosis.

[0005] In 2012, Alnylam Pharmaceuticals, a US company, covalently attached the tri-antennary GalNAc structure previously studied by previous researchers to small interfering RNA (siRNA) and achieved liver-targeted delivery of siRNA in vivo. Using this technology, researchers developed treatments for amyloidosis, hemophilia, hypercholesterolemia, hepatic porphyria, hepatitis B, and other diseases. In 2014, ISISP Pharmaceuticals, a US company, covalently attached tri-antennary GalNAc to antisense nucleic acids to achieve liver-targeted drug delivery in animals. After attachment, the activity of the antisense nucleic acid was improved by 10-fold (Prakash TP et al., Nucleic Acids Res. 42, 8796-807).

[0006] However, ASGPR receptor-mediated liver-targeting oligonucleotide technology still requires further development and improvement, and research into other structures different from the traditional triantennary GalNAc structure is still actively ongoing. Summary of the Invention

[0007] In order to solve the above problems, the present invention aims to provide a three-cluster galactose-based compound that maintains good liver targeting affinity, has excellent liver targeting properties, good hydrophilicity, low toxicity, and is easy to synthesize, and that differs from conventional three-branched GalNAc structures.

[0008] To develop novel three-cluster galactose compounds, the inventors attempted to synthesize compounds with various branched structures using various amino acids, such as glutamic acid, aspartic acid, and lysine. However, these structures did not significantly improve ASGPR receptor affinity. After extensive trial and research, the inventors discovered that three-cluster galactose compounds obtained by using a branched structure formed by condensing L-serine and serinol have good hydrophilicity, low toxicity, and are highly useful in clinical settings. [ka] [Means for solving the problem]

[0009] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: [ka]

[0010] (wherein each group is defined as follows): In another aspect, the present invention provides a conjugate having the structure shown in formula (III):

[0011] [ka]

[0012] (wherein each group is defined as follows): In another aspect, the present invention provides a pharmaceutical composition comprising a conjugate of the present invention, optionally a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, and optionally other therapeutic agents.

[0013] In another aspect, the present invention provides the use of a conjugate of the present invention in the preparation of a medicament for treating or preventing a disease associated with the expression or overexpression of a gene in liver cells.

[0014] In another aspect, the present invention provides a method for treating or preventing a disease associated with expression or overexpression of a gene in liver cells in a subject, the method comprising administering to the subject a conjugate of the present invention or a pharmaceutical composition of the present invention.

[0015] In another aspect, the present invention provides a conjugate of the present invention or a pharmaceutical composition of the present invention for use in treating or preventing a disease associated with the expression or overexpression of a gene in liver cells.

[0016] In particular embodiments, the gene is selected from the HBV genome, HCV genome, PCSK9, xanthine oxidase, URAT1, APOB, liver fibrosis-related genes (AP3S2, AQP2, AZINI, DEGSI, STXBP5L, TLR4, TRPM5), non-alcoholic fatty liver disease-related genes (PNPLA3, FDFT1) or primary biliary cirrhosis-related genes (HLA-DQB1, IL-12, IL-12RB2), or a combination thereof.

[0017] In another specific embodiment, the present invention is used to treat or prevent at least one of hereditary angioedema, familial tyrosinemia type 1, Alagille syndrome, alpha-1-antitrypsin deficiency, disorders of bile acid synthesis metabolism, biliary atresia, cystic fibrosis liver disease, idiopathic neonatal hepatitis, mitochondrial liver disease, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, transthyretin amyloidosis, hemophilia, homozygous familial hypercholesterolemia, hyperlipidemia, hepatitis B (HBV), hepatitis C (HCV), steatohepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), disorders associated with hyperglycemia or abnormally increased hepatic glucose production resembling type 1 or type 2 diabetes, hepatitis, and hepatic porphyria.

[0018] definition chemistry definition Definitions of specific functional groups and chemical terms are discussed in more detail below.

[0019] When a range of values ​​is listed, it is intended that each value and subrange within the stated range be included. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Contains alkyl.

[0020] "C 1~10 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, and C 1~2 Alkyl is preferred. 1~6 Examples of alkyl include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), t-butyl (C4), s-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-pentyl (C5), and n-hexyl (C6). 1~6The term "alkyl" further includes heteroalkyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, or phosphorus). Alkyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0021] "C 2~6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2~4 Alkenyl is preferred. 2~6 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 2~6 The term "alkenyl" further includes heteroalkenyl 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, or phosphorus). Alkenyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0022] "C 2~6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2~4 Alkynyl is preferred. 2~6Examples of alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. 2~6 The term "alkynyl" further 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, or phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0023] "C 1~25 "Alkylene" means C 1~25 It refers to the divalent group obtained by removing another hydrogen from an alkyl, which may be substituted or unsubstituted. 5~25 Alkylene, C 1~20 Alkylene, C 3~20 Alkylene, C 5~20 Alkylene, C 8~20 Alkylene, C 10~17 Alkylene, C 1~17 Alkylene, C 3~17 Alkylene, C 1~10 Alkylene, C 3~10 Alkylene, C 1~6 Alkylene, C 3~6 Alkylene, C 4~6 Alkylene, C 1~4 Alkylene, C 2~4 Alkylene, and C 1~3Alkylene is preferred. In some embodiments, C6 alkylene and C4 alkylene are preferred. The unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Examples of substituted alkylene include, for example, the alkylene substituted with one or more alkyls (methyl), such as substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-). 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2C(CH3)2-), and the like. In some embodiments, straight chain alkylene is preferred.

[0024] "C 0~6 Alkylene is a chemical bond and the above "C 1~6 "C" refers to "alkylene" 0~4 Alkylene is a chemical bond and the above "C 1~4 It refers to alkylene.

[0025] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0026] For this reason, "C 1~10 Haloalkyl refers to the above "C 1~10 "Alkyl" refers to alkyl substituted with one or more halogen groups. In some embodiments, C 1~6 Haloalkyl, C 1~5 Haloalkyl, C 1~4 Haloalkyl, and C 1~3 Haloalkyl is particularly preferred, more preferably C1~2 It is a haloalkyl. Examples of the haloalkyl include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, and 2,2,2-trifluoro-1,1-dimethyl-ethyl. The haloalkyl group can be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] "C 3~10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms, and optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 5~10 Cycloalkyl, C 3~7 Cycloalkyl, and C 3~6 Cycloalkyl is particularly preferred, more preferably C 5~7 Cycloalkyl, and C 5~6Cycloalkyl. Cycloalkyl further includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons still represents the number of carbons in the cycloalkyl system. Cycloalkyl further includes the above-mentioned cycloalkyl rings, where substituents on any non-adjacent carbon atoms are linked to form a bridged ring, thereby forming a polycycloalkane that shares two or more carbon atoms. Cycloalkyl further includes the above-mentioned cycloalkyl rings, where substituents on the same carbon atom are linked to form a ring, thereby forming a polycycloalkane that shares one carbon atom. Examples of the cycloalkyl 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), and cycloheptatrienyl (C7), etc. The cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] "3- to 10-membered heterocyclyl" refers to a saturated or unsaturated group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, where each heteroatom is independently at least one selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and the 3- to 10-membered heterocyclyl optionally contains 1, 2, or 3 double or triple bonds. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as valency permits. In some embodiments, 5- to 10-membered heterocyclyls that are 5- to 10-membered non-aromatic ring systems having ring carbon atoms and 1 to 5 ring heteroatoms are preferred. In some embodiments, the heterocyclyl is preferably a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, a 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, and more preferably a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl further includes ring systems in which the heterocyclyl ring described above is fused to one or more cycloalkyls, where the point of attachment is on the heterocyclyl ring, or heterocyclyl further includes ring systems in which the heterocyclyl ring described above is fused to one or more aryls or heteroaryls, where the point of attachment is on the heterocyclyl ring. In this case, the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Heterocyclyl further includes the above heterocyclyl rings, where substituents on any non-adjacent carbon or nitrogen atoms are linked to form a bridged ring, jointly forming a polycyclic heteroalkane that shares two or more carbon or nitrogen atoms. Heterocyclyl further includes the above heterocyclyl rings, where substituents on the same carbon atom are linked to form a ring, jointly forming a polycyclic heteroalkane that shares one carbon atom. Examples of 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl.Examples of 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyls containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Examples of 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of 5-membered heterocyclyls (also referred to herein as 5,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Examples of 6-membered heterocyclyls (also referred to herein as 6,6-bicyclic heterocyclyls) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.Heterocyclyl also includes the above heterocyclyl which shares one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl to form a bridged or screw ring, and the shared atom may be a carbon or nitrogen atom as long as the valence allows. Heterocyclyl also includes the above heterocyclyl and heterocyclyl groups which may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] "C 6~10 "Aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring systems (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, an aryl has 6 ring carbon atoms ("C6 aryl," e.g., phenyl). In some embodiments, an aryl has 10 ring carbon atoms ("C 10 Aryl includes "aryl" (e.g., naphthyl, e.g., 1-naphthyl, and 2-naphthyl). Aryl further includes ring systems in which the above-mentioned aryl ring is fused to one or more cycloalkyls or heterocyclyls, and the point of attachment is on the aryl ring, in which case the number of carbon atoms still represents the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] "5-10-membered heteroaryl" refers to a 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π-electrons arranged in a ring) having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as long as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. Heteroaryls further include ring systems in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyls or heterocyclyls, where the point of attachment is on the heteroaryl ring, and in this case, the number of carbon atoms still represents the number of carbon atoms in the heteroaryl ring system. In some other embodiments, 5- to 6-membered heteroaryls that are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms are particularly preferred. Examples of 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Examples of 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. Examples of 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl. Examples of 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, benzoxepinyl, and thiepinyl.Examples of 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanazinyl, and purinyl. Examples of 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, quinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] "C 6~10 "Arylene" means C 6~10 It refers to a divalent group obtained by removing another hydrogen atom from an aryl, and may be substituted or unsubstituted. In some embodiments, phenylene, for example, [ka] is preferred.

[0032] "C 5~10 "Heteroarylene" means C 5~10 It refers to a divalent group formed by removing another hydrogen atom from a heteroaryl, and may be substituted or unsubstituted. 5~9 Heteroarylene, C 5~6 Heteroarylene, C6 heteroarylene, and C5 heteroarylene, for example [ka] ,for example [ka] is particularly preferred.

[0033] Divalent groups formed by removing another hydrogen from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined above are collectively referred to as "ylenes." Ring-forming groups such as cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are collectively referred to as "ring groups."

[0034] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc., groups defined above are optionally substituted groups.

[0035] Examples of substituents on carbon atoms include halogen, -C≡N, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NRbb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd is substituted by a group, Or, two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is replaced by R aa are each independently any one selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups are joined to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd is replaced by R bb are each independently hydrogen, -OH, or -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc)2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, at least one selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R bb The groups are joined to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd is replaced by R cc are each independently at least one selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups are joined to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd is replaced by R dd are each independently 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(Rff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, at least one selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents may be joined to form =O or =S; R eeare each independently at least one selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg is replaced by R ff are each independently at least one selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff The groups are joined to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R gg is replaced by R gg are each independently a halogen, -C≡N, -NO2, -N3, -SO2H, -SO3H, -OH, or -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclyl, and C5-C 10 At least one of heteroaryl or two geminal R gg The substituents may be joined to form =O or =S, where X - is the counterion.

[0036] Examples of substituents on nitrogen atoms include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, at least one of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R linked to a nitrogen atom ccThe groups are joined to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd substituted by a group, where R aa , R bb , R cc and R dd is as described above.

[0037] Other definitions The term "oligonucleotide chain" refers to an oligomeric compound having a length of less than about 100 nucleotides (e.g., 1-20 nucleotides or 1-50 nucleotides) and containing multiple or all chemically modified or unmodified nucleotides. In certain embodiments, a non-nucleic acid binding group may be included in the oligonucleotide chain. In certain embodiments, the oligonucleotide comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or oligopeptide nucleotide (PNA). In certain embodiments, the oligonucleotide chain may be double-stranded or single-stranded. In certain embodiments, the oligonucleotide chain is an siRNA, an aptamer, an antisense nucleic acid, sgRNA, tractRNA, or crRNA.

[0038] The term "conjugate group" refers to an atom or group of atoms attached to an oligonucleotide chain. In some cases, conjugate groups alter one or more properties of the oligonucleotide to which they are attached, including, but not limited to, pharmacodynamics, pharmacokinetics, binding, absorption, cellular distribution, cellular uptake, charge, and / or clearance properties.

[0039] The term "conjugate" refers to the attachment of a compound of the invention to an oligonucleotide chain.

[0040] The term "receptor" refers to a biological macromolecule composed of glycoproteins or lipoproteins present in the cell membrane, cytoplasm or nucleus, with different receptors having specific structures and arrangements.

[0041] The term "ligand" refers to a substance or compound capable of recognizing and binding to a receptor. In certain embodiments, the ligand is a ligand that binds to the asialoglycoprotein receptor (ASGPR). In certain embodiments, the ligand is a carbohydrate, such as a monosaccharide and / or a polysaccharide, including, but not limited to, galactose, N-acetylgalactosamine, mannose, glucose, glucosamine, and fucose, including D-mannopyranose, L-mannopyranose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, β- -D-Mannopyranose, β-D-Mannopyranose, α-D-Glucopyranose, β-D-Glucopyranose, α-D-Glucofuranose, β-D-Glucofuranose, α-D-Fructofuranose, α-D-Fructopyranose, α-D-Galactopyranose, β-D-Galactopyranose, α-D-Galactofuranose, β-D-Galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine N-propionylgalactosamine, Nn-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose, N-glycolyl-α-neuraminic acid, 5-thiazolinone, These include, but are not limited to, O-β-D-glucopyranose, methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside, 2,5-anhydro-D-allosenitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0042] As used herein, the term "polysaccharide" refers to a polymer in which multiple monosaccharide groups are linked by glycosidic bonds. In the present invention, polysaccharides include oligosaccharides and / or oligosaccharides. Generally, "oligosaccharide" refers to a polymer in which 2 to 10 monosaccharide groups are linked by glycosidic bonds, and "oligosaccharide" refers to a polymer in which less than 20 monosaccharide groups are linked by glycosidic bonds.

[0043] A "protecting group" or "protecting group" refers to any atom or group of atoms added to a molecule to prevent an existing group in the molecule from undergoing an undesired chemical reaction. A "protecting group" may be a labile chemical moiety known in the art that is used to protect a reactive group, such as hydroxyl, amino, or thiol, to prevent undesired or undesired reactions during chemical synthesis. Protecting groups are typically used to selectively and / or orthogonally protect this site during reactions at other reactive sites, and can then be removed to leave the unprotected group intact or available for further reactions.

[0044] A non-limiting list of protecting groups includes benzyl; substituted benzyl; alkylcarbonyl and alkoxycarbonyl (e.g., t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyl and arylalkoxycarbonyl (e.g., benzyloxycarbonyl); substituted methyl ethers (e.g., methoxymethyl ether); substituted ethyl ethers; substituted benzyl ethers; tetrahydropyranyl ethers; silyl (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tris-isopropylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl, or t-butyldiphenylsilyl); esters (e.g., benzoate); carbonates. (e.g., methoxymethyl carbonate); sulfonates (e.g., tosylate or methyl methanesulfonate); acyclic ketals (e.g., dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1,3-dioxolane, and those described herein); acyclic acetals; cyclic acetals (e.g., those described herein); acyclic hemiacetals; cyclic hemiacetals; cyclic disulfide ketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein), and triarylmethyl (e.g., trityl; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4''-trimethoxytrityl (TMTr); and those described herein).Preferred protecting groups are selected from acetyl (Ac), benzoyl (Bzl), benzyl (Bn), isobutyryl (iBu), phenylacetyl, benzyloxymethyl acetal (BOM), ββ-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), para-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), triphenylmethyl (Trt), methoxytrityl[(4-methoxyphenyl)diphenylmethyl] (MMT), dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl (DMT)], trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), tris-isopropylsilyloxymethyl (TOM), tris-isopropylsilyl (TIPS), methyl ether, ethoxyethyl ether (EE), N,N-dimethylformamidine, and 2-cyanoethyl (CE).

[0045] The term "hydroxy-protecting group" refers to a group that can protect a hydroxyl from chemical reactions and can be removed under specific conditions to restore the hydroxyl. Examples of protecting groups include silane-type protecting groups, acyl-type protecting groups, and ether-type protecting groups, but the following protecting groups are preferred:

[0046] Trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc ), benzyl (Bn), p-methoxybenzyl (PMB), allyl, dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4"-trimethoxytrityl (TMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), and p-methoxybenzyloxymethyl (PMBM).

[0047] In some embodiments, the hydroxy protecting group is preferably dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr) or 4,4',4"-trimethoxytrityl (TMTr), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS), preferably selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr) or 4,4',4"-trimethoxytrityl (TMTr), preferably 4,4'-dimethoxytrityl (DMTr).

[0048] In some embodiments, the hydroxy protecting group is preferably:

[0049] At least one of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS), preferably t-butyldimethylsilyl (TBDMS).

[0050] The term "carboxyl-protecting group" refers to a group that can protect carboxyl from chemical reactions and can be removed under specific conditions to restore carboxyl. It mainly includes protecting groups that form esters with carboxyl. The carboxyl-protecting group is preferably one of the following:

[0051] C 1~6 Alkyl, benzyl, allyl, [ka] , and [ka] At least one of the above. 1~6 Alkyl may be unsubstituted or substituted and includes, but is not limited to, methyl, substituted methyl, beta-substituted ethyl, t-butyl, and the like.

[0052] "Amino-protecting group" refers to a group that can protect an amino from chemical reaction and can be removed under certain conditions to restore the amino. Examples of protecting groups include, but are not limited to, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), methoxycarbonyl, and ethoxycarbonyl. In some embodiments, t-butoxycarbonyl (Boc) is preferred.

[0053] "Condensation activator" refers to a substance that can increase the rate of a condensation reaction.

[0054] As used herein, the term "about" should be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the meaning is not clear to one of ordinary skill in the art from the context in which the term is used, "about" means that the deviation will not exceed plus or minus 10% of the particular value or range.

[0055] As used herein, the term "treatment" refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the noun "treating" refers to the action of treating, which is the verb just defined.

[0056] As used herein, the term "pharmaceutically acceptable salts" refers to carboxylate salts, amino acid addition salts of the compounds of the present invention that are, within the scope of medical judgment, suitable for contact with patient tissues, do not produce undue toxicity, irritation, allergic response, and the like, are reliable and effective for their expected use, commensurate with a reasonable benefit / risk ratio, and include (where possible) zwitterionic forms of the compounds of the present invention.

[0057] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, etc. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and prucaine.

[0058] The base addition salts of acidic compounds can be prepared in the conventional manner by contacting the free acid form with the required amount of base to produce the salt. The free acid can be regenerated in the conventional manner by contacting the salt form with an acid and isolating the free acid. The free acid forms may differ somewhat from their respective salt forms in some physical properties, such as solubility in polar solvents, but for purposes of this invention, the salts are still equivalent to their respective free acids.

[0059] The salts may be sulfate, pyrosulfate, bisulfite, sulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, isethionate, and the like. Salts may be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also included are salts of amino acids such as arginine, gluconic acid, galacturonic acid, and the like (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference).

[0060] The "subject" to be administered includes, but is not limited to, a human (i.e., a male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent), or an adult subject (e.g., a young adult, middle-aged adult, or older adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. As used herein, the terms "human," "patient," and "subject" can be used interchangeably.

[0061] The terms "disease," "disorder," and "condition" can be used interchangeably herein.

[0062] Unless otherwise specified, the term "treatment" as used herein includes actions that occur once a subject has a particular disease, disorder, or condition, and includes actions that reduce the severity of or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0063] In general, an "effective amount" of a compound is an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological purpose, the pharmacokinetics of the compound, the disease being treated, the administration pattern, the age, health condition and symptoms of the subject, etc. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0064] Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit during treatment of a disease, disorder, or condition, or an amount that delays or minimizes one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effect of another therapeutic agent.

[0065] Unless otherwise specified, a "prophylactically effective amount" of a compound as used herein is an amount 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 compound means an amount of a 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 include an amount that improves overall prophylaxis or an amount that enhances the prophylactic effect of another prophylactic agent.

[0066] "Combination" and related terms refer to simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, a compound of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. [Brief explanation of the drawings]

[0067] [Figure 1] 1 shows the binding curve of G1-12 of the present invention to the ASPGR receptor. [Figure 2] 1 shows the binding curve of G4-12 of the present invention to the ASPGR receptor. [Figure 3] 1 shows the binding curve between G5-12 of the present invention and ASPGR receptor. [Figure 4] 1 shows the results of a test of G1-12 of the present invention applied to liver targeting in mice. DETAILED DESCRIPTION OF THE INVENTION

[0068] The embodiments of the present invention will be described in more detail below with reference to examples. However, those skilled in the art will understand that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention. Unless specific conditions are specified in the examples, the examples are carried out according to standard conditions or conditions suggested by the manufacturer. Unless the manufacturers of the reagents or instruments used are specified, they are all standard products available commercially.

[0069] As used herein, the term "compound of the present invention" refers to a compound of the following formula (I), formula (II), etc., or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polycrystalline form, hydrate, or solvate thereof, and the term "conjugate of the present invention" refers to a conjugate of the following formula (III), etc.

[0070] For compounds having asymmetric centers, it is understood that all optical isomers and mixtures thereof are included (unless otherwise specified). Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention may exist in Z and E forms with carbon-carbon double bonds. Compounds exist in different tautomeric forms, and the compounds are not limited to a particular tautomeric form, but are intended to encompass all tautomeric forms.

[0071] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. [ka] ,

[0072] (where, M1 is independently at least one selected from -O-, -S-, -NR6-, -CHR7-, -C(O)-, -S(O)-, and -S(O)2-; R1 is an asialoglycoprotein receptor (ASGPR) ligand residue; R2 is hydroxy, carboxy, -OR p ,-OPG2, [ka] , and [ka] At least one selected from PG1 is a carboxy protecting group, PG2 is a hydroxy protecting group, R p teeth, [ka] and PG3 is independently selected from a phosphate protecting group; R and R' are each independently an amino protecting group, or R and R' together with the N atom to which they are attached optionally form a 5- to 10-membered heterocyclyl; R3 is independently [ka] and M 3a are independently a chemical bond, -O-, -S-, -NR6-, -CHR7-, -C(O)-, or -S(O) 1~2 -, -NR6C(O)-, -C(O)NR6-, -NR6S(O) 1~2 -, -S(O) 1~2 NR6-, -OC(O)-, -C(O)O-, -OS(O) 1~2 - and -S(O) 1~2 O-, M 3bare independently -O-, -S-, -NR6-, -CHR7-, -CH=CH-, -C≡C-, -C(O)-, -S(O) 1~2 -, -C(O)NR6-, -NR6C(O)-, -OC(O)-, -C(O)O-, -S(O) 1~2 O-Y1-, -OS(O) 1~2 -Y1-, -OS(O) 1~2 O-, -S(O) 1~2 NR6-Y1-, -NR6S(O) 1~2 -Y1-, C 6~10 arylene, 5- to 10-membered heteroarylene, [ka] , [ka] , and [ka] At least one selected from Y1 independently represents C 6~10 arylene or 5- to 10-membered heteroarylene; R6 is independently H, C 1~10 Alkyl, C 1~10 Haloalkyl, C 3~10 at least one selected from cycloalkyl and 3- to 10-membered heterocyclyl; R7 is independently H, halogen, CN, NO2, or C 1~10 Alkyl, C1- 10 Haloalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 and at least one selected from aryl, and 5- to 10-membered heteroaryl, wherein one or more methylenes in the alkyl or haloalkyl are optionally and independently selected from -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -S-(CH2) 0~6-S-, -NR6-, C 6~10 Arylene, 5- to 10-membered heteroarylene, -CH=CH-, -C≡C-, and -O-(CH2) 1~6 -O-, n2 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is independently 1, 2, 3, 4, 5, or 6; R4 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 at least one selected from alkoxy; Link1, Link2, Link3, and Link4 are each independently C 1~25 A straight chain alkylene, wherein one or more methylenes in said straight chain alkylene are optionally and independently replaced by R*, and R* is independently -O-, -S-, -NR6-, -CHR7-, -C(O)-, -S(O) 1~2 -, -NR6C(O)-, -C(O)NR6-, -NR6S(O) 1~2 -, -S(O) 1~2 NR6-, -OC(O)-, -C(O)O-, -OS(O) 1~2 - and -S(O) 1~2 O-, m1, m2, and m3 are each independently 1, 2, 3, 4, or 5; However, in Link 4, the methylene connected to the carbonyl on the left side is not replaced by R*. M1: In one embodiment, M1 is -O-. In another embodiment, M1 is -S-. In another embodiment, M1 is -NR6-, such as -NH-. In another embodiment, M1 is -CHR7-, such as -CH2-. In another embodiment, M1 is -C(O)-. In another embodiment, M1 is -S(O)-. In another embodiment, M1 is -S(O)2-.

[0073] In one specific embodiment, M1 is independently at least one selected from -O-, -S-, -NH-, -CH2-, -C(O)-, -S(O)-, and -S(O)2-; in another more specific embodiment, M1 is independently at least one selected from -O-, -S-, and -NH-; in another more specific embodiment, M1 is -O-.

[0074] R1: In one embodiment, R1 is an asialoglycoprotein receptor ligand residue. In another embodiment, the asialoglycoprotein receptor ligand is D-mannopyranose. In another embodiment, the asialoglycoprotein receptor ligand is L-mannopyranose. In another embodiment, the asialoglycoprotein receptor ligand is L-arabinose. In another embodiment, the asialoglycoprotein receptor ligand is D-arabinose. In another embodiment, the asialoglycoprotein receptor ligand is D-xylofuranose. In another embodiment, the asialoglycoprotein receptor ligand is L-xylofuranose. In another embodiment, the asialoglycoprotein receptor ligand is D-glucose. In another embodiment, the asialoglycoprotein receptor ligand is L-glucose. In another embodiment, the asialoglycoprotein receptor ligand is D-galactose. In another embodiment, the asialoglycoprotein receptor ligand is L-galactose. In another embodiment, the asialoglycoprotein receptor ligand is α-D-mannofuranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-mannofuranose. In another embodiment, the asialoglycoprotein receptor ligand is α-D-mannopyranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-mannopyranose. In another embodiment, the asialoglycoprotein receptor ligand is α-D-glucopyranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-glucopyranose. In another embodiment, the asialoglycoprotein receptor ligand is α-D-glucofuranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-glucofuranose. In another embodiment, the asialoglycoprotein receptor ligand is α-D-fructofuranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-fructofuranose. In another embodiment, the asialoglycoprotein receptor ligand is α-D-fructopyranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-fructopyranose.In another embodiment, the asialoglycoprotein receptor ligand is α-D-galactopyranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-galactopyranose. In another embodiment, the asialoglycoprotein receptor ligand is α-D-galactofuranose. In another embodiment, the asialoglycoprotein receptor ligand is β-D-galactofuranose. In another embodiment, the asialoglycoprotein receptor ligand is glucosamine. In another embodiment, the asialoglycoprotein receptor ligand is sialic acid. In another embodiment, the asialoglycoprotein receptor ligand is galactosamine. In another embodiment, the asialoglycoprotein receptor ligand is N-acetylgalactosamine. In another embodiment, the asialoglycoprotein receptor ligand is N-trifluoroacetylgalactosamine. In another embodiment, the asialoglycoprotein receptor ligand is N-propionylgalactosamine. In another embodiment, the asialoglycoprotein receptor ligand is Nn-butyrylgalactosamine. In another embodiment, the asialoglycoprotein receptor ligand is N-isobutyrylgalactosamine. In another embodiment, the asialoglycoprotein receptor ligand is 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose. In another embodiment, the asialoglycoprotein receptor ligand is 2-deoxy-2-methylamino-L-glucopyranose. In another embodiment, the asialoglycoprotein receptor ligand is 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose. In another embodiment, the asialoglycoprotein receptor ligand is 2-deoxy-2-sulfoamino-D-glucopyranose. In another embodiment, the asialoglycoprotein receptor ligand is N-glycolyl-α-neuraminic acid. In another embodiment, the asialoglycoprotein receptor ligand is 5-thio-β-D-glucopyranose. In another embodiment, the asialoglycoprotein receptor ligand is methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside.In another embodiment, the asialoglycoprotein receptor ligand is 4-thio-β-D-galactopyranose. In another embodiment, the asialoglycoprotein receptor ligand is ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside. In another embodiment, the asialoglycoprotein receptor ligand is 2,5-anhydro-D-allosenitrile. In another embodiment, the asialoglycoprotein receptor ligand is ribose. In another embodiment, the asialoglycoprotein receptor ligand is D-ribose. In another embodiment, the asialoglycoprotein receptor ligand is D-4-thioribose. In another embodiment, the asialoglycoprotein receptor ligand is L-ribose. In another embodiment, the asialoglycoprotein receptor ligand is L-4-thioribose.

[0075] In one specific embodiment, R1 are independently a residue of the following structure: D-mannopyranose; L-mannopyranose, L-arabinose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-Glucofuranose, β-D-Glucofuranose, α-D-Fructofuranose, β-D-Fructofuranose, α-D-Fructopyranose, β-D-Fructopyranose, α-D-Galactopyranose, β-D-Galactopyranose, α-D-Galactofuranose, β-D-Galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine Nn-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose, N-glycolyl-α-neuraminic acid, 5-thio-β-D-gluconate pyranose, methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside, 2,5-anhydro-D-allosenitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0076] In another specific embodiment, R1 is independently at least one selected from residues of the following structures: D-galactose, L-galactose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, Nn-butyrylgalactosamine, N-isobutyrylgalactosamine, and β-D-galactopyranose.

[0077] In another specific embodiment, R1 is independently at least one selected from residues of the following structures: galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, Nn-butyrylgalactosamine, and N-isobutyrylgalactosamine.

[0078] In another specific embodiment, R1 is an N-acetylgalactosamine residue.

[0079] In another specific embodiment, R1 is [ka] is.

[0080] R2: In one embodiment, R2 is hydroxy. In another embodiment, R2 is carboxy. In another embodiment, R2 is -OR p ,for example [ka] In another embodiment, R2 is -OPG2. In another embodiment, R2 is [ka] ,for example [ka] ,for example [ka] In another embodiment, R2 is [ka] ,for example [ka] ,for example [ka] ,for example [ka] ,for example [ka] ,for example [ka] ,for example [ka] is.

[0081] In one specific embodiment, R2 is hydroxy, carboxy, -OR p ,-OPG2, [ka] , and [ka] In another specific embodiment, R2 is at least one selected from -OR p , [ka] , and [ka] In another specific embodiment, R2 is at least one selected from: [ka] and [ka] In another specific embodiment, R2 is at least one selected from: [ka] , [ka] and [ka] In another specific embodiment, R2 is at least one selected from: [ka] or [ka] In another specific embodiment, R2 is selected from [ka] or [ka] In another specific embodiment, R2 is [ka] , [ka] and [ka] In another specific embodiment, R2 is at least one selected from: [ka] or [ka] In another specific embodiment, [ka] teeth [ka] or [ka] In another specific embodiment, [ka] teeth [ka] In another specific embodiment, [ka] teeth [ka] is.

[0082] PG1: In one embodiment, PG is a carboxy protecting group, e.g., C 1~6 Alkyl, for example methyl, for example t-butyl, for example benzyl, for example allyl, for example [ka] ,for example [ka] ,for example [ka] is.

[0083] In one specific embodiment, PG1 is C 1~6 Alkyl, benzyl, allyl, [ka] and [ka] At least one selected from:

[0084] In another more specific embodiment, PG1 is methyl, t-butyl, benzyl, allyl, [ka] , and [ka] In another more specific embodiment, PG1 is at least one selected from: [ka] and [ka] In another more specific embodiment, PG1 is at least one selected from [ka] In another more specific embodiment, PG1 is [ka] is.

[0085] In one embodiment, R 2s is H. In another embodiment, R 2s is halogen, for example F. In another embodiment, R 2s is C 1~10 Alkyl, e.g., C 1~6 In another embodiment, R 2s is C 1~10 Haloalkyl, e.g., C 1~6 It is haloalkyl.

[0086] In one specific embodiment, R 2s are independently H, halogen, C 1~10 Alkyl, and C 1~10 haloalkyl. In another specific embodiment, R 2s are independently H, halogen, C 1~6 Alkyl, and C 1~6haloalkyl. In another specific embodiment, R 2s is H or halogen. In another specific embodiment, R 2s is F.

[0087] In one embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment, q is 4. In another embodiment, q is 5.

[0088] PG2: In one embodiment PG2 is a hydroxy protecting group, such as trimethylsilyl (TMS), for example triethylsilyl (TES), for example dimethylisopropylsilyl (DMIPS), for example diethylisopropylsilyl (DEIPS), for example t-butyldimethylsilyl (TBDMS), for example t-butyldiphenylsilyl (TBDPS), for example triisopropylsilyl (TIPS), for example acetyl (Ac), for example chloroacetyl, for example dichloroacetyl, for example trichloroacetyl, for example trifluoroacetyl (TFA), for example benzoyl, for example p-methoxybenzoyl, for example 9-fluorenylmethoxycarbonyl (Fmoc), for example allyloxycarbonyl (Alloc), for example 2,2,2-trichloroethoxycarbonyl (Troc), for example benzyloxycarbonyl (Cbz) , for example t-butoxycarbonyl (Boc), for example benzyl (Bn), for example p-methoxybenzyl (PMB), for example allyl, for example dimethoxytrityl (DMT), for example monomethoxytrityl (MMT), for example 9-phenylxanthen-9-yl (Pixyl), for example 9-(p-methoxyphenyl)xanthen-9-yl (Mox), for example trityl (Tr), for example 4-methoxytrityl (MMTr), for example 4,4'-dimethoxytrityl (DMTr), for example 4,4',4"-trimethoxytrityl (TMTr), for example methoxymethyl (MOM), for example phenoxymethyl (BOM), for example 2,2,2-trichloroethoxymethyl, for example 2-methoxyethoxymethyl (MEM), for example methylthiomethyl (MTM), for example p-methoxybenzyloxymethyl (PMBM).

[0089] In one specific embodiment, PG2 is selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), t-butoxycarbonyl, and the like. and at least one selected from the group consisting of methyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), and p-methoxybenzyloxymethyl (PMBM).

[0090] In another specific embodiment, PG2 is at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4"-trimethoxytrityl (TMTr), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS).

[0091] In another specific embodiment, PG2 is at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), and 4,4',4"-trimethoxytrityl (TMTr).

[0092] In another specific embodiment, PG2 is 4,4'-dimethoxytrityl (DMTr).

[0093] R p : In one embodiment, R p teeth, [ka] ,for example [ka] is.

[0094] PG3: In one embodiment, PG3 is a phosphate protecting group, such as 2-cyanoethyl, e.g., C 1~6 Alkyl, for example methyl.

[0095] In one more specific embodiment, PG3 is independently 2-cyanoethyl and C 1~6 In one more specific embodiment, PG3 is independently at least one selected from 2-cyanoethyl and methyl. In one more specific embodiment, PG3 is 2-cyanoethyl.

[0096] R and R': In one embodiment, R and R′ are each independently an amino protecting group, such as C 1~6 alkyl, for example isopropyl, for example R and R' together with the N atom to which they are attached optionally form a 5-6 membered heterocyclyl.

[0097] R3: In one embodiment, R3 is independently [ka] In another embodiment, R3 is [ka] In another embodiment, R3 is [ka] is.

[0098] In one embodiment, [ka] is A1. In another embodiment, [ka] is A2. In another embodiment, [ka] is A3. In another embodiment, [ka] is A4. In another embodiment, [ka] is A5. In another embodiment, [ka] is A6. In another embodiment, [ka] is A7. In another embodiment, [ka] is A8. In another embodiment, [ka] is A9. In another embodiment, [ka] is A10. In another embodiment, [ka] is A11. In another embodiment, [ka] is A12. In another embodiment, [ka] is A13. In another embodiment, [ka] is A14. In another embodiment, [ka] is A15. In another embodiment, [ka] is A16. In another embodiment, [ka] is A17. In another embodiment, [ka] is A18. In another embodiment, [ka] is A19. In another embodiment, [ka] is A20. In another embodiment, [ka] is A21. In another embodiment, [ka] is A22. In another embodiment, [ka] is A23. In another embodiment, [ka] is A24.

[0099] The structures of A1-A24 are as follows: [ka] In one specific embodiment, [ka] is independently a structure selected from A1 to A24. In another more specific embodiment, [ka] is independently at least one selected from A2, A3, A4, A6, and A9. In another more specific embodiment, [ka] is independently at least one selected from A2, A3, and A9. In another more specific embodiment, [ka] is independently A3 or A9.

[0100] M 3a : In one embodiment, M 3a is a chemical bond. In another embodiment, M 3a is -O-. In another embodiment, M 3a is -S-. In another embodiment, M 3a is -NR6-, e.g., -NH-. In another embodiment, M 3a is -CHR7-, for example -CH2-. In another embodiment, M 3a is —C(O)—. In another embodiment, M 3a -S(O) 1~2 In another embodiment, M 3a is -NR6C(O)-, e.g., -NHC(O)-. In another embodiment, M 3a is —C(O)NR—, e.g., —C(O)NH—. In another embodiment, M 3a Ha-NR6S(O) 1~2 In another embodiment, M 3a -S(O) 1~2 In another embodiment, M 3a is -OC(O)-. In another embodiment, M 3a is -C(O)O-. In another embodiment, M 3a -OS(O) 1~2In another embodiment, M 3a -S(O) 1~2 It is O-.

[0101] In one specific embodiment, M 3a are independently a chemical bond, -O-, -S-, -NR6-, -CHR7-, -C(O)-, or -S(O) 1~2 -, -NHC(O)-, -C(O)NH-, -NHS(O) 1~2 -, -S(O) 1~2 NH-, -OC(O)-, -C(O)O-, -OS(O) 1~2 - and -S(O) 1~2 In another specific embodiment, M 3a is independently at least one selected from a chemical bond, —O—, —S—, —NR6—, —C(O)—, —NHC(O)—, —C(O)NH—, —OC(O)—, and —C(O)O—. In another specific embodiment, M 3a is independently at least one selected from a chemical bond, —NHC(O)—, —C(O)NH—, —OC(O)—, and —C(O)O—. In another specific embodiment, M 3a is independently at least one selected from a chemical bond, —NHC(O)—, and —C(O)NH—. In another specific embodiment, M 3a are independently a chemical bond or —C(O)NH—.

[0102] M 3b : In one embodiment, M 3b is -O-. In another embodiment, M 3b is -S-. In another embodiment, M 3b is -NR6-. In another embodiment, M 3b is -CHR7-. In another embodiment, M 3b is -CH=CH-. In another embodiment, M 3b is -C≡C-. In another embodiment, M 3b is —C(O)—. In another embodiment, M 3b -S(O) 1~2In another embodiment, M 3b is —C(O)NR—, e.g., —C(O)NH—. In another embodiment, M 3b is -NR6C(O)-, e.g., -NHC(O)-. In another embodiment, M 3b is -OC(O)-. In another embodiment, M 3b is -C(O)O-. In another embodiment, M 3b -S(O) 1~2 In another embodiment, M 3b -OS(O) 1~2 In another embodiment, M 3b -OS(O) 1~2 In another embodiment, M 3b -S(O) 1~2 In another embodiment, M 3b Ha-NR6S(O) 1~2 In another embodiment, M 3b is C 6~10 arylene, for example phenylene. In another embodiment, M 3b is a 5- to 10-membered heteroarylene, for example a 5- to 6-membered heteroarylene, for example [ka] ,for example [ka] In another embodiment, M 3b teeth [ka] In another embodiment, M 3b teeth [ka] In another embodiment, M 3b teeth [ka] is.

[0103] In one specific embodiment, M 3b are independently -O-, -S-, -NR6-, -CHR7-, -CH=CH-, -C≡C-, -C(O)-, -S(O) 1~2 -, -C(O)NH-, -NHC(O)-, -OC(O)-, -C(O)O-, -S(O) 1~2 O-Y1-, -OS(O) 1~2 -Y1-, -OS(O) 1~2 O-, -S(O) 1~2 NH-Y1-, -NHS(O) 1~2 -Y1-, phenylene, 5- to 6-membered heteroarylene, [ka] , [ka] , and [ka] In another specific embodiment, M 3b are independently -O-, -S-, -NR6-, -CHR7-, -CH=CH-, -C≡C-, -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -C(O)O-, -OS(O) 1~2 -Y1-, -OS(O) 1~2 O-, -NHS(O) 1~2 -Y1-, 5- to 6-membered heteroarylene, [ka] , [ka] , and [ka] In another specific embodiment, M 3b is independently at least one selected from -C(O)NH-, -NHC(O)-, -OC(O)-, and -C(O)O-. 3b is —C(O)NH— or —NHC(O)—. In another specific embodiment, M 3b is -NHC(O)-. In another specific embodiment, M 3b 5-6 membered heteroarylene as [ka] or [ka] is.

[0104] Y1: In one embodiment, Y is C 6~10 In another embodiment, Y1 is arylene, such as phenylene. In another embodiment, Y1 is 5-10 membered heteroarylene, such as 5-6 membered heteroarylene.

[0105] In one specific embodiment, Y1 is independently phenylene or 5-6 membered heteroarylene. In another more specific embodiment, Y1 is phenylene, e.g. [ka] is.

[0106] R6: In one embodiment, R6 is H. In another embodiment, R6 is C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g. -CH3, e.g. [ka] ,for example [ka] ,for example [ka] In another embodiment, R6 is C 1~10 Haloalkyl, e.g., C 1~6 In another embodiment, R6 is C 3~10 Cycloalkyl, e.g., C 3~7 In another embodiment, R6 is 3- to 10-membered heterocyclyl, such as 3- to 7-membered heterocyclyl.

[0107] In a more specific embodiment, each R6 is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~7 In another more specific embodiment, each R6 is independently at least one selected from H, C 1~6 Alkyl, and C 1~6 In another more specific embodiment, each R6 is independently selected from H, -CH3, [ka] , [ka] , and [ka] In another more specific embodiment, R6 is H.

[0108] R7: In one embodiment, R7 is H. In another embodiment, R7 is halogen, such as -F, such as -Cl, such as -Br. In another embodiment, R7 is -C≡N. In another embodiment, R7 is -NO2. In another embodiment, R7 is C 1~10 In another embodiment, R7 is C1- 10 In another embodiment, R7 is C 3~10 In another embodiment, R7 is cycloalkyl. In another embodiment, R7 is 3-10 membered heterocyclyl. In another embodiment, R7 is C 6~10 In another embodiment, R7 is aryl. In another embodiment, R7 is 5-10 membered heteroaryl.

[0109] In one embodiment, one or more methylenes in the alkyl or haloalkyl as R7 are optionally and independently selected from -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -S-(CH2) 0~6 -S-, -NR6-, C 6~10 Arylene, 5- to 10-membered heteroarylene, -CH=CH-, -C≡C-, and -O-(CH2) 1~6 At least one group selected from -O-, for example -C(O)-, for example -C(O)NH-, for example -NHC(O)-, for example -OC(O)-, for example -O-, for example -C(O)O-, for example -S-, for example -S-(CH2) 0~6 -S-, e.g. -NR6-, e.g. C 6~10 Arylene, for example, 5-10 membered heteroarylene, for example, -CH=CH-, for example, -C≡C-, for example, -O-(CH2) 1~6 In another embodiment, one, two or three methylenes in alkyl or haloalkyl as R7 are optionally and independently replaced with a group selected from the foregoing.

[0110] In a more specific embodiment, each R7 is independently H, halogen, CN, C 1~6 Alkyl, C1-6 haloalkyl, C 3~7In another more specific embodiment, each R7 is independently selected from H, halogen, CN, C 1~6 In another more specific embodiment, each R is independently at least one selected from H, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0111] In a more specific embodiment, one or more methylenes in the alkyl or haloalkyl as R7 are optionally and independently selected from -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -S-(CH2) 0~3 -S-, -NR6-, phenylene, 5- to 6-membered heteroarylene, -CH=CH-, -C≡C-, and -O-(CH2) 1~3 In another more specific embodiment, one, two, or three methylenes in the alkyl or haloalkyl as R7 are optionally and independently selected from -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -SS-, -NR6-, [ka] , [ka] , -CH=CH-, -C≡C-, and -O-(CH2)2-O-. In another more specific embodiment, the halogen as R7 is -F, -Cl, or -Br.

[0112] n2: In one embodiment, n2 is 0. In another embodiment, n2 is 1. In another embodiment, n2 is 2, and in another embodiment, n2 is 3. In another embodiment, n2 is 4. In another embodiment, n2 is 5. In another embodiment, n2 is 6. In another embodiment, n2 is 7. In another embodiment, n2 is 8. In another embodiment, n2 is 9. In another embodiment, n2 is 10.

[0113] n3: In one embodiment, n3 is 1. In another embodiment, n3 is 2, and in another embodiment, n3 is 3. In another embodiment, n3 is 4. In another embodiment, n3 is 5. In another embodiment, n3 is 6.

[0114] R4: In one embodiment, R4 is H. In another embodiment, R4 is C 1~6 Alkyl, e.g., C 1~5 Alkyl, e.g., C 1~3 In another embodiment, R4 is C 1~6 Haloalkyl, e.g., C 1~5 Haloalkyl, e.g., C 1~3 In another embodiment, R4 is C 1~6 It is an alkoxy.

[0115] In one more specific embodiment, R4 is H, C 1~5 Alkyl, C 1~5 Haloalkyl, and C 1~5 In another more specific embodiment, R4 is at least one selected from H, C 1~3 Alkyl, and C 1~3 In another more specific embodiment, R4 is H.

[0116] Link1, Link2, and Link3: In one embodiment, Link1 is C 1~25 Linear alkylene, e.g., C 1~10 Linear alkylene, e.g., C1~6 Linear alkylene, e.g., C 4~6 Straight chain alkylene, for example -(CH2)4-, for example -(CH2)6-.

[0117] In one embodiment, Link2 is C 1~25 Linear alkylene, e.g., C 1~10 Linear alkylene, e.g., C 1~6 Linear alkylene, e.g., C 4~6 Straight chain alkylene, for example -(CH2)4-, for example -(CH2)6-.

[0118] In one embodiment, Link3 is C 1~25 Linear alkylene, e.g., C 1~10 Linear alkylene, e.g., C 1~6 Linear alkylene, e.g., C 4~6 Straight chain alkylene, for example -(CH2)4-, for example -(CH2)6-.

[0119] In one embodiment, one or more methylenes in Link1, Link2, and Link3 are optionally and independently replaced by R*. In another embodiment, one, two, or three methylenes in Link1, Link2, and Link3 are optionally and independently replaced by R*. In another embodiment, one methylene in Link1, Link2, and Link3 is optionally and independently replaced by R*.

[0120] In a more specific embodiment, Link1, Link2, and Link3 are each independently C 1~10 In another more specific embodiment, Link1, Link2, and Link3 are each independently C 1~6 In another more specific embodiment, Link1, Link2, and Link3 are each independently C 4~6 In another more specific embodiment, Link1, Link2, and Link3 are each independently —(CH2)4— or —(CH2)6—.

[0121] In one embodiment, Link1, Link2, and Link3 are each independently: [ka] is.

[0122] In one embodiment, n1 is 1. In another embodiment, n1 is 2, and in another embodiment, n1 is 3. In another embodiment, n1 is 4. In another embodiment, n1 is 5. In another embodiment, n1 is 6. In another embodiment, n1 is 7. In another embodiment, n1 is 8. In another embodiment, n1 is 9. In another embodiment, n1 is 10.

[0123] Link4: In one embodiment, Link4 is C 1~25 Linear alkylene, e.g., C 5~25 Linear alkylene, e.g., C 1~20 Linear alkylene, e.g., C 5~20 Linear alkylene, e.g., C 8~20 Linear alkylene, e.g., C 1~17 Linear alkylene, e.g., C 10~17 Linear alkylene, e.g., C 1~10 Linear alkylene, e.g., C 3~20 Linear alkylene, e.g., C 3~17 Linear alkylene, e.g., C 3~10 Straight chain alkylene, for example -(CH2)3-, for example -(CH2) 10 -It is.

[0124] In one embodiment, one or more methylenes in Link4 are optionally and independently replaced by R*. In another embodiment, one, two, or three methylenes in Link4 are optionally and independently replaced by R*. In another embodiment, one methylene in Link4 is optionally and independently replaced by R*, e.g., Link4 is -(CH2)3-C(O)NH-(CH2)6-, e.g., Link4 is -(CH2) 10 In another embodiment, in Link4, the methylene connected to the carbonyl to its left is not replaced by R*.

[0125] In one more specific embodiment, Link4 is -(CH2)3-, -(CH2) 10 -, -(CH2)3-C(O)NH-(CH2)6-, and -(CH2) 10 In another more specific embodiment, Link4 is at least one selected from -(CH2)3-, -(CH2) 10 -, and -(CH2)3-C(O)NH-(CH2)6-. In another more specific embodiment, Link4 is at least one selected from -(CH2)3- or -(CH2) 10 In another more specific embodiment, Link4 is -(CH2) 10 -, -(CH2)3-C(O)NH-(CH2)6-, and -(CH2) 10 In another more specific embodiment, Link4 is at least one selected from -C(O)NH-(CH2)6-. 10 -or-(CH2) 10 -C(O)NH-(CH2)6-.

[0126] R*: In one embodiment, R* is -O-. In another embodiment, R* is -S-. In another embodiment, R* is -NR6-. In another embodiment, R* is -CHR7-. In another embodiment, R* is -C(O)-. In another embodiment, R* is -S(O)1~2 In another embodiment, R* is -NR6C(O)-, such as -NHC(O)-. In another embodiment, R* is -C(O)NR6-, such as -C(O)NH-. In another embodiment, R* is -NR6S(O) 1~2 In another embodiment, R* is -S(O) 1~2 In another embodiment, R* is -NR6-. In another embodiment, R* is -OC(O)-. In another embodiment, R* is -C(O)O-. In another embodiment, R* is -OS(O) 1~2 In another embodiment, R* is -S(O) 1~2 It is O-.

[0127] In one more specific embodiment, R* is independently at least one selected from -O-, -NR-, -CHR-, -C(O)-, -NRC(O)-, -C(O)NR-, -OC(O)-, and -C(O)O-. In another more specific embodiment, R* is independently at least one selected from -C(O)NH-, -NHC(O)-, -C(O)O-, and -OC(O)-. In another more specific embodiment, R* is independently at least one selected from -C(O)NH- and -C(O)O-. In another more specific embodiment, R* is independently at least one selected from -C(O)NH- and -NHC(O)-. In another more specific embodiment, R* is -C(O)NH-.

[0128] In one embodiment, there are 1 to 15 methylenes between R* and the left carbonyl of Link4, such as 1 methylene, for example 2 methylenes, for example 3 methylenes, for example 4 methylenes, for example 5 methylenes, for example 6 methylenes, for example 7 methylenes, for example 8 methylenes, for example 9 methylenes, for example 10 methylenes, for example 11 methylenes, for example 12 methylenes, for example 13 methylenes, for example 14 methylenes, for example 15 methylenes.

[0129] In one more specific embodiment, there are 1 to 15 methylenes between R* and the carbonyl on the left side of Link4. In another more specific embodiment, there are 1 to 12 methylenes between R* and the carbonyl on the left side of Link4. In another more specific embodiment, there are 1 to 10 methylenes between R* and the carbonyl on the left side of Link4. In another more specific embodiment, there are 1 to 3 methylenes between R* and the carbonyl on the left side of Link4. In another more specific embodiment, there are 3 to 10 methylenes between R* and the carbonyl on the left side of Link4.

[0130] In one embodiment, R* and R2 are separated by 1 to 12 methylenes, such as 1 methylene, for example 2 methylenes, for example 3 methylenes, for example 4 methylenes, for example 5 methylenes, for example 6 methylenes, for example 7 methylenes, for example 8 methylenes, for example 9 methylenes, for example 10 methylenes, for example 11 methylenes, for example 12 methylenes.

[0131] In one more specific embodiment, 1 to 12 methylenes separate R* from R2. In another more specific embodiment, 1 to 10 methylenes separate R* from R2. In another more specific embodiment, 1 to 6 methylenes separate R* from R2.

[0132] m1, m2, and m3: In one embodiment, m1 is 1. In another embodiment, m1 is 2. In another embodiment, m1 is 3. In another embodiment, m1 is 4. In another embodiment, m1 is 5.

[0133] In one embodiment, m2 is 1. In another embodiment, m2 is 2. In another embodiment, m2 is 3. In another embodiment, m2 is 4. In another embodiment, m2 is 5.

[0134] In one embodiment, m3 is 1. In another embodiment, m3 is 2. In another embodiment, m3 is 3. In another embodiment, m3 is 4. In another embodiment, m3 is 5.

[0135] In a more specific embodiment, m1, m2, and m3 are each independently 1, 2, or 3.

[0136] The present invention also provides a conjugate having the structure shown in formula (III): [ka]

[0137] (wherein L is a structure represented by formula (I') or formula (II').) [ka] [ka] [ka] teeth, [ka] , [ka] , [ka] , and [ka] At least one selected from:

[0138] RD are drug molecules, wherein the drug molecules are independently at least one selected from a cytotoxic agent, a chemotherapeutic agent, somatostatin, a toxin, a radioisotope, and an oligonucleotide chain; d is 1 or 2, preferably 1; The remaining groups are as defined herein.

[0139] L: In one embodiment, L is a structure represented by formula (I'). In another embodiment, L is a structure represented by formula (II'). In another embodiment, L is L1. In another embodiment, L is L2. In another embodiment, L is L3. In another embodiment, L is L4. The structures of L1, L2, L3, and L4 are as defined herein.

[0140] In one more specific embodiment, L is at least one selected from L1, L2, L3, and L4. In another more specific embodiment, L is at least one selected from L1, L2, and L4.

[0141] [ka] In one embodiment, [ka] teeth [ka] In another embodiment, [ka] teeth [ka] ,for example [ka] ,for example [ka] In another embodiment, [ka] teeth [ka] ,for example [ka] ,for example [ka] In another embodiment, [ka] teeth [ka] ,for example [ka] ,for example [ka] is.

[0142] In one more specific embodiment, [ka] teeth, [ka] , [ka] and [ka] In another more specific embodiment, [ka] teeth, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] In another more specific embodiment, [ka] teeth, [ka] , [ka] , [ka] , and [ka] In another more specific embodiment, [ka] teeth, [ka] and [ka] At least one selected from:

[0143] R D : In one embodiment, R D is a drug molecule, eg a cytotoxic agent, eg a chemotherapeutic agent, eg somatostatin, eg a toxin, eg a radioisotope, eg an oligonucleotide chain.

[0144] In one embodiment, the oligonucleotide strand is a single-stranded oligonucleotide. In another embodiment, the oligonucleotide strand is a double-stranded oligonucleotide.

[0145] In one embodiment, M2 is linked to the 5'-end of at least one strand of the oligonucleotide strands by a phosphoester bond. In another embodiment, M2 is linked to the 3'-end of at least one strand of the oligonucleotide strands by a phosphoester bond. In another embodiment, M2 is linked to any nucleotide from the 5'-end to the 3'-end of at least one strand of the oligonucleotide strands by a phosphoester bond. In another embodiment, M2 is linked to the sense strand of the oligonucleotide strands by a phosphoester bond. In another embodiment, M2 is linked to the antisense strand of the oligonucleotide strands by a phosphoester bond.

[0146] In one embodiment, the phosphate bond is a phosphodiester bond. In another embodiment, the phosphate bond is a modified phosphate bond, e.g., a thio-modified phosphate bond, e.g., an amino-modified phosphate bond.

[0147] d: In one embodiment, d is 1. In another embodiment, d is 2.

[0148] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof in M1 can be combined with R1, R2, PG1, PG2, R p , PG3, R, R', R3, M1, M2, M 3a , M 3b , Y1, R6, R7, n1, n2, n3, R4, R D , d, Link1, Link2, Link3, Link4, and L, or any combination thereof. The present invention is intended to include all combinations of these technical solutions, but for convenience, they will not be described one by one.

[0149] In a more specific embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: [ka]

[0150] (where, M1 is independently at least one selected from -O-, -S-, -NR6-, -CHR7-, -C(O)-, -S(O)-, and -S(O)2-; R1 is an asialoglycoprotein receptor (ASGPR) ligand residue; R2 is hydroxy, carboxy, -OR p ,-OPG2, [ka] , and [ka] At least one selected from PG1 is a carboxy protecting group, PG2 is a hydroxy protecting group, R p teeth, [ka] and PG3 is independently selected from a phosphate protecting group; R and R' are each independently an amino protecting group, or R and R' together with the N atom to which they are attached optionally form a 5- to 10-membered heterocyclyl; R3 is independently [ka] and M 3aare independently a chemical bond, -O-, -S-, -NR6-, -CHR7-, -C(O)-, or -S(O) 1~2 -, -NR6C(O)-, -C(O)NR6-, -NR6S(O) 1~2 -, -S(O) 1~2 NR6-, -OC(O)-, -C(O)O-, -OS(O) 1~2 - and -S(O) 1~2 O-, M 3b are independently -O-, -S-, -NR6-, -CHR7-, -CH=CH-, -C≡C-, -C(O)-, -S(O) 1~2 -, -C(O)NR6-, -NR6C(O)-, -OC(O)-, -C(O)O-, -S(O) 1~2 O-Y1-, -OS(O) 1~2 -Y1-, -OS(O) 1~2 O-, -S(O) 1~2 NR6-Y1-, -NR6S(O) 1~2 -Y1-, C 6~10 arylene, 5- to 10-membered heteroarylene, [ka] , [ka] , and [ka] At least one selected from Y1 independently represents C 6~10 arylene or 5- to 10-membered heteroarylene; R6 is independently H, C 1~10 Alkyl, C 1~10 Haloalkyl, C 3~10 at least one selected from cycloalkyl and 3- to 10-membered heterocyclyl; R7 is independently H, halogen, -C≡N, -NO2, C 1~10 Alkyl, C1~10 Haloalkyl, C 3~10 Cycloalkyl, 3-10 membered heterocyclyl, C 6~10 and at least one selected from aryl, and 5- to 10-membered heteroaryl, wherein one or more methylenes in the alkyl or haloalkyl are optionally and independently selected from -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -S-(CH2) 0~6 -S-, -NR6-, C 6~10 Arylene, 5- to 10-membered heteroarylene, -CH=CH-, -C≡C-, and -O-(CH2) 1~6 -O-, n2 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n3 is independently 1, 2, 3, 4, 5, or 6; R4 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, and C 1~6 at least one selected from alkoxy; Link1, Link2, Link3, and Link4 are each independently C 1~25 A straight chain alkylene, wherein one or more methylenes in said straight chain alkylene are optionally and independently replaced by R*, and R* is independently -O-, -S-, -NR6-, -CHR7-, -C(O)-, -S(O) 1~2 -, -NR6C(O)-, -C(O)NR6-, -NR6S(O) 1~2 -, -S(O) 1~2 NR6-, -OC(O)-, -C(O)O-, -OS(O) 1~2 - and -S(O) 1~2 O-, m1, m2, and m3 are each independently 1, 2, 3, 4, or 5; However, in Link 4, the methylene connected to the carbonyl on the left side is not replaced by R*. In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein M1 is independently at least one selected from -O-, -S-, -NH-, -CH2-, -C(O)-, -S(O)-, and -S(O)2-, preferably at least one selected from -O-, -S-, and -NH-, preferably -O-.

[0151] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R1 is independently a residue of the following structure: D-mannopyranose, L-mannopyranose, L-arabinose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose. , β-D-mannopyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, β-D-fructofuranose, α-D-fructopyranose, β-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoromethyl N-acetylgalactosamine, N-propionylgalactosamine, Nn-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose, N-glycolyl-α-neuramine and at least one selected from the group consisting of methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside, 5-thio-β-D-galactopyranose, methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside, 2,5-anhydro-D-allosenitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose.

[0152] Preferably, R1 is independently at least one selected from the following residues: D-galactose, L-galactose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, Nn-butyrylgalactosamine, N-isobutyrylgalactosamine, and β-D-galactopyranose, preferably at least one selected from galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, Nn-butyrylgalactosamine, and N-isobutyrylgalactosamine, preferably N-acetylgalactosamine.

[0153] Preferably, R1 is [ka] is.

[0154] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2 is hydroxy, carboxy, -OR p ,-OPG2, [ka] , and [ka] At least one selected from, preferably, -OR p [ka] , and [ka] At least one selected from, preferably [ka] and [ka] or preferably R2 is at least one selected from [ka] , [ka] , and [ka] At least one selected from, preferably [ka] or [ka] , preferably [ka] or [ka] is.

[0155] Preferably, [ka] teeth, [ka] or [ka] , preferably [ka] is.

[0156] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein PG is C 1~6 Alkyl, benzyl, allyl, [ka] , and [ka] where R 2s are independently H, halogen, C 1~10 Alkyl, and C 1~10 haloalkyl; and q is 0, 1, 2, 3, 4, or 5.

[0157] Preferably, PG1 is methyl, t-butyl, benzyl, allyl, [ka] , and [ka] At least one selected from, preferably [ka] and [ka] At least one selected from, preferably [ka] is.

[0158] Preferably, R 2s are independently H, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl, preferably H or halogen, preferably -F, and preferably PG1 is [ka] is.

[0159] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein PG2 is trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), At least one selected from benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc), benzyl (Bn), p-methoxybenzyl (PMB), allyl, dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), and p-methoxybenzyloxymethyl (PMBM).

[0160] Preferably, PG2 is at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4"-trimethoxytrityl (TMTr), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS), preferably at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), and 4,4',4"-trimethoxytrityl (TMTr), preferably 4,4'-dimethoxytrityl (DMTr).

[0161] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein PG is independently 2-cyanoethyl and C 1~6 At least one selected from alkyl, preferably 2-cyanoethyl, and at least one selected from methyl, preferably 2-cyanoethyl.

[0162] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R and R′ are each independently selected from the group consisting of C 1~6 Alkyl, preferably isopropyl.

[0163] In a more specific embodiment, the present invention provides compounds of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R and R′ together with the N atom to which they are attached optionally form a 5- to 6-membered heterocyclyl.

[0164] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R p teeth [ka] is.

[0165] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein M 3a are independently a chemical bond, -O-, -S-, -NR6-, -CHR7-, -C(O)-, or -S(O) 1~2 -, -NHC(O)-, -C(O)NH-, -NHS(O) 1~2 -, -S(O) 1~2 NH-, -OC(O)-, -C(O)O-, -OS(O) 1~2 - and -S(O) 1~2 At least one selected from -O-, preferably at least one selected from a chemical bond, -O-, -S-, -NR6-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, and -C(O)O-, preferably at least one selected from a chemical bond, -NHC(O)-, -C(O)NH-, -OC(O)-, and -C(O)O-, preferably at least one selected from a chemical bond, -NHC(O)-, and -C(O)NH-, preferably a chemical bond or -C(O)NH-.

[0166] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein M 3b are independently -O-, -S-, -NR6-, -CHR7-, -CH=CH-, -C≡C-, -C(O)-, -S(O) 1~2 -, -C(O)NH-, -NHC(O)-, -OC(O)-, -C(O)O-, -S(O) 1~2 O-Y1-, -OS(O) 1~2 -Y1-, -OS(O) 1~2 O-, -S(O)1~2 NH-Y1-, -NHS(O) 1~2 -Y1-, phenylene, 5- to 6-membered heteroarylene, [ka] , [ka] , and [ka] At least one selected from:

[0167] Preferably, M 3b each independently represents -O-, -S-, -NR6-, -CHR7-, -CH=CH-, -C≡C-, -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -C(O)O-, -OS(O)2-Y1-, -OS(O)2O-, -NHS(O)2-Y1-, 5- to 6-membered heteroarylene, [ka] , [ka] , and [ka] at least one selected from, preferably at least one selected from -C(O)NH-, -NHC(O)-, -OC(O)-, and -C(O)O-, preferably -C(O)NH- or -NHC(O)-, preferably -NHC(O)-.

[0168] Preferably, M 3b The 5- to 6-membered heteroarylene as [ka] or [ka] is.

[0169] Preferably, Y1 is independently phenylene or 5- to 6-membered heteroarylene, preferably phenylene, preferably [ka] is.

[0170] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: [ka] has the following structure: [ka] At least one selected from:

[0171] Preferably, it is at least one selected from A2, A3, A4, A6, and A9, preferably at least one selected from A2, A3, and A9, preferably A3 or A9.

[0172] In a more specific embodiment, the present invention provides compounds of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein each R6 is independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~7 At least one selected from cycloalkyl and 3- to 7-membered heterocyclyl, preferably H, C 1~6 Alkyl, and C 1~6at least one selected from haloalkyl, preferably H, -CH3, [ka] , [ka] and [ka] At least one selected from the following is more preferably H.

[0173] In a more specific embodiment, the present invention provides compounds of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein each R7 is independently H, halogen, —C≡N, C 1~6 Alkyl, C1-6 haloalkyl, C 3~7 At least one selected from cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, preferably H, halogen, —C≡N, C 1~6 At least one selected from alkyl, and C haloalkyl, preferably H, halogen, C 1~6 alkyl, and C1-6 haloalkyl.

[0174] Preferably, one or more methylenes in the alkyl or haloalkyl as R7 are optionally and independently -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -S-(CH2) 0~3 -S-, -NR6-, phenylene, 5- to 6-membered heteroarylene, -CH=CH-, -C≡C-, and -O-(CH2) 1~3 At least one selected from -O-, preferably -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -SS-, -NR6-, [ka] , [ka] , -CH=CH-, -C≡C-, and -O-(CH2)2-O-.

[0175] Preferably, the halogen as R7 is -F, -Cl, or -Br.

[0176] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein n2 is independently 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, or 3, preferably 0 or 3.

[0177] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein n3 is independently 1, 2, or 3, preferably 2.

[0178] In a more specific embodiment, the present invention provides compounds of formula (I) above, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R4 is H, C 1~5 Alkyl, C 1~5 Haloalkyl, and C 1~5 At least one selected from alkoxy, preferably H, C 1~3 Alkyl, and C 1~3 At least one selected from haloalkyl, preferably H.

[0179] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Link1, Link2, and Link3 are each independently C 1~10 Linear alkylene, preferably C 1~6Linear alkylene, preferably C 4~6 It is a straight chain alkylene, preferably -(CH2)4- or -(CH2)6-.

[0180] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Link4 is C 1~20 Linear alkylene, preferably C 1~17 Linear alkylene, preferably C 1~10 Linear alkylene, preferably C 3~20 Linear alkylene, preferably C 3~17 Linear alkylene, preferably C 3~10 It is a straight chain alkylene.

[0181] Preferably, one or more methylenes in the linear alkylene as Link4 are preferably 1, 2 or 3 methylenes, and preferably one methylene is optionally and independently replaced by R*.

[0182] Preferably, R* is independently at least one selected from —O—, —NR—, —CHR—, —C(O)—, —NRC(O)—, —C(O)NR—, —OC(O)—, and —C(O)O—, preferably at least one selected from —C(O)NH—, —NHC(O)—, —C(O)O—, and —OC(O)—, preferably at least one selected from —C(O)NH— and —C(O)O—, preferably at least one selected from —C(O)NH— and —NHC(O)—, preferably —C(O)NH—.

[0183] Preferably, 1 to 15 methylenes, preferably 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 1 to 3 methylenes, preferably 3 to 10 methylenes are present between R* and the carbonyl on the left side of Link4.

[0184] Between R and R2, 1 to 12 methylenes, preferably 1 to 10 methylenes, and preferably 1 to 6 methylenes are present.

[0185] Preferably, Link4 is -(CH2)3-, -(CH2) 10 -, -(CH2)3-C(O)NH-(CH2)6-, and -(CH2) 10 At least one selected from -C(O)NH-(CH2)6-, preferably -(CH2)3-, -(CH2) 10 - and -(CH2)3-C(O)NH-(CH2)6-, preferably -(CH2)3- or -(CH2) 10 - or preferably Link4 is -(CH2) 10 -, -(CH2)3-C(O)NH-(CH2)6-, and -(CH2) 10 At least one selected from -C(O)NH-(CH2)6-, preferably -(CH2) 10 -or-(CH2) 10 -C(O)NH-(CH2)6-.

[0186] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein m1, m2, and m3 are each independently 1, 2, or 3, preferably 1.

[0187] In a more specific embodiment, the present invention provides a compound of formula (I) above, having the following structural formula: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof: [ka] ,

[0188] (where, n2 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; The remaining groups are as defined herein. In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: R2 is hydroxy, carboxy, -OR p ,-OPG2, [ka] , and [ka] At least one selected from PG1 is a carboxy protecting group, preferably methyl, t-butyl, benzyl, allyl, [ka] , and [ka] At least one selected from R 2s are independently H, halogen, C 1~6 Alkyl, and C 1~6 haloalkyl; q is 0, 1, 2, 3, 4, or 5; PG2 is a hydroxy protecting group, preferably at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4"-trimethoxytrityl (TMTr), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS); R p teeth [ka] and PG3 is independently selected from phosphate protecting groups, preferably selected from 2-cyanoethyl and methyl, more preferably 2-cyanoethyl; R and R' are each independently an amino protecting group, preferably C 1~6 alkyl, preferably isopropyl; M 3a is at least one selected from a chemical bond, —NHC(O)—, —C(O)NH—, —OC(O)—, and —C(O)O—, preferably at least one selected from a chemical bond, —NHC(O)—, and —C(O)NH—; n1 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n2 is independently 0, 1, 2, 3, 4, 5, or 6; n3 is independently 1, 2, 3, 4, 5, or 6; m1, m2, and m3 are each independently 1, 2, 3, 4, or 5; Link4 is C 1~25 linear alkylene, preferably C 20 linear alkylene, wherein one, two, or three methylenes in said linear alkylene are optionally and independently replaced by R*, wherein R* is independently at least one selected from —C(O)NH—, —NHC(O)—, —C(O)O—, and —OC(O)—, preferably at least one selected from —C(O)NH— and —NHC(O)—; However, in Link 4, the methylene connected to the carbonyl on the left side is not replaced by R*. In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: R2 is -OR p , [ka] , and [ka] At least one selected from, preferably [ka] , [ka] , and [ka] At least one selected from, preferably [ka] or [ka] and PG1 is [ka] and [ka] At least one selected from R 2s are independently H or halogen, preferably —F; q is 0, 1, 2, 3, 4, or 5; PG2 is at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), and 4,4',4"-trimethoxytrityl (TMTr), preferably 4,4'-dimethoxytrityl (DMTr); R p teeth [ka] and PG3 is 2-cyanoethyl, R and R' are each independently C 1~4 alkyl, preferably isopropyl; M 3a is a chemical bond or -C(O)NH-, n1 is independently 4, 5, or 6; n2 is independently 0, 1, 2 or 3; n3 is independently 1 or 2; m1, m2, and m3 are each independently 1, 2, or 3, preferably 1; Link4 is C 1~17 linear alkylene, preferably C 1~10 and straight chain alkylene, wherein one methylene in said straight chain alkylene is optionally replaced by R*, and R* is -C(O)NH-.

[0189] Preferably, 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 1 to 3 methylenes are present between R* and the carbonyl on the left side of Link4, Between R* and R2, 1 to 12 methylenes, preferably 1 to 10 methylenes, and preferably 1 to 6 methylenes are present.

[0190] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: R2 is [ka] , [ka] , and [ka] At least one selected from, preferably [ka] or [ka] and M 3a is a chemical bond or -C(O)NH-, n1 is independently 4 or 6; n2 is independently 0 or 3; n3 is 2, m1, m2, and m3 are all 1; Link4 is -(CH2)3-, -(CH2) 10 -, -(CH2)3-C(O)NH-(CH2)6- or -(CH2) 10 -C(O)NH-(CH2)6-, preferably -(CH2)3-, -(CH2) 10 - and -(CH2)3-C(O)NH-(CH2)6-, preferably -(CH2)3- or -(CH2) 10 -It is.

[0191] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein said compound is at least one selected from the following: [ka] [ka] [ka] [ka] [ka] In a more specific embodiment, the present invention provides a conjugate having the structure shown in formula (III): [ka]

[0192] (where, L is a structure represented by formula (I') or formula (II'), [ka] , [ka] [ka] teeth, [ka] , [ka] , [ka] , and [ka] At least one selected from, preferably [ka] , [ka] , and [ka] At least one selected from, preferably [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , and [ka] At least one selected from, preferably [ka] , [ka] , [ka] , and [ka] At least one selected from, preferably [ka] and [ka] At least one selected from R D are drug molecules, said drug molecules independently selected from a cytotoxic agent, a chemotherapeutic agent, somatostatin, a toxin, a radioisotope, and an oligonucleotide chain; d is 1 or 2, preferably 1; The remaining groups are as defined herein. Preferably, Link4 is C 5~25 Linear alkylene, preferably C 5~20 Linear alkylene, preferably C 8~20 Linear alkylene, preferably C 10~17 straight chain alkylene.

[0193] Preferably, the one or more methylenes in Link4 are preferably one, two or three methylenes, and preferably one methylene is optionally and independently replaced by R*, where R* is independently at least one selected from —C(O)NH—, —NHC(O)—, —C(O)O—, and —OC(O)—, preferably at least one selected from —C(O)NH— and —C(O)O—, preferably at least one selected from —C(O)NH— and —NHC(O)—, preferably —C(O)NH—.

[0194] Preferably, 1 to 15 methylenes, preferably 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 3 to 10 methylenes are present between R* and the carbonyl on the left side of Link4; Between R* and R2, 1 to 12 methylenes, preferably 1 to 10 methylenes, and preferably 1 to 6 methylenes are present.

[0195] Preferably, Link4 is -(CH2) 10 -, -(CH2)3-C(O)NH-(CH2)6-, and -(CH2) 10 At least one selected from -C(O)NH-(CH2)6-, preferably -(CH2) 10 -or-(CH2) 10 -C(O)NH-(CH2)6-.

[0196] In a more specific embodiment, the present invention provides a conjugate of formula (III) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R D is an oligonucleotide strand, optionally said oligonucleotide strand is a single-stranded oligonucleotide, a double-stranded oligonucleotide or a composition thereof.

[0197] Preferably, M2 is linked by a phosphate ester bond to any nucleotide at the 5'-end, 3'-end, or from the 5'-end to the 3'-end of at least one strand of the oligonucleotide chain, preferably to the 5'-end or 3'-end of at least one strand, preferably to the 5'-end of at least one strand, preferably to the 3'-end of at least one strand.

[0198] Preferably, M2 is linked to the sense strand of said oligonucleotide strand by a phosphate bond.

[0199] Preferably, said phosphate ester bond is a phosphodiester bond or a modified phosphate ester bond, preferably a phosphodiester bond, and preferably said modified phosphate ester bond is selected from a thio-modified phosphate ester bond and / or an amino-modified phosphate ester bond, preferably a thio-modified phosphate ester bond.

[0200] Preferably, the [ka] teeth, [ka] , [ka] , [ka] , and [ka] At least one structure selected from, preferably [ka] , [ka] , [ka] , [ka] , [ka] , [ka] and [ka] At least one structure selected from, preferably [ka] , [ka] , [ka] , and [ka] and at least one structure selected from: [ka] represents an oligonucleotide chain.

[0201] In a more specific embodiment, the present invention provides a conjugate of formula (III) above, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein said oligonucleotide strand comprises unmodified nucleotides and / or modified nucleotides.

[0202] Preferably, the modified nucleotides are each independently at least one selected from 2'-methoxyethyl-modified nucleotides, 2'-O-alkyl-modified nucleotides, 2'-O-allyl-modified nucleotides, 2'-C-allyl-modified nucleotides, 2'-fluoro-modified nucleotides, 2'-deoxy-modified nucleotides, 2'-hydroxy-modified nucleotides, thiophosphorylated backbone-modified nucleotides, locked nucleotide-modified nucleotides, glycol nucleic acid (GNA)-modified nucleotides, and unlocked nucleic acid (UNA)-modified nucleotides, and preferably at least one selected from 2'-O-alkyl-modified nucleotides, 2'-fluoro-modified nucleotides, 2'-deoxy-modified nucleotides, and thiophosphorylated backbone-modified nucleotides.

[0203] Preferably, the 2'-O-alkyl is 2'-OC 1~6 Alkyl, preferably 2'-O-methyl.

[0204] Preferably, the length of the oligonucleotide chain is 5-100 bp.

[0205] In a more specific embodiment, the present invention provides a conjugate of formula (III) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the oligonucleotide strand is an siRNA, an ASO, or a microRNA, preferably an siRNA.

[0206] In a more specific embodiment, the present invention provides a conjugate of formula (III) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the oligonucleotide chain comprises a terminal modification selected from cholesterol, polyethylene glycol, a fluorescent probe, biotin, a polypeptide, a vitamin, or a tissue-targeting molecule, or a combination thereof.

[0207] In a more specific embodiment, the present invention provides a conjugate of formula (III) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the ribose-phosphate backbone of the oligonucleotide chain is replaced by a polypeptide nucleic acid (PNA) or a morpholine ring antisense nucleotide (PMO).

[0208] In a more specific embodiment, the present invention provides a conjugate of formula (III) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein L is [ka] [ka] L2, [ka] L3, [ka] Selected from the L4 structure, Preferably, [ka] [ka] [ka] L4.

[0209] In a more specific embodiment, the present invention provides a conjugate of formula (III) above, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein said conjugate is at least one selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] Z6, [ka] [ka] [ka] In a more specific embodiment, the present invention also provides a pharmaceutical composition comprising a conjugate of the present invention, optionally a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, and optionally other therapeutic agents.

[0210] In a more specific embodiment, the present invention also provides the use of a conjugate of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament for treating or preventing a disease associated with the expression or overexpression of a gene in liver cells.

[0211] In a more specific embodiment, the present invention also provides a method for treating or preventing a disease associated with the expression or overexpression of a gene in hepatocytes in a subject, comprising administering to said subject a conjugate of the present invention or a pharmaceutical composition of the present invention.

[0212] In a more specific embodiment, the present invention also provides the conjugate of the present invention or the pharmaceutical composition of the present invention for use in treating or preventing a disease associated with the expression or overexpression of a gene in liver cells.

[0213] In a more specific embodiment, the gene is selected from the HBV genome, HCV genome, PCSK9, xanthine oxidase, URAT1, APOB, liver fibrosis-related genes (AP3S2, AQP2, AZINI, DEGSI, STXBP5L, TLR4, TRPM5), non-alcoholic fatty liver disease-related genes (PNPLA3, FDFT1) or primary biliary cirrhosis-related genes (HLA-DQB1, IL-12, IL-12RB2), or a combination thereof.

[0214] In more specific embodiments, the disease is at least one selected from hereditary angioedema, familial tyrosinemia type 1, Alagille syndrome, alpha-1-antitrypsin deficiency, disorders of bile acid synthesis metabolism, biliary atresia, cystic fibrosis liver disease, idiopathic neonatal hepatitis, mitochondrial liver disease, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, transthyretin amyloidosis, hemophilia, homozygous familial hypercholesterolemia, hyperlipidemia, hepatitis B (HBV), hepatitis C (HCV), steatohepatitis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), diseases associated with hyperglycemia or abnormally increased hepatic glucose production resembling type 1 or type 2 diabetes, hepatitis, and hepatic porphyria.

[0215] In a more specific embodiment, the present invention also provides compounds of formula (C): [ka]

[0216] (where PG2 and PG4 are protection groups.) Preferably, PG2 is a hydroxy protecting group and PG4 is an amino protecting group.

[0217] Preferably, the PG2 is at least one selected from trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS), preferably t-butyldimethylsilyl (TBDMS); Preferably, the PG4 is at least one selected from benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), methoxycarbonyl, and ethoxycarbonyl, preferably t-butoxycarbonyl (Boc).

[0218] In a more specific embodiment, the present invention also provides a method for preparing a compound of formula (C), comprising reacting compound A with compound B to produce compound C. [ka]

[0219] (wherein PG2 and PG4 are as defined in the present invention.) Preferably, the reaction conditions of the method include a condensing agent and a base.

[0220] Preferably, the condensing agent is at least one selected from a carbodiimide-based condensing agent, an onium salt-based condensing agent, and an organic phosphorus-based condensing agent.

[0221] Preferably, the reaction conditions further comprise a condensation activator.

[0222] Preferably, the reaction conditions further comprise a solvent.

[0223] Preferably, the method is carried out in a nitrogen atmosphere.

[0224] Preferably, the base is an organic amine base, preferably at least one of DIEA (N,N-diisopropylethylamine), TEA (triethylamine), NMM (N-methylmorpholine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DMAP (4-dimethylaminopyridine), pyridine, 2,6-dimethylpyridine, and 2,2,6,6-tetramethylguanidine, preferably DIEA.

[0225] Preferably, the carbodiimide-based condensing agent is at least one selected from DCC (N,N'-dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), and EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), and preferably EDCI.

[0226] Preferably, the onium salt condensing agent is at least one selected from HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HCTU (O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), BOP (Carter condensing agent), and PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate).

[0227] Preferably, the organophosphorus condensing agent is at least one selected from DPP-Cl (diphenylphosphinic chloride), DPPA (diphenylphosphoric azide), and BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphoryl chloride).

[0228] Preferably, the condensation activator is at least one selected from DMAP (4-dimethylaminopyridine), HOBt (1-hydroxybenzotriazole), and HOAt (N-hydroxy-7-benzotriazole), preferably HOBt.

[0229] Preferably, the solvent is at least one selected from DCM (methylene chloride), DCE (1,2-dichloroethane), DMF (N,N-dimethylformamide), DMAC (N,N-dimethylacetamide), tetrahydrofuran, and 2-methyltetrahydrofuran, preferably DCM.

[0230] Preferably, the molar ratio of compound A:compound B is (0.5-3):1, preferably (1-2):1, preferably (1-1.5):1, preferably 1.1:1.

[0231] Preferably, the molar ratio of condensing agent:compound B is (1-3):1, preferably (1-2):1, preferably (1-1.5):1, preferably 1.2:1.

[0232] Preferably, the molar ratio of condensation activator:compound B is (1-3):1, preferably (1-2):1, preferably (1.2-1.8):1, preferably 1.5:1.

[0233] Preferably, the molar ratio of base:compound B is (0.5-5):1, preferably (1-4):1, preferably (1-3):1, preferably 2:1.

[0234] Preferably, the process is carried out at a temperature of about -20°C to about 50°C, preferably about -10°C to about 25°C, preferably about -10°C to about 0°C.

[0235] In a more specific embodiment, the present invention also provides compounds of formula (D): [ka] In a more specific embodiment, the present invention also provides a method for preparing a compound of formula (D), comprising the step of removing a protecting group from said compound C of the present invention to obtain compound D. [ka]

[0236] (wherein PG2 and PG4 are as defined in the present invention.) Preferably, the process is carried out under acidic conditions.

[0237] Preferably, the reaction conditions of the method include an acid and a solvent.

[0238] Preferably, the acid is HCl and / or H2SO4, preferably HCl.

[0239] Preferably, the solvent is an organic solvent, preferably an alcoholic solvent, preferably at least one selected from methanol, ethanol, propanol, butanol, isopropanol, cyclohexanol, 2-methyl-2-propanol, and 2-ethyl-1-propanol, preferably methanol.

[0240] Preferably, the concentration of HCl in the reaction system is 0.1 mol / L to 3 mol / L, preferably 0.2 mol / L to 2 mol / L, preferably 0.5 mol / L to 1.5 mol / L, preferably 0.5 mol / L to 1.0 mol / L, preferably 0.75 mol / L.

[0241] Preferably, the method is carried out in a nitrogen atmosphere.

[0242] Preferably, the process is carried out at a temperature of about -20°C to about 50°C, preferably about -10°C to about 25°C, preferably about -10°C to about 0°C.

[0243] The compounds of the present invention or conjugates of the present invention may contain one or more asymmetric centers and therefore may exist in multiple stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis.

[0244] The compounds of the present invention or the conjugates of the present invention may exist in tautomeric forms. Tautomers are functional group isomers that arise from the rapid movement of an atom in a molecule between two positions, and tautomers are isomers of a specific functional group. Tautomer pairs can be interconverted, but the more stable isomer usually predominates.

[0245] Pharmaceutical compositions, formulations, and kits The present invention provides pharmaceutical compositions comprising a compound or conjugate of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0246] The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound or conjugate incorporated therein. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, a partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol alcohol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0247] The present invention also includes kits (e.g., pharmaceutical packages). The provided kits include a compound of the invention, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other suitable containers) containing the compound of the invention and the other therapeutic agent. In some embodiments, the provided kits may optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or the other therapeutic agent. In some embodiments, the compound of the invention and the other therapeutic agent provided in the first and second containers are combined to form a unit dosage form.

[0248] The pharmaceutical compositions of the present invention can be administered by many routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, via implants, or other methods of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intracerebrospinal, intralesional, and intracranial injection or infusion techniques.

[0249] Generally, an effective amount of the compound provided herein is administered. The amount of the compound actually administered can be determined by a doctor depending on the condition to be treated, the selected administration route, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient, and other factors.

[0250] When used to prevent the conditions described herein, the compounds provided herein are typically administered under the advice and supervision of a physician at the dosage levels described above to subjects at risk of developing the condition. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or subjects who have been determined by genetic testing or screening to be susceptible to developing the condition.

[0251] The pharmaceutical compositions provided herein can also be administered for extended periods of time ("long-term administration"). Long-term administration means that the compound or pharmaceutical composition thereof can be administered for extended periods of time, such as, for example, 3 months, 6 months, 1 year, 2 years, 3 years, and 5 years, or can be administered continuously indefinitely, such as for the remaining life of the subject. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood for an extended period of time, e.g., within a therapeutic range.

[0252] Various administration methods can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered as a bolus injection, e.g., to rapidly increase the concentration of the compound in the blood to an effective level. The amount of the bolus dose depends on the target systemic level of the active ingredient. For example, an intramuscular or subcutaneous bolus dose will slowly release the active ingredient, whereas a bolus dose delivered directly into a vein (e.g., via IV infusion) will release and deliver the active ingredient more rapidly, quickly increasing the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, e.g., via IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered initially, followed by a continuous infusion.

[0253] The transdermal dose is selected to provide a blood concentration equivalent to or lower than that of an injection dose, and is about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0254] For about 1 to about 120 hours, particularly 24 to 96 hours, injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain more stable levels, a pre-bolus of about 0.1 mg / kg to about 10 mg / kg or more may be given. For a 40-80 kg human patient, the maximum total dose should not exceed about 2 g / day.

[0255] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As noted above, in such compositions, the active compound is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0256] The foregoing components of compositions for injection or topical administration are merely representative. Other materials and processing techniques are described in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0257] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials is found in Remington's Pharmaceutical Sciences.

[0258] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention, hi one embodiment, the formulation comprises water.

[0259] Drug combinations The compounds or conjugates of the invention described herein can be used in combination with one or more other active ingredients in pharmaceutical compositions or methods for treating the diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or drugs that alleviate or treat side effects of treatment against the intended disease target. Such combinations may be used to enhance the efficacy of the compounds of the invention, ameliorate other disease symptoms, reduce one or more side effects, or reduce the required dosage. The additional active ingredients may be formulated as a pharmaceutical composition separate from the compounds of the invention, or may be included in a single pharmaceutical composition with the compounds of the invention. The additional active ingredients may be administered simultaneously with, before, or after the administration of the compounds of the invention.

[0260] The combination drug includes active ingredients known or observed to be effective in treating the diseases and conditions described herein, including those effective against other targets associated with the disease. For example, the compositions and formulations, and treatment methods of the present invention may further include other drugs, such as other agents useful for treating or ameliorating the target disease or associated symptoms or conditions. The pharmaceutical compositions of the present invention may further include one or more of the activators, and the treatment methods may further include administering an effective amount of one or more of the activators.

[0261] Beneficial effects of the present invention:

[0262] (1) This invention uses serine as a starting material and, through a condensation reaction with serinol, generates a new molecular peptide backbone with the α-carbon atom of serine as a central branch point. The new molecular backbone satisfies the following structural characteristics: (i) It has one central branch structure. (ii) The spacer is based on multiple peptide bond linkers that are both flexible and amphiphilic. (iii) The spacer distance between the central branch structure and the GalNAc group is 20-30 Å. (iv) The length of the spacer can be easily modified.

[0263] (2) The novel three-cluster galactose derivatives of the present invention have superior hydrophilicity and low toxicity. The formed conjugates have high affinity for binding to the ASGPR receptor, with Kd values ​​of less than 10 and sometimes as low as about 2. Compared with negative control siRNAs without GalNAc linkages, the conjugates of the present invention have significantly increased distribution in mouse liver, effectively achieving liver-targeted delivery in vivo and significantly knocking down target gene mRNA expression.

[0264] (3) The present invention is a trivalent GalNAc cluster derivative based on a new scaffold, which is easily synthesized and covalently conjugated to ASOs using a mature phosphoramidite solid-phase synthesis coupling strategy. It is inexpensive and readily available, which can improve the clinical efficacy of ASO drugs without increasing the complexity and cost of existing oligonucleotide drug production methods. It can be efficiently assembled, synthesized, and produced on a large scale using existing raw materials. Example The technical solutions of the present invention are clearly and completely described below with reference to the accompanying drawings, and it is obvious that the described embodiments are only a part of, but not all of, the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts fall within the scope of protection of the present invention.

[0265] Example 1: Synthesis of G1 [ka] [ka]

[0266] Compound 1 (100 g) was dissolved in dry DCM (500 mL), and under ice bath and nitrogen protection, DMAP (1 g) and EtN (5 eq) were added, and TBDMSCl (2.5 eq) was slowly added. After the reaction was completed, the mixture was washed with NaHCO solution and purified by chromatography to obtain compound 2.

[0267] Compound 3 (100 g) was dissolved in anhydrous DMF (500 mL), and imidazole (3.2 eq) was added under ice bath and nitrogen protection. TBDMSCl (1.4 eq) was slowly added. After the reaction was completed, the mixture was washed with saturated NaHCO3 and saturated brine, concentrated, and purified by chromatography to obtain compound 4.

[0268] Compound 4 (50 g) was dissolved in anhydrous DCM (30 mL), and HOBt (1.5 eq) was added under ice bath and nitrogen protection, followed by slow addition of EDCI (1.2 eq). After 20 min of reaction, compound 2 (1.1 eq) was added under ice bath and nitrogen protection, followed by addition of DIEA (2 eq). After completion of the reaction, the mixture was washed successively with saturated NaHCO3, 10% aqueous citric acid solution, and saturated brine, concentrated, and purified by chromatography to obtain compound 5.

[0269] Compound 5 (30 g) was dissolved in MeOH (60 mL), and a solution of HCl in MeOH (20 mL, 3 mol / L) was added under ice bath and nitrogen protection, and the reaction was carried out at room temperature. After completion of the reaction, the mixture was concentrated and washed with ethyl acetate to obtain compound 6.

[0270] Compound 6 (20 g) was dissolved in anhydrous DMSO (100 mL), and NaOH (1.3 eq) was added under ice bath and nitrogen protection. t-Butyl acrylate (6 eq) was slowly added. After the reaction was completed, the solution was washed with EA and saturated brine, concentrated, and purified by chromatography to give compound 7.

[0271] Compound 7 (15 g) was dissolved in anhydrous DCM (300 mL), and under ice bath and nitrogen protection, monomethyl dodecanoate (1.1 eq) and HOBt (1.5 eq) were added, and EDCI (1.2 eq) was slowly added. After reacting for 20 min, DIEA (2 eq) was added, and the mixture was washed successively with saturated NaHCO3, 10% aqueous citric acid, and saturated brine, concentrated, and purified by chromatography to obtain compound 8.

[0272] Compound 8 (15 g) was dissolved in HCOOH (30 mL), and after the reaction was completed, the mixture was concentrated and chromatographed to give compound 9.

[0273] Compound 9 (10 g) was dissolved in dry DMF (60 mL), and HOBt (1.25 eq), EDCI (1.2 eq), and Nt-butoxycarbonyl-1,3-propylenediamine (1.2 eq) were added. DIEA (2 eq) was added under an ice bath and nitrogen protection. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution and 0.5 N hydrochloric acid solution, and then purified by chromatography to obtain compound 10.

[0274] Compound 10 (9.3 g) was dissolved in dry DCM (60 mL), and a solution of HCl in MeOH (20 mL, 2 mol / L) was added under ice bath and nitrogen protection, and compound 11 was obtained upon completion of the reaction.

[0275] N-acetylgalactosamine (15 g) was dissolved in anhydrous DMF (100 mL), and HOBt (1.5 eq) was added under ice bath and nitrogen protection. EDCI (1.2 eq) was slowly added and the reaction was continued for 20 min. DIEA (2 eq) and compound 11 (9.3 g) were added and the reaction was continued. After the reaction was completed, the mixture was washed with saturated NaHCO3, 0.5 N aqueous hydrochloric acid, and saturated brine, concentrated, and purified by chromatography to obtain compound 12.

[0276] Compound 12 (4 g) was dissolved in dry MeOH (20 mL), and NaOMe (30%, MeOH, 3 mL) was added under ice bath and nitrogen protection. After the reaction was completed, the mixture was concentrated to give the crude product. The crude product was added to MeOH / HO and reacted at room temperature. After the reaction was completed, the pH was adjusted to neutral with EtN HCl salt and the mixture was concentrated to give the crude product. Next, the crude product was added to Py (20 mL) and AcO (5 mL) and reacted at room temperature. After the reaction was completed, compound 13 was obtained by chromatography.

[0277] Compound 13 (1 g) was dissolved in DCM (10 mL), EDCI (1.5 eq) and pentafluorophenol (1.5 eq) were added, and after the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution, concentrated, and purified by chromatography to give compound G1 (0.5 g) in a 50% yield.

[0278] 1H NMR (500 MHz, CDCl3) δ:7.61- 7.30 (m, 3H), 5.31-5.19 (m, 3H), 5.03 (d, J = 11.1 Hz, 3H), 4.49 (d, J = 8.3Hz, 3H), 4.15-3.96 (m, 9H), 3.86 (m, 6H), 3.71-3.55 (m, 9H), 3.50-3.39 (m, 12H), 3.16 (m, 6H), 2.59 (t, J=7.6Hz, 2H), 2.35 (dt,J=4.9Hz, 6H), 2.26-2.03 (m, 20H), 2.03 - 1.81 (m, 30H), 1.55 (m, 8H), 1.19 (m, 20H), ESI-Tof -MS m / z:2264.10[M+Cl] - ;C 99 H 150 F5N 11 O 40 .

[0279] Example 2: Synthesis of G2 [ka] Compound G5-11 (2 g) was dissolved in DCM (10 mL), and HBTU (1.2 eq), HOBT (3 eq), DIPEA (3 eq), and proline (1.05 eq) were added. After the reaction was completed at room temperature, the mixture was washed with saturated sodium bicarbonate solution and concentrated to obtain a crude product, which was then purified by chromatography to obtain compound G2-12.

[0280] Compound G2-12 (1 g) was dissolved in anhydrous DCM (10 mL), DIPEA (3 eq) was added, and phosphoramidite monomer (1.5 eq) was added under nitrogen protection at low temperature. After the reaction was completed at room temperature, the mixture was washed with saturated sodium bicarbonate solution, concentrated, and purified by chromatography to give G2 (0.5 g) in a 41% yield.

[0281] 1H NMR (500 MHz, CDCl3) :δ 7.29 (t, J = 7.9 Hz, 2H), 7.24 - 7.06 (m, 10H), 6.91 (s, 1H), 6.78 - 6.69 (m, 6H), 6.62 - 6.41 (m,3H), 5.28 (s, 3H), 5.19 (d, J = 9.2 Hz,3H), 4.61 (s,3H), 4.45 (m, 2H), 4.07 (m, 6H), 3.93 (m, 3H), 3.89 - 3.76 (m, 6H), 3.69 (m, 12H), 3.57 - 3.28 (m, 10H), 3.13 (m, 6H), 3.04 (m, 2H), 2.52 (dd, J = 12.0, 5.7 Hz, 2H), 2.37 (m, 6H), 2.19 (m, 4H), 1.99 (m, 36H), 1.72 (m, 16H), 1.60 - 1.36 (m, 16H), 1.34 - 0.93 (m, 22H); 31 PNMR (202MHz, CDCl3) δ: 147.37,(s). ESI-Tof-MS m / z:2491.25[MH] - ;C 122 H 186 N 11 O 41 P.

[0282] Example 3: Synthesis of G3 [ka] [ka] Compound G4-11 (2 g) was dissolved in DCM (10 mL), EDCI (1.5 eq) was added, HOBT (2 eq), DIPEA (3 eq), and compound b (1.2 eq) were added, and the reaction was completed at room temperature. After completion of the reaction, the mixture was washed with saturated sodium bicarbonate solution, concentrated, and purified by chromatography to give G3-12 (1.5 g).

[0283] Compound G3-12 (2 g) was dissolved in THF (20 mL), triethylamine trihydrofluoride (1.5 eq) was added, and the reaction was completed at room temperature. After concentration, the mixture was washed with DCM and saturated sodium bicarbonate solution, concentrated, and purified by chromatography to give G3-13 (1.3 g).

[0284] Compound G3-13 (1.2 g) was dissolved in anhydrous DCM (10 mL), DIPEA (3 eq) was added, and under nitrogen protection at low temperature, phosphoramidite monomer (1.5 eq) was added. After the reaction was completed at room temperature, the mixture was washed with saturated sodium bicarbonate solution, concentrated, and purified by chromatography to give compound G3 (0.6 g) in a 46% yield.

[0285] 1 H NMR (500 MHz, CDCl3) :δ 7.16 (s, 1H), 7.04 (t, J = 14.7 Hz, 2H), 6.83 (d, J = 5.5 Hz, 2H), 6.69 (d, J = 5.7 Hz, 1H), 6.56 (d, J = 8.8 Hz, 2H), 6.42 (s, 1H), 5.35 (d, J = 2.5 Hz, 3H), 5.30 - 5.23 (m, 3H), 4.68 (d, J = 8.3 Hz, 3H), 4.21 - 4.06 (m, 8H), 3.99 (dd, J = 19.4, 8.8 Hz, 3H), 3.94 - 3.83 (m, 6H), 3.63 (m, 6H), 3.46 (dd, J = 15.8, 6.6 Hz, 4H), 3.34 - 3.16 (m, 16H), 2.68 (t, J = 7.3 Hz, 2H), 2.42 (t, J = 5.2 Hz, 6H), 2.33-2.22 (m, 4H), 2.21-1.88 (m, 38H), 1.79 (m, 14H), 1.63 - 1.43 (m, 18H), 1.30 (d, J = 43.5 Hz, 12H); 31 P NMR (202MHz, CDCl3) δ: 147.37,(s). ESI-Tof-MS m / z:2033.40[MH] - ;C 93 H156 N 11 O 36 P.

[0286] Example 4: Synthesis of G4 [ka] [ka] Compound 7 (25 g) was dissolved in anhydrous DCM (50 mL), and Na2CO3 (200 mL, 25% aqueous solution) was added under ice bath and nitrogen protection. CbzCl (2 eq) was slowly added. After the reaction was completed, the mixture was washed with saturated brine, concentrated, and purified by chromatography to give G4-8 (30 g).

[0287] Compound G4-8 (8 g) was dissolved in HCOOH (30 mL), and after the reaction was completed, the mixture was concentrated and chromatographed to give G4-9 (5 g).

[0288] Compound G4-9 (8 g) was dissolved in anhydrous DCM (50 mL), and HOBt (3.3 eq) was added under ice bath and nitrogen protection. EDCI (3.3 eq) was slowly added and the mixture was allowed to react for 20 min. N-acetylgalactosamine (3.3 eq) and DIEA (6 eq) were added. After the reaction was completed, the mixture was washed with saturated NaHCO3, 0.5 mol / L hydrochloric acid solution, and saturated brine, concentrated, and purified by chromatography to give G4-10 (6.4 g).

[0289] Compound G4-10 (3 g) was dissolved in anhydrous THF (50 mL), succinic anhydride (1.5 eq) was added, and 10% Pd / C (1 g) was slowly added. After the reaction was completed in a hydrogen atmosphere, the mixture was filtered, concentrated, and chromatographed to give G4-11 (2.5 g).

[0290] Compound G4-11 (1 g) was dissolved in DCM (10 mL), and EDCI (1.5 eq) and pentafluorophenol (1.5 eq) were added. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution, concentrated, and purified by chromatography to give G4 (0.5 g) in a 40% yield.

[0291] 1 H NMR (500MHz, CDCl3):δ 7.29 - 7.20 (m, 2H), 7.11 (m, 1H), 6.91 - 6.68 (m, 3H), 6.56 - 6.39 (m, 2H), 5.34 (d, J = 2.5 Hz, 3H), 5.25 (d, J = 11.1 Hz, 3H), 4.66 (d, J = 8.3 Hz, 3H), 4.71 - 4.50 (m, 2H), 4.13 (tt, J = 18.0, 8.9 Hz, 6H), 3.98 (dd, J = 18.4, 9.2 Hz, 3H), 3.88 (ddd, J = 15.5, 11.8, 6.3 Hz, 6H), 3.79 - 3.63 (m, 6H), 3.56 - 3.35 (m, 9H), 3.21 (td, J = 12.5, 6.2 Hz, 6H), 2.76 (t, J = 7.3 Hz, 2H), 2.43 (dd, J = 15.3, 7.7 Hz, 8H), 2.19-1.86 (m, 38H), 1.62-1.42 (m, 12H), 1.28 (m, 12H). ESI-MS m / z:1957.30[MH] - ;C 86 H 127 F5N8O 37 .

[0292] Example 5: Synthesis of G5 [ka] Compound 9 (8 g) was dissolved in anhydrous DCM (50 ml), and under ice bath and nitrogen protection, HOBt (1.5 eq) was added, EDCI (1.2 eq) was slowly added, and the reaction was allowed to proceed for 20 min. N-acetylgalactosamine (3.3 eq) and DIEA (2 eq) were added, and after the reaction was completed, the mixture was washed with saturated NaHCO3, 0.5 mol / L hydrochloric acid solution, and saturated brine, successively, and concentrated to obtain the crude product, which was then purified by chromatography to obtain G5-10.

[0293] Compound G5-10 (4 g) was dissolved in dry MeOH (20 mL), and NaOMe (30% in MeOH, 3 mL) was added under ice bath and nitrogen protection. After the reaction was completed, the mixture was treated and concentrated. The crude product was added to a 1:1 MeOH / HO mixture and reacted at room temperature for 16 hours. The pH was adjusted to neutral with EtN HCl salt, and the mixture was concentrated to obtain the crude product. Py (20 mL) and AcO (5 mL) were added, and the mixture was reacted at room temperature for 24 hours. The mixture was concentrated and purified by chromatography to obtain G5-11 (2 g).

[0294] Compound G5-11 (1 g) was dissolved in DCM (10 mL), and EDCI (1.5 eq) and pentafluorophenol (1.5 eq) were added. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution, concentrated, and purified by chromatography to give G5 (0.5 g) in a 40% yield.

[0295] 1H NMR (500 MHz, CDCl3):δ 7.25-7.17 (m, 1H), 6.93-6.73 (m, 4H), 6.54-6.42 (m, 3H), 5.34 (d, J=2.5 Hz, 3H), 5.29-5.21 (m, 3H), 4.66 (d, J=8.2 Hz, 3H), 4.20-4.06 (m,8H), 4.03-3.80 (m,6H), 3.80-3.63(m, 8H), 3.58-3.34 (m, 10H), 3.31-3.11 (m, 6H), 2.64 (t, J=7.4 Hz, 2H), 2.52-2.33 (m, 6H), 2.31-2.20 (m, 8H), 2.09-1.88 (m, 27H), 1.68-1.43 (m, 16H), 1.34 (m, 24H). ESI-Tof-MS m / z:2057.49 [M+H] + , 2079.48 [M+Na] + ;C 93 H 141 F5N8O 37 .

[0296] Biological experiments Experimental Example 1: Measurement of affinity to ASGPR receptors in hepatocytes The siRNA sequence synthesized with reference to Chinese invention patent CN109957567B is as follows:

[0297] dG*fU*dAfUdGfUfUdGfCfCfCdGfUfUfUdGfU*fC*fC(SEQ ID NO. 1) mG*fG*mA*fCmAfAmAfCmGfGmGfCmAfAmCfAmUfA*mC*mC*mU(SEQ ID NO. 2) Compounds G1, G4, and G5 obtained in Examples 1, 4, and 5 were bound to the above siRNA as shown in Table 1 to form conjugates.

[0298] Table 1. Conjugate structures [Table 1] NOTE: Above, A is adenine ribonucleotide, G is guanine ribonucleotide, C is cytosine ribonucleotide, U is uracil ribonucleotide, d is deoxyribonucleotide modification, f is 2'-fluoro modification, m is 2'-O-methyl modification, * is phosphorothioate backbone modification, and Cy5 is fluorescently labeled Cy5.

[0299] Here, the structure of G1-12 is shown in Z1. When G4 and G5 are linked to siRNA, the phosphate bond needs to be modified. In this example, the amino acid at C6 [ka] Modifications are used such that the structure of G4-12 is shown in Z4 and the structure of G5-12 is shown in Z5.

[0300] 1. Dilution of GalNac-siRNA G1-12, G4-12, and G5-12 (1 μM) were each diluted in a gradient as shown in the table below.

[0301] [Table 2] 2. Cell Preparation 4 × 10 cells in DMEM medium containing 2% FBS 5 Diluted to a concentration of cells / mL.

[0302] 3. Mixing, Sample Injection, and Incubation For each sample, 200 μL of cells and 200 μL of siRNA were mixed uniformly. For the blank control, 200 μL of cells and 200 μL of medium were mixed uniformly. 100 μL of each mixture was added to three wells of a U-bottom 96-well plate. After sample injection for each siRNA concentration, the samples were placed in an icebox, placed on a decolorizing shaker, and incubated in the dark for 2 h.

[0303] 4. Detection The U-bottom 96-well plate was centrifuged at 50g for 2 min at 4°C. 80µL of the supernatant was aspirated with a pipette, and 10µg / mL propidium iodide was prepared in 2% FBS-containing PBS. 100µL of PI reagent was added to each well and stained for 15 min. After staining was complete, the U-bottom 96-well plate was centrifuged at 50g for 2 min at 4°C. After washing twice with 2% FBS-containing PBS, 100µL of 2% FBS-containing PBS was added and resuspended. The cells were then detected using a flow cytometer, and the mean fluorescence intensity of Cy5 fluorescence in the live cell population was counted.

[0304] 5. Data Analysis As shown in Figures 1-3, the mean fluorescence intensity of Cy5 fluorescence in each experimental group was subtracted from the mean fluorescence intensity of the blank group, and the data were fitted to a binding saturation curve using GraphPad Prism software. Nonlinear regression (curve fit) and one-site binding (hyperbolic) were used as parameters to obtain the dissociation equilibrium constant (Kd). Table 3 shows that G1-12, G4-12, and G5-12 achieve high affinity binding to the ASGPR receptor.

[0305] Table 3. Kd values ​​of conjugates [Table 3] Experimental Example 2 In vivo liver targeting of GalNac-siRNA Male Balb / c-nu mice (weight 18-22 g) were randomly divided into three groups (5 mice per group): a blank control group, a negative control group, and a target group. The dose was 10 mg / kg. The negative control group received a single injection of the negative control (NC, Ribobio, siM200922112438) test substance via the tail vein. The target group received a single injection of the G1-12 test substance obtained in Example 6 via the tail vein. The blank control group received an equal volume of saline. Six hours after drug administration, the livers of all animals were removed and immediately placed in liquid nitrogen. They were then stored at -80°C. The siRNA drug concentrations in the liver tissue were measured using qPCR.

[0306] 1. Preparation of a calibration curve: A standard sample mother solution with an siRNA concentration of 500 nM was prepared according to the instructions for the siRNA antisense strand standard (Ribobio, ssR190807024906). The standard sample mother solution (50 nM to 0.05 pM) was diluted 10-fold to create a total of seven gradients. After incubation at 95°C for 10 minutes, pre-cooled RTmix was quickly added, and reverse transcription and qPCR were performed. Reverse transcription was performed according to the instructions for the Bulge-Loop® miRNA qRT-PCR Starter Kit (Ribobio, C10211-2), and qPCR was performed according to the instructions for the riboSCRIPT™ Reverse Transcription Kit (Ribobio, C11027-2). The average Ct value obtained at each reference point was calculated from the obtained Ct values. A calibration curve was created with the logarithm of the standard point concentration on the horizontal axis and the average Ct value on the vertical axis, and the regression equation and R were used. 2 (R 2 >0.99).

[0307] 2. Sample processing: Mouse liver samples were ground to powder using liquid nitrogen grinding, and the mass of the powder was weighed. A corresponding amount of 0.25% Triton X-100 (100 mg / mL) preheated to 95°C was added according to the mass, followed by vortex shaking. The mixture was mixed well and incubated at 95°C for 10 min. The lysate was cooled on ice and centrifuged at 20,000 g for 20 min at 4°C. The supernatant was collected. The supernatant was diluted 10,000-fold with RNase-free water, and 20 μL of the diluted solution was placed in a PCR instrument and incubated at 95°C for 10 min. Pre-chilled RTmix was quickly added, followed by reverse transcription and qPCR. Reverse transcription was performed according to the instructions for the Bulge-Loop (registered trademark) miRNA qRT-PCR Starter Kit (Ribobio, C10211-2), and qPCR was performed according to the instructions for the riboSCRIPT™ Reverse Transcription Kit (Ribobio, C11027-2).

[0308] 3. Data analysis: The Ct values ​​of the samples were substituted into the regression equation of the standard curve to calculate the siRNA content in the samples.

[0309] As shown in Figure 4, compared with the negative control siRNA without GalNAc linkage, the distribution of G1-12 in the GalNAc-siRNA construct was significantly increased in the mouse liver, indicating that G1-12 can achieve liver-targeted delivery in vivo.

[0310] Experimental Example 3: Knockdown effect on PCSK9 mRNA expression The siRNA sequence synthesized with reference to Chinese invention patent CN109957567B is as follows:

[0311] mG*mG*mUmCmUmGfGfAfAmUmGmCmAmAmAmG*mU*mC*mA(SEQ ID NO. 3) mU*fG*mAfCmUfUmUfGmCfAmUfUmCfCmAfG*mA*mC*mC(SEQ ID NO. 4) As shown in Table 4, compounds G2, G4, and G5 obtained in Examples 2, 4, and 5 were each bound to the above siRNA to form conjugates.

[0312] Table 4. Conjugate structures [Table 4] NOTE: In the above, A is an adenine ribonucleotide, G is a guanine ribonucleotide, C is a cytosine ribonucleotide, U is a uracil ribonucleotide, f is a 2'-fluoro modification, m is a 2'-O-methyl modification, * is a phosphorothioate backbone modification, and 5'-phos* is a phosphorothioate at the 5' end.

[0313] Here, the structure of G2-34 is shown in Z2. When G4 and G5 are linked to siRNA, the phosphate bond needs to be modified. In this example, the amino acid at C6 [ka] Modifications are used such that the structure of G4-34 is shown in Z4 and the structure of G5-34 is shown in Z5.

[0314] Hep3B cells (ATCC, HB-8064) were cultured to a relatively uniform cell density of approximately 30%-50% before transfection.

[0315] Each conjugate sample in Table 4 was prepared at a 20 μM stock solution and used as a test group. In addition to the test groups, a normal cell control group (Blank), a transfection reagent control group (Mock), negative control group 1 (NC001, Ribobio, siM211215011852), and negative control group 2 (NC002, Ribobio, siM211215011852) were also used. Cells were transfected according to the Lipofectamine® 3000 Transfection Reagent (Thermo Fisher, L300001) instructions. Both experimental and control groups were repeated three times.

[0316] Total RNA was extracted according to the instructions for MagZol Reagent (Magen, R4801).

[0317] Reverse transcription was performed according to the instructions for the riboSCRIPT™ Reverse Transcription Kit (Ribobio, C11027-2).

[0318] The human housekeeping gene actin was used as an internal reference gene. For actin gene, the upstream primer sequence was 5'-TCAAGATCATTGCTCCTCCTGAG-3' and the downstream primer sequence was 5'-ACATCTGCTGGAAGGTGGACA-3'. For human PCSK9 gene, the upstream primer sequence was 5'-AAGCCAAGCCTCTTCTTACTTCA-3' and the downstream primer sequence was 5'-CCTGGGTGATAACGGAAAAAG-3'. Real-time fluorescent quantitative PCR reactions were performed using 2X SYBR Green Mix (Ribobio, C10712F-1mL) and a fluorescent quantitative PCR instrument (BioRad, CFX96). After PCR reactions were completed, the Ct error for nine replicates of samples (three transfection replicates and three QPCR replicates) should be ±0.5. Relative quantification analysis was then performed using CFX 2.1 software.

[0319] As shown in Table 5, conjugates formed with different GalNAc structures and the same siRNA sequence could knockdown the target gene PCSK9 with approximately 60% efficiency in Hep3B cells, significantly reducing the expression of target gene mRNA.

[0320] Table 5. Relative expression levels of PCSK9 mRNA [Table 5] While embodiments of the present invention have been illustrated and described, it will be understood that those skilled in the art can make various changes, modifications, substitutions, and variations to these embodiments without departing from the principles and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 【Chemical 1】 (where, M １ are independently —O—, —S—, or —NR ６ --, --CHR ７ -, -C(O)-, -S(O)-, and -S(O) ２ - at least one selected from R １ is the asialoglycoprotein receptor (ASGPR) ligand residue, R ２ is hydroxy, carboxy, -OR ｐ , -OPG ２ , 【Chemistry 2】 , and 【Chemistry 3】 At least one selected from PG １ is a carboxy protecting group, PG ２ is a hydroxy protecting group, R ｐ teeth, 【Chemistry 4】 and PG ３ are independently selected from phosphate protecting groups; R and R' are each independently an amino protecting group, or R and R' together with the N atom to which they are attached optionally form a 5- to 10-membered heterocyclyl; R ３ is, independently, 【Chemistry 5】 and M ３ａ are independently a chemical bond, —O—, —S—, or —NR ６ --, --CHR ７ -, -C(O)-, -S(O) １～２ -, -NR ６ C(O)-, -C(O)NR ６ -, -NR ６ S (O) １～２ -, -S(O) １～２ NR ６ -, -OC(O)-, -C(O)O-, -OS(O) １～２ - and -S(O) １～２ O-, M ３ｂ are independently —O—, —S—, or —NR ６ --, --CHR ７ -, -CH=CH-, -C≡C-, -C(O)-, -S(O) １～２ -, -C(O)NR ６ -, -NR ６ C(O)-, -OC(O)-, -C(O)O-, -S(O) １～２ O-Y １ -, -OS(O) １～２ -Y １ -, -OS(O) １～２ O-, -S(O) １～２ NR ６ -Y １ -, -NR ６ S (O) １～２ -Y １ -, C ６～１０ arylene, 5- to 10-membered heteroarylene, 【Chemistry 6】 、 【Chemistry 7】 , and 【Chemistry 8】 At least one selected from Y １ are independently ６～１０ arylene or 5- to 10-membered heteroarylene; R ６ are each independently H, C １～１０ Alkyl, C １～１０ Haloalkyl, C ３～１０ at least one selected from cycloalkyl, and 3- to 10-membered heterocyclyl; R ７ are each independently H, halogen, —C≡N, or —NO ２ , C １～１０ Alkyl, C １ - １０ Haloalkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ and at least one selected from aryl, and 5- to 10-membered heteroaryl, wherein one or more methylenes in said alkyl or haloalkyl are optionally and independently selected from -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -O-, -C(O)O-, -S-, -S-(CH ２ ) ０～６ -S-, -NR ６ -, C ６～１０ Arylene, 5- to 10-membered heteroarylene, —CH═CH—, —C≡C—, and —O—(CH ２ ) １～６ -O-, n ２ is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n ３ is independently 1, 2, 3, 4, 5, or 6; R ４ is H, C １～６ Alkyl, C １～６ Haloalkyl, and C １～６ at least one selected from alkoxy; Link １ , Link ２ , Link ３ , and Link ４ are each independently C １～２５ A straight chain alkylene, wherein one or more methylenes in said straight chain alkylene are optionally and independently replaced by R*, and R* is independently -O-, -S-, -NR ６ --, --CHR ７ -, -C(O)-, -S(O) １～２ -, -NR ６ C(O)-, -C(O)NR ６ -, -NR ６ S (O) １～２ -, -S(O) １～２ NR ６ -, -OC(O)-, -C(O)O-, -OS(O) １～２ - and -S(O) １～２ O-, m １ , m ２ , and m ３ are each independently 1, 2, 3, 4, or 5; However, Link ４ In the formula, the methylene connected to the carbonyl on the left side is not replaced by R*.

2. M １ are independently —O—, —S—, —NH—, or —CH ２ -, -C(O)-, -S(O)-, and -S(O) ２ -, preferably at least one selected from -O-, -S-, and -NH-, preferably -O-, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

3. R １ are independently residues of the following structures: D-mannopyranose, L-mannopyranose, L-arabinose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose , β-D-glucofuranose, α-D-fructofuranose, β-D-fructofuranose, α-D-fructopyranose, β-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyl L-galactosamine, N-isobutyrylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose, N-glycolyl-α-neuraminic acid, 5-thio-β-D-glucopyrano at least one selected from the group consisting of methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside, 4-thio-β-D-galactopyranose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside, 2,5-anhydro-D-allosenitrile, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose; Preferably, the R １ is independently at least one selected from residues of the following structures: D-galactose, L-galactose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, N-isobutyrylgalactosamine, and β-D-galactopyranose, and preferably, １ is independently at least one selected from galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, and N-isobutyrylgalactosamine, preferably N-acetylgalactosamine; Preferably, R １ teeth 【Chemistry 9】 3. The compound of formula (I) according to claim 1 or 2, wherein:

4. R ２ is hydroxy, carboxy, -OR ｐ , -OPG ２ , 【Chemistry 10】 , and 【Chemistry 11】 and preferably, at least one selected from the group consisting of R ２ is -OR ｐ , 【Chemistry 12】 , and 【Chemistry 13】 At least one selected from the group consisting of ２ teeth, 【Chemistry 14】 and / or 【Chemistry 15】 and Or preferably, the R ２ teeth, 【Chemistry 16】 、 【Chemistry 17】 , and 【Chemistry 18】 At least one selected from, preferably 【Chemistry 19】 or 【Chemistry 20】 , preferably 【Chemical 21】 or 【Chemical 22】 and Preferably, 【Chemical 23】 teeth, 【Chemistry 24】 or 【Chemistry 25】 , preferably 【Chemical 26】 4. The compound of formula (I) according to any one of claims 1 to 3, wherein:

5. PG １ is C １～６ Alkyl, benzyl, allyl, 【Chemical 27】 , and 【Chemical 28】 wherein R ２ｓ are independently H, halogen, C １～１０ Alkyl, and C １～１０ haloalkyl, and q is 0, 1, 2, 3, 4, or 5; Preferably, PG １ is methyl, t-butyl, benzyl, allyl, 【Chemical 29】 , and 【Chemistry 30】 and preferably, １ teeth, 【Chemical 31】 and 【Chemical 32】 and preferably, １ teeth 【Chemical 33】 and Preferably, R ２ｓ are independently H, halogen, C １～６ Alkyl, and C １～６ haloalkyl, preferably H or halogen, preferably —F, and preferably １ teeth 【Chemical 34】 5. The compound of formula (I) according to any one of claims 1 to 4, wherein:

6. PG ２ are trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), acetyl (Ac), chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl (TFA), benzoyl, p-methoxybenzoyl, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc), at least one selected from benzyl (Bn), p-methoxybenzyl (PMB), allyl, dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4"-trimethoxytrityl (TMTr), methoxymethyl (MOM), phenoxymethyl (BOM), 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), and p-methoxybenzyloxymethyl (PMBM); Preferably, PG ２ from dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4"-trimethoxytrityl (TMTr), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS).

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compound is at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), and 4,4',4"-trimethoxytrityl (TMTr), preferably 4,4'-dimethoxytrityl (DMTr).

7. PG ３ are independently 2-cyanoethyl and C １～６ alkyl, and preferably, ３ is independently at least one selected from 2-cyanoethyl and methyl, preferably 2-cyanoethyl, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

8. R and R′ are each independently C １～６ A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R is alkyl, preferably isopropyl.

9. 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R and R' together with the N atom to which they are attached optionally form a 5- to 6-membered heterocyclyl.

10. R ｐ teeth 【Chemical 35】 10. The compound of formula (I) according to any one of claims 1 to 9, wherein:

11. M ３ａ are independently a chemical bond, —O—, —S—, or —NR ６ --, --CHR ７ -, -C(O)-, -S(O) １～２ -, -NHC(O)-, -C(O)NH-, -NHS(O) １～２ -, -S(O) １～２ NH-, -OC(O)-, -C(O)O-, -OS(O) １～２ - and -S(O) １～２ O-, and preferably, ３ａ are independently a chemical bond, —O—, —S—, or —NR ６ -, -C(O)-, -NHC(O)-, -C(O)NH-, -OC(O)-, and -C(O)O-, and preferably, ３ａ is independently at least one selected from a chemical bond, —NHC(O)—, —C(O)NH—, —OC(O)—, and —C(O)O—, and preferably, ３ａ is independently at least one selected from a chemical bond, —NHC(O)—, and —C(O)NH—, and preferably, ３ａ is independently a chemical bond or —C(O)NH—, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

12. M ３ｂ are independently —O—, —S—, or —NR ６ --, --CHR ７ -, -CH=CH-, -C≡C-, -C(O)-, -S(O) １～２ -, -C(O)NH-, -NHC(O)-, -OC(O)-, -C(O)O-, -S(O) １～２ O-Y １ -, -OS (O) １～２ -Y １ -, -OS (O) １～２ O-, -S(O) １～２ NH-Y １ -, -NHS(O) １～２ -Y １ -, phenylene, 5- to 6-membered heteroarylene, 【Chemical 36】 、 【Chemical 37】 , and 【Chemical 38】 At least one selected from Preferably, the M ３ｂ are independently —O—, —S—, or —NR ６ --, --CHR ７ -, -CH=CH-, -C≡C-, -C(O)-, -C(O)NH-, -NHC(O)-, -OC(O)-, -C(O)O-, -OS(O) ２ -Y １ -, -OS(O) ２ O-, -NHS(O) ２ -Y １ -, 5- to 6-membered heteroarylene, 【Chemical Formula 39】 、 【Chemistry 40】 , and 【Chemistry 41】 At least one selected from the group consisting of ３ｂ is independently at least one selected from —C(O)NH—, —NHC(O)—, —OC(O)—, and —C(O)O—, and preferably, ３ｂ are independently —C(O)NH— or —NHC(O)—, and preferably, ３ｂ are independently —NHC(O)—, Preferably, the M ３ｂ The 5- to 6-membered heteroarylene as 【Chemistry 42】 or 【Chemistry 43】 and Preferably, Y １ are independently phenylene or 5- to 6-membered heteroarylene, preferably phenylene, preferably 【Chemical 44】 12. The compound of formula (I) according to any one of claims 1 to 11, wherein:

13. 【Catalog 45】 has the following structure: 【Chemistry 46】 At least one selected from Preferably, the 【Chemistry 47】 is at least one selected from A2, A3, A4, A6, and A9, and preferably 【Chemistry 48】 is at least one selected from A2, A3, and A9, and preferably 【Chemistry 49】 is A3 or A9, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

14. R ６ are each independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ cycloalkyl, and 3- to 7-membered heterocyclyl, and preferably, ６ are each independently H, C １～６ Alkyl, and C １～６ haloalkyl, and preferably, ６ are each independently H, —CH ３ , 【Chemistry 50】 、 【Chemistry 51】 , and 【Chemistry 52】 and more preferably, at least one selected from the group consisting of R ６ are each independently H, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

15. R ７ are each independently H, halogen, —C≡N, C １～６ Alkyl, C １ - ６ Haloalkyl, C ３～７ At least one selected from cycloalkyl, 3- to 7-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, preferably ７ are each independently H, halogen, —C≡N, C １～６ Alkyl, and C １ - ６ haloalkyl, and preferably, ７ are each independently H, halogen, or C １～６ Alkyl, and C １ - ６ haloalkyl; Preferably, R ７ One or more methylenes in the alkyl or haloalkyl as ２ ) ０～３ -S-, -NR ６ -, phenylene, 5- to 6-membered heteroarylene, -CH=CH-, -C≡C-, and -O-(CH ２ ) １～３ At least one selected from —O—, preferably —C(O)—, —C(O)NH—, —NHC(O)—, —OC(O)—, —O—, —C(O)O—, —S—, —S—S—, and —NR ６ -, 【Chemistry 53】 、 【Chemical Formula 54】 , —CH═CH—, —C≡C—, and —O—(CH ２ ) ２ -O-, Preferably, the R ７ The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein halogen as is -F, -Cl, or -Br.

16. n ２ is independently 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2 or 3, preferably 0 or 3. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

17. n ３ is independently 1, 2 or 3, preferably 2; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

18. R ４ is H, C １～５ Alkyl, C １～５ Haloalkyl, and C １～５ At least one selected from alkoxy, preferably, ４ is H, C １～３ Alkyl, and C １～３ haloalkyl, and preferably, ４ is H, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

19. Link １ , Link ２ , and Link ３ are each independently C １～１０ Linear alkylene, preferably C １～６ Linear alkylene, preferably C ４～６ Linear alkylene, preferably —(CH ２ ) ４ - or - (CH ２ ) ６ 19. The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

20. Link ４ is C １～２０ Linear alkylene, preferably C １～１７ Linear alkylene, preferably C １～１０ Linear alkylene, preferably C ３～２０ Linear alkylene, preferably C ３～１７ Linear alkylene, preferably C ３～１０ is a linear alkylene; Preferably, Link ４ One or more methylenes in the linear alkylene as are preferably one, two or three methylenes, and preferably one methylene is optionally and independently replaced by R*; Preferably, R* is independently —O—, —NR ６ --, --CHR ７ -, -C(O)-, -NR ６ C(O)-, -C(O)NR ６ at least one selected from -, -OC(O)-, and -C(O)O-, preferably at least one selected from -C(O)NH-, -NHC(O)-, -C(O)O-, and -OC(O)-, preferably at least one selected from -C(O)NH- and -C(O)O-, or preferably at least one selected from -C(O)NH- and -NHC(O)-, further preferably -C(O)NH-; Preferably, R* and Link ４ and there are 1 to 15 methylenes, preferably 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 1 to 3 methylenes, preferably 3 to 10 methylenes between the carbonyl on the left side of R and R ２ and 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 1 to 6 methylenes are interposed between them. Preferably, Link ４ is -(CH ２ ) ３ -, -(CH ２ ) １０ -, -(CH ２ ) ３ -C(O)NH-(CH ２ ) ６ - and -(CH ２ ) １０ -C(O)NH-(CH ２ ) ６ -, preferably -(CH ２ ) ３ -, -(CH ２ ) １０ - and -(CH ２ ) ３ -C(O)NH-(CH ２ ) ６ -, preferably -(CH ２ ) ３ - or - (CH ２ ) １０ - and Or preferably, the Link ４ is -(CH ２ ) １０ -, -(CH ２ ) ３ -C(O)NH-(CH ２ ) ６ - and -(CH ２ ) １０ -C(O)NH-(CH ２ ) ６ -, preferably -(CH ２ ) １０ - or - (CH ２ ) １０ -C(O)NH-(CH ２ ) ６ 20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

21. m １ , m ２ , and m ３ is each independently 1, 2 or 3, preferably 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

22. The following structural formula: 【Chemistry 55】 (where, n ２ is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; The remaining radicals are as defined in any one of claims 1 to 21.

22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, having the formula:

23. R ２ is hydroxy, carboxy, -OR ｐ , -OPG ２ , 【Chemical 56】 , and 【Chemical 57】 At least one selected from PG １ is a carboxy protecting group, preferably methyl, t-butyl, benzyl, allyl, 【Chemistry 58】 , and 【Chemical Formula 59】 At least one selected from R ２ｓ are independently H, halogen, C １～６ Alkyl, and C １～６ haloalkyl; q is 0, 1, 2, 3, 4, or 5; PG ２ is a hydroxy protecting group, preferably at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), 9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthen-9-yl (Mox), trityl (Tr), 4-methoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS); R ｐ teeth 【Chemistry 60】 and PG ３ are independently selected from phosphate protecting groups, preferably at least one selected from 2-cyanoethyl and methyl, more preferably 2-cyanoethyl; R and R′ are each independently an amino protecting group, preferably C １～６ alkyl, preferably isopropyl; M ３ａ is at least one selected from a chemical bond, —NHC(O)—, —C(O)NH—, —OC(O)—, and —C(O)O—, and preferably, ３ａ is at least one selected from a chemical bond, —NHC(O)—, and —C(O)NH—; n １ is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n ２ is independently 0, 1, 2, 3, 4, 5, or 6; n ３ is independently 1, 2, 3, 4, 5, or 6; m １ , m ２ , and m ３ are each independently 1, 2, 3, 4, or 5; Link ４ is C １～２５ Linear alkylene, preferably C １～２０ straight chain alkylene, wherein one, two or three methylenes in said straight chain alkylene are optionally and independently replaced by R*, and R* is independently at least one selected from —C(O)NH—, —NHC(O)—, —C(O)O—, and —OC(O)—, preferably at least one selected from —C(O)NH— and —NHC(O)—; However, Link ４ 23. The compound of formula (II) according to claim 22, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

24. R ２ is -OR ｐ , 【Hua 61】 and 【Hua 62】 At least one selected from, preferably 【Chemistry 63】 、 【Hua 64】 , and 【Chemistry 65】 At least one selected from, preferably 【Hua 66】 or 【Chemical 67】 and PG １ teeth, 【Chemistry 68】 and 【Chemical Formula 69】 At least one selected from R ２ｓ are independently H or halogen, preferably —F; q is 0, 1, 2, 3, 4, or 5; PG ２ is at least one selected from dimethoxytrityl (DMT), monomethoxytrityl (MMT), trityl (Tr), 4-methoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), and 4,4',4"-trimethoxytrityl (TMTr), and preferably, ２ is 4,4'-dimethoxytrityl (DMTr), R ｐ teeth, 【Chemistry 70】 and PG ３ is 2-cyanoethyl, R and R′ are each independently C １～４ alkyl, preferably isopropyl; M ３ａ is a chemical bond or —C(O)NH—, n １ is independently 4, 5, or 6; n ２ is independently 0, 1, 2 or 3; n ３ is independently 1 or 2, m １ , m ２ , and m ３ are each independently 1, 2 or 3, preferably 1; Link ４ is C １～１７ Linear alkylene, preferably C １～１０ straight chain alkylene, wherein one methylene in said straight chain alkylene is optionally replaced by R*, and R* is —C(O)NH—; Preferably, R* and Link ４ and 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 1 to 3 methylenes are interposed between the carbonyl on the left side of R* and R ２ and R are substituted or unsubstituted by 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 1 to 6 methylenes, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

25. R ２ teeth, 【Chemical 71】 、 【Chemical 72】 , and 【Chemical 73】 At least one selected from, preferably 【Chemical 74】 or 【Chemistry 75】 and M ３ａ is a chemical bond or —C(O)NH—, n １ is independently 4 or 6; n ２ is independently 0 or 3; n ３ is 2, m １ , m ２ , and m ３ are all 1, Link ４ is -(CH ２ ) ３ -, -(CH ２ ) １０ -, -(CH ２ ) ３ -C(O)NH-(CH ２ ) ６ - or - (CH ２ ) １０ -C(O)NH-(CH ２ ) ６ -, preferably -(CH ２ ) ３ -, -(CH ２ ) １０ - and -(CH ２ ) ３ -C(O)NH-(CH ２ ) ６ -, preferably -(CH ２ ) ３ - or - (CH ２ ) １０ 25. The compound of formula (II) according to claim 24, wherein: - or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

26. 2. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the compound is at least one selected from the following: 【Chemical 76】 【Chemical 77】 【Chemical 78】 【Chemical 79】 【Chemistry 80】

27. A conjugate having a structure shown in formula (III): 【Chemistry 81】 (where, L is a structure represented by formula (I') or formula (II'), 【Chemistry 82】 、 【Chemistry 83】 【Chemistry 84】 teeth, 【Chemistry 85】 、 【Chemistry 86】 、 【Hua 87】 , and 【Hua 88】 At least one selected from, preferably 【Chemistry 89】 、 【Chemistry 90】 , and 【Chemistry 91】 At least one selected from Or preferably, 【Chemistry 92】 teeth, 【Chemistry 93】 、 【Chemistry 94】 、 【Chemistry 95】 、 【Chemistry 96】 、 【Chemistry 97】 、 【Chemistry 98】 , and 【Hua99】 At least one selected from, preferably 【Chemistry 100】 、 【Chemistry 101】 、 【Chemistry 102】 , and 【Chemistry 103】 At least one selected from, preferably 【Chemistry 104】 and 【Chemistry 105】 At least one selected from R Ｄ are drug molecules, wherein the drug molecules are independently at least one selected from a cytotoxic agent, a chemotherapeutic agent, somatostatin, a toxin, a radioisotope, and an oligonucleotide chain; d is 1 or 2, preferably 1; the remaining radicals are as defined in any one of claims 1 to 25, Preferably, Link ４ is C ５～２５ Linear alkylene, preferably C ５～２０ Linear alkylene, preferably C ８～２０ Linear alkylene, preferably C １０～１７ linear alkylene; Preferably, Link ４ wherein one or more methylenes are preferably one, two or three methylenes, and preferably one methylene is optionally and independently replaced by R*, and R* is independently at least one selected from —C(O)NH—, —NHC(O)—, —C(O)O—, and —OC(O)—, preferably at least one selected from —C(O)NH— and —C(O)O—, or preferably at least one selected from —C(O)NH— and —NHC(O)—, further preferably —C(O)NH—; Preferably, R* and Link ４ and 1 to 15 methylenes, preferably 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 3 to 10 methylenes are present between the carbonyl on the left side of R* and R ２ and 1 to 12 methylenes, preferably 1 to 10 methylenes, preferably 1 to 6 methylenes are interposed between them. Preferably, Link ４ is -(CH ２ ) １０ -, -(CH ２ ) ３ -C(O)NH-(CH ２ ) ６ - and -(CH ２ ) １０ -C(O)NH-(CH ２ ) ６ -, preferably -(CH ２ ) １０ - or - (CH ２ ) １０ -C(O)NH-(CH ２ ) ６ - is.)

28. R Ｄ is an oligonucleotide strand, optionally said oligonucleotide strand is a single-stranded oligonucleotide, a double-stranded oligonucleotide or a composition thereof; Preferably, M ２ is linked by a phosphate bond to any nucleotide at the 5' end, 3' end, or from the 5' end to the 3' end of at least one strand of the oligonucleotide chain, preferably to the 5' end or 3' end of at least one strand, preferably to the 5' end of at least one strand, preferably to the 3' end of at least one strand; Preferably, M ２ is linked to the sense strand of the oligonucleotide strand by a phosphate bond, Preferably, said phosphate ester bond is a phosphodiester bond or a modified phosphate ester bond, preferably a phosphodiester bond; preferably, said modified phosphate ester bond is selected from a thio-modified phosphate ester bond and / or an amino-modified phosphate ester bond, preferably a thio-modified phosphate ester bond; Preferably, the 【Chemistry 106】 【Chemistry 107】 、 【Chemistry 108】 、 【Chemistry 109】 and 【Chemistry 110】 At least one structure selected from the group consisting of: 【Chemistry 111】 、 【Chemistry 112】 、 【Chemistry 113】 、 【Chemistry 114】 、 【Chemistry 115】 、 【Chemistry 116】 and 【Chemistry 117】 At least one structure selected from, preferably 【Chemistry 118】 、 【Chemistry 119】 、 【Chemistry 120】 , and 【Chemistry 121】 and at least one structure selected from: 【Chemical 122】 28. The conjugate of formula (III) according to claim 27, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: represents an oligonucleotide chain.

29. the oligonucleotide strand comprises unmodified nucleotides and / or modified nucleotides, Preferably, the modified nucleotides are each independently at least one selected from 2'-methoxyethyl modified nucleotides, 2'-O-alkyl modified nucleotides, 2'-O-allyl modified nucleotides, 2'-C-allyl modified nucleotides, 2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides, 2'-hydroxy modified nucleotides, thiophosphorylated backbone modified nucleotides, locked nucleotide modified nucleotides, glycol nucleic acid (GNA) modified nucleotides, and unlocked nucleic acid (UNA) modified nucleotides, preferably at least one selected from 2'-O-alkyl modified nucleotides, 2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides, and thiophosphorylated backbone modified nucleotides; Preferably, the 2'-O-alkyl is 2'-O-C １～６ alkyl, preferably 2'-O-methyl; 29. The conjugate of formula (III) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof according to claim 27 or 28, wherein the length of the oligonucleotide chain is preferably 5 to 100 bp.

30. 30. The conjugate of formula (III) according to any one of claims 27 to 29, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the oligonucleotide strand is siRNA, ASO or microRNA, preferably siRNA.

31. 31. The conjugate of formula (III) according to any one of claims 27 to 30, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the oligonucleotide chain has a terminal modification, and the terminal modification is selected from cholesterol, polyethylene glycol, a fluorescent probe, biotin, a polypeptide, a vitamin or a tissue-targeting molecule, or a combination thereof.

32. 32. The conjugate of formula (III) according to any one of claims 27 to 31, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the ribose-phosphate backbone of the oligonucleotide chain is replaced by a polypeptide nucleic acid (PNA) or a morpholine ring antisense nucleotide (PMO).

33. Here, L is 【Chemical 123】 【Chemical 124】 【Chemistry 125】 【Chemical 126】 a structure selected from Preferably, 【Chemistry 127】 【128】 【Chemical 129】 L ４ 33. The conjugate of formula (III) according to any one of claims 27 to 32, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, having at least one structure selected from:

34. 29. The conjugate of formula (III) of claim 28, wherein the conjugate is at least one structure selected from the following: 【Chemistry 130】 【Chemistry 131】 【132】 【Chemistry 133】 【134】 【Chemistry 135】 【Chemistry 136】 【Chemistry 137】 and 【Chemistry 138】

35. 35. A pharmaceutical composition comprising the conjugate of any one of claims 27 to 34, optionally a pharmaceutically acceptable carrier, excipient, adjuvant or vehicle, and optionally other therapeutic agents.

36. Use of the conjugate of any one of claims 27 to 34, or the pharmaceutical composition of claim 35, in the preparation of a medicament for treating or preventing a disease associated with the expression or overexpression of a gene in liver cells.

37. 1. A method for treating or preventing a disease associated with expression or overexpression of a gene in a liver cell in a subject, comprising: A method comprising administering to the subject a conjugate according to any one of claims 27 to 34 or a pharmaceutical composition according to claim 35.

38. The conjugate of any one of claims 27 to 34 or the pharmaceutical composition of claim 35, for use in treating or preventing a disease associated with the expression or overexpression of a gene in liver cells.

39. The use according to claim 36, the method according to claim 37, or the use of the conjugate or pharmaceutical composition according to claim 38, wherein the gene is selected from the HBV genome, HCV genome, PCSK9, xanthine oxidase, URAT1, APOB, liver fibrosis-related genes (AP3S2, AQP2, AZINI, DEGSI, STXBP5L, TLR4, TRPM5), non-alcoholic fatty liver disease-related genes (PNPLA3, FDFT1), or primary biliary cirrhosis-related genes (HLA-DQB1, IL-12, IL-12RB2), or a combination thereof.

40. 39. The use of claim 36, the method of claim 37, or the use of the conjugate or pharmaceutical composition of claim 38, wherein the disease is at least one selected from hereditary angioedema, familial tyrosinemia type 1, Alagille syndrome, alpha-1-antitrypsin deficiency, disorders of bile acid synthesis metabolism, biliary atresia, cystic fibrosis liver disease, idiopathic neonatal hepatitis, mitochondrial liver disease, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, transthyretin amyloidosis, hemophilia, homozygous familial hypercholesterolemia, hyperlipidemia, hepatitis B (HBV), hepatitis C (HCV), steatohepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), diseases associated with hyperglycemia or abnormally increased hepatic glucose production resembling type 1 or type 2 diabetes, hepatitis, and hepatic porphyrin.

41. Compound of formula (C). 【Chemistry 139】 (Here, P.G. ２ and P.G. ４ is a protection group, Preferably, PG ２ is a hydroxy protecting group, PG ４ is an amino protecting group, Preferably, the PG ２ is at least one selected from trimethylsilyl (TMS), triethylsilyl (TES), dimethylisopropylsilyl (DMIPS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS), preferably t-butyldimethylsilyl (TBDMS); Preferably, the PG ４ is at least one selected from benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), methoxycarbonyl, and ethoxycarbonyl, preferably t-butoxycarbonyl (Boc).

42. A process for preparing a compound of formula (C), comprising the steps of: reacting compound A with compound B to produce compound C; Preferably, the reaction conditions include a condensing agent and a base; Preferably, the condensing agent is at least one selected from a carbodiimide-based condensing agent, an onium salt-based condensing agent, and an organic phosphorus-based condensing agent; Preferably, the reaction conditions further comprise a condensation activator; Preferably, the reaction conditions further comprise a solvent; Preferably, the method is carried out in a nitrogen atmosphere; Preferably, the base is an organic amine base, preferably at least one of DIEA, TEA, NMM, DBU, DMAP, pyridine, 2,6-dimethylpyridine, and 2,2,6,6-tetramethylguanidine, preferably DIEA. 【Chemistry 140】 (Here, P.G. ２ and P.G. ４ is as defined in claim 41.

43. Formula (D) compound. 【Chemistry 141】

44. A process for preparing a compound of formula (D), comprising the steps of: removing the protecting group from compound C of claim 41 to obtain compound D; Preferably, the process is carried out under acidic conditions, Preferably, the reaction conditions of the method comprise an acid and a solvent; Preferably, the acid is HCl and / or H ２ SO ４ , preferably HCl, Preferably, the solvent is an organic solvent, preferably an alcoholic solvent, and preferably, the alcoholic solvent is at least one selected from methanol, ethanol, propanol, butanol, isopropanol, cyclohexanol, 2-methyl-2-propanol, and 2-ethyl-1-propanol, preferably methanol. 【142】 (Here, P.G. ２ and P.G. ４ is as defined in claim 41.

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